# Patent

## Title
Modified amino acids, pharmaceuticals containing these compounds and method for their production

## Abstract

The present invention relates to modified amino acids of general formula




wherein

A, Z, X, n, m, R, R2, R3, R4 and R11 are defined as in claims 1 to 5, their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.

## Background
This is a continuation of Ser. No. 10/119,875 filed Apr. 10, 2002, which is a continuation of Ser. No. 09/789,391 filed Feb. 21, 2001, now abandoned, which is a continuation of Ser. No. 09/254,281 filed Oct. 12, 1999, now U.S. Pat. No. 6,344,449, which is a 371 of PCT/P97/04862.


The present invention relates to modified amino acids of general formula




their tautomers, their diastereomers, their enantiomers, their mixtures and salts thereof, particularly physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them.

In the above general formula I

    R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-di-oxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups and the substituents may be identical or different,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
        
            whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position

        
        
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo-[4,5-b]pyridin-3-yl- group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom, containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, or the group of formula

    
    






wherein

    
    
        p denotes the number 1 or 2,
        o denotes the number 2 or 3 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
        Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
        Y2 is the nitrogen atom or the group >CH—,
        R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
        R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
        R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
        RN denotes a hydrogen atom or a C1-6-alkyl group which may be mono- or disubstituted in the ω-position
        
            by a C5-7-cycloalkyl group, by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group or by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
        
        
        a C5-7-cycloalkyl group, a phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl or diazinylamino group,
        a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxido-thiadiaza-heterocycle.
        
            wherein the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
            may contain one or two carbonyl groups adjacent to a nitrogen atom,
            may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
            may be substituted at one or two carbon atoms by a branched or unbranched alkyl group or by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, wherein the substituents may be the same or different,
            and wherein a C3-6-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
        
        
        or if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group,
        or, if Y1 is a carbon atom, RN together with R5, including Y1, also denotes a carbonyl group or a saturated or mono-unsaturated 5- or 6-membered 1,3-diaza-heterocycle which may optionally contain one or two carbonyl groups in the ring and, if it is unsaturated, may be benzofused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo, thieno, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluormethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino, benzoylaminocarbonylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group
        and unless otherwise specified the alkyl groups contained in the above-mentioned radicals may contain 1 to 5 carbon atoms,
    
    
    X denotes an oxygen atom or 2 hydrogen atoms,
    Z denotes a methylene group or the group —NR1, wherein
    
        R1 denotes a hydrogen atom or an alkyl or phenylalkyl group,
    
    
    R11 denotes a hydrogen atom, a C1-3-alkyl group, an alkoxycarbonyl group having a total of 2 to 4 carbon atoms or a phenylmethyl group,
    n denotes the number 1 or 2 or, if m is 1, n may also be 0,
    m denotes the number 0 or 1,
    R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
    
        whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched alkyl groups, C3-8-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, and the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, amino or acetylamino group,
    
    
    A denotes a bond or the divalent group of formula






(which is linked to the NR3R4 group via the —CX group)

wherein

    
    
        R8 and R9 together denote an n-propylene group or
        R8 denotes a hydrogen atom or an alkyl- or phenylalkyl group and
        R9 denotes a hydrogen atom or a branched or unbranched C1-5-alkyl group which, if it is unbranched, may be substituted in the ω-position by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles, phenyl and naphthyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different, and wherein the hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted with the protecting groups commonly used in peptide chemistry, preferably with the acetyl, benzyloxycarbonyl or tert.butyloxycarbonyl group,
    
    
    R3 denotes a hydrogen atom,

a C1-7-alkyl group which may be substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(l-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(ω-hydroxyalkyl)-1-piperazinyl group,

a phenyl or pyridinyl group,
    
        wherein the above-mentioned heterocyclic groups and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
    
    
    R4 denotes a hydrogen atom or a C1-3-alkyl group optionally substituted by a phenyl or pyridinyl group or
    R3 and R4 together with the enclosed nitrogen atom denote a group of general formula






wherein

    
    
        Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
        r denotes the number 0, 1 or 2,
        q denotes the number 0, 1 or 2,
        R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
        a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl- or phenylcarbonyl-group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
        a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
        a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
        a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza- or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
        
            wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
            may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl- or cycloalkylalkyl group, by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally substituted in the ring,
            
                whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
                the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
            
            
        
        
        R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)-group,
        
            whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
        
        
        R12 denotes a hydrogen atom,
        a C1-4-alkyl group, wherein an unbranched alkyl group may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl- or hexahydro-1H-1-azepinyl group,
        an alkoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
        R13 and R14 in each case denote a hydrogen atom or,
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 7 carbon atoms, unless otherwise specified,

all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 10 carbon atoms, unless otherwise specified, and

the term “aroyl group” used above denotes, for example, the benzoyl or naphthoyl group.

    
    


The protecting groups mentioned in the foregoing definitions and hereinafter are the protecting groups which are commonly known from peptide chemistry, particularly
a phenylalkoxycarbonyl group having 1 to 3 carbon atoms in the alkoxy moiety, optionally substituted in the phenyl nucleus by a halogen atom, by a nitro or phenyl group or by one or two methoxy groups,


    
    
        for example the benzyloxycarbonyl, 2-nitro-benzyloxycarbonyl, 4-nitro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 2-chloro-benzyloxycarbonyl, 3-chloro-benzyloxycarbonyl, 4-chloro-benzyloxycarbonyl, 4-Biphenylyl-α,α-dimethyl-benzyloxycarbonyl or 3,5-dimethoxy-α,α-dimethyl-benzyloxycarbonyl group,

an alkoxycarbonyl group having a total of 1 to 5 carbon atoms in the alkyl moiety,

        for example the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, 1-methylpropoxycarbonyl, 2-methylpropoxycarbonyl or tert.butyloxycarbonyl group,

the allyloxycarbonyl, 2,2,2-trichloro-(1,1-dimethylethoxy)carbonyl or 9-fluorenylmethoxycarbonyl group or

the formyl, acetyl or trifluoroacetyl group.

    
    


The present invention relates to racemates, where the compounds of general formula I have only one chiral element. However, the application also covers the individual diastereomeric pairs of antipodes or mixtures thereof which occur when there is more than one chiral element in the compounds of general formula (I).
Particularly preferred are compounds of general formula I wherein Z denotes NR1 and m assumes the value 0 and which are in the D- or (R)-configuration with regard to the partial amino acid structure of the formula




and which are in the L- or (S)-configuration with regard to the partial amino acid structure of formula





which may be present in the group A. As for the other compounds covered by general formula I, the preferred isomers are those which are spatially constructed analogously to the (R)-configured partial structure of formula V with regard to the partial structure of formula VI





The compounds of general formula I have valuable pharmacological properties based on their selective CGRP-antagonistic properties. The invention further relates to medicaments containing these compounds, their use and the preparation thereof.
A subgroup of compounds of general formula I which deserves special mention comprises those wherein

    A, R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined and
    R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.

    
    


Another subgroup of compounds of general formula I deserving special mention comprises those wherein

    R2, R3, R4, R11, X, Z and m and n are defined as for the first subgroup hereinbefore,
    R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl-group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl- or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl-group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or in addition to a nitrogen atom contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
        
            whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl- and biphenylyl-groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, and

A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers and the salts thereof.

        
        
    
    


Preferred compounds of the above general formula I are those wherein

    R denotes an unbranched C1-5-alkyl group which may be substituted in the ω-position
    
        by a C4-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-positions by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom and containing one or two nitrogen atoms,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a C1-3-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position

        
        
        by a C4-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group may be attached to both the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl and alkylamino groups in the ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, or the group of formula

    
    






wherein

    
    
        p denotes the number 1 or 2,
        o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, o may also denote 1.
        Y1 denotes the nitrogen atom if R5 is a free pair of electrons, or the carbon atom,
        Y2 is the nitrogen atom or the group >CH—,
        R5 is a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl, aminocarbonylamino, phenylmethyl or phenyl group,
        R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may denote an additional bond,
        R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together constitute an additional bond, R7 together with RN may also denote a 1,4-butadienylene group,
        RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
        
            by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino,.dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, alkylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
        
        
        a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonyl-amino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
        a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza- or S,S-dioxidothiadiaza heterocycle,
        
            whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
            may contain one or two carbonyl groups adjacent to a nitrogen atom,
            may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, aroyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
            may be substituted at one or two carbon atoms by a branched or unbranched alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, whilst the substituents may be identical or different,
            and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned unsaturated heterocycles may be fused with a benzene, pyridine, diazine, 1,3-oxazole, thiophene, furan, thiazole, pyrrole, N-methyl-pyrrole, quinoline, imidazole or N-methyl-imidazole ring,
        
        
        or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote the 1,4-butadienylene group or,
        if Y1 denotes a carbon atom, RN together with R5, with the inclusion of Y1, may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diazaheterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        whilst the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in the residues mentioned under R5, R7 and RN, as well as benzo-, thieno-, pyrido- and diazinofused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C4-7-cycloalkyl groups, nitro, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, alkylaminocarbonylamino, alkanoyl, cyano, trifluoromethoxy, trifluormethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the alkyl groups contained in the above-mentioned groups may contain 1 to 3 carbon atoms unless otherwise specified,
    
    
    X denotes the oxygen atom or 2 hydrogen atoms,
    Z denotes the methylene group or the group —NR1— wherein
    
        R1 denotes a hydrogen atom or a C1-3-alkyl group,
    
    
    R11 denotes a hydrogen atom, a C1-3-alkyl group or an alkoxycarbonyl group having 2 to 4 carbon atoms altogether,
    n denotes the number 1 or 2 or, if m is 1, n may also be 0,
    m denotes the number 0 or 1,
    R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, 1H-indazol-3-yl, 1-methyl-1H-indazol-3-yl, benzo[b]fur-3-yl, benzo[b]thien-3-yl, pyridinyl, quinolinyl or isoquinolinyl group,
    
        whilst the above-mentioned aromatic and heteroaromatic groups in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, or by branched or unbranched alkyl groups, C4-7-cycloalkyl groups, phenylalkyl groups, alkenyl, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonyl, carboxy, dialkylaminoalkyl, dialkylaminoalkoxy, hydroxy, nitro, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, methylsulphonyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkanoyl, cyano, tetrazolyl, phenyl, pyridinyl, thiazolyl, furyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, and the substituents may be identical or different,
    
    
    A denotes a bond or the divalent group of formula






(linked to the R3R4N-group of general formula (I) via the carbonyl group)

wherein

    
    
        R8 and R9 together denote an n-propylene group or
        R8 denotes a hydrogen atom or a C1-3-alkyl group and
        R9 denotes a hydrogen atom or a branched or unbranched C1-4-alkyl group which, if it is unbranched, may be substituted in the ω-position
        
            by a hydroxy, mercapto, amino, alkylamino, dialkylamino, 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1-azepinyl, methylthio, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-naphthyl, 2-naphthyl- or pyridinyl group, whilst the above-mentioned heterocycles and phenyl groups may in turn be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, trifluoromethoxy, methylsulphonyloxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and any hydroxy, mercapto, amino, guanidino, indolyl and imidazolyl groups contained in the groups mentioned for R9 may be substituted by a protecting group,
        
        
    
    
    R3 denotes a hydrogen atom,

a C1-4-alkyl group which may be substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-azepin-1-yl, [bis-(2-hydroxyethyl)]amino, 4-methyl-1-piperazinyl- or 4-(ω-hydroxyalkyl)-1-piperazinyl group,

a phenyl or pyridinyl group,
    
        wherein the above-mentioned heterocyclic radicals and phenyl groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by methyl, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups and the substituents may be identical or different,
    
    
    R4 denotes a hydrogen atom or a methyl or ethyl group optionally substituted by a phenyl or pyridinyl group
    or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula






wherein

    
    
        Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be the nitrogen atom,
        r denotes the number 0, 1 or 2,
        q denotes the number 0, 1 or 2,
        R10 denotes a hydrogen atom or an amino, alkylamino, dialkylamino, alkyl, cycloalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoiminomethyl, aminocarbonylamino, alkylaminocarbonylamino, cycloalkylaminocarbonylamino, phenylaminocarbonylamino, aminocarbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl or carboxy group,
        a phenyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl-oder trifluoromethylsulphonyl groups, whilst the substituents may be identical or different,
        a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or fused at the double bond to a benzene, pyridine or diazine ring,
        a 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl group,
        a 4- to 10-membered azacycloalkyl group, a 5- to 10-membered oxaza, thiaza or diazacycloalkyl group or a 6- to 10-membered azabicycloalkyl group,
        
            wherein the above-mentioned mono- and bicyclic heterocycles may be bound via a nitrogen or carbon atom and
            may be substituted by a C1-7-alkyl group, by an alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxyalkandyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally alkyl substituted in the ring,
            
                whilst the alicyclic parts contained in these substituents may comprise 3 to 10 ring members and the heteroalicyclic parts may comprise 4 to 10 ring members and
                the above-mentioned phenyl and pyridinyl groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, methylsulphonyloxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, carbalkoxy, carboxyalkyl, carbalkoxyalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω(carboxy)alkanoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different, or
            
            
        
        
        R10 together with R12 and Y3 denotes a 4- to 7-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(alkyl)-group,
        
            whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group,
        
        
        R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-azepin-1-yl-group,
        an alkoxycarbonyl, cyano- or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
        R13 and R14 in each case denote a hydrogen atom or,
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- to 7-membered mono- or bicyclic carbocycle or heterocycle,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise specified,

all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified, and

the term “aroyl group” used above denotes, for example, the benzoyl or naphthoyl group;

their tautomers, their diastereomers, their enantiomers and their salts.

    
    


One subgroup of preferred compounds of general formula I deserving special mention comprises those wherein
A, R2, R3, R4, R11, X, Z and m and n are defined as given hereinbefore defined for the preferred compounds of general formula I,


    R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a C1-3-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxo-imidazo[4,5-b]pyridin-3-yl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, and containing a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1 or 2 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms, unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.

    
    


Another subgroup of compounds of general formula I deserving special mention comprises those wherein
R2, R3, R4, R11, X, Z and m and n are defined as for the first preferred subgroup hereinbefore,


    R denotes an unbranched C1-5-alkyl group which may be substituted in the ω-position
    
        by a C4-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight-chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups, and the substituents may be identical or different,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or in addition to a nitrogen atom contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one or two nitrogen atoms,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the l,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C5-7-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group, and

        
        
    
    
    A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 4 carbon atoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.



Preferred compounds of the above general formula I are those wherein

    R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may be substituted in the carbon skeleton by a phenyl, pyridinyl or diazinyl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, wherein a nitrogen of an imino group may be substituted by an alkyl group,
        or may be substituted by a pyridinyl group,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

or an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position

        
        
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a pyridinyl group,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl and alkylamino groups in the ω-position as well as optionally partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be the same or different,

or the group of formula

        
        
    
    






wherein

    
    
        p denotes the number 1 or 2,
        o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
        Y1 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
        Y2 denotes the nitrogen atom or the group >CH—,
        R5 denotes a free pair of electrons if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 denotes a hydrogen atom, a C1-3-alkyl group, a hydroxy, cyano, aminocarbonyl, carboxy, alkoxycarbonyl or aminocarbonylamino group or a phenylmethyl or phenyl group optionally substituted at the aromatic moiety by a fluorine, chlorine or bromine atom or by a methyl, methoxy, ethoxy, trifluoromethyl, hydroxy, amino or acetylamino group,
        R6 denotes the hydrogen atom or, if Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
        R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
        RN denotes the hydrogen atom or a C1-3-alkyl group, which may be monosubstituted in the ω-position
        
            by a C5-7-cycloalkyl group or by a 1-naphthyl, 2-naphthyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, pyrrolidinyl, hexahydro-1H-1-azepinyl, aminocarbonyl, methylaminocarbonyl, acetylamino, cyano, aminocarbonylamino or alkylaminocarbonylamino group, or may be mono- or disubstituted by phenyl, pyridinyl or diazinyl groups, whilst these substituents may be identical or different,
        
        
        a cyclohexyl, phenyl, pyridinyl, cyano, amino, benzoylamino, aminocarbonyl, alkylaminocarbonyl, alkoxycarbonyl, phenylalkoxycarbonyl, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, N-(aminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-alkylamino, N-(alkylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(alkylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-alkylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, phenylalkylaminocarbonylamino, pyridinylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino, N-(alkylaminocarbonyl)-N-phenylamino, N-(aminocarbonylaminocarbonyl)-N-phenylamino, N-(pyridinyl)-N-(aminocarbonyl)amino, N-(pyridinyl)-N-(alkylaminocarbonyl)amino, phenylamino, pyridinylamino, diazinylamino or 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl group,
        a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxidothiadiaza heterocycle,
        
            whilst the above-mentioned heterocycles may be linked via a carbon or nitrogen atom and
            may contain one or two carbonyl groups adjacent to a nitrogen atom,
            may be substituted at one of the nitrogen atoms by an alkyl, alkanoyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
            may be substituted at one or two carbon atoms by a methyl, phenyl, phenylmethyl, naphthyl, biphenylyl, thienyl, pyridinyl or diazinyl group, wherein the substituents may be identical or different,
            and wherein a C3-4-alkylene group may additionally be attached to the above-mentioned heterocycles via two adjacent carbon atoms or an olefinic double bond of one of the above-mentioned heterocycles may be fused to a thiophene, benzene, pyridine, quinoline or diazine ring,
        
        
        or, if Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 may also denote a 1,4-butadienylene group or,
        if Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or a saturated or monounsaturated 5- or 6-membered 1,3-diazaheterocycle which may contain one or two carbonyl groups in the ring adjacent to a nitrogen atom and, if it is unsaturated, may also be benzo-fused at the double bond and may be substituted at one of the nitrogen atoms by a methyl, aminocarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, phenylalkoxycarbonylalkyl, phenylmethyl or phenyl group,
        
            whilst the phenyl, pyridinyl or diazinyl groups contained in the groups mentioned under RN and the thieno-, benzo-, pyrido- or diazino-condensed heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by methyl groups, nitro, methoxy, ethoxy, methylsulphonylamino, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, hydroxy, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, hydroxyalkylaminocarbonyl, (4-morpholinyl)-carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, aminocarbonylaminoalkyl, methylaminocarbonylamino, acetyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,
            and the alkyl groups contained in the above-mentioned radicals may contain 1 to 3 carbon atoms, unless otherwise specified,
        
        
    
    
    X denotes an oxygen atom or 2 hydrogen atoms,
    Z denotes a methylene group or the group —NR1— wherein
    
        R1 is a hydrogen atom or a methyl group,
    
    
    R11 denotes the hydrogen atom or a methyl or methoxycarbonyl group,
    n denotes the number 1 or 2 or, if m is the number 1, n may also denote 0,
    m denotes the number 0 or 1,
    R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-formyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 4-imidazolyl, 1-methyl-4-imidazolyl, 2-thienyl, 3-thienyl, thiazolyl, pyridinyl or quinolinyl group,
    
        wherein the above-mentioned aromatic and heteroaromatic groups may additionally be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by branched or unbranched C1-5-alkyl groups, allyl, vinyl, methoxy, ethoxy, propoxy, 1-methylethoxy, dimethylaminoethoxy, trifluoromethyl, hydroxy, nitro, amino, acetylamino, propionylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetyl, cyano, methylsulphonyloxy or trifluoromethoxy groups, by tetrazolyl, phenyl pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, or
    
    
    A denotes a bond or the divalent group of formula






(linked to the NR3R4-group of general formula (I) via the carbonyl group)

wherein

    
    
        R8 and R9 together denote an n-propylene group or
        R8 denotes the hydrogen atom or the methyl group and
        R9 denotes a hydrogen atom or an unbranched C1-4-alkyl group which may be substituted in the ω-position
        
            by a hydroxy, amino, methylamino, dimethylamino, hydroxycarbonyl, aminocarbonyl, aminoiminomethylamino, aminocarbonylamino, phenyl or pyridinyl group, wherein the phenyl and pyridinyl group may in turn be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group and wherein any hydroxy, amino and guanidino groups contained in the groups given for R9 may be substituted by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
        
        
    
    
    R3 denotes a hydrogen atom,

a C1-4-alkyl group optionally substituted in the ω-position by a cyclohexyl, phenyl, pyridinyl, hydroxy, amino, methylamino, dimethylamino, carboxy, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-(1-piperidinyl)-1-piperidinyl group,

a phenyl or pyridinyl group,
    
        whilst the above-mentioned phenyl and pyridinyl groups may additionally be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl or cyano group,
    
    
    R4 denotes the hydrogen atom or a C1-2-alkyl group optionally substituted by a phenyl or pyridinyl group
    or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula






wherein

    
    
        Y3 denotes a carbon atom or, if R12 denotes a free pair of electrons, Y3 may also be a nitrogen atom,
        r denotes the number 0, 1 or 2,
        q denotes the number 0, 1 or 2,
        
            with the proviso that the sum of the numbers given for r and q is 0, 1, 2 or 3,
        
        
        R10 denotes a hydrogen atom, an alkyl, cycloalkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group,
        a phenyl, pyridinyl, diazinyl, pyridinylcarbonyl or phenylcarbonyl group which may be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, or by methyl, ethyl, propyl, methoxy, hydroxy, ω-(dialkylamino)-alkyl, ω-(dialkylamino)hydroxyalkyl or alkanoyl groups, whilst the substituents may be identical or different,
        a 1,3-dihydro-2-oxo-2H-imidazolyl, 2,4(1H,3H)-dioxopyrimidinyl or 3,4-dihydro-2(1H)-oxopyrimidinyl group bound via a nitrogen atom, which may be substituted by a phenyl group or may be fused at the double bond to a benzene, pyridine or diazine ring,
        a 5- to 7-membered azacycloalkyl group, a 4- to 7-membered oxaza- or diazacycloalkyl group or a 7- to 9-membered azabicycloalkyl group,
        
            wherein the above-mentioned mono- and bicyclic heterocycles are bound via a nitrogen or a carbon atom and
            may be substituted by a C1-7-alkyl group, or by an alkanoyl, dialkylamino, phenylcarbonyl, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl or alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy moiety, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group or by an azacycloalkylcarbonyl or diazacycloalkylcarbonyl group optionally alkylsubstituted in the ring,
            
                whilst the alicyclic groups contained in these substituents may comprise 3 to 7 ring members and the heteroalicyclic groups may comprise 4 to 7 ring members and
                the above-mentioned phenylcarbonyl group may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, trifluoromethyl, hydroxy, amino or acetylamino group, or
            
            
        
        
        R10 together with R12 and Y3 denotes a 4- to 6-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(CH3)-group,
        
            whilst a hydrogen atom bound to a nitrogen atom within the group R10 may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
        
        
        R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a phenyl, pyridinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
        a methoxycarbonyl or ethoxycarbonyl, cyano or aminocarbonyl group or a free pair of electrons, if Y3 denotes a nitrogen atom, and
        R13 and R14 each denote a hydrogen atom or,
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom, or
        if Y3 is a carbon atom, R12 together with R14 also denotes another carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes a partially hydrogenated or aromatic 5- or 6-membered mono- or bicyclic carbocycle or heterocycle, containing one or two nitrogen atoms,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups named may contain 1 to 3 carbon atoms, unless otherwise stated, and

all the above-mentioned cycloalkyl groups and the cycloalkyl groups present within the other groups named may contain 5 to 7 carbon atoms, unless otherwise specified,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.

    
    


One subgroup of particularly preferred compounds of general formula I deserving special mention comprises those wherein
A, R2, R3, R4, R11, X, Z and m and n are defined as for the particularly preferred compounds of general formula I hereinbefore and


    R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2(1H)-oxoquinolin-3-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a pyridinyl group,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and also to the pyridinyl group, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkylamino groups in the ω-position, as well as optionally any partially hydrogenated mono- and bicyclic heteroaromatic rings, may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups, whilst the substituents may be identical or different,

whilst all the above-mentioned alkyl and alkoxy groups and the alkoxy groups present within the other named radicals may contain 1 to 3 carbon atoms unless otherwise stated,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.

        
        
    
    


Another subgroup of particularly preferred compounds of general formula I which deserves special mention comprises those compounds wherein

    R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined for the first-mentioned particularly preferred subgroup,
    R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, whilst the latter two groups may be substituted in the carbon skeleton by a phenyl, pyridinyl or diazinyl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom and containing a nitrogen, oxygen or sulphur atom or two nitrogen atoms, wherein a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a pyridinyl group,
        
            whilst a 1,4-butadienylene group may be attached both to the 5-membered heteroaromatic monocyclic rings and also to the pyridinyl group via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned hereinbefore for the substitution of the alkyl groups in the ω-position as well as optionally any partially hydrogenated mono- and bicyclic heteroaromatic rings may additionally be mono- or disubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms or by alkyl, nitro, alkoxy, trifluoromethyl, hydroxy, amino, acetylamino, propionylamino, alkanoyl, cyano or trifluoromethoxy groups wherein the substituents may be identical or different,

        
        
    
    
    and A denotes a single bond,

whilst all the above-mentioned alkyl and alkoxy groups and the alkyl groups present within the other groups mentioned may contain 1 to 3 carbon atoms unless otherwise specified,

their tautomers, their diastereomers, their enantiomers and their salts.



More particularly preferred compounds of the above general formula I are those wherein

    R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group, whilst the above-mentioned aromatic groups may additionally be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, amino or acetylamino group,
        by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,

or an unbranched C1-4-alkylamino group which is optionally additionally substituted at the nitrogen atom by a methyl or ethyl group and which may be substituted in the ω-position

        by a C5-7-cycloalkyl group,
        by a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or by methyl, nitro, methoxy, trifluoromethyl, hydroxy, amino or acetylamino groups, whilst the substituents may be identical or different,
        by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,

or the group of formula

    
    






wherein

    
    
        p denotes the number 1 or 2,
        o denotes the number 2 or, if Y1 and Y2 are not simultaneously nitrogen atoms, it may also denote the number 1,
        Y1 denotes the nitrogen atom if R5 denotes a free pair of electrons, or the carbon atom,
        Y2 denotes the nitrogen atom or the group >CH—,
        R5 denotes a free pair of electrons, if Y1 denotes the nitrogen atom or, if Y1 denotes the carbon atom, R5 may denote the hydrogen atom, a C1-2-alkyl group or the cyano or phenyl group,
        R6 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom, R6 together with R5 may also denote an additional bond,
        R7 denotes the hydrogen atom or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, R7 together with RN may also denote the 1,4-butadienylene group,
        RN denotes the hydrogen atom or a C1-3-alkyl group, which may be substituted in the ω-position
        
            by one or two phenyl or pyridinyl groups, wherein the substituents may be identical or different,
            or by a hydroxy or methoxy group,
        
        
        a phenyl group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl groups, nitro, methoxy, ethoxy, trifluoromethyl, hydroxy or cyano groups, whilst the substituents may be identical or different, or a phenyl group substituted by a methylenedioxy group,
        a 2-pyridinyl or 4-pyridinyl group,
        an amino, benzoylamino, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonylamino, methylaminocarbonylamino, N-(aminocarbonyl)-N-methylamino, N-(methylaminocarbonyl)-N-methylamino, N-(aminocarbonyl)-N-(4-fluorophenyl)amino, N-(methyl-aminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(methylamino)]carbonylamino, N-(phenylamino-carbonyl)-N-methylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino group or a phenylamino group optionally substituted in the phenyl ring by an aminocarbonylamino or methylsulphonylamino group,
        a 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, a 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxobenzimidazol-1-yl, 1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl, 1H-indol-3-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl, 1,3(2H)-dioxo-1H-isoindol-2-yl, 1H-benzimidazol-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 2(3H)-oxobenzoxazol-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidin-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl, 3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl, 2(1H)-bxoquinolin-3-yl, 3,4-dihydro-2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 2,4(1H,3H)-dioxothieno[3,4-d]-pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl, 1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl, 2,5-dioxo-4-phenylimidazolidin-1-yl, 2,5-dioxo-4-(phenylmethyl)-imidazolidin-1-yl, 3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl, 1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 4-phenyl-2(1H)-oxopyrimidin-1-yl, 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2[1H]-oxopyrido[4,3-d]pyrimidin-3-yl or 2,3-dihydro-4(1H)-oxoquinazolin-3-yl group,
        
            wherein the above-mentioned mono- and bicyclic heterocycles may be substituted at one of the nitrogen atoms by a methoxycarbonylmethyl group and/or
            the above-mentioned mono- and bicyclic heterocycles may be mono-, di- or trisubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by fluorine, chlorine or bromine atoms, or by methyl, trifluoromethyl, methoxy, hydroxy, amino, nitro, phenyl, phenylmethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-piperidinyl)carbonyl or (4-methyl-1-piperazinyl)carbonyl groups wherein the substituents may be identical or different and multiple substitution with the last three substituents is ruled out,
        
        
        or, provided that Y1 is not a nitrogen atom and R5 and R6 together denote an additional bond, RN together with R7 also denotes the 1,4-butadienylene group,
        or, provided that Y1 denotes a carbon atom, RN together with R5 with the inclusion of Y1 may also denote a carbonyl group or saturated or monounsaturated five- or six-membered 1,3-diaza-heterocycle,
        
            which may contain a carbonyl group in the ring, adjacent to a nitrogen atom,
            may be substituted by a phenyl group at one of the nitrogen atoms
            and, if it is unsaturated, may also be benzo-condensed at the double bond,
        
        
    
    
    X denotes an oxygen atom or 2 hydrogen atoms,
    Z denotes a methylene group or the group —NR1, wherein
    
        R1 denotes a hydrogen atom or a methyl group,
    
    
    R11 denotes a hydrogen atom, a methoxycarbonyl, ethoxycarbonyl or methyl group,
    n denotes the number 1 and m denotes the number 0 or
    n denotes the number 0 and m denotes the number 1,
    R2 denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl, thiazolyl or alkylthiazolyl group having 1 to 3 carbon atoms in the alkyl moiety, a pyridinyl or quinolinyl group,
    
        wherein the above-mentioned phenyl and naphthyl groups may be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by branched or unbranched C1-5-alkyl groups, by C1-3-alkoxy groups, by vinyl, allyl, trifluoromethyl, methylsulphonyloxy, 2-(dimethylamino)ethoxy, hydroxy, cyano, nitro or amino groups, by tetrazolyl, phenyl, pyridinyl, thiazolyl or furyl groups and the substituents may be identical or different, and multiple substitution with the last five substituents is ruled out,
    
    
    A denotes a bond or the divalent group of formula






(linked to the group —NR3R4 of formula (I) via the carbonyl group)

wherein

    
    
        R8 and R9 together denote an n-propylene group or
        R8 denotes the hydrogen atom or the methyl group and
        R9 denotes the hydrogen atom or an unbranched C1-4-alkyl group,
        which may be substituted in the ω-position by an amino, methylamino, dimethylamino, aminoiminomethylamino or aminocarbonylamino group, whilst in the above-mentioned substituents a hydrogen atom bound to a nitrogen atom may be replaced by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group,
    
    
    R3 denotes a hydrogen atom or

a C1-4-alkyl group optionally substituted in the (ω-position by an amino, methylamino, dimethylamino- or 4-(1-piperidinyl)-1-piperidinyl group,

    R4 denotes a hydrogen atom or a methyl or ethyl group
    or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula






wherein

    
    
        Y3 denotes the carbon atom or, if R12 denotes a free pair of electrons, Y3 may also denote a nitrogen atom,
        r denotes the number 1,
        q denotes the number 1,
        R10 denotes the hydrogen atom, an alkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl or carboxy group or a cycloalkyl group having 4 to 7 carbon atoms in the ring,
        a benzoyl, pyridinylcarbonyl, phenyl, pyridinyl or diazinyl group, each of which may be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom, or by an acetyl, methyl, ethyl or methoxy group, or by a dimethylaminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety optionally hydroxysubstituted in the alkyl moiety,
        a 1,3-dihydro-2-oxo-2H-imidazolyl group bound via a nitrogen atom, which may be fused to a benzene or pyridine ring at the double bond,
        a 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl, 4-piperidinyl or 4-morpholinyl group, wherein the nitrogen atom of the 4-piperidinyl group may be substituted by an alkanoyl- or alkyl group each having 1 to 7 carbon atoms or by a benzoyl, methylsulphonyl, 3-carboxy-propionyl, cyclopropylmethyl, alkoxycarbonylmethyl or carboxymethyl group or by a protecting group, e.g. the phenylmethoxycarbonyl or tert.butyloxycarbonyl group, or it may represent a hexahydro-1H-1-azepinyl, 8-methyl-8-azabicyclo[3,2,1]oct-3-yl, 4-alkyl-1-piperazinyl, hexahydro-4-alkyl-1H-1,4-diazepin-1-yl, 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl group,
        or
        R10 together with R12 and Y3 denotes a 5-membered cycloaliphatic ring in which a methylene group may be replaced by an —NH— or —N(CH3)— group,
        R12 denotes a hydrogen atom, a C1-2-alkyl group which may be substituted in the ω-position by a 1-pyrrolidinyl, 1-piperidinyl or 4-methyl-1-piperazinyl group,
        a methoxycarbonyl or ethoxycarbonyl or a cyano group,
        a free pair of electrons if Y3 denotes a nitrogen atom, and
        R13 and R14 each denote a hydrogen atom or,
        provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond, wherein R10 is as hereinbefore defined and R13 denotes a hydrogen atom or,
        provided that Y3 is a carbon atom, R12 together with R14 may also denote an additional carbon-carbon bond and R10 together with R13 and the enclosed double bond denotes an indole group fused on via the 5-membered ring,

whilst all the above-mentioned alkyl groups and the alkyl groups present within the other named groups may contain 1 to 3 carbon atoms, unless otherwise specified,

their tautomers, their diastereomers, their enantiomers and their salts.

    
    


A subgroup of most particularly preferred compounds of general formula I deserving special mention comprises those wherein
A, R2, R3, R4, R11, X, Z and m and n are as hereinbefore defined for the most particularly preferred compounds of general formula I and


    R denotes an unbranched C1-4-alkylamino group optionally substituted at the nitrogen atom by a methyl or ethyl group, which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by a phenyl group, which may be mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, nitro, methoxy, trifluoromethyl, hydroxy, amino or acetylamino groups, wherein the substituents may be identical or different, or
        by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl or isoquinolinyl group,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and salts thereof.

    
    


Another subgroup of most particularly preferred compounds of general formula I deserving special mention comprises those wherein
R2, R3, R4, R11, X, Z and m and n are as defined hereinbefore for the first-mentioned particularly preferred subgroup,


    R denotes an unbranched C1-3-alkyl group which may be substituted in the ω-position
    
        by a C5-7-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or (4-biphenylyl) group, whilst the above-mentioned aromatic groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy, amino or acetylamino group,
        or by a 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indol-3-yl, quinolinyl- or isoquinolinyl group,
    
    
    and A denotes a single bond,

their tautomers, their diastereomers, their enantiomers, mixtures thereof and the salts thereof.



The following are mentioned as examples of most particularly preferred compounds:

    (1) 1-[N2—[N-[[[2-(2-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (2) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (3) 1-[N2—[N-[[[2-(2,5-Dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (4) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine
    (5) 1-[N2—[N-[[[2-(2,3-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (6) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (7) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-piperidinyl)-piperazine
    (8) 1-[N2—[N-[[[2-(3,4-dihydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    (9) 1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (10) 1-[N2—[N-[4-(3-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (11) 1-[N2—[N-[[(2-Phenylethyl)amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (12) 1-[N2—[N-[[[2-(4-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (13) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3-(1-naphthyl)-D-alanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (14) 1-[N2—[N-[[[2-(3-Hydroxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (15) 1-[N2—[N-[3-(3-Methoxyphenyl)-1-oxopropyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (16) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]methylamino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (17) 1-[N2—[N-(4-Phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (18) 1-[N2—[N-[4-(2-Methylphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (19) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (20) 1-[N2—[N-[[[2-(3-Methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    (21) 1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidin
    (22) 1-[N2—[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-di-bromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (23) 1-[N2—[N-(4-Phenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (24) 1-[N2—[N-[4-(4-Fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (25) 1-[N2—[N-[4,4-Diphenyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (26) 1-[N2—[N-[4-Cyclohexyl-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (27) 1-[N2—[N-[4-(4-Acetylaminophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (28) 1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dichloro-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    (29) 1-[N2—[N-[4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl]-carbonyl]-3,5-dibromo-D,L-tyrosyl]-D,L-lysyl]-4-(4-pyridinyl)-piperazine
    (30) 1-[N2—[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (31) 1-[N2—[N-[4-(3,4-Methylenedioxyphenyl)-1-piperazinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (32) 1-[N2—[N-(4-Methyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (33) 1-[N2—[N-[4-(2-Hydroxyethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (34) 1-[N2—[N-[4-(4-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (35) 1-[N2—[N-[4-(2-Pyridinyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (36) 1-[N2—[N-[4-(Diphenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (37) 1-[N2—[N-[4-(Phenylmethyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (38) 1-[N2—[N-[4-(4-Nitrophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (39) 1-[N2—[N-[4-(Ethoxycarbonyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (40) 1-[N2—[N-[[[3-(2-Methoxyphenyl)propyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (41) 1-[N2—[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (42) 1-[N2—[N-[[[2-(3-Nitrophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (43) 1-[N2—[N-[[[2-(3-Acetylaminophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (44) 1-[N2—[N-[[[2-(3-Bromophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-ly-syl]-4-(4-pyridinyl)-piperazine
    (45) 1-[N2—[N-[(1,2,4,5-Tetrahydro-3H-3-benzazepin-3-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (46) 1-[N2—[N-[[[2-[3-(Trifluoromethyl)phenyl]ethyl]amino]-carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (47) 1-[N2—[N-[[[2-(3-Fluorophenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (48) 1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-fluorophenyl)-piperazine
    (49) 1-[N2-[4-Amino-3,5-dibromo-N-[[(2-phenylethyl)amino]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (50) 1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (51) 1-[N2—[N-[4-(3-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (52) 1-[N2—[N-[4-(2-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (53) 1-[N2—[N-[(4-Biphenylyl)acetyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (54) 1-[N2—[N-[4-(4-Bromophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (55) 1-[N2—[N-[4-(1H-Indol-3-yl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (56) 1-[N2—[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (57) 1-[N2—[N-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (58) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (59) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (60) 1-[N2—[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (61) 1-[N2—[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (62) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(2-pyridinyl)-piperazine
    (63) 1-[N2—[N-[[[2-(2-Cyclohexyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (64) 1-[N2—[N-[4-(2-Chlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (65) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (66) 1-[N2—[N-[4-(Aminocarbonyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (67) 1-[N2—[N-[[[2-(1H-Indol-3-yl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (68) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine
    (69) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine
    (70) 1-[N2—[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine
    (71) 1-[N2—[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine
    (72) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (73) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (74) 1-[N2—[N-[4-(2,3-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (75) 1-[N2—[N-[4-(3,5-Dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (76) 1-[N2—[N-[4-(2-Cyanphenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (77) 1-[N2—[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (78) 1-[N2—[N-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N6-(1,1-dimethyl-ethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (79) 1-[N2—[N-[4-[4-Chloro-3-(trifluoromethyl)phenyl]-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (80) 1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (81) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (82) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (83) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (84) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-[1-(1-methylethyl)-4-piperidinyl]-piperidine
    (85) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-benzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-phenylpiperazine
    (86) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (87) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (88) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5,6-dichloro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(4-pyridinyl)-piperazine
    (89) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-3-(methoxy-carbonylmethyl)-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (90) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine
    (91) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (92) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (93) 1-[4-Amino-3,5-dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (94) 1-[4-Amino-3,5-dibromo-N-[(4-Oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (95) 1-[3,5-Dibromo-N-[[4-(benzoylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (96) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-6-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (97) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-methyl-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (98) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosinamide
    (99) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-methylpiperazine
    (100) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)piperazine
    (101) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine
    (102) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N,N-diethyl-D-tyrosinamide
    (103) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(4-(dimethylamino)butyl]-D-tyrosinamide
    (104) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (105) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (106) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(1,1-di-methylethoxycarbonyl)-4-piperidinyl]piperazine
    (107) 1-[4-Amino-3,5-dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (108) 1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (109) 1-[3,5-Dibromo-N-[(4-cyan-4-phenyl-1-piperidinyl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (110) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    (111) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyrimidinyl)-piperazine
    (112) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine
    (113) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4(pyrazinyl)-piperazine
    (114) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    (115) 1-[3,5-Dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)carbonyl]-D-tyrosyl]-4-(2-pyridinyl)-piperazine
    (116) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (117) 1-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (118) 1-[3,5-Dibromo-N-[[4-(aminocarbonyl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (119) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(pyrazinyl)-piperazine
    (120) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-pyrimidinyl)-piperazine
    (121) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-imidazo-[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (122) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxo-imidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(4-pyridinyl)-piperazine
    (123) cis-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (124) trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (125) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperazine
    (126) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine
    (127) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dimethyl-D,L-tyrosyl]-4-(1-piperidinyl)-piperidine
    (128) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    (129) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(pyrazinyl)-piperazine
    (130) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine
    (131) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(2-methoxyphenyl)-piperazine
    (132) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    (133) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-methoxyphenyl)-piperazine
    (134) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (135) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (136) 1-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (137) 1-[4-Amino-N-[[4-(1H-benzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (138) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3(2H)-dioxo-1H-isoindol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (139) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (140) 1-[N2-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethyl-ethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (141) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (142) 1-[N2-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (143) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (144) 1-[3,5-Dibromo-N-[(4′(3′H)-oxospiro[piperidine-4,2′(1′H)-quinazolin]-1-yl)carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (145) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo-[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (146) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-3-(4-pyridinyl)alanyl]-4-(4-pyridinyl)-piperazine
    (147) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (148) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (149) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (150) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (151) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (152) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (153) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-5-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (154) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (155) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine
    (156) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(2-fluorophenyl)-piperazine
    (157) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine
    (158) 1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (159) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (160) 1-[3,5-Dibromo-N-[[4-(aminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (161) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    (162) 1-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (163) 1-[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (164) 1-[4-Amino-3,5-dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (165) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    (166) 1-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (167) 1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (168) 1-[N2—[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    (169) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine
    (170) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    (171) 1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (172) 1-[3,5-Dibromo-N-[[4-(phenylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (173) 1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (174) 1-[2,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (175) 1-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)-N-phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (176) 1-[N2-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    (177) 1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    (178) 1-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)-methyl-amino]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (179) 1-[N2—[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (180) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    181) 1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (182) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)amino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (183) 1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (184) 1-[N2—[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (185) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (186) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (187) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (188) 1-[N2—[N-[[4-[2(3H)-Oxobenzoxazol-3-yl]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (189) 1-[4-Amino-3,5-dibromo-N-[[4-(1H-indol-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (190) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-di-methylethoxycarbonyl)-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (191) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (192) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (193) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperazine
    (194) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-cyclohexyl-4-piperidinyl)-piperazine
    (195) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine
    (196) 1-[N2—[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine
    (197) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (198) 1-[N2—[N-[[4-(2-Cyanophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (199) 1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (200) 1-[3,5-Dichloro-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (201) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-6-hydroxy-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine
    (202) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine
    (203) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidine
    (204) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine
    (205) 1-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (206) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine
    (207) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(methoxycarbonyl)-4-phenylpiperidine
    (208) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (209) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    (210) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    (211) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine
    (212) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    (213) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (214) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine
    (215) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine
    (216) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridin-3-yl)-piperidine
    (217) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (218) 1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (219) (R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine
    (220) (R)-1-[2-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]amino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine
    (221) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    (222) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[(2-(4-(1-piperidinyl)-1-piperidinyl]ethyl]-D-tyrosinamide
    (223) 1-[3,5-Dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (224) 1-[3,5-Dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]-carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (225) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (226) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (227) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (228) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (229) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxoimidazo-[4,5-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (230) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (231) 1-[4-Amino-3,5-dibromo-N-[[4-(2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (232) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (233) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (234) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (235) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (236) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (237) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (238) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (239) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (240) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (241) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine
    (242) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (243) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (244) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (245) (R)-1-[2-[N-[[4-(3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]-3-(4-amino-3,5-dibromophenyl)-propyl]-4-(1-piperidinyl)-piperidine
    (246) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (247) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-di-methylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    (248) 1-[N2-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (249) 1-[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]-carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-4-[(1-piperidinyl)methyl]-piperidine
    (250) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (251) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (252) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (253) 1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (254) 1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (255) 1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (256) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (257) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(4-pyridinyl)-piperazine
    (258) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (259) 1-[4-Amino-3,5-dibromo-N-[[4-(benzoylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (260) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-β-alanyl]-4-(4-pyridinyl)-piperazine
    (261) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(4-pyridinyl)-piperazine
    (262) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(phenylaminocarbonyl)-phenylamino)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (263) 1-(N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-[3-(2-thienyl)-D-alanyl]-4-(1-piperidinyl)-piperidine
    (264) 4-Amino-3,5-dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methyl-N-[3-(4-methyl-1-piperazinyl)propyl]-D-phenylalaninamide
    (265) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-glycyl]-4-(1-piperidinyl)-piperidine
    (266) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(4-pyridinyl)-piperazine
    (267) 1-[N2-[4-Amino-3,5-dibromo-N-((4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl)-4-(1-piperidinyl)-piperidine
    (268) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-alanyl]-4-(1-piperidinyl)-piperidine
    (269) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (270) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (271) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine
    (272) 1-[N2-[[4-(1,3-Dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-1-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-piperidinyl)-piperidine
    (273) 1-[N-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N-methylglycyl]-4-(1-piperidinyl)-piperidine
    (274) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (275) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinoxalin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (276) 1-[4-Amino-3,5-dibromo-N-[[4-[N-(aminocarbonyl)-N-(4-fluorophenyl)amino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (277) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (278) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine
    (279) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-dimethylamino)propyl]-piperidine
    (280) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (281) 1-[N-[[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tryptyl]-4-(1-piperidinyl)-piperidine
    (282) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (283) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine
    (284) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (285) (R,S)-l -[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    (286) 3,5-Dibromo-N2-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-D-tyrosinamide
    (287) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (288) 1-[3,5-Dibromo-N-[[4-(7,9-dihydro-6,8-dioxo-1H-purin-9-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (289) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (290) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    (291) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine
    (292) (R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (293) 1-[N6-Acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (294) 1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    (295) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine
    (296) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine
    (297) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (298) (R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (299) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (300) (R)-1-[3-(4-Amino-3-bromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (301) (R)-1-[3-(3,5-Dibromo-4-hydroxyphenyl)-2-[N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (302) (R,S)-1-[2-(4-Amino-3,5-dibromobenzoyl)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-4-oxobutyl]-4-(1-piperidinyl)-piperidine
    (303) 1-[4-Amino-N-[[4-[2-(aminocarbonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (304) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (305) 1-(4-Amino-N-[[4-[2-(methylsulphonylamino)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (306) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (307) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxy-carbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (308) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (309) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (310) 1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinylicarbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (311) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (312) 1-[4-Amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (313) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (314) 1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (315) 1-[4-Amino-3,5-dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (316) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (317) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    (318) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine
    (319) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-fluorophenyl)-piperazine
    (320) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(2-fluorophenyl)-piperazine
    (321) 1-[3,5-Dibromo-N-[[4-(1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (322) trans-1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-cyclohexyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (323) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-6,7-dimethoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (324) 1-[N-[[4-(5-Chloro-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (325) 1-[3,5-Dibromo-N-[[3-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-pyrrolidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (326) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (327) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (328) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-8-methoxy-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (329) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (330) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxy-phenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (331) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(4-methoxy-phenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (332) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (333) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (334) 1-[N-[[4-(1,3-dihydro-4-[3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine
    (335) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (336) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (337) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (338) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (339) (R)-1-[3-(4-Amino-3,5-dibromophenyl)-2-[N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
    (340) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (341) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (342) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (343) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (344) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (345) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (346) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (347) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (348) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (349) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (350) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (351) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (352) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (353) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (354) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-tyrosyl]-4-(4-pyridinyl)-piperidine
    (355) 1-[4-Amino-3,5-dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (356) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (357) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-thienyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (358) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (359) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (360) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine
    (361) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (362) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (363) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (364) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (365) 1-[N2-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (366) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    (367) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    (368) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperidine
    (369) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[4-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperazine
    (370) 1-[4-Amino-3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    (371) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    (372) 4-(1-Acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-piperidine
    (373) 1-[4-Amino-N-[[4-(6-bromo-3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (374) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (375) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (376) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (377) 1-[47Amino-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (378) 1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
    (379) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperazine
    (380) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-fluorophenyl)-piperazine
    (381) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine
    (382) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(3-pyridinyl)-piperazine
    (383) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    (384) 1-[3,5-Dibromo-N-[[4-[1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (385) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(3-pyridinyl)-piperazine
    (386) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (387) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    (388) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(2-pyridinyl)-piperazine
    (389) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(phenylaminocarbonylamino)-piperidine
    (390) 1-[4-Amino-3,5-dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (391) 1-[3,5-Dibromo-N-[[4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (392) 1-[3,5-Dibromo-N-[[4-[4-phenyl-2(1H)-oxopyrimidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (393) 4-Cyano-1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-phenylpiperidine
    (394) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    (395) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyrimidinyl)-piperazine
    (396) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    (397) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyrimidinyl)-piperazine
    (398) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (399) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine
    (400) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (401) 2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole
    (402) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (403) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (404) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-ethylphenyl)-piperazine
    (405) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine
    (406) 1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (407) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (408) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine
    (409) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)phenyl]-piperazine
    (410) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorobenzoyl)-piperidine
    (411) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyano-4-phenylpiperidine
    (412) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-fluorophenyl)-piperidine
    (413) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(hexahydro-1-methyl-4-pyridinyl)carbonyl]-piperazine
    (414) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine
    (415) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[3-(dimethylamino)propyl]-piperazine
    (416) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (417) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (418) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,l]oct-3-yl)-piperazine
    (419) 1-[N-[4-[[1,3-Dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (420) 1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (421) 1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (422) 1-[3,5-Dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (423) 1-[3,5-Dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (424) 1-[4-Amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H) -oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (425) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-morpholinyl)-piperidine
    (426) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxo-quinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(dimethylamino)-piperidine
    (427) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-pyrrolidinyl)-piperidine
    (428) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-morpholinyl)-piperidine
    (429) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(dimethylamino)-piperidine
    (430) 1-[4-Amino-3,5-dibromo-N-[[4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H) -oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (431) 1-[4-Amino-3,5-dibromo-N-[[4-(2,5-dioxo-4-phenylimidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (432) 1-[3,5-Dibromo-N-[[4-(2,5-dioxo-4-phenylimidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (433) 1-[4-Amino-3,5-dibromo-N-[[4-[2,5-dioxo-4-(phenyl-methyl)-imidazolidin-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (434) 1-[3,5-Dibromo-N-[[4-[2,5-dioxo-4-(phenylmethyl)imidazolidin-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (435) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-pyrrolidinyl)-piperidine
    (436) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (437) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (438) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-cyclohexylpiperazine
    (439) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclohexylpiperazine
    (440) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-piperidinyl)-piperidine
    (441) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (442) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2,2-dioxido-2,1,3-benzothiadiazin-3-yl)-1-piperidinyl]carbonyl]-D-phenyl-alanyl]-4-(4-pyridinyl)-piperidine
    (443) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (444) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (445) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperazine
    (446) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (447) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (448) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (449) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (450) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosyl]-4-(4-pyridinyl)-piperidine
    (451) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    (452) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    (453) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (454) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (455) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (456) 1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (457) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperidine
    (458) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (459) (R,S)-1-[2-[(3,5-Dibromo-4-hydroxyphenyl)methyl]-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (460) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cycloheptylpiperazine
    (461) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-cyclopentylpiperazine
    (462) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-4-methoxy-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (463) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (464) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (465) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (466) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (467) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (468) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (469) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (470) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (471) 1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(4-biphenylyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine
    (472) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-biphenylyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (473) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (474) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (475) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (476) 1-[3,5-Bis-(trifluoromethyl)-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (477) 1-[3,4-Dichloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (478) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (479) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (480) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (481) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (482) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (483) 1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (484) 1-[4-Amino-N-[[4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (485) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine
    (486) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine
    (487) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine
    (488) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine
    (489) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine
    (490) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (491) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (492) 1-[3,5-Dibromo-N-[[4-(2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazol-2-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (493) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine
    (494) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine
    (495) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (496) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-pyridinyl)carbonyl]-piperazine
    (497) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine
    (498) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    (499) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    (500) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperidinyl)carbonyl]-piperazine
    (501) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)piperidine
    (502) 1-[3,5-Dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    (503) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)piperidine
    (504) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine
    (505) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)carbonyl]-piperidine
    (506) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (507) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (508) (R,S)-1-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (509) 1-[4-Amino-3,5-dibromo-N-[[4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (510) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (511) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (512) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (513) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (514) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (515) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-methoxy-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    (516) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    (517) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine
    (518) 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
    (519) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (520) 1-[4-Amino-N-[[4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (521) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine
    (522) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine
    (523) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine
    (524) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine
    (525) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine
    (526) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine
    (527) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(1-piperidinyl)-piperidine
    (528) 1-[N-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-3-(2-methyl-4-thiazolyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine
    (529) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperi-dinyl)-piperidine
    (530) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (531) (R,S)-1-[2-[(3-Methoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (532) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (533) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido-[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(l-piperidinyl)-piperidine
    (534) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (535) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (536) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (537) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxopyrido[4,3-d]pyrimidin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine
    (538) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (539) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (540) (R,S)-1-[2-[(1-Naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (541) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (542) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H) -oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (543) (R,S)-1-[2-[(3-Ethoxyphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (544) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (545) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (546) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (547) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (548) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (549) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (550) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-[2-(dimethylamino)ethoxy]phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperazinyl)-piperidine
    (551) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperidine
    (552) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    (553) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    (554) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    (555) 1-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[4-(1-oxoethyl)-1-piperazinyl]-piperidine
    (556) 1-[4-Amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    (557) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    (558) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(4-pyridinyl)carbonyl]-piperazine
    (559) 1-[4-Amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (560) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    (561) 1-[4-Amino-3,5-dibromo-N-[[4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    (562) 1-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    (563) 1-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[(1-methyl-4-piperazinyl)carbonyl]-piperazine
    (564) 1-[4-Amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (565) 1-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (566) 1-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (567) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (568) 1-[4-Amino-3,5-dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (569) 1-[3,5-Dibromo-N-[[4-[2(1H)-oxoquinolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (570) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (571) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (572) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (573) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (574) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (575) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (576) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (577) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (578) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (579) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (580) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (581) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (582) 1-[4-Amino-3,5-dibromo-N-[[4-(2,3-dihydro-4(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (583) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (584) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-methyl-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (585) 1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (586) 1-[4-Amino-N-[[4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (587) 1-[N2-[[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (588) 1-[N2-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-N′-(1,1-dimethylethoxycarbonyl)-D-tryptyl]-4-[4-(dimethylamino)-1-piperidinyl]-piperidine
    (589) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (590) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (591) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (592) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3,4-difluoro-5-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (593) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonyl)-piperidine
    (594) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidine
    (595) (R,S)-2-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-6-methyl-2,6-diazaspiro[3,4]octane
    (596) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine
    (597) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (598) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (599) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (600) (R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (601) (R,S)-1-[4-[4-(Aminocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (602) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (603) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-carboxypiperidine
    (604) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,5-dibromo-4-methoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (605) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (607) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-fluor-3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (607) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-ethyl-4-piperidinyl)-piperazine
    (608) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (609) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (610) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperazine
    (611) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(trifluoromethyl)-D,L-phenylalanyl]-4-(4-pyridinyl)-piperidine
    (612) (R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (613) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (614) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (615) 1-[3-Chloro-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(cyclopentyl)-piperazine
    (616) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-methylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (617) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(hexahydro-1H-1-azepinyl)-piperidine
    (618) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(exo-8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-piperazine
    (619) 1-[3-Bromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (620) 1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (621) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (622) 1-[N-[[4-(1,3-Dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (623) 1-[3-Methyl-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (624) 1-[N-[[4-[1,3-Dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (625) 1-[N-[[4-[1,3-Dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-3-methyl-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (626) 1-[3-Bromo-N-[[4-[1,3-dihydro-4-[(3-(trifluoromethyl)-phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (627) 1-[3-Bromo-N-[[4-[3,4-dihydro-2(1H)-oxothieno[3,4-d]-pyrimidin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (628) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (629) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperazine
    (630) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)-phenyl]methyl]-1,4-dioxobutyl]-4-(4-pyridinyl)-piperazine
    (631) (R,S)-4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)-phenyl]methyl]-N-[2-(4-methyl-1-piperazinyl)ethyl]-butanamide
    (632) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (633) 1-[3-Bromo-N-[[4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine
    (634) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (635) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (636) 1-[N-[[4-[3,4-Dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-nitro-D,L-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (637) (R,S)-1-[2-[(4-Amino-3,5-dibromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H) -oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (638) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[2-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (639) (R,S)-1-[2-[[3,5-Bis-(trifluoromethyl)phenyl]methyl]-4-[4-(3,4-dihydro-2 (1H) -oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (640) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (641) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(2-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (642) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dimethoxyphenyl)methyl]-1,4-dioxobutyl)-4-(1-piperidinyl)-piperidine
    (643) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(4-piperidinyl)-piperidine
    (644) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (645) (R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (646) (R,S)-1-[2-[(3-Bromophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (647) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-propen-3-yl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (648) (R,S)-1-[2-[3-(Biphenylyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (649) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(pyridinyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (650) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-thiazolyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (651) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(2-furyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (652) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-propylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (653) (R,S)-1-[4-(2,4-Dihydro-5-phenyl-3(3H)-oxotriazol-2-yl)-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (654) (R,S)-1-[4-[1,3-Dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl]-1-piperidinyl]-2-[[3-(trifluoromethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (655) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (656) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (657) 1-[2-[(1,2,3,4-Tetrahydro-1-naphthyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine (mixture of diastereomers)
    (658) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (659) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dibromophenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (660) (R,S)-1-[2-[(4-Quinolinyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (661) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (662) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (663) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-hydroxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (664) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-piperidinyl)-piperidine
    (665) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (666) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(4-methoxy-3,5-dimethylphenyl)methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (667) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine
    (668) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine
    (669) (R,S)-1-[2-[3,5-Dibromo-4-methylphenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-[4-(dimethylamino)butyl]phenyl]-piperazine
    (670) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (671) (R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-1,4-dioxobutyl]-4-(1-methyl-4-piperidinyl)-piperidine
    (672) (R,S)-1-[2-[(3,4-Dichlorophenyl)methyl]-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-1,4-dioxobutyl]-4-[4-(dimethylaminomethyl)phenyl]-piperidine

and the salts thereof.



The compounds of general formula I are prepared by methods which are known in principle, particularly using processes derived from peptide chemistry (cf. for example Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2). The amino protecting groups used may be those described in Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/1, of which urethane protecting groups such as the fluorenylmethoxycarbonyl, phenylmethoxycarbonyl or tert.-butyloxycarbonyl group are preferred. Any functional groups present in the groups R2 and/or A of the compounds of general formula I or in the precursors thereof are additionally protected by suitable protecting groups in order to prevent side reactions (cf. for example: G. B. Fields et al., Int. J. Peptide Protein Res. 35, 161 (1990); T. W. Greene, Protective Groups in Organic Synthesis). Examples of side-chain-protected amino acids of this kind include, in particular, Arg(NO2), Arg(Mtr), Arg(di-Z), Arg(Pmc), Lys(Boc), Lys(Z), Orn(Boc), Orn(Z), Lys(Cl-Z) which are commercially obtainable, possibly in the form of derivatives. Particular care should be taken to ensure that so-called orthogonal combinations of protecting groups are used to protect the α-amino and the side chain amino group, e.g.:











Protection of the N



(side chain)
Nα-protection







p-Toluenesulphonyl
Phenylmethoxycarbonyl



tert.Butyloxycarbonyl


Phenylmethoxycarbonyl
(4-Methoxyphenyl)methoxycarbonyl



tert.Butoxycarbonyl



Adamantyloxycarbonyl



Biphenylylisopropyloxycarbonyl



Isonicotinoyloxycarbonyl



o-Nitrophenylsulphenyl



Formyl


tert.Butoxycarbonyl
Phenylmethoxycarbonyl



p-Toluenesulphonyl



o-Nitrophenylsulphenyl



Biphenylylisopropyloxycarbonyl



9-Fluorenylmethoxycarbonyl


Acetyl, Trifluoroacetyl,
tert.Butyloxycarbonyl


Formyl, (2-Chlorophenyl)-


methoxycarbonyl, (4-Chloro-


phenyl)methoxycarbonyl,


4-(Nitrophenyl)methoxycar-


bonyl, Phthaloyl









Instead of protecting amino groups in the side chain, amino acids or derivatives thereof which carry precursor functions and in particular are substituted by nitro or cyano in the side chain, such as 5-o-cyanonorvalin may also be used.

The basic functions in the side chains of α-amino acids which are not commercially obtainable and which are characterised, for example, by (aminoiminomethyl) groups, may be protected in the same way as is used for protecting the side chains of arginine and its derivatives (cf. also M. Bodanszky, “Peptide Chemistry”, Springer-Verlag, 1988, p. 94-97); protecting groups which are particularly suitable for the (aminoiminomethyl)- group are the p-toluenesulphonyl, mesitylene sulphonyl- (Mts), methoxytrimethylphenylsulphonyl- (Mtr), 2,2,5,7,8-pentamethyl-chroman-6-sulphonyl- (Pmc), pentachlorophenoxycarbonyl- and nitro-protecting groups.
For the actual coupling, the methods known from peptide chemistry are used (see Houben-Weyl, for example, Methoden der Organischen Chemie, Vol. 15/2). It is preferable to use carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)N,N-N′,N′-tetramethyluronium-hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By the addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) racemisation may additionally be suppressed, if desired, or the reaction rate may be increased. The couplings are normally carried out with equimolar amounts of the coupling components and the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30 and +30° C., preferably between −20 and +20° C. If necessary, N-ethyl-diisopropylamine (DIEA) is preferred as an additional auxiliary base (Hünig base).
The so-called “anhydride method” (cf. also M. Bodanszky, “Peptide Chemistry”, Springer-Verlag 1988, p. 58-59; M. Bodanszky, “Principles of Peptide Synthesis”, Springer-Verlag 1984, p. 21-27) was used as another coupling method for the synthesis of compounds of general formula I. The “mixed anhydride method” is preferred, in the variant according to Vaughan (J. R. Vaughan Jr., J. Amer. Chem. Soc. 73, 3547 (1951)), in which the mixed anhydride is obtained from the optionally N2-protected α-amino acid which is to be coupled, and the mono-isobutylcarbonate, using isobutylchlorocarbonate in the presence of base such as 4-methylmorpholine or 4-ethylmorpholine. The preparation of this mixed anhydride and the coupling with amines are carried out in a one-pot process using the above-mentioned solvents at temperatures between −20 and +20° C., preferably between 0 and +20° C.
Any protecting groups present in the side chains of α-amino acid partial structures are finally cleaved, after the formation of the N— and C-terminally substituted amino acid derivative, with suitable reagents which are also known from the literature in principle, specifically arylsulphonyl and hetarylsulphonyl protecting groups, preferably by acidolysis, i.e. by the action of strong acids, preferably trifluoroacetic acid, nitro- and arylmethoxycarbonyl protecting groups are preferably cleaved by hydrogenolysis, e.g. using hydrogen in the presence of palladium black and with glacial acetic acid as solvent. If the substrate contains functions which are sensitive to hydrogenolysis, e.g. halogen atoms such as chlorine, bromine or iodine, a phenylmethanol or hetarylmethanol function or some other benzyl heteroatom bond, particularly a benzyl-oxygen bond, the nitro group may also be cleaved non-hydrogenolytically, e.g. with zinc/2N trifluoroacetic acid (cf. also A. Turan, A. Patthy and S. Bajusz, Acta Chim. Acad. Sci. Hung, Tom. 85 (3), 327-332 [1975]; C.A. 83, 206526y [1975]), with tin(II)-chloride in 60% aqueous formic acid (see also: SUNSTAR KK, JA-A-3271-299), with zinc in the presence of acetic acid (cf. also: A. Malabarba, P. Ferrari, G. Cietto, R. Pallanza and M. Berti, J. Antibiot. 42 (12), 1800-1816 (1989)) or excess aqueous 20% titanium(III)-chloride in aqueous methanol and in the presence of aqueous ammonium acetate buffer at 24° C. (see also: R. M. Freidinger, R. Hirschmann and D. F. Veber, J. Org. Chem. 43 (25), 4800-4803 [1978]).
Any precursor functions which may be present in the side chain of the α-amino acid may also subsequently be converted by hydrogenolysis into the desired amino functions; nitroalkyl groups yield aminoalkyl groups under conditions which will be familiar to the chemist, whilst the cyano group is converted into the aminomethyl group.
Alternatively, nitrile functions may also be reduced with complex hydrides which are selective in relation to other critical functions contained in the molecule, particularly amide groups (cf. also: J. Seyden-Penne, “Reductions by the Alumino- and Borohydrides in Organic Synthesis”, VCH Publishers Inc., 1991, p. 132ff.), e.g. with sodium borohydride in methanol and in the presence of cobalt(II)-chloride, with sodium borohydride in tetrahydrofuran in the presence of trifluoroacetic acid or with tetrakis-(n-butyl)-ammonium borohydride in dichloromethane; the reduction of aliphatic nitro function to the primary amino-function is also possible with sodium borohydride in the presence of tin(II)-chloride or copper(II)-acetylacetonate, without affecting the carboxamide groups present in type I compounds (see also: J. Seyden-Penne, ibid. p. 137ff.).
The following methods are particularly suitable for preparing the compounds of general Formula I according to the invention:

    a) In order to prepare compounds of general formula I, wherein
    R denotes an unbranched C1-7-alkyl group which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-2H-2-oxoimidazopyridinyl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 1,3-dihydro-2H-2-oxoimidazol-1-yl or 3,4-dihydro-2(1H)-oxopyrimidin-3-yl group, wherein the latter two groups may each be mono- or disubstituted in the 4- and/or 5-position or in the 5- and/or 6-position by lower straight chained or branched alkyl groups, by phenyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl-1-methylpyrazolyl, imidazolyl- or 1-methylimidazolyl-groups and the substituents may be identical or different,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group,
        or by a 6-membered heteroaromatic ring linked via a carbon atom, which contains one, two or three nitrogen atoms,
        whilst a 1,4-butadienylene group may be attached both to the above-mentioned 5-membered heteroaromatic monocyclic rings and to the 6-membered heteroaromatic monocyclic rings, in each case via two adjacent carbon atoms, and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group, and

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the (ω-position and optionally also partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms or by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, wherein the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups may in turn additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

or the group of formula

    
    






wherein

    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined,
    Y2 denotes a CH— group and
    Z denotes an NR1— group, wherein R1 is as hereinbefore defined:
    coupling carboxylic acids of general formula VII,

RCO2H   (VII)

wherein

R is as hereinbefore defined,

with compounds of general formula VIII,







wherein

R2, R3, R4, R11, A, X, m and n are as hereinbefore defined, and

Z denotes an NR1— group, wherein R1 is as hereinbefore defined, and, if necessary, subsequently cleaving any protecting groups or modifying precursor functions in accordance with the methods described hereinbefore.

The coupling is carried out using the methods known from peptide chemistry described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.

    b) In order to prepare compounds of general formula I wherein R is defined as in a), Z denotes the NR1— group and R1, R2, R3, R4, R11, A, X, m and n are as hereinbefore defined:

coupling compounds of general formula IX,

R—CO—Nu   (IX)

wherein

R is defined as in a) and

Nu denotes a leaving group, for example a halogen atom such as the chlorine, bromine- or iodine atom, an alkylsulphonyloxy group having 1 to 10 carbon atoms in the alkyl moiety, a phenylsulphonyloxy or naphthylsulphonyloxy group optionally mono-, di- or trisubstituted by chlorine or bromine atoms or by methyl- or nitro groups, wherein the substituents may be identical or different, a 1H-imidazol-1-yl, a 1H-pyrazol-1-yl-optionally substituted by 1 or 2 methyl groups in the carbon skeleton, a 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3,4-tetrazol-1-yl, a vinyl, propargyl, p-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl, pyranyl or pyridinyl, a dimethylaminyloxy, 2(1H)-oxopyridin-1-yloxy, 2,5-dioxopyrrolidin-1-yloxy, phthalimidyloxy, 1H-benzotriazol-1-yloxy or azide group,

with compounds of general formula VIII,







wherein

R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and

Z denotes an NR1— group, whilst R1 is as hereinbefore defined,

and, if necessary, subsequently cleaving protecting groups or modifying precursor functions using the methods described above.

The reaction is carried out under Schotten-Baumann- or Einhorn-conditions, i.e. the components are reacted in the presence of at least one equivalent of an auxiliary base at temperatures between −50° C. and +120° C., preferably between −10° C. and +30° C., optionally in the presence of solvents. Auxiliary bases which may be used are preferably alkali-metal and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates, e.g. sodium carbonate, potassium carbonate or cesium carbonate, alkali metal acetate, e.g. sodium- or potassium acetate, as well as tertiary amines, e.g. pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyl-diisopropylamine, N-ethyl-dicyclohexylamine, 1,4-Diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene, whilst the solvents which may be used include, for example, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof; if alkali metal or alkaline earth metal hydroxides, alkali metal carbonates or -acetates are used as auxiliary bases, water may also be added to the reaction mixture as a cosolvent.

    c) In order to prepare compounds of general formula I wherein
    R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group,

or the group of formula

    
    






wherein

    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined,
    Y2 denotes the N-atom and
    Z denotes the NR1— group, wherein R1 is as hereinbefore defined:

reacting amines of general formula X

R—H   (X)

wherein

    R is as hereinbefore defined, with carbonic acid derivatives of general XI






wherein

    X1 is a nucleofugic group, preferably the 1H-imidazol-1-yl, 1H-1,2,4-triazol-1-yl, trichloromethoxy- or 2,5-dioxopyrrolidin-1-yloxy group,

and with compounds of general formula VIII,







wherein

    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and
    Z denotes an NR1— group, wherein R1 is as hereinbefore defined,
    and, if necessary, subsequently cleaving any protecting groups or modifying any precursor functions using the method described hereinbefore.


The theoretically two-step reactions are generally carried out as one-pot processes, preferably by reacting one of the two components X or VIII with equimolar amounts of the carbonic acid derivative of general formula XI in a suitable solvent at fairly low temperature, in the first step, and then adding at least equimolar amounts of the other component VIII or X and finishing the reaction at elevated temperature. The reactions with bis-(trichloromethyl)-carbonate are preferably carried out in the presence of at least 2 equivalents (based on bis-(trichloromethyl)-carbonat) of a tertiary base, e.g. triethylamine, N-ethyl-diisopropylamine, pyridine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo-[5,4,0]undec-7-ene. Examples of solvent, which should be anhydrous, include tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or acetonitrile, if bis-(trichloromethyl)-carbonate is used as the carbonyl component, anhydrous chlorohydrocarbons such as dichloromethane, 1,2-dichloroethane or trichloroethylene are preferred. The reaction temperatures are between −30 and +25° C. for the first step of the reaction, preferably between −5 and +10° C., and between +15° C. and the boiling temperature of the solvent used, preferably between +20° C. and +70° C. for the second step of the reaction (cf. also: H. A. Staab and W. Rohr, “Synthesen mit heterocyclischen Amiden (Azoliden)”, Neuere Methoden der Praparativen Organischen Chemie, Band V, p. 53-93, Verlag Chemie, Weinheim/Bergstr., 1967; P. Majer and R. S. Randad, J. Org. Chem. 59, 1937-1938 (1994); K. Takeda, Y. Akagi, A. Saiki, T. Sukahara und H. Ogura, Tetrahedron Letters 24 (42), 4569 -4572 (1983)).

    d) In order to prepare compounds of general formula I wherein the carbonyl group linked to the groups R and Z denotes a urea carbonyl group, in which the urea carbonyl is flanked by at least one NH— group, and wherein
    R denotes an unbranched C1-6-alkylamino group optionally additionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a l-naphthyl, 2-naphthyl- or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

    
    
    or the group of formula






wherein

    
    
        R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and
        Y2 denotes the N-atom,
    
    
    Z denotes the group NR1 and
    
        R1 denotes a hydrogen atom or, provided that, R denotes an unbranched alkylamino group unsubstituted at the nitrogen atom and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group:

Reacting amines of general formula X′,

R—H   (X′)

wherein R is as hereinbefore defined,

with carbonic acid derivatives of general formula XI′,

    
    






wherein

    X2 denotes a phenoxy group, if X3 is the (1H)-1,2,3,4-tetrazol-1-yl group, the 4-nitrophenoxy group, if X3 is the 4-nitropheoxy group, and the chlorine atom if X3 is the 2,4,5-trichlorophenoxy group, and with compounds of general formula VIII′,






wherein

    R2, R3, R4, R11, X, A, m and n are as hereinbefore defined and
    R1 denotes a hydrogen atom or, provided that R is an unbranched alkylamino group unsubstituted at the nitrogen and optionally substituted in the ω-position, R1 may also denote an alkyl or phenylalkyl group, and

if necessary, subsequently cleaving protecting groups or modifying precursor functions using the methods described hereinbefore.



The reactions are in two steps, in principle, with intermediate formation of urethanes, which can be isolated. However, the reactions may also be carried out as one-pot reactions. Preferably, in the first step, one of the two components X′ or VIII′ is reacted with equimolar amounts of the carbonic acid derivative of general formula XI′in a suitable solvent at low temperature, then at least equimolar amounts of the other component VIII′ or X′ are added and the reaction is completed at elevated temperature. The reactions are preferably carried out in anhydrous solvents, e.g. in tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, acetonitrile or anhydrous chlorohydrocarbons e.g. dichloromethane, 1,2-dichloroethane or trichloroethylene. The reaction temperatures are between −15 and +40° C., preferably between −10 and +25° C. for the first step, between +20° C. and the boiling temperature of the solvent used, preferably between +20° C. and 100° C. for the second reaction step (cf. also: R. W. Adamiak and J. Stawinski, Tetrahedron Letters 1977, 22, 1935 -1936; A. W. Lipkowski, S. W. Tam and P. S. Portoghese, J. Med. Chem. 29, 1222 -1225 (1986); J. Izdebski and D. Pawlak, Synthesis 1989, 423 -425).

    e) In order to prepare compounds of general formula I wherein Z denotes the group NH and
    R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a Cl16-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

or the group of formula

    
    






wherein

    R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and Y2 denotes an N-atom:

Reacting isocyanates of general formula XII,







wherein

    R2, R3, R4, R11, A, X, m and n are as hereinbefore defined, with amines of general formula X,

R—H   (X)

wherein

    R is as hereinbefore defined and, if necessary, subsequently cleaving protecting groups or modifying precursor functions using the processes described above.


The reaction is carried out at temperatures between 0° C. and 150° C., preferably between 20° C. and 100° C., optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone or mixtures thereof.

    f) In order to prepare compounds of general formula I wherein
    R denotes an unbranched C1-6-alkylamino group unsubstituted at the nitrogen atom, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl- or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl- or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino- and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino- or acetylamino group, and

    
    
    Z denotes the NR1— group wherein R1 is as hereinbefore defined:

Reacting isocyanates of general formula XIII,

R═C═O   (XIII)

wherein R is as hereinbefore defined, with compounds of general formula VIII,







wherein R2, R3, R4, R11, A, X, m and n are as hereinbefore defined and

    Z denotes an NR1— group, wherein R1 is as hereinbefore defined,

and, if necessary, subsequently cleaving any protecting groups or modifying the precursor functions using the methods described hereinbefore.



The reaction is carried out at temperatures between 0 and 150° C., preferably at temperatures between 20 and 100° C., and optionally in the presence of anhydrous solvents, e.g. tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or 1,3-dimethyl-2-imidazolidinone.

    g) In order to prepare compounds of general formula I wherein R, Z, R2, R3, R4, R11, A, m and n have the meanings given hereinbefore and X is as hereinbefore defined, provided that A does not denote a bond or X denotes an oxygen atom, if A denotes a single bond:

Coupling carboxylic acids of general formula XIV,







wherein

    R, Z, R11, m and n are as hereinbefore defined,
    R2′ has the meanings given for R2 hereinbefore or denotes a group R2 substituted by the above-mentioned protecting groups, A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, it optionally bears in the side chain a precursor group for the group R9, e.g. a cyanopropyl group,

to compounds of general formula XV,

H—NR3R4   (XV)

wherein

    R3 and R4 are as hereinbefore defined,

and if necessary subsequent cleaving of protective groups or modification of precursor functions using the methods described above.



The coupling is carried out using the methods known from peptide chemistry and described hereinbefore, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
If the starting compound XIV used is enantiomerically pure, partial racemisation of the C-terminal amino acid must be expected during the coupling step and possibly quantitative racemisation must be expected if triethylamine is used as the auxiliary base and dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone is used as solvent.

    h) In order to prepare compounds of general formula I wherein X denotes the oxygen atom:

Coupling carboxylic acids of general formula XVI,







wherein

    R, Z, R11, m and n are as hereinbefore defined and
    R2′ has the meanings given for R2 hereinbefore or denotes a group R2 substituted by the above-mentioned protecting groups,

to compounds of general formula XVII,







wherein

    A′ has the meanings given for A hereinbefore or, if A denotes the divalent group of an amino acid, A′ optionally bears in the side chain a precursor group for the group R9, e.g. a cyanopropyl group, and
    R3 and R4 are as hereinbefore defined,
    and if necessary subsequently cleaving protecting groups or modifying precursor functions using the methods described above.


The coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.
If the starting compound XVI used is enantiomerically pure, during the coupling step partial racemisation must be expected or, if triethylamine is used as the auxiliary base and dimethylformamide, dimethylacetamide or N-methyl-pyrrolidone is used as solvent, quantitative racemisation must be expected based on the chiral centre of XVI.

    i) In order to prepare compounds of general formula I wherein
    R denotes an unbranched C1-6-alkylamino group optionally substituted at the nitrogen atom by a C1-6-alkyl group or by a phenylmethyl group, which may be substituted in the ω-position
    
        by a C4-10-cycloalkyl group,
        by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or biphenylyl group,
        by a 1H-indol-3-yl, 1,3-dihydro-2H-2-oxobenzimidazol-1-yl, 2,4(1H,3H)-dioxoquinazolin-1-yl, 2,4(1H,3H)-dioxoquinazolin-3-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-1-yl, 3,4-dihydro-2(1H)-oxoquinazolin-3-yl, 2(1H)-oxoquinolin-3-yl, 2(1H)-oxoquinoxalin-3-yl, 1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazol-1-yl, 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinolin-3-yl, 3,4-dihydro-5-phenyl-2(1H)-oxopyrimidin-3-yl, 3,4-dihydro-6-phenyl-2(1H)-oxopyrimidin-3-yl- or 1,3-dihydro-2H-2-oxoimidazo[4,5-b]pyridin-3-yl-group,
        by a 5-membered heteroaromatic ring linked via a carbon atom, which contains a nitrogen, oxygen or sulphur atom or, in addition to a nitrogen atom, contains an oxygen, sulphur or an additional nitrogen atom, whilst a nitrogen atom of an imino group may be substituted by an alkyl group, or
        by a 6-membered heteroaromatic ring linked via a carbon atom and containing 1, 2 or 3 nitrogen atoms, whilst a 1,4-butadienylene group may be attached both to the 5-membered and to the 6-membered heteroaromatic monocyclic rings via two adjacent carbon atoms in each case and the bicyclic heteroaromatic rings thus formed may also be bound via a carbon atom of the 1,4-butadienylene group,

whilst the phenyl, naphthyl and biphenylyl groups mentioned above for the substitution of the alkyl moiety of the alkylamino groups in the ω-position and optionally partially hydrogenated mono- and bicyclic heteroaromatic rings in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine or bromine atoms, by alkyl groups, C3-8-cycloalkyl groups, nitro, alkoxy, phenyl, phenylalkoxy, trifluoromethyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxy, carboxyalkyl, dialkylaminoalkyl, hydroxy, amino, acetylamino, propionylamino, benzoyl, benzoylamino, benzoylmethylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1H-azepin-1-yl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, (4-morpholinyl)carbonyl, alkanoyl, cyano, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, whilst the substituents may be identical or different and the above-mentioned benzoyl, benzoylamino and benzoylmethylamino groups in turn may additionally be substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by an alkyl, trifluoromethyl, amino or acetylamino group,

or the group of formula

    
    






wherein

    
    
        R5, R6, R7, RN, Y1, o and p are as hereinbefore defined and Y2 denotes an N-atom,
    
    
    Z represents the methylene group,
    X denotes two hydrogen atoms,
    A denotes a single bond,
    m denotes the value 1 and
    n denotes the value 0:

Coupling carboxylic acids of general formula XVIII,







wherein

    R2, R3 and R4 are as hereinbefore defined,

with amines of general formula X,

R—H   (X)

    wherein R is as hereinbefore defined.


The coupling is carried out using the methods known from peptide chemistry and described above, particularly using DCC, DIC, HBTU, TBTU or BOP as reagents or using the mixed anhydride method.

    j) In order to prepare compounds of general formula I wherein R3 and R4 have the meanings given hereinbefore with the exception of the hydrogen atoms, Z denotes a methylene group, X denotes two hydrogen atoms, A denotes a single bond, m is the number 1 and n is the number 0:

Reacting secondary amines of general formula XVa,

H—NR3′R4′  (XVa)

wherein

R3′ and R4′ have the meanings given for R3 and R4 hereinbefore with the exception of hydrogen atoms,

with formaldehyde and CH-acid compounds of general formula XIX,







wherein

    R is as hereinbefore defined and
    R2 is as hereinbefore defined, but with the proviso that any acid functions present such as hydroxy groups are appropriately protected by suitable protecting groups.


The reaction is preferably carried out in a slightly acidic medium, using alcohols, e.g. methanol or ethanol, or lower aliphatic carboxylic acids, such as glacial acetic acid, as solvents and at temperatures between room temperature and the boiling point of the solvent in question. In a preferred variant, an inorganic acid salt such as the hydrochloride of a secondary amine of general formula XVa is heated with paraformaldehyde and a ketone of general formula XIX in glacial acetic acid to temperatures between 50° C. and 80° C.

    k) In order to prepare compounds of general formula I wherein
    R, R2, R3, R4, R11, X, Z, m and n are as hereinbefore defined and A denotes the divalent group of formula III






(linked to the NR3R4-group via the —CX— group)

wherein

    
    
        R8 denotes the hydrogen atom or an alkyl or phenylalkyl group and
        R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by an aminoiminomethylamino group:

Reacting compounds of general formula XX,

    
    






wherein

    
    
        R, R2, R3, R4, R11, X, Z, m and n are as hereinbefore defined,
        R8 denotes a hydrogen atom or an alkyl or phenylalkyl group and
        R9 denotes an unbranched C1-5-alkyl group substituted in the ω-position by a primary amino group,

with carbonic acid derivatives of general formula XXI,

    
    






wherein

    Nu2 is a leaving group, e.g. an alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl group each having 1 to 10 carbon atoms in alkyl moiety, e.g. a methoxy, ethoxy, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, methylsulphonyl or ethylsulphonyl group, the chlorine atom, the SO2H, SO3H— or OPOCl2— group, or the group of general formula XXII,






wherein

    R15 and R16, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups.


Occasionally, for example when Nu2 is an alkoxy group, instead of using the compounds of general formula XXI it is advantageous to use the inorganic acid salts thereof, e.g. the neutral sulphates or hydrochlorides thereof.
The reactions are carried out analogously to methods known from the literature (see G. B. L. Smith, J. Amer. Chem. Soc. 51, 476 [1929]; B. Rathke, Chem. Ber. 17, 297 [1884]; R. Phillips and H. T. Clarke, J. Amer. Chem. Soc. 45, 1755 [1923]; S. J. Angyal and W. K. Warburton, J. Amer. Chem. Soc. 73, 2492 [1951]; H. Lecher and F. Graf, Chem. Ber. 56, 1326 [1923]; J. Wityak, S. J. Gould, S. J. Hein and D. A. Keszler, J. Org. Chem. 52, 2179 [1987]; T. Teraji, Y. Nakai, G. J. Durant, WO-A-81/00109, Chem. Abstr. 94, 192336z [1981]; C. A. Maryanoff, R. C. Stanzione, J. N. Plampin and J. E. Mills, J. Org. Chem. 51, 1882-1884 [1986]; A.E. Miller and J.J. Bischoff, Synthesis 1986, 777; R. A. B. Bannard, A. A. Casselman, W. F. Cockburn and G. M. Brown, Can. J. Chem. 36, 1541 [1958]; Aktieselskabet Grea, Kopenhagen, DE 28 26 452-C2; K. Kim. Y-T. Lin and H. S. Mosher, Tetrah. Letters, 29, 3183-3186 [1988]; H. B. Arzeno et al., Synth. Commun. 20, 3433-3437 [1990]; H. Bredereck and K. Bredereck, Chem. Ber. 94, 2278 [1961]; H. Eilingsfeld, G. Neubauer, M. Seefelder and H. Weidinger, Chem. Ber. 97, 1232 [1964]; P. Pruszynski, Can. J. Chem. 65, 626 [1987]; D. F. Gavin, W. J. Schnabel, E. Kober and M. A. Robinson, J. Org. Chem. 32, 2511 [1967]; N. K. Hart, S. R. Johns, J. A. Lamberton and R. I. Willing, Aust. J. Chem. 23, 1679 [1970]; CIBA Ltd., Belgisches Patent 655 403; Chem. Abstr. 64, 17481 [1966]; R. A. B. Bannard, A. A. Casselman, W. F. Cockburn and G. M. Brown, Can. J. Chem. 36, 1541 [1958]; J. P. Greenstein, J. Org. Chem. 2, 480 [1937]; F. L. Scott and J. Reilly, J. Amer. Chem. Soc. 74, 4562 [1952]; W. R. Roush and A. E. Walts, J. Amer. Chem. Soc. 106, 721 [1984], M. S. Bernatowicz, Y. Wu and G. R. Matsueda, J. Org. Chem. 57, 2497-2502 [1992]; H. Tsunematsu, T. Imamura and S. Makisumi, J. Biochem. 94, 123-128 [1983]) at temperatures between 0° C. and +100° C., preferably between +40° C. and +80° C., using inert solvents, e.g. dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylformamide, dimethylacetamide, N-methyl-pyrrolidone or mixtures thereof and, depending on the nature of the Nu2-group, frequently in the presence of auxiliary bases, especially alkali metal carbonates such as sodium- or potassium carbonate, or tertiary amines, preferably N-ethyl-diisopropylamine or triethylamine.
The amino acids of general formula I modified according to the invention contain at least one chiral centre. If the group A is also chiral, the compounds may occur in the form of two diastereomeric pairs of antipodes. The invention includes the individual isomers as well as the mixtures thereof.
The diastereomers are separated on the basis of their different physicochemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography using chiral or preferably achiral stationary phases.
Racemates covered by general formula I may be separated, for example, by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated by means of the diastereomeric optically active salts which are formed on reacting with an optically active acid, e.g. (+)- or (−)-tartaric acid, (+)- or (−)-diacetyl tartaric acid, (+)- or (−)-monomethyltartrate or (+)-camphor sulphonic acid or an optically active base such as (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.
According to a conventional process for separating isomers, the racemate of a compound of general formula I is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the crystalline, diastereomeric, optically active salts obtained are separated on the basis of their different solubilities. This reaction may be carried out in solvents of any kind provided that they are sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof are used, e.g. in a ratio by volume of 50:50. Then each of the optically active salts is dissolved in water, neutralised with a base such as sodium carbonate or potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, and in this way the corresponding free compound is obtained in the (+)- or (−)-form.
The (R)-enantiomer alone or a mixture of two optically active diastereomeric compounds coming within the scope of general formula I may also be obtained by carrying out the syntheses described above with a suitable reaction component in the (R)-configuration.
The starting materials of general formulae VII, IX, X, X′, XI, XI′, XIII, XV, XVa, XVII, XXI, XXII required to synthesis the compounds of general formula I as well as the amino acids used are commercially available or may be prepared by methods known from the literature.
Compounds of general formula VIII wherein Z denotes the group NR1 and those of general formula VIII′ wherein X denotes the oxygen atom may be obtained from commonly available starting materials using methods familiar to peptide chemists.
Isocyanates of general formula XII can easily be obtained from α-amino acid derivatives of general formula VIII′ wherein R1 denotes a hydrogen atom and the other groups are as hereinbefore defined, or from the hydrochlorides thereof by reacting with phosgene, diphosgene or triphosgene in the presence of pyridine (see also: J. S. Nowick, N. A. Powell, T. M. Nguyen and G. Noronha, J. Org. Chem. 57, 7364-7366 [1992]).
Carboxylic acids of general formulae XIV and XVI may be obtained from the corresponding carboxylic acid esters by saponification, preferably in the presence of lithium hydroxide.
The carboxylic acids of general formula XVIII are obtained by saponifying corresponding carboxylic acid esters which are in turn prepared from suitable secondary amines, 4-aryl-4-oxobutanoic acid esters and formaldehyde by Mannich reaction.
Compounds of general formula XIX may be obtained from suitable 4-oxobutanoic acids and amines of general formula X using conventional methods.
The intermediate compounds of general formula XX come under general formula I and are thus within the scope of the present application. These compounds may be obtained, for example, using processes a) to h) described herein.
The compounds of general formula I may be converted into their physiologically acceptable salts with inorganic or organic acids, particularly for pharmaceutical applications. Examples of suitable acids for this purpose include hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I thus obtained contain an acid function, for example a carboxy group, they may if desired be converted into the addition salts thereof with inorganic or organic bases, more particularly for pharmaceutical use, into the physiologically acceptable addition salts thereof. Bases which may be considered include, for example, sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The new compounds of general formula I and the physiologically acceptable salts thereof have CGRP-antagonistic properties and exhibit good affinities in CGRP-receptor binding studies. The compounds exhibit CGRP-antagonistic properties in the pharmacological test systems described hereinafter.
The following experiments were carried out to demonstrate the affinity of compounds of general formula I for human CGRP-receptors and their antagonistic properties:
A. Binding Studies with SK-N-MC-Cells Expressing Human CGRP-Receptor
SK-N-MC-cells are cultivated in Dulbecco's modified Eagle Medium. The medium of confluent cultures is removed. The cells are washed twice with PBS-buffer (Gibco 041-04190 M), detached by the addition of PBS-buffer mixed with 0.02% EDTA and isolated by centrifuging. After resuspension in 20 ml of Balanced Salts Solution [BSS (in mM): NaCl 120, KC1 5.4, NaHCO3 16.2, MgSO4 0.8, NaHPO4 1.0, CaCl2 1.8, D-Glucose 5.5, HEPES 30, pH7.40] the cells are centrifuged twice at 100×g and resuspended in BSS. After the cell number has been determined the cells are homogenised using an Ultra-Turrax and centrifuged for 10 minutes at 3000×g. The supernatent is discarded and the pellet is recentrifuged and resuspended (1 ml/1000000 cells) in Tris-buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40), enriched with 1% bovine serum albumin and 0.1% bacitracin. The homogenate is frozen at −80° C. The membrane preparations are stable for more than 6 weeks under these conditions.
After thawing, the homogenate is diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCl, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenised for 30 seconds with an Ultra-Turrax. 230 μl of the homogenate are incubated at ambient temperature for 180 minutes with 50 pM of 125I-Iodotyrosyl-Calcitonin-Gene-Related Peptide (Amersham) and increasing concentrations of the test substances in a total volume of 250 μl. Incubation is ended by rapid filtration using GF/B-glass fibre filters treated with polyethyleneimine (0.1%) by means of a cell harvester. The protein-bound radioactivity is measured using a gammacounter. The non-specific binding is defined as the radioactivity bound after the presence of 1 μM of human CGRP-alpha during incubation.
The concentration binding curves are analysed using a computer-aided non-linear curve adaptation.
The compounds of general formula I show IC50 values≦10000 nM in the test described.
B. CGRP-Antagonism in SK-N-MC-cells
SK-N-MC-cells (1 million cells) are washed twice with 250 μl of incubation buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) and pre-incubated at 37° C. for 15 minutes. After the addition of CGRP (10 μl) as agonist in increasing concentrations (10−11 to 10−6 M) or additionally of substance in 3 to 4 different concentrations, incubation is continued for a further 15 minutes.
Intracellular cAMP is then extracted by the addition of 20 μl of 1M HCl and centrifugation (2000×g, 4° C. for 15 minutes). The supernatants are frozen in liquid nitrogen and stored at −20° C.
The cAMP contents of the samples are determined by radioimmunoassay (Amersham) and the pA2-values of antagonistically acting substances are determined graphically.
The compounds of general formula I display CGRP-antagonistic properties in a dosage range between 10−11 and 10−5 M in the in vitro test model described.
In view of their pharmacological properties the compounds of general formula I and the salts thereof with physiologically acceptable acids or bases are thus suitable for acute and prophylactic treatment of headache, particularly migraine and cluster headaches. Moreover, the compounds of general formula I also have a beneficial effect on the following diseases: non-insulin-dependent diabetes mellitis (NIDDM), cardiovascular diseases, skin diseases, particularly thermal and radiation-induced skin damage including sunburn, inflammatory diseases, e.g. inflammatory joint diseases (arthritis), inflammatory lung diseases, allergic rhinitis, asthma, diseases which involve excessive vasodilation and resultant reductions in circulation, e.g. shock and sepsis, as well as morphine tolerance. In addition, the compounds of general formula I have the effect of alleviating pain in general.
The dosage needed to achieve such effects is appropriately 0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of body weight, by intravenous or subcutaneous route, and 0.01 to 10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight, when administered orally, nasally or by inhalation, in each case 1 to 3 times a day.
For this purpose, the compounds of general formula I prepared according to the invention may be formulated, optionally in combination with other active substances, such as antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin-antagonists, anti-convulsants, histamine-H1-receptor antagonists, antimuscarinics, β-blockers, α-agonists and α-antagonists, ergot alkaloids, mild analgesics, non-steroidal antiphlogistics, corticosteroids, calcium-antagonists, 5-HT1D-agonists or other antimigraine agents, together with one or more inert conventional carriers and/or diluents, e.g. corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearylalcohol, carboxymethyl-cellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metering aerosol or suppositories.
Thus, additional active substances which may be considered for the above-mentioned combinations include, for example, meloxicam, ergotamine, dihydroergotamine, metoclopramide, domperidon, diphenhydramine, cyclizine, promethazine, chlorpromazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, valproate, amitryptilin, lidocaine, diltiazem or sumatriptan and other 5-HT1D-agonists such as naratriptan, zolmitriptan, avitriptan, rizatriptan and eletriptan. The dosage for these active substances is appropriately 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dosage, i.e. 20 to 100 mg of sumatriptan, for example.
The invention further relates to the use of the compounds of general formula I as valuable auxiliary agents for the production and purification (by affinity chromatography) of antibodies and, after suitable radiolabelling, e.g. by direct labelling with 125I or 131I or by tritiation of suitable precursors for example by replacing halogen atoms with tritium, in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
The Examples which follow are intended to illustrate the invention:
Preliminary Remarks:
There are satisfactory elementary analyses, IR, UV, 1H-NMR and generally mass spectra as well, for all the compounds. Unless otherwise specified, Rf values were determined using TLC ready-made plates of silica gel 60 F254 (E. Merck, Darmstadt, Product No. 5729) without chamber saturation. If there are no details of configuration, it is undecided whether this is the pure enantiomer or whether partial or total racemisation has occurred. The following eluants or eluant mixtures were used for chromatography:

    FM1=dichloromethane/cyclohexane/methanol/ammonia 7/1.5/1.5/0.2 (v/v/v/v)
    FM2=dichloromethane/methanol/ammonia 7.5/2.5/0.5 (v/v/v)
    FM3=dichloromethane/methanol 8/2 (v/v)
    FM4=dichloromethane/ethyl acetate/methanol/cyclohexane/conc. aqueous ammonia=59/25/7,5/7,5/1 (v/v/v/v/v)
    FM5=ethyl acetate/dichloromethane=7/3 (v/v)
    FM6=ethyl acetate/petroleum ether=1/1 (v/v)
    FM7=dichloromethane/methanol/conc. aqueous ammonia=80/20/1 (v/v/v)


The following abbreviations were used in the descriptions of the experiments:

    Mp.: melting point
    (D): (decomposition)
    DIEA: N,N-diisopropyl-ethylamine
    Boc: (1,1-dimethylethoxy)carbonyl
    TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate
    HOBt: 1-hydroxybenzotriazole-hydrate
    CDT: 1,1′-carbonyldi(1,2,4-triazole)
    THF: tetrahydrofuran
    DMF: dimethylformamide
    Fmoc: (9-fluorenylmethoxy)carbonyl
    EE: ethyl acetate
    PE: petroleum ether
    LM: solvent
    Lfd. No.: item number


The meanings of the symbols made up of letters and numbers used in the Examples are given in the following summary:









































































































A. Preparation of Intermediate Compounds
EXAMPLE A1
Preparation of compounds of the general structure:




1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
a) 4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
To a mixture of 20.0 g (0.10 mol) of 4-amino-1-(1,1-dimethylethoxycarbonyl)piperidine, 8.2 g (0.1 mol) of anhydrous sodium acetate and 150 ml of dichloromethane was added dropwise, with stirring and whilst maintaining a reaction temperature of from 0° C. to +10° C., a solution of 25.0 g (0.109 mol) of 3-methoxyphenacylbromide in 50 ml of dichloromethane was added dropwise. The mixture was stirred for 5 hours at room temperature, then 19.5 g (0.296 mol) of sodium cyanate, 18 ml of glacial acetic acid and 10 ml of water were added and stirring was continued for 12 hours at room temperature. The mixture was stirred into 1 l of ice water, the dichloromethane phase was separated off, washed twice with 200 ml of water, 5% aqueous sodium hydrogen carbonate solution, 20% aqueous citric acid solution and once more with water, dried over magnesium sulphate and evaporated down in vacuo. The residue was taken up in methanol.
It was left to stand overnight, the precipitate which crystallised out was suction filtered, washed thoroughly with tert. butyl-methylether and after drying in vacuo 11.5 g (30.8% of theory) of colourless crystals were obtained.
MS: M+=373
The following were obtained accordingly:

    (1) 4-[1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Rf: 0.51 (FM4)
(2) 4-[1,3-dihydro-4-(4-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine
yield: 23.8% of theory

    (3) 4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


IR(KBr): 1685.7 cm−1 (C═O)

    (4) 4-[1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Rf: 0.23 (dichloromethane/methanol 9/1 v/v)
IR(KBr): 1687.6 cm−1 (C═O)
MS: M+=357

    (5) 4-[1,3-dihydro-4-(3-nitrophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 29.1% of theory
MS: M+=388

    (6) 4-[4-(3-bromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 13.1% of theory
IR(KBr): 1685 cm−1 (C═O)
MS: M+=421/423 (Br)

    (7) 4-[1,3-dihydro-4,5-diphenyl-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


IR(KBr): 1680, 1699 cm−1 (C═O)
MS: M+=419

    (8) 4-[1,3-dihydro-4-(4-fluorophenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


IR(KBr): 1682 cm−1 (C═O)
MS: M+=388

    (9) 4-[4-(4-biphenylyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 21.6% of theory, colourless crystals
Rf: 0.6 (ethyl acetate)
IR(KBr): 1681.8 cm−1 (C═O)

    (10) 4-[1,3-dihydro-4-(2-naphthyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 30% of theory, crystals
IR(KBr): 1679.9 cm−1 (C═O)

    (11) 4-[1,3-dihydro-4-(2-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Rf: 0.86 (FM1)

    (12) 4-[4-(3,4-dichlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 62% of theory, colourless crystals
Rf: 0.34 (ethyl acetate)
IR(KBr): 1687 cm−1 (C═O)

    (13) 4-[4-(3-chlorophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


yield: 21% of theory
Rf: 0.6 (ethyl acetate/methanol 9/1 v/v)

    (14) 4-[1,3-dihydro-4-(3-hydroxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Yield: 60% of theory
IR(KBr): 1682 cm−1 (C═O)
MS: M+=359

    (15) 4-[4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Yield: 3.2% of theory
IR(KBr): 1687.6 cm−1 (C═O)
Rf: 0.95 (dichloromethane/methanol 9/1 v/v)

    (16) 4-[4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxycarbonyl)-piperidine


Yield: 4.6% of theory
IR(KBr): 1684 cm−1 (C═O)
Rf: 0.48 (FM4; Macherey-Nagel POLYGRAM® SIL G/TV254 ready-made films for TLC)
b) 1,3-dihydro-4-(3-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one
The solution of 11.5 g (0.0308 mol) of 4-[1,3-dihydro-4-(3-methoxyphenyl)-2(2H)-oxoimidazol-1-yl]-1-(1,1-dimethylethoxy-carbonyl)-piperidine in 150 ml of dichloromethane was mixed with 15 ml of trifluoroacetic acid and then stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 10 ml of water and made distinctly ammoniacal. The resulting precipitate was suction filtered, washed thoroughly with water and dried overnight at 50° C. in vacuo. 7.0 g (83.1% of theory) of colourless crystals were obtained, Rf value 0.2 (dichloromethane/methanol 9/1 v/v).
The following were obtained accordingly:

    (1) 1,3-dihydro-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one,


Rf: 0.22 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254 ready-made films for TLC)
IR(KBr): 1672 cm−1 (C═O)

    (2) 1,3-dihydro-4-(4-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one


IR(KBr): 1670 cm−1 (C═O)
MS: M+=273

    (3) 1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-1-(4-piperidinyl)-2H-imidazol-2-one


IR(KBr): 1687.6 cm−1 (C═O)

    (4) 1,3-dihydro-5-methyl-4-phenyl-1-(4-piperidinyl)-2H-imidazol-2-one


yield: 76.2% of theory
IR (KBr): 1679.9 cm−1 (C═O)
MS: M+=257

    (5) 1,3-dihydro-4-(3-nitrophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one


yield: 94% of theory
IR(KBr): 1677.8 (C═O); 1137.8, 1197.6, 1349.9 (NO2) cm−1 

    (6) 4-(3-bromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


yield: quantitative
IR(KBr): 1676 cm−1 (C═O)

    (7) 1,3-dihydro-4,5-diphenyl-1-(4-piperidinyl)-2H-imidazol-2-one


IR(KBr): 1670 cm−1 (C═O)
MS: M+=319

    (8) 1,3-dihydro-4-(4-fluorophenyl)-1-(4-piperidinyl)-2H-imidazol-2-one


yield: 30% of theory
Rf: 0.2 (eluant: ethyl acetate/methanol/conc. ammonia 9/1/0.3 v/v/v)
IR(KBr): 1682 cm−1 (C═O)

    (9) 4-(4-biphenylyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


yield: quantitative
IR(KBr) of the trifluoroacetate: 1679.9 cm−1 (C═O)

    (10) 1,3-dihydro-4-(2-naphthyl)-1-(4-piperidinyl)-2H-imidazol-2-one


yield: 28.2% of theory
Rf: 0.03 (FM1)
IR(KBr) of the trifluoroacetate: 1678 cm−1 (C═O)

    (11) 7-(2-methoxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one


yield: 18.8% of theory
Rf: 0.22 (FM1)
IR(KBr) of the trifluoroacetate: 1681.6 cm−1 (C═O)

    (12) 4-(3,4-dichlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


yield: quantitative
IR(KBr) of the trifluoroacetate: 3197 (N—H); 1685 (C═O)cm−1 

    (13) 4-(3-chlorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


Yield: 98% of theory
Rf: 0.25 (eluant: ethyl ethanoate/methanol/conc. ammonia 9/1/0.3 v/v/v)

    (14) 1,3-dihydro-4-(3-hydroxyphenyl)-1-(4-piperidinyl)-2H-imidazol-2-one


Yield: 90% of theory
Rf: 0.075 (FM1)
IR(KBr): 1670 (C═O) cm−1 
MS: M+=259

    (15) 4-[3,5-bis-(trifluoromethyl)phenyl]-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


Yield: 71% of theory
Rf: 0.15 (FM1)
IR(KBr): 1701 (C═O) cm−1 
MS: M+=379

    (16) 4-(4-amino-3,5-dibromophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-imidazol-2-one


Yield: 44% of theory
Rf: 0.71 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254 ready-made films for TLC)
IR(KBr): 1676 (C═O) cm−1 
EXAMPLE A2
2,4-dihydro-5-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one
a) 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)hydrazone
A mixture of 16.0 g (0.05 mol) of 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone, 7.25 g (0.055 mol) of tert. butyl hydrazinoformate and 250 ml of ethanol was refluxed for 1 hour. The solvent was distilled off in vacuo, the oily residue remaining was triturated with diethylether. The crystalline precipitate thus formed was suction filtered and washed with a little diethylether. After the product had been dried in vacuo 21.7 g (99.7% of theory) of colourless crystals were obtained, m.p. 156-158° C. (decomposition).
b) N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-yl-methoxycarbonyl)-4-piperidinyl]-hydrazine
A solution of 21.7 g (0.05 mol) of 1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinone-(1,1-dimethylethoxycarbonyl)-hydrazone in 200 ml of glacial acetic acid was hydrogenated in the presence 2.0 g platinum (IV) oxide at room temperature and 3 bar of hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the filtrate was evaporated down in vacuo and the residue was dissolved in a little diethylether. The crystals precipitated after standing for 3 hours at room temperature were suction filtered, washed with a little diethylether and dried in vacuo at room temperature. 21.8 g (99.6% of theory) of colourless crystals of m.p. 135-137° C. and Rf=0.235 (eluant 3) were obtained.
ESI-MS: (M+H)+=438
c) [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine-hydrochloride
21.8 g (0.0498 mol) of N-(1,1-dimethylethoxycarbonyl)-N′-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine were dissolved in 100 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The excess trifluoroacetic acid was removed in vacuo, the residue was dissolved in 50 ml of water and made alkaline with 10% aqueous sodium carbonate solution. The solution was extracted thoroughly with dichloromethane, the combined extracts were dried over magnesium sulphate and evaporated down in vacuo. The residue thus obtained was taken up in ethyl acetate and converted into the hydrochloride by the addition of ethereal hydrogen chloride solution. After recrystallisation from anhydrous ethanol 6.2 g (33.3% of theory) of colourless crystals of melting point 160-162° C. were obtained. 
C20H23N3O2+HCl (373.88)




















Calculated:
C
64.25
H
6.47
N
11.24
Cl
9.48


Found:

64.14

6.46

10.99

9.46









d) 2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one
The solutions of 5.56 g (0.0165 mol) of [1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-hydrazine in 60 ml of tetrahydrofuran and 3.7 g (0.0177 mol) of N-(ethoxycarbonyl)-benzothionamide in 30 ml of tetrahydrofuran were combined and refluxed for 1 hour, whereupon hydrogen sulphide was released. The solvent was distilled off in vacuo, the oily residue remaining was boiled with a little acetonitrile. The mixture was allowed to cool, then additionally cooled from outside with ice water and the resulting precipitate was suction filtered. 4.0 g (52% of theory) of colourless crystals were obtained, melting point 142° C. and Rf=0.38 (eluant 4).
IR (KBr): 1685.7 cm−1 (C═O)
e) 2,4-dihydro-5-phenyl-2-(4-piperidinyl)-3H-1,2,4-triazol-3-one
A mixture of 9.0 g (0.0193 mol) of 2,4-dihydro-5-phenyl-2-[1-(9H-fluoren-9-ylmethoxycarbonyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one, 50 ml of tetrahydrofuran and 70 ml of diethylamine was stirred at room temperature until the end of the reaction monitored by thin layer chromatography. The solvent was removed in vacuo, the residue remaining was mixed with 300 ml of water and subjected to ultrasound treatment for 30 minutes. The insoluble matter was separated off by suction filtering and the aqueous filtrate was evaporated down in vacuo. The residue thus obtained was boiled with a little methanol and after cooling it was suction filtered. After drying 0.58 g (12.3% of theory) of colourless crystals of melting point 294° C. (D) and Rf=0.1 (eluant 1) were obtained.
IR (KBr): 1681.8 cm−1 (C═O)
EXAMPLE A3
Preparation of Compounds of General Structure:




3,4-dihydro-3-(4-piperidinyl)-2 (1H-pyrido[2,3-d]-pyrimidinone
a) N-(2-Pyridinyl)-2,2-dimethylpropanamide
To a solution of 94.1 g (1.0 mol) of 2-aminopyridine and 173 ml (1.25 mol) of triethylamine in 400 ml of dichloromethane were added dropwise, whilst cooling with ice water, 132.5 g (1.099 mol) of pivaloyl chloride in 150 ml of dichloromethane. The. mixture was stirred for 2 hours at room temperature and filtered to remove the triethylamine hydrochloride formed. The filtrate was washed with water and twice with 5% aqueous sodium hydrogen carbonate solution, then dried over sodium sulphate. After working up in the usual way 157.5 g (88.4% of theory) of colourless crystals of melting point 74-76° C. were obtained.
The following was obtained in the same way:
N-(4-Pyridinyl)-2,2-dimethylpropanamide
Yield: 74% of theory
Mp. 137-140° C. (diisopropylether)
IR (KBr): 1687 cm−1 (C═O)
b) N-(3-formyl-2-pyridinyl) -2,2-dimethylpropanamide
whilst maintaining a reaction temperature of −78° C., 781 ml (1.25 mol) of a 1.6-molar solution of n-butyllithium in n-hexane were added dropwise to a solution of 89.1 g (0.5 mol) of N-(2-pyridinyl)-2,2-dimethylpropanamide in 300 ml of anhydrous tetrahydrofuran. The mixture was allowed to heat slowly up to 0° C. and stirred for 3 hours at this temperature. Then the mixture was again cooled to −78° C. and whilst maintaining this temperature the solution of 109.6 g (1.5 mol) of dimethyformamide in 150 ml of anhydrous tetrahydrofuran was added dropwise thereto. The mixture was allowed to come up to 0° C. and then stirred into 1 l of ice water. It was initially acidified with 12% aqueous hydrochloric acid, then made alkaline by the addition of solid potassium carbonate and extracted thoroughly with diethylether. The combined ether extracts were dried over sodium sulphate and evaporated down. The crystalline residue, after recrystallisation from diisopropylether, had an m.p. of 83° C. Yield: 94.0 g (91.2% of theory).
The following were obtained in the same way:

    (1) N-(4-formyl-3-pyridinyl)-2,2-dimethylpropanamide


Yield: 52% of theory
Rf: 0.5 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
IR (KBr) of the hydrochloride: 1695 cm−1 (C═O)
MS: M+=206

    (2) N-(3-formyl-4-pyridinyl)-2,2-dimethylpropanamide


The reddish oil obtained in a quantitative yield was further processed without more purification
c) N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide
A solution of 8.2 g (0.0398 mol) of N-(3-formyl-2-pyridinyl)-2,2-dimethylpropanamide and 7.6 g (0.04 mol) of 4-amino-1-(phenylmethyl)piperidine in 80 ml of methanol was combined in batches with a total of 1.7 g (0.045 mol) of sodium borohydride and refluxed for a total of 24 hours. The solvent was removed in vacuo, the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and freed from solvent. The residue was triturated with diisopropylether and suction filtered. 6.0 g (39.6% of theory) of colourless crystals of melting point 138° C. were obtained.
The following were obtained in the same way:

    (1) N-[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-pyridinyl]-2,2-dimethylpropanamide


Yield: 94% of theory
Rf: 0.4 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
The yellowish oil was used in the following stage without further purification

    (2) N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-4-pyridinyl]-2,2-dimethylpropanamide


Yield: 11.6% of theory
IR(KBr): 1689 (C═O) cm−1 
d) 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]-amino]methyl]-pyridine
A mixture of 6.0 g (0.0158 mol) of N-[3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-2-pyridinyl]-2,2-dimethylpropanamide and 100 ml of conc. hydrochloric acid was refluxed for 3 hours. The mixture was evaporated down in vacuo, the residue remaining was dissolved in a little water and made alkaline by the addition of solid potassium carbonate. It was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was thoroughly triturated with diisopropylether and yielded 4.2 g (89.7% of theory) of colourless crystals of melting point 114° C.
The following were obtained in the same way:

    (1) 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine


Yield: 96% of theory
Rf: 0.42 (dichloromethane/methanol/conc. ammonia 90/10/0.1 v/v/v)
The yellowish oil was used in the following stage without further purification

    (2) 4-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine


Yield: quantitative
The yellowish oil was used in the following stage without further purification
e) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone
A mixture of 4.2 g (0.0142 mol) of 2-amino-3-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-pyridine, 2.4 g (0.0148 mol) of N,N′-carbonyldiimidazole and 50 ml of dimethylformamide was heated to 100° C. for 30 minutes. The still warm mixture was stirred into 300 ml of ice water, the precipitate formed was suction filtered and recrystallised from acetonitrile. After drying in vacuo 4.5 g (98.3% of theory) of colourless crystals of melting point 187° C. were obtained.
The following were obtained in the same way:

    (1) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone

Colourless crystals



Yield: 33% of theory
IR (KBr): 1676 cm−1 (C═O)
MS: M+=322

    (2) 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pydrio[4,3-d]-pyrimidinone


Mp. 155° C. (D)
Yield: 99% of theory
IR (KBr): 1680 cm−1 (C═O)
f) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone
A solution of 4.7 g (0.0146 mol) of 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-pyrido[2,3-d]-pyrimidinone in 50 ml of methanol was hydrogenated at a temperature of 50° C. and in the presence of 2.0 g of 20% palladium/charcoal until the uptake of hydrogen ceased. After removal of the catalyst and solvent 3.3 g (97.3% of theory) of a colourless oil of Rf=0.35 (FM1) were obtained.
IR (KBr): 1660.6 cm−1 (C═O)
The following were obtained in the same way:

    (1) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[3,4-d]-pyrimidinone


Colourless crystals
Yield: 95% of theory
IR (KBr): 1662 cm−1 (C═O)
MS: M+=232

    (2) 3,4-dihydro-3-(4-piperidinyl]-2(1H)-pyrido[4,3-d]-pyrimidinone


Yellowish resin
Yield: 97% of theory
IR (KBr): 1672 cm−1 (C═O)
Rf: 0.12 (FM1)
EXAMPLE A4
Methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate
a) (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene
A mixture of 98.3 g (0.504 mol) of methyl 4-methyl-3-nitrobenzoate, 78.0 g (0.655 mol) of N,N-dimethylformamide dimethylacetal and 1 l of dimethylformamide was heated to 140° C. for 3 hours. The solvent was distilled off in vacuo, the residue was triturated thoroughly with 1 l methanol. After drying in vacuo 119.5 g (94.7% of theory) of a red amorphous substance was obtained, which was further processed without any more purification.
b) 4-(Methoxycarbonyl)-2-nitrobenzaldehyde
To a mixture of 119.5 g (0.478 mol) of (E)-1-(dimethylamino)-2-[4-(methoxycarbonyl)-2-nitrophenyl]-ethene and 1.3 l of water/tetrahydrofuran mixture (1/1 v/v) were added, in batches, 308.0 g (1.44 mol) of sodium metaperiodate, whilst the reaction temperature was regulated at under +30° C. by external cooling with ice water. The mixture was stirred for a further 2.5 hours at room temperature and then filtered. The precipitate was thoroughly washed with ethyl acetate. The organic phase was separated off, the aqueous phase was thoroughly extracted with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulphate and evaporated down in vacuo. The oil which crystallised after one day was further processed without any more purification. Yield: 87 g (87% of theory).
c) Methyl 4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate
To a solution of 41.0 g (0.215 mol) of 4-amino-1-(phenylmethyl)-piperidine and 45.0 g (0.215 mol) of 4-(methoxycarbonyl)-2-nitrobenzaldehyde in 1 l methanol were added in batches, at room temperature, 8.3 g (0.22 mol) of sodium borohydride and the mixture was then stirred for 30 minutes at the same temperature. The mixture was stirred into 1 l of ice water and thoroughly extracted with tert. butyl-methylether. The combined extracts were dried over sodium sulphate and evaporated down in vacuo, the residue was dissolved in as little methanol as possible and converted into the hydrochloride by treatment with methanolic hydrogen chloride solution. The crystalline salt was suction filtered, washed with methanol and diethylether, then taken up in water and made alkaline with saturated aqueous potassium carbonate solution. The mixture obtained was extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts were dried over sodium sulphate and evaporated down. 58.2 g (70.6% of theory) of a brownish-yellow oil were obtained, which was further processed without any more purification.
d) Methyl 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate
A solution of 58.0 g (0.151 mol) of methyl 4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-3-nitrobenzoate in 800 ml of methanol was hydrogenated in the presence of 10 g of 5% rhodium/charcoal for 7 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated down in vacuo. 50.0 g (93.7% of theory) of colourless crystals were obtained, which were further processed without any more purification.
e) Methyl 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylate
Prepared analogously to Example A3e) from methyl 3-amino-4-[[[1-(phenylmethyl)-4-piperidinyl]amino]methyl]-benzoate and N,N′-carbonyl-diimidazole in a yield of 66.3% of theory.
Slightly yellowish crystals.
IR (KBr): 1714.6; 1664.5 cm−1 (C═O)
f) Methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazolin-7-carboxylate
A solution of 35.5 g (0.0936 mol) of methyl 3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-oxoquinazolin-7-carboxylate in 400 ml of methanol was hydrogenated in the presence of 5 g of 10% palladium/charcoal for 5 hours at 50° C. The catalyst was filtered off, the filtrate was evaporated down in vacuo. The residue was triturated with 150 ml of ethyl acetate and then suction filtered. After drying in vacuo 20.4 g (75.3w of theory) of colourless crystals were obtained, which were further processed without any more purification.
IR (KBr): 1718.5; 1672.2 cm−1 (C═O)
The following were prepared analogously:

    (1) 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone


Rf: 0.3 (FM1)
IR (KBr): 1662.5 cm−1 (C═O)

    (2) 3,4-dihydro-8-methoxy-3-(4-piperidinyl)-2(1H)-quinazolinone


Rf: 0.35 (FM1)
(3) 3,4-dihydro-6,7-dimethoxy-3-(4-piperidinyl)-2(1H)-quinazolinone
Rf: 0.40 (FM1)
EXAMPLE A5
3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluoroacetate
a) Methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate
A mixture of 50.0 g (0.258 mol) of methyl 4-aminothiophen-3-carboxylate-hydrochloride, 700 ml of toluene, 26 g (0.257 mol) of triethylamine and 27 ml (0.283 mol) of ethyl chlorocarbonate was refluxed for 5 hours. The insoluble matter was filtered off, the filtrate was evaporated down in vacuo and the residue was crystallised from petroleum ether. 59.0 g (99.8% of theory) of colourless crystals of melting point 52° C. were obtained.
In the same way, crystalline methyl 3-(ethoxycarbonylamino)-thiophen-2-carboxylate was obtained from methyl 3-aminothiophene-2-carboxylate and ethyl chlorocarbonate in a yield of 98.7% of theory.
IR (KBr): 1739.7; 1622 cm−1 (C═O, C═C)
b) 4-(ethoxycarbonylamino)-thiophene-3-carboxaldehyde
Into an ice-cold suspension of 12.9 g (0.34 mol) of lithium aluminium hydride in 800 ml of tert. butyl-methylether was added dropwise, at a reaction temperature of about 0° C., a solution of 59.1 g (0.258 mol) of methyl 4-(ethoxycarbonylamino)-thiophene-3-carboxylate in 200 ml of tert. butyl-methylether, and the mixture was then stirred for a further 2 hours at 10° C. Then 13 ml of water, 13 ml of 2N aqueous sodium hydroxide solution and 39 ml of water were added dropwise one after another and the mixture was stirred for 1 hour at room temperature. It was filtered, and 500 g of activated manganese (IV) oxide were added in batches to the filtrate with stirring. After the completion of the reaction, which could be monitored by thin layer chromatography, the mixture was filtered again and the filtrate was then evaporated down in vacuo. The crystalline residue which solidified was further processed without any more purification. yield: 28.2 g (54.9% of theory).
In the same way 3-(ethoxycarbonylamino)-thiophene-2-carboxaldehyde was obtained from methyl 3-(ethoxycarbonylamino)-thiophene-2-carboxylate in a yield of 71.9% of theory.
c) 4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene
A mixture of 28.2 g (0.142 mol) of 4-(ethoxycarbonyl-amino)-thiophene-3-carboxaldehyde, 28.2 g (0.141 mol) of 4-amino-1-(1,1-dimethyl-ethoxycarbonyl)piperidine and 300 ml of toluene was refluxed using a water separator until water formation had ceased. The solvent was removed in vacuo, the residue was dissolved in 300 ml of methanol and at room temperature combined batchwise with 5.5 g (0.145 mol) of sodium borohydride. The mixture was stirred for a further hour at room temperature, then evaporated down in vacuo and the residue was distributed between water and tert. butyl-methylether. The organic phase was dried over sodium sulphate and freed from solvent in vacuo. The oily residue was further processed without purification.
Yield: 54.0 g (99.9% of theory).
In the same way 2-[[[1-(1,1-dimpethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene was obtained from 3-(ethoxycarbonylamino)-thiophene-2-carboxaldehyde, 4-amino-1-(1,1-dimethylethoxycarbonyl)piperidine and sodium borohydride in a yield of 100% of theory.
IR (KBr): 1728.1; 1693.4 cm−1 (C═O)
d) 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one
A solution of 54.0 g (0.141 mol) of 4-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonylamino)-thiophene in 300 ml of dimethylformamide was refluxed for 4 hours. After the end of the reaction, which could be monitored by thin layer chromatography, the still warm mixture was stirred into 1 l of ice water. The crystalline precipitate was suction filtered and dried at 30° C. in a circulating air drier.
Yield: 47.5 g (99.8% of theory).
In the same way 3,4-dihydro-3-[1-(1,1-dimthylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,2-d]pyrimidin-2-one was obtained from 2-[[[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]amino]methyl]-3-(ethoxycarbonyl-amino)-thiophene in a yield of 71% of theory. Colourless crystals of melting point 200° C. (acetonitrile).
IR (KBr): 1683.8; 1654.8 cm−1 (C═O)
e) 3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,4-d]pyrimidin-2-one-trifluoroacetate
A mixture of 10.0 g (0.0296 mol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno[3,4-d]pyrimidin-2-one and 50 ml of trifluoroacetic acid was stirred at room temperature for 30 minutes. The residue remaining after removal of the excess trifluoroacetic acid was triturated with diethylether and suction filtered. 5.8 g (55.8% of theory) of colourless crystals were obtained, which were used without further purification.
IR (KBr): 1664.5 cm−1 (C═O)
In the same way, crystalline 3,4-dihydro-3-(4-piperidinyl)-1H-thieno[3,2-d]pyrimidin-2-one-trifluoracetate was obtained from 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-1H-thieno-[3,2-d]pyrimidin-2-one and trifluoroacetic acid in a yield of 100% of theory.
IR (KBr): 1685.7; 1656.8 cm−1 (C═O)
EXAMPLE A6
3,4-dihydro-3-(4-piperidinyl)-2(1H)quinolone-hydrochloride
A mixture of 1.1 g (4.949 mmol) of 3-(4-pyridinyl)-2(1H)-quinolone (D. R. Bragg and D. G. Wibberley, J. Chem. Soc. 1961, 5074-5077), 100 ml of ethanol, 5 ml (5 mmol) of 1N hydrochloric acid and 0.2 g platinum (IV) oxide was hydrogenated for 4 hours at room temperature. The catalyst was filtered off, the filtrate evaporated down in vacuo and the residue was triturated with isopropanol. The precipitated crystals were suction filtered, washed with isopropanol and diethylether and dried in vacuo. Yield: 0.64 g (56.2% of theory).
IR (KBr): 1666.4 cm−1 (C═O)
MS: M+=230 m/e=146, 84
EXAMPLE A7
3-(4-Piperidinyl-2(1H)-quinolone
A mixture of 8.6 g (0.0387 mol) of 3-(4-pyridinyl)-2(1H)-quinolone, 1.2 l of ethanol, 39 ml (0.039 mol) of 1N hydrochloric acid and 8.0 g of 10% palladium/charcoal was hydrogenated at a temperature of 40° C. until about 0.08 mol of hydrogen had been taken up. The mixture was freed from catalyst, the filtrate was evaporated down in vacuo, the residue was taken up in 200 ml of water and made ammoniacal. Common salt was added up to saturation point and the mixture was continuously extracted with dichloromethane using a perforator. The dichloromethane phase was evaporated down, the residue remaining was separated from byproducts by chromatography over silica gel using FM1 as eluant. The appropriate fractions were combined, freed from solvent, dissolved in a little isopropanol and converted with ethanolic hydrogen chloride solution into the hydrochloride. Colourless crystals. Yield: 2.68 g (26.2% of theory).
MS: M+=228
IR (KBr): 1651 cm−1 (C═O)
EXAMPLE A8
5-chloro-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone
An ice-cold solution of 6.3 g (0.0177 mol) of 5-chloro-3,4-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(1H)-quinazolinone (prepared analogously to Example A4e)) in 50 ml of dichloromethane was mixed dropwise with 3.34 g (0.0234 mol) of (α-chloroethyl chlorocarbonate whilst maintaining a reaction temperature of 0° C., after which the mixture was allowed to come back slowly to room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 50 ml of methanol and refluxed for 4 hours. After cooling, the colourless precipitate formed was suction filtered. Yield: 2.0 g (42.5% of theory).
IR (KBr): 1666.4 cm−1 (C═O)
6-bromo-3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-hydrobromide
To a solution of 6.16 g (0.075 mol) of sodium acetate and 11.565 g (0.05 mol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a mixture of 150 ml of glacial acetic acid and 35 ml of water a solution of 8.8 g (0.055 mol) of anhydrous bromine in 20 ml of glacial acetic acid was added dropwise, with stirring and whilst maintaining a reaction temperature of 13 to 15° C. The mixture was filtered and the filtrate was evaporated down in vacuo. To remove any inorganic components the residue was taken up five times in 50 ml of dichloromethane, filtered and evaporated down, then triturated with a little acetonitrile, whereupon crystallisation occurred. The crystals were suction filtered, washed with acetonitrile/diethylether (1/1 v/v) and after drying in vacuo 5.5 g of colourless crystals of melting point 288° C. (decomposition) were obtained. By working up the mother liquors a further 4.5 g of material of the same quality was obtained. Total yield: 10.0 g (51% of theory).
C13H17Br2N3O (391.10)




















Calculated:
C
39.92
H
4.38
Br
40.86
N
10.74


Found:

39.72

4.36

41.56

10.24








IR (KBr):
1670.3 cm − 1 (C═O)









EXAMPLE A10
3-(4-piperidinyl)-2,4 (1H,3H)-quinazolindione
a) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzamide
To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 21⁄2 hours at room temperature and 21⁄2 hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
IR (KBr): 1620 cm−1 (C═O)
MS: M+=309
b) 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione
Prepared analogously to Example A3e) from 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzamide and N,N′-carbonyldiimidazole in a yield of 97.8% of theory. Colourless crystals of melting point 223° C.
IR (KBr): 1720; 1647 cm−1 (C═O)
MS: M+=335
c) 3-(4-piperidinyl)-2,4(1H,3H)-qinazolindione
Prepared analogously to Example A3f) from 3-[1-(phenylmethyl)-4-piperidinyl]-2,4(1H,3H)-quinazolindione by hydrogenolysis in the presence of palladium/charcoal in a yield of 70% of theory.
Rf: 0.075 (FM1)
IR (KBr): 1703; 1657 cm−1 (C═O)
EXAMPLE A11
3,4-dihydro-3-[1-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone
a) 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone
A mixture of 5.75 g (0.0249 mol) of 3,4-dihydro-3-(4-piperidinyl-2(1H)-quinazolinone, 4.75 g (0.0251 mol) of 1-(phenylmethyl)-4-piperidinone and 100 ml of ethanol was treated for 30 minutes in an ultrasound bath, then mixed with 9.5 ml (0.031 mol) of titanium (IV) isopropoxide, whereby after 10 minutes a crystal mass was formed. Then heating was continued using the ultrasound bath for a further 21⁄2 hours to a maximum of 35° C., the mixture was allowed to cool to room temperature and 1.05 g (0.0167 mol) of sodium cyanoborohydride were then added in batches, whilst maintaining the pH at 5-6 using dilute methanolic hydrogen chloride solution, and it was then kept for 24 hours at room temperature. After this time another 1.05 g (0.0167 mol) of sodium cyanoborohydride were added and the same procedure was used as above. After a total of 48 hours reaction time the mixture was decomposed by the addition of water and worked up in the usual way. The crude product obtained was purified by column chromatography over silica gel using FM4 as eluant. 7.05 g (70% of theory)of a colourless crystalline substance were obtained.
In the same way exo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazine was obtained from tropinone and 1-(phenylmethyl)piperazine in a yield of 48.9% of theory.
Colourless, amorphous substance, Rf=0.36 (FM1).
b) 3,4-dihydro-3-[l-(4-piperidinyl)-4-piperidinyl]-2(1H)-quinazolinone
Prepared analogously to Example A3f) from 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone by hydrogenolysis, but using Pearlman's catalyst, in a yield of 92% of theory. Colourless crystals, Rf=0.48 (Macherey-Nagel, POLYGRAM® SIL G/UV254ready-made films for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/20/10/5 v/v/v/v).
IR (KBr): 1660.6 cm−1 (C═O)
MS: M+=314
EXAMPLE A12
3-(4-piperidinyl)-3,4,4a,5,6,7,8,8a-octahydro-2(1H)-quinazolinone-acetate
A solution of 5.0 g (17.17 mmol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-acetate in 70 ml of methanol was hydrogenated at room temperature and in the presence of 1.0 g rhodium (III) oxide-platinum (IV) oxide hydrate catalyst (46.45% rhodium, 20.15% platinum) until the hydrogen uptake had ceased. The catalyst and solvent were removed, the residue was triturated with 10 ml of diisopropylether and a few drops of isopropanol and the resulting crystals were suction filtered. After drying in vacuo 4.4 g (86.2% of theory) of colourless crystals were obtained, Rf=0.3 (eluant: dichloromethane/methanol/conc. ammonia 7.5/2.5/0.5 v/v/v).
IR (KBr): 1641 cm−1 (C═O)
MS: M+=237
EXAMPLE A13
1,1-dioxido-2-(4-piperidinyl)-3(4H-1,2,4-benzothiadiazinone
a) 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide
Whilst carrying out external cooling with ice water a solution of 44.3 g (0.2 mol) of 2-nitrobenzenesulphonyl chloride in 250 ml of chloroform was added dropwise to a solution of 38.0 g (0.2 mol) of 4-amino-1-(phenylmethyl)piperidine and 22.0 g (0.22 mol) of triethylamine in 250 ml of chloroform. After the cooling was stopped the mixture was stirred for a further 30 minutes at room temperature, the reaction mixture was then extracted twice with 1 l water. The aqueous extracts were extracted once more with 100 ml of dichloromethane, the combined organic phases were then dried over sodium sulphate and evaporated down in vacuo. The highly viscous light-brown substance obtained in a yield of 75.0 g (99.9% of theory) was further processed without any more purification.
IR (KBr): 3363.7 (NH); 1541.0 (NO2); 1365.5 (NO2 or SO2); 1346.2 (NO2 or SO2); 1168.8 (SO2) cm−1 
b) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide
To a solution of 75.0 g (0.2 mol) of 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide in 2.0 l ethanol was added dropwise, at room temperature, a solution of 174.0 g ( 0.828 mol) of sodium dithionite-dihydrate in 700 ml of water. After the heat of the exothermic reaction had died away the mixture was refluxed for 4.5 hours, then the ethanol was distilled off and the aqueous phase remaining was extracted thoroughly with dichloromethane.
The combined dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was purified by column chromatography over silica gel using dichloromethane/methanol/conc. ammonia 80/20/0.25 (v/v/v) as eluant. 6.5 g (8.6% of theory) of a highly viscous oil were obtained.
IR(KBr): 1319.2, 1153.4 cm−1 (SO2)
c) 1,1-dioxido-2-[1-(phenylmethyl)-4-piperidinyl]-3(4H)-1,2,4-benzothiadiazinone
Prepared analogously to Example A3e) from 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide and N, N′-carbonyldiimidazole in a yield of 78% of theory. Colourless crystals of melting point 169-171° C.
IR(KBr): 1693.4 (C═O); 1359.7, 1340.4, 1188.1 (SO2) cm−1 
d) 1,1-dioxido-2-(4-piperidinyl)-3(4H)-1,2,4-benzothiadiazinone
Prepared analogously to Example A3f), but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 90% of theory. Colourless, amorphous substance.
IR(KBr): 1705.0 (C═O) cm−1 
EXAMPLE A14
3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine
a) 3,4-dihydro-2,2-dioxido-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine
A solution of 11.0 g (0.0372 mol) of 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-benzenemethanamine in 200 ml of pyridine was added dropwise within 1.5 hours and at reflux temperature to a solution of 3.4 g (0.0354 mol) of sulphamide in 200 ml of pyridine and the mixture was then refluxed for 6 hours. The mixture was freed from solvent, the residue was purified by column chromatography using ethyl acetate/methanol 9/1 (v/v) as eluant. 5.5 g (43.5% of theory) of a colourless amorphous substance were obtained.
IR(KBr): 1344.3, 1166.9 cm−1 (SO2)
b) 3,4-dihydro-2,2-dioxido-3-(4-piperidinyl)-2,1,3-benzothiadiazine
Prepared analogously to Example A3f) from 3,4-dihydro-2,2-dioxide-3-[1-(phenylmethyl)-4-piperidinyl]-2,1,3-benzothiadiazine by catalytic hydrogenation in the presence of palladium/charcoal in a quantitative yield. Colourless, amorphous substance.
IR(KBr): 1263.3, 1105.1 cm−1 (SO2)
EXAMPLE A15
D,L-4-phenyl-1-(4-piperidinyl)-imidazolidine-2,5-dione
a) N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide
A mixture of 10.0 g (0.0398 mol) of N2-(1,1-dimethylethoxycarbonyl)-D,L-phenylglycine, 7.57 g (0.0398 mol) of 4-amino-1-(phenylmethyl)piperidine, 10 ml of triethylamine, 12.8 g (0.0399 mol) of TBTU and 5.4 g (0.0353 mol) of N-hydroxy-benzotriazole-hydrate in 200 ml of THF-DMF mixture (1/1 v/v) was stirred overnight at room temperature. The residue remaining after removal of the solvent was taken up in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. 14.8 g (87.8% of theory) of a colourless, amorphous substance were obtained.
IR(KBr): 1701.1, 1676.0, 1652.9 cm−1 (C═O)
Analogously N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide was obtained from N2-(1,1-dimethylethoxycarbonyl)-D,L-phenylalanine and 4-amino-1-(phenylmethyl)piperidine in a yield of 85% of theory. Colourless, amorphous substance, Rf=0.83 (eluant: dichloromethane/cyclohexane/metha-nol/conc.  ammonia=70/15/15/2 v/v/v/v).
IR(KBr): 1683.8, 1651.0 cm−1 (C═O)
b) N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide-bis-trifluoroacetate
Prepared analogously to Example A5e) from N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide and trifluoroacetic acid in a quantitative yield. Colourless, amorphous substance, Rf=0.56 (FM1)
Analogously N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide-bis-trifluoracetate was obtained from N2-(1,1-dimethylethoxycarbonyl)-N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide in a yield of 92% of theory.
IR(KBr): 1670.3 cm−1 (C═O)
c) D,L-4-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione
Prepared analogously to Example A3e) from N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylglycinamide and N, N′-carbonyldiimidazole in a yield of 57.3% of theory. Colourless crystals,

    Rf=0.68. IR(KBr): 1774.4, 1712.7 cm−1 (C═O)


Analogously D,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione was obtained from N-[1-(phenylmethyl)-4-piperidinyl]-D,L-phenylalaninamide in a yield of 93% of theory. Colourless, fine crystals, Rf=0.6 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia=7/1.5/1.5/0.2 v/v/v/v).
IR(KBr): 1764.8, 1708.8 cm−1 (C═O)
MS: M+=363
d) D,L-4-phenyl-1-(4-piperidinyl)-imidazolidine-2,5-dione
Prepared analogously to Example A3f) from D,L-4-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione by hydrogenolysis in the presence of palladium/charcoal in a yield of 84.3% of theory. Colourless, amorphous substance, Rf=0.5.
IR(KBr): 1766.7, 1706.9 cm−1 (C═O)
Analogously D,L-4-(phenylmethyl)-1-(4-piperidinyl)-imidazolidine-2,5-dione was obtained from D,L-4-(phenylmethyl)-1-[1-(phenylmethyl)-4-piperidinyl]-imidazolidine-2,5-dione. Colourless crystals, Rf=0.24 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia=7/1.5/1.5/0.2 v/v/v/v).
IR(KBr): 1766.7, 1705.0 cm−1 (C═O)
EXAMPLE A16
1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone
a) 1-[2-(acetylamino)phenyl]-2-bromoethanone
45.0 g (0.282 mol) of dry bromine were added dropwise to a boiling solution of 50.0 g (0.282 mol) of 1-[2-(acetylamino)phenyl]ethanone in 400 ml of chloroform at room temperature. The solvent was distilled off, the residue was distributed between dichloromethane and saturated ice-cold sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, evaporated down in vacuo, the residue was triturated with diethylether and suction filtered. After drying in vacuo 35.4 g (49% of theory) of colourless crystals were obtained, Rf=0.48 (eluant: petroleum ether/ethyl acetate 2/1 v/v).
IR(KBr): 1685.69, 1664.47 cm−1 (C═O)
MS: M+=255/257 (Br)
b) 4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-one
To a solution of 26.3 g (0.138 mol) of 4-amino-1-(phenylmethyl)piperidine and 17.8 g (0.138 mol) of DIEA in 300 ml of dichloromethane was added dropwise a solution of 35.4 g (0.138 mol) of 1-[2-(acetylamino)phenyl]-2-bromoethanone in 150 ml of dichloromethane and the mixture was kept for a further 2 hours at room temperature. With external cooling with ice 13.5 g (0.20 mol) of sodium cyanate and 12 ml of glacial acetic acid were then added and the mixture was stirred overnight in a thawing ice bath. It was washed with water and saturated sodium hydrogen carbonate solution, dried over sodium sulphate and freed from solvent. The residue was triturated with 50 ml of ethyl acetate-methanol mixture (9/1 v/v), the resulting crystals were suction filtered, washed with ethyl acetate and dried in vacuo. 37.0 g (68.7% of theory) of colourless crystals were obtained, Rf=0.41 (eluant: dichloromethane/methanol 9/1 v/v).
IR(KBr): 1678 cm−1 (C═O)
MS: M+=390 (Br)
c) 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one
A mixture of 3.0 g (7.68 mmol) of 4-[2-(acetylamino)phenyl]-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one, 50 ml of 5 N sodium hydroxide solution and 25 ml of ethanol was refluxed for 3 hours. After cooling the organic phase was separated off, dried over sodium sulphate and evaporated down in vacuo. A colourless amorphous substance was obtained in a quantitative yield, Rf=0.53 (eluant: dichloromethane/methanol 9/1 v/v).
d) 1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone
A solution of 2.67 g (7.66 mmol) of 4-(2-aminophenyl)-1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-imidazol-2-one in 50 ml of chloroform was mixed with 3.0 g of paraformaldehyde and refluxed for 3.5 hours. The residue remaining after evaporation of the solvent was taken up in 100 ml of methanol and acidified with methanolic hydrogen chloride solution. After stirring for one hour at room temperature the mixture was poured into 300 ml of saturated sodium hydrogen carbonate solution. The resulting mixture was extracted thoroughly with ethyl acetate, the combined extracts were dried over sodium sulphate and evaporated down in vacuo. The residue was purified by column chromatography over silica gel using FM4 as eluant. From the appropriate fractions 0.5 g (18.2% of theory) of a colourless, amorphous substance were isolated, Rf=0.24 (FM4).
IR(KBr): 1689 cm−1 (C═O)
MS: M+=358 (Br)
e) 1,3-dihydro-3-(4-piperidinyl)-2(2H)-imidazo[4,5-c]quinolone
Prepared analogously to Example A3f) from 1,3-dihydro-3-[1-(phenylmethyl)-4-piperidinyl]-2(2H)-imidazo[4,5-c]quinolone by hydrogenolysis in the presence of palladium/charcoal in a yield of 98.5% of theory. Colourless crystals, Rf=0.63 (FM1).
EXAMPLE A17
Preparation of β-(methoxycarbonyl)-arenebutanoic acids
3,5-dibromo-4-hydroxy-β-(methoxycarhonyl)-benzenebutanoic acid
a) 4-(phenylmethoxy)-benzaldehyde
To a solution of 36.6 g (0.3 mol) of 4-hydroxybenzaldehyde in 100 ml of ethanol were added dropwise, one after another, a solution of 12.0 g (0.3 mol) of sodium hydroxide in 100 ml of water and a solution of 36.5 ml of (0.307 mol) of benzylbromide in 100 ml of ethanol and the mixture was then kept for 1 hour at 50° C. The ethanol was extensively distilled off, finally in vacuo, the remaining aqueous emulsion was divided between water and ethyl acetate. The ethyl acetate phase was dried over sodium sulphate and evaporated down in vacuo. The residue remaining crystallised on trituration with petroleum ether and was recrystallised from diisopropylether. 48.0 g (75.4% of theory) of colourless crystals of melting point 118-122° C. were obtained.
b) 3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid
To a freshly prepared solution of 2.3 g (0.1 mol) of sodium in 300 ml of anhydrous methanol were added 14.6 g (0.1 mol) of dimethyl succinate and after half an hour's stirring a solution of 21.2 g (0.1 mol) of 4-(phenylmethoxy)-benzaldehyde in 100 ml of anhydrous methanol were added dropwise. Then the mixture was refluxed for 6 hours, the methanol was distilled off under normal pressure and the remaining residue was kept for 30 minutes at a reaction temperature of 80° C. The viscous slurry obtained was stirred into 1 l of a glacial acetic acid-water mixture (1/1 v/v), the resulting mixture was extracted thoroughly with ethyl acetate. The combined ethyl acetate extracts were in turn extracted with saturated potassium carbonate solution. The potassium carbonate extracts were carefully acidified with acetic acid and then extracted thoroughly with ethyl acetate. These extracts were washed with water, dried over sodium sulphate and freed from solvent in vacuo. The residue was purified by column chromatography over silica gel using dichloromethane/petroleum ether/glacial acetic acid 25/74/1 (v/v/v). The colourless, partly crystallised mixture of diastereomers was obtained in a yield of 16.0 g (49% of theory). Rf=0.68 (eluant: ethyl acetate/petroleum ether 1:2 v/v).
IR(KBr): 1699.2 cm−1 (C═O)
The following were obtained analogously:

    (1) 3-(methoxycarbanyl)-4-[3-(trifluoromethyl)phenyl]-3-butenoic acid was obtained from 3-(trifluoromethyl)benzaldehyde and dimethyl succinate in a yield of 21% of theory.


















IR (KBr):
1738, 1726 cm−1 (C═0)











ESI-MS:
(M − H)− =
287




(M + H)+ =
289




(M + Na)+ =
311










    (2) 3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid was obtained from 1-naphthaldehyde and dimethyl succinate in a yield of 60% of theory.


Colourless oil
IR(KBr): 1712 cm−1 (C═O)
MS: M+=270

    (3) 3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenoic acid was obtained from 3,5-dimethyl-4-phenyl-methoxybenzaldehyde and dimethyl succinate in a yield of 66% of theory.


Colourless oil which could be further processed without purification.

    (4) 4-(4-amino-3,5-dibromophenyl)-3-(methoxycarbonyl)-3-butenoic acid was obtained from 4-amino-3,5-dibromobenzaldehyde and dimethyl succinate in a yield of 21% of theory.
    (5) 3-(Methoxycarbonyl)-4-(3-phenylmethoxyphenyl)-3-butenoic acid was obtained from 3-phenylmethoxybenzaldehyde and dimethyl succinate in a yield of 37% of theory.


c) 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid
Prepared analogously to Example A3f) from 3-(methoxycarbonyl)-4-[(4-phenylmethoxy)phenyl]-3-butenoic acid by hydrogenolysis in the presence of palladium/charcoal in a yield of 96% of theory. Colourless oil, Rf=0.5 (eluant: ethyl acetate/petroleum ether/glacial acetic acid 66.3/33.3/0.4 v/v/v).
The following were obtained analogously:

    (1) β-(methoxycarbonyl)-3-(trifluoromethyl)-benzenebutanoic acid was obtained from 3-(methoxycarbonyl)-4-[3-(trifluoromethyl)phenyl]-3-butenoic acid in a yield of 80% of theory. Rf=0.59 (eluant: ethyl acetate/petroleum ether 1/1/ v/v).


ESI-MS: (M−H)−=289

    (2) β-(methoxycarhonyl)-1-naphthalinebutanoic acid was obtained from 3-(methoxycarbonyl)-4-(1-naphthyl)-3-butenoic acid, however using platinum(IV)-oxide as a catalyst, in a yield of 31% of theory.


IR (KBr): 1734, 1711 (C═O) cm−1 
MS: M+=272
β-(methoxycarbonyl)-1,2,3,4-tetrahydro-1-naphthaline-butanoic acid was isolated as a by-product in a yield of 8.4% of theory
IR (KBr): 1736, 1712 (C═O) cm−1 
MS: M+=276

    (3) 3,5-dimethyl-4-hydroxy-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(methoxycarbonyl)-4-[3,5-dimethyl-4-phenylmethoxyphenyl]-3-butenoic acid in a yield of 48% of theory.


Rf=0.11 (FM1)
IR (KBr): 1716 (C═O) cm−1
MS: M+=266

    (4) 3-Hydroxy-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(Methoxycarbonyl)-4-(3-phenylmethoxyphenyl)-3-butenoic acid in a yield of 59% of theory.


Rf=0.24 (petroleum ether/ethyl acetate/glacial acetic acid 6/4/0.2 v/v/v)
IR (KBr): 1714 (C═O) cm−1
MS: M+=238

    (5) 4-Amino-β-(methoxycarbonyl)-benzene butanoic acid was obtained from 3-(methoxycarbonyl)-4-(4-amino-3,5-dibromophenyl)-3-butenoic acid and in the presence of triethylamine in a quantitative yield.


Rf=0.53 (eluant: dichloromethane/methanol/glacial acetic acid 90/10/1.5 v/v/v))
IR (KBr): 1728 (C═O) cm−1 
MS: M+=237
d) 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid
To a solution of 12.0 g (0.05 mol) of 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of glacial acetic acid were added 150 ml of water and 8.0 g sodium acetate and then a solution of 15.58 g (0.0975 mol) of bromine in 60 ml of glacial acetic acid was added dropwise. The mixture was stirred for a further hour at room temperature, then evaporated down to two thirds in vacuo and the residue was divided between water and ethyl acetate. The ethyl acetate extracts were washed with water, dried over sodium sulphate and evaporated down in vacuo. After stirring with diisopropylether a colourless crystal was obtained. Yield: 12.0 g (62.2% of theory). Rf=0.4 (eluant: ethyl acetate/petroleum ether/glacial acetic acid 49.8/49.8/0.4 v/v/v).
IR(KBr): 1724 cm−1 (C═O)
MS: M+=394/396/398 (Br2)
EXAMPLE A18
1-(3-pyridinyl)piperazine
a) 1-(phenylmethyl)-3-(3-pyridinyl)piperazine
To a solution of 5.0 g (0.0515 mol) of 3-fluoropyridine and 43.5 ml of 1-(phenylmethyl)piperazine in 300 ml of anhydrous diethylether was added dropwise, at boiling temperature, within 2.5 hours, 56 ml (0.112 mol) of a 2 molar solution of phenyl-lithium in a cyclohexane-diethylether mixture (7/3 v/v) and the resulting mixture was then kept at reflux temperature for a further 4 hours. The crude reaction product obtained as an oil after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane (7/3 v/v) as eluant. 12.0 g (92% of theory) of a colourless oil were obtained, Rf 0.52 (FM4; Macherey-Nagel, POLYGRAM® SIL G/UV254 Pre-coated plastic sheets for TLC).
MS: M+=253
b) 1-(3-Pyridinyl)piperazine
Prepared analogously to Example A3f) from 1-(phenylmethyl)-3-(3-pyridinyl)piperazine by hydrogenolysis in the presence of palladium/charcoal in a yield of 55% of theory. Colourless oil,
Rf 0.35 (FM1).
IR(KBr): 1652.9 cm1 (C═N)
EXAMPLE A19
1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifuoroacetate
a) 1-(1,1-dimethylethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine
A solution of 15.0 g ( 0.8054 mol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of 1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to a pH of between 5 and 6 by dropwise addition of acetic acid and mixed in batches with a total of 4.13 g ( 0.0624 mol) of 95% sodium cyanoborohydride, whilst taking care to maintain a pH of 5 to 6 by further dropwise addition of acetic acid. After stirring for 18 hours at room temperature the mixture was evaporated down in vacuo, the residue was made alkaline with soda and divided between water and ethyl acetate. After working up the ethyl acetate phase in the usual way 21.76 g (75.2% of theory) of a highly viscous colourless oil were obtained, Rf 0.66 (FM1).
b) 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine
Prepared analogously to Example A3f) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-[1-(phenylmethyl)-4-piperidinyl]piperazine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a yield of 79.7% of theory.
Colourless crystals, Rf=0.3 (FM1).
c) 1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazine
Prepared analogously to Example A19a) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
MS: M+=251
d) 1-(1-cyclohexyl-4-piperidinyl)piperazine-tris-trifluoroacetate
Prepared analogously to Example A5e) from 1-(1,1-dimethylethoxycarbonyl)-4-(1-cyclohexyl-4-piperidinyl)piperazine and trifluoroacetic acid in a quantitative yield. Colourless crystals, Rf=0.2 (FM1).
EXAMPLE A20
1-(1 -ethyl-4-piperidinyl)piperazine-trihydrochloride
a) 1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine
Prepared analogously to Example A19a) from 1-ethyl-4-piperidinone and 1-(phenylmethyl)piperazine in a yield of 71% of theory. Colourless, amorphous substance, Rf=0.46 (FM4).
b) 1-(1-ethyl-4-piperidinyl)piperazine-trihydrochloride
A mixture of 36.3 g (0.126 mol) of 1-(1-ethyl-4-piperidinyl)-4-(phenylmethyl)piperazine, 300 ml of 1N hydrochloric acid and 200 ml of methanol was hydrogenated at room temperature and in the presence of 4.0 g of 10% palladium/charcoal until the up-take of hydrogen had ceased. After working up in the usual way 22.9 g (59.3% of theory) of a colourless, crystalline substance was obtained.
MS: M+=197
In the same way exo-1-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)piperazine-trihydrochloride was obtained from exo-4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-(phenylmethyl)piperazine (see Example A11a)) by hydrogenolysis in the presence of palladium/charcoal in a yield of 91% of theory.
MS: M+=209
EXAMPLE A21
1-ethyl-4-(4 -piperidinyl)piperidine
a) 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine
To a mixture of 72.375 g (0.3 mol) of bipiperidine-dihydrochloride, 1500 ml of methanol, 75 ml of water and 100 mg of bromophenol blue were added dropwise, simultaneously, with stirring and at room temperature, a solution of 51.18 g (0.3 mol) of benzyl chlorocarbonate in 75 ml of toluene and 6 N sodium hydroxide solution (about 80 ml) were added, so that the indicator colour changed continuously. After all had been added, which took about 4 hours, the mixture was diluted with 300 ml of water and the organic solvent was distilled off in vacuo. The aqueous phase remaining was acidified with hydrochloric acid, whilst being externally cooled, extracted thoroughly with diethylether and then made alkaline with 50% potassium hydroxide solution. The mixture was extracted thoroughly with dichloromethane, the combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo. The colourless, highly viscous, slowly crystallising oil remaining was further processed without any more purification.
Yield: 87.3 g (96.2% of theory).
IR(KBr): 1701.1 cm−1 (C═O)
b) 1-ethyl-4-[1-(phenylmethoxycarbonyl)-4-piperidinyl]piperidine
To a solution of 18.14 g (0.061 mol) of 1-(phenylmethoxycarbonyl)-4-(4-piperidinyl)piperidine in 450 ml of a methanol/water mixture (1/1 v/v) were added, with stirring, whilst maintaining a temperature of 15 to 20° C., 10.05 g (0.152 mol) of 95% sodium cyanoborohydride and 50 mg of bromocresol purple. Then a solution of 10.57 g (0.24 mol) of acetaldehyde in 50 ml of methanol and 1N hydrochloric acid were alternately added dropwise so that the colour of the mixture changed continuously from blue to yellow. After all had been added and the reaction had finished the mixture was adjusted to pH 2 with hydrochloric acid and extracted twice with 200 ml of diethylether. The aqueous phase was then made alkaline and extracted thoroughly with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulphate and evaporated down in vacuo. The colourless crystallising residue remaining was purified by column chromatography over silica gel (30-60 μm) using FM1 as eluant. Yield of colourless crystals of melting point 93-96° C.: 7.9 g (39.2% of theory).
IR(KBr): 1699.2 cm−1 (C═O)
c) 1-ethyl-4-(4-piperidinyl)piperidine
A solution of 7.6 g (0.023 mol) of 1-ethyl-4-[1-(phenylmethoxy-carbonyl)-4-piperidinyl]piperidine in a mixture of 70 ml of methanol, 30 ml of water and 10 ml of glacial acetic acid was hydrogenated in the presence of 10% palladium/charcoal at room temperature and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. After working up in the usual way the desired compound was obtained as a colourless oil in a quantitative yield.
EXAMPLE A22
Hexahydro-1-methyl-4-(4-piperidinyl)-1H-1,4-diazepine
a) Hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine
Prepared analogously to Example A11a) from hexahydro-1-methyl-1H-1,4-diazepine and 1-(phenylmethyl)-4-piperidinone in a yield of 35% of theory. Colourless viscous oil.
MS: M+=287
The following were prepared in the same way:

    (1) 1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-piperazine from 1-methylpiperazine and 1-(phenylmethyl)-4-piperidinone


Yield: 39.9% of theory, colourless viscous oil

    (2) 1-acetyl-4-[1-(phenylmethyl)-4-peridinyl]piperazine from 1-acetylpiperazine and 1-(phenylmethyl)-4-piperidinone


Yield: 24.2% of theory, colourless viscous oil
Rf: 0.46 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)
IR(KBr): 1647 cm−1 (C═O)
MS: M+=301
(3) 4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]-piperidine from 4-(dimethylamino)piperidine and 1-(phenylmethyl)-4-piperidinone
Yield: 28.9% of theory; colourless viscous oil
Rf: 0.58 (eluant: ethyl acetate/methanol/conc. ammonia 50/50/2 v/v/v)
MS: M+=301

    (4) 1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine


from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinone and 1-(phenylmethyl)piperazine
Yield: 86.6% of theory. Colourless, amorphous substance
Rf: 0.58 (eluant: dichloromethane/methanol 9/1 v/v)
b) Hexahydro-1-methyl-4-(4 -piperidinyl)-1H-1,4-diazepine
Prepared analogously to Example A3f) from hexahydro-1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]-1H-1,4-diazepine by hydrogenolysis, but using Pearlman's catalyst instead of palladium/charcoal, in a quantitative yield. Colourless viscous oil.
MS: M+=197
The following were obtained in the same way:

    (1) 1-methyl-4-(4-piperidinyl)piperazine from 1-methyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a quantitative yield. Colourless viscous oil.


MS: M+=183

    (2) 1-acetyl-4-(4-piperidinyl)piperazine from 1-acetyl-4-[1-(phenylmethyl)-4-piperidinyl]piperazine in a yield of 81.9% of theory. Colourless crystals.


IR(KBr): 1631 cm−1 (C═O)

    (3) 4-(dimethylamino)-1-(4-piperidinyl)piperidine from 4-(dimethylamino)-1-[1-(phenylmethyl)-4-piperidinyl]-piperidine in a yield of 76.8% of theory. Colourless, amorphous substance.
    (4) 1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine-hydrochloride from 1-(1,1-dimethylethoxycarbonyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine-hydrochloride.


Yield: 96% of theory. Colourless crystals
Rf: 0.23 (eluant: dichloromethane/methanol 9/1 v/v)
EXAMPLE A23
4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetate
a) 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid
To a mixture of 25.9 g (0.2 mol) of piperidine-4-carboxylic acid, 200 ml (0.2 mol) of 1N sodium hydroxide solution and 200 ml of tetrahydrofuran were added 48.0 g (0.22 mol) of di-tert.-butyl pyrocarbonate and the mixture was stirred overnight at room temperature. The tetrahydrofuran was distilled off, finally in vacuo, and the remaining aqueous solution was acidified with citric acid. The colourless crystals precipitated were suction filtered and dried at 40° C. in a circulating air drier. Yield: 45.5 g (99.2% of theory).
IR(KBr): 1733.9, 1662.5 cm−1 (C═O)
b) 1-(1,1-dimethylethoxycarbonyl)-4-[(4-methyl-1-piperazinyl)-carbonyl]-piperidine
Prepared analogously to Example A15a) from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid and 1-methylpiperazine in the presence of TBTU in a yield of 76% of theory. Colourless, amorphous substance, Rf=0.64 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).
IR(KBr): 1693, 1678 cm−1 (C═O)
The following were prepared in the same way:

    (1) 1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine from 1-methyl-4-piperidinecarboxylic acid and 1-(1,1-dimethyl-ethoxycarbonyl)piperazine in a yield of 97% of theory.


Colourless crystals.
IR(KBr): 1683.8, 1629.8 cm−1 (C═O)

    (2) 1-(1,1-methylethoxycarbonyl)-4-(isonicotinoyl)piperazine from 1-(1,1-dimethylethoxycarbonyl)-piperazine and 4-pyridine-carboxylic acid in a yield of 76.8% of theory. Colourless crystals of melting point 139.2-140.2° C. and Rf=0.84 (eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).


IR(KBr): 1689.5, 1625.9 cm−1 (C═O)
c) 4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine-bis-trifluoroacetate
prepared analogously to Example A5e) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-[(4-methyl-1-piperazinyl)carbonyl]-piperidine and trifluoroacetic acid in a yield of 89% of theory.
Colourless, amorphous substance.
The following were prepared in the same way:

    (1) 1-methyl-4-[(1-piperazinyl)carbonyl]-piperidine from 1-methyl-4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-piperidine and trifluoroacetic acid in a yield of 57% of theory. Colourless, amorphous substance.


IR(KBr): 1679.9, 1645.2 cm−1 (C═O)
MS: M+=211

    (2) 4-(isonicotinoyl)piperazine-trifluoroacetate from 1-(1,1-dimethylethoxycarbonyl)-4-(isonicotinoyl)piperazine and trifluoroacetic acid in a yield of 98.3% of theory.


Colourless, amorphous substance.
IR(KBr): 1676.0 cm−1 (C═O)
EXAMPLE A24
Preparation of Compounds of the General Structure:

Boc-A-NR3R4 

1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
To a mixture of 18.8 g (0.0494 mol) of Boc-Lys(Z)-OH, 6.5 g (0.05 mol) of DIEA, 16 g (0.05 mol) of TBTU, 6.6 g (0.049 mol) of HOBt and 100 ml of dimethylformamide were added dropwise, with stirring, 8.1 g (0.0494 mol) of 1-(4-pyridinyl)piperazine, dissolved in 40 ml of DMF, and the mixture was stirred over-night at room temperature. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was then washed three times successively with 70 ml of saturated aqueous sodium hydrogen carbonate solution and once with 70 ml of saturated aqueous saline solution, dried over sodium sulphate and evaporated down in vacuo. 24.2 g (93.2% of theory) of a yellowish oil were obtained, which was used for the following reactions without further purification.
IR (KBr): 1650, 1713 cm−1 (C═O)
Rf (FM1): 0.59
The following were prepared analogously:



















%





A
NR3R4
Remarks
Yield
Rf
Eluant
IR [cm−1]





















A9
C1
THF as LM
63.2
0.4
FM1
(KBr): C═O




KHSO4/NaCl



1705.0; 1649




soln


A4
C1

93.2
0.59
FM1
(KBr): C═O








1647.7; 1712.7


A5
C1

66
0.55
FM1
(KBr): C═O








1655; 1709


A5
C8

54
0.8
FM1
(KBr): C═O








1653; 1713


A6
C8

91
0.8
FM1
(KBr): C═O








1645; 1710.8


A10
C1

63
0.5
FM1
(KBr): C═O








1665; 1695


A10
C8

30
0.41
FM4
(KBr): C═O








1662; 1699









EXAMPLE A25
Preparation of Compounds ofGeneralFormula:

Cbz-A-NR3R4 

1-[N2-(phenylmethoxycarbonyl)-N6-(1,1-dimethyl-ethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
To a mixture of 100 g (0.263 mol) of Z-Lys(Boc)-OH, 86.1 g (0.268 mol) of TBTU and 36.3 g (0.263 mol) of HOBt in 600 ml of dimethylformamide were added 43.0 g (0.263 mol) of 1-(4-pyridinyl)-piperazine and 47.2 ml (0.268 mol) of DIEA with stirring and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate and aqueous saturated sodium hydrogen carbonate solution. The aqueous phase was extracted twice more with a mixture of ethyl acetate/methanol (10/1, v/v) and the combined organic phases were washed once with saturated sodium hydrogen carbonate solution. The organic phase was, after drying over sodium sulphate, evaporated down in vacuo and the residue was taken up in 750 ml of ethyl acetate and washed four times with 100 ml of water, six times with 100 ml of 1% potassium hydrogen sulphate solution, once with 100 ml of water, twice with 100 ml of 3% aqueous ammonia solution and twice with 100 ml of water. The organic phase was evaporated down after drying over sodium sulphate. 120 g (87% of theory) of the desired product were obtained as an oil, which was used without further purification for the subsequent reactions.
IR (KBr): 1709 cm−1 (C═O)
Rf (FM1): 0.59
EI-MS: M+=525
The following were prepared analogously:




















%






A
NR3R4
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]






















A3
C4

100






A3
C3
Triethylamine as
100

0.8
FM1
(KBr): C═O




base




1643.3; 1710.8


A11
C1

98.8

0.5
FM1
(KBr): C═O









1705.0; 1643.3


A3
C1

81
EI: M + = 525
0.59
FM1
(KBr): C═O









1708.8;


A3
C5
LC/SiO2/FM4
95
YED: M = 525
0.67
FM4


A3
C6
THF, LC/SiO2/FM4
92

0.82
FM4
(KBr): C═O









1710.8; 1641.3


A3
C8
Further reacted as
100




crude product









EXAMPLE 26
Preparation of Compounds ofGeneralFormula:

H-A-NR3R4 

1-[N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine
To a mixture of 24.2 g (46 mmol) of 1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine and 150 ml of methylene chloride were added 50 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried and evaporated down in vacuo. 12 g (62% of theory) of the desired compound were obtained as a colourless oil.
IR (KBr): 1648 cm−1 (C═O)
Rf (FMI) 0.5
The following were prepared analogously:
















A
NR3R4
Remarks
% Yield
Rf
Eluant
IR [cm−1]





















A9
C1

100
0.4
FM2
(KBr): C═O








1676.0; 1645.2


A4
C1

61.5
0.48
FM1
(KBr): C═O








1647.7; 1712.7


A5
C1

55
0.42
FM1
(KBr): C═O








1651


A5
C8
further
100
0.19
FM1




reacted as




crude




product


A6
C1

82
0.3
FM1
(KBr): C═O








1647; 1676


A6
C8
further
100
0.23
FM1
(KBr): C═O




reacted as



1674




crude




product


A10
C1

38
0.55
FM1
(KBr): C═O








1643


A10
C8
further
100
0.15
FM1




reacted as




crude




product









EXAMPLE A27
Preparation of Compounds ofGeneralFormula:

H-A-NR3R4 

1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
A solution of 120 g (0.228 mol) of 1-[N2-(phenylmethoxycarbonyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine in 1000 ml of methanol and 240 ml of 1M aqueous potassium hydrogen sulphate solution was hydrogenated in the presence of 30 g palladium on charcoal (10%) at 20° C. and 3 bar of hydrogen pressure until the uptake of hydrogen had ceased. The catalyst was filtered off, the filtrate evaporated down in vacuo, the residue was taken up in isopropanol/methanol and adjusted to pH 7-8 by the addition of a concentrated aqueous ammonia solution. The solution was filtered and evaporated to dryness. 87 g (97w of theory) of an oil were obtained.
IR (KBr): 1634, 1701 cm−1 (C═O) Rf: 0.79 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v)
The following were prepared analogously:

















A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]






















A3
C4

93
ESI: M + H = 391
0.6
FM1
(KBr): C═O






(M + Na = 413)


1637.5; 1706.9


A3
C3

100

0.3
FM1
(KBr): C═O









1641.3; 1705


A11
C1

78.5

0.2
FM1
(KBr): C═O









1701.1; 1641.3


A7
C1
without KHSO4
80.2

0.2
FM7


A3
C1

97

0.79
ethyl
(KBr): C═O








acetate/methanol/
1633.6; 1701.1








conc. aqueous








ammonia 6/4/1








(v/v/v)


A3
C5
without KHSO4
53

0.39
FM4
(KBr): C═O









1733.9; 1624.0


A3
C6
without KHSO4
89

0.38
FM4
(KBr): C═O









1706.9; 1645.2


A3
C8
further reacted as
100

0.3
FM1




crude product









EXAMPLE A28
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
To a mixture of 2.58 g (5.88 mmol) of N-[(1,1-dimethylethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 1.03 g (8 mmol) of DIEA, 1.93 g (6 mmol) of TBTU, 0.79 g (5.8 mmol) of HOBt and 100 ml of dimethylformamide were added dropwise, 2.5 g (5.88 mmol) of 1-[N6-[(phenylmethoxy)-carbonyl]-L-lysyl]-4-(4-pyridinyl)piperazine, dissolved in 50 ml of dimethylformamide, with stirring. The reaction mixture was stirred overnight at room temperature, then evaporated down in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed twice with aqueous saturated sodium hydrogen carbonate solution and once with aqueous saturated saline solution, dried and evaporated down in vacuo. The purification was carried out by column chromatography (aluminium oxide, activity stage III (6% water content) (ICN Biomedical), eluant: ethyl acetate/methanol/ammonia=8/2/0.5 (v/v/v), followed by methanol/ammonia=7/3 (v/v)). 4.0 g (80% of theory) of an amorphous substance were obtained.
IR (KBr): 1643, 1709 cm−1 (C═O)
Rf: 0.52(FM1)
ESI-MS: (M+H)+=845/847/849 (Br2)
The following were prepared analogously (in each case n=1):


















R2
A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]























AS7
A0
C4
LM: THF;
100









reacted as





crude product


AS1
A0
C11
reacted as
69





crude product


AS4
A0
C20

59
ESI: (M + H)+ =


(KBr): C═O







600/2/4 (Br2)


1639; 1707


AS1
A0
C4

71


AS4
A0
C11

53

0.5
FM1


AS7
A0
C1
reacted as
100



(KBr): C═O





crude product




1644


AS4
A7
C1
NEt3 as base;
100

0.4
FM8





reacted as





crude product


AS1
A4
C1

80
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O







845/7/9 (Br2)


1643.3;










1708.8


AS4
A0
C5
Boc-AS4
83
EI: M+ =
0.69
FM5
(KBr): C═O





LC/SiO2/FM5

581/3/5(Br2)


1706.9;










1641.3


AS4
A0
C15
LC/SiO2/FM4
86
EI: M+ =
0.83
FM4
(KBr): C═O







382/4/6(Br2)


1706.9;










1641.3


AS1
A0
C5
LC/SiO2/FM5
81

0.5
FM5
(KBr): C═O










1705.0;










1637.5


AS4
A0
C16
LC/SiO2/FM4
85
EI: (M + H)+ =
0.42
FM4
(KBr): C═O





THF

582/4/6(Br2)


1706.9;










1643.3


AS1
A0
C15
THF
76

0.53
FM4
(KBr): C═O





LC/SiO2/FM4




1701.1;










1637.5


AS4
A0
C3
LC/SiO2/FM6
83
ESI: (M + H)+ =
0.71
FM6
(KBr): C═O







598/600/2(Br2)


1706.9;










1641.3


AS1
A0
C16
LC/SiO2/FM4
85

0.35
FM1
(KBr): C═O










1705;










1641.3


AS1
A0
C6
LC/SiO2/FM6
84

0.54
FM6
(KBr): C═O










1701.1;










1635.5


AS4
A0
C18
LC/SiO2/FM4
95

0.66
FM4
(KBr): C═O










1705;










1641.3


AS1
A0
C37

90

0.43
FM1
(KBr): C═O










1645;










1714.5


AS4
A0
C37

95

0.51
FM4
(KBr): C═O










1643.3;










1705


AS4
A0
C22

75



(KBr): C═O










1635.5;










1708.8


AS4
A0
C21

92
M+ =
0.42
FM4
(KBr): C═O







582/4/6(Br2)


1643; 1705


AS4
A5
C1

69
ESI: (M + H)+ =


(KBr): C═O







939/41/43(Br2)


1653; 1709


AS4
A0
C23

85



(KBr): C═O










1645; 1709


AS4
A10
C1

65
M+: 652/4/6


(KBr): C═O










1649; 1707


AS4
A0
C24

79
M+: 589/91/93


(KBr): C═O










1643; 1707


AS4
A5
C8

76



(KBr): C═O










1643; 1713


AS4
A6
C1

95



(KBr): C═O










1645; 1710.8


AS4
A6
C8

88
M+: 657/9/61


(KBr): C═O










1628; 1713


AS4
A10
C8

46
ESI: (M + H)+ =


(KBr): C═O







858/60/62(Br2)


1647; 1707


AS4
A0
C26

46



(KBr): C═O










1637.5; 1707


AS1
A0
C1
further
100





reacted as





crude product


AS1
A0
C8

55

0.3
dichloro-
(KBr): C═O









methane/
1632









methanol









9/1


AS1
A0
C18

84
ESI: (M + H)+ =
0.4
FM4
(KBr): C═O







613/5/7(Br2)


1641; 1707


AS1
A0
C3

81



(KBr): C═O










1638; 1701


AS1
A0
C21

70

0.28
FM4
(KBr): C═O










1643; 1707


AS4
A0
C6

47



(KBr): C═O










1639; 1707


AS4
A0
C19

90



(KBr): C═O










1639; 1707


AS9
A0
C1
further
47





reacted as





crude product


AS1
A7
C1
NEt3 as base;
83

0.28
FM1





further





reacted as





crude product


AS4
A0
C38

67

0.5
FM1


AS4
A0
C37

84


AS4
A0
C39

100

0.68
FM1






(raw)


AS4
A0
C40

36


AS1
A0
C42

90

0.43
FM1
(KBr): C═O










1645/1715


AS4
A0
C42

100

0.51
FM4
(KBr): C═O










1643/1705


AS1
A0
C43

78

0.9
EE/MeOH
(KBr): C═O









95/5
1636/1676/










1659


AS1
A0
C44

47

0.9
EE/MeOH
(KBr): C═O









95/5
1638/1701


AS1
A0
C45

72
EI: M+ =
0.9
EE/MeOH
(KBr): C═O







591/3/5 (Br2)

9/1
1638/1695


AS1
A0
C47

80
EI: M+ =
0.95
EE/MeOH
(KBr): C═O







596/98/600

9/1
1636/1705







(Br2)


AS1
A0
C49

89

0.9
EE/MeOH
(KBr): C═O









9/1
1636/1684


AS4
A0
C44

69

0.9
EE/MeOH
(KBr): C═O









9/1
1643/1707;










CN 2235


AS1
A0
C50

93
EI: M+ =
0.9
EE/MeOH
(KBr): C═O







598/600/602

9/1
1636/1705







(Br2)


AS1
A0
C51

100

0.1
EE/MeOH/
(KBr): C═O









NH4OH
1638/1707









5/5/0.1


AS4
A0
C52

63

0.56
FM1
(KBr): C═O










1641/1705


AS4
A0
C53

83
EI: M+ =


(KBr): C═O







601/3/5 (Br2)


1638/1705


AS4
A0
C64

41
ESI: (M + H)+ =


(KBr): C═O







610/12/14


1639/1701







(Br2)


AS1
A0
C53

66

0.45
CH2Cl2/
(KBr): C═O









MeOH/
1639/1709









NH4OH









70/30/1


AS4
A0
C51

88

0.35
CH2Cl2/
(KBr): C═O









MeOH/
1641/1691









NH4OH









50/50/0.5


AS4
A0
C66

77
EI: M+ =
0.75
CH2Cl2/
(KBr): C═O







629/31/33

MeOH/
1641/1707







(Br2)

NH4OH









9/1/0.1


AS16
A0
C8

100

0.8
FM1


AS16
A0
C1

56

0.5
EE/MeOH/
(KBr): C═O









NH4OH
1695









9/1/1


AS4
A0
C8

100


AS1
A0
C53

70.0
EI: M+ =
0.10
CH2Cl2/MeOH/
(KBr): C═O







502/4/6 (Br2)

NH4OH 70/30/1
1676


AS4
A0
C70

47.0



(KBr): C═O










1645/1707


AS1
A0
C64

31.0

0.50
CH2Cl2/MeOH/
(KBr): C═O









NH4OH 90/10/1
1639/1707


AS1
A0
C70

20.0


AS4
A0
C72

50.0

0.50
CH2Cl2/MeOH/









NH4OH 90/10/1


AS19
A0
C8

98.0


AS35
A0
C8

92.0

0.70
FM1


AS36
A0
C8

65.0









EXAMPLE A29
Preparation of Compounds ofGeneralFormula:




1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)-piperazine
A mixture of 39 g (0.089 mol) of 4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanine, 35.7 g (0.111 mol) of TBTU, 12.3 g (0.089 mol) of HOBt, 14.5 g.(0.089 mol) of 1-(4-pyridinyl)-piperazine and 19.6 ml of (0.111 mol) of DIEA in 1000 ml of tetrahydrofuran was stirred overnight at room temperature. The reaction mixture was extracted once with saturated aqueous saline solution and twice with saturated aqueous sodium hydrogen carbonate solution. The combined aqueous phases were extracted once with tetrahydrofuran and the combined tetrahydrofuran phases were washed once with saturated aqueous saline solution. After drying the organic phase with sodium sulphate it was evaporated down in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate phase was filtered after drying again and evaporated down in vacuo. 52.5 g of the intermediate compound were obtained as a viscous oil, which was then mixed with 300 ml of methylene chloride and 8.0 ml of trifluoroacetic acid and stirred overnight at room temperature. The reaction mixture was evaporated down in vacuo, the residue formed was triturated with ether. 45.8 g (72% of theory) of the desired product were obtained as a white amorphous solid.
IR (KBr): 1643, 1674 cm−1 (C═O)
Rf: 0.36 (ethyl acetate/methanol=6/4 (v/v))
The following were prepared analogously (in each case n=1):


















R2
A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]























AS7
A0
C8
Crude product;
84









Boc-cleaving





with pure TFA


AS4
A0
C8

63
ESI: (M + H)+ =


(KBr): C═O







486/88/90(Br2)


1632


AS4
A0
C4

63
ESI: (M + H)+ =


(KBr): C═O







481/3/5(Br2)


1620


AS1
A9
C1

55

0.25
FM2
(KBr): C═O










1674.1; 1643.3


AS4
A0
C8

81
ESI: (M + H)+ =
0.6
FM2
(KBr): C═O







486/8/90(Br2)


1629.8


AS4
A0
C1

72

0.38
ethyl acetate/
(KBr): C═O









methanol = 6/4
1643.3; 1674.1









(v/v)


AS1
A0
C20

30


AS4
A0
C65

41
EI: M+ =


(KBr): C═O







515/17/19(Br2)


1618


AS1
A0
C65

15
ESI: (M + H)+ =
0.08
FM1
(KBr): C═O







517/19/21(Br2)


1635


AS4
A0
C78

77.0
ESI: (M + H)+ =
0.30
CH2Cl2/MeOH/
(KBr): C═O







529/31/33(Br2)

NH4OH = 90/10/1
1674


AS1
A0
C78

60.0
ESI: (M + H)+ =
0.10
CH2Cl2/MeOH/
(KBr): C═O







531/33/35(Br2)

NH4OH = 80/20/1
1670


AS4
A0
C71

43.0

0.20
CH2Cl2/MeOH/
(KBr): C═O









NH4OH = 90/10/1
1678


AS31
A0
C20

39.0
EI: M+ = 382
0.30
CH2Cl2/MeOH/
(KBr): C═O









NH4OH = 80/20/1
1678


AS31
A0
C53

83.0
EI: M+ = 383


(KBr): C═O










1678









EXAMPLE A30
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
A mixture of 63 g (0.1123 mol) of N-[(9-fluorenylmethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123 mol) of 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine, 39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt, 21.7 ml (0.1235 mol) of DIEA and 600 ml of dimethylformamide was stirred for 20 hours at room temperature. The reaction mixture was evaporated down in vacuo and the residue divided between ethyl acetate/methanol (10/1 v/v) and saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed once with saturated aqueous sodium hydrogen carbonate solution and after drying evaporated down in vacuo. The residue was recrystallised twice from isopropanol (22.6 g; 22% of theory), the mother liquors were combined, evaporated down and purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM; eluant: ethyl acetate/methanol=8/2 (v/v)). A further 28.0 g (26.7% of theory)of the desired end product were obtained. Total yield: 49% of theory.
IR (KBr): 1641, 1705 cm−1 (C═O)
Rf: 0.46 (ethyl acetate/methanol=6/4 (v/v))
ESI-MS: (M+H)+=933/935/937 (Br2)
The following were prepared analogously:


















R2
A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]























AS1
A3
C1

48
ESI: (M + H)+ =
0.46
Ethyl acetate/
(KBr): C═O







933/5/7(Br2)

methanol = 6/4
1641.3; 1705.5









(v/v)


AS1
A3
C5
THF/SiO2/FM4
80
ESI: (M + H)+ =
0.72
FM1
(KBr): C═O







933/5/7(Br2)


1701.1; 1635.5


AS1
A3
C6
THF
60
ESI: M− =
0.47
FM4
(KBr): C═O







960/2/4(Br2)


1712.7; 1631.7


AS5
A3
C1
THF
61
ESI: (M + H)+ =
0.36
FM4
(KBr): C═O





LC/SiO2/FM4

917/19/21(Br2)


1708.8; 1645.2





Diastereomers


AS10
A0
C1
THF
90

0.52
FM4


AS1
A3
C18

73

0.46
FM1
(KBr): C═O










1635.5; 1712.7


AS10
A3
C1
THF
85



(KBr): C═O










1643.3; 1708.8


AS10
A3
C4
THF
82



(KBr): C═O










1639.4; 1710.8


AS10
A3
C1
THF
85



(KBr): C═O










1643; 1709


AS4
A3
C18

94
ESI: (M + H)+ =


(KBr): C═O







963/5/7(Br2)


1633.6; 1711


AS15
A0
C8

90



(KBr): C═O










1635.5; 1617.5


AS12
A0
C8

44
ESI: (M + H)+ =


(KBr): C═O







577


1630; 1714.6


AS10
A0
C4

88

0.49
FM4
(KBr): C═O










1635.5; 1716.5


AS1
A3
C1

70

0.7
FM7









EXAMPLE A31
Preparation of Compounds ofGeneralFormula:




1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
To a mixture of 63 g (0.1123 mol) of N-[(9-fluorenylmethoxy)-carbonyl]-3,5-dibromo-D-tyrosine, 44 g (0.1123 mol) of 1-[N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine, 39.7 g (0.1235 mol) of TBTU, 15.5 g (0.1123 mol) of HOBt and 1500 ml of tetrahydrofuran were slowly added dropwise 21.7 ml (0.1235 mol) of DIEA and the reaction mixture was then stirred for 2 hours at room temperature. After the addition of 200 ml of diethylamine the mixture was again stirred overnight at room temperature. The reaction mixture was mixed with 1000 ml of saturated saline solution, stirred thoroughly and the aqueous phase was separated off. After extracting the aqueous phase three times with 500 ml of tetrahydrofuran and combining the organic phases the mixture was washed three times with 500 ml of saturated aqueous saline solution, three times with 200 ml of saturated aqueous sodium hydrogen carbonate solution and once with 500 ml of saturated aqueous saline solution. The organic phase was dried and then evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=8/1/0.25 (v/v/v)). 40.0 g (50w of theory)of the desired end product were obtained.
IR (KBr): 1641, 1699 cm−1 (C═O)
Rf: 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))
ESI-MS: (M+H)+=711/713/715 (Br2)
The following were prepared analogously (in each case n=1):


















R2
A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]























AS4
A3
C8
crude
43






AS4
A3
C1
crude
100

0.4
FM1


AS4
A3
C4

79
ESI: (M + H)+ =
0.7
FM7
(KBr): C═O







709/11/13


1637.5; 1705







(Br2)


AS4
A0
C69

82
ESI: (M + H)+ =


(KBr): C═O







587/9/81


1618/1645/







(Br2)


1690


AS4
A0
C46

38

0.55
CH2Cl2/
(KBr): C═O









MeOH/
1614/1639









NH4OH









90/10/1


AS4
A0
C48

54
EI: M+ =
0.52
CH2Cl2/
(KBr): C═O







522/4/6(Br2)

MeOH/
1638









NH4OH









90/10/2


AS11
A0
C53

71.0
EI: M+ = 469
0.20
CH2Cl2/
(KBr): C═O









MeOH/
1637/1732









NH4OH









90/10/1


AS11
A0
C20

45.0
EI: M+ = 468
0.40
CH2Cl2/
(KBr): C═O









MeOH/
1635/1732









NH4OH









90/10/1


AS31
A0
C72

100.0
EI: M+ = 411
0.45
FM1
(KBr): C═O










1664


AS11
A0
C72

33.0
EI: M+ = 497
0.30
FM1
(KBr): C═O










1630/1641









EXAMPLE A32
Preparation of Compounds ofGeneralFormula:




1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4 -pyridinyl)-piperazine
To a mixture of 4 g (4.7 mmol) of 1-[N2—[N-(1,1-dimethylethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine and 80 ml of methylene chloride were added 20 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried over sodium sulphate and evaporated down in vacuo. 2.2 g (64% of theory) of an amorphous solid were obtained.
IR (KBr): 1643, 1680 cm−1 (C═O)
Rf: 0.5 (FM1)
ESI-MS: (M+H)+=745/747/749 (Br2)
The following were prepared analogously (in each case n=1):























%







R2
A
NR3R4
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]
Mp. (°C.)
























AS7
A0
C4
crude product;
51

0.30
FM1







pure TFA


AS1
A0
C11

95
ESI: (M + H)+ =


(KBr): C═O







503/5/7 (Br2)


1676


AS4
A0
C20

100
ESI: (M + H)+ =







500/2/4 (Br2)


AS1
A0
C4

100
ESI: (M + H)+ =


(KBr): C═O







481/3/5 (Br2)


1678


AS4
A0
C11

74


AS7
A0
C1
reacted as
100





crude





product


AS4
A7
C1
reacted as
100

0.40
EE/MeOH





crude



7/3 v/v





product


AS1
A4
C1

64
ESI: (M + H)+ =
0.50
FM1
(KBr): C═O







745/7/9 (Br2)


1643.3; 1679.9


AS4
A0
C5

89

0.32
FM4
(KBr): C═O










1637.5


AS4
A0
C15

93

0.33
FM4
(KBr): C═O










1618.2


AS1
A0
C5

89

0.25
FM4
(KBr): C═O
154-157










1639.4


AS4
A0
C16
LC/SiO2/
90

0.30
FM4
(KBr): C═O





FM4




1635.5


AS1
A0
C15

89

0.20
FM4
(KBr): C═O
160-164










1639.4


AS4
A0
C3
LC/SiO2/
98

0.37
FM4
(KBr): C═O





FM4




1683.8;


AS4
A0
C6

89

0.28
FM4
(KBr): C═O










1637.5


AS1
A0
C16

95

0.57
FM1
(KBr): C═O










1683.8


AS1
A0
C6
LC/SiO2/
56
EI: M+ =
0.24
FM4
(KBr): C═O





FM4

511/3/5 (Br2)


1637.5


AS4
A0
C18

90
EI: M+ =
0.50
FM1
(KBr): C═O







512/4/6 (Br2)


1624.0


AS4
A0
C37

93

0.24
FM4
(KBr): C═O










1635.5; 1684


AS4
A0
C22

88
M+ =


(KBr): C═O







502/4/6 (Br2)


1618.2


AS4
A0
C21

52
M+ =
0.55
FM1
(KBr): C═O







482/4/6 (Br2)


1681.8


AS1
A0
C37

89

0.32
FM1
(KBr): C═O










1681.8


AS4
A5
C1

crude



(KBr): C═O










1645; 1676


AS4
A0
C23

88



(KBr): C═O










1643


AS4
A10
C1

47
ESI: (M + H)+ =


(KBr): C═O







553/5/7 (Br2)


1653


AS4
A5
C8

67
M+ = 543/5/7


(KBr): C═O










1645


AS4
A6
C1

59



(KBr): C═O










1643


AS4
A0
C24

94
M+ =


(KBr): C═O







489/91/93


1618; 1637.5


AS4
A6
C8

70



(KBr): C═O










1639.4


AS4
A10
C8

82
M+ = 557/9/61


(KBr): C═O










1651


AS4
A0
C26

88



(KBr): C═O










1626


AS1
A0
C1

96
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O







483/5/7 (Br2)


1680


AS1
A0
C8
crude
69


AS1
A0
C18

82

0.27
FM1
(KBr): C═O










1684


AS1
A0
C3

100

0.38
FM1
(KBr): C═O










1682


AS1
A0
C21

89

0.26
FM1
(KBr): C═O










1595; 1615


AS4
A0
C3

99

0.37
FM4
(KBr): C═O










1618; 1636;










1683


AS4
A0
C19

98
ESI: (M + H)+ =
0.47
FM4
(KBr): C═O







498/500/502 (Br2)


1638; 1682


AS9
A0
C1
Crude
96





product


AS1
A7
C1

37

0.42
FM7


AS4
A0
C38

80

0.25
FM1


AS4
A0
C37

86


AS4
A0
C39

73


AS4
A0
C40

92
EI: M+ = 515/7/9


(KBr): C═O










1674


AS1
A0
C42

100

0.32
FM1
(KBr): C═O






crude



1682


AS4
A0
C42

95

0.24
FM4
(KBr): C═O










1636/1684


AS1
A0
C43

66

0.1
FM7
(KBr): C═O










1659


AS1
A0
C44

59

0.15
CH2Cl2/
(KBr): C═O









MeOH/
1676









NH4OH









90/10/1


AS1
A0
C45

82
ESI: (M + H)+ =
0.10
EE/MeOH
(KBr): C═O







492/4/6 (Br2)

9/1
1678


AS1
A0
C47

89

0.52
FM7
(KBr): C═O










1634/1666


AS1
A0
C49

84

0.15
CH2Cl2/
(KBr): C═O









MeOH/
1678









NH4OH


AS4
A0
C44

93
EI: M+ =
0.45
EE/
(KBr): C═O







504/6/8 (Br2)

MeOH 9/1
1653; CN










2239


AS1
A0
C50

100
EI: M+ =
0.10
EE/
(KBr): C═O







498/500/502 (Br2)

MeOH 9/1
1636


AS1
A0
C51

100
EI: M+ =
0.05
EE/
(KBr): C═O







530/2/4 (Br2)

MeOH/
1678









NH4OH









5/5/0.1


AS4
A0
C52

97

0.15
FM1
(KBr): C═O










1620/1688


AS4
A0
C53

58
ESI: (M + H)M+ =
0.05
EE/MeOH/
(KBr): C═O







502/4/6 (Br2)

NH4OH 5/5/0.1
1678


AS4
A0
C64

100



(KBr): C═O










1647/1678


AS1
A0
C53

70
EI: M+ =
0.15
CH2Cl2/MeOH/
(KBr): C═O







502/4/6 (Br2)

NH4OH 70/30/1
1676


AS4
A0
C51

100

0.05
CH2Cl2/MeOH/
(KBr): C═O









NH4OH
1680


AS4
A0
C66

100

0.27
CH2Cl2/MeOH/









NH4OH


AS16
A0
C8

76

0.40
FM1


AS16
A0
C1

28

0.20
EE/MeOH/









NH4OH 9/1/1


AS4
A0
C70

96

0.20
EE/MeOH/
(KBr): C═O









NH4OH
1676









80/20/0.5


AS1
A0
C64

100
EI: M+ =


(KBr): C═O







510/1214


1674


AS1
A0
C70

100



(KBr): C═O










1674


AS4
A0
C72

100
ESI: (M + H)M+ =
0.10
CH2Cl2/MeOH/
(KBr): C═O







530/2/4 (Br2)

NH4OH 80/20/1
1678


AS19
A0
C8

100


AS35
A0
C8

72

0.60
FM1


AS36
A0
C8

80

0.52
FM1
(KBr): C═O










1674









EXAMPLE A33
4-(4-pyridinyl)-1-[3-(4-pyridinyl)-D,L-alanyl]-piperazine-hydrochloride
16.4 g (0.04 mol) of 1-[N-[(1,1-dimethylethoxy)carbonyl]-3-(4-pyridinyl)-D,L-alanyl]-4-(4-pyridinyl)-piperazine, dissolved in 100 ml of methanol, were mixed with 20 ml of ethereal hydrochloric acid and the reaction mixture was heated to 40° C. The desired compound crystallised out of the reaction mixture.
yield: 9.2 g (60% of theory)
Rf: 0.1 (FM1)
Mp.: 198-200° C.
EXAMPLE A34
Preparation of Compounds ofGeneralFormula:




1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
A mixture of 50 g (53.5 mmol) of 1-[N2—[N-(9-fluorenylmethoxycarbonyl)-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine and 300 ml of diethylamine was heated to 60° C. with stirring. 100 ml of methanol were added and stirring was continued for a further 5 hours at 60° C. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 26 g (68% of theory) of a white foam were obtained.
IR (KBr): 1641, 1691 cm−1 (C═O)
Rf: 0.2 (ethyl acetate/methanol/conc. aqueous ammonia=6/4/1 (v/v/v))
ESI-MS: (M+H)+=710/712/714 (Br2)
The following were prepared analogously:
























%






R2
A
NR3R4
n
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]
























AS1
A3
C4
1

85
ESI: M + H =
0.2
FM1
(KBr): C═O








710/2/4(Br2)


1635.5; 1695.3


AS1
A3
C8
1

98



(KBr): C═O











1635; 1705


AS1
A3
C1
1

68
EI:
0.2
ethyl
(KBr): C═O








M+ = 71 0/2/4

acetate/
1641.3; 1691.5








(Br2)

methanol/










NH4OH =










6/4/1










(v/v/v)


AS1
A3
C5
1
THF as solvent; purified by
56
ESI: M + H =
0.3
FM1
(KBR):C═O






column chromatography:

711/3/5(Br2)


1695.3; 1635.5






silica gel/FM1


AS1
A3
C6
1
THF as solvent; purified by
90
EI: M+ =
0.49
FM1
(KBr): C═O






column chromatography:

739/41/43


1695.3; 1629.8






silica gel/FM1

(Br2)


AS5
A3
C1
1
THF as solvent; purified by
93

0.25/
FM4
(KBr): C═O






column chromatography:


0.37

1705.0; 1643.3






silica gel/FM4;






diastereomers


AS10
A0
C1
1

71

0.5
FM1
(KBr): C═O











1641.3


AS1
A3
C18
1

94



(KBr): C═O











1647; 1722.5


AS10
A3
C1
1

49
M+ = 694/6/8


(KBr): C═O








(Br2)


1643; 1703


AS10
A3
C4
1

46
ESI: M + H =


(KBr): C═O








694/6/8 (Br2)


1639.4; 1705


AS10
A3
C4
1

46
ESI: M + H =


(KBr): C═O








694/6/8(Br2)


1639.4; 1705


AS10
A3
C1
1

49
M+ =


(KBr): C═O








694/68/70


1643; 1703








(Br2)


AS4
A3
C18
1

46
ESI: M + H =


(KBr): C═O








741/3/5 (Br2)


1641.3; 1705


AS15
A0
C8
1

100
M+: 321


(KBr): C═O











1637.5


AS12
A0
C8
1

81



(KBr): C═O











1630


AS10
A0
C4
1
THF as solvent
68

0.38
FM4
(KBr): C═O











1635.5


AS1
A3
C1
0
crude product
100

0.3
FM7









EXAMPLE A35
1-[N2—[N-[[[2-(2-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
To a solution of 1.0 g (1.34 mmol) of 1-[N2-(-3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine in 80 ml of tetrahydrofuran were added 0.28 g (1.6 mmol) of 2-methoxyphenethyl isocyanate and the mixture was stirred for 3 days at room temperature. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/ammonia=350/75/75/10 (v/v/v/v)). 0.5 g (40% of theory) of a colourless amorphous solid was obtained.
IR (KBr): 1639 cm1 (C═O)
Rf: 0.49 (FM1)
ESI-MS: (M+H)+=922/924/926 (Br2)
EXAMPLE A36
Preparation of Compounds ofGeneralFormula:




methyl 4-amino-3,5-dibromo-N2-[[(2-phenylethyl)amino]-carbonyl]-D-phenylalanine
A mixture of 1.27 g (7.73 mmol) of CDT in 150 ml of tetrahydrofuran was mixed, whilst cooling with ice, with 0.72 ml (5.15 mmol) of triethylamine and 2.0 g (5.15 mmol) of methyl-4-amino-3,5-dibromo-D-phenylalanine-hydrochloride, stirred for a further 30 minutes whilst cooling with ice and stirred for 1 hour at room temperature. Then 0.82 ml (6.44 mmol) of benzene ethanamine were added and the mixture was refluxed for 5 hours. The reaction mixture was evaporated down in vacuo, the residue was taken up in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. After drying the organic phase the solvent was removed in vacuo, the residue was stirred with ether and the precipitate was filtered off. 1.69 g (66% of theory) of an amorphous solid were obtained.
IR (KBr): 1632, 1732 cm−1 (C═O)
Rf: 0.63 (ethyl acetate)
ESI-MS: (M+H)+=498/500/502 (Br2)
The following were prepared in the same way (in each case n=1):




















%






RCO
R2
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]






















N6
AS1
further reacted
100

0.60
FM1





as crude product


N15
AS6
DMF/THF = 1/1
100
ESI:
0.65
FM1
(KBr): C═O




(v/v) as solvent

(M + H)+ = 517/9


1745.5; 1676.0






(Br)


N2
AS1

99

0.53
FM1
(KBr): C═O









1716.5


N8
AS4

66
ESI: (M + H)+ =
0.63
ethyl acetate
(KBr): C═O






498/500/502


1631.7; 1732.0






(Br2)


N15
AS4

92

0.85
ethyl acetate/
(KBr): C═O








methanol = 8/2
1620.1; 1737.8








(v/v)


N23
AS4

95
EI: M+ =
0.86
ethyl acetate/
(KBr): C═O






572/4/6/8

methanol = 8/2
1732.0; 1641.3






(Br2Cl)

(v/v)


N2
AS2

100
EI: M+ = 406
0.86
FM1
(KBr): C═O









1629.8; 1722.3;









1741.6


N15
AS1
DIEA
47

0.75
FM1


N15
AS3

38

0.60
t-butyl-
(KBr): C═O








methylether/
1695.5








petroleum ether =








9/1 (v/v)


N66
AS21

76

0.60
EE
(KBr): C═O









1662/1734


N66
AS1

100


N66
AS4

63

0.56
FM1


N122
AS1

95


N122
AS4

88


N66
AS17

22
ESI: (M + H)+ =
0.25
FM1
(KBr): C═O






623/5/7 (Br2)


1663/1740


N66
AS18

65

0.53
EE


N66
AS19

79

0.50
FM1
(KBr): C═O









1663/1734


N66
ASS

90
ESI: (M + H)+ =
0.78
FM1
(KBr): C═O






607/09/11 (Br2)


1637/1663/









1740


N66
AS22

68

0.74
FM1


N66
AS23

100



(KBr): C═O









1738/1662


N66
AS25

100
ESI: (M + H)+ =
0.52
FM1






472


N66
AS49

100

0.80
FM1









EXAMPLE A37
Preparation of Compounds ofGeneralFormula:




4-amino-3,5-dibromo-N2-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanine
To a solution of 2.8 g (4.9 mmol) of methyl 4-amino-3,5-dibromo-N2-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenyl-alanine in a mixture of 30 ml of methanol and 20 ml of water were added 0.25 g (10.0 mmol) of lithium hydroxide and the mixture was then stirred for 3 hours at room temperature. After the addition of 2.0 g (50 mmol) of sodium hydroxide the mixture was diluted with 50 ml of water. The reaction mixture was stirred for 15 minutes in an ultrasound bath, then stirred over-night at room temperature and evaporated down in vacuo. The residue was mixed with 100 ml of water and the aqueous phase was extracted twice with 50 ml of ether. By the addition of 2 M aqueous hydrochloric acid the aqueous phase was adjusted to a pH of 3-4 and extracted three times with ethyl acetate. The combined ethyl acetate phases were washed once with water, then dried and evaporated down in vacuo. 1.6 g (58% of theory) of a yellowish-brown oil were obtained.
IR (KBr): 1616, 1724 cm−1 (C═O)
Rf: 0.33 (ethyl acetate/methanol=8/2 (v/v))
ESI-MS: (M+H)+=557/559/561/563 (Br2, Cl)
The following were prepared in the same way (in each case n=1):






















%






RCO
Z
R2
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]























N8
N—H
AS4

62
ESI: (M − H)− =
0.61
Ethyl acetate/
(KBr): C═O







482/4/6 (Br2)

methanol = 6/4
1612.4;









(v/v)
1724.3; —OH,










—NH— 3386.8;










3483.2


N15
N—H
AS4

64
ESI: (M − H)− =
0.10
Ethyl acetate/
(KBr): C═O







578/80/82

methanol = 8/2
1703.0







(Br2); (M + H)+ =

(v/v)







580/2/4 (Br2);







(M + Na)+ =







602/4/6 (Br2)


N23
N—H
AS4

58
ESI: (M − H)− =
0.33
Ethyl acetate/
(KBr): C═O







557/59/61/63

methanol = 8/2
1616.3;







(Br2, Cl)

(v/v)
1724.3


N15
N—H
AS1
No addition
59
ESI: (M − H)− =
0.72
EE/MeOH/
(KBr): C═O





of sodium

579/81/83 (Br2)

NH4OH = 6/4/1
1695.3





hydroxide



(v/v/v)


N66
N—H
AS21

95

0.48
EE/AcOH
(KBr): C═O









10/0.02 (v/v)
1639


N66
CH2
AS1

85

0.38
CH2Cl2/MeOH/









AcOH 9/1/0.15









(v/v/v)


N71
CH2
AS1

66.6
ESI: (M + H)+ =
0.38
CH2Cl2/MeOH/
(KBr): C═O







606/08/10 (Br2)

AcOH 9/1/0.15
1622/1680









(v/v/v)


N66
N—H
AS18

100
ESI: (M − H)− =
0.26
EE/AcOH 9/0.01







557

(v/v)


N66
N—H
AS19

98

0.22
CH2Cl2/MeOH/
(KBr): C═O









AcOH 9/1/0.15
1665/1740









(v/v/v)


N66
N—H
ASS

73
ESI: (M − H)− =
0.23
FM1
(KBr): C═O







577/79/81 (Br2)


1632/1705


N66
N—H
AS22

78

0.30
FM1
(KBr): C═O










1668/1739


N66
CH2
AS21

79

0.34
EE/AcOH 9/0.01
(KBr): C═O









(v/v)
1643/1703


N66
CH2
AS1

90

0.30
EE/MeOH 9/1









(v/v)


N15
CH2
AS1

78
ESI: (M − H)− =
0.30
EE/AcOH 9/0.01
(KBr): C═O







578/80/82 (Br2)

(v/v)
1728/1672


N66
N—H
AS25

99


N66
CH2
AS2

100



(KBr): C═O










1645/1712


N66
CH2
AS23

70


N139
CH2
AS2

50



(KBr): C═O










1630/1662/










1707


N66
CH2
AS27

93

0.20
FM1


N66
CH2
AS28
LiOH
100

0.30
FM1


N66
CH2
AS4

72

0.53
FM1
(KBr): C═O










1639/1701


N66
CH2
AS36

74
ESI: (M − H)− =
0.36
FM1
(KBr): C═O







434


1645/1701


N66
CH2
AS38

69


N66
CH2
AS48

47
EI: M+ =
0.30
FM1
(KBr): C═O







489


1645


N66
N—H
AS49

47

0.10
FM1


N66
CH2
AS18

60

0.15
EE


N66
CH2
AS39

96


N109
CH2
AS21

81


N113
CH2
AS21

76

0.20
EE/AcOH









99/1


N134
CH2
AS21

89

0.15
EE/AcOH









99/1


N66
CH2
AS47

100
ESI: (M + H)+ =


(KBr): C═O







476


1645/1716


N66
CH2
AS7

60

0.20
FM1
(KBr): C═O










1649/1722


N66
CH2
AS52

95
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O







480


1643/1722









EXAMPLE A38
Preparation of Compounds ofGeneralFormula:




3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine
A mixture of 24 g (46.3 mmol) of methyl 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine and 5.0 g (50 mmol) of lithium hydroxide in 200 ml of water was stirred for 1 hour at 60 C. The solid product was suction filtered and the filtrate was washed with 200 ml of ethyl acetate. By the addition of 1 M aqueous hydrochloric acid the aqueous phase was adjusted to a pH of 3-4 and extracted 3 times with 150 ml of ethyl acetate. The combined ethyl acetate phases were washed once with water, dried over sodium sulphate and evaporated down in vacuo. The residue was triturated with ether. 9.1 g (38% of theory) of a colourless solid were obtained.
IR (KBr): 1719 cm−1 (C═O)
Rf: 0.57 (ethyl acetate/methanol/glacial acetic acid=9.5/0.5/0.2 (v/v/v))
The following were prepared in the same way (in each case n=1):






















%






RCO
Z
R2
Remarks
Yield
MS
R1
Eluant
IR [cm−1]























N6
N—H
AS1

100

0.20
FM1
(KBr): C═O










1625.9; 1730


N15
N—H
AS6
H2O/MeOH =
85
ESI:
0.53
EE/MeOH/
(KBr): C═O





1/1 (v/v) as

(M − H)− =

AcOH = 9/1/0.1
1695.3





solvent

501/3 (Br)

(v/v/v)


N2
N—H
AS1

75

0.57
EE/methanol/
(KBr): C═O









glacial acetic
1718.5









acid = 9.5/0.5/0.2









(v/v/v)


N2
N—H
AS2

71

0.20
FM1
(KBr): C═O










1625.9;










1693.4;










1718.5; —NH—










3357.9


N15
N—H
AS3
H2O/MeOH =
57

0.30
EE/MeOH = 1/1
(KBr): C═O





1/1 (v/v) as



(v/v)
1693.4





solvent


N66

AS1

75

0.05
EE/MeOH 8/2


N66

AS4

85


N122

AS1

44


N122

AS4

85


N66
N—CH3
AS1

58
ESI: (M − H)− =
0.20
EE
(KBr): C═O







607/09/11 (Br2)


1607/1655/










1711


N66
N—H
AS17

55

0.03
FM1


N15
CH2
AS1

78
ESI: (M − H)− =
0.30
EE/MeOH 9/1
(KBr): C═O







578/80/82 (Br2)

(v/v)
1672/1728


N66
N—H
AS23

79.0

0.22
FM1
(KBr): C═O










1738/1664









EXAMPLE A39
methyl N6-[(1,1-dimethylethoxy)carbonyl]-N2—[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine
To a mixture of 10 g (19.4 mmol) of 3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosine, 2.6 g (20 mmol) of DIEA, 6.4 g (20 mmol) of TBTU, 2.64 g (19.5 mmol) of HOBt and 200 ml of dimethylformamide was added dropwise, with stirring, a solution of 5.04 g (19.4 mmol) of H-Lys(Boc)-OMe in 50 ml of dimethylformamide and the mixture was stirred over-night at room temperature. The reaction mixture was evaporated down in vacuo and the residue was taken up in 250 ml of ethyl acetate. The ethyl acetate phase was then washed twice with 100 ml of saturated aqueous sodium hydrogen carbonate solution, once with 100 ml of 20% aqueous citric acid solution and finally once with 100 ml of saturated aqueous saline solution. The organic phase was dried with sodium sulphate, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/petroleum ether=2/1 (v/v)). After removal of the solvent in vacuo the residue was triturated with ether, the amorphous solid obtained (9.5 g; 660 of theory) was suction filtered and dried.
















IR (KBr):
1632, 1657, 1682, 1734 cm−1 (C═0)



Rf:
0.64 (ethyl acetate)











ESI-MS:
(M + H)+ =
757/759/761 (Br2)




(M + Na)+ =
779/781/783 (Br2)










EXAMPLE A40
N6-[(1,1-dimethylethoxy)carbonyl]-N2—[N-[[(2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-n-tyrosyl]-L-lysine
A mixture of 7.75 g (10.4 mmol) of methyl N6-[(1,1-dimethyl-ethoxy)carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine, 3.5 g (140 mmol) of lithium hydroxide and 150 ml of water was stirred overnight at room temperature. The aqueous phase was washed once with ethyl acetate, acidified by the addition of 1 M aqueous potassium hydrogen sulphate solution and then extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated down in vacuo. 6.9 g (910 of theory) of a yellowish oil were obtained.
IR (KBr): 1653 cm−1 (C═O)
Rf: 0.7 (ethyl acetate/methanol/glacial acetic acid=9/0.5/0.5 (v/v/v))
ESI-MS (M-H)−=741/743/745 (Br2)
EXAMPLE A41
1-[N2—[N-(phenylmethoxycarbonyl)-3,5-dichloro-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
A mixture of 5 g (13.0 mmol) of 3,5-dichloro-N-[(phenylmethoxy)carbonyl]-D-tyrosine, 5.1 g (13.0 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 1.81 g (14 mmol) of DIEA, 4.17 g (13 mmol) of TBTU, 1.75 g (13.0 mmol) of HOBt and 200 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction mixture was evaporated down in vacuo, the residue was taken up in ethyl acetate/methanol (95/5) and washed twice with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=6/4 (v/v)). 6.0 g (61% of theory) of a yellowish oil were obtained.
Rf: 0.47 (FM1)
ESI-MS (M+H)+=757/759/761 (Cl2)
EXAMPLE A42
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethylethoxy)-carbonyl]-L-lysyl]-4-(1-methyl-4 -]piperidinyl)-piperazine
To a mixture of 1.1 g (1.5 mmol) of N6-[(dimethylethoxy)-carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine, 0.79 g (6.1 mmol) of DIEA, 0.52 g (1.6 mmol) of TBTU, 0.2 g (1.5 mmol) of HOBt and 100 ml of dimethylformamide was added dropwise a solution of 0.44 g (1.5 mmol) of 1-(1-methyl-4-piperidinyl)-piperazine in 30 ml of dimethylformamide at room temperature, the mixture was then stirred overnight and evaporated down in vacuo. The residue was taken up in ethyl acetate/methanol (95/5), washed twice with 70 ml of aqueous saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. 1.1 g (81% of theory) of a colourless foam were obtained.

    Rf: 0.34 (ethyl acetate/methanol/conc. aqueous ammonia 7/2/1 (v/v/v))


The following was prepared analogously (n=1)























%





RCO
R2
A
NR3R4
Remarks
Yield
Rf
Eluant
IR [cm−1]







N15
AS1
A11
C1
KHSO4 solution
70
0.40
FM3
(KBr): C═O










1697.3; 1641.3









EXAMPLE A43
1-[N2-(3,5-dichloro-D-tyrosyl)-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
A solution of 6 g (7.9 mmol) of 1-[N2—[N-[(phenylmethoxy)carbonyl]-3,5-dichloro-D-tyrosyl]-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in a mixture of 200 ml of methanol and 20 ml of aqueous 1 M potassium hydrogen sulphate solution was hydrogenated in the presence of 0.5 g palladium black as catalyst at room temperature under 3 bar of hydrogen pressure for 40 minutes. The catalyst was filtered off, the reaction mixture was evaporated to dryness in vacuo and the residue adjusted to a pH of about 10 by the addition of 2 ml of concentrated aqueous ammonia solution. The product was extracted several times with isopropanol, the combined isopropanol extracts were evaporated down in vacuo and the residue was purified by column chromatography (LiChroprep, Si60 particle size: 20-40 μm, Messrs. Merck (Darmstadt); eluant: methylene chloride/methanol/ammonia=350/75/75/10 (v/v/v/v)). 2.5 g (51% of theory) of a colourless amorphous solid substance were obtained.
IR (KBr): 1641, 1705 cm−1 (C═O)
Rf: 0.27 (FM1)
EXAMPLE A44
Preparation of Compounds ofGeneralFormula:

Fmoc-A-NR3R4 

1-[N2-[(9-fluorenylmethoxy)carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine
To a mixture of 7.0 g (10.6 mmol) of Fmoc-Arg(Pmc)-OH, 1.42 g (11.0 mmol) of DIEA, 3.53 g (11.0 mmol) of TBTU, 1.35 g (11.0 mmol) of HOBt and 50 ml of DMF was added dropwise with stirring a solution of 1.74 g (10.6 mmol) of 1-(4-pyridinyl)-piperazine in 20 ml of DMF. The reaction mixture was stirred for a further 3.5 hours at room temperature and then evaporated down at 40° C. in a high vacuum. The residue was dissolved in ethyl acetate, the organic phase was washed twice with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated down in vacuo. The residue was triturated with diethylether, suction filtered and dried. 7.85 g (96% of theory) of the desired end product were obtained, which was reacted without further purification.
Rf: 0.5 (FM1)
The following was prepared analogously:




















%






A
NR3R4
Yield
Rf
Eluant
IR [cm−1]









A3
C18
60
0.55
FM4
(KBr): C═O








1643; 1711










EXAMPLE A45
Preparation of compounds of general formula:

H-A-NR3R4 

1-[NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl )-piperazine
A solution of 8.5 g (11.1 mmol) of 1-[N2-[(9-fluorenylmethoxy)carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-L-arginyl]-4-(4-pyridinyl)-piperazine in 100 ml of THF was mixed with 16 ml of diethylamine and then stirred for 2.5 hours at room temperature. The reaction mixture was evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: FM1). 3.3 g (54% of theory) of an amorphous solid were obtained.
Rf:=0.19(FM1)
IR(KBr): 1637 cm−1 (C═O)
The following was prepared analogously:




















%






A
NR3R4
Yield
Rf
Eluant
IR [cm−1]









A3
C18
80


(KBr): C═O








1637.5; 1705










EXAMPLE A46
1-[N6,N6-dimethyl-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
9.6 g (18.3 mmol) of 1-[N6-[(1,1-dimethylethoxy)carbonyl]-N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were stirred overnight in 200 ml of a 5% solution of trifluoroacetic acid in dichloromethane. The reaction mixture was then evaporated down in vacuo. 13.47 g (97% of theory) of the desired 1-[N2-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine were obtained as the trifluoroacetate salt. Then 7.0 g (9.1 mmol) of the crude product were dissolved in 200 ml of water and 4.1 ml of a 40% formaldehyde solution (45.6 mmol) were added whilst cooling with an ice bath. The reaction mixture was stirred for 10 minutes at room temperature, carefully mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath, then mixed with 4.1 ml of a 40% formaldehyde solution (45.6 mmol) whilst cooling externally with ice, after which the reaction mixture was stirred for a further 10 minutes at room temperature and again mixed with 1.5 g (40 mmol) of sodium borohydride whilst cooling with an ice bath. The pH of the reaction mixture was monitored continuously during the reaction and kept between pH 3 and pH 6 by dropwise addition of trifluoroacetic acid. The mixture was then stirred for 30 minutes at 5° C., adjusted to pH 10 by the addition of potassium carbonate and extracted four times with 50 ml of ethyl acetate. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol/conc. aqueous ammonia=6.5/3/0.3 (v/v/v)). 2.3 g (56% of theory) of a colourless oil were obtained.
IR (KBr): 1711, 1649 cm−1 (C═O)
Rf: 0.2 (FM7)
ESI-MS: (M+H)+=454.
EXAMPLE A47
Preparation of compounds of general formula:




methyl (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoate
A mixture of 10 g (27 mmol) of methyl 4-amino-3,5-dibromo-γ-oxo-benzenebutanoate, 5.4 g (27 mmol) of 4-(4-pyridinyl)-piperidine and 1.5 g (45 mmol) of paraformaldehyde was suspended in 20 ml of glacial acetic acid and heated with stirring in an oil bath (bath temperature: 100° C.). After 3 hours a further 1.5 g (45 mmol) of paraformaldehyde were added and the mixture was stirred for a further 3 hours at 100° C. and then for 1 hour at 125° C. The solvent was removed in vacuo and the residue was taken up in 800 ml of water. The aqueous phase was made alkaline by the addition of sodium carbonate and extracted twice with 500 ml of ethyl acetate. The combined ethyl acetate extracts were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey Nagel, 70-230 mesh ASTM, eluant: ethyl acetate/methanol=9:1)). 1.0 g (6.8% of theory) of the desired end product were obtained as an oil.
IR(KBr): 1716.5 cm−1 
Rf: 0.7 (FM1)
The following was prepared analogously:

















%





A
NR3R4
Yield
Rf
Eluant
IR [cm−1]







AS4
C8
35
0.68
FM1
KBr: C═O







1672.2; 1733.9









EXAMPLE A48
Preparation of compounds of general formula:




(R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoic acid
A mixture of 1.0 g (1.9 mmol) of methyl (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-phenyl-butanoate, 5 ml of 1 N sodium hydroxide solution and 50 ml of dioxane was stirred overnight at room temperature and for 1 hour at 60° C. The reaction mixture was then neutralised by the addition of 5 ml of 1N hydrochloric acid, evaporated down in vacuo and the residue was dried in a vacuum drying chamber. 0.97 g (100% of theory) of the desired product was obtained, which was further reacted without any purification.
Rf: 0.15 (FM1)
The following was prepared analogously:




















%






A
NR3R4
Yield
Rf
Eluant
IR [cm−1]









AS4
C8
96
0.2
FM1
KBr: C═O








1660










EXAMPLE A49
3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenitannic acid
To a solution of 12 g (0.043 mol) of 4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 200 ml of acetic acid were added 150 ml of water and 8 g of sodium acetate, a solution of 5 ml of bromine in 60 ml of acetic acid was added dropwise with stirring, then the reaction mixture was extensively evaporated down in vacuo and the residue was stirred into water. The aqueous phase was repeatedly extracted with ethyl acetate, and the combined organic phases were washed with water. The organic extracts were dried, evaporated down in vacuo and the solid residue was recrystallised from diisopropylether. 12 g (70% of theory) of the desired end product were obtained.
Rf: 0.4 (ethyl acetate/petroleum ether/glacial acetic acid=5/5/0.4 (v/v/v)
ESI-MS: (M+H)+=394/6/8 (Br2)
EXAMPLE A50
Preparation of compounds of general formula:




methyl (R,S)-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-4-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]-4-oxo-butanoate
A solution of 2.0 g (5 mmol) of 3,5-dibromo-4-hydroxy-β-(methoxycarbonyl)-benzenebutanoic acid in 80 ml of THF was mixed with 1.6 g (5 mmol) of TBTU, 0.76 g (5 mmol) of HOBt, 1.25 g (5 mmol) of 4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidine and 1.03 g (8 mmol) of DIEA with stirring. The reaction mixture was stirred for 6 hours at room temperature and then evaporated down in vacuo. The residue was mixed with saturated aqueous sodium hydrogen carbonate solution and extracted several times with ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated down in vacuo. 3.0 g (50% of theory) of the desired product was obtained, which was further reacted without purification.
IR (KBr): 1714.8 cm−1 (C═O)
Rf: 0.7 (ethyl acetate/petroleum ether=7/3 (v/v))
The following were prepared analogously:


















%






RCO
R2
Yield
MS
Rf
Eluant
IR [cm−1]





















N66
AS1
98

0.66
FM1



N66
AS2
100

0.77
FM1
(KBr): C═O








1664/1734


N139
AS2
100
EI: M+ =
0.30
FM1
(KBr): C═O





486


1643/1672/








1732


N66
AS4
28
EI: M+ =
0.33
FM4
(KBr): C═O





606/08/10


1666/1734





(Br2)


N66
AS36
63

0.56
FM4


N66
AS38
92


N66
AS48
100

0.68
FM1


N66
AS18
22


N66
AS39
100


N109
AS21
39

0.35
EE
(KBr): C═O








1639/1734


N113
AS21
57

0.15
EE/PE 95/5


N134
AS21
80

0.15
EE


N66
AS7
100

0.75
FM1


N66
AS53
40









EXAMPLE A51
(R)-1-[2-amino-3-(3,5-dibromo-4-hydroxyphenyl)propyl]-4-(1-piperidinyl)-piperidine
To a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 400 ml of THF were added in batches, with stirring and at room temperature, 14.4 g (20 mmol) of 1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine within 30 minutes. The reaction mixture was kept for 30 minutes at room temperature and refluxed for 2 hours and then neutralised by the careful addition of 1 ml of water and 5.1 ml of concentrated aqueous hydrochloric acid. After the addition of 100 ml of methanol the solid precipitate was suction filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 5.4 g (57% of theory) of the desired product was obtained as an amorphous solid.
IR (KBr): 3420 cm−1 (NH2)
Rf: 0.4 (FM2)
ESI-MS: M+=473/475/477 (Br2)
The following was prepared analogously:
(R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-(1-piperidinyl)-piperidine from 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(1-piperidinyl)-piperidine in a yield of 56.5% of theory, Rf 0.12 (eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 7/1.5/1.5/0.2 (v/v/v/v)).
EXAMPLE A52
(R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propyl]-4-(1-piperidinyl)-piperidine
To a solution of 10 g (0.017 mol) of 1-[4-amino-3,5-dibromo-N-[(1,1-dimethylethoxy)carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in 350 ml of dioxane were added 3.1 g (0.082 mol) of sodium borohydride and the reaction mixture was cooled to 5° C. Then a solution of 4.92 g (0.082 mol) of acetic acid in 100 ml of dioxane was added dropwise with stirring. The reaction mixture was stirred for a further hour at room temperature and for 3 hours at 85° C. Then ice water was added, the organic solvent was removed in vacuo and the aqueous residue was repeatedly extracted with methylene chloride. The combined organic phases were dried, evaporated down in vacuo and the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/methanol/cyclohexane/conc. aqueous ammonia=3600/150/150/20 (v/v/v/v). 4.1 g (42% of theory) of a colourless foam were obtained.
IR (KBr): 1705 cm−1 (C═O)
EXAMPLE A53
(R)-1-[2-amino-3-(4-amino-3,5-dibromophenyl)propyl]-4-(1-piperidinyl)-piperidine
To a mixture of 4 g (7 mmol) of (R)-1-[3-(4-amino-3,5-dibromophenyl)-2-[N-[(1,1-dimethylethoxy)carbonyl]-amino]propyl]-4-(1-piperidinyl)-piperidine and 100 ml of methylene chloride, 40 ml of trifluoroacetic acid were slowly added dropwise, with stirring, at 10° C. The reaction mixture was stirred for 2 hours at room temperature and then evaporated down in vacuo. The residue was mixed with ice water, made basic by the addition of concentrated aqueous ammonia solution and extracted three times with 200 ml of diethylether. The combined ether extracts were dried and evaporated down in vacuo. 3.4 g (100% of theory) of an amorphous solid were obtained.
IR (KBr): 1683.8, 1616.3 (C═O)
Rf: 0.02(FM 4)
EXAMPLE A54
methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)phenyl]-methyl]-butannate
Prepared analogously to Example A15a) from methyl (R,S)-3-carboxy-2-[[3-(trifluoromethyl)phenyl]methyl]-propanoate and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 27.3% of theory. Colourless, amorphous substance, Rf=0.25 (eluant: ethyl acetate).
MS: M+=503
The following was obtained in the same way:
methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoate from methyl (R,S)-3-carboxy-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-propanoate and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a yield of 98% of theory, Rf=0.66 (eluant: dichloromethane/cyclohexane/methanol/conc. ammonia 7/1.5/1.5/0.2 (v/v/v/v)).
EXAMPLE A55
(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoic acid
A mixture of 3.0 g (4.92 mmol) of methyl (R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[(3,5-dibromo-4-hydroxyphenyl)methyl]-butanoate, 30 ml (30 mmol) of 1N sodium hydroxide solution and 20 ml of methanol was stirred for 3 hours at room temperature, then diluted with 100 ml of water and 30 ml of 1N hydrochloric acid were added dropwise. The precipitate was suction filtered and dried at 50° C. in a circulating air drier. Colourless, amorphous substance , Rf=0.38 (eluant: dichloromethane/methanol/glacial acetic acid 9/1/0.15 (v/v/v)). Yield: 2.5 g (85.4% of theory).
The following was obtained in the same way:
(R,S)-4-[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)phenyl]methyl]-butanoic acid from methyl(R,S)-4-[4-[3,4-dihydro-2(1H)-oxo-quinazolin-3-yl]-1-piperidinyl]-4-oxo-2-[[3-(trifluoromethyl)-phenyl]methyl]-butanoate in a yield of 79% of theory, Rf=0.34 (eluant: ethyl acetate/glacial acetic acid 99.8/0.2 (v/v)).
IR(KBr): 1703, 1643 cm−1 (C═O)
EXAMPLE A56
Methyl 3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosine
a) 1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-yl]piperidine
To a mixture of 7.0 ml (about 14 mmol) of a 20% solution of phosgene in toluene and 2.02 g (20 mmol) of triethylamine in 300 ml of tetrahydrofuran was added in batches, while maintaining a reaction temperature of about 0° C., a suspension of 1.5 g (5.60 mmol) of 4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine-hydrochloride in 100 ml of tetrahydrofuran. The mixture was stirred for another hour at a temperature between 0° C. and +5° C., filtered to remove the resulting triethylamine-hydrochloride and the filtrate was freed from solvent. The residue was triturated with diisopropyl ether and suction filtered. After drying in vacuo 0.7 g (42.6% of theory) of colourless crystals were obtained, Rf=0.17 (eluant: dichloromethane/acetone 9.5/0.5 (v/v)), which was further processed without any further purification.
b) Methyl 3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-N-methyl-D-tyrosine
To a solution of 4.9 g ( 13.3 mmol) of methyl 3,5-dibromo-N-methyl-D-tyrosine and 4.04 g (40 mmol) of triethylamine in 500 ml of tetrahydrofuran was added dropwise, at room temperature, within 3 hours, a solution of 3.92 g (13.34 mmol) of 1-(chlorocarbonyl)-4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]piperidine in 1 l tetrahydrofuran. The mixture was then heated for 12 hours to reflux temperature, left to cool and filtered to remove the precipitated triethylamine. The filtrate was evaporated down, the residue was divided between ethyl acetate and 20% aqueous citric acid. The organic phase was dried over sodium sulphate, again evaporated down in vacuo, the residue was purified by column chromatography over silica gel using ethyl acetate/petroleum ether 9/1 (v/v) as eluant. Working up the appropriate fractions yielded 3.2 g (38.5% of theory) of a colourless, amorphous substance, Rf=0.45 (eluant: ethyl acetate)
















IR (KBr):
1739.7, 1660.6 cm−1 (C═O)



ESI-MS:
(M + H)+ = 623/625/627 (Br2)




(M + Na)+ = 0 645/647/649 (Br2)




(M + K)+ = 661/663/665 (Br2)










EXAMPLE A57
Methyl 3,5-dibromo-4-methoxy-D-phenylalanine
To a mixture of 5.5 g (14.12 mmol) of 3,5-dibromo-4-methoxy-D-phenylalanine-hydrochloride and 55 ml of methanol were added 150 ml of a saturated methanolic hydrogen chloride solution and the mixture was stirred for 20 hours at room temperature. The residue remaining after evaporation of the solvent was stirred with 50 ml of water and adjusted to pH 8 with saturated sodium hydrogen carbonate solution. The precipitate was suction filtered, stirred with 10 ml of isopropanol and left to stand overnight. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. The residue was further reacted as a crude product. Yield: 1.0 g (28.7% of theory) of a colourless oil , Rf=0.55 (eluant:dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia=300/80/25/25/3 (v/v/v/v/v)).
EXAMPLE A58
1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)-piperazine
a) 1-(2-chloro-4-pyrimidinyl )-4-(phenylmethyl)piperazine
A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml of water and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heated to 40° C. for 2 hours in an ultrasound bath. After cooling the mixture was made alkaline with potassium carbonate and extracted thoroughly with ethyl acetate. The crude product obtained after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriate fractions yielded 7.4 g (38.6% of theory) of a colourless oil, Rf=0.51 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
MS: M+=288/290 (Cl)
b) 1-(4-pyrimidinyl)piperazine
A solution of 7.4 g (0.0256 mol) of 1-(2-chloro-4-pyrimidinyl)-4-(phenylmethyl)piperazine in 100 ml of ethanol was hydrogenated in the presence of 2 g of 10% palladium/charcoal for 4 hours at 40° C. under 5 bar of hydrogen pressure. The crude product obtained after conventional working up was purified by column chromatography over silica gel (30-60 μm) using FM1/cyclohexane 9/1 (v/v) as eluant. Colourless crystals, Rf=0.3 (FM1/cyclohexane 9/1 (v/v)); Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC). Yield: 1.7 g (40.7% of theory).
c) 1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine
Prepared analogously to Example A15a) from 4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanine and 1-(4-pyrimidinyl)piperazine in the presence of TBTU in a yield of 92% of theory. Colourless, amorphous substance, Rf=0.42 (FM4; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
IR(KBr): 1705.0, 1643.3 cm−1 (C═O)
MS: M+=582/584/586 (Br2)
d) 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine
Prepared analogously to Example A1b) from 1-[4-amino-3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-phenylalanyl)-4-(4-pyrimidinyl)piperazine in a yield of 52% of theory. Colourless, amorphous substance, Rf=0.55 (FM1; Macherey-Nagel POLYGRAM® SIL G/UV254, ready-made films for TLC).
IR(KBr): 1681.8 cm−1 (C═O)
MS: M+=482/484/486 (Br2)
EXAMPLE A59
Preparation of Compounds ofGeneralFormula:




(R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimpthylathyl)phenyl]methyl]-4-oxobutanoic acid
A mixture of 4.8 g (8.3 mMol) of ethyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)-phenyl]methyl]-2-(ethoxycarbonyl)-4-oxobutanoate, 200 ml of ethanol and 41.5 ml of 1N sodium hydroxide solution was refluxed for 3 hours.
The ethanol was removed in vacuo, then the residue was diluted with 50 ml of water and adjusted to pH 3 with 1N aqueous hydrochloric acid. The precipitated substance was suction filtered, thoroughly washed with water and then dried in vacuo. 3.8 g (96w of theory) of colourless crystals of Mp. 139  141° C. were obtained, Rf=0.65 (eluant:EE/MeOH/glacial acetic acid 90/10/1 v/v/v).
IR(KBr): 1724, 1647 cm−1 (C═O)
MS: no M+, m/e=246, 231, 147
The following were prepared analogously:


















%






R2
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]





















AS29

100






AS16

17
ESI: (M + H)+ =
0.30
EE/MeOH/





488/90/92 (Cl2)

AcOH 80/10/1


ASS

62

0.60
CH2Cl2/MeOH/







NH4OH 90/10/1


AS32

100
ESI: (M + Na)+ =
0.67
EE/MeOH/
(KBr): C═O





614/6/8 (Br2)

AcOH 90/10/1
1645/1728


AS33

90
EI: M+ = 525
0.20
EE/MeOH/
(KBr): C═O







AcOH 90/10/1
1643/1701


AS31

100

0.20
CH2Cl2/MeOH/







NH4OH 80/20/1


AS17

100
ESI: (M + H)+ =
0.50
EE/MeOH/
(KBr): C═O





608/10/12 (Br2)

AcOH 90/10/1
1643


AS34

76
ESI: (M − H)− =
0.65
EE/MeOH/





506

AcOH 90/10/1


AS19

70

0.46
EE/MeOH/
(KBr): C═O







AcOH 9/1/0.5
1643/1701


AS46

78
ESI: (M − H)− =
0.20
FM1
(KBr): C═O





471


1647


AS50

97

0.05
EE


AS2
LiOH instead
86
ESI: (M + H)+ =


(KBr): C═O



of NaOH

472


1643/1705


AS29

100
ESI: (M − H)− =


(KBr): C═O





448


1645/1705


AS31

87









EXAMPLE A60
Preparation of Compounds ofGeneralFormula:




Ethyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[4-(1,1-dimethylethyl)phenyl]methyl]-2-(ethoxy-carbonyl)-4-oxobutanoate
A mixture of 2.31 g (10 mMol) of 4-(3,4-dihydro-2(1H)-oxo-quinazolin-3-yl)-piperidine, 3.64 g (10 mMol) of β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid, 5 ml of triethylamine, 3.5 g (11 mMol) of TBTU, 200 ml of tetrahydrofuran and 20 ml dimethylformamide was stirred for 5 hours at room temperature. The solvent was removed in vacuo and the residue taken up in dichloromethane, the resulting solution was dried over sodium sulphate and freed from the solvent. After purification by column chromatography on 400 g of silica gel (Amicon, 35-70 μm, ethyl acetate as eluant), 4.8 g (83% of theory) of a colourless, amorphous substance were obtained, Rf=0.63 (eluant:EE).
IR(KBr): 1734, 1668, 1653 cm−1 (C═O)
MS: M+=577 (Br2)
The following were prepared analogously:















R2
% Yield
MS
Rf
Eluant
IR [cm−1]







AS29
75

0.8
FM1



AS16
59

0.5
EE


AS5
65
EI: M+ =
0.7
FM4
(KBr): C═O




677/79/81


1649/1668/




(Br2)


1734


AS32
74

0.5
FM4
(KBr): C═O







1647/1668/







1734


AS33
85

0.5
EE
(KBr): C═O







1649/1734


AS31
82
EI: M+ = 574
0.5
CH2Cl2/MeOH/
(KBr): C═O






NH4OH 90/10/1
1658/1741


AS17
93
EI: M+ =
0.5
EE
(KBr): C═O




707/09/11


1645/1666/




(Br2)


1736/1759


AS34
75
EI: M+ = 607
0.8
EE
(KBr): C═O







1649/1668/







1736


AS19
67

0.8
FM1
(KBr): C═O







1647/1668/







1734


AS46
80
EI: M+ = 572
0.8
FM1
(KBr): C═O







1737


AS50
78
EI: M+ =
0.6
EE
(KBr): C═O




677/9/81 (Br2)


1645/1666/







1730


AS2
51









EXAMPLE A61
Preparation of Compounds ofGeneralFormula:




β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoic acid
Produced analogously to Example A1b) from tert.-butyl β,β-bis-(ethoxycarbonyl)-1-methyl-1H-indol-3-butanoate through the action of trifluoroacetic acid in dichloromethane in a yield of 63.5% of theory. Colourless crystals of Mp. 127-130° C. (diisopropylether).
IR(KBr): 1738, 1712 cm−(C═O)
The following were prepared analogously:















R2
% Yield
MS
Rf
Eluant
IR [cm−1]




















AS29
100






AS16
100

0.7
EE/MeOH/






AcOH






97.5/2.2/0.25


AS5
100

0.5
PE/EE 2/1


AS32
100

0.58
PE/EE 2/1
(KBr): C═O







1759/1711


AS33
100



(KBr): C═O







1736


AS17
52



(KBr): C═O







1707/1726/







1755


AS34
90

0.8
EE/MeOH/
(KBr): C═O






AcOH
1705/1743






97.5/2.5/0.25


AS19
100

0.76
PE/EE/
(KBr): C═O






AcOH 6/3/1
1738


AS46
92

0.35
FM1
(KBr): C═O







1732


AS50
71



(KBr): C═O







1712/1734/







1759


AS2
31
EI: M+ = 272
0.42
PE/EE/
(KBr): C═O






AcOH 6/4/0.2
1711/1734









EXAMPLE A62
Preparation of Compounds ofGeneralFormula:




Tert.-butyl β,β-bis-(ethoxycarbonyl)-3,5-dimethylbenzene-butanoate
To a solution of 13.8 g (50.2 mMol) of diethyl [(1,1-dimethyl-ethoxycarbonyl)methyl]-malonoate in 400 ml of anhydrous tetrahydrofuran, 2.3 g (52.7 mMol) of sodium hydride was added whilst being externally cooled with iced water. After stirring for 30 minutes, and maintaining a reaction temperature of 0 to +5° C., the solution of 10.0 g (50.2 mMol) of 3,5-dimethylbenzylbromide in 80 ml tetrahydrofuran was added dropwise and the mixture allowed to warm to room temperature within 14 hours. The reaction mixture was freed from the solvent in vacuo, 200 ml of 10% citric acid was added to the residue and the resulting mixture was thoroughly extracted with ethyl acetate. After the usual working up, the combined extracts yielded 19.7 g (100% of theory) of a colourless oil of Rf=0.67 (eluant:dichloromethane), which was used in the following steps without further purification.
The following were prepared analogously:
















R2
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]





















AS29

100






AS16

62

0.6
CH2Cl2


AS5

91
ESI: (M + H)+ =
0.8
PE/EE
(KBr): C═O





521/3/5 (Br2)

2/1
1734


AS32

96

0.76
PE/EE
(KBr): C═O







2/1
1734


AS33

78

0.55
CH2Cl2
(KBr): C═O








1736


AS31
with use of 3-
74
EI: M+ = 417
0.7
toluene/
(KBr): C═O



(dimethylaminomethyl)-



t-BME 4/1
1734



1-methyl-1H-indol-



methoiodide


AS17

70
EI: M+ =
0.5
CH2Cl2
(KBr): C═O





550/52/54 (Br2)


1734


AS34

93
EI: M+ = 450
0.5
CH2Cl2/
(KBr): C═O







PE 1/1
1736


AS19

87

0.89
CH2Cl2
(KBr): C═O








1736


AS46

54
EI: M+ = 415
0.7
FM4


AS50

60
EI: M+ =
0.7
CH2Cl2
(KBr): C═O





520/22/24 (Br2)


1734









EXAMPLE A63
(phenylmethyl)-β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoate
Prepared analogously to Example A62 from diethyl[(phenylmethoxycarbonyl)methyl]-malonoate and 4-(1,1-dimethylethyl)-benzylbromide in the presence of sodium hydride in a yield of 53% of theory.
Colourless oil of Rf=0.21 (eluant:dichloromethane/petroleum ether 2/1 v/v).
IR(KBr): 1738 cm−1 (C═O)
EXAMPLE A64
Methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[[3-(1-methylethoxy)phenyl]methyl]-4-oxobutanoate
To a solution of 2.0 g (4.43 mMol) of methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)-methyl]-4-oxobutanoate in 30 ml of anhydrous dimethylformamide, 0.2 g (4.4 mMol) of a 55% suspension of sodium hydride in paraffin oil was added. After stirring for 30 minutes at room temperature, 0.5 ml (4.8 mMol) of isopropyliodide was added dropwise, and kept for two hours each at room temperature and at 70° C. The residue remaining after removal of the volatile constituents was divided between water and ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and was again evaporated down. The raw product was purified by column chromatography on silica gel (60 μm), first using dichloromethane, later methanol/conc. ammonia (9/1 v/v) as eluants. Yield was 0.9 g (42% of theory) of a colourless, amorphous substance of Rf=0.32 (FM4).
IR(KBr): 1734, 1668 cm−1 (C═O)
MS: M+=493
In the same way, methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-ethoxyphenyl)methyl]-4 -oxobutanoate was obtained from methyl 4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3-hydroxyphenyl)methyl]-4-oxobutanoate and ethyliodide in a yield of 67% of theory. Colourless, amorphous substance of Rf=0.29 (FM4).
IR(KBr): 1734, 1666 cm−1 (C═O)
MS: M+=479
EXAMPLE A65
β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoic acid
Prepared analogously to example A58b) from phenyl methyl β,β-bis-(ethoxycarbonyl)-4-(1,1-dimethylethyl)-benzenebutanoate by catalytic hydrogenation in the presence of palladium/charcoal in a yield of 95% of theory. Colourless, highly-viscous oil of Rf=0.16 (eluant:dichloromethane).
IR(KBr): 1739 cm−1 (C═O)
EXAMPLE A66
1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoro-acetate)
a) 4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazine
To a solution of 1.1 g of triphosgene (3.7 mMol) in 20 ml of dichloromethane, a mixture of 1.2 g (10 mMol) of 1-methyl-piperazine, 0.38 ml (22 mMol) of DIEA and 35 ml of dichloromethane was added dropwise at room temperature within 30 minutes, and then the solution of 1.9 g (10 mMol) of 1-(1,1-dimethyl-ethoxycarbonyl)piperazine and 0.38 ml of DIEA in 20 ml dichloromethane were added. After stirring for an hour at room temperature, insoluble matter was filtered off and the filtrate evaporated down in vacuo. After purification of the raw product on silica gel (Amicon, 35-70 μm), using dichloromethane/methanol/conc. ammonia(80/20/1 v/v/v) for elution, 700 mg (22% of theory) of colourless crystals were obtained of Mp. 130° C.
IR(KBr): 1691, 1641 cm−1 (C═O)
b) 1-methyl-4-[(1-piperazinyl)carbonyl]-piperazine-bis-(trifluoroacetate)
Prepared analogously to Example A1b), but omitting the treatment with aqueous ammonia, from 4-[[4-(1,1-dimethylethoxycarbonyl)-1-piperazinyl]carbonyl]-1-methylpiperazine and trifluoroacetic acid in a yield of 99.6% of theory. Colourless, amorphous substance of Rf=0.17 (eluant:dichloromethane/methanol/conc. ammonia 50/50/0.5).
IR(KBr): 1678 cm−1 (C═O)
MS: M+=212
EXAMPLE A67
1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride
a) N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide
To a solution of 30.5 g (0.155 Mol) of 4-fluoro-γ-oxobenzenebutanoic acid in 470 ml tetrahydrofuran, 35.0 g (0.216 Mol) of N,N′-carbonyldiimidazole was added with stirring and at room temperature and held at room temperature for a further 2.5 hours. Then, 13.7 g (0.304 Mol) of dimethylamine was added under strong external cooling by means of an ice-ethanol mixture. After the mixture had stood at room temperature for 12 hours, the solvent was removed in vacuo, the residue was divided between dichloromethane and 10% aqueous citric acid solution, the organic phase was dried over sodium sulphate and once again evaporated down in vacuo. After purification by column chromatography (eluant:ethyl acetate) on silica gel the crude product yielded 30.22 g (87% of theory) of colourless crystals of Rf=0.31 (eluant:ethyl acetate/glacial acetic acid 99.99/0.01).
IR(KBr): 1680, 1647 cm−1 (C═O)
b) N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide
The mixture of 33.48 g (0.15 Mol) of N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide, 29.6 g (0.168 Mol) of 1-(phenyl-methyl)piperazine and 6 ml of DIEA was refluxed for 6 hours. Another 30 g (0.17 Mol) of (phenylmethyl)piperazine was added, and the mixture was refluxed for a further 7 hours. The mixture was taken up in a little dichloromethane, and purified by column chromatography on silica gel, using dichloromethane/methanol/conc. ammonia 99/1/0.5 for elution. The residue obtained from the appropriate fractions was stirred with diisopropylether, the formed crystals were then recrystallised from ethanol. 42.22 g (74% of theory) of colourless crystals were obtained, Rf=0.69 (eluant:dichloromethane/methanol/conc. ammonia 95/5/0.5 v/v/v).
IR(KBr): 1662, 1643 cm−1 (C═O)
c) 4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenyl-methyl)piperazine
Prepared analogously to example A51 from N,N-dimethyl-γ-oxo-4-[4-(phenylmethyl)-1-piperazinyl]-benzenebutanoic acid amide by reduction with lithium aluminium hydride in a yield of 61% of theory. Colourless, amorphous substance of Rf=0.62 (eluant:ethyl acetate/methanol 1/1 v/v).
MS: Me+=367
d) 1-[4-[4-(dimethylamino)butyl]phenyl]-piperazine-dihydrochloride
Prepared analogously to example A20b) from 4-[4-[4-(dimethylamino)-1-hydroxybutyl]phenyl]-1-(phenylmethyl)piperazine by catalytic hydrogenation in the presence of palladium/charcoal and hydrochloric acid in a quantitative yield. Colourless, amorphous substance of Rf=0.37 (eluant:ethyl acetate/methanol 50/50/0.5 v/v/v).
B. Preparation of the Final Compounds
EXAMPLE 1
Preparation of Compounds ofGeneralFormula:




1-[N-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-4-(4-pyridinyl)-piperazine (No. 83)
A mixture of 2 g (3.44 mmol) of 3.5-dibromo-N2-[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl)-carbonyl]-D-tyrosine, 0.59 g (3.6 mmol) of 1-(4-pyridinyl)-piperazine, 1.27 g (3.96 mmol) of TBTU, 0.47 g (3.44 mmol) of HOBt, 0.7 ml (3.96 mmol) of DIEA and 100 ml tetrahydrofuran was stirred overnight at ambient temperature. The reaction mixture was extracted once with saturated aqueous saline solution, twice with saturated aqueous sodium hydrogen carbonate solution and again with saturated aqueous saline solution. The organic phase was dried, evaporated down in vacuo and the crude product was then purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol=9/1/(v/v/)). 550 mg (22% of theory) of an amorphous solid were obtained.
IR (KBr): 1601, 1636, 1696 cm−1 (C═O)
Rf: 0.67 (FM2)
ESI-MS: (M+H)+=726/728/730 (Br2)
The following were prepared analogously (in each case n=1):





















No.
RCO
Z
R2
A
NR3R4
Remarks
% Yield
MS
Rf
Eluant
IR [cm−1]



























N6
N—H
AS1
A3
C4

88
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O










928/30/32


1629.8;










(Br2)


1708.8


193
N15
N—H
AS6
A0
C7
DMF as
26
ESI:
0.9
EE/MeOH/
(KBr): C═O








solvent

(M + H)+ =

AcOH
1693.4;










647/9 (Br)

75/23/2 v/v/v
1622.0


194
N66
N—H
AS1
A0
C67

49
ESI:
0.33
FM1
(KBr): C═O










(M + H)+ =


1622/1664










828/30/32










(Br2)


202
N15
N—H
AS1
A0
C36
DMF as
9
ESI:
0.49
FM1
(KBr): C═O








solvent;

(M + H)+ =


1695.3;








DIEA

733/5/7


1622.0










(Br2)


NH 3417.7


203
N15
N—H
AS1
A0
C29
DMF as
41
ESI:
0.58
EE/MeOH
(KBr): C═O








solvent;

(M − H)− =

9/1 v/v
1695.3








DIEA

718/20/22










(Br2)


204
N15
N—H
AS1
A0
C30
DMF as
27
ESI:
0.1
FM1
(KBr): C═O








solvent;

(M + H)+ =


1695.3;








DIEA

691/3/5


1624.0










(Br2)


205
N15
N—H
AS6
A0
C8
DMF as
23
ESI:
0.46
FM1
(KBr): C═O








solvent;

(M + H)+ =


1695.3;








DIEA

653/5 (Br)


1622.0


206
N15
N—H
AS1
A0
C31
DMF as
33
ESI:
0.25
FM1
(KBr): C═O








solvent;

(M + H)+ =


1695.3;








DIEA

717/19/21


1624.0










(Br2)


207
N15
N—H
AS1
A0
C32
DMF as
55
ESI:
0.46
FM1
(KBr): C═O








solvent;

(M − H)− =


1690; 1650








DIEA

780/2/4










(Br2)


212
N15
N—H
AS1
A7
C1
DMF as
37
ESI:
0.27
FM1
(KBr): C═O








solvent;

(M + H)+ =


1697.3;








DIEA

882/4/6


1639.4










(Br2)


NH 3423.4


217
N15
N—H
AS6
A3
C1

51

0.9
FM1
(KBr): C═O













1693.4;













1641.3


222
N15
N—H
AS1
A0
C27
THF/DMF
10
ESI:
0.35
FM1
(KBr): C═O








1/1 as

(M + H)+ =


1695.3








solvent; NEt3

774/6/8








as base

(Br2)


286
N15
N—H
AS1
A0
C28
THF/DMF
9
ESI:
0.4
FM1
(KBr): C═O








1/1 as

(M + H)+ =


1699.2








solvent; NEt3

706/8/10








as base

(Br2)


81
N15
N—H
AS4
A0
C4

64
ESI: (M + H)+ =
0.75
FM1
(KBr): C═O










724/6/8


1618.2;










(Br2);


1703.0










(M + Na)+=










746/48/50










(Br2)


82
N15
N—H
AS4
A0
C1

53
ESI: (M + H)+ =
0.55
FM3
(KBr): C═O










725/7/9


1620.1; 1703.0










(Br2)


84
N66
N—H
AS21
A0
C68

31
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O










683


1608/1628/













1666


85
N15
N—H
AS4
A0
C7

42
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O










724/6/8


1618.2; 1697.3;










(Br2);


—NH—, —NH2










(M + Na)+=


3379.1










746/48/50










(Br2)


90
N15
N—H
AS1
A0
C8

40
ESI: (M + H)+ =
0.78
FM2
(KBr): C═O










731/3/5


1624.0; 1697.3










(Br2)



N2
N—H
AS2
A3
C1
DMF as
73
ESI: (M + H)+ =
0.42
FM1
(KBr): C═O








solvent;

766


1654.2; 1708.8








DIEA


354
N15
N—H
AS1
A0
C4

21
ESI: (M + H)+ =
0.76
FM2
(KBr): C═O










725/7/9


1622.0; 1695.3;










(Br2);


—OH, —NH—










(M + Na)+=


3417.7










747/49/51










(Br2)


98
N15
N—H
AS1
A0
C9

60
ESI: (M + H)+ =
0.41
FM2
(KBr): C═O










580/2/4


1624.0; 1685.7;










(Br2); (M −


—OH, —NH—










H)−=


3421.5










578/80/82










(Br2);










(M + Na)+ =










602/4/6










(Br2)


102
N15
N—H
AS1
A0
C12

43
ESI: (M + H)+ =
0.76
FM2
(KBr): C═O










636/38/40


1622.0; 1695.3;










(Br2);










(M + Na)+=










658/60/62










(Br2)


99
N15
N—H
AS1
A0
C10

54
ESI: (M + H)+ =
0.61
FM2
(KBr): C═O










663/5/7


1622.9; 1700.9;










(Br2)


—OH, —NH—













3421.5


100
N15
N—H
AS1
A0
C11

54
ESI: (M + H)+ =
0.5
FM2
(KBr): C═O










746/48/50


1624.0; 1695.3;










(Br2)


—NH—, —OH













3423.4;


101
N15
N—H
AS1
A0
C7

62
ESI: (M + H)+ =
0.82
FM2
(KBr): C═O










725/7/9


1622.0; 1695.3;










(Br2);


—OH, —NH—










(M + Na)+=


3253.7










747/49/51










(Br2)


103
N15
N—H
AS1
A0
C13

37
ESI: (M + H)+ =
0.72
FM2
(KBr): C═O










679/81/83


1625.9;










(Br2)


1693.4;













1666.4; —OH,













—NH— 3409.9


106
N15
N—H
AS1
A0
C14

72
ESI: (M + H)+ =
0.66
FM1
(KBr): C═O










832/4/6


1674.1;










(Br2);


1689.5










(M + Na)+=










854/6/8 (Br2)


104
N15
N—H
AS6
A0
C4

36
ESI: (M + H)+ =
0.71
FM1
(KBr): C═O










647/9 (Br);


1695.3










(M + Na)+ =










669/71 (Br);










(M − H)− 645/7










(Br)


105
N15
N—H
AS6
A0
C1

25
ESI: (M + H)+ =
0.25
FM3
(KBr): C═O










648/50 (Br)


1695.3



N2
N—H
AS1
A12
C1
DMF as
72
ESI:
0.4
FM1
KBr: C═O








solvent;

(M + H)+ =


1641








DIEA

1082/4/6










(Br2)


199
N15
N—H
AS3
A0
C8
THF/DMF =
86
ESI: (M + H)+ =
0.37
ethyl
KBr: C═O








9/1 (v/v)

643/5/7

acetate/
1697; 1624








as solvent

(Br2)

methanol/












petroleum












ether =












1/2/1 (v/v/v)


200
N15
N—H
AS3
A0
C1

40
ESI: (M + H)+ =
0.45
ethyl
KBr: C═O










638/40/42

acetate/
1695; 1636










(Br2)

methanol/












petroleum












ether =












1/2/1 (v/v/v)


419
N66
N—H
AS21
A0
C38

28
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O










682


1628/1662


425
N66
N—H
AS1
A0
C36

42
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










747/49/51


1624/1657










(Br2)


426
N66
N—H
AS4
A0
C30

66
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O










704/6/8


1618/1663










(Br2)


427
N66
N—H
AS1
A0
C31

38
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










731/3/5


1630/1653










(Br2)


428
N66
N—H
AS4
A0
C36

40
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










746/48/50


1618/1662










(Br2)


429
N66
N—H
AS1
A0
C30

47
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O










705/7/9


1635/1653










(Br2)


435
N66
N—H
AS4
A0
C31

20
ESI: (M + H)+ =
0.55
FM1
(KBr): C═O










730/2/4


1608/1631










(Br2)


436
N66
N—H
AS1
A0
C11

15
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O










760/2/4 (Br2)


1624/1653


437
N66
N—H
AS4
A0
C11

25
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










759/61/63


1622/1661










(Br2)


438
N66
N—H
AS4
A0
C54

13
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O










744/6/8


1620/1660










(Br2)


439
N66
N—H
AS1
A0
C54

31
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










745/7/9


1626/1661










(Br2)


443
N122
N—H
AS1
A0
C11

44
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O










790/2/4


1624/1680










(Br2)


444
N122
N—H
AS1
A0
C8

62
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O










775/7/9


1624/1678










(Br2)


445
N122
N—H
AS1
A0
C1

60
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










770/2/4


1630/1680










(Br2)


446
N122
N—H
AS1
A0
C20

59
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O










789/91/93


1622/1680










(Br2)


447
N122
N—H
AS4
A0
C1

54
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










769/71/73


1622/1682










(Br2)


448
N122
N—H
AS4
A0
C20

68
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










788/90/92


1620/1682










(Br2)


449
N122
N—H
AS4
A0
C8

59
ESI: (M + H)+ =
0.58
FM1
(KBr): C═O










774/6/8


1620/1682










(Br2)


450
N66
N—CH3
AS1
A0
C4

36
ESI: (M + H)+ =
0.39
FM1
(KBr): C═O










753/5/7


1653










(Br2)


451
N66
CH2
AS1
A0
C1

20
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










739/41/43


1638










(Br2)


452
N71
CH2
AS1
A0
C1

16
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










751/53/55


1638/1680










(Br2)


453
N66
CH2
AS1
A0
C11

17
ESI: (M + H)+ =
0.13
FM1
(KBr): C═O










758/60/62


1636










(Br2)


454
N66
CH2
AS1
A0
C20

33
ESI: (M + H)+ =
0.23
FM1
(KBr): C═O










757/59/61


1632










(Br2)


455
N71
CH2
AS1
A0
C8

35
EI: M+ =
0.42
FM1
(KBr): C═O










755/7/9 (Br2)


1624/1684


457
N71
CH2
AS1
A0
C4

49
ESI: (M + H)+ =
0.77
FM1
(KBr): C═O










750/2/4


1626/1682










(Br2)


458
N71
CH2
AS1
A0
C37

25
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










769/71/73


1638/1682










(Br2)


459
N66
CH2
AS1
A0
C37

50
EI: M+ =
0.2
FM1
(KBr): C═O










757/59/61


1636










(Br2)


460
N66
N—H
AS1
A0
C55

72
ESI: (M + H)+ =
0.27
EE/MeOH/
(KBr): C═O










759/61/63

NH4OH =
1626/1661










(Br2)

8/1.5/0.1












v/v/v


461
N66
N—H
AS1
A0
C56

77
ESI: (M + H)+ =
0.77
FM1
(KBr): C═O










731/3/5


1626/1661










(Br2)


462
N66
N—H
AS17
A0
C8

51
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O










759/61/63


1628/1663










(Br2)


463
N66
N—H
AS18
A0
C1

59
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O










704


1661


464
N66
N—H
AS18
A0
C8

51
ESI: (M + H)+ =
0.76
FM1
(KBr): C═O










709


1628/1663


465
N66
N—H
AS18
A0
C37

73
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O










723


1628/1663


469
N66
N—H
AS19
A0
C8

34
ESI: (M + H)+ =
0.34
FM1
(KBr): C═O










651/53 (Br)


1626/1664


471
N66
N—H
AS20
A0
C8

41
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










649


1624/1684


472
N66
N—H
AS5
A0
C8

26
ESI: (M + H)+ =
0.73
FM1
(KBr): C═O










729/31/33


1626/1664










(Br2)


475
N66
N—H
AS18
A0
C20

58
ESI: (M + H)+ =
0.22
FM1
(KBr): C═O










723


1628/1664


476
N66
N—H
AS18
A0
C11

44
ESI: (M + H)+ =
0.27
MeOH
(KBr): C═O










724


1630/1662


478
N66
N—H
AS19
A0
C37

62
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O










665/7 (Br)


1626/1662


479
N66
N—H
AS19
A0
C20

55
ESI: (M + H)+ =
0.64
FM1
(KBr): C═O










665/7 (Br)


1664


480
N66
N—H
AS19
A0
C4

55
ESI: (M + H)+ =
0.77
FM1
(KBr): C═O










645/7 (Br)


1628/1662


506
N66
N—H
AS21
A0
C20

46
ESI: (M + H)+ =
0.75
FM1
(KBr): C═O










655


1626/1664


507
N66
N—H
AS22
A0
C8

65
ESI: (M + H)+ =
0.78
FM1
(KBr): C═O










607/9 (Cl)


1624/1664


508
N66
CH2
AS21
A0
C20

15
ESI: (M + H)+ =
0.15
MeOH
(KBr): C═O










654


1639/1670


246
N15
CH2
AS1
A0
C8

19
ESI: (M + H)+ =
0.35
EE/MeOH/
(KBr): C═O










730/2/4

NH4OH
1635/1707










(Br2)

9/1/0.5 v/v/v


285
N15
CH2
AS1
A0
C4

42
ESI: (M + H)+ =
0.45
EE/MeOH/
(KBr): C═O










724/6/8

NH4OH
1684/1711










(Br2)

9/1/0.5 v/v/v


289
N66
CH2
AS1
A0
C8

40
ESI: (M + H)+ =
0.38
EE/MeOH/
(KBr): C═O










744/6/8

NH4OH
1635/1668










(Br2)

9/1/0.5 v/v/v


290
N66
CH2
AS1
A0
C4

30
ESI: (M + H)+ =
0.45
EE/MeOH/
(KBr): C═O










738/40/42

NH4OH
1634/1664










(Br2)

9/1/0.5 v/v/v


511
N66
N—H
AS23
A0
C8
DMF
80
ESI: (M + H)+ =
0.57
FM1
(KBr): C═O










603


1664/1626


512
N66
N—H
AS23
A0
C11
DMF
60
ESI: (M + H)+ =
0.30
FM1
(KBr): C═O










618


1645


513
N66
N—H
AS23
A0
C1
DMF
54
ESI: (M + H)+ =
0.50
FM1
(KBr): C═O










598


1662/1712


514
N66
N—H
AS23
A0
C38
DMF
65
ESI: (M + H)+ =
0.20
FM1
(KBr): C═O










644


1664/1626/













1712


515
N66
N—H
AS23
A0
C40
DMF
7
ESI: (M + H)+ =
0.40
FM1
(KBr): C═O










632


1630/1662


527
N66
N—H
AS25
A0
C8

49
ESI: (M + H)+ =
0.48
FM1
(KBr): C═O










594


1647


528
N66
N—H
AS25
A0
C1

29
ESI: (M + H)+ =
0.48
FM1
(KBr): C═O










589


1646


529
N66
CH2
AS2
A0
C8

27
ESI: (M + H)+ =
0.50
FM1
(KBr): C═O










622


1635/1668/













1716


530
N66
CH2
AS2
A0
C20

5
EI: M+ = 635
0.49
FM1
(KBr): C═O













1637/1668/













1714


531
N66
CH2
AS23
A0
C8

30
EI: M+ = 601
0.50
FM1



N66
CH2
AS23



95


538
N139
CH2
AS2
A0
C20

49
EI: M+ = 636
0.30
FM1
(KBr): C═O













1635/1674


539
N139
CH2
AS2
A0
C53

52
EI: M+ = 637
0.30
FM1
(KBr): C═O













1637/1674


540
N139
CH2
AS2
A0
C8

60

0.37
FM1
(KBr): C═O













1635/1674


541
N66
CH2
AS27
A0
C53

32
EI: M+ = 630
0.65
FM1
(KBr): C═O













1639/1670


542
N66
CH2
AS27
A0
C8

32
EI: M+ = 615
0.80
FM1
(KBr): C═O













1639/1670


543
N66
CH2
AS27
A0
C20

21
EI: M+ = 629
0.59
FM1
(KBr): C═O













1639/1672


544
N66
CH2
AS28
A0
C20

35
EI: M+ = 643
0.50
FM1
(KBr): C═O













1641/1670


545
N66
CH2
AS28
A0
C53

54
EI: M+ = 644
0.50
FM1
(KBr): C═O













1639/1670


546
N66
CH2
AS28
A0
C8

53
EI: M+ = 629
0.60
FM1
(KBr): C═O













1639/1672


547
N66
CH2
AS29
A0
C8

14
EI: M+ = 599
0.53
FM1
(KBr): C═O













1630


548
N66
CH2
AS29
A0
C53

12
EI: M+ = 614
0.48
FM1


549
N66
CH2
AS29
A0
C20

15
EI: M+ = 613
0.48
FM1
(KBr): C═O













1637/1668


550
N66
CH2
AS30
A0
C53

4

0.48
FM1


574
N66
CH2
AS16
A0
C20

55
EI: M+ =
0.80
CH2Cl2/
(KBr): C═O










653/5/7 (Cl2)

MeOH/
1635/1670












NH4OH












80/20/1


575
N66
CH2
AS16
A0
C53

54
EI: M+ =
0.20
EE/MeOH/
(KBr): C═O










654/6/8 (Cl2)

NH4OH
1635/1668












70/30/3


578
N66
CH2
AS5
A0
C53

32
EI: M+ =
0.30
FM5
(KBr): C═O










742/4/6 (Br2)


1637/1670


579
N66
CH2
AS5
A0
C20

37
EI: M+ =
0.50
FM5
(KBr): C═O










741/3/5 (Br2)


1635/1670


589
N66
CH2
AS32
A0
C53

49
EI: M+ =
0.33
FM5
(KBr): C═O










756/58/60


1639/1670










(Br2)


590
N66
CH2
AS32
A0
C20

36
EI: M+ =
0.47
FM5
(KBr): C═O










755/7/9 (Br2)


1658/1672


591
N66
CH2
AS33
A0
C20

43
EI: M+ = 689
0.40
EE/MeOH/
(KBr): C═O












NH4OH
1637/1670












50/50/0.5


592
N66
CH2
AS33
A0
C53

52
EI: M+ = 690
0.20
EE/MeOH/
(KBr): C═O












NH4OH
1633/1668












70/30/5


593
N66
CH2
AS16
A0
C29

11
EI: M+=
0.65
EE/MeOH
(KBr): C═O










628/30/32

9/1
1606/1637/










(Cl2)


1668/













1728


594
N66
CH2
AS16
A0
C73

48
EI: M+ =
0.50
EE/MeOH
(KBr): C═O










628/30/32

9/1
1637/1668/










(Cl2)


1736


595
N66
CH2
AS16
A0
C74

10
EI: M+ =
0.30
EE/MeOH/










597/99/601

NH4OH










(Cl2)

50/50/0.5


597
N66
CH2
AS31
A0
C53

25
EI: M+ = 639
0.30
CH2Cl2/
(KBr): C═O












MeOH/
1635/1668












NH4OH












90/10/1


598
N66
CH2
AS31
A0
C20

31
EI: M+ = 638
0.10
CH2Cl2/
(KBr): C═O












MeOH/
1635/1668












NH4OH












90/10/0.3


600
N73
CH2
AS31
A0
C20

10
ESI: (M + H)+ =
0.15
CH2Cl2/
(KBr): C═O










551

MeOH/
1628












NH4OH












90/10/1


602
N66
CH2
AS17
A0
C53

56
EI: M+ =
0.25
EE/MeOH/
(KBr): C═O










772/4/6 (Br2)

NH4OH
1637/1668












50/50/0.5


603
N66
CH2
AS16
A0
C33

93
EI: M+ =
0.75
EE/MeOH/
(KBr): C═O










600/02/04

AcOH 70/30/1
1635/1716










(Br2)


604
N66
CH2
AS17
A0
C20

47
EI: M+ =
0.20
EE/MeOH/
(KBr): C═O










771/3/5 (Br2)

NH4OH
1635/1668












50/50/0.5


605
N66
CH2
AS34
A0
C53

70
EI: M+ = 672
0.25
EE/MeOH/
(KBr): C═O












NH4OH
1633/1666












60/40/0.5


606
N66
CH2
AS34
A0
C20

45
EI: M+ = 671
0.15
EE/MeOH/
(KBr): C═O












NH4OH
1635/1668












50/50/0.5


607
N66
N—H
AS21
A0
C40

27
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O










670


1608/1628/













1664


608
N66
N—H
AS21
A0
C11

34
ESI: (M + H)+ =
0.50
FM1
(KBr): C═O










656


1606/1628/













1664


609
N66
N—H
AS21
A0
C8

30
ESI: (M + H)+ =
0.80
FM1
(KBr): C═O










641


1626/1664


610
N66
N—H
AS21
A0
C1

55
ESI: (M + H)+ =
0.80
FM1
(KBr): C═O










636


1635/1662


611
N66
N—H
AS21
A0
C4

80
ESI: (M + H)+ =
0.70
FM1
(KBr): C═O










635


1606/1628/













1664


612
N66
CH2
AS4
A0
C8

43
EI: M+ =
0.85
FM1
(KBr): C═O










742/4/6 (Br2)


1668/1631/













1606


613
N66
N—H
AS22
A0
C20

62
ESI: (M + H)+ =
0.73
FM1
(KBr): C═O










621/23 (Cl)


1626/1664


614
N66
N—H
AS22
A0
C37

55
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










621/23 (Cl)


1626/1664


615
N66
N—H
AS22
A0
C56

77
ESI: (M + H)+ =
0.76
FM1
(KBr): C═O










593


1628/1664


616
N66
CH2
AS36
A0
C8

32
ESI: (M + H)+ =
0.76
FM1
(KBr): C═O










585


1637/1668


617
N66
CH2
AS21
A0
C37

15
EI: M+ = 653
0.15
MeOH
(KBr): C═O













1639/1670


618
N66
CH2
AS21
A0
C38

24
EI: M+ = 680
0.10
MeOH
(KBr): C═O













1639/1670


628
N66
CH2
AS21
A0
C8

31
EI: M+ = 639
0.25
MeOH
(KBr): C═O













1639/1670


629
N66
CH2
AS21
A0
C11

43
EI: M+ = 654
0.10
MeOH
(KBr): C═O













1641/1668


630
N66
CH2
AS21
A0
C1

74
EI: M+ = 634
0.10
MeOH
(KBr): C═O













1641/1668


631
N66
CH2
AS21
A0
C28

63
EI: M+ = 614
0.30
MeOH
(KBr): C═O













1666


634
N66
CH2
AS38
A0
C8

35
ESI: (M + H)+ =
0.25
MeOH
(KBr): C═O










622


1635/1668


635
N66
CH2
AS48
A0
C8

40
EI: M+ = 639
0.68
FM1
(KBr): C═O













1643/1670


636
N66
N—H
AS49
A0
C20

25
ESI: (M + H)+ =
0.40
EE/MeOH/
(KBr): C═O










632

NH4OH
1664












9/1/0.5


637
N66
CH2
AS4
A0
C20

11
ESI: (M + H)+ =
0.60
FM1
(KBr): C═O










757/59/61


1635/1668










(Br2)


638
N66
CH2
AS48
A0
C20

11
ESI: (M + H)+ =
0.66
FM1
(KBr): C═O










654


1641/1668


639
N66
CH2
AS18
A0
C20

4
EI: M+ = 721
0.10
MeOH
(KBr): C═O













1637/1670


640
N66
CH2
AS39
A0
C20

38
EI: M+ = 645
0.80
CH2Cl2/
(KBr): C═O












MeOH/
1635/1670












NH4OH












8/2/0.3


641
N66
CH2
AS38
A0
C20

49
EI: M+ = 635
0.80
CH2Cl2/
(KBr): C═O












MeOH/
1635/1668












NH4OH












8/2/0.3


642
N66
CH2
AS39
A0
C8

45
EI: M+ = 631
0.10
EE/MeOH/
(KBr): C═O












NH4OH
1635/1670












9/1/0.3



N66
CH2
AS21
A0
C69

70
EI: M+ = 739


(KBr): C═O













1684


644
N109
CH2
AS21
A0
C20

46
ESI: (M + H)+ =
0.10
MeOH
(KBr): C═O










659


1643


645
N66
CH2
AS19
A0
C20

21
EI: M+ =
0.53
FM1
(KBr): C═O










763/5 (Br)


1669/1634


646
N66
CH2
AS19
A0
C8

45
EI: M+ =
0.60
FM1
(KBr): C═O










649/651 (Br)


1637/1668


653
N113
CH2
AS21
A0
C20

55
EI: M+ = 666
0.60
FM1
(KBr): C═O













1630/1701


654
N134
CH2
AS21
A0
C20

22
EI: M+ = 690
0.60
FM1
(KBr): C═O













1714


655
N66
CH2
AS46
A0
C20

43
EI: M+ = 636
0.50
FM1
(KBr): C═O













1630/1664


656
N66
CH2
AS46
A0
C8

71
EI: M+ = 622
0.60
FM1
(KBr): C═O













1635


657
N66
CH2
AS47
A0
C20

63
EI: M+ = 639
0.50
FM1
(KBr): C═O













1635/













1668/













1716


658
N66
CH2
AS50
A0
C20

70
ESI: (M + H)+ =
0.20
EE/MeOH/
(KBr): C═O










741/3/5

NH4OH
1635/1668










(Br2)

50/50/0.5


659
N66
CH2
AS50
A0
C53

60
ESI: (M + H)+ =
0.20
EE/MeOH/
(KBr): C═O










743/5/7

NH4OH
1635/1668










(Br2)

50/50/0.5


660
N66
CH2
AS46
A0
C53

41
EI: M+ = 637
0.65
FM1
(KBr): C═O













1630


661
N66
CH2
AS7
A0
C8

75
EI: M+ = 615
0.70
FM1
(KBr): C═O













1626/1660


662
N66
CH2
AS7
A0
C53

41
EI: M+ = 630
0.55
FM1
(KBr): C═O













1628/1662


663
N66
CH2
AS7
A0
C20

78
EI: M+ = 629
0.60
FM1
(KBr): C═O













1628/1662


664
N66
CH2
AS52
A0
C8

66
EI: M+ = 629
0.75
FM1
(KBr): C═O













1635


665
N66
CH2
AS52
A0
C53

37
EI: M+ = 644
0.70
FM1
(KBr): C═O













1633/1664


666
N66
CH2
AS52
A0
C20

61
EI: M+ = 643
0.80
FM1
(KBr): C═O













1635/1664


667
N66
CH2
AS2
A0
C53

47
EI: M+ = 636
0.60
FM1
(KBr): C═O













1630/1664



N66
CH2
AS2
A0
C69

78

0.75
FM1


669
N66
CH2
AS32
A0
C71

44
EI: M+ =
0.20
EE/MeOH/
(KBr): C═O










834/6/8 (Br2)

NH4OH
1641/1670












50/50/0.5


670
N66
CH2
AS51
A0
C20
Prelimi-
47
EI: M+ = 641
0.15
EE/MeOH/
(KBr): C═O








nary stage



NH4OH
1635/1664








special



50/50/0.5








cases


671
N66
CH2
AS51
A0
C53

45
EI: M+ = 642
0.15
EE/MeOH/
(KBr): C═O












NH4OH
1637/1670












50/50/0.5


672
N66
CH2
AS16
A0
C76

55
EI: M+ =
0.66
FM1
(KBr): C═O










689/91/93


1635










(Cl2)









EXAMPLE 2
Preparation of Compounds ofGeneralFormula:




1-[N2-[4-amino-N-[[4-(2-chlorophenyl)-1-piperazinyl]-carbonyl]-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)piperazine-bis-(trifluoroacetate) (No. 61)
A mixture of 0.56 g (1.0 mmol) of 4-amino-N2-[[4-(2-chlorophenyl)-nyl)-1-piperazinyl]carbonyl]-3.5-dibromo-D-phenylalanine, 0.41 g (1.05 mmol) of 1-[N6-(1.1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine, 0.35 g (1.10 mmol) of TBTU, 0.14 g (1.0 mmol) of HOBt, 0.2 ml (1.10 mmol) of DIEA and 100 ml of dimethylformamide was stirred overnight at ambient temperature. The reaction mixture was evaporated down in vacuo and divided between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic phase was then extracted once with saturated aqueous sodium hydrogen carbonate solution and with water, dried and evaporated down in vacuo. The crude product was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol=8/2 (v/v/)), taken up in 30 ml of methylene chloride and stirred with 3 ml of trifluoroacetic acid for 3 hours at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was triturated with ether and the obtained amorphous solid (0.43 g, 37% of theory) was suction filtered.
IR (KBr): 1643, 1678 cm−1 (C═O)
Rf: 0.6 (FM1)
ESI-MS: (M+H)+=832/834/836/838 (Br2, Cl)
The following were prepared analogously (in each case n=1):



















No.
RCO
R2
A
NR3R4
% Yield
MS
Rf
Eluant
IR [cm−1]
























48
N6
AS1
A1
C3
79
ESI: M + H =
0.3
FM1
(KBr): C═O








946/48/50


1652.9; 1674.1








(Br2)


213
N15
AS6
A1
C8
14.7
ESI: M + H =
0.45
FM2
(KBr): C═O








781/3 (Br)


1691.5; 1629.8


49
N8
AS4
A1
C1
57.14
ESI: M + H =
0.5
FM1
(KBr): C═O








757/59/61


1643.3; 1676.0








(Br2)


58
N15
AS4
A1
C4
21
ESI: M + H =
0.57
FM1
(KBr): C═O








852/4/6 (Br2)


1635.5; 1695.3


59
N15
AS4
A1
C1
45.6
ESI: M + H =
0.44
FM1
(KBr): C═O








853/5/7 (Br2)


1635.5; 1695.3


60
N23
AS4
A1
C4
19.2
ESI: M + H =
0.65
FM1
(KBr): C═O








831/3/5/7


1633.6








(Br2, Cl)


61
N23
AS4
A1
C1
36.6
ESI: M + H =
0.6
FM1
(KBr): C═O








832/4/6/8


1643.3; 1678.0








(Br2, Cl)









EXAMPLE 3
Preparation of Compounds ofGeneralFormula:




1-[N2-[3,5-dibromo-N-[[[(2-methoxyphenyl)methyl]amino]-carbonyl]-D,L-tyrosyl]-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine
A tetrahydrofuran solution (50 ml) of 1.0 g (1.34 mmol) of 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine was added dropwise over a period of 40 minutes to a suspension of 0.33 g (2.01 mmol) of CDT in 50 ml of tetrahydrofuran cooled to −10 ° C. and stirred. The reaction mixture was then stirred for 2 hours at ambient temperature and mixed with 0.22 ml (1.675 mmol) of 2-methoxy-benzenemethanamine. Then the mixture was refluxed for 2 hours and stirred overnight at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was triturated with ether and the solid obtained (1.1 g; 90% of theory) was suction filtered and dried.
















IR (KBr):
1641, 1717 cm−1  (C═O)



ESI-MS:
(M + H)+ = 908/910/912 (Br2)




(M + H + Na)++ = 466.7 (Br2)










The following were prepared analogously:































%




Mp.


No.
RCO
R2
n
X
A
NR3R4
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]
(° C.)




























195
N15
AS1
1
O
A3
C8

21
ESI: (M + H)+ =
0.8
FM7
(KBr): C═O












959/61/63


1699.2;











(Br2)


1635.5


196
N51
AS1
1
O
A3
C8

 26;
ESI: (M + H)+ =
0.85
FM7
(KBr): C═O










 1
929/31/33


1710; CN











(Br2)


2219.8


201
N101
AS4
1
O
A0
C8
DIEA
34
ESI: (M + H)+ =
0.58
FM1
(KBr): C═O











746/8/50


1693.4;











(Br2)


1618.2


215
N15
AS1
1
O
A0
C34
NEt3 as
92
ESI: (M − H)− =
0.36
FM1
(KBr): C═O









base

778/80/82


1695.3











(Br2)


216
N15
AS1
1
O
A0
C35
NEt3 as
69
ESI: (M − H)− =
0.3
FM1
(KBr): C═O









base

779/81/82


1701.1











(Br2)


221
N15
AS4
1
O
A7
C1
NEt3 as
39
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O









base

881/3/5


1697.3;











(Br2)


1637.5


288
N85
AS1
1
O
A0
C8
THF/DMF
30
ESI: (M + H)+ =
0.3
MeOH
(KBr): C═O









as solvent;

749/51/53


1683.8;









NEt3 as

(Br2)


1624.0;









base




OH 3429.2


293
N66
AS1
1
O
A9
C1
DIEA
11
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O











910/2/4


1645.2











(Br2)


295
N66
AS1
1
O
A7
C1
NEt3 as
70
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O









base

896/8/900


1716.5;











(Br2)


1647.1


303
N86
AS4
1
O
A0
C8
DIEA
20
ESI: (M + H)+ =
0.7
FM 2
(KBr): C═O











747/9/51


1618.2











(Br2)


304
N87
AS4
1
O
A0
C8
THFas
30
ESI: (M + H)+ =
0.75
FM1
(KBr): C═O









solvent;

802/4/6


1720.4;









NEt3 as

(Br2)


1668.3;









base




1620.1;














NH, NH2














3431.2;














3379.1


305
N88
AS4
1
O
A0
C8
DIEA
45
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O











782/4/6


1616; SO2











(Br2)


1323.1;














1151.4


308
N90
AS4
1
O
A0
C8
DIEA
27
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O











750/2/4


1637.5











(Br2)


80
N15
AS1
1
O
A3
C1

62
ESI: (M + H)+ =
0.8
FM2
(KBr): C═O











954/6/8


1697.3;











(Br2)


1639.4



N8
AS1
1
O
A3
C1

66
ESI: (M + H)+ =
0.22
EtOAc/
(KBr): C═O











858/60/62

methanol =
1641.3











(Br2)

6/4 (v/v)



N9
AS1
1
O
A3
C1

59
ESI: (M + H)+ =
0.22
EtOAc/
(KBr): C═O











888/90/92

methanol =
1652.9











(Br2)

6/4 (v/v)



N2
AS1
1
O
A4
C1

40
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O











922/4/6 (Br2);


1641.3;











(M + Na)+=


1710.8;











944/6/8 (Br2)


OH, NH














3396.4



N4
AS1
1
O
A4
C1

73
ESI: (M + H)+ =
0.13
FM1
(KBr): C═O











952/4/6 (Br2)


1641.3;














1714.6


62
N15
AS1
1
O
A3
C5
purified by
65
ESI: (M + H)+ =
0.27
FM1
(KBR): C═O









column

1003/5/7 (Br2);


1685.7;









chromatog-

(M + Na)+=


1635.5; OH,









raphy: silica

1025/7/9 (Br2)


NH: 3419.6









gel/FM4



N15
AS1
1
O
A3
C6
purified by
86
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O









column

983/5/7 (Br2)


1695.3;









chromatog-




1633.6









raphy: silica









gel/FM4


73
N15
AS5
1
O
A3
C1
purified by
64
ESI: (M + H)+ =
0.75
FM1
(KBr):









column

938/40/42 (Br2)


C═O









chromatog-




1699.2;









raphy: silica




1641.3









gel/FM4;









diastereo-









mers


78
N45
AS5
1
O
A3
C1
purified by
44
ESI: (M + H)+ =
0.73
FM1
(KBr): C═O









column

952/4/6 (Br2)


1712.7,









chromatog-




1637.5; —NH—









raphy: silica




3300.0









gel/FM4;









diastereo-









mers


110
N15
AS4
1
O
A0
C5
purified by
82
ESI: (M + H)+ =
0.79
FM1
(KBr): C═O









column

725/7/9 (Br2)


1620.1;









chromatog-




1514.0









raphy: silica









gel/FM4


111
N15
AS4
1
O
A0
C15
purified by
58
ESI: M+ =
0.77
FM1
(KBr): C═O









column

726/28/30 (Br2)


1697.3;









chromatog-




1620.1









raphy: silica









gel/FM4


114
N45
AS4
1
O
A0
C5
purified by
75
ESI: (M + H)+ =
0.78
FM1
(KBr): C═O









column

739/41/43 (Br2)


1710.8;









chromatog-




1620.1









raphy: silica









gel/FM4


112
N15
AS1
1
O
A0
C5
purified by
45
ESI: (M + H)+ =
0.33
FM1
(KBr): C═O









column

726/28/30 (Br2)


1695.3;









chromatog-




1624.0









raphy: silica









gel/FM4


115
N45
AS1
1
O
A0
C5
purified by
28
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O









column

740/2/4 (Br2)


1710.8;









chromatog-




1622









raphy: silica









gel/FM4


113
N15
AS4
1
O
A0
C16
purified by
56
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O
173-176









column

726/8/30 (Br2)


1699.2;









chromatog-




1618.2









raphy: silica









gel/FM4


119
N45
AS4
1
O
A0
C16
purified by
81
ESI: (M + H)+ =
0.69
FM1
(KBr): C═O
148-152









column

762/4/6 (Br2)


1710.8;









chromatog-




1618.2









raphy: silica









gel/FM4


120
N15
AS1
1
O
A0
C15
purified by
27
ESI: (M + H)+ =
0.31
FM1
(KBr): C═O
173-175









column

749/51/53 (Br2)


1695.3









chromatog-









raphy: silica









gel/FM4


128
N15
AS4
1
O
A0
C3
purified by
61
ESI: (M + Na)+ =
0.72
FM1
(KBr): C═O
174-177









column

764/6/8 (Br2)


1699.2;









chromatog-




1618.2









raphy: silica









gel/FM4


130
N15
AS4
1
O
A0
C6
purified by
60
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O
150-154









column

754/6/8 (Br2)


1703;









chromatog-




1620.1









raphy: silica









gel/FM4


129
N15
AS1
1
O
A0
C16
purified by
18
ESI: (M − H)− =
0.27
FM1
(KBr): C═O
173-176









column

725/7/9 (Br2)


1693.4;









chromatog-




1627.8









raphy: silica









gel/FM4


131
N45
AS4
1
O
A0
C6
purified by
69
ESI: (M + H)+ =
0.73
FM1
(KBr): C═O
159-162









column

768/70/72 (Br2)


1712.7;









chromatog-




1620.1









raphy: silica









gel/FM4


132
N45
AS4
1
O
A0
C3
purified by
27
ESI: (M + Na)+ =
0.72
FM1
(KBr): C═O
142-146









column

778/80/2 (Br2)


1712.7;









chromatog-




1618.2









raphy: silica









gel/FM4


133
N15
AS1
1
O
A0
C6
purified by
24
ESI: (M + H)+ =
0.33
FM1
(KBr): C═O
161-164









column

755/7/9 (Br2)


1697.3;









chromatog-




1624.0









raphy: silica









gel/FM4


134
N15
AS4
1
O
A0
C18
purified by
69
ESI: (M + H)+ =
0.59
FM1
(KBr): C═O
171-174









column

756/8/60 (Br2)


1699.2;









chromatog-




1618.2









raphy: silica









gel/FM4


135
N15
AS1
1
O
A0
C18
Purified by
17
ESI: (M + H)+ =
0.25
FM1
(KBr): C═O
74-77









column

757/9/61 (Br2)


1691.5; 1625.9









chromatog-









raphy: silica









gel/FM4



N29
AS1
1
O
A3
C1

61
ESI: (M + H)+ =
0.62
FM7
(KBr): C═O











903/5/7 (Br2)


1641.3



N36
AS1
1
O
A3
C1

33
ESI: (M + H)+ =
0.49
FM7
(KBr): C═O











915/7/9 (Br2)


1641.3


44
N34
AS1
1
O
A3
C1

35
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O











936/38/40/42


1641.3











(Br3)


378
N15
AS1
0
O
A3
C1

30
ESI: (M + H)+ =
0.13
FM1
(KBr): C═O











940/2/4 (Br2)


1701.1; 1641.3



N48
AS1
1
O
A3
C1

52

0.58
FM7
(KBr): C═O














1641.3



N77
AS1
1
O
A3
C4

32
ESI: (M + H)+ =


(KBr): C═O











955/7/9 (Br,)


1645; 1713


294
N66
AS4
1
O
A7
C1
NEt3 as base
31
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O











895/7/9 (Br2)


1653; 1772.5;














1716.5


323
N104
AS1
1
O
A0
C4
DIEA
18
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O











799/801/803


1624











(Br2)


324
N105
AS1
1
O
A0
C4
DIEA
24
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O











773/5/7/9


1624/1667











(Br2/Cl)


325
N106
AS1
1
O
A0
C4
DIEA
22
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O











725/7/9 (Br2)


1626/1662.5


326
N71
AS1
1
O
A0
C1
DIEA
20
ESI: (M + H)+ =
0.16
FM1
(KBr): C═O











752/4/6 (Br2)


1624/1680


327
N71
AS4
1
O
A0
C4
DIEA
24
ESI: (M + H)+ =
0.48
FM1
(KBr): C═O











750/2/4 (Br2)


1618/1682


328
N107
AS1
1
O
A0
C4
DIEA
17
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O











769/71/73 (Br7)


1651


329
N108
AS4
1
O
A0
C4
DIEA
16
ESI: (M + H)+ =
0.31
FM1
(KBr): C═O











781/83/85 (Br2)


1620/1674


330
N108
AS4
1
O
A0
C1
DIEA/DMF
15
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O











781/83/85 (Br2)


1620/1678


331
N108
AS4
1
O
A0
C20
DIEA/DMF
15
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O











800/802/804


1616/1680











(Br2)


332
N109
AS1
1
O
A0
C4
DIEA/DMF
39
ESI: (M + H)+ =
0.32
FM1
(KBr): C═O











745/7/9 (Br2)


1665


333
N110
AS1
1
O
A0
C4
DIEA/DMF
52
ESI: (M + H)+ =
0.34
FM1
(KBr): C═O











745/7/9 (Br2)


1636


334
N111
AS14
1
O
A0
C1
DIEA/DMF
18
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O











649


1626/1688


335
N109
AS4
1
O
A0
C4
DIEA/DMF
46
ESI: (M + H)+ =
0.47
FM1
(KBr): C═O











744/6/8 (Br2)


1618


336
N110
AS1
1
O
A0
C8
DIEA/DMF
25
ESI: (M + H)+ =
0.22
FM1
(KBr): C═O











751/3/5 (Br2)


1645


337
N109
AS1
1
O
A0
C8
DIEA/DMF
32
ESI: (M + H)+ =
0.21
FM1
(KBr): C═O











751/3/5 (Br2)


1645


338
N109
AS4
1
H2
A0
C8
DIEA/
38
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O









DMF

736/8/40 (Br2)


1653


339
N110
AS4
1
H2
A0
C8
DIEA/
39
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O









DMF

736/8/40 (Br2)


1653


340
N66
AS1
1
O
A0
C20
DIEA/
33
ESI: (M + H)+ =
0.12
FM1
(KBr): C═O









DMF

759/61/63 (Br2)


1618/1657


341
N71
AS1
1
O
A0
C20
DIEA/
31
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









DMF

771/3/5 (Br2)


1620/1680


342
N112
AS4
1
O
A0
C20
DIEA/
27
ESI: (M + H)+ =
0.47
FM1
(KBr): C═O









DMF

776/8/80 (Br2)


1618/1682


343
N112
AS1
1
O
A0
C20
DIEA/
26
ESI: (M + H)+ =
0.11
FM1
(KBr): C═O









DMF

777/9/81 (Br2)


1624/1678


344
N71
AS1
1
O
A0
C37
DIEA/
52
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O









DMF

771/3/5 (Br2)


1622/1680


345
N66
AS1
1
O
A0
C37
DIEA/
50
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O









DMF

759/61/63 (Br2)


1626/1659


346
N71
AS4
1
O
A0
C37
DIEA/
37
ESI: (M + H)+ =
0.75
FM1
(KBr): C═O









DMF

770/72/74 (Br2)


1620/1682


347
N6
AS4
1
O
A0
C37
DIEA/
45
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O









DMF

758/60/62 (Br2)


1620/1663


348
N113
AS4
1
O
A0
C20
DIEA/
24
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O









DMF

771/3/5 (BR2)


1616/1701


349
N113
AS4
1
O
A0
C8
DIEA/
40
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O









DMF

757/59/61 (Br2)


1616/1699


350
N111
AS4
1
O
A0
C20

33
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O











838/40/42 (Br2)


1620/1688


351
N111
AS4
1
O
A0
C8

39
ESI: (M + H)+ =
0.64
FM1
(KBr): C═O











824/6/8 (Br2)


1620/1688


352
N111
AS1
1
O
A0
C8

36
ESI: (M + H)+ =
0.37
FM1
(KBr): C═O











825/7/9 (Br2)


1644/1688


353
N112
AS1
1
O
A0
C8

24
ESI: (M + H)+ =
0.28
FM1
(KBr): C═O











763/5/7 (Br2)


1624/1684


355
N113
AS4
1
O
A0
C11
DIEA/
 6
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O









DMF

772/4/6 (Br2)


1620/1697


356
N66
AS4
1
O
A0
C38
DIEA/
31
ESI: (M + H)+ =
0.23
FM1
(KBr): C═O









DMF

785/7/9 (Br2)


1624/1664


357
N112
AS4
1
O
A0
C11
DIEA/
 5
ESI: (M + H)+ =
0.37
FM1









DMF

777/79/81 (Br2)


358
N111
AS1
1
O
A0
C11
DIEA/
13
ESI: (M + H)+ =
0.09
FM1
(KBr): C═O









DMF

840/42/44 (Br2)


1624/1686


359
N111
AS4
1
O
A0
C11
DIEA/
24

0.39
FM1
(KBr): C═O









DMF




1622/1686


360
N109
AS4
1
O
A0
C8
DIEA/
25
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O









DMF

750/52/54 (Br2)


1618/1657


361
N110
AS4
1
O
A0
C11
DIEA/
35
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O









DMF

750/52/54 (Br2)


1622/1649


362
N110
AS4
1
O
A0
C8
DIEA/
24
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O









DMF

750/52/54 (Br2)


1649


363
N111
AS4
1
O
A0
C37
DIEA/
25

0.53
FM1
(KBr): C═O









DMF




1622/1688


364
N111
AS1
1
O
A0
C37
DIEA/
24
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O









DMF

839/41/43 (Br2)


1624/1686


366
N66
AS4
1
O
A0
C39

67
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O











772/4/6 (Br2)


1618/1665


367
N71
AS4
1
O
A0
C39
DIEA/
12
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O









DMF

784/6/8 (Br2)


1618/1684


368
N111
AS4
1
O
A0
C39
DIEA/
37
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O









DMF

852/4/6 (Br2)


1618/1686


369
N114
AS4
1
O
A0
C8

15
ESI: (M + H)+ =
0.58
FM1
(KBr): C═O











824/6/8 (Br2)


1618/1686


370
N66
AS4
1
O
A0
C40
DIEA/
35
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O









DMF

773/5/7 (Br2)


1622/1660


371
N111
AS4
1
O
A0
C40
DIEA/
58
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O









DMF

853/5/7 (Br2)


1622/1687


373
N115
AS4
1
O
A0
C8
DIEA/
43
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O









DMF

822/4/6/8 (Br3)


1620/1670


374
N116
AS4
1
O
A0
C20

27
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O











784/6/8 (Br)


1618/1680


375
N117
AS4
1
O
A0
C20

23
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O











815/7/9 (Br)


1620/1687


376
N118
AS4
1
O
A0
C20

30

0.56
FM1
(KBr): C═O














1620/1684


377
N119
AS4
1
O
A0
C20

74
ESI: (M + H)+ =
0.61
FM1
(KBr): C═O











848/50/52/54


1616/1685











(Br3)


418
N111
AS4
1
O
A0
C38
DIEA/
23
ESI: (M + H)+ =
0.27
FM1
(KBr): C═O









DMF

865/7/9 (Br)


1622/1687


490
N113
AS1
1
O
A0
C20
DIEA/
37
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









DMF

772/4/6 (Br2)


1622/1699


491
N113
AS1
1
O
A0
C8
DIEA/
94
ESI: (M + H)+ =
0.37
FM1
(KBr): C═O









DMF

758/60/62 (Br2)


1624/1691


492
N113
AS1
1
O
A0
C11
DIEA/
42
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









DMF

773/5/7 (Br2)


1678


495
N133
AS4
1
O
A0
C20

45
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O











846/48/50 (Br2)


1620/1682


379
N71
AS1
1
O
A0
C3

39
ESI: (M + H)+ =
0.41
FM4
(KBr): C═O











769/71/73 (Br2)


1680


380
N71
AS4
1
O
A0
C3

40
ESI: (M + H)+ =
0.47
FM4
(KBr): C═O











768/70/72 (Br2)


1618/1682


381
N71
AS1
1
O
A0
C42

11
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O











752/54/56 (Br2)


1624/1682


382
N66
AS1
1
O
A0
C42

18
ESI: (M + H)+ =
0.16
FM4
(KBr): C═O











740/42/44 (Br2)


1630/1653


383
N66
AS4
1
O
A0
C42

47
ESI: (M + H)+ =
0.25
FM4
(KBr): C═O











739/41/43 (Br2)


1626/1659


384
N93
AS1
1
O
A0
C1

11
ESI: (M + H)+ =
0.20
FM7
(KBr): C═O











790/92/94 (Br2)


1636/1705


385
N71
AS4
1
O
A0
C42

37
ESI: (M + H)+ =
0.30
FM4
(KBr): C═O











751/53/55 (Br2)


1620/1680


386
N71
AS4
1
O
A0
C18

26
ESI: (M + H)+ =
0.27
FM4
(KBr): C═O











782/4/6 (Br2)


1620/1682


387
N66
AS4
1
O
A0
C5

62
ESI: (M + H)+ =
0.38
FM4
(KBr): C═O











739/41/43 (Br2)


1626/1663


388
N71
AS4
1
O
A0
C5

55
ESI: (M + H)+ =
0.39
FM4
(KBr): C═O











751/3/5 (Br2)


1618/1684


389
N66
AS1
1
O
A0
C43

59
ESI: (M + H)+ =
0.32
CH2Cl2/MeOH/
(KBr): C═O











796/98/800

NH4OH 9/1/0.1
1653











(Br2)


390
N135
AS4
1
O
A0
C18

 5
ESI: (M + H)+ =
0.71
FM1
(KBr): C═O











853/5/7 (Br2)


1622/1653


391
N135
AS1
1
O
A0
C18

 6
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O











854/6/8 (Br2)


1659


392
N120
AS1
1
O
A0
C4

12
ESI: (M + H)+ =
0.41
CH2Cl2/MeOH/
(KBr): C═O











763/5/7 (Br2)

NH4OH 9/1/0.1
1618/1639


393
N66
AS1
1
O
A0
C44

28
ESI: (M + H)+ =
0.50
CH2Cl2/MeOH/
(KBr): C═O











763/5/7 (Br2)

NH4OH 9/1/0.1
1659


394
N66
AS4
1
O
A0
C21

37
ESI: (M + H)+ =
0.35
EE/MeOH/
(KBr): C═O











740/42/44 (Br2)

AcOH 75/25/0.5
1659


396
N71
AS1
1
O
A0
C21

49
ESI: (M + H)+ =
0.30
EE/MeOH/
(KBr): C═O











753/5/7 (Br2)

AcOH 75/25/0.5
1622/1678


397
N66
AS1
1
O
A0
C21

62
ESI: (M + H)+ =
0.35
EE/MeOH/
(KBr): C═O











741/3/5 (Br2)

AcOH 75/25/0.5
1649


398
N121
AS4
1
O
A0
C8

80
ESI: (M + H)+ =
0.55
CH2Cl2/MeOH/
(KBr): C═O











743/5/7 (Br2)

NH4OH 9/1/0.1
1618/1668


399
N122
AS4
1
O
A0
C18

40
ESI: (M + H)+ =
0.62
FM1
(KBr): C═O











800/2/4 (Br2)


1622/1682


400
N136
AS4
1
O
A0
C8

11
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O











741/3/5 (Br2)


1622/1653


401
N66
AS1
1
O
A0
C45

19
ESI: (M + H)+ =
0.65
CH2Cl2/MeOH/
(KBr): C═O











749/51/53 (Br2)

NH4OH 9/1/0.1
1659


402
N136
AS4
1
O
A0
C1

10
ESI: (M + H)+ =
0.42
CH2Cl2/MeOH/
(KBr): C═O











736/8/40 (Br2)

NH4OH 9/1/0.1
1649


403
N121
AS4
1
O
A0
C1

25
ESI: (M + H)+ =
0.43
CH2Cl2/MeOH/
(KBr): C═O











738/40/42 (Br2)

NH4OH 9/1/0.1
1626/1676


404
N66
AS4
1
O
A0
C46

58
ESI: (M + H)+ =
0.29
CH2Cy MeOH/
(KBr): C═O











766/8/70 (Br2)

NH4OH 9/1/0.1
1624/1663


405
N66
AS1
1
O
A0
C47

40
ESI: (M − H)− =
0.3
EE/MeOH 9/1
(KBr): C═O











752/4/6 (Br2)


1659


406
N136
AS1
1
O
A0
C1

16
ESI: (M + H)+ =
0.34
FM7
(KBr): C═O











737/39/41 (Br2)


1645


407
N121
AS1
1
O
A0
C1

15
ESI: (M + H)+ =
0.36
FM7
(KBr): C═O











739/41/43 (Br2)


1638


408
N71
AS4
1
O
A0
C48

47
ESI: (M + Hr =
0.17
CH2Cl2/MeOH/
(KBr): C═O











792/4/6 (Br2)

NH4OH 9/1/0.1
1620/1680


409
N66
AS4
1
O
A0
C48

31
ESI: (M + H)+ =
0.43
CH2Cl2/MeOH/
(KBr): C═O











780/2/4 (Br2)

NH4OH 9/1/0.1
1665/1736


410
N66
AS1
1
O
A0
C49

51

0.24
EE/MeOH 9/1
(KBr): C═O














1661


411
N71
AS4
1
O
A0
C44

45
ESI: (M + Na)+ =
0.35
EE/MeOH 9/1
(KBr): C═O











796/98/800


1728











(Br2)


412
N66
AS1
1
O
A0
C50

58
ESI: (M + H)+ =
0.47
EE/MeOH 9/1
(KBr): C═O











756/58/60 (Br2)


1642/1661


413
N66
AS1
1
O
A0
C51

16
ESI: (M + H)+ =
0.47
EE/MeOH/
(KBr): C═O











788/90/92 (Br2)

NH4OH 5/5/0.1
1631


414
N66
AS4
1
O
A0
C52

34
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O











747/49/51 (Br2)


1622/1662


415
N71
AS4
1
O
A0
C52

35
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O











759/61/63 (Br2)


1620/1682


416
N66
AS4
1
O
A0
C53

53
ESI: (M + H)+ =
0.45
CH2Cl2/MeOH/
(KBr): C═O











759/61/63 (Br2)

NH4OH 9/1/0.1
1620/1664


417
N71
AS4
1
O
A0
C53

39
ESI: (M + H)+ =
0.43

(KBr): C═O











771/3/5 (Br2)


1620/1684


496
N66
AS4
1
O
A0
C64

57

0.5
CH2Cl2/MeOH/
(KBr): C═O













NH4OH 9/1/0.1
1635


497
N66
AS1
1
O
A0
C53

60
ESI: (M + H)+ =
0.31
CH2Cl2/MeOH/
(KBr): C═O











760/2/4 (Br2)

NH4OH
1676













50/50/0.5


498
N66
AS4
1
O
A0
C65

60
ESI: (M + H)+ =
0.39
FM1
(KBr): C═O











760/2/4 (Br2)


1676


499
N71
AS4
1
O
A0
C65

53
ESI: (M + H)+ =
0.39
FM1
(KBr): C═O











785/7/9 (Br2)


1618/1684


500
N66
AS4
1
O
A0
C51

71
ESI: (M + H)+ =
0.15
CH2Cl2/MeOH/
(KBr): C═O











787/89/91 (Br2)

NH4OH 9/1/0.1
1628


501
N71
AS1
1
O
A0
C53

71
ESI: (M + H)+ =
0.25
CH2Cl2/MeOH/
(KBr): C═O











772/4/6 (Br2)

NH4OH
1676













50/50/0.5


502
N66
AS1
1
O
A0
C65

42
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O











774/6/8 (Br2)


1626/1657


503
N71
AS1
1
O
A0
C65

48
ESI: M + H)+ =
0.12
FM1
(KBr): C═O











786/88/90 (Br2)


1620/1682


504
N66
AS4
1
O
A0
C66

67
ESI: (M + H)+ =
0.65
CH2Cl2MeOH/
(KBr): C═O











787/89/91 (Br2)

NH4OH
1624













50/50/0.5


297
N71
AS4
1
H2
A0
C8

 9
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











742/4/6 (Br2)


1684


298
N71
AS13
1
H2
A0
C8

 6
ESI: (M + H)+ =
0.16
FM1
(KBr): C═O











664/6 (Br)


1622/1682


299
N66
AS4
1
H2
A0
C8

21
ESI: (M + H)+ =
0.25
FM1
(KBr): C═O











730/2/4 (Br2)


1666


300
N66
AS13
1
H2
A0
C8

14
ESI: (M + H)+ =
0.19
FM1
(KBr): C═O











652/4 (Br)


1666


301
N71
AS1
1
H2
A0
C8

26
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











743/5/7 (Br2)


1682


420
N87
AS1
1
O
A0
C4

45
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O











797/99/801


1624/1665/











(Br2)


1719


422
N87
AS1
1
O
A0
C8

35
ESI: (M + H) + =
0.54
FM1
(KBr): C═O











805/7/9 (Br2)


1628/1668/














1720


431
N125
AS4
1
O
A0
C8

89
ESI: (M + H)+ =
0.75
FM1
(KBr): C═O











772/4/6 (Br2)


1713/1773


432
N125
AS1
1
O
A0
C4

59
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O











767/69/71 (Br2)


1622/1711/














1773


433
N126
AS4
1
O
A0
C4

33
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O











780/2/4 (Br2)


1709/1769


434
N126
AS1
1
O
A0
C8

53
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O











787/89/91 (Br2)


1626/1707


440
N127
AS4
1
O
A0
C8

67
ESI: (M + H)+ =
0.67
FM1
(KBr): C═O











780/2/4 (Br2)


1618


441
N127
AS4
1
O
A0
C20

89
ESI: (M + H)+ =
0.24
EE/MeOH/
(KBr): C═O











794/6/8 (Br2)

NH4OH
1618













8/1.5/0.3


442
N127
AS4
1
O
A0
C4

83
ESI: (M + H)+ =
0.37
EE/MeOH/
(KBr): C═O











774/6/8 (Br2)

NH4OH
1616/1732













8/1.5/0.3


456
N66
AS16
1
O
A0
C8

83
ESI: (M + H)+ =
0.32
EE/MeOH/
(KBr): C═O











641/3/5 (Cl2)

NH4OH
1624/1665













8/1.5/0.1


466
N128
AS4
1
O
A0
C8

13
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O











832/4/6 (Br2)


1684


467
N129
AS4
1
O
A0
C8

16
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O











806/08/10 (Br2)


1618/1682


468
N129
AS1
1
O
A0
C8

28
ESI: (M + H)+ =
0.29
FM1
(KBr): C═O











807/09/11 (Br2)


1630/1680


470
N128
AS1
1
O
A0
C8

81
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O











835/7/9 (Br2)


1684


473
N130
AS1
1
O
A0
C8

40
ESI: (M + H)+ =
0.51
FM1
(KBr): C═O











787/89/91 (Br2)


1624/1678


474
N130
AS4
1
O
A0
C8

17
ESI: (M + Hr =
0.71
FM1
(KBr): C═O











786/88/90 (Br2)


1618/1684


477
N66
AS16
1
O
A0
C1

33
ESI: (M + H)+ =
0.53
EE/MeOH/
(KBr): C═O











636/38/40 (Cl2)

NH4OH 9/1/1
1661













(v/v/v)


481
N131
AS4
1
O
A0
C37

30
ESI: (M + H)+ =
0.15
CH2Cl2/
(KBr): C═O











838/40/42/44

MeOH 7/3
1618/1685











(Br2; Cl2)

(v/v)


482
N131
AS4
1
O
A0
C20

24
ESI: (M + H)+ =
0.15
CH2Cl2/
(KBr): C═O











838/40/42/44

MeOH 7/3
1618/1685











(Br2; Cl2)

(v/v)


483
N132
AS4
1
O
A0
C20

62
ESI: (M + H)+ =
0.55
FM1
(KBr): C═O











804/6/8/10


1684











(Br2; Cl)


484
N132
AS4
1
O
A0
C37

85
ESI: (M + H)+ =
0.60
FM1
(KBr): C═O











804/6/8/10


1616/1686











(Br2; Cl)


505
N134
AS4
1
O
A0
C8

81
ESI: (M + H)+ =
0.74
FM1
(KBr): C═O











781/3/5 (Br2)


1616/1714


292
N66
AS1
1
H2
A0
C8

 6
ESI: (M + H)+ =
0.25
FM1
(KBr): C═O











731/3/5 (Br2)


1607/1664


245
N72
AS4
1
H2
A0
C8

19
ESI: (M + H)+ =
0.30
FM1
(KBr): C═O











731/3/5 (Br2)


1668


220
N15
AS1
1
H2
A0
C8

 6
ESI: (M + H)+ =
0.30
FM1
(KBr): C═O











717/19/21 (Br2)


1697.3


307
N87
AS4
1
O
A0
C4

27
ESI: (M + H)+ =
0.50
FM1
(KBr): C═O











796/98/800


1618/1670/











(Br2)


1718


178
N74
AS1
1
O
A0
C4

33
ESI: (M + H)+ =
0.60
EE/MeOH/
(KBr): C═O











679/81/83 (Br2)

AcOH
1624













50/50/1













(v/v/v)


395
N71
AS4
1
O
A0
C21

22
ESI: (M + H)+ =
0.25
EE/MeOH/











752/4/6 (Br2)

AcOH













50/25/0.5













(v/v/v)


509
N119
AS4
1
O
A0
C38
DMF
45
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











875/7/9/81


1687/1618











(Br3)


510
N118
AS4
1
O
A0
C38
DMF
34
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O











827/29/31 (Br2)


1682/1620


519
N137
AS4
1
O
A0
C20
THF/
62
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









DMF

786/88/90 (Br2)


1618/1678


520
N138
AS4
1
O
A0
C20
THF/DMF
31
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O











906/08/10


1693











(Bra)



N66
AS4
1
O
A0
C69
DMF
100 


533
N139
AS1
1
O
A0
C8

44
ESI: (M + H)+ =
0.1
FM5
(KBr): C═O











746/48/50


1628











(Br2)


534
N139
AS4
1
O
A0
C20

60
ESI: (M + H)+ =
0.2
FM5
(KBr): C═O











759/61/63


1618/1672











(Br2)


535
N139
AS1
1
O
A0
C53

34
ESI: (M + H)+ =
0.1
FM5
(KBr): C═O











761/63/65


1624/1670











(Br2)


536
N140
AS4
1
O
A0
C8

40
ESI: (M + H)+ =
0.37
FM1
(KBr): C═O











745/7/9


1616/1676











(Br2)


537
N140
AS1
1
O
A0
C8

  33.4
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O











746/48/50


1614/1672











(Br2)


551
N66
AS1
1
O
A0
C66

41
ESI: (M + H)+ =
0.3
EE/MeOH/
(KBr): C═O











788/90/92

NH4OH
1628











(Br2)

50/50/0.5


552
N66
AS4
1
O
A0
C78

83
ESI: (M + H)+ =
0.6
CH2Cl2/MeOH/
(KBr): C═O











787/89/91

NH4OH
1620











(Br2)

80/20/1


553
N66
AS1
1
O
A0
C78

30
ESI: (M + H)+ =
0.5
CH2Cl2/MeOH/
(KBr): C═O











788/90/92

NH4OH
1626











(Br2)

80/20/1


554
N71
AS4
1
O
A0
C78

67
ESI: (M + H)+ =
0.5
CH2Cl2/MeOH/
(KBr): C═O











799/801/803

NH4OH
1622/1684











(Br2)

80/20/1


555
N71
AS1
1
O
A0
C78

26
ESI: (M + H)+ =
0.5
CH2Cl2/MeOH/
(KBr): C═O











800/02/04

NH4OH
1624/1684











(Br2)

80/20/1


556
N66
AS4
1
O
A0
C70

71
ESI: (M + H)+ =
0.6
CH2Cl2/MeOH/
(KBr): C═O











788/90/92

NH4OH
1653











(Br2)

50/50/0.5


557
N71
AS4
1
O
A0
C70

27
ESI: (M + H)+ =
0.8
CH2Cl2/MeOH/











800/02/04

NH4OH











(Br2)

50/50/0.5


558
N66
AS1
1
O
A0
C64

61
ESI: (M + H)+ =
0.3
CH2Cl2/MeOH/
(KBr): C═O











790/92/94

NH4OH
1635











(Br2)

90/10/1


559
N141
AS4
1
O
A0
C20

80
ESI: (M + H)+ =
0.3
CH2Cl2/MeOH/
(KBr): C═O











626/28/30

NH4OH
1618/1714











(Br2)

90/10/1


560
N66
AS4
1
O
A0
C71

59
ESI: (M + H)+ =
0.3
CH2Cl2/MeOH/
(KBr): C═O











837/39/41

NH4OH
1628/62











(Br2)

90/10/1


561
N71
AS4
1
O
A0
C71

56
ESI: (M + H)+ =
0.2
CH2Cl2/
(KBr): C═O











849/51/53 (Br2)

MeOH/
1618/1684













NH4OH













90/10/1


562
N66
AS1
1
O
A0
C70

15
ESI: (M + H)+ =
0.6
CH2Cl2/
(KBr): C═O











789/91/93 (Br2)

MeOH/
1676













NH4OH













50/50/0.5


563
N71
AS1
1
O
A0
C70

27
ESI: (M + H)+ =
0.6
CH2Cl2/
(KBr): C═O











801/3/5 (Br2)

MeOH/
1678













NH4OH













70/30/1


565
N66
AS4
1
O
A0
C72

51
ESI: (M + H)+ =
0.2
CH2Cl2/
(KBr): C═O











787/89/91 (Br2)

MeOH/
1622/1658













NH4OH













80/20/1


566
N71
AS4
1
O
A0
C72

65
ESI: (M + H)+ =
0.2
CH2Cl2/
(KBr): C═O











799/801/803

MeOH/
1620/1682











(Br2)

NH4OH













80/20/1


567
N136
AS4
1
O
A0
C53

65
ESI: (M + H)+ =
0.5
CH2Cl2/
(KBr): C═O











756/58/60 (Br2)

MeOH/
1641













NH4OH













80/20/1


568
N136
AS4
1
O
A0
C72

76
ESI: (M + H)+ =
0.2
CH2Cl2/
(KBr): C═O











784/6/8 (Br2)

MeOH/
1637













NH4OH













80/20/1


569
N136
AS1
1
O
A0
C53

63
ESI: (M + H)+ =
0.4
CH2Cl2/
(KBr): C═O











757/59/61 (Br2)

MeOH/
1643













NH4OH













80/20/1


570
N66
AS31
1
O
A0
C20

88
ESI: (M + H)+ =
0.6
CH2Cl2/
(KBr): C═O











640

MeOH/
1622/1664













NH4OH













80/20/1


571
N66
AS31
1
O
A0
C53

82
ESI: (M + H)+ =
0.8
CH2Cl2/
(KBr): C═O











641

MeOH/
1664













NH4OH













80/20/1


572
N71
AS31
1
O
A0
C20

100 
ESI: (M + H)+ =
0.4
CH2Cl2/
(KBr): C═O











652

MeOH/
1620/1684













NH4OH













80/20/1


573
N71
AS31
1
O
A0
C53

48
ESI: (M + H)+ =
0.4
CH2Cl2/
(KBr): C═O











653

MeOH/
1622/1684













NH4OH













80/20/1


576
N66
AS11
1
O
A0
C53

35
ESI: (M + H)+ =
0.65
CH2Cl2/
(KBr): C═O











727

MeOH/
1664/1732













NH4OH













80/20/1


577
N71
AS11
1
O
A0
C53

73
ESI: (M + H)+ =
0.18
EE/
(KBr): C═O











739

MeOH/
1684/1734













NH4OH













50/50/0.5


580
N66
AS11
1
O
A0
C20

65
ESI: (M + H)+ =
0.5
CH2Cl2/
(KBr): C═O











706

MeOH/
1664/1732













NH4OH













80/20/1


581
N71
AS11
1
O
A0
C20

38
ESI: (M + H)+ =
0.2
CH2Cl2/
(KBr): C═O











738

MeOH/
1684/1734













NH4OH













90/10/1


582
N143
AS4
1
O
A0
C20

61
ESI: (M + H)+ =
0.5
CH2Cl2/
(KBr): C═O











758/60/62

MeOH/
1615













NH4OH













90/10/1


583
N66
AS31
1
O
A0
C72

50
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O











669


1664


584
N71
AS31
1
O
A0
C72

68
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O











681


1622/1684


585
N144
AS4
1
O
A0
C8

50
ESI: (M + H)+ =
0.43
FM5
(KBr): C═O











927/29/31/33


1616/1684











(Br4)


586
N144
AS4
1
O
A0
C53

85
ESI: (M + H)+ =
0.67
FM1
(KBr): C═O











942/4/6/8 (Br4)


1680


587
N66
AS11
1
O
A0
C72

37
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O











755


1622/1658/














1732


588
N71
AS11
1
O
A0
C72

81
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O











767


1684/1732


619
N71
AS19
1
O
A0
C8

  27.9

0.3
EE/MeOH/
(KBr): C═O













NH4OH
1622/1684













9/1/0.3


620
N66
AS35
1
O
A0
C8

36
ESI: (M − H)− =
0.25
MeOH
(KBr): C═O











598


1628/1664


621
N66
AS36
1
O
A0
C8

32
ESI: (M − H)− =
0.56
FM1
(KBr): C═O











587


1626/1666


622
N71
AS36
1
O
A0
C8

32
ESI: (M − H)− =
0.44
FM1
(KBr): C═O











599


1622/1684


623
N109
AS36
1
O
A0
C8

37
ESI: (M − H)− =
0.6
FM1
(KBr): C═O











593


1626/1649


624
N118
AS36
1
O
A0
C8

55
ESI: (M − H)− =
0.6
FM1
(KBr): C═O











629


1622/1684


625
N111
AS36
1
O
A0
C8

47
ESI: (M − H)− =
0.61
FM1
(KBr): C═O











667


1624/1687


626
N111
AS19
1
O
A0
C8

20
ESI: (M − H)− =
0.28
EE/MeOH/
(KBr): C═O











731/3 (Br)

NH4OH
1624/1687













9/1/0.3


627
N109
AS19
1
O
A0
C8

16
ESI: (M − H)− =
0.28
EE/MeOH/
(KBr): C═O











657/9 (Br)

NH4OH
1653













9/1/0.3


633
N118
AS19
1
O
A0
C8

20
ESI: (M + H)+ =
0.18
EE/MeOH/
(KBr): C═O











693/5 (Br)

NH4OH
1622/1684













9/1/0.3



N66
AS1
1
O
A0
C69

100 

0.3
FM4
(KBr): C═O














1668









EXAMPLE 4
Preparation of Compounds ofGeneralFormula:




1-[4-amino-3,5-dibromo-N-[4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperazine (No. 91)
A mixture of 0.35 g (2.1 mmol) of CDT, 1.0 g (1.4 mmol) of 4-(1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazol-1-yl)-piperidine, 0.5 ml of (2.8 mmol) of DIEA and 100 ml of tetrahydrofuran was stirred for 1 hour whilst cooling with ice and then for 30 minutes at ambient temperature. With stirring 0.46 g (1.75 mmol) of 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(4-pyridinyl)piperazine and 0.32 ml of (1.8 mmol) of DIEA were added and refluxed for 3 hours. The reaction mixture was diluted with 100 ml of ethyl acetate and the organic phase was washed twice with aqueous saturated sodium hydrogen carbonate solution. The combined aqueous phases were then extracted once with ethyl acetate/tetrahydrofuran=1/1 (v/v) and the combined organic phases were washed once with saturated aqueous saline solution. After drying the organic phase and eliminating the solvent in vacuo the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol=9/1 (v/v)). 120 mg (12% of theory) of a colourless foam were obtained.
IR (KBr): 1626. 1686 cm−1 (C═O)
















IR (KBr):
1626. 1686 cm−1  (C═O)



Rf:
0.62 (FM3)



ESI-MS:
(M + H)+ = 731/733/735 (Br2)




(M + H + Na)++ = 377/378/379 (Br2)










The following were prepared analogously (in each case n=1):





























%




M.p.


No.
RCO
R2
A
NR3R4
n
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]
(° C.)




























N16
AS1
A3
C1
1
NEt3 as base
31
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











974/6/8 (Br2)


1641.3; 1695.3


86
N53
AS4
A0
C1
1
DMF as solvent
23
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










739/41/43 (Br2)


1641.3; 1697.3


87
N54
AS4
A0
C1
1
DMF als
81
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O








Lösemittel

739/41/43 (Br2)


1620.1; 1697.3


92
N57
AS4
A0
C1
1
DMF as solvent
60
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










712/4/6 (Br2)


1597; 1635.5


93
N47
AS4
A0
C1
1

23
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










636/8/40 (Br2)


1622; 1675


94
N45
AS4
A0
C1
1

45
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










739/41/43 (Br2)


1598.9; 1620.1


95
N57
AS1
A0
C1
1
DMF as solvent
13
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










713/5/7 (Br2)


1637.5


96
N53
AS1
A0
C1
1
DMF as solvent
15
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










740/2/4 (Br2)


1633.6; 1687.6


97
N54
AS1
A0
C1
1
DMF as solvent
31
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










740/2/4 (Br2)


1635.5; 1695.3


107
N59
AS4
A0
C1
1

76
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O










694/6/8 (Br2)


1597; 1635.5


108
N45
AS1
A0
C1
1

37
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










740/2/4 (Br2)


1633.6; 1708.8


109
N59
AS1
A0
C1
1

30
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










695/7/9 (Br2)


1647.4


116
N60
AS4
A0
C1
1
DMF as solvent
80
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










753/5/7 (Br2)


1623.7; 1676.1;













1712.7


117
N60
AS1
A0
C1
1
DMF as solvent
50
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










754/6/8 (Br2)


1617; 1650;













1670; 1712.7


118
N47
AS1
A0
C1
1

29
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O










637/9/41 (Br2)


1639.4


121
N61
AS1
A0
C1
1

12.4
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










727/9/31 (Br2)


1635.5; 1705


122
N61
AS4
A0
C1
1

42
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










726/8/30 (Br2)


1620.1; 1706.9


125
N15
AS7
A0
C1
1
NEt3 as base
4.4
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










598


1708.8


126
N15
AS7
A0
C4
1
NEt3 as base
57
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O
188.0










597


1622; 1708.8


127
N15
AS7
A0
C8
1
NEt3 as
16
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O
168-








base

603


1622; 1697.3
170


137
N94
AS4
A0
C4
1

42
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O










708/10/12 (Br2)


1618


138
N95
AS4
A0
C8
1
NEt3 as
29
ESI: (M + H)+ =
0.8
FM1
(KBr): C═O








base

743/5/7 (Br2)


1713


139
N61
AS1
A3
C1
1

41
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










955/7/9 (Br2)


1640; 1709


140
N60
AS1
A3
C1
1

66
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










982/4/6 (Br2)


1645; 1712


143
N66
AS1
A0
C4
1
DMF as
69
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O








solvent

739/41/43 (Br2)


1624; 1659


144
N96
AS1
A0
C4
1

54
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O










725/7/9 (Br2)


1616


145
N61
AS1
A0
C4
1

48
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










724/6/8 (Br2)


1624; 1709


146
N15
AS14
A0
C1
1
DMF as
53
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O








solvent

555


1636; 1701


147
N61
AS4
A0
C11
1

30
ESI: (M + H)+ =
0.7
FM1
(KBr): C═O










746/48/50 (Br2)


1620; 1713


148
N66
AS1
A0
C8
1
THF/DMF
58
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O








as solvent

745/7/9 (Br2)


1628; 1663


149
N69
AS1
A0
C4
1
THF/DMF
61
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O








as solvent

739/41/43 (Br2)


1624; 1675


150
N97
AS1
A0
C4
1
THF/DMSO
32
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O








as solvent

783/85/87 (Br2)


1709


152
N71
AS1
A0
C4
1

40
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










751/53/55 (Br2)


1622; 1684


153
N65
AS1
A0
C4
1

51
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










751/53/55 (Br2)


1626; 1678



N66
AS1
A3
C1
1

37


225
N66
AS1
A0
C1
1
THF/DMF
48
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O








as solvent

740/42/44 (Br2)


1650; 1670


226
N66
AS4
A0
C8
1
THF/DMF
88
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O








as solvent

744/6/8 (Br2)


1618; 1661


227
N69
AS4
A0
C8
1
THF/DMF
72
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O








as solvent

744/6/8 (Br2)


1618; 1680


228
N69
AS1
A0
C8
1
THF/DMF
69
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O








as solvent

745/7/9 (Br2)


1628


229
N70
AS1
A0
C4
1
THF/DMF
39
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O








as solvent

727/29/31 (Br2)


1730


230
N66
AS4
A0
C20
1

49
ESI: (M + H)+ =
0.55
FM1
(KBr): C═O










758/60/62 (Br2)


1614


231
N99
AS4
A0
C8
1
THF/DMF as
68
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O








solvent

758/60/62 (Br2)


1624


239
N71
AS1
A0
C8
1
THF/DMF as
59
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O








solvent

757/59/61 (Br2)


1626; 1680


240
N71
AS4
A0
C11
1

35
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










771/3/5 (Br2)


1615; 1684


241
N71
AS4
A0
C8
1

88
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










756/58/60 (Br2)


1620; 1682


242
N71
AS4
A0
C1
1

40
ESI: (M + H)+ =
0.64
FM1
(KBr): C═O










751/3/5 (Br2)


1615; 1684


243
N71
AS4
A0
C20
1

38
ESI: (M + H)+ =
0.65
FM1
(KBr): C═O










770/2/4 (Br2)


1618; 1684


244
N71
AS1
A0
C11
1

36
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O










772/4/6 (Br2)


1622; 1684



N5
AS1
A3
C1
1
NEt3 as base
24
ESI: (M + H)+ =
0.06
FM1
(KBr): C═O










890/2/4 (Br2)


1641.3



N10
AS1
A3
C1
1
NEt3 as base
55
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O










874/6/8 (Br2)


1641.3



N12
AS1
A3
C1
1
NEt3 as base
35480
ESI: (M + H)+ =
0.43
FM1
(KBr): C═O










902/4/6 (Br2)


1639.4



N22
AS1
A3
C1
1
NEt3 as base
35.5

0.5
FM1



N23
AS1
A3
C1
1
NEt3 as base
31

0.5
FM1



N24
AS1
A3
C1
1
NEt3 as base
35607

0.5
FM1



N46
AS1
A3
C1
1
NEt3 as base
36.2

0.5
FM1
(KBr): C═O













1641.3


83
N15
AS1
A0
C1
1

36.7
ESI: (M + H)+ =
0.62
FM2
(KBr): C═O










726/28/30 (Br2)


1641.3; 1695.3


84
N15
AS1
A0
C4
1

36.3
ESI: (M + H)+ =
0.69
FM2
(KBr): C═O










725/7/9 (Br2);


1624.0; 1699.2










(M + Na)+=










747/49/51 (Br2)


88
N55
AS4
A0
C1
1

93.6
ESI: (M + H)+ =
0.75
FM3
(KBr): C═O










793/5/7/9 (Br2; Cl2)


1641.3; 1708.8


89
N56
AS4
A0
C1
1

30
ESI: (M + H)+ =
0.81
FM1
(KBr): C═O










797/799/801 (Br2)


1641.3; 1697.3;













1749.3


136
N15
AS9
A0
C1
1

14.6
ESI: (M + H)+ =
0.55
FM3
(KBr): C═O










570


1635.5; 1701.1


91
N64
AS4
A0
C1
1

11.7
ESI: (M + H)+ =
0.62
FM3
(KBr): C═O










731/733/735


1625.9; 1685.7



N16
AS1
A3
C5
1
Purification
74
ESI: (M + H)+ =
0.48
FM4
(KBr): C═O








by column

974/976/978 (Br2)


1685.7; 1635.5








chromatog-








raphy: silica








gel/FM4


155
N15
AS1
A0
C3
1

34
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O
165-9










743/5/7 (Br2)


1626; 1695


156
N15
AS1
A0
C19
1

40
ESI: (M + H)+ =
0.47
FM1
(KBr): C═O
155-9










743/5/7 (Br2)


1624; 1695


157
N15
AS4
A0
C19
1

54
ESI: (M + H)+ =
0.79
FM1
(KBr): C═O
151-4










742/4/6 (Br2)


1616; 1697


158
N79
AS4
A0
C1
1

15
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O
132-5










727/29/31 (Br2)


1616; 1695;













1732


159
N77
AS4
A0
C8
1

34
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O










732/4/6 (Br2)


1632


160
N73
AS1
A0
C4
1

12
ESI: (M − H)− =
0.14
FM1
(KBr): C═O










649/651/653 (Br2)


1626


170
N15
AS4
A0
C37
1

62
ESI: (M − H)− =
0.45
FM1
(KBr): C═O
165-70










725/7/9 (Br2)


1620; 1701


171
N79
AS1
A0
C1
1

60
ESI: (M + H)+ =
0.21
FM1
(KBr): C═O
193-7










728/30/32 (Br2)


1637.5


172
N79
AS1
A0
C8
1

27
ESI: (M + H)+ =
0.32
FM1
(KBr): C═O
163-9










733/5/7 (Br2)


1622


185
N77
AS4
A0
C4
1

66
ESI: (M + H)+ =
0.49
FM1
(KBr): C═O










726/28/30 (Br2)


1624


186
N77
AS4
A0
C1
1

76
ESI: (M + H)+ =
0.63
FM1
(KBr): C═O










727/29/31 (Br2)


1635.5


187
N77
AS1
A0
C4
1

67
ESI: (M + H)+ =
0.33
FM1
(KBr): C═O










727/29/31 (Br2)


1627.8


188
N78
AS1
A3
C1
1

63
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O










955/7/9 (Br2)


1637.5;













1774.4; 1701


189
N103
AS4
A0
C8
1

50
ESI: (M + H)+ =
0.71
FM1
(KBr): C═O










713/5/7 (Br2)


1616.3


192
N77
AS1
A0
C1
1

47
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O










728/30/32 (Br2)


1643.3


247
N15
AS10
A3
C4
1

60
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










937/39/41 (Br2)


1639.4; 1701


249
N15
AS4
A0
C22
1

52
ESI: (M + H)+ =
0.59
FM1
(KBr): C═O










744/6/8 (Br2)


1695.3


161
N15
AS4
A0
C21
1

32
ESI: (M + H)+ =
0.61
FM1
(KBr): C═O
163-7










726/28/30 (Br2)


1622; 1701


162
N78
AS1
A0
C4
1

15
ESI: (M + H)+ =
0.48
FM1
(KBr): C═O










726/28/30 (Br2)


1624; 1772.5


163
N73
AS1
A0
C1
1

43
ESI: (M + H)+ =
0.07
FM1
(KBr): C═O










752/4/6 (Br2)


1637.5


164
N79
AS4
A0
C8
1

48
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O
127-32










732/4/6 (Br2)


1616.3


165
N15
AS1
A0
C21
1

27
ESI: (M + H)+ =
0.26
FM1
(KBr): C═O
184-9










727/29/31 (Br2)


1697.3


166
N76
AS1
A0
C4
1

17
ESI: (M + H)+ =
0.23
FM1
(KBr): C═O










665/7/9 (Br2)


1616; 1734


167
N75
AS1
A0
C4
1

20
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O










665/7/9 (Br2)


1624


168
N73
AS1
A3
C4
1

39
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O










879/81/83 (Br2)


1631.7


169
N15
AS1
A0
C37
1

17
ESI: (M + H)+ =
0.31
FM1
(KBr): C═O
156-61










726/28/30 (Br2)


1627.8; 1697.3


173
N15
AS10
A0
C4
1

66
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O
283-4










709/11/13 (Br2)


1627.8; 1656.8;













1695.3


174
N15
AS10
A0
C1
1

42
ESI: (M + H)+ =
0.61
FM1
(KBr): C═O
266-9










710/2/4 (Br2)


1706.9


175
N77
AS1
A0
C8
1

36
ESI: (M + H)+ =
0.24
FM1
(KBr): C═O










733/5/7 (Br2)


1641.3


176
N76
AS1
A3
C4
1

47
ESI: (M + H)+ =
0.21
FM1
(KBr): C═O










893/5/7 (Br2)


1635.5


177
N75
AS1
A3
C4
1

53
ESI: (M + H)+ =
0.14
FM1
(KBr): C═O










893/5/7 (Br2)


1637.5


180
N74
AS1
A3
C4
1

44
ESI: (M + H)+ =
0.26
FM1
(KBr): C═O










907/9/11 (Br2)


1631.7; 1689.5


190
N15
AS1
A3
C18
1

44
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O










985/7/9 (Br2)


1635.5; 1695.3


191
N15
AS10
A3
C1
1

64
ESI: (M + H)+ =
0.56
FM1
(KBr): C═O










938/40/42 (Br2)


1645.2; 1701



N15
AS10
A3
C4
1

91
ESI: (M + H)+ =


(KBr): C═O










937/39/41 (Br2)


1643.3; 1701



N15
AS10
A3
C1
1

64
ESI: (M + H)+ =


(KBr): C═O










938/40/42 (Br2)


1645; 1701


254
N77
AS1
A3
C1
1

37
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










956/8/60 (Br2)


1641



N15
AS4
A3
C18
1

90
ESI: (M + H)+ =


(KBr): C═O










984/6/8 (Br2)


1641.3; 1699


257
N15
AS4
A5
C1
1

17
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O










782/4/6 (Br2)


1643; 1697


258
N100
AS4
A0
C1
1

69
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O










755/7/9 (Br2)


1627.8; 1705


259
N100
AS4
A0
C8
1

70
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O










760/2/4 (Br2)


1695


260
N15
AS4
A0
C23
1

39
ESI: (M + H)+ =
0.36
FM1
(KBr): C═O










796/798/800 (Br2)


1635.5; 1699


261
N15
AS4
A10
C1
1

26
ESI: (M + H)+ =
0.38
FM1
(KBr): C═O










796/798/800 (Br2)


1631.4; 1701


265
N15
AS4
A5
C8
1

20
ESI: (M + H)+ =
0.41
FM1
(KBr): C═O










787/9/91 (Br2)


1635.5; 1697


266
N15
AS4
A6
C1
1

24
ESI: (M + H)+ =
0.43
FM1
(KBr): C═O










796/798/800 (Br2)


1647; 1689.5


262
N80
AS4
A0
C1
1

25
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O










803/5/7 (Br2)


1637.5


263
N15
AS15
A0
C8
1

64
ESI: (M + H)+ =
0.43
FM1
(KBr): C═O










565


1627.8; 1707


264
N15
AS4
A0
C24
1

62
ESI: (M + H)+ =
0.4
FM1
(KBr): C═O










733/5/7 (Br2)


1622; 1701


267
N81
AS4
A3
C8
1

46
ESI: (M + H)+ =
0.55
FM1
(KBr): C═O










974/6/8 (Br2)


1641; 1707


268
N15
AS4
A6
C8
1

27
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










801/3/5 (Br2)


1633.6; 1697


269
N82
AS4
A0
C8
1

86
ESI: (M + H)+ =
0.66
FM1
(KBr): C═O










742/4/6 (Br2)


1620; 1649


270
N82
AS4
A0
C1
1

56
ESI: (M + H)+ =
0.59
FM1
(KBr): C═O










737/39/41 (Br2)


1641


272
N15
AS11
A0
C8
1

76
ESI: (M + H)+ =
0.6
FM1
(KBr): C═O










698


1627.8; 1714.6


273
N15
AS4
A10
C8
1

68
ESI: (M + H)+ =
0.52
FM1
(KBr): C═O










801/3/5 (Br2)


1637.5; 1701


274
N102
AS4
A0
C1
1

76
ESI: (M + H)+ =
0.56
FM1
(KBr): C═O










738/40/42 (Br2)


1664.5


275
N102
AS4
A0
C8
1

55
ESI: (M + H)+ =
0.59
FM1
(KBr): C═O










743/5/7 (Br2)


1618; 1664.5


276
N83
AS4
A0
C1
1

30
ESI: (M + H)+ =
0.48
FM1
(KBr): C═O










745/7/9 (Br2)


1633.6


277
N84
AS4
A0
C8
1

63
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O










744/6/8 (Br2)


1616; 1691.5


278
N84
AS4
A3
C4
1

88
ESI: (M + H)+ =
0.53
FM1
(KBr): C═O










966/8/70(Br2)


1633.6; 1691.5


279
N15
AS4
A0
C26
1

75
ESI: (M + H)+ =
0.44
FM1
(KBr): C═O










732/4/6 (Br2)


1618; 1709


281
N15
AS12
A0
C8
1

21
ESI: (M + H)+ =
0.42
FM1
(KBr): C═O










598


1697


282
N66
AS1
A0
C18
1

19
ESI: (M + H)+ =
0.51
FM1
(KBr): C═O










770/2/4 (Br2)


1624; 1660.6;













1734


284
N66
AS1
A0
C18
1

29
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










771/3/5 (Br2)


1630; 1655


314
N93
AS4
A0
C8
1

81
ESI: (M + H)+ =
0.5
FM1
(KBr): C═O










794/6/8 (Br2)


1618; 1701


315
N93
AS4
A0
C1
1

77
ESI: (M + H)+ =
0.49
FM1
(KBr): C═O










789/91/93 (Br2)


1627.6; 1705


316
N65
AS1
A0
C18
1

15
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O










783/5/7 (Br2)


1624; 1681.8


317
N66
AS4
A0
C3
1

51
ESI: (M + H)+ =
0.62
FM1
(KBr): C═O










778/80/82 (Br2)


1627.6; 1662.5


318
N66
AS1
A0
C3
1

40
ESI: (M + H)+ =
0.41
FM1
(KBr): C═O










557/559/561 (Br2)


1659


319
N66
AS4
A0
C19
1

55
ESI: (M + H)+ =
0.68
FM1
(KBr): C═O










778/780/782 (Br2)


1664.5


320
N65
AS4
A0
C19
1

61
ESI: (M + H)+ =
0.62
FM1
(KBr): C═O










768/70/72 (Br2)


1618; 1682


321
N93
AS1
A0
C4
1

29
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O










789/91/93 (Br2)


1622; 1705



N15
AS1
A3
C5
1

47

0.32
FM1



N19
AS1
A3
C1
1

80
ESI: (M + H)+ =


(KBr): C═O










933/5/7 (Br2)


1641.3









EXAMPLE 5
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine (No. 17)
To a solution of 800 mg (0.86 mmol) of 1-[N2—[N-(4-phenyl-1-piperazinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(1,1-dimethyl-ethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in methanol were added 2 ml of methanol saturated with hydrogen chloride and the mixture was stirred overnight at ambient temperature. The reaction mixture was mixed with ethyl acetate until the hydrochloride was totally precipitated and the precipitate formed was filtered off. After washing the precipitate with water it was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol/conc. aqueous ammonia=5/5/0.5 (v/v/v)). 0.38 g (55% of theory) of an amorphous solid were obtained.
















IR (KBr):
1639 cm−1 (C═O)



Rf:
0.55 (FM2)



ESI-MS:
(M + H)+ = 799/801/803 (Br2)




(M + 2H)++ = 400/401/402 (Br2)










The following were prepared analogously (in each case n=1):




















No.
RCO
R2
A
n
NR3R4
% Yield
MS
Rf
Eluant
IR [cm−1]

























11
N8
AS1
A1
1
C1
70
ESI: (M + H)+ =
0.43
FM2
(KBr): C═O









758/60/62 (Br2)


1656.8


12
N9
AS1
A1
1
C1
60
ESI: (M + H)+ =
0.46
FM2
(KBr): C═O









788/90/92 (Br2)


1643.3


8
N5
AS1
A1
1
C1
53.7
ESI: (M + H)+ =
0.2
methanol/
(KBr): C═O









790/2/4 (Br2)

glacial acetic
1641.3











acid/water =











9/1/1 (v/v/v)


15
N11
AS1
A1
1
C1
56
ESI: (M + H)+ =
0.4
FM2









773/5/7 (Br2)


6
N2
AS1
A1
1
C11
66.4
ESI: (M + H)+ =
0.39
FM2
(KBr): C═O









808/10/12 (Br2)


1656.8


7
N2
AS1
A1
1
C2
46.2
ESI: (M + H)+ =
0.13
FM2
(KBr): C═O









794/6/8 (Br2)


1637.5


13
N2
AS2
A1
1
C1
84.7
ESI: (M + H)+ =
0.46
FM2
(KBr): C═O









666


1641.3









EXAMPLE 6
Preparation of Compounds ofGeneralFormula:




1-[4-amino-3,5-dibromo-N2—[N-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate) (No. 61)
To a mixture of 0.42 g (0.45 mmol) of 1-[4-amino-3,5-dibromo-N2-[4-(2-chlorophenyl)-1-piperazinyl]carbonyl]-D-phenylalanyl]-N6-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in 30 ml of methylene chloride were added 3 ml of trifluoroacetic acid. The reaction mixture was stirred for 3 hours at ambient temperature and then evaporated down in vacuo. The remaining residue was triturated with ether and the resulting beige amorphous solid (0.43 g; 37% of theory) was suction filtered.
IR (KBr): 1643, 1678 cm−1 (C═O)
Rf: 0.6 (FM1)
ESI-MS: (M+H)+=832/834/836/838 (Br2, Cl)
The following were prepared analogously:






























%






No.
RCO
Z
R2
A
NR3R4
n
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]



























21
N6
N—H
AS1
A1
C4
1

65
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O











828/30/32 (Br2)


1635.5


22
N16
N—H
AS1
A1
C1
1

98
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











874/6/8 (Br2)


1643.3; 1676


141
N61
N—H
AS1
A1
C1
1

46
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O











855/7/9 (Br2)


1634; 1705


142
N60
N—H
AS1
A1
C1
1

50
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O











882/4/6 (Br2)


1643; 1711


154
N66
N—H
AS1
A1
C1
1

60
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O











868/70/72 (Br2)


1645; 1653


197
N15
N—H
AS1
A1
C8
1

21
ESI: (M + H)+ =
0.18
FM7
(KBr): C═O











859/61/63 (Br2)


1678;














1201.6; CF3














1180.4; 1134.1


198
N51
N—H
AS1
A1
C8
1

27
ESI: (M + H)+ =
0.22
FM7
(KBr): C═O











829/31/33 (Br2)


1676; CN














2221.9; CF3














1203.5; 1180.4;














1132


218
N15
N—H
AS6
A1
C1
1

25.7
ESI: (M + H)+ =
0.45
FM1
(KBr): C═O











776/8 (Br)


1695.3; 1635.5


287
N15
N—H
AS1
A8
C1
1

36.5
ESI: (M + H)+ =
0.5
FM2
(KBr): C═O











840/2/4 (Br2)


1695.3; 1637.5


19
N15
N—H
AS1
A1
C1
1

44
ESI: (M + H)+ =
0.43
FM2
(KBr): C═O











854/6/8 (Br2)


1695.3; 1637.5


14
N10
N—H
AS1
A1
C1
1

25.5
ESI: (M + H)+ =
0.33
FM2
(KBr): C═O











774/6/8 (Br2)


1683.8


16
N12
N—H
AS1
A1
C1
1

64.4
ESI: (M + H)+ =
0.55
FM2
(KBr): C═O











802/4/6 (Br2)


1639.4


29
N22
N—H
AS1
A1
C1
1

91.2
ESI: (M + H)+ =
0.5
FM2
(KBr): —NH—











867/69/71 (Br2)


3427.3; C═O














1643.3; 1678.0


30
N23
N—H
AS1
A1
C1
1

83.3
ESI: (M + H)+ =
0.5
FM2
(KBr): C═O











833/5/7/9 (Br2, Cl)


1643.3; 1676.0


31
N24
N—H
AS1
A1
C1
1

100
ESI: (M + H)+ =
0.51
FM2
(KBr): C═O











843/5/7 (Br2)


1645.2; 1676.0


63
N46
N—H
AS1
A1
C1
1

100
ESI: (M + H)+ =
0.58
FM2
(KBr): C═O











764/6/8 (Br2)


1643.3; 1676.0


68
N15
N—H
AS1
A1
C6
1

80
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O











833/5/7 (Br2)


1683.8


69
N15
N—H
AS1
A1
C5
1

74
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O











854/6/8 (Br2)


1683.8; 1639.4


70
N45
N—H
AS1
A1
C6
1

89
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











897/9/901 (Br2)


1695.3; 1676.0


71
N16
N—H
AS1
A1
C5
1

82
ESI: (M + H)+ =
0.22
FM1
(KBr): C═O











874/6/8 (Br2)


1678.0; 1639.4


72
N15
N—H
AS5
A1
C1
1

97
ESI: (M + H)+ =
0.16/0.2
FM1
(KBr): C═O











838/40/42 (Br2)


1685.7; 1643.3


77
N45
N—H
AS5
A1
C1
1

66
ESI: (M + H)+ =
0.33/0.4
FM1
(KBr): C═O











852/4/6 (Br2)


1683.8; 1645.2














NH3 3427.3


24
N18
N—H
AS1
A1
C1
1

94
ESI: (M + H)+ =
0.11
FM1
(KBr): C═O











775/7/9 (Br2)


1676.0; 1643.3


25
N19
N—H
AS1
A1
C1
1

92
ESI: (M + H)+ =
0.13
FM1
(KBr): C═O











833/5/7 (Br2)


1676.0; 1643.3


26
N20
N—H
AS1
A1
C1
1

98
EI: M+ = 762/4/6
0.11
FM1
(KBr): C═O











(Br2)


1676.0; 1643.3


27
N21
N—H
AS1
A1
C1
1

98
ESI: (M + H)+ =
0.04
FM1
(KBr): C═O











814/6/8 (Br2)


1676.0; 1645.2


41
N34
N—H
AS1
A1
C1
1

97
ESI: (M + H)+ =
0.08
FM1
(KBr): C═O











835/38/40/42


1676.0; 1643.3











(Br3)


42
N35
N—H
AS1
A1
C1
1

83
ESI: (M + H)+ =
0.09
FM1
(KBr): C═O











803/5/7 (Br2)


1676.0; 1643.3


43
N36
N—H
AS1
A1
C1
1

87
ESI: (M + H)+ =
0.04
FM1
(KBr): C═O











815/7/9 (Br2)


1676.0; 1645.2


53
N42
N—H
AS1
A1
C1
1

89
ESI: (M + H)+ =
0.11
FM1
(KBr): C═O











805/7/9 (Br2)


1676.0; 1634.3


54
N43
N—H
AS1
A1
C1
1

84
ESI: (M + H)+ =
0.11
FM1
(KBr): C═O











835/7/9/41 (Br3)


1678.0; 1643.3


55
N44
N—H
AS1
A1
C1
1

95
ESI: (M + H)+ =
0.07
FM1
(KBr): C═O











796/8/800 (Br2)


1676.0; 1643.3


67
N48
N—H
AS1
A1
C1
1

90
ESI: (M + H)+ =
0.06
FM1
(KBr): C═O











797/99/801 (Br2)


1682.9; 1643.3


184
N77
N—H
AS1
A1
C4
1

88
ESI: (M + H)+ =
0.11
FM1
(KBr): C═O











855/7/9 (Br2)


1637.5; 1676


248
N78
N—H
AS1
A1
C1
1

97
ESI: (M + H)+ =
0.14
FM1
(KBr): C═O











855/7/9 (Br2)


1643.3; 1676;














1772.5


181
N75
N—H
AS1
A1
C4
1

95
ESI: (M + H)+ =
0.04
FM1
(KBr): C═O











793/5/7 (Br2)


1637.5; 1676


182
N76
N—H
AS1
A1
C4
1

93
ESI: (M + H)+ =
0.04
FM1
(KBr): C═O











793/5/7 (Br2)


1637.5; 1678


183
N74
N—H
AS1
A1
C4
1

91
ESI: (M + H)+ =
0.08
FM1
(KBr): C═O











807/9/11 (Br2)


1635.5; 1678


250
N15
N—H
AS1
A1
C18
1

98
ESI: (M + H)+ =
0.14
FM1
(KBr): C═O











885/7/9 (Br2)


1633.6; 1680


251
N15
N—H
AS10
A1
C4
1

84
ESI: (M + H)+ =
0.27
FM1
(KBr): C═O











837/39/41 (Br2)


1635.5; 1693.4


252
N15
N—H
AS10
A1
C4
1

87
ESI: (M + H)+ =
0.31
FM1
(KBr): C═O











837/39/41 (Br2)


1637.5; 1685.7


253
N15
N—H
AS10
A1
C1
1

82
ESI: (M + H)+ =
0.18
FM1
(KBr): C═O











838/40/42 (Br2)


1690


255
N77
N—H
AS1
A1
C1
1

94
ESI: (M + H)+ =
0.08
FM1
(KBr): C═O











856/8/60 (Br2)


1645; 1676


256
N15
N—H
AS4
A1
C18
1

74
ESI: (M + H)+ =
0.28
FM1
(KBr): C═O











884/6/8 (Br2)


1633.6; 1683.8


271
N81
N—H
AS4
A1
C8
1

76
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O











874/6/8 (Br2)


1674


280
N84
N—H
AS4
A1
C4
1

66
ESI: (M + H)+ =
0.26
FM1
(KBr): C═O











866/8/70 (Br2)


1635.5; 1685.7



N15
N—H
AS1
A1
C1
0

98
ESI: (M + H)+ =
0.2
ButOH/
(KBr): C═O











840/2/4 (Br2)

AcOH/H2O =
1643; 1680













4/1/1













(v/v/v)


179
N73
N—H
AS1
A1
C4
1

86
ESI: (M + H)+ =
0.03
FM1
(KBr): C═O











779/81/83 (Br2)


1642.8; 1676



N66
N—H
AS4
A0

1

75
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O











744/6/8 (Br2)


1620/1666


516
N66
N—H
AS1
A1
C1
1
Isomer to
82

0.1
FM1









No. (154)


517
N66
N—H
AS1
A1
C1
1
Isomer to
80

0.1
FM1









No. (154)


518
N66
N—H
AS1
A1
C1
1
Isomer to
89

0.1
FM1









No. (154)


521
N66
N—H
AS4
A0
C17
1
THF/DMF
75
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O











744/6/8 (Br2)


1666/1620


522
N66
N—H
AS1
A0
C17
1
THF/DMF
100
ESI: (M + H)+ =
0.15
FM1
(KBr): C═O











745/7/9 (Br2)


1624/1655


643
N66
CH2
AS21
A0
C17
1

53
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O











640


1635/1668



N66
CH2
AS2
A0
C17
1

100
EI: M+ = 621
0.35
FM1
(KBr): C═O














1670









EXAMPLE 7
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-[[[(2-methoxyphenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
A mixture of 910 mg (1.0 mmol) of 1-[N2—[N-[[[2-(2-methoxy-phenyl)methyl]amino]carbonyl]-3,5-dibromo-D,L-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred overnight at ambient temperature. The reaction mixture was stirred into diethylether and the sticky precipitate formed was suction filtered. The crude product was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.37 g (48% of theory) of an amorphous solid were obtained.
















IR (KBr):
1630 cm−1 (C═O)











ESI-MS:
(M + H)+ =
774/776/778 (Br2)




(M + 2H)++ =
387.7/388.7/389.7 (Br2)










The following were prepared analogously (in each case n=1):



















No.
RCO
R2
A
NR3R4
% Yield
MS
Rf
Eluant
IR [cm−1]
























1
N1
AS1
A1
C1
46.9
ESI: (M + H)+ =
0.36
FM1
(KBr): C═O








788/90/92 (Br2)


1627.8


2
N2
AS1
A1
C1
100
ESI: (M + H)+ =
0.48
FM2
(KBr): C═O








788/90/92 (Br2)


1641.3; NH,











NH+ 3419.6


4
N4
AS1
A1
C1
2.8
ESI: (M + H)+ =
0.52
FM2








818/20/22 (Br2)









EXAMPLE 8
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-[4-(4-fluorophenyl)-1-oxobutyl]-3,5-dibromo-D-tyrosyl]-N6-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine
To a solution of 0.18 g (0.001 mol) 4-(4-fluorophenyl)-butanoic acid in a mixture of 4 ml of dimethylformamide and 10 ml of tetrahydrofuran was added with stirring a mixture of 0.71 g (0.001 mol) 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 0.32 g (0.001 mol) TBTU and 0.13 g (0.001 mol) DIEA and the mixture was stirred in a nitrogen atmosphere for 2 days. The reaction mixture was then evaporated down in vacuo and the remaining residue was taken up in dichloromethane. The organic phase was with 20% aqueous citric acid solution and then extracted with 10% aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated down in vacuo. After stirring the residue with ether 0.68 g (77% of theory) of the desired product remain as an amorphous residue.
















IR (KBr):
1641, 1676 cm−1 (C═0)



Rf:
0.65 (FM2)











ESI-MS:
(M + H)+ =
875/877/879 (Br2)




(M + H + Na)++ =
449/450/451 (Br2)










The following were prepared analogously (in each case n=1):


























%






No.
RCO
R2
A
NR3R4
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]

























123
N62
AS1
A0
C1
DMF/THF as
20
ESI: (M + H)+ =
0.3
FM 1
(KBr): C═O







solvent

725/7/9 (Br2)


1641.3; 1691.5


124
N63
AS1
A0
C1
DMF/THF as
53
ESI: (M + H)+ =
0.2
FM 1
(KBr): C═O







solvent

725/7/9 (Br2)


1641.3; 1691.5


322
N63
AS1
A0
C8
DMF/THF as
19
EI: M+ =
0.3
FM 1
(KBr): C═O







solvent

729/31/33 (Br2)


1629.8; 1695.3



N11
AS1
A3
C1

46
ESI: (M + H)+ =


(KBr): C═O









873/5/7 (Br2)


1625.9; 1645.2



N18
AS1
A3
C1
THF/DMF as
77
ESI: (M + H)+ =
0.78
FM7
(KBr): C═O







solvent

875/7/9 (Br2)


1641.3



N20
AS1
A3
C1
THF/DMF as
88
ESI: (M + H)+ =
0.67
FM7
(KBr): C═O







solvent

863/5/7 (Br2)


1643.3



N21
AS1
A3
C1
THF/DMF as
78
ESI: (M + H)+ =
0.47
FM7
(KBr): C═O







solvent

917/6/8 (Br2)


1643.3



N46
AS1
A3
C1
THF/DMF as
80
ESI: (M + H)+ =
0.65
FM7
(KBr): C═O







solvent

905/7/9 (Br2)


1643.3



N43
AS1
A3
C1
THF/DMF as
75

0.75
FM7
(KBr): C═O







solvent




1645.2



N44
AS1
A3
C1
THF/DMF as
79
ESI: (M + H)+ =
0.65
FM7
(KBr): C═O







solvent

896/98/900 (Br2)


1629.8









EXAMPLE 9
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-[[[(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dichloro-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate (No. 20)
To a suspension of 0.33 g (2 mmol) of CDT and 1 ml of triethylamine in about 30 ml of tetrahydrofuran, cooled to −10° C., was added dropwise, with stirring, a solution of 1.0 g (1.6 mmol) of 1-[N2(-3.5-dichloro-D-tyrosyl]-N6-[(1.1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine in 50 ml of tetrahydrofuran within 60 minutes. The reaction mixture was stirred for 1 hour at 0° C., then stirred for 2 hours at ambient temperature, mixed with a tetrahydrofuran solution of 0.24 g (1.6 mmol) of (3-methoxyphenyl)-ethanamine, refluxed for 3 hours and stirred overnight at ambient temperature. After elimination of the solvent in vacuo the residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:FM1). The resulting intermediate compound was stirred in a mixture of 5 ml of trifluoroacetic acid and 80 ml of dichloromethane overnight, the solvent was eliminated in vacuo and the residue triturated with ether. 709 mg (43% of theory) of the desired compound as an amorphous solid.
















IR (KBr):
1643, 1676 cm−1 (C═0)



Rf:
0.41 (FM2)











ESI-MS
(M + H)+ =
700/702/704 (Br2)




(M + 2H)++ =
350.7/351.7/352.7 (Br2)










The following were prepared analogously (in each case n=1):


























%






No.
RCO
R2
A
NR3R4
Remarks
Yield
MS
Rf
Eluant
IR [cm−1]

























23
N17
AS1
A1
C1
NEt3 as base
55
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O









798/800/802 (Br2)


1643.3; 1676


47
N39
AS1
A1
C1
NEt3 as base
69.4
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









676/78/80 (Br2)


1645.2; 1676


50
N64
AS1
A1
C1
NEt3 as base
76
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O









828/830/832 (Br2)


1643.3; 1678


51
N40
AS1
A1
C1
NEt3 as base;
79.7
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O







dehydration

826/828/30 (Br2)


1643.3; 1678


52
N41
AS1
A1
C1
NEt3 as base;
21.8
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O







dehydration

826/828/30 (Br2)


1645.2; 1679.9


56
N16
AS1
A1
C4
NEt3 as base
5
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O









873/75/77 (Br2)


1637.5; 1676


57
N45
AS1
A1
C4
NEt3 as base
32
ESI: (M + H)+ =
0.2
FM1
(KBr): C═O









867/9/71 (Br2)


1635.5; 1678


66
N47
AS1
A1
C4
NEt3 as base
28.4
ESI: (M + H)+ =
0.1
FM1
(KBr): C═O









764/6/8 (Br2)


1635.5; 1676


46
N38
AS1
A1
C1
NEt3 as base
86
ESI: (M + H)+ =
0.35
FM1
(KBr): C═O









826/28/30 (Br2)


1645.2; 1684


232
N66
AS4
A1
C8

69
ESI: (M + H)+ =
0.33
FM1
(KBr): C═O









872/4/6 (Br2)


1645


233
N66
AS4
A1
C1
THF/DMF as
16
ESI: (M + H)+ =
0.32
FM1
(KBr): C═O







solvent

867/69/71 (Br2)


1653


234
N66
AS4
A1
C4

68
ESI: (M + H)+ =
0.42
FM1
(KBr): C═O









867/69/71 (Br2)


1645


235
N66
AS1
A1
C8

26
ESI: (M + H)+ =
0.27
FM1
(KBr): C═O









873/5/7 (Br2)


1645


236
N71
AS1
A1
C1

30
ESI: (M + H)+ =
0.22
FM1
(KBr): C═O









880/2/4 (Br2)


1636; 1678


237
N71
AS4
A1
C8

28
ESI: (M + H)+ =
0.25
FM1









884/6/8 (Br2)


238
N71
AS4
A1
C1

20
ESI: (M + H)+ =
0.3
FM1
(KBr): C═O









879/81/83 (Br2)


1641; 1682


18
N14
AS1
A1
C1
Cleaving of Boc
26.3
ESI: (M + H)+ =
0.55
FM2
(KBr): C═O







protecting group with

813/5/7 (Br2)


1641.3; 1716.5







methanolic HCl







solution


17
N13
AS1
A1
C1
Cleaving of Boc
55.2
ESI: (M + H)+ =
0.55
FM2
(KBr): C═O







protecting group with

799/801/803 (Br2)


1639.4







methanolic HCl







solution


9
N6
AS1
A1
C1
Cleaving of Boc
41.3
ESI: (M + H)+ =
0.44
FM2
(KBr): C═O







protecting group with

829/31/33 (Br2)


1639.4







methanolic HCl







solution


10
N7
AS1
A1
C1
Cleaving of Boc
57.6
ESI: (M + H)+ =
0.32
FM2
(KBr): C═O







protecting group with

829/31/33 (Br2)


1639.4







methanolic HCl







solution


20
N2
AS5
A1
C1

43
ESI: (M + H)+ =
0.41
FM2
(KBr): C═O









700/2/4 (Br2)


1643.3; 1676.0


283
N102
AS4
A3
C4
NEt3 as base
65
ESI: (M + H)+ =
0.24
FM1
(KBr): C═O









864/6/8 (Br2)


1637.5; 1676









EXAMPLE 10
Preparation of Compounds ofGeneralFormula:




1-[N2—[N-[4-(2,3-dichlorophenyl)-1-piperazinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine-tris-(trifluoroacetate) (No. 74)
To a solution of 0.35 g (2.1 mmol) of CDT in 50 ml of tetrahydrofuran were added with cooling (0° C.) and stirring 1.0 g (1.4 mmol) of 1-[N2-(3,5-dibromo-D-tyrosyl)-N6-[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine and the mixture was stirred for 30 minutes at 0° C. and for a further 30 minutes at ambient temperature. After the addition of 0.47 g (1.75 mmol) of 1-(2,3-dichlorophenyl)piperazine-hydrochloride and 0.25 ml of triethylamine the reaction mixture was refluxed for 5 hours and after cooling mixed with 70 ml of saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated off, the aqueous phase was extracted twice with 50 ml of tetrahydrofuran. The combined organic phases were washed with saturated aqueous saline solution, dried over magnesium sulphate, filtered and evaporated down in vacuo. The residue was triturated with ether, suction filtered and then stirred for 2 hours with a mixture of 50 ml of dichloromethane and 5 ml of trifluoroacetic acid. After evaporation of the reaction mixture in vacuo and trituration of the residue with ether, 0.8 g (47% of theory) of an amorphous solid are left.
















IR (KBr):
1643.3, 1676 cm−1 (C═0)



Rf:
0.78 (FM7)











ESI-MS:
(M + H)+ =
867/869/871/873/875 (Br2, Cl2)




(M + 2H)++ =
434/435/436/437 (Br2, Cl2)










The following were prepared in the same way (in each case n=1):
























%






No.
RCO
R2
A
NR3R4
Yield
MS
Rf
Eluant
IR [cm−1]
























36
N29
AS1
A1
C1
17.3
ESI: (M + H)+ =
0.35
MeOH/NH4OH =
(KBr): C═O








889/91/93 (Br2)

9/1 (v/v)
1643.3; 1674.1


208
N15
AS1
A1
C1
53.5
ESI: (M + H)+ =
0.43
FM2
(KBr): C═O








854/6/8 (Br2)


1691.5; 1635.5


209
N15
AS1
A1
C1
47.7
ESI: (M + H)+ =
0.55
FM2
(KBr): C═O








854/6/8 (Br2)


1695.3; 1637.5


210
N15
AS1
A1
C1
28
ESI: (M + H)+ =
0.48
FM2
(KBr): C═O








854/6/8 (Br2)


1689.5; 1639.4


75
N50
AS1
A1
C1
16.5
ESI: (M + H)+ =
0.63
FM2
(KBr): C═O








867/69/71/73/75


1643.3; 1676.0;








(Br2, Cl2)


74
N49
AS1
A1
C1
47
ESI: (M + H)+ =
0.65
FM2
(KBr): C═O








867/69/71/73/75


1643.3; 1676.0








(Br2, Cl2)


76
N51
AS1
A1
C1
13.4
ESI: (M + H)+ =
0.58
FM2
(KBr): C═O








824/6/8 (Br2)


1643.3; 1676.0;











CN 2219.9


79
N52
AS1
A1
C1
11.4
ESI: (M + H)+ =
0.59
FM2
(KBr): C═O








901/3/5/7


1645.2; 1676.3








(Br2, Cl)


45
N37
AS1
A1
C1
43
ESI: (M + H)+ =
0.6
FM2
(KBr): C═O








784/6/8 (Br2)


1643.3; 1678.0


39
N32
AS1
A1
C1
48.3
ESI: (M + H)+ =
0.57
FM2
(KBr): C═O








795/7/9 (Br2)


1643.3; 1678.0


38
N31
AS1
A1
C1
54.1
ESI: (M + H)+ =
0.6
FM2
(KBr): C═O








844/6/8 (Br2)


1643.3; 1678.0;











NO2 1543.0


37
N30
AS1
A1
C1
61.6
ESI: (M + H)+ =
0.6
FM2
(KBr): C═O








813/5/7 (Br2)


1643.3; 1676.0


35
N28
AS1
A1
C1
74.8
ESI: (M + H)+ =
0.55
FM2
(KBr): C═O








800/2/4 (Br2)


1639.4;


34
N27
AS1
A1
C1
36.8
ESI: (M + H)+ =
0.43
FM2
(KBr): C═O








800/2/4 (Br2)


1641.3; 1714.6;











NH+ 3409.9


32
N25
AS1
A1
C1
50.0
ESI: (M + H)+ =
0.44
FM2
(KBr): C═O








737/39/41 (Br2)


1645.2; 1678.3


33
N26
AS1
A1
C1
42
ESI: (M + H)+ =
0.33
FM2
(KBr): C═O








767/69/71 (Br2)


1676.0


40
N33
AS1
A1
C1
14.5
ESI: (M + H)+ =
0.58
FM2
(KBr): C═O








802/4/6 (Br2)


1643.3; 1676.0


28
N6
AS3
A1
C1
67.2
ESI: (M + H)+ =
0.43
FM2
(KBr): C═O








741/3/5 (Cl2)


1641.3; 1716.5


64
N23
AS1
A1
C4
39
ESI: (M + H)+ =
0.68
FM2
(KBr): C═O








832/4/6/8


1627.8; 1678.0








(Br2, Cl)


65
N15
AS1
A1
C4
41
ESI: (M + H)+ =
0.61
FM2
(KBr): C═O








853/5/7 (Br2)


1631.7; 1695.3


365
N111
AS1
A1
C1
36.9
ESI: (M + H)+ =
0.09
FM1
(KBr): C═O








839/41/43 (Br2)


1626/1676









EXAMPLE 11
1-[N2—[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5 dibromo-D,L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine (No. 3)
A mixture of 0.8 g (0.84 mmol) of 1-[N2—[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred for 12 hours at ambient temperature. The reaction mixture was stirred into diethylether and the resulting precipitate was suction filtered. The solid residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.3 g (44% of theory) of the desired product was obtained as an amorphous solid.













IR (KBr):
1643.3 cm−2 1 (C═O)


Rf:
0.17 (ethyl acetate/methanol/conc. aqueous ammonia =



6/4/1)









ESI-MS:
(M + H)+ =
818/820/822 (Br2)



(M + 2H)++ =
409.5/410.5/411.5 (Br2)









EXAMPLE 12
1-[N2-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine-bis-(trifluoroacetate) (No. 4)
A stirred mixture of 20 ml of trifluoroacetic acid, 1.3 ml of anisole and 0.9 ml of ethanedithiol was mixed with 2.1 g (1.9 mmol) of solid 1-[N2-[3,5-dibromo-N-[[[2-(3-methoxyphenyl)-ethyl]amino]carbonyl]-NG-(2,2,5,7,8-pentamethylchroman-6-sulphonyl)-D-tyrosyl]-L-arginyl]-4-(4-pyridinyl)-piperazine whilst cooling with ice and stirred for a further 45 minutes whilst cooling with ice, then for 3 hours at ambient temperature. The resulting precipitate was suction filtered and discarded, the filtrate was evaporated down in vacuo, the residue remaining was mixed with toluene and again evaporated down in vacuo. The resulting solid residue was triturated with a mixture of diethylether and acetone and the white solid formed was suction filtered and dried. 1.7 g (65% of theory) of the desired title compound were obtained.
















IR (KBr):
1674, 1645 cm−2 1 (C═O)



Rf:
0.15 (FM: BuOH/AcOH/H2O 4/1/1 (v/v/v)











ESI-MS:
(M + H)+ =
816/818/820 (Br2)




(M + 2H)++ =
408.6/409.6/410.6 (Br2)










EXAMPLE 13
Preparation of Compounds of General Formula:




(R,S)-1-[2-(4-amino-3,5-dibromobenzoyl)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-4-oxobutyl]-4-(4-pyridinyl)-piperidine (No. 291)
A mixture of 0.97 g (1.8 mmol) of (R,S)-4-amino-3,5-dibromo-γ-oxo-β-[[4-(4-pyridinyl)-1-piperidinyl]methyl]-benzenebutanoic acid, 0.48 g (1.8 mmol) of 4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-piperidine, 2 ml of triethylamine, 0.58 g (1.8 mmol) of TBTU, 0.24 g (1.8 mmol) of HOBt, 25 ml of THF and 25 ml of DMF was stirred for 4 hours at ambient temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in a mixture of ethyl acetate and methanol (95/5 (v/v)) and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried and evaporated down in vacuo. The residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol=9/1 (v/v); then MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant: methylene chloride/ethanol=9/1 (v/v)). 0.2 g (15% of theory) of the desired product were obtained as a white amorphous solid.
















IR (KBr):
1668.3 cm−1 (C═O)



Rf):
0.5 (FM2)











ESI-MS:
(M + H)+ =
737/739/741 (Br2)




(M + Na)+ =
759/761/763 (Br2)










The following were prepared analogously:






















%






No.
RCO
R2
NR3R4
Yield
MS
Rf
Eluant
IR [cm−1]







291
N66
AS4
C4
15
ESI: (M + H)+ =
0.36
CH2Cl2/
(KBr): C═O







737/39/41 (Br2)

EtOH
1668


296
N66
AS4
C8
14
ESI: (M + H)+ =
0.66
FM1
(KBr): C═O







743/5/7 (Br2)


1668


302
N71
AS4
C8
19
ESI: (M + H)+ =
0.54
FM1
(KBr): C═O







755/7/9 (Br2)


1682









EXAMPLE 14
1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperdine (No. 312)
a) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine (No. 307)
Prepared analogously to Example 3 from methyl 3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and CDT in a yield of 27.2% of theory. Colourless, amorphous substance, Rf 0.5 (eluant:dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
















IR (KBr):
1718.5, 1670.3, 1618.2 cm−2 1 (C═O)











ESI-MS:
(M + H)+ =
796/798/800 (Br2)




(M + Na)+ =
818/820/822 (Br2)










The following were obtained accordingly:
From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and CDT in a yield of 30.3% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 304), Rf=0.75 (FM1).
















IR (KBr):
1720.4, 1668.3, 1620.1 cm−2 1 (C═O)











ESI-MS:
(M + H)+ =
802/804/806 (Br2)




(M + Na)+ =
824/826/828 (Br2)










From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-(3,5-dibromo-D-tyrosyl)-4-(1-piperidinyl)-piperidine and CDT in a yield of 35% of theory: 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine (No. 422), Rf 0.54 (eluant:dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
















IR (KBr):
1720.4, 1668.3, 1627.8 cm−2 1 (C═O)











ESI-MS:
(M + H)+ =
803/805/807 (Br2)




(M + Na)+ =
825/827/829 (Br2)










From methyl-3,4-dihydro-3-(4-piperidinyl)-2(1H)-oxoquinazoline-7-carboxylate, 1-(3,5-dibromo-D-tyrosyl)-4-(4-pyridinyl)-piperidine and CDT in a yield of 45% of theory: 1-[3,5-dibromro-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine
(No. 420), Rf 0.56 (FM1).
















IR (KBr):
1718.5, 1664.5, 1624.0 cm−2 1 (C═O)











ESI-MS:
(M + H)+ =
797/799/801 (Br2)




(M + Na)+ =
819/821/823 (Br2)










b) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine (No. 309)
Prepared analogously to Example A37) from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine by saponification with lithium hydroxide in a yield of 95% of theory. Colourless, amorphous substance, Rf 0.25 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
IR (KBr): 1666.4, 1614.3 cm−1 (C═O)
ESI-MS: (M—H)−=780/782/784 (Br2)
The following were obtained accordingly:
From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(methoxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine in a yield of 60.2% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 306), Rf 0.15 (FM1).
















IR(KBr):
1635.5 cm−1, broad (C═O)











ESI-MS:
(M + H)+ =
788/790/792 (Br2)




(M + Na)+ =
810/812/814 (Br2)










From 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine in a yield of 62% of theory: 1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(1-piperidinyl)-piperidine (No. 423), Rf 0.03 (eluant:dichloromethane/cyclohexane/methanol/conc. ammonia=7/1.5/1.5/0.2 (v/v/v/v)).
IR (KBr): 1635.5 cm−1, broad(C≡O)
ESI-MS: (M+H)+=789/791/793 (Br2)
From 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(methoxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in a yield of 80% of theory: 1-[3,5-dihbrcmo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 151). Colourless, amorphous substance.
















IR(KBr):
1701.1, 1625.9 cm−1 (C═O)











ESI-MS:
(M + H)+ =
767/769/771 (Br2)




(M + 2H)++ =
383/384/385 (Br2)










From 1-[3,5-dibromo-N-[[4-[7-(methoxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in a yield of 82% of theory: 1-[3,5-dibromo-N-[[4-[7-(hydroxycarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 421), Rf 0.03 (FM1). Colourless, amorphous substance.
















IR (KBr):
1625 wide cm−1 (C═O)



ESI-MS:
(M + H)+ = 783/785/787 (Br2)




(M + Na)+ = 805/807/809 (Br2)










c) 1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(4-pyridinyl)-piperidine (No. 312)
Prepared analogously to Example 1 from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and ammonium carbonate in the presence of TBTU in a yield of 40.6% of theory. Colourless, amorphous substance, Rf 0.8 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
















IR (KBr):
1670.3, 1616.3 cm−1 (C═O)



ESI-MS:
(M + H)+ = 781/783/785 (Br2)




(M + Na)+ = 803/805/807 (Br2)










The following were obtained accordingly:
From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and ethanolamine in a yield of 34.6% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 313) Rf=0.7 (eluant:dichloromethane/methanol/conc. ammonia =7.5/2.5/0.5 v/v/v).
















IR (KBr):
1662.5, 1618.2 cm−1 (C═O)



ESI-MS:
(M + H)+ = 825/827/829 (Br2)




(M + Na)+ = 847/849/851 (Br2)




(M + 2H)++ = 413/414/415 (Br2)




(M + H + Na)++ = 424/425/426 (Br2)










From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and 1-methylpiperazine in a yield of 44.9% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-[(4-methyl-1-piperazinyl)carbonyl]-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 430) Rf=0.28 (eluant:ethyl acetate/methanol/conc. ammonia=8/1.5/0.3 v/v/v).
















IR (KBr):
1618.2 cm−1 (C═O)



ESI-MS:
(M + H)+ = 864/866/868 (Br2)




(M + Na)+ = 886/888/890 (Br2)




(M + 2H)++ = 432/433/434.7 (Br2)










From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine and methylammonium chloride in a yield of 37% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(methylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-pyridinyl)-piperidine, (No. 424) Rf=0.49 (FM1)
















IR (KBr):
1662.5, 1622 cm−1 (C═O)



ESI-MS:
(M + H)+ = 795/797/799 (Br2)




(M + Na)+ = 817/819/821 (Br2)










From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and ammonium carbonate in a yield of 12% of theory: 1-[4-amino-N-[[4-[7-(aminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 310), Rf=0.7 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 v/v/v)).
IR (KBr): 1670.3, 1618.2 cm−1 (C═O)
ESI-MS: (M+H)+=787/789/791 (Br2)
From 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-7-(hydroxycarbonyl)-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine and ethanolamine in a yield of 11.4% of theory: 1-[4-amino-3,5-dibromo-N-[[4-[7-(2-hydroxyethylaminocarbonyl)-3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 311), Rf=0.65 (eluant:dichloromethane/methanol/conc. ammonia=7.5/2.5/0.5 (v/v/v)).
















IR (KBr):
1660.6, 1620.1 cm−1 (C═O)



ESI-MS:
(M + H)+ = 831/833/835 (Br2)




(M + 2H)++ = 416/417/418 (Br2)




(M + H + Na)++ = 427/428/429 (Br2)










EXAMPLE 15
4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-([[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-piperidine (No. 372)
a) 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine
A mixture of 5.60 g (0.01 mol) of 4-amino-3,5-dibromo-N -(9-fluorenylmethoxycarbonyl)-D-phenylalanine, 1.35 g (0.01 mol) HOBt, 3.21 g (0.01 mol) TBTU, 1.29 g (0.01 mol) DIEA, 2.68 g (0.01 mol) 4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine and 150 ml of tetrahydrofuran was stirred for 2 hours at room temperature. After the reaction was complete 20 ml of diethylamine were added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was evaporated down in vacuo, the residue was taken up in 200 ml of dichloromethane and washed successively with 100 ml of saturated sodium chloride solution and saturated sodium hydrogen carbonate solution and dried over magnesium sulphate. The reddish oil remaining after elimination of the solvent was purified by column chromatography on silica gel (30-60 μm) using firstly dichloromethane, then FM4 as eluant. The title compound was obtained in the form of a colourless amorphous substance and in a yield of 4.31 g (73.3% of theory).
IR(KBr): 1687.6 cm+1 (C═O) 
MS: M+=586/588/590 (Br2)
b) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine
Prepared analogously to Example 4 from 1-[4-amino-3,5-dibromo-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine, CDT and 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone in a quantitative yield. Colourless, amorphous substance.
















IR (KBr):
1676 cm−1 (C═O)



MS:
(M + H)+ = 844/846/848 (Br2)




(M + Na)+ = 866/868/870 (Br2)










c) 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine (No. 521)
Prepared analogously to Example A1b), but using sodium hydroxide solution instead of ammonia, from 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-carbonyl]-D-phenylalanyl]-4-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-piperidine by treating with trifluoroacetic acid in a yield of 75% of theory. Colourless, amorphous substance.
















IR (KBr):
1666.4, 1620.1 cm−1 (C═O)



MS:
(M + H)+ = 744/746/748 (Br2)




(M + 2H)++ = 372/373/374.5 (Br2)










d) 4-(1-acetyl-4-piperidinyl)-1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-piperidine (No. 372)
A solution of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine and 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixed with 0.043 g (5.48 mmol) of acetylene chloride dropwise whilst cooling externally with ice-water and then stirred for 1 hour at room temperature. The solvent was eliminated in vacuo, the residue was stirred with water and filtered. The filter residue was dried in vacuo and purified by column chromatography on silica gel (30-60 μm) using FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 230 mg (58.5% of theory) of colourless crystals were obtained.
















IR (KBr):
1622 cm−1 (C═O)



MS:
(M + H)+ = 786/788/790 (Br2)




(M + Na)+ = 808/810/812 (Br2)










The following were obtained accordingly:
1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2 (1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-benzoyl-4-piperidinyl)-piperidine (No. (485).
Colourless crystals
Rf 0.74 (FM1)
IR(KBr): 1626,1668 cm−1 (C═O)
ESI-MS: (M+H)+=848/850/852 (Br2)
EXAMPLE 16
1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-methylsulfonyl-4-piperidinyl)-piperidine (No. 486)
A solution of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine and 0.07 g (5.5 mmol) of DIEA in 50 ml of dichloromethane was mixed dropwise with 0.063 g (5.5 mmol) of methanesulphonylchloride whilst cooling externally with ice-water and then stirred for 1 hour at room temperature. The solvent was eliminated in vacuo, the residue was stirred with water and filtered. The filter residue was dried in vacuo and purified by column chromatography over silica gel (30-60 μm) using initially dichloromethane, then FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 220 mg (53.5% of theory) of colourless crystals were obtained.
















IR (KBr):
1668, 1618 cm−1 (C═O)



MS:
(M + H)+ = 822/824/826 (Br2)




(M + Na)+ = 844/846/848 (Br2)




(M + K)+ = 860/862/864 (Br2)










The following were obtained accordingly:
(1) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl-1-piperidinyl]carbonyl]-4-(methylsulphonyloxy)-D-phenylalanyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine (No. (523)) in a yield of 12% of theory.
Rf 0.54 (FM1)
IR(KBr): 1628,1665 cm31 1 (C═O)
ESI-MS: (M+H)+=901/903/905 (Br2)
(2) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(methylsulphonyl)-4-piperidinyl]-piperidine (No. (524) in a yield of 12% of theory.
Rf 0.50 (FM1)
ESI-MS: (M+H)+=833/825/827 (Br2)
(3) (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(1-naphthyl)methyl]-1,4-dioxobutyl]-4-(1-methylsulphonyl-4-piperidinyl)-piperidine (No. (668) in a yield of 56% of theory.
Rf 0. 70 (FM1)
IR(KBr): 1630,1666 cm−1 (C═O)
MS: M+=699
EXAMPLE 17
1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(3-carboxy-1-oxopropyl)-4-piperidinyl]-piperidine (No. 487)
A mixture of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, 0.11 g (1.1 mmol) of succinic anhydride and 150 ml of tetrahydrofuran was refluxed for 1 hour. The reaction mixture was freed from solvent in vacuo, the residue was purified by column chromatography on silica gel (30-60 μm) using FM1 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 175 mg (41.5% of theory) of colourless crystals were obtained.
















IR (KBr):
1668, 1608 cm−1 (C═O)



MS:
(M − H)− = 842/844/846 (Br2)




(M + Na)+ = 868/870/872 (Br2)










EXAMPLE 18
1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-hexyl-4-piperidinyl)-piperidine (No. 488)
A mixture of 0.372 g (0.499 mmol) of 1-[4-amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(4-piperidinyl)-piperidine, 0.05 g (0.499 mmol) of hexanal, 0.03 g (0.5 mmol) of glacial acetic acid and 150 ml of tetrahydrofuran was stirred for 1 hour at room temperature. After the addition of 0.116 g (0.52 mmol) of 95% sodium triacetoxyborohydride the mixture was kept for a further 2.5 hours at room temperature. The solvent was eliminated in vacuo, the residue was divided between 20% aqueous sodium carbonate solution and dichloromethane, the organic phase was dried over magnesium sulphate and evaporated down. The residue was purified by column chromatography on silica gel (30-60 μm) using FM4 as eluant. The suitable eluates were evaporated down, the residue was triturated with diethylether and suction filtered. 100 mg (24.2% of theory) of colourless crystals were obtained.
















IR (KBr):
1666, 1620 cm−1 (C═O)



MS:
(M + H)+ = 828/830/832 (Br2)




(M + Na)+ = 850/852/854 (Br2)










The following were obtained accordingly:
(1) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-(1-cyclopropylmethyl-4-piperidinyl)-piperidine (No. (489) in a yield of 23% of theory.
Rf 0.65 (FM1)
IR(KBr): 1622,1666 cm−1 (C═O)
ESI-MS: (M+H)+=798/800/802 (Br2)
(2) 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine (No. (493) in a yield of 43% of theory.
Rf 0.72 (FM1)
IR(KBr): 1620,1666 cm−1 (C═O)
ESI-MS: (M+H)+=730/732/734 (Br2)
(3) 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(cyclopropylmethyl)-4-piperidinyl]-piperidine (No. (525) in a yield of 46.5% of theory.
Rf 0.50 (FM1)
IR(KBr): 1622,1662 cm−1 (C═O)
ESI-MS: (M+H)+=799/801/803 (Br2)
EXAMPLE 19
Preparation of Compounds of General Formula:




1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-3-ethenyl-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine (No. 532)
The mixture of 200 mg (3 mmol) 1-[3-bromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(hexahydro-1H-1-azepinyl)-piperidine, 108 mg (0.33 mMol) vinyl-tributyl tin (ALDRICH No. 27143-8), 50 mg tetrakis-(triphenylphosphine)-palladium (Merck No. 818193), a trace of 2,6-di-tert.-butyl-4-methylphenol and 10 ml anhydrous toluene was refluxed for 5 hours. The cooled reaction mixture was filtered over an activated charcoal filter, the filtrate was evaporated in a vacuum. The residue was purified for elution by column chromatography over silica gel, initially using pure dichloromethane, then methanol/conc. ammonia (9/1 v/v). The suitable eluates were triturated and suction filtered with tert.-butyl-methylether. Yield was 60 mg (32.6% of theory) of colourless crystals of Rf 0.25 (FM1).
MS: M+=612
The following were prepared analogously: (in each case, n=1):


























%






No.
RCO
Z
R2
A
NR3R4
Yield
MS
Eluant
Rf
IR [cm−1]

























647
N66
CH2
AS40
A0
C8
75
EI: M+ = 611
FM1
0.6
(KBr): C═O












1639/1668


648
N66
CH2
AS41
A0
C8
56
EI: M+ = 647
FM1
0.7
(KBr): C═O












1639/1668


649
N66
CH2
AS42
A0
C8
8
EI: M+ = 648
FM1
0.6
(KBr): C═O












1635/1668


650
N66
CH2
AS43
A0
C8
11
EI: M+ = 654
FM1
0.6
(KBr): C═O












1635/1666


651
N66
CH2
AS44
A0
C8
84
EI: M+ = 637
FM1
0.6
(KBr): C═O












1633/1664


652
N66
CH2
AS45
A0
C8
83
EI: M+ = 613
FM1
0.6
(KBr): C═O












1637/1667









EXAMPLE 20
Preparation of Compounds ofGeneralFormula:




(R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine (No. 599)
Produced analogously to Example 1 from (R,S)-4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoic acid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 10% of theory. Colourless, amorphous substance of Rf=0.2 (dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).
IR (KBr): 1722, 1662, 1637 cm−1 (C═O)
MS: M+=711
Accordingly, (R,S)-1-[4-[4-(amincocarbonylamino)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-1,4-dioxobutyl]-4-(4-methyl-1-piperazinyl)-piperidine (No. 601) was obtained from (R,S)-4-[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]-2-(ethoxycarbonyl)-2-[[1-methyl-1H-indol-3-yl]methyl]-4-oxobutanoic acid, 4-(4-methyl-1-piperazinyl)piperidine and TBTU in a yield of 20% of theory. Colourless, amorphous substance of Rf=0.25 (dichloromethane/methanol/conc. ammonia 90/10/1 v/v/v).
















ESI-MS:
(M + H)+ = 624




(M + Na)+ = 646




(M + H + Na)+ + = 323.8










EXAMPLE 21
1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(hydroxycarbonyl)-piperidine (No. 211)
Produced analogously to Example A38 from 1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(ethoxycarbonyl)-piperidine and aqueous lithium hydroxide solution in a yield of 79% of theory. Colourless, amorphous substance of Rf 0.54 (ethyl ethanoate/methanol/glacial acetic acid 9/1/0.3 v/v/v).
IR(KBr): 1691.5,1622.0 cm−1 (C═O) ESI-MS: (M−H)−=690/2/4 (Br2)
EXAMPLE 22
1-[3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperazine (No. 214)
Produced analogously to Example A24 from 3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosine, 1-(1,1-dimethylethoxycarbonyl)-4-(1-piperazinyl)piperidine and TBTU, and additional conversion of the obtained intermediate product with trifluoroacetic acid (in accordance with Example A1b) in a yield of 4.2% of theory. Colourless, amorphous substance of Rf 0.25 (FM1).
IR(KBr): 1624.0 cm−1 (C═O)
ESI-MS: (M+H)+=732/4/6 (Br2)
EXAMPLE 23
(R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine (No. 219)
a) 1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine
To a solution of 3.0 g (13.8 mmol) 4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)piperidine and 2.7 ml (15 mMol) DIEA in 100 ml toluene, a solution of 1.8 ml (14.9 mMol) diphosgene in 15 ml toluene was added dropwise under external cooling with iced water, and the mixture was additionally kept at room temperature for 17 hours. The precipitate was suction filtered, washed with petroleum ether and dissolved in 50 ml dichloromethane. The obtained solution was agitated twice each with 50 ml 7% aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated in a vacuum. Yield was 3.0 g (78% of theory) of a colourless substance of Rf 0.25 (dichloromethane/acetone 9/1 v/v), which was further processed without more purification.
b) (R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidinyl)-piperidine
To a suspension of 2.3 g (60 mmol) lithium aluminium hydride in 100 ml anhydrous tetrahydrofuran, a solution of 11.0 g (18.66 mmol) 1-[3,5-dibromo-N-(1,1-dimethylethoxycarbonyl)-D-tyrosyl]-4-(1-piperidinyl)piperidine in 100 ml anhydrous tetrahydrofuran was added dropwise at room temperature whilst being stirred. It was stirred for a further 15 minutes at room temperature and then refluxed for 3 hours. 3 ml 20% aqueous ammonium chloride solution was added to the cooled mixture, then it was dried with magnesium sulphate. The filter cake was filtered and washed with 300 ml of an ethyl ethanoate-methanol mixture (1/1 v/v), and the combined filtrates were evaporated in a vacuum. The residue was purified by column chromatography over silica gel using ethyl ethanoate/methanol (8/2 v/v) for elution.
1. 2.9 g (31% of theory) of a colourless substance of Rf 0.13 (eluant: methanol) was isolated from the suitable fractions, which was identified as 1-(3,5-dibromo-N-methyl-D-tyrosyl)-4-(1-piperidinyl)piperidine:
IR(KBr): 1668.3 cm−1 (C═O)
MS: M+=501/3/5 (Br2)
and
2. 1.8 g (20% of theory) of a colourless substance of Rf 0.05 (eluant: methanol), which was identified as the sought compound:
















ESI-MS:
(M + H)+ = 488/490/492 (Br2)




(M + 2H)++ = 244/245/246.5 (Br2)










c) (R)-1-[2-[N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-N-methylamino]-3-(3,5-dibromo-4-hydroxyphenyl)-propyl]-4-(1-piperidinyl)-piperidine (No. 219)
A solution of 0.57 g (2.02 mmol) 1-(chlorocarbonyl)-4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-piperidine in 30 ml dimethylformamide was added dropwise to the mixture of 0.9 g (1.84 mmol) (R)-1-[3-(3,5-dibromo-4-hydroxyphenyl)-2-(N-methylamino)-propyl]-4-(1-piperidinyl)-piperidine and 0.65 ml (3.7 mmol) DIEA in a mixture of 50 ml tetrahydrofuran and 20 ml dimethylformamide. It was stirred overnight at room temperature and the deposit was evaporated in a vacuum. The residue was treated with 300 ml of a tetrahydrofuran ethyl ethanoate mixture (1/1 v/v) and the resulting solution was agitated twice each with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate and evaporated in a vacuum. The residue was purified over silica gel by column chromatography using dichloromethane/methanol (8.5/1.5 v/v) for elution. 390 mg (29% of theory) of a colourless substance of Rf 0.46 (dichloromethane cyclohexane/methanol/conc. ammonia 75/15/15/2 v/v/v/v) were isolated from the suitable fractions:
IR(KBr): 1695.3,1624.0 cm−1 (C═O)
ESI-MS: (M+H)+=731/3/5 (Br2)
EXAMPLE 24
1-[3,5-dibromo-N-[[4-[5-[(4-morpholinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 223)
100 mg (0.6 mMol) N,N′-carbonyldiimidazole was added to a solution of 400 mg (0.5 mMol) 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine in 10 ml anhydrous tetrahydrofuran at room temperature, heated to 50° C. for 30 minutes and then 90 mg (1 mMol) morpholine was added. After heating to 50-60° C. for two hours, the solution was removed in a vacuum and the residue was purified over silica gel(30-60 μm) by column chromatography, initially using dichloromethane, then dichloromethane/methanol 9/1 (v/v), and finally dichloromethane/methanol/conc. ammonia 9/1/0.2 (v/v/v) as eluants. 250 mg (60% of theory) of an amorphous, colourless substance was yielded from the suitable extracts.
















IR (KBr):
1712.7, 1625.9 cm−1 (C═O)



ESI-MS:
(M + H)+ = 838/840/842 (Br2)




(M + 2H)++ = 419/420/421.5 (Br2)










The following were obtained accordingly:
1-[3,5-dibromo-N-[[4-[5-[(4-methyl-1-piperazinyl)carbonyl]-1,3-dihydro-2(2H)-oxobenzimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)-piperidine (No. 224) from 1-[3,5-dibromo-N-[[4-(1,3-dihydro-5-(hydroxycarbonyl)-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-pyridinyl)piperidine, 1-methylpiperazine and N,N′-carbonyldiimidazole in yield of 52% of theory. Colourless, amorphous substance.
















IR (KBr):
1710.8, 1625.9 cm−1 (C═O)



ESI-MS:
(M + H)+ = 851/853/855 (Br2)




(M + 2H)++ = 426/427/428 (Br2)










EXAMPLE 25
1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(carboxymethyl)-4-piperidinyl]-piperidine (No. 494)
Produced analogously to Example A37, but using tetrahydrofuran instead of methanol, from 1-[4-amino-3,5-dibromo-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D-phenylalanyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine by the action of aqueous lithium hydroxide solution in a yield of 51% of theory. Colourless, amorphous substance.
















ESI-MS:
(M − H)− = 800/802/804 (Br2)




(M + H)+ = 802/804/806 (Br2)




(M + Na)+ = 824/826/828 (Br2)










EXAMPLE 26
1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(hydroxycarbonylmethyl)-4-piperidinyl]-piperidine (No. 526)
Produced analogously to Example 18 from 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-(4-piperidinyl)-piperidine, ethyl glyoxylate and sodium triacetoxyborhydride and additional saponification with soda lye of the 1-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-4-[1-(ethoxycarbonylmethyl)-4-piperidinyl]-piperidine, obtained as an intermediate product but not characterised, according to Example A55. A colourless, amorphous substance is obtained in a yield of 35% of theory.
















IR (KBr):
1625.9 wide cm−1 (C═O)











ESI-MS:
(M + H)+ =
803/805/807 (Br2)




(M + Na)+ =
825/827/829 (Br2)










EXAMPLE 27
1-[4-amino-N-[(4-amino-1-piperidinyl)carbonyl]-3,5-dibromo-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine (No. 564)
653 mg (10.4 mMol) 95% sodium cyanoborohydride (Aldrich 15.615-9) was stirred into the mixture of 930 mg (1.48 mMol) 1-[4-amino-3,5-dibromo-N-[(4-oxo-1-piperidinyl)carbonyl]-D-phenylalanyl]-4-(1-methyl-4-piperidinyl)-piperidine, 1143 mg (14.8 mMol) ammonium acetate (Merck No. 1115) and 30 ml anhydrous methanol at room temperature, and was stirred overnight. The deposit was adjusted to pH ≦2 with conc. hydrochloric acid and was evaporated in a vacuum. The residue is taken up in water and made alkaline with 40% soda lye. Exhaustive extraction with dichloromethane followed, then the combined extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was purified over 100 g silica gel (Amicon, 35-70 μm) by column chromatography using dichloromethane/methanol/conc. ammonia(60/40/5 v/v/v) for elution. From the suitable fractions, 250 mg (27% of theory) of the sought substance was isolated as a colourless, amorphous product of Rf 0.15 (dichloromethane/methanol/conc. ammonia 50/50/0.5 v/v/v).
















IR (KBr):
1618 wide cm−1 (C═O)



ESI-MS:
(M + H)+ = 627/629/631 (Br2)




(M + Na)+ = 649/651/653 (Br2)




(M + 2H)++= 314/315/316 (Br2)










EXAMPLE 28
(R,S)-1-[4-[4-(3,4-Dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorphenyl)methyl]-1,4-dioxobutyl]-4-(hydroxycarbonylmethyl)-piperidine (No. 596)
Produced analogously to Example A55 from (R,S)-1-[4-[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]-2-[(3,4-dichlorophenyl)methyl]-1,4-dioxobutyl]-4-(ethoxycarbonylmethyl)-piperidine by saponification with soda lye in a yield of 86% of theory. Colourless, amorphous substance of Rf 0.76 (ethyl ethanoate/methanol/glacial acetic acid 70/30/1 v/v/v).
















IR (KBr):
1716, 1635 cm−1 (C═O)



ESI-MS:
(M − H)−= 613/615/617 (Cl2)




(M + H)+ = 615/617/619 (Cl2)




(M + Na)+ = 637/639/641 (Cl2)










EXAMPLE 29
1-[N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]-carbonyl]-3-(1H-tetrazol-5-yl)-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine (No. 632)
8.5 g (35 mMol) tributyl tin(IV)-azide (Synthesis 1976, 330) was added to a solution of 1.6 g (2.68 mMol) 1-[3-cyano-N-[[4-[3,4-dihydro-2(1H)-oxoquinazolin-3-yl]-1-piperidinyl]carbonyl]-D,L-phenylalanyl]-4-(1-piperidinyl)-piperidine in 400 ml toluene and the mixture was refluxed for 4 days. The residue remaining after dispellation of the solvent was stirred with ethyl ethanoate, the obtained precipitate was suction filtered and purified over silica gel by column chromatography using FM1 as an eluent. After the usual further processing, yield is 400 mg (24% of theory) of colourless crystals of Rf 0.2 (FM1).
















IR (KBr):
1653 cm−1 (C═O)



ESI-MS:
(M + H)+ = 641




(M + Na)+ = 663










The following Examples describe the preparation of pharmaceutically useful forms which contain as active substance any desired compound of general formula I:
EXAMPLE I










Capsules for powder inhalation containing


1 mg of active substance

















Composition:



1 capsule for powder inhalation contains:










Active substance
 1.0 mg



Lactose
20.0 mg



Hard gelatine capsules
50.0 mg




71.0 mg










Method of Preparation:
The active substance is ground to the particle size required for inhalants. The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.
EXAMPLE II










Inhalable solution for Respimat ® containing


1 mg of active substance

















Composition:



1 stroke contains:











Active substance
1.0
mg



Benzalkonium chloride
0.002
mg



Disodium edetate
0.0075
mg



Purified water ad
15.0
μl










Method of Preparation:
The active substance and benzalkonium chloride are dissolved in water and transferred into Respimat® cartridges.
EXAMPLE III










Inhalable solution for nebulisers containing


1 mg of active substance

















Composition:



1 vial contains:











Active substance
0.1
g



Sodium chloride
0.18
g



Benzalkonium chloride
0.002
g



Purified water ad
20.0
ml










Method of Preparation:
Active substance, sodium chloride and benzalkonium chloride are dissolved in water.
EXAMPLE IV










Propellant gas metering aerosol containing


1 mg of active substance

















Composition:



1 stroke contains:











Active substance
1.0
mg










Lecithin
0.1%











Propellant gas ad
50.0
μl










Method of Preparation:
The micronised active substance is homogeneously suspended in a mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with metering valve.
EXAMPLE V










Nasal spray containing 1 mg of active substance

















Composition:











Active substance
1.0
mg



Sodium chloride
0.9
mg



Benzalkonium chloride
0.025
mg



Disodium edetate
0.05
mg



Purified water ad
0.1
ml










Method of Preparation:
The active substance and adjuvants are dissolved in water and transferred into a suitable container.
EXAMPLE VI










Injectable solution containing 5 mg of active substance per 5 ml

















Composition:











Active substance
5
mg



Glucose
250
mg



Human-serum-albumin
10
mg



Glycofurol
250
mg



Water for injections ad
5
ml










Preparation:
Glycofurol and glucose are dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into ampoules under nitrogen gas.
EXAMPLE VII










Injectable solution containing 100


mg of active substance per 20 ml

















Composition:











Active substance
100
mg



Monopotassium dihydrogen phosphate = KH2PO4
12
mg



Disodium hydrogen phosphate = Na2HPO4•2H2O
2
mg



Sodium chloride
180
mg



Human-serum-albumin
50
mg



Polysorbate 80
20
mg



Water for injections ad
20
ml










Preparation:
Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into ampoules.
EXAMPLE VIII










Lyophilisate containing 10 mg of active substance


















Composition:




Active substance
10 mg



Mannitol
300 mg 



Human-serum-albumin
20 mg










Preparation:
Mannitol is dissolved in water for injections (WfI); human-serum-albumin is added; active substance is dissolved with heating; solution is made up to required volume with WfI; transferred into vials and freeze-dried.

















Solvent for lyophilisate:





Polysorbate 80 = Tween 80
20
mg



Mannitol
200
mg



Water for injections ad
10
ml










Preparation:
Polysorbate 80 and mannitol are dissolved in water for injections (WfI) and transferred into ampoules.
EXAMPLE IX










Tablets containing 20 mg of active substance


















Composition:




Active substance
20 mg



Lactose
120 mg 



Corn starch
40 mg



Magnesium stearate
 2 mg



Povidon K 25
18 mg










Preparation:
Active substance, lactose and corn starch are homogeneously mixed; granulated with an aqueous solution of Povidon; mixed with magnesium stearate; pressed in a tablet press; weight of tablet 200 mg.
EXAMPLE X










Capsules containing 20 mg of active substance


















Composition:




Active substance
20 mg



Corn starch
80 mg



Highly dispersed silicic acid
 5 mg



Magnesium stearate
2.5 mg 










Preparation:
Active substance, corn starch and silicic acid are homogeneously mixed; mixed with magnesium stearate; then the mixture is packed into size 3 hard gelatine capsules using a capsule filling machine.
EXAMPLE XI










Suppositories containing 50 mg of active substance


















Composition:




Active substance
50 mg



Hard fat (adeps solidus) q.s. ad
1700 mg 










Preparation:
Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; then after cooling to about 35° C. the melt is poured into chilled moulds.
EXAMPLE XII










Aqueous solution for nasal application


containing 10 mg active substance



















Composition:





Active substance
10.0
mg



Hydrochloric acid in quantity required
0.01
mg



for formation of a neutral salt



Methylparahydroxybenzoate (PHB)



Propylparahydroxybenzoate (PHB)
0.005
mg



Purified water ad
1.0
ml










Preparation:
The active substance is dissolved in purified water; Hydrochloric acid is added until the solution is clear; PHB methyl and propyl esters are added; the solution is made up to required volume with purified water; the solution is sterile-filtered and is transferred into an appropriate container.
EXAMPLE XIII










Aqueous solution for nasal application


containing 5 mg active substance



















Composition:





Active substance
5
mg



1,2-propandiol
300
mg



Hydroxyethyl cellulose
5
mg



Sorbic acid
1
mg



Purified water ad
1
ml










Preparation:
The active substance is dissolved in 1,2-propandiol; a hydroxy-ethyl-cellulose solution is prepared in purified water containing sorbic acid and is added to the active substance solution; the solution is sterile-filtered and is transferred into an appropriate container.
EXAMPLE XIV










Aqueous solution for intravenous application


containing 5 mg active substance



















Composition:





Active substance
5
mg



1,2-propandiol
300
mg



Mannitol
50
mg



Water for injections (WfI) ad
1
ml










Preparation:
The active substance is dissolved in 1,2-propandiol; the solution is approximately made up to the required volume with WfI; the mannitol is added and the solution is made up to required volume with WfI; the solution is sterile-filtered, transferred into individual containers and autoclaved.
EXAMPLE XV










Liposomal formulation for intravenous injection


containing 7.5 mg active substance



















Composition:





Active substance
7.5
mg



Egg-lecithin, e.g. lipoid E 80
100.0
mg



Cholesterol
50.0
mg



Glycerine
50.0
mg



Water for injections ad
1.0
ml










Preparation:
The active substance is dissolved in a mixture of lecithin and cholesterol; the solution is added to a mixture of glycerine and WfI and is homogenised by means of high-pressure homogenisation or microfluidiser technology; the liposomal formulation obtained in this manner is transferred into an appropriate container under aseptic conditions.
EXAMPLE XVI










Suspension for nasal application


containing 20 mg active substance



















Composition:





Active substance
20.0
mg



Carboxymethylcellulose (CMC)
20.0
mg










Sodium monohydrogen phosphate/sodium-
q.s.



dihydrogen phosphate buffer pH 6.8











Sodium chloride
8.0
mg



Methylparahydroxybenzoate
0.01
mg



Propylparahydroxybenzoate
0.003
mg



Purified water ad
1.0
ml










Preparation:
The active substance is suspended in an aqueous CMC solution; the other components are added to the suspension one after another and the suspension is made up to required volume with purified water.
EXAMPLE XVII










Aqueous solution for subcutaneous application


containing 10 mg active substance



















Composition:





Active substance
10.0
mg



Sodium monohydrogen phosphate/sodium
7.0



dihydrogen phosphate buffer q.s. ad pH



Sodium chloride
4.0
mg



Water for injections ad
0.5
ml










Preparation:
The active substance is dissolved in the phosphate buffer solution, after addition of the sodium chloride the solution is made up to required volume with water. The solution is sterile-filtered and is autoclaved after being transferred into an appropriate container.
EXAMPLE XVIII










Aqueous solution for subcutaneous application


containing 5 mg active substance



















Composition:





Active substance
5.0
mg



Polysorbate 80
0.5
mg



Water for injections ad
0.5
ml










Preparation:
The active substance is suspended in the polysorbate 80 solution and is reduced to a particle size of approx. 1 μm by means of a suitable dispersion technique (e.g. wet milling, high-pressure homogenisation, micro-fluidisation, etc.). The suspension is transferred into an appropriate container under aseptic conditions.

## Claims

1. A compound of the formula I




wherein
R denotes a group of formula





wherein

p denotes the number 1,
o denotes the number 2,
Y1 denotes the carbon atom,
Y2 denotes the nitrogen atom,
R5, R6 and R7 each denote the hydrogen atom,
RN denotes a N-(aminocarbonyl)-N-phenylamino group or
a mono- or bicyclic heterocycle selected from the group consisting of 1,3-dihydro-4-phenyl-2H-2-oxoimidazol-1-yl,
1,3-dihydro-5-phenyl-2H-2-oxoimidazol-1-yl,
1,3-dihydro-2(2H)-oxobenzimidazol-1-yl,
3,4-dihydro-2(1H)-oxothieno [3,4-d]pyrimidin-3-yl,
1H-benzimidazol-1-yl,
3,4-dihydro-2(1H)-oxoquinazolin-3-yl,
3,4-dihydro-2(1H)-oxoquinazolin-1-yl,
2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepin-3-yl,
2(1H)-oxoquinolin-3-yl, or
1,1-dioxido-3(4H)-oxo-1,2,4-benzothiadiazin-2-yl,
wherein said mono- and bicyclic heterocycles optionally are monosubstituted in the carbon skeleton and/or at the phenyl groups contained in these groups by a chlorine atom, or by a methyl, or hydroxy group,

X denotes an oxygen atom or 2 hydrogen atoms,
Z denotes a methylene group or the group —NR1, wherein
R1 denotes a hydrogen atom or a methyl group,

R11 denotes a hydrogen atom,
n denotes the number 1 and m denotes the number 0 or
n denotes the number 0 and m denotes the number 1,
R2 denotes an aromatic group selected from phenyl, 1-naphthyl and 2-naphthyl, wherein said aromatic group optionally is
mono- or disubstituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, hydroxy or amino groups and the substituents may be identical or different, or trisubstituted by two bromine atoms and either one hydroxy, one amino, one methyl, one methoxy group or
trisubstituted by two chlorine atoms and one hydroxy group or
trisubstituted by two methyl groups and either one hydroxy or one methoxy group,

or R2 denotes a 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl or pyridinyl group,
A denotes the divalent group of formula




 (linked to the group —NR3R4 of formula (I) via the carbonyl group)

wherein

R8 denotes the hydrogen atom or the methyl group and
R9 denotes the hydrogen atom or an unbranched C1-4-alkyl group, which may be substituted in the ω-position by an amino, methylamino, dimethylamino or amino iminomethylamino group,

R3 denotes a hydrogen atom or
a C1-4-alkyl group optionally substituted in the ω-position by an amino, methylamino or dimethylamino group,
R4 denotes a hydrogen atom, a methyl or ethyl group,
or R3 and R4 together with the enclosed nitrogen atom denote a group of general formula





wherein

Y3 denotes the carbon atom or, if R12 denotes a free pair of electrons, Y3 denotes a nitrogen atom,
r denotes the number 1,
q denotes the number 1,
R10 denotes a C1-3-alkyl group which may be substituted in the ω-position by a dialkylamino group having 1 to 3 carbon atoms in each alkyl moity, or

a phenyl, pyridinyl or diazinyl group, each of which may be substituted in the carbon skeleton by methyl or methoxy group,
a 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl or 4-piperidinyl group, wherein the nitrogen atom of the 4-piperidinyl group may be substituted by an alkyl group having 1 to 3 carbon atoms,
R12 denotes a hydrogen atom, or
a free pair of electrons if Y3 denotes a nitrogen atom, and
R13 and R14 each denote a hydrogen atom,

or a tautomer or salt thereof

2. A compound of the formula I according to claim 1, wherein the partial amino acid structure of the formula




is in the D- or (R)-configuration and is in the L- or (S)-configuration with regard to the partial amino acid structure of formula




which may be present in the group A, or wherein the partial structure of formula VI




is spatially constructed analogously to the (R)-configured partial structure of formula V.

3. A compound selected from the group consisting of:
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl ]-L-lysyl]-4-(4-pyridinyl)-piperazine;
(22) 1-[N2-[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
(23) 1-[N2-[N-(4-Phenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(2-Methoxyphenyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(3-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl ]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(2-Methoxyphenyl)-1,2,5,6-tetrahydro-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl ]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-4-amino-3,5-dibromo-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl ]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(2-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[4-(Aminocarbonyl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-methoxyphenyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine;
1-[N2—[N-(4,4-Diphenyl-1-piperidinyl)carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(2-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D,L-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[4-(1,3-Dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(2,4(1H,3H)-dioxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2—[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(methylaminocarbonylamino)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[[4-(Aminocarbonylamino)-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(aminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)amino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(methylaminocarbonyl)methylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2—[N-[[4-[2(3H)-Oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine;
1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3-Bromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl ]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl ]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl ]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)oxoquinazolin-3-yl)-1-piperidinyl ]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-4-phenyl-2(2H)-oxoimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-[2(3H)-oxobenzoxazol-3-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine;
1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-L-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[2,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-[N-(Aminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(5-methoxy-4-pyrimidinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-[N-(methylaminocarbonyl)phenylamino]-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(1-piperidinyl)-piperidine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-4-methyl-1-piperidinyl]carbonyl]-D-phenylalanyl]-L-lysyl]-4-(4-pyridinyl)-piperidine;
1-[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N6-Acetyl-N2-[3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[4-Amino-3,5-dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-phenylalanyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6,N6-dimethyl-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-[1,3-dihydro-4-[3-(trifluoromethyl)phenyl]-2(2H)-oxoimidazol-1-yl]-1-piperidinyl]carbonyl]-D-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
1[N2-[3,5-Dibromo-N-[[4-(1,3-dihydro-2(2H)-oxobenzimidazol-1-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-N6-(1,1-dimethylethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)-piperazine;
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-D-lysyl]-4-(4-pyridinyl)-piperazine; and
1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-L-tyrosyl]-L-lysyl]-4-(4-pyridinyl)-piperazine;
or a tautomer or salt thereof.

4. A physiologically acceptable salt of a compound in accordance with claim 2, 1 or 3.

5. A pharmaceutical composition containing a compound according to claim 2, 1 or 3 or a physiologically acceptable salt thereof, together with an inert carrier or diluent.