# Patent

## Title
Retinoic acid mimetic anilides

## Abstract

The present invention is concerned with compounds of formula




the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein X represents O, S or NR3; R1 represents hydrogen, hydroxy, C1-6alkyl or aryl; R2 represents hydrogen; optionally substituted C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; Het1; R3 represents hydrogen, optionally substituted C1-6alkyl, aryl, Het1; R4 represents hydrogen; hydroxy; mercapto; C1-6alkyloxy; C1-6alkylthio; aryloxy; arylthio; Het1-oxy; Het1-thio; optionally substituted C1-12alkyl; optionally substituted C2-8alkenyl; optionally substituted C2-8alkynyl; optionally substituted C3-7cycloalkyl; optionally substituted C5-7cycloalkenyl; aryl; Het1; or -Alk-NR3R5 (i) or —NR3R5 (ii) wherein Alk represents C1-6alkanediyl; and R5 represents hydrogen, C1-6alkyl, aryl, Het1, (aryl or Het1)C1-6alkyl, (aryl or Het1)carbonyl or (aryl or Het1)C1-6alkyloxycarbonyl; aryl represents optionally substituted indanyl, indenyl, naphtyl, 5,6,7,8-tetrahydro-2-naphtalenyl or phenyl; Het is triazolyl; and Het1 represents an optionally substituted monocyclic or bicyclic heterocycle; having retinoic mimetic activity; their preparation, compositions containing them and their use as a medicine.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of prior application U.S. Ser. No. 11/551,045, filed on Oct. 19, 2006, which is a divisional of prior application U.S. Ser. No. 11/081,393, filed on Mar. 16, 2005, now U.S. Pat. No. 7,179,825, which is a divisional of prior application U.S. Ser. No. 09/962,551, filed Sep. 25, 2001, now U.S. Pat. No. 6,936,626, which is a divisional of prior application U.S. Ser. No. 09/555,775, filed Jun. 1, 2000, now U.S. Pat. No. 6,319,939, the contents of all of which are incorporated herein by reference.


The present invention concerns anilides, their N-oxides and addition salts; it further relates to processes for their preparation, compositions comprising them. The compounds of the present invention are potent inhibitors of the retinoic acid metabolism, and hence, their use as a medicine is also described.
EP-A-0,260,744, published on Mar. 23, 1988, discloses (1H-imidazol-1-ylmethyl) substituted benzimidazoles as inhibitors of the androgen formation from C21-steroids, as inhibitors of the biosynthesis of thromboxane A2, and also having the capability to increase the excretion of ureic acid. EP-A-0,371,559, published on Jun. 6, 1990, discloses said benzimidazoles and analogous benzotriazoles as potent suppressers of the plasma elimination of endogenously or exogenously administered retinoic acid.
Retinoic acid (RA) is a key molecule in the regulation of growth and differentiation of epithelial tissues. However, RA is very rapidly metabolized by a series of enzymatic reactions, which results in its deactivation. Inhibition of RA-metabolism leads to enhanced RA levels in plasma and tissue. Therefore, compounds with such an inhibitory action, also called retinoic mimetic activity, have therapeutic and/or preventive potential in the field of dermatology and oncology.
The present invention is concerned with compounds of formula




the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

    X represents O, S or NR3;
    R1 represents hydrogen, hydroxy, C1-6alkyl or aryl;
    R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; Het1; or C1-12alkyl substituted with one or two substituents selected from C3-7cycloalkyl, hydroxy, C1-4alkyloxy, cyano, amino, mono- and di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, di(arylC1-4alkyl)aminocarbonyloxy, (C1-4alkyl) (arylC1-14alkyl)amino, mono- and di(aryl)amino, (C1-14alkyl)(di(C1-4alkyl)-aminoC1-4alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl, mono- and di(C1-4alkyl)aminocarbonyl, aryl, aryloxy and arylthio; or
    R1 and R2 taken together may form a bivalent radical of formula —R1—R2— wherein —R1—R2— represents —(CH2)n— wherein n is 2, 3, 4, 5 or 6;
    R3 represents hydrogen, C1-6alkyl, aryl, Het1 or C1-6alkyl substituted with aryl or Het1;
    R4 represents hydrogen; hydroxy; mercapto; C1-6alkyloxy; C1-6alkylthio; aryloxy; arylthio; Het1-oxy; Het1-thio; C1-12alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, mercapto, C1-6alkyloxy, C1-6alkylthio, aryloxy, arylthio, Het1-oxy, Het1-thio, C3-7cycloalkyl optionally substituted with hydroxycarbonylC1-6alkyl, carboxyl, C1-6alkyloxy-carbonyl, arylC1-6alkyloxy, arylC1-6alkylthio, aryl, Het1; C2-8alkenyl optionally substituted with one, two or three substituents selected from halo, C3-7cycloalkyl, aryl, Het1; C2-8alkynyl optionally substituted with halo, C3-7cycloalkyl, aryl; C3-7cycloalkyl optionally substituted with C1-6alkyl or aryl; C5-7cycloalkenyl optionally substituted with C1-6alkyl or aryl; aryl; Het1; or

-Alk-NR3R5  (i)

or

—NR3R5  (ii)
    
        wherein Alk represents C1-6alkanediyl; and
        
            R5 represents hydrogen, C1-6alkyl, aryl, Het1, (aryl or Het1)C1-6alkyl, (aryl or Het1)carbonyl or (aryl or Het1)C1-6alkyloxycarbonyl;
        
        
    
    
    aryl represents indanyl, indenyl, naphtyl, 5,6,7,8-tetrahydro-2-naphtalenyl, phenyl; said indanyl, indenyl, naphtyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from hydroxy, halo, nitro, cyano, amino, azido, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, C1-6alkyl, polyhaloC1-6alkyl, hydroxyC1-6alkyl, phenyl, phenyloxy, phenylC1-6alkyloxy, pyridinylC1-6alkyloxy, C1-6alkyloxy, formyl, carboxyl and C1-6alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C1-12alkanediyl or polyhaloC1-12alkanediyl;
    Het represents an unsaturated heterocycle selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl and pyridinyl; each of said unsaturated heterocycles may optionally be substituted with amino, mercapto, C1-6alkyl, C1-6alkylthio or aryl; and
    Het1 represents a monocyclic heterocycle selected from pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,3,4-triazolyl, 1,2,4-triazolyl, tetrahydrofuranyl, furanyl, thiolanyl, thienyl, dioxolanyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, pyranyl, morpholinyl and dioxanyl; each of said monocyclic heterocycles may be optionally substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl; or a bicyclic heterocycle selected from indolinyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, 2H-1-benzopyranyl, 3,4-dihydro-2H-1-benzopyranyl, benzthiazolyl, isoquinolinyl, quinolinyl, 3,4-dihydroquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, chromanyl, 1,4-benzodioxinyl, 1,4-benzoxathianyl, benzodioxanyl and benzodioxolanyl; each of said bicyclic heterocycles may be substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl.


As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C5-7cycloalkenyl is generic to cyclopentenyl, cyclohexenyl and cycloheptenyl; C2-8alkenyl defines straight and branch chained hydro-carbon radicals containing one double bond and having from 2 to 8 carbon atoms such as, for example, ethenyl, 1-propenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-heptenyl, 2-octenyl and the like; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C1-12alkyl is meant to include C1-6alkyl and the higher homologues thereof having from 7 to 12 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, 2-methylhexyl, 3-ethyloctyl and the like; C1-12alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 12 carbon atoms such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl, 1,1,4,4-tetra-methylbutane-1,4-diyl and the like; polyhaloC1-6alkyl is defined as polyhalosubstituted C1-6alkyl, in particular C1-6alkyl substituted with 1 to 6 halogen atoms, more in particular difluoro- or trifluoromethyl; polyhaloC1-12alkanediyl is defined as polyhalo-substituted C1-12alkanediyl, in particular C1-12alkanediyl substituted with 1 to 12 halogen atoms; triazolyl is meant to include 1,2,4-triazolyl and 1,3,4-triazolyl; tetrazolyl is meant to include 1H-tetrazolyl and 2H-tetrazolyl; benzodioxanyl is meant to include 2,3-dihydro-1,4-benzodioxinyl.
The unsaturated heteroaryl group represented by Het may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. Thus, for example, when the heteroaryl group is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is triazolyl, it may be 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,4-triazol-1-yl and 1,3,4-triazol-2-yl.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form. The acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term “stereochemically isomeric forms” as used hereinbefore and hereinafter defines all the possible stereoisomeric forms in which the compounds of formula (I) exist. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
In particular, some of the compounds of formula (I) and some of the intermediates hereinafter have at least one stereogenic center in their structure. This stereogenic center may be present in a R and a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. In particular, compounds of formula (I) wherein R3 is hydrogen may exist in their corresponding tautomeric form.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxides, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
Whenever used hereinafter, R1 to R4 and Het are defined as under formula (I) unless otherwise indicated.
A special group of compounds are those compounds of formula (I) wherein one or more of the following restrictions apply:

    (a) X represents O, S, NH or N(aryl); more in particular X is O or S;
    (b) R1 represents hydrogen, hydroxy or C1-6alkyl;
    (c) R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; Het1; or C1-12alkyl substituted with one or two substituents selected from hydroxy, C1-4alkyloxy, cyano, mono- and di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)-amino, di(arylC1-4alkyl)aminocarbonyloxy, (C1-4alkyl)(arylC1-4alkyl)amino, (C1-4alkyl)(di(C1-4alkyl)aminoC1-4alkyl)amino, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, morpholinyl, C1-4alkyloxycarbonyl, aryl, aryloxy and arylthio; or
    
        R1 and R2 taken together may form a bivalent radical of formula —R1—R2— wherein —R1—R2— represents —(CH2)n— wherein n is 2;
    
    
    (d) R3 represents hydrogen or C1-6alkyl; more in particular R3 is hydrogen;
    (e) R4 represents hydrogen; C1-6alkyloxy; aryloxy; C1-12alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-6alkyloxy, C1-6alkylthio, aryloxy, arylthio, Het1-thio, C3-7cycloalkyl optionally substituted with hydroxycarbonylC1-6alkyl, carboxyl, C1-6alkyloxycarbonyl, arylC1-6alkylthio, aryl, Het1; C2-8alkenyl optionally substituted with one, two or three substituents selected from halo, C3-7cycloalkyl, aryl, Het1; C2-8alkynyl optionally substituted with aryl; C3-7cycloalkyl optionally substituted with C1-6alkyl or aryl; C5-7cycloalkenyl; aryl; Het1; or

-Alk-NR3R5  (i)

or

—NR3R5  (ii)
    
        wherein Alk represents C1-6alkanediyl; and
        
            R5 represents hydrogen, C1-6alkyl, aryl, Het1, arylC1-6alkyl, arylcarbonyl or arylC1-6alkyloxycarbonyl.
        
        
    
    


Aryl is suitably indenyl, naphtyl, 5,6,7,8-tetrahydro-naphtalenyl, phenyl; said indenyl, naphtyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from hydroxy, halo, nitro, amino, azido, C1-6alkylcarbonylamino, C1-6alkyl, polyhaloC1-6alkyl, phenyl, C1-6alkyloxy.
Het is suitably imidazolyl, triazolyl and pyridinyl; each of said unsaturated heterocycles may optionally be substituted with C1-6alkyl, more in particular, Het is 1H-1-imidazolyl or 1,2,4-triazol-1-yl.
Het1 is suitably pyrrolyl, furanyl, thienyl, isoxazolyl, thiazolyl, piperidinyl, pyridinyl, piperazinyl, pyrimidinyl, pyrazinyl, morpholinyl and dioxanyl; each of said monocyclic heterocycles may be optionally substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl; or indolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, 2H-1-benzopyranyl, 3,4-dihydro-2H-1-benzopyranyl, benzthiazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, 1,4-benzodioxinyl, benzodioxanyl and benzodioxolanyl; each of said bicyclic heterocycles may be substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl.
Particular compounds are those compounds of formula (I) wherein R2 is C1-12alkyl optionally substituted with mono- and di(C1-4alkyl)amino, more in particular, R2 is 3-pentyl, 2-propyl, 2-(dimethylamino)-ethyl or 2-(diethylamino)-ethyl.
Other particular compounds are those compounds of formula (I) wherein R4 is C1-12alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-6alkyloxy, C1-6alkylthio, aryloxy, arylthio, Het1-thio, C3-7cycloalkyl optionally substituted with hydroxycarbonylC1-6alkyl, carboxyl, C1-6alkyloxycarbonyl, arylC1-6alkylthio, aryl, Het1; aryl; Het1; or a radical of formula (ii).
Preferred compounds are those compounds of formula (I) wherein R3 is hydrogen; X is O and R4 is aryl or C1-12alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-6alkyloxy, C1-6alkylthio, aryloxy, arylthio, Het1-thio, C3-7cycloalkyl optionally substituted with hydroxycarbonylC1-6alkyl, carboxyl, C1-6alkyloxycarbonyl, arylC1-6alkylthio, aryl, Het1; or a radical of formula (ii).
Other preferred compounds are those compounds of formula (I) wherein R3 is hydrogen, X is S and R4 is a radical of formula (ii).
More preferred are the compounds of formula (I) wherein X is O; Het is 1,2,4-triazol-1-yl; R1 and R3 are hydrogen; R2 is C1-6alkyl optionally substituted with dialkylamino; and R4 is C1-4alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-6alkyloxy, C1-6alkylthio, aryloxy, arylthio, Het1-thio, C3-7cycloalkyl optionally substituted with hydroxycarbonylC1-6alkyl, carboxyl, C1-6alkyloxycarbonyl, arylC1-6alkylthio, aryl or Het1.
Most Preferred are 4-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-α-hydroxybenzeneacetamide; the N-oxides, the pharmaceutically acceptable addition salts and stereoisomeric forms thereof.
In general, the compounds of formula (I) can be prepared by reacting an intermediate of formula (II) wherein W1 is an appropriate leaving group such as, for example, a halogen, hydroxy or an alkylsulfonyloxy group, with an intermediate of formula (III) or a functional derivative thereof. For instance, a functional derivative of imidazole may be 1,1′-carbonyldiimidazole.




Said reaction may be performed in a reaction-inert solvent such as, for example, acetonitrile, dichloromethane or tetrahydrofuran, in the presence of a suitable base such as, for example, potassium carbonate. In case W1 is an hydroxy group, it may be convenient to perform the above reaction in the presence of triphenylphosphine and diethyl azodicarboxylate or a functional derivative of any of said reagents, or in the presence of 1-hydroxy-1H-benzotriazole and dicyclohexylcarbodiimide.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
Alternatively, compounds of formula (I) may be prepared by N-alkylation of an intermediate of formula (IV) with an intermediate of formula (V) wherein W2 is an appropriate leaving group such as, for example, hydroxy, a phenoxy group or a halogen, in a reaction-inert solvent such as, for example, water, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylacetamide, 2-propanone, benzene or the like, and optionally in the presence of a suitable base such as, for example, triethylamine, pyridine or sodiumcarbonate.




Also functional derivatives of intermediates of formula (V) may be used such as, for example, an anhydride, e.g. glutaric anhydride, dihydro-2-H-pyran-2,6(3H)-dione, acetic acid anhydride; a cyanate; a thiocyanate; an isocyanate or an isothiocyanate. In some instances, it may be convenient to add an acid to the reaction medium such as, for instance, acetic acid may be used together with a cyanate.
Compounds of formula (I) wherein R4 is a Het1C1-12alkyl or a radical of formula (i), said R4 being represented by R4′ and said compounds being represented by formula (I-a), can be prepared by reacting an intermediate of formula (VI) wherein W3 is a suitable leaving group such as, for example, a halogen, with an intermediate of formula R4′—H (VII) in a reaction-inert solvent such as, for example, acetonitrile, and in the presence of an appropriate base such as, for example, potassium carbonate.




Compounds of formula (I) wherein R1 is hydroxy, said compounds being represented by formula (I-b), may be prepared by reacting an intermediate of formula (VIII) with Het-H (III) or a functional derivative thereof, in the presence of an appropriate reagent such as, for example, n-butyllithium, in a reaction-inert solvent such as tetrahydrofuran and diethylether, and optionally in the presence of chlorotriethylsilane.




Compounds of formula (I) wherein R3 is hydrogen and R4 is attached by a nitrogen atom to the remainder of the molecule, said compounds being represented by formula (I-c), may be prepared by reacting a primary or secondary amine of formula (VIII) with an intermediate of formula (IX) in a reaction-inert solvent such as, for example, acetonitrile.




Compounds of formula (I) wherein R2 is optionally substituted hydroxymethyl, being represented by formula (I-d), may be prepared by reacting an intermediate of formula (XI) with Het-H (XII) or a functional derivative thereof, in a reaction-inert solvent such as, for example N,N-dimethylformamide.




Compounds of formula (I) can also be prepared by reacting an intermediate of formula (XIII) wherein W4 is a suitable leaving group such as, for example, hydroxy, with an intermediate of formula (XIV) in an appropriate solvent such as, for example, acetic acid, and in the presence of an acid such as, for example, concentrated sulfuric acid.




Compounds of formula (I) wherein R2 is C1-4alkyloxyC1-12alkyl can be prepared by reacting an intermediate corresponding to a compound of formula (I) wherein R2 is LG-C1-12alkyl wherein LG is an appropriate leaving group such as, for example, a alkylsulfonyloxy group, with C1-4alkylO−M+ wherein M+ is a suitable metal ion such as, for example Na+, in a suitable solvent such as methanol.
Compounds of formula (I) wherein R2 is optionally substituted C1-12alkyl, said R2 being represented by R2′ and said compounds being represented by formula (I-e), can be prepared by reducing an intermediate of formula (XV) using a suitable reducing agent such as, for example, sodiumborohydride, in a suitable solvent such as methanol.




Compounds of formula (I) wherein R1, R3 and R4 are hydrogen, said compounds being represented by formula (I-f), can be prepared by reacting an intermediate of formula (XXIII) with formamide in the presence of an acid such as, for example, acetic acid.




The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
For example, compounds of formula (I) wherein R3 is hydrogen may be converted to compounds of formula (I) wherein R3 is other than hydrogen using art-known techniques.
Compounds of formula (I) containing an aliphatic double bond may be converted to compounds of formula (I) wherein said aliphatic double bond is reduced to a single bond using art-known hydrogenation techniques such as, for example, a reaction with hydrogen in methanol in the presence of palladium on activated charcoal as catalyst.
Compounds of formula (I) containing a carboxyl group may be esterified using art-known esterification techniques. Conversely, compounds of formula (I) containing ester may be hydrolysed to compounds of formula (I) containing the corresponding carboxyl moiety.
Also, compounds of formula (I) containing a C1-6alkyloxycarbonyl substituent, may be transformed to compounds of formula (I) wherein said substituent is reduced to hydroxymethyl using for instance, lithium aluminium hydride in tetrahydrofuran; and if desired, said hydroxymethyl substituent may be further transformed to a formyl group. Said C1-6alkyloxycarbonyl may also be entirely removed. Analogously, other moieties which may serve the purpose of protective group such as, for example, phenylmethyl, may also be removed using art-known techniques.
Compounds of formula (I) wherein R1 is hydroxy can be converted to compounds of formula (I) wherein R1 is hydrogen using a suitable reagent such as stannous chloride.
Compounds of formula (I) wherein R4 is a phenoxy group may be converted to the ureum derivatives thereof using art-known replacement techniques. For instance, a primary or secondary amine may be used optionally in the presence of dimethylamino-pyridine and a base such as triethylamine, and 1,4-dioxane may be used as solvent.
Compounds of formula (I) wherein X is O may be converted to compounds of formula (I) wherein X is S using art-known techniques such as, for example, the use of phosphorous pentasulfide in pyridine.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the compounds of formula (I) and some of the intermediates in the present Invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase such as, for example, a Chiracel AD column.
Some of the intermediates and starting materials are known compounds, may be commercially available or may be prepared according to art-known procedures.
In particular, intermediates of formula (II) wherein R1 is hydrogen and W1 is hydroxy, said intermediates being represented by formula (II-1), may be prepared by reducing a ketone of formula (VIII). The reduction may be performed in the presence of a suitable reducing agent in an appropriate reaction-inert solvent such as, for example, sodiumborohydride in methanol or lithiumaluminiumhydride in tetrahydrofuran and water.




In some instances, it may be convenient to replace the hydroxy group in intermediates of formula (II-1) by another leaving group such as, for example, a halogen or a sulfonyl derivative, e.g. p-toluenesulfonyloxy group or a alkylsulfonyloxy group, thus forming intermediates of formula (II-2) or (II-3). Said reaction can be performed in a reaction-inert solvent, such as, for example, chloroform, and in the presence of a suitable reagent such as, for example, thionylchloride or methylsulfonyl chloride.




Intermediates of formula (IV) may be prepared by reacting an intermediate of formula (XVI), wherein P is a protective group such as, for example, C1-4alkylcarbonyl, benzoyl or C1-4alkyloxycarbonyl, with an intermediate of formula (III), and by subsequently reacting the thus formed amide derivative with an acid such as, for example, hydrochloric acid. The preparation of the intermediate amide derivative may be performed using the same procedure as the one used for the preparation of compounds of formula (I) starting from an intermediate of formula (II) and (III).




Intermediates of formula (IV) wherein R3 is hydrogen, said intermediates being represented by formula (IV-1), may be prepared by reducing a nitro derivative of formula (XVII). Said reduction may be performed in the presence of a suitable reducing agent such as, for example, hydrogen, in an appropriate solvent such as, for example, methanol and in the presence of a suitable catalyst such as, for example, raney nickel.




Intermediates of formula (VI) can be prepared by further reacting an intermediate of formula (IV) with an intermediate of formula (XVIII) wherein W3 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, dichloromethane, and in the presence of a base such as, for example, sodium carbonate.




Intermediates of formula (X) may be prepared by reacting an intermediate of formula (IV-1) with a reagent of formula (XIX) in a reaction inert solvent such as, for example, dichloromethane, and in the presence of a suitable base such as, for example, sodium hydroxide.




Intermediates of formula (XI) may be prepared by reductively reacting intramolecularly an intermediate of formula (XX) wherein W4 is a suitable leaving group such as, for example, a halogen in the presence of a suitable reagent such as, for example, sodiumborohydride, in a reaction inert solvent such as, for example, methanol, and in the presence of a suitable base such as, for example, sodium hydroxide.




Intermediates of formula (XI) can be prepared by first dehydrating and deprotecting an intermediate of formula (XXI) wherein P is a protecting group such as, for example, C1-4alkylcarbonyl, benzoyl or C1-4alkyloxycarbonyl, using a suitable reagent such as, for example, an acid, e.g. hydrochloric acid, thus forming an intermediate of formula (XXII). Consequently, said intermediate of formula (XXII) may be further reacted with an intermediate of formula (V) in the same manner as described for the reaction between intermediates (IV) and (V).




Intermediates of formula (XXIII) can be prepared by first reacting an intermediate of formula (XXIV) with Het-H (III) or a functional derivative thereof, in the presence of an appropriate reagent such as, for example, n-butyllithium, in a reaction-inert solvent such as tetrahydrofuran and diethylether, and optionally in the presence of chlorotriethylsilane. The thus formed nitro derivative of formula (XXV) may then be reduced using for example a 15% solution of TiCl3 in water as reducing agent in a suitable solvent such as, for example, tetrahydrofuran.




The compounds of formula (I) suppress the plasma elimination of retinoids, such as all-trans-retinoic acid, 13-cis retinoic acid and their derivatives, resulting in more sustained plasma and tissue concentrations of retinoic acid and improved control of the differentiation and growth of various cell types. This action of the present compounds is also called retinoic mimetic activity because administering a compound of formula (I) causes the same effect as if retinoids were administered. As such, the present compounds can be used to control the rate of growth and differentiation of normal, preneoplastic and neoplastic cells, whether they are epithelial or mesenchymal; whether they are of ectodermal, endodermal or mesodermal origin.
The property to delay the metabolism of retinoic acid can be evidenced in various in vitro and in vivo experiments. A particular in vitro procedure is described in example C.1 and tests the inhibitory activity of the compounds of formula (I) on the metabolism of retinoic acid in human breast cancer cells. The compounds of the present invention were also effective in suppressing induced vaginal keratinization effects in ovariectomized rats as is described in example C.2.
In addition, the compounds of formula (I) show little or no endocrinological side-effects and they have good oral availability.
In view of the above described pharmacological properties, in particular their retinoic mimetic activity, the present compounds are useful in the treatment and/or the prevention of disorders characterized by abnormal proliferation and/or abnormal differentiation of cells, in particular of cells of which the growth and differentiation is sensitive to the actions of retinoids. Such disorders are situated in the field of oncology, for example, head- and neck cancer, lung cancer, breast cancer, uterine cervix cancer, gastrointestinal tract cancer, skin cancer, bladder cancer and prostate cancer and similar disorders; and in the field of dermatology, for example, keratinization disorders such as rosacea, acne, psoriasis, severe psoriasis, lamellar ichthyosis, plantar warts, callosities, acanthosis nigricans, lichen planus, molluscum, melasma, corneal epithelial abrasion, geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and keloids, epidermolytic hyperkeratosis, Darier's disease, pityriasis rubra pilaris, congenital ichthyosiform erythroderma, hyperkeratosis palmaris et plantaris, melasma, hyperpigmentation and similar disorders.
Further, the compounds of formula (I) are useful in suppressing the metabolism of exogenously administered and of endogenously formed 1α,25-dihydroxy-vitamin D3 (calcitriol). The inhibitory activity of the compounds of formula (I) on the metabolic degradation of calcitriol may be evidenced by measuring the impact of said compounds on the calcitriol degradation in human foreskin keratinocytes, pig kidney cells and human hepatoma cells. In view of their inhibitory effect on the calcitriol metabolism, the compounds of formula (I) can be used in the treatment of vitamin D deficiency states. The “classic” application of vitamin D compounds lies in the field of metabolic bone disorders. Calcitriol has also been described to influence the effects and/or production of interleukins. Further, calcitriol is of use in the treatment of diseases characterized by abnormal cell proliferation and/or differentiation, in particular, keratinization disorders such as those described hereinabove (Bouillon et al., Endocrine Reviews, 1995, 16, 200-257).
In view of the above described uses of the compounds of formula (I), it follows that the present invention provides a method of treating warm-blooded animals suffering from diseases which are characterized by an abnormal proliferation and/or abnormal differentiation of normal, preneoplastic or neoplastic cells, whether they are epithelial or mesenchymal; whether they are of ectodermal, endodermal or mesodermal origin. Said method comprises the systemic or topical administration of a retinoic mimetic amount of a compound of formula (I) effective in treating the above described disorders, in particular oncology disorders and keratinization disorders, optionally in the presence of an effective amount of a retinoic acid, a derivative or a stereochemically isomeric form thereof. The present invention further concerns a method of treating patients suffering from a pathological condition which may be beneficially influenced by the administration of calcitriol or a prodrug thereof, in particular oncology disorders and keratinization disorders, said method consisting of administering to a patient (a) an effective amount of calcitriol or a prodrug thereof and (b) an effective amount of a compound of formula (I).
The compounds of formula (I) may conveniently be used in combination with a chemotherapeutic agent, in particular an anti-neoplastic agent such as, e.g. daunorubicin, doxorubicin, vincristine, vinblastine, etoposide, taxol, taxotere, dactinomycin, mitoxantrone, mitomycin, trimetrexate and the like. The combination may be administered separately, simultaneously, concurrently or consecutively, or the combination may also be presented in the form of one pharmaceutical formulation. Thus, the present invention also involves a pharmaceutical product comprising (a) a compound of formula (I) and (b) a chemotherapeutic agent, as a combined preparation for simultaneous, separate or sequential use in the therapeutic or prophylactic treatment of warm-blooded animals suffering from disorders characterized by abnormal proliferation and/or abnormal differentiation of cells. Such a product may comprise a kit comprising a container containing a pharmaceutical composition of a compound of formula (I), and another container comprising a pharmaceutical composition of the chemotherapeutic agent. The product with separate compositions of the two active ingredients has the advantage that appropriate amounts of each component, and timing and sequence of administration can be selected in function of the patient. The present invention further concerns a method of treating patients suffering from disorders characterized by abnormal proliferation and/or abnormal differentiation of cells, said method consisting of administering to a patient (a) an effective amount of a compound of formula (I) and (b) an effective amount of a chemotherapeutic agent.
Thus, the present invention also relates to compounds of formula (I) as defined hereinabove for use as a medicine, in particular, for use in the manufacture of a medicament for the treatment of oncology disorders and keratinization disorders. The present invention further relates to compounds of formula (I) as defined hereinabove in combination with a retinoic acid, a derivative or a stereochemically isomeric form thereof, or in combination with calcitriol or a prodrug thereof, or in combination with a chemotherapeutic agent, in particular an anti-neoplastic agent, for use as a medicine.
For ease of administration, the subject compounds may be formulated into various pharmaceutical forms. As appropriate compositions there may be cited all compositions usually employed for systemically or topically administering drugs. To prepare the pharmaceutical compositions of this invention, a retinoic mimetic effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g. as a transdermal patch, as a spot-on or as an ointment. Addition salts of compounds of formula (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellent such as nitrogen, carbon dioxide, a freon, or without a propellent such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular compositions, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (included scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Other such compositions are preparations of the cosmetic type, such as toilet waters, packs, lotions, skin milks or milky lotions. Said preparations contain, besides the active ingredient, components usually employed in such preparations. Examples of such components are oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, and the like. If desired, further ingredients may be incorporated in the compositions, e.g. antiinflamatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, or other anti-acne agents.
The present invention also provides particular pharmaceutical or cosmetical compositions which comprise a pharmaceutically acceptable carrier, an effective amount of a compound of formula (I) and an effective amount of a retinoic acid, a derivative thereof or a stereochemically isomeric form thereof. Said retinoic acid containing compositions are particularly useful for treating acne or for retarding the effects of aging of the skin and generally improve the quality of the skin, particularly human facial skin.
Further, the invention also relates to particular pharmaceutical or cosmetical compositions which comprise a pharmaceutically acceptable carrier, an effective amount of a compound of formula (I) and an effective amount of calcitriol or a prodrug thereof. The latter compositions are particularly useful in treating keratinization disorders.
The invention also relates to a product containing retinoic acid or a derivative thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in dermatological or oncological disorders. The invention also relates to a product containing calcitriol or a prodrug thereof and a compound of formula (I) as a combined preparation for simultaneous, separate or sequential use in dermatological or oncological disorders. Such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing calcitriol or a retinoid Such a product may have the advantage that a physician can select on the basis of the diagnosis of the patient to be treated the appropriate amounts of each component and the sequence and timing of the administration thereof.
Those of skill in the treatment of the disorders described hereinabove could determine the effective therapeutic daily amount from the test results presented in the experimental part. An effective therapeutic daily amount would be from about 0.01 mg/kg to about 40 mg/kg body weight, more preferably from about 0.1 mg/kg to about 10 mg/kg body weight. It may be appropriate to administer the therapeutically effective dose once daily or as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.1 mg to 500 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient as well as other medication the patient may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines. The following examples are intended to illustrate the scope of the present invention.


EXPERIMENTAL PART
Of some compounds of formula (I) the absolute stereochemical configuration of the stereogenic carbon atom(s) therein was not experimentally determined. In those cases the stereochemically isomeric form which was first isolated is designated as “A” and the second as “B”, without further reference to the actual stereochemical configuration. Said “A” and “B” forms of those compounds of formula (I) wherein two asymmetric carbon atoms are present were separated in their pure stereochemically isomeric forms and designated as “A1” and “A2”, and “B1” and “B2”, without further reference to the actual stereochemical configuration.
As used hereinafter, “THF” is defined as tetrahydrofuran, “EtOAc” is defined as ethylacetate, “DIPE” is defined as diisopropyl ether and “RT” is defined as room temperature.
A) Preparation of the Intermediate Compounds
EXAMPLE A1
Methanesulfonyl chloride (0.308 mol) was added dropwise to a solution of N-[4-(1-hydroxy-2-methylpropyl)phenyl]acetamide (0.1514 mol) and triethylamine (0.308 mol) in CH2Cl2(600 ml) and the mixture was stirred at 0° C. for 1 hour. The solvent was evaporated, yielding 44 g (100%) of (±)-4-(acetylamino)-α-(1-methylethyl)benzenemethanol methanesulfonate(ester) (interm. 1).
EXAMPLE A2
A mixture of (±)—N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (0.095 mol) in HCl (3N) (250 ml) was stirred and heated at 60° C. for 5 hours. The mixture was cooled, poured into ice, basified with concentrated NH4OH and extracted with CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was crystallized from 2-propanone/(C2H5)2O and filtered off, yielding 15.5 g (75%) of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (interm. 2; mp. 117.8° C.).
In a similar manner were also prepared:

    (A)-4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]benzenamine (interm. 3);
    (B)-4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]benzenamine (interm. 4); and
    (±)-4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]benzenamine (interm. 5).


EXAMPLE A3
1,2-Dichloroethanone (0.027 mol) was added dropwise at RT to a solution of intermediate (5) (0.0246 mol) in sodium carbonate (10%) (450 ml) and CH2Cl2 (600 ml). The mixture was stirred for 3 hours and then extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 7 g (89%) of (±)-2-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide (interm. 6).
EXAMPLE A4
a) (±)-4-(2-methyl-3-phenylpropyl)pyridine (0.114 mol) was added portionwise at 0° C. to sulfonic acid (63 ml), the mixture was stirred at 0° C. for 1 hour and then at RT for 2 hours. The mixture was poured into ice, basified with NH4OH and the precipitate was filtered off, yielding 29.31 g (100%) of (±)-4-[2-methyl-1-(4-nitrophenyl)propyl]-pyridine (interm. 7).
b) Intermediate (7) (0.183 mol) in methanol (470 ml), NH4OH (47 ml) and a solution of thiophene in methanol (4%; 1 ml) was hydrogenated at RT with palladium on activated carbon (10%; 7.7 g) as a catalyst over a 2 hour period under a 3 bar pressure in a Parr apparatus. After uptake of hydrogen, the catalyst was filtered through celite and the filtrate was evaporated, yielding 42.79 g of product. A sample (3 g) was taken up in CH2Cl2 and purified on a glass filter over silica gel (eluent: CH2Cl2/CH3OH 99.5/0.5). The pure fractions were collected and evaporated. The residue was purified further by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fractions were collected and evaporated. The residue was recrystallized from (C2H5)2O and filtered off, yielding 0.86 g of (±)-4-[2-methyl-1-(3-pyridinyl)propyl]benzenamine (interm. 8; mp. 101.5° C.).
EXAMPLE A5
a) A mixture of N-[4-(2-chloro-1-oxopropyl)phenyl]acetamide (0.19 mol), N-methyl-methanamine hydrochloride (1:1)(0.38 mol) and K2CO3 (78.8 g) in CH3CN (1400 ml) was stirred and refluxed for 12 hours. The mixture was cooled, poured into water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent was evaporated, yielding 39.77 g (89%) of (±)—N-[4-[2-(dimethylamino)-1-oxopropyl]phenyl]-acetamide (interm. 9).
b) Sodium tetrahydroborate (2.6 mol) was added portionwise at 0° C. under N2 flow to a mixture of intermediate (9) (2.18 mol) in methanol (5000 ml). The mixture was stirred for 1 hour, poured out into ice water (5000 ml) and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 357 g (70%) of (±)—N-[4-[1-hydroxy-2-(dimethylamino)propyl]phenyl]acetamide (interm. 10).
EXAMPLE A6
Sodium tetrahydroborate (0.0502 mol) was added portionwise at 0° C. to a mixture of (±)—N-[4-(2-chloro-1-oxopropyl)phenyl]-3,4-dimethoxybenzeneacetamide (0.0502 mol) in methanol (280 ml). The mixture was stirred at 0° C. for 1 hour, then poured out into a mixture of NaOH (280 ml) and ice, stirred for 1 hour and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 15.48 g (94%) of (±)-3,4-dimethoxy-N-[4-(3-methyl-2-oxiranyl)phenyl]benzeneacetamide (interm. 11).
EXAMPLE A7
a) n-Buthyl-lithium in hexane (1.6M; 71.6 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methylimidazole (0.1146 mol) in THF (195 ml). The mixture was stirred at −70° C. for 30 minutes. Chlorotrietylsilane (0.1146 mol) was added. The mixture was brought slowly to 10° C. and cooled again to −70° C. n-Buthyl-lithium in hexane (1.6M; 71.6 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, brought to −15° C. and cooled again to −70° C. A mixture of 4-chlorophenyl-4-nitrophenyl-methanone (0.095 mol) in THF (150 ml) was added dropwise. The mixture was stirred at −70° C. for 30 minutes, hydrolyzed and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The desired fractions were collected and their solvents were evaporated, yielding 6.5 g (20%) of (±)-α-(4-chlorophenyl)-1-methyl-α-(4-nitrophenyl)-1H-imidazole-2-methanol (interm 12), 8.7 g (26.6%) of (±)-α-(4-chlorophenyl)-1-methyl-α-(4-nitrophenyl)-1H-imidazole-5-methanol (interm 13) and 18 g (53%) of the mixture of intermediate 12 and 13.
b) A mixture of intermediate 12 and 13 (0.09 mol) in THF (600 ml) was cooled on an ice bath. TiCl3 in H2O (15%; 400 ml) was added dropwise quickly. The mixture was stirred at RT for 90 minutes, poured out on ice, alkalized with NaOH 10N, then filtered over celite, pasted up and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 94/6). Two pure fractions were collected and their solvents were evaporated. Both residues were crystallized from CH3CN and DIPE. Each phe precipitate was filtered off and dried, yielding 2 g (7.1%) of (±)-α-(4-aminophenyl)-α-(4-chlorophenyl)-1-methyl-1H-imidazole-2-methanol (interm. 14) and 1.5 g (5.3%) of (±)-α-(4-aminophenyl)-α-(4-chlorophenyl)-1-methyl-1H-imidazole-5-methanol (interm. 15).
B) Preparation of the Compounds of Formula (I)
EXAMPLE B1
A mixture of (±)-4-(acetylamino)-α-(1-methylethyl)benzenemethanol methane sulfonate (ester) (0.1541 mol), 1H-1,2,4-triazole (0.308 mol) and K2CO3 (0.308 mol) in CH3CN (500 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated, yielding 10 g (25%) of (±)—N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (compound 153).
EXAMPLE B2
A solution of 2-methyl-3-phenyl-2-propenoyl chloride (0.0554 mol) in CH2Cl2 (50 ml) was added dropwise to a solution of (±)-4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-benzenamine (0.037 mol) in pyridine (8 ml) and CH2Cl2 (100 ml) and the mixture was stirred at RT for 4 hours. The solvent was evaporated and the residue was taken up in water/EtOAc. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O/methylethylketone, yielding 2.7 g (21%) of (±)-(E)-2-methyl-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]-3-phenyl-2-propenamide (compound 154).
EXAMPLE B3
A mixture of 1-hydroxy-1H-benzotriazole (0.0227 mol) in THF (90 ml) was added dropwise at 5° C. under N2 flow to a solution of (A)-4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]benzenamine (0.015 mol) and (±)-4-chloro-α-hydroxybenzeneacetic acid (0.0227 mol) in THF (95 ml). A mixture of N,N-methanetetraylbis[cyclohexanamine] (0.0227 mol) in CH2Cl2 (37 ml) was added dropwise at 5° C. under N2 flow. The mixture was stirred at RT for 15 hours. The precipitate was filtered off and washed with CH2Cl2. The filtrate was taken up in K2CO3 10% and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (9.25 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 4.8 g (78%) of (±)-(A)-4-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-α-hydroxybenzeneacetamide (compound 16).
EXAMPLE B4
(±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-methyl-3-phenyl-2-propenamide (0.0144 mol) in methanol (200 ml) was hydrogenated with palladium-on-charcoal 10% (0.52 g) as a catalyst at RT over a 5 hour period under a 1 bar pressure in a Parr apparatus. After uptake of hydrogen, the catalyst was filtered through celite and the solvent was evaporated. The residue was crystallized from 2-butanone/DIPE, yielding 4.9 g (94%) of (±)—N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-α-methyl-benzenepropanamide (compound 164).
EXAMPLE B5
A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0185 mol) in formic acid (20 ml) was stirred and heated at 120° C. for 15 minutes. The mixture was poured into water, basified with NaOH 3N and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated, yielding 3.9 g (86.6%) of (±)—N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]formamide (compound 177).
EXAMPLE B6
a) A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.023 mol) and dihydro-2H-pyran-2,6(3H)-dione (0.03 mol) in THF (200 ml) was stirred and refluxed for 12 hours. When the reaction was complete, the solvent was evaporated, yielding 7.5 g (±)-5-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-5-oxopentanoic acid (compound 218).
b) A mixture of (compound 218) (0.023 mol) in ethanol (200 ml) and H2SO4 (3 ml) was stirred and refluxed for 12 hours. When the reaction was complete, the solvent was evaporated, the residue was taken up in water and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated. The residue was crystallized from 2-butanone and DIPE, yielding 1.45 g (18%) of (±)-ethyl 5-[[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]amino]-5-oxopentanoate (compound 219).
EXAMPLE B7
A mixture of (A)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-4-nitrobenzene-acetamide (0.0005 mol) in methanol (50 ml) was hydrogenated at RT (p=2 bar) for 4 hours with Raney Nickel (0.2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off over celite, washed with CH3OH and the solvent was evaporated. The residue (0.12 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96.5/3.5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.035 g (19%) of (A)-4-amino-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]benzeneacetamide (compound 145).
EXAMPLE B8
A solution of NaNO2 (0.0023 mol) in water (6 ml) was added at 0° C./−5° C. to a solution of (B)-4-amino-N-[4-[1-[(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-iodobenzeneacetamide (0.0021 mol) in HCl 2N (17 ml). The mixture was stirred at 0° C. for 15 minutes. A solution of NaN3 (0.0023 mol) in water (6 ml) was added. The mixture was stirred at 0° C. for 2 hours, then neutralized with K2CO3 10% and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered off and dried, yielding 0.46 g (44%) (B)-4-azido-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-3-iodobenzenacetamide (compound 259).
EXAMPLE B9
A mixture of (±)-2-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]acetamide (0.0218 mol), 1-methylpiperazine (0.0436 mol) and K2CO3 (0.0436 mol) in CH3CN (150 ml) was stirred and refluxed for 4 hours. The mixture was cooled, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (8.13 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 3 g (35.8%) (±)—N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-4-methyl-1-piperazineacetamide (compound 15).
EXAMPLE B10
Compound (16) (0.0116 mol) was separated into its enantiomers by column chromatography (eluent: hexane/2-propanol 50/50; column: CHIRACEL OD 20 μm). Two pure fractions were collected and their solvents were evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 1.77 g (35%) (±)-A1-4-chloro-N-[4-[2-ethyl-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-α-hydroxybenzeneacetamide (compound 17) and 1.72 g (42%) (±)-(A2)-4-chloro-N-[4-[2-ethyl)-1-(1H-1,2,4-triazol-1-yl)butyl]phenyl]-α-hydroxybenzeneacetamide (compound 18).
EXAMPLE B11
HCl conc. (3.6 ml) was added at RT to a mixture of (±)-1,1-dimethylethyl4-[[[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]amino]carbonyl]-1-piperidinecarboxylate (0.0032 mol) in EtOAc (30 ml). The mixture was stirred at RT for 4 hours, then basified with a concentrated NaOH solution and extracted with EtOAc and then CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (1 g) was converted into the hydrochloric acid salt (1:1) in 2-propanol. The precipitate was filtered off and dried, yielding 0.85 g (68%) (±)—N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]-phenyl]-4-piperidinecarboxamide monohydrochloride (compound 57).
EXAMPLE B12
A mixture of α-(4-chlorophenyl)-3-pyridinemethanol (0.364 mol) and N-phenyl acetamide (0.364 mol) in HOAc (360 ml) and H2SO4 36N (38.6 ml) was stirred and refluxed for 6 days. The solvent was evaporated, yielding 122.6 g (±)—N-[4-[(4-chloro-phenyl)(3-pyridinyl)methyl]phenyl]acetamide (compound 673).
EXAMPLE B13
Butyllithium, 1.6M in hexane (146 ml) was added dropwise at −78° C. under N2 flow to a solution of 2-bromopyridine (0.1348 mol) in THF (300 ml). The mixture was stirred at −78° C. for 20 minutes. A solution of N-(4-formylphenyl)acetamide (0.1226 mol) in THF (300 ml) was added at −60° C./−70° C. The mixture was stirred at −60° C./−70° C. for 1 hour, then poured out into ice water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether and 2-propanone. The precipitate was filtered off and dried, yielding 5.09 g (17%) (±)—N-[4-[hydroxy(2-pyridinyl)methyl]phenyl]acetamide (compound 688).
EXAMPLE B14
To a solution of 4-[2-methyl-1-(3-pyridinyl)propyl]benzenamine (0.187 mol) into CH2Cl2 (400 ml) was added dropwise Al2O (100 ml). The mixture was stirred for 24 hours at RT. The mixture was hydrolyzed by H2O and neutralized by NH4OH. The organic layer was washed with water and dried. The filtrate was evaporated, yielding 50 g of N-[4-[2-methyl-1-(3-pyridinyl)propyl]phenyl]acetamide (compound 671).
EXAMPLE B15
1H-1,2,4-triazole (0.19 mol) and triphenylphosphine (0.19 mol) were added to a mixture of (±)—N-[4-[1-hydroxy-2-(dimethylamino)propyl]phenyl]acetamide (0.1269 mol) in THF (300 ml). The mixture was cooled to 0° C. Diethyl 1,2-hydrazinedicarboxylate (0.19 mol) was added dropwise. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was taken up in EtOAc and HCl 1N was added. The mixture was separated into its layers. The aqueous layer was washed with EtOAc, basified with a K2CO3 solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 93/7/0.1 and 80/20/0.1). Two pure fractions were collected and their solvents were evaporated. The desired fraction was recrystallized from 2-propanone/EtOAc. The precipitate was filtered off and dried, yielding 1.2 g of (±)-(B)—N-[4-[2-(dimethylamino)-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (compound 631).
EXAMPLE B16
A mixture of (±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-[(4-nitrophenyl)-methylene]propanamide (0.00742 mol) in THF (80 ml) and TiCl3 (30 ml) was stirred at 0° C. for 15 minutes. The mixture was poured into water, ice and NaOH 3N and extracted with CH2Cl2 (2×100 ml). The combined organic layers were dried, filtered and the solvent evaporated. The residue was taken up in CH2Cl2 and (C2H5)2O. The precipitate was filtered off and stirred K2CO3 10% and CH2Cl2, dried, filtered off and evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off, taken up in Na2CO3 10% and CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O, yielding 1.5 g (±)-(E)-2-[(4-aminophenyl)methylene]-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]propanamide (compound 611).
EXAMPLE B17
1,1′-Carbonyldiimidazole (0.236 mol) was added at 60° C. to a solution of (±)—N-[4-[1-hydroxy-2-methylpropyl]phenyl]acetamide (0.115 mol) in tetrahydrofuran (240 ml) and the mixture was stirred at 60° C. for 12 hours. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone, yielding 28.27 g (67%) (±)—N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]acetamide (compound 521).
EXAMPLE B18
LiAlH4 (0.0117 mol) was added portionwise at 0° C. to a solution of (±)-ethyl (A)-β-[4-[[(3,4-dimethoxyphenyl)acetyl]amino]phenyl]-α-methyl-1H-imidazol-1-propanoate (0.0117 mol) in THF (78 ml). The mixture was allowed to warm to RT overnight and then cooled to 0° C. LiAlH4 (0.0117 mol) was added portionwise at 0° C. The mixture was allowed to warm to RT, then stirred at RT for 2 hours, poured out on ice and filtered over celite. The filtrate was extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1 and 90/10/0.2). Two pure fractions (F1 and F2) were collected and their solvents were evaporated. F1 was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (±)-(A)-3,4-dimethoxy-N-[4-[1-(1H-imidazol-1-yl)-2-(hydroxymethyl)propyl]phenyl]benzeneacetamide (19%) (compound 386). F2 was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and the solvent was evaporated. The residue was purified by column chromatography over amino phase (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g (±)-(B)-3,4-dimethoxy-N-[4-[1-(1H-imidazol-1-yl)-2-(hydroxymethyl)propyl]phenyl]benzeneacetamide (10%) (compound 394).
EXAMPLE B19
A mixture of (±)-3,4-dimethoxy-N-[4-[1-(1H-imidazol-1-yl)-2-[methyl(phenylmethyl)-amino]propyl]phenyl]benzenacetamide (0.0066 mol) in ethanol (150 ml) was hydrogenated (p=3 bar) for 90 minutes with palladium-on-charcoal 10% (3.3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off over celite, washed with CH3OH and the solvent was evaporated. The residue (2.72 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/1). Two pure fractions were collected and their solvents were evaporated. Each residue was crystallized from 2-butanone and diethyl ether. The precipitate was filtered off and dried, yielding 0.39 g (14.5%) of (±)-(A)-3,4-dimethoxy-N-[4-[1-(1H-imidazol-1-yl)-2-(methylamino)propyl]phenyl]benzeneacetamide (compound 400).
EXAMPLE B20
A mixture of (±)-3,4-dimethoxy-N-[4-(3-methyl-2-oxiranyl)phenyl]benzeneacetamide (0.0442 mol) and 1H-imidazole (0.221 mol) in DMF (116 ml) was stirred and refluxed for 6 hours. The mixture was poured out into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.3). The desired fraction was taken up in CH2Cl2, washed with a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 93/7/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 1.53 g (9%) of (±)-(B)-3,4-dimethoxy-N-[4-[2-hydroxy-1-(1H-imidazol-1-yl)propyl]phenyl]benzeneacetamide monohydrate (compound 402).
EXAMPLE B21
A mixture of (±)-(A)-3-[4-[[(3,4-dimethoxyphenyl)acetyl]amino]phenyl]-3-(1H-imidazol-1-yl)-2-methylpropyl methanesulfonate (0.0011 mol) in NaOCH3 (1 ml) and methanol (5 ml) was stirred at 80° C. for 3 hours. The mixture was poured out on ice and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (0.56 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.2 g (43%) of (±)-(A)-3,4-dimethoxy-N-[4-[1-(1H-imidazol-1-yl)-3-methoxy-2-methylpropyl]phenyl]benzene-acetamide (compound 404).
EXAMPLE B22
a) A mixture of compound (698) (0.0329 mol) in NaOH 3N (300 ml) was stirred and refluxed for 2 hours. The mixture was cooled, poured into ice, neutralized with concentrated HCl and extracted with CH2Cl2. The organic layer was dried, filtered and the solvent evaporated, yielding 7.91 g (88%) of (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenylthiourea (compound 699).
b) An alternative reaction procedure is the following: A solution of trifluoroacetic acid (0.0715 mol) in benzene (5 ml) was added dropwise to a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0511 mol) and NaSCN (0.102 mol) in benzene (70 ml), the mixture was stirred at RT for 1 hour and stirred further at 60° C. for 24 hours. The mixture was cooled to 30° C., and extracted with CH2Cl2 and K2CO3 10%. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.5 to 90/10/0.5) (35-70 μm) and purified further by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0.5) (15-40 μm). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone and (C2H5)2O and filtered off. The product was taken up in CH2Cl2, CH3OH and norit. The product was recrystallized from 2-propanone and (C2H5)2O and filtered off, yielding 1.42 g (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-phenylthiourea (10%) (compound 699).
EXAMPLE B23
A mixture of compound (206) (0.0104 mol), 2-pyridinamine (0.0104 mol) and N,N-dimethyl-4-pyridinamine (0.0052 mol) in 1,4-dioxane (100 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed with a 10% aqueous K2CO3 solution, with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE. The precipitate was filtered off and dried, yielding 1.10 g (34.3%) (±)—N-(2-pyridinyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]urea (compound 274).
EXAMPLE B24
n-Butyllithium 1.6M in hexane (101.5 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methyl-1H-imidazole (0.162 mol) in THF (244 ml). The mixture was stirred at −70° C. for 30 minutes. Chlorotriethylsilane (0.162 mol) was added. The mixture was allowed to warm to RT. n-Butyllithium 1.6M in hexane (101.5 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and brought to −15° C. A mixture of intermediate (9) (0.065 mol) in THF (152 ml) was added dropwise at −70° C. The mixture was allowed to warm to RT, stirred overnight, then poured out into a saturated NH4Cl solution and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.5 and 80/20/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 1.5 g (±)—N-[4-[2-(dimethylamino)-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-propyl]phenyl]acetamide (compound 771).
EXAMPLE B25
Benzoylchloride (0.067 mol) was added to a solution of NH4SCN (5.09 g) in 2-propanone (150 ml) and the mixture was stirred and refluxed for 20 minutes. A solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0557 mol) in 2-propanone (150 ml) was added and the mixture was stirred and refluxed at 80° C. overnight. The mixture was cooled, filtered through celite and the filtrate was evaporated. The residue was taken up in CH2Cl2. The organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone and DIPE, yielding (±)—N-benzoyl-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]thiourea (compound 698).
EXAMPLE B26
A mixture of compound (689) (0.0309 mol) and iodomethane (0.062 mol) in acetonitrile (100 ml) was stirred at 50° C. for 2 hours. The solvent was evaporated, yielding 10.9 g (91%) (±)—N-[4-[1-hydroxy-1-(3-pyridinium)methyl]phenyl]acetamide iodide (compound 770)
EXAMPLE B27
A mixture of 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-imidazole (0.0123 mol) and 2-benzothiazolamine (0.0148 mol) in acetonitrile (80 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97.5/2.5/0.1). The desired fractions were collected and the solvent was evaporated. The residue was purified again by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered off and dried, yielding 0.44 g (9%) (±)—N-(2-benzothiazolyl)-N-[4-[1-(1H-imidazol-1-yl)-2-ethylbutyl]phenyl]-thiourea (compound 705).
EXAMPLE B28
A mixture of compound (651) (0.0136 mol) and phosphorous pentasulfide (0.0136 mol) in pyridine (200 ml) was stirred and heated at 120° C. for 12 hours. The solvent was evaporated, the residue was taken up in water, NH4OH, CH2Cl2 and CH3OH (10%), and the mixture was stirred at RT for 15 minutes. The organic layer was decanted off, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1). The desired fractions were collected and evaporated. The residue was recrystallized from 2-propanone and DIPE, filtered off and dried, yielding (22%) 1.15 g 4-chloro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]benzenethane-thioamide (compound 764).
EXAMPLE B29
A solution of methyl N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]carbamimidothioate (0.0094 mol) in NH3/CH3OH (60 ml) was stirred and heated in autoclave at 40° C. for 3 days. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.2 to 90.10/0.5). The pure fractions were collected and evaporated. The residue was crystallized from 2-propanone and (C2H5)2O and filtered off, yielding 0.89 g (46%) N′-(3-fluorophenyl)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]guanidine (compound 744).
EXAMPLE B30
A solution of KOCN (2.25 g) in water was added dropwise at RT to a mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0278 mol) in acetic acid (4 ml) and water (50 ml) and the mixture was stirred at RT for 1 hour. The mixture was neutralized with NaOH 3N and extracted with CH2Cl2 and CH3OH. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.3). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone, yielding 2.7 g (51.4%) (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenylurea (compound 266).
EXAMPLE B31
4-Fluorophenylisocyanate (0.017 mol) was added to a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.014 mol) in dry THF (100 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was cooled, the precipitate was filtered off and recrystallized from 2-propanone and CH3OH, yielding 1.6 g (32%) (±)—N-(4-fluorophenyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]urea (compound 740).
EXAMPLE B32
CH3I (0.00814 mol) was added at RT to a mixture of compound 792 (0.00814 mol) in 2-propanone (30 ml). The mixture was stirred at RT for 6 hours, poured out into H2O and a concentrated NH4OH solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.18 g of methyl[4-[(2,5-dichlorophenyl)(1H-imidazol-1-yl)methyl]phenyl]carbamimidothioate (comp. 796).
EXAMPLE B33
Formamide (130 ml) was added to a mixture of intermediate 15 (0.043 mol) in acetic acid (130 ml). The mixture was stirred at 150° C. for 2 hours, cooled, poured out into ice water and basified with a concentrated NH4OH solution. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2 and a small amount of CH3OH. The organic solution was dried, filtered and the solvent was evaporated. This fraction was crystallized from CH2Cl2, CH3OH and DIPE. The precipitate was filtered off and dried, yielding 2.2 g (15.1%) of (±)—N-[4-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-phenyl]formamide (comp. 793).
EXAMPLE B34
Compound (779) (0.0132 mol) was separated into its enantiomers by column chromatography over silica gel (eluent: hexane/C2H5OH 80/20; column: CHIRACEL OD 20 μm). Two pure fractions were collected and their solvents were evaporated. The residue was dissolved in 2-propanone and 2-propanol and converted into the oxalic acid salt (1:1). The precipitate was filtered off and dried, yielding 2.55 g of (A)-N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-3-hydroxybenzeneacetamide ethanedioate (1:1) (comp. 780) and 2.95 g of (B)—N-[4-[2-ethyl-1-(1H-imidazol-1-yl)butyl]phenyl]-3-hydroxy-benzeneacetamide ethanedioate (1:1) (comp. 781).
Tables 1 to 20 list the compounds of formula (I) which were prepared analogous to one of the above examples.







TABLE 1













 










Co. No
X; R4; stereochemical descriptor if



(Ex No)
not racemic and/or addition salt







 1 (B1)
N; CH3



 2 (B2)
N; C(CH3)═CHC6H5; (E)



 3 (B2)
N; C6H5



 4 (B3)
N; CH(OH)(4-Cl—C6H4)



 5 (B2)
N; (1,3-benzodioxolan-5-yl)methyl



 6 (B2)
N; (3,4-diOCH3)C6H3



 7 (B2)
N; (2,3-dihydro-1,4-benzodioxin-6-




yl)methyl



 8 (B3)
N; (CH2)3(3,4-diOCH3—C6H3)



 9 (B2)
N; OC6H5



10 (B3)
N; (CH2)2(3,4-diOCH3—C6H3)



11 (B3)
N; CH(OH)(3,4-diCH3—C6H3)



12 (B2)
N; CH2O(2-OCH3—C6H4)



13 (B3)
N; (2-NH2-benzothiazol-6-yl)-CH2



14 (B2)
N; CH2Cl



15 (B9)
N; (4-CH3-1-piperazinyl)-CH2



16 (B3)
N; CH(OH)(4-Cl—C6H4); (A)



17 (B10)
N; CH(OH)(4-Cl—C6H4); (A, A)



18 (B10)
N; CH(OH)(4-Cl—C6H4); (A, B)



19 (B3)
N; CH(OH)(4-Cl—C6H4); (B)



20 (B10)
N; CH(OH)(4-Cl—C6H4); (B, A)



21 (B10)
N; CH(OH)(4-Cl—C6H4); (B, B)



22 (B2)
CH; phenyl



23 (B2)
CH; 2,3-dihydro-1,4-benzodioxin-




2-yl



24 (B3)
CH; C(OH)(CH3)2



25 (B2)
CH; 1,4-benzodioxin-2-yl



26 (B2)
CH; (2,3-dihydro-1,4-benzodioxin-




2-yl)-CH2



27 (B2)
CH; 2-pyrazinyl



28 (B2)
CH; (1,3-benzodioxolan-5-yl)-CH2



29 (B2)
CH; 3,4-dihydro-2H-1-benzopyran-




2-yl



30 (B2)
CH; 5,5,8,8-tetramethyl-5,6,7,8-




tetrahydro-2-naphtalenyl



31 (B2)
CH; 2H-1-benzopyran-3-yl



32 (B2)
CH; (CH2)2(3,4-diOCH3—C6H3)



37 (B2)
CH; CH2O(2-OCH3—C6H4)



33 (B2)
CH; 3,4-dihydro-2H-1-




benzopyran-3-yl



34 (B2)
CH; 1,3-benzodioxolan-2-yl



35 (B2)
CH; 4-OC2H5—C6H4



36 (B2)
CH; (2,3-dihydro-1,4-




benzodioxin-6-yl)-CH2



38 (B2)
CH; (5,5,8,8-tetramethyl-5,6,7,8-




tetrahydro-2-naphtalenyl)-CH2



39 (B2)
CH; (CH2)2(4-OC2H5—C6H4)



40 (B5)
CH; H



41 (B2)
CH; CH2-(4-C6H5—C6H4)



42 (B2)
CH; CH2Cl



43 (B9)
CH; (1-piperidinyl)methyl



44 (B9)
CH; (4-CH3-1-piperazinyl)-CH2



45 (B3)
CH; 2-methoxy-5-pyridinyl



46 (B3)
CH; 1-(C6H5—CO)-4-piperidinyl



47 (B9)
CH; (4-morpholinyl)-CH2



48 (B3)
CH; (CH2)3(4-OC2H5—C6H4)



49 (B3)
CH; CH2O(2-OH—C6H4)



50 (B2)
CH; CH(SCH3)(C6H5)



51 (B3)
CH; (2-OCH3-5-pyridinyl)-CH2



52 (B3)
CH; (CH2)3(3,4-diOCH3—C6H3)



53 (B3)
CH; 1-(tert-butoxy-carbonyl)-4-




piperdinyl



54 (B3)
CH; CH(OH)(4-Cl—C6H4)



55 (B3)
CH; CH2N(CH3)2



56 (B3)
CH; CH(OH)(3,4-diOCH3—C6H3)



57 (B11)
CH; 4-piperidinyl



58 (B3)
H; (2-NH2-6-benzothiazolyl)-CH2



59 (B3)
CH; 1-methyl-4-piperidinyl



60 (B2)
CH; OC6H5



61 (B10)
CH; (CH2)2(4-OC2H5—C6H4); (A)



62 (B10)
CH; (CH2)2(4-OC2H5—C6H4); (B)



63 (B23)
N; 2-benzothiazolyl-NH—



64 (B23)
CH; 2-benzothiazolyl-NH—



777 (B3)
N; 2-benzothiazolyl



778 (B3)
CH; 2-benzothiazolyl; oxalic acid




(1:1)

















TABLE 2













 















(Rb)n; stereochemical



Co.
Ex.

descriptor if not racemic



No.
No.
X
and/or addition salt
















65
B2
N
4-CH3



66
B2
N
4-Cl



67
B3
N
3-OH



68
B2
N
4-F



69
B3
N
4-OH



70
B2
N
3-OCH3



71
B2
N
4-OC2H5



72
B3
N
3-OCH3; 4-OH



73
B2
N
3-OCH3; 4-OCH3



74
B2
N
3-Cl; 4-OCH3



75
B2
N
3-Cl; 4-OC2H5



76
B2
N
3-CH3; 4-OC2H5



77
B2
N
3-CH3; 4-CH3



78
B3
N
3-CH3; 4-OCH3



79
B3
N
3-Cl; 4-OH



80
B2
N
3-OCH3; 4-OCH3; 5-OCH3



81
B2
N
3-CH3; 4-CH3; 5-CH3



82
B3
N
3-OC2H5; 4-OC2H5



83
B3
N
3-OCH3; 4-Cl



84
B3
N
3-OCH3; 4-CH3



85
B10
N
3-CH3; 4-OCH3; (A)



86
B10
N
3-CH3; 4-OCH3; (B)



87
B2
CH
4-Cl



88
B2
CH
4-F



89
B2
CH
2-OCH3



90
B2
CH
3-OCH3



91
B2
CH
3-OCH3; 4-OCH3



92
B2
CH
4-OCH(CH3)2



93
B2
CH
4-O(CH2)2CH3



94
B2
CH
4-CH3



95
B2
CH
4-OC2H5



96
B2
CH
4-O(CH2)3CH3



97
B3
CH
3-OCH3; 4-OH;






oxalic acid (1:1)



98
B2
CH
2-OCH3; 5-OCH3



99
B3
CH
4-N(CH3)2



100
B2
CH
3-CH3



101
B2
CH
3-OC2H5; 4-OC2H5



102
B2
CH
2-OCH3; 3-OCH3



103
B2
CH
4-OC6H5



104
B2
CH
2-CH3



105
B2
CH
4-OCH3



106
B2
CH
2-CH3; 5-CH3



107
B3
CH
2-OH



108
B3
CH
3-OH; 4-OCH3



109
B3
CH
3-OH; oxalic acid (1:1)



110
B2
CH
3-OCH3; 4-CH3



111
B3
CH
4-OH



112
B2
CH
3-CH3; 4-CH3



113
B2
CH
2-OCH3; 4-Cl



114
B2
CH
2-OCH3; 6-OCH3



115
B2
CH
2-OCH2C6H5; 3-OCH3



116
B2
CH
3-Cl; 4-OCH3



117
B3
CH
3-Cl; 4-OH



118
B2
CH
3-Cl; 4-OC2H5



119
B2
CH
3-OCH3; 5-OCH3



120
B2
CH
2-OCH2C6H5; 5-OCH3



121
B3
CH
4-(2-pyridinylmethoxy)



122
B2
CH
2-OCH3; 5-CH3



123
B2
CH
3-CH3; 4-OCH3



124
B3
CH
2-OH; 5-CH3



125
B2
CH
3-CH3; 4-OC2H5



126
B3
CH
2-OCH3; 4-OCH3



127
B3
CH
4-(4-pyridinylmethoxy)



128
B3
CH
3-OC2H5; 4-OCH2C6H5



129
B3
CH
2-CH3; 4-OH



130
B3
CH
4-(3-pyridinylmethoxy)



779
B3
CH
3-OH



780
B34
CH
3-OH; (A); oxalic acid (1:1)



781
B34
CH
3-OH; (B); oxalic acid (1:1)



782
B34
N
3-OCH3; 4-CH3; (A)



783
B34
N
3-OCH3; 4-CH3; (B)

















TABLE 3













 















(Rb)n; stereochemical



Co.
Ex.

descriptor if not racemic



No.
No.
X
and/or addition salt







131
B2
N
4-Cl



132
B2
N
4-F



133
B2
N
4-CH3



134
B3
N
4-OH



135
B2
N
4-OC2H5



136
B2
N
3-OCH3; 4-OCH3;






hydrate (1:1)



137
B3
N
3-OH



138
B3
N
3-OCH3; 4-OH



139
B2
CH
3-OCH3; 4-OCH3; 5-OCH3



140
B2
CH
3-OCH3; 4-OCH3



141
B3
CH
2-Cl; 4-Cl



142
B3
CH
3-OCH3; 4-OH



143
B3
CH
3-Cl; 4-Cl



144
B2
CH
4-NO2; (A)



145
B7
CH
4-NH2; (A)



146
B2
CH
4-NO2; (B)



147
B7
CH
4-NH2; (B)



148
B3
CH
3-I; 4-NH2



149
B3
CH
3-I; 4-NH2; (B)



150
B3
CH
3-I; 4-NH2; (A)



151
B2
CH
4-NO2



152
B7
CH
4-NH2

















TABLE 4













 










Co No
X; R4; stereochemical descriptor



(Ex No)
if not racemic and/or addition salt







153 (B1)
N; CH3



154 (B2)
N; C(CH3)═CHC6H5; (E)



155 (B2)
N; CH═CHC6H5; (E)



156 (B2)
N; C(CH3)═CH(3-Cl—C6H4); (E)



157 (B2)
N; C(CH3)═CH(4-F—C6H4); (E)



158 (B2)
N; C(CH3)═CH(4-pyridinyl); (E)



159 (B2)
N; C(CH3)═CH(4-CF3—C6H4); (E)



160 (B2)
N; CF═CHC6H5; (Z)



161 (B2)
N; 1,3-benzodioxolan-2-yl



162 (B2)
N; (2,3-dihydro-1,4-benzodioxin-




2-yl)methyl



163 (B2)
CH; C2H5



164 (B4)
CH; CH(CH3)—CH2(C6H5)



165 (B2)
CH; CH(CH3)—CH═CHC6H5; (E)



166 (B2)
CH; C6H5



167 (B2)
CH; 2-benzofuranyl



168 (B2)
CH; 2-benzothienyl



169 (B2)
CH; 2-furanyl



170 (B2)
CH; 2-pyrazinyl



171 (B2)
CH; C(CH3)═C(C6H5)




(3 -pyridinyl); (E + Z)



172 (B2)
CH; 3-furanyl



173 (B2)
CH; 3-thienyl



174 (B2)
CH; 1-cyclohexenyl



175 (B2)
CH; 2,3-dihydro-1,4-benzodioxin-




2-yl



176 (B2)
CH; C(CH3)═C(C6H5)(CH3); (E)



177 (B5)
CH; H



178 (B2)
CH; 2-indolyl



179 (B2)
CH; 2-naphtalenyl



180 (B2)
CH; 1-methyl-2-indenyl



181 (B2)
CH; 2-oxolanyl



182 (B2)
CH; 1-naphtalenyl



183 (B2)
CH; OC2H5



184 (B2)
CH; 1-methylbenzotriazol-6-yl



185 (B2)
CH; 3-oxolanyl



186 (B2)
CH; 2-phenyl-4-thiazolyl



187 (B2)
CH; 2-thienyl



188 (B2)
CH; (CH2)2CH2Cl



189 (B2)
CH; C(CH3)(C6H5)2



190 (B2)
CH; 1-C6H5-cyclopropyl



191 (B2)
CH; 1-C6H5-cyclopentyl



192 (B2)
CH; cyclopentyl



193 (B2)
CH; cyclohexyl



194 (B3)
CH; 4-pyridinyl



195 (B3)
CH; 1-methyl-2-pyrrolyl



196 (B3)
CH; 3-pyridinyl



197 (B2)
CH; 2-methylcyclopropyl



198 (B3)
CH; C═C(C6H5)



199 (B3)
CH; cyclopropyl



200 (B2)
CH; 1-C6H5-cyclohexyl



201 (B2)
CH; 1-methylcyclohexyl



202 (B2)
CH; 2-methylcyclohexyl



203 (B3)
CH; C(CH3)═C(C6H5)—C2H5; (Z)



204 (B2)
CH; 2-phenylcyclopropyl;




oxalic acid (1:1)



205 (B2)
CH; 3,4-dihydro-2(1H)-




quinolinone-6-yl



206 (B2)
CH; OC6H5



207 (B3)
CH; C(CH3)═C(C6H5)(2-




furanyl); (E)



208 (B3)
CH; 2-pyridinyl



209 (B2)
CH; CH(CH3)CH3



210 (B3)
CH; CH2—S—CH2C6H5



211 (B3)
CH; CH2—OC6H5



212 (B3)
CH; CH2—OCH3



213 (B3)
CH; CH2—NH—C6H5



214 (B3)
CH; 6-quinoxalinyl



215 (B3)
CH; 2-quinolinyl



216 (B3)
CH; 2-quinoxalinyl



217 (B2)
CH; 3,4-dihydro-2H-1-benzopyran-




2-yl



218 (B6a)
CH; (CH2)3C(═O)OH



219 (B6b)
CH; (CH2)3C(═O)OC2H5



220 (B2)
CH; 5-bromo-2-furanyl



221 (B2)
CH; 3-F—C6H4



222 (B3)
CH; C(CH3)2[O(4-Cl—C6H4)]



223 (B3)
CH; CH2—S—C6H5



224 (B3)
CH; (2-pyrimidinylthio)methyl



225 (B3)
CH; 5-methyl-2-pyrazinyl



226 (B2)
CH; 3-methyl-2-furanyl



227 (B3)
CH; 4-quinolinyl



228 (B3)
CH; 1,2-dihydro-2(1H)-pyridinone-




3-yl



229 (B3)
CH; 1-isoquinolinyl



230 (B2)
CH; 2,3-dihydro-1,4-benzodioxin-




5-yl



231 (B2)
CH; 3,4-(OCH3)2—C6H3



232 (B2)
CH; 1,3-benzodioxolan-5-yl



233 (B3)
CH; 5-quinoxalinyl



234 (B2)
CH; 1,4-benzodioxin-2-yl



235 (B2)
CH; 2-furanylmethyl



236 (B3)
CH; C(OH)(CH3)2



237 (B2)
CH; (2,3-dihydro-1,4-benzodioxin-




2-yl)methyl



238 (B2)
CH; 4-(C6H5)—C6H4



239 (B3)
CH; (4-pyridinylthio)methyl



240 (B3)
CH; (2-naphtalenyl)methyl



241 (B3)
CH; 3-quinolinyl



242 (B3)
CH; 3,5-dimethyl-4-isoxazolyl



243 (B2)
CH; 2,3-dihydro-1,4-benzoxathiin-




2-yl



244 (B3)
CH; 2-thienylmethyl



245 (B3)
CH; 3-thienylmethyl



246 (B3)
CH; 1-naphtalenylmethyl



247 (B3)
CH; 2-pyridinylmethyl



248 (B2)
CH; 1,3-benzodioxolan-2-yl



249 (B3)
CH; CH(OH)—CH3



250 (B3)
CH; 5-methyl-3-phenyl-4-isoxazolyl



251 (B3)
CH; 3-pyridinylmethyl



252 (B2)
CH; 5,6,7,8-tetrahydro-5,5,8,8-




tetramethyl-2-naphtalenyl



253 (B2)
CH; 3,4-dihydro-2H-1-benzopyran-




3-yl



254 (B2)
CH; 2H-1-benzopyran-3-yl



255 (B2)
CH; (2,3-dihydro-1,4-benzodioxin-




6-yl)methyl



256 (B2)
CH; (5,6,7,8-tetrahydro-5,5,8,8-




tetramethyl-2-naphtalenyl)methyl



257 (B1)
CH; CH3; (A)



258 (B1)
CH; CH3; (B)



259 (B8)
CH; CH2(3-iodo-4-azido-C6H3); (B)



260 (B8)
CH; CH2(3-iodo-4-azido-C6H3); (A)



261 (B3)
CH; CH2—NH—C(═O)—C6H5



262 (B3)
CH; CH2—NH—C(═O)—O—CH2—C6H5



263 (B23)
CH; N(CH3)—CH2—C6H5



264 (B6a)
CH; CH2-[1-(CH2COOH)cyclopentyl]



265 (B6a)
CH; (CH2)2—C(═O)—OH



266 (B30)
CH; NH2



267 (B23)
CH; NH—CH3



268 (B23)
CH; NH—C(CH3)2



269 (B23)
CH; NH—CH2—C6H5



270 (B23)
CH; NH-(3-pyridinyl)



271 (B23)
CH; NH-(2-pyrazinyl)



272 (B31)
CH; NH-(1-naphtalenyl)



273 (B23)
CH; NH—CH2-(4-Cl—C6H4)



274 (B23)
CH; NH-(2-pyridinyl)



275 (B23)
CH; NH-(4-pyridinyl)



276 (B23)
CH; NH-(6-benzodioxanyl)



277 (B23)
CH; NH-(1-CH3-2-benzimidazolyl)

















TABLE 5













 













(Rb)n; stereochemical


Co.
Ex.

descriptor if not racemic


No.
No.
X
and/or addition salt





278
B2
N
3-OCH3; 4-OCH3; (A)


279
B3
N
3-Cl; 4-OCH3; (A)


280
B3
N
3-CH3; 4-CH3; (B)


281
B3
N
4-OCH3; 3-CH3; (B)


282
B3
N
3-CH3; 4-CH3; (A)


283
B3
N
4-Cl; (B)


284
B3
N
3-Cl; 4-OH; (A)


285
B3
N
3-OC2H5; 4-OC2H5; (A)


286
B3
N
3-CH3; 4-OCH3; (A)


287
B3
N
3-OCH3; 4-OCH3; (B)


288
B3
N
3-Cl; 4-OCH3; (B)


289
B3
N
3-Cl; 4-OH; (B)


290
B3
N
3-CH3; 4-CH3; 5-CH3; (A)


291
B3
N
3-CH3; 4-CH3; 5-CH3; (B)


292
B3
N
3,4,5-(OCH3)3; (B)


293
B3
N
3-OC2H5; 4-OC2H5; (B)


294
B3
N
3-OCH3; 4-CH3; (A)


295
B3
N
3-OCH3; 4-CH3; (B)


296
B3
N
3-OCH3; 4-Cl; (A)


297
B3
N
3-OCH3; 4-Cl; (B)


298
B10
N
3-Cl; 4-OH; (A, A)


299
B10
N
3-Cl; 4-OH; (A, B)


300
B3
CH
3-OC2H5; 4-OC2H5; (A)


301
B3
CH
3-OC2H5; 4-OC2H5; (B)


302
B3
CH
3,4,5-(OCH3)3; (A)


303
B3
CH
3-Cl; 4-OH; (A)


304
B2
CH
3-Cl; 4-OCH3; (A)


305
B3
CH
3-Cl; 4-OCH3; (B)


306
B3
CH
3-CH3; 4-CH3; (B)


307
B3
CH
3-Cl; 4-OH; (B)


308
B3
CH
3-CH3; 4-CH3; 5-CH3; (A)


309
B3
CH
3-CH3; 4-CH3; 5-CH3; (B)


310
B3
CH
3-OCH3; 4-Cl; (A)


311
B3
CH
3-OCH3; 4-Cl; (B)


312
B3
CH
3-CH3; 4-OCH3; (A)


313
B3
CH
3-CH3; 4-OCH3; (B)


314
B3
CH
3-OCH3; 4-CH3; (A)


315
B3
CH
3-OCH3; 4-CH3; (B)


316
B3
CH
4-OCH(CH3)2; (B)


317
B3
CH
4-N(CH3)2; (A)


318
B3
CH
3-OCH3; 4-OCH3; (A)


319
B3
CH
4-O(CH2)3CH3; (A)


320
B3
CH
4-O(CH2)3CH3; (B)


321
B3
CH
4-OCH(CH3)2; (A)


784
B34
N
4-Cl; (B, A)


785
B34
N
4-Cl; (B, B)
















TABLE 6













 








Co No
X; R4; stereochemical descriptor


(Ex No)
if not racemic and/or addition salt





322 (B3)
N; (2,3-dihydro-1,4-benzodioxin-



6-yl)methyl; (A)


323 (B2)
N; OC6H5; (A)


324 (B2)
N; 3,4-diOCH3—C6H3 (A)


325 (B2)
N; (1,3-benzodioxolan-5-yl)-



methyl; (A)


326 (B3)
N; (CH2)3(3,4-diOCH3—C6H3); (A)


327 (B3)
N; 3,4-diOCH3—C6H3; (B)


328 (B3)
N; (CH2)2(3,4-diOCH3—C6H3); (B)


329 (B3)
N; (CH2)3(3,4-diOCH3—C6H3); (B)


330 (B3)
N; (1,3-benzodioxolan-5-



yl)methyl; (B)


331 (B5)
N; H; (B)


332 (B3)
N; C(CH3)═CH(C6H5); [B-(E)]


333 (B3)
N; (2,3-dihydro-1,4-benzodioxin-



6-yl)methyl; (B)


334 (B2)
N; OC6H5; (B)


335 (B5)
N, H; (A)


336 (B3)
CH; (CH2)3(3,4-diOCH3—C6H3); (B)


337 (B3)
CH; (1,3-benzodioxolan-5-yl)-



methyl; (B)


338 (B3)
CH; (2,3-dihydro-1,4-benzodioxin-



6-yl)methyl; (A)


339 (B3)
CH; (2,3-dihydro-1,4-benzodioxin-



6-yl)methyl; (B)


340 (B2)
CH; (1,3-benzodioxolan-5-yl)



methyl; (A)


341 (B3)
CH; 3,4-diOCH3—C6H3; (A)


342 (B3)
CH; 3,4-diOCH3—C6H3; (B)


343 (B2)
CH; OC6H5; (A)


344 (B2)
CH; OC6H5


345 (B5)
CH; H; (A)


346 (B3)
CH; (CH2)2(4-OC2H5—C6H4); (A)


347 (B9)
CH; 4-methylpiperazinyl; (A)


348 (B3)
CH; (CH2)2(4-OC2H5—C6H4)


349 (B9)
CH; 4-methylpiperazinyl; (B)


350 (B3)
CH; CH[O(2-OCH3—C6H4)]; (A)


351 (B3)
CH; CH[O(2-OCH3—C6H4)]; (B)


352 (B3)
CH; (4-CH3-piperazinyl)methyl; (A)


353 (B3)
CH; (4-CH3-piperazinyl)methyl; (B)


354 (B3)
CH; (4-CH3-piperazinyl)ethyl
















TABLE 7













 








Co No
R1; stereochemical descriptor if


(Ex No)
not racemic and/or addition salt





355 (B2)
(CH2)2CH(CH3)2


356 (B3)
4-Cl—C6H4


357 (B2)
C6H5


358 (B2)
CH3


359 (B2)
CH2CH(CH3)2


360 (B2)
CH2—C(CH3)3


361 (B2)
3-CF3—C6H4


362 (B2)
cyclohexyl


363 (B2)
(CH2)2CH3


364 (B2)
CH(CH3)CH2CH3


365 (B2)
C(CH3)3


366 (B3)
1-(1-piperidinyl)ethyl; (A)


367 (B2)
CH[N(CH3)2]CH3; (A)


368 (B2)
CH[N(CH3)2]CH3; (B)


369 (B2)
CH(S—C6H5)CH3; (B)


370 (B2)
CH(O—C6H5)CH3; (A)


371 (B2)
CH(CH3)CH2CN; (A + B)


372 (B2)
C2H5


373 (B2)
5,6,7,8-tetrahydro-5,5,8,8-



tetramethyl-2-naphtalenyl


374 (B2)
CH(CH3)C3H7; (B)


375 (B2)
CH2[N(CH3)2]


376 (B2)
CH(S—C6H5)CH3; (A)


377 (B2)
CH(CH3)CH2C6H5
















TABLE 8













 










Co No
R1; stereochemical descriptor if



(Ex No)
not racemic and/or addition salt







378 (B2)
CH(C3H7)2



379 (B3)
CH(CH3)[N(CH3)2]; (B)



380 (B3)
CH2[N(CH3)2]



381 (B3)
CH[C(═O)OC2H5]CH3; (A)



382 (B3)
CH[C(═O)OC2H5]CH3; (B)



383 (B3)
CH[N(C2H5)2CH3; (B)



384 (B3)
CH(CH3)C5H11; (A)



385 (B3)
CH(CH3)C5H11; (B)



386 (B18)
CH(CH3)CH2OH; (A)



387 (B3)
CH[N(C2H5)2]CH3; (A)



388 (B3)
CH[N(CH3)2]C2H5; (B)



389 (B3)
[1-CH3-2-(1-piperidinyl)]C2H5; (B)



390 (B3)
[1-CH3-2-(1-piperidinyl)]C2H5; (A)



391 (B3)
CH(CH3)[CH2[N(CH3)2]]; (B)



392 (B3)
CH(CH3)[CH2[N(CH3)2]]; (A)



393 (B3)
[1-N(CH3)2]C3H7; (A)



394 (B18)
(1-CH3)C2H5OH; (B)



395 (B3)
CH2C(═O)OC2H5



396 (B3)
CH[N(CH3)(CH2C6H5)]CH3; (B)



397 (B17)
CH2OCH3



398 (B3)
CH[N(CH3)(CH2C6H5)]CH3; (A)



399 (B3)
CH[N(CH3)(CH2C6H5)]CH3



400 (B19)
CH[NH(CH3)]CH3; (A)



401 (B19)
CH[NH(CH3)]CH3; (B); hydrate (1:1)



402 (B20)
CH(OH)CH3; (B); hydrate (1:1)



403 (B18)
(CH2)2(OH)



404 (B21)
CH(CH3)CH2OCH3; (A)



405 (B21)
CH(CH3)CH2OCH3; (B)



406 (B3)
CH[N(CH3)(C4H9)]CH3; (A)



407 (B3)
CH[N(CH3)[(CH2)2(CH3)2]]CH3; (A)



408 (B3)
1-(4-morpholinyl)ethyl; (A)



409 (B3)
1-(4-morpholinyl)ethyl; (B)



410 (B3)
1-methyl-3-piperidinyl; (A)



411 (B3)
1-methyl-2-piperidinyl; (A)



412 (B3)
1-(4-methyl-1-piperazinyl)ethyl; (A);




hydrate (1:1)



413 (B3)
CH[N(CH3)(C3H7)]CH3; (A)



414 (B3)
CH[N(CH3)(C3H7)]CH3; (B)



415 (B3)
CH[N(CH3)[(CH2)2C6H5]]CH3



416 (B3)
CH[N(CH3)(C2H5)]CH3; (A)



417 (B3)
CH[OC(═O)N(CH2C6H5)2]CH3; (A)



418 (B3)
CH[N(CH2C6H5)2]CH3; (B)



419 (B3)
CH[N(CH2C6H5)2]CH3; (A)

















TABLE 9













 












Co.
Ex.



R4; stereochemical descriptor if not


No.
No.
X
R1
R3
racemic and/or addition salt





420
B3
CH
C6H5
H
CH(OH)C6H5


421
B2
CH
CH(CH3)2
CH3
C(CH3)═CHC6H5; (E)


422
B2
CH
CH(CH3)2
C2H5
C(CH3)═CHC6H5; (E)


423
B3
CH
4-Cl—C6H4
H
CH(OH)C6H5


424
B2
CH
C6H5
H
2-pyrazinyl


425
B2
CH
C6H5
H
2,3-dihydro-1,4-benzodioxin-2-yl


426
B2
CH
C6H5
H
(2,3-dihydro-1,4-benzodioxin-2-yl)-







methyl


427
B2
CH
CH(C2H5)2
CH3
CH2(3,4-diOCH3—C6H3)


428
B3
CH
CH[N(CH3)2]CH3
H
CH2(3,4,5-triOCH3—C6H2); (B)


429
B3
CH
CH[N(CH3)2]CH3
H
(CH2)2(3,4-diOCH3—C6H3); (B)


430
B3
CH
CH[N(CH3)2]CH3
H
(CH2)2(3,4-diOCH3—C6H3); (A)


431
B3
CH
CH[N(CH3)2]CH3
H
(CH2)3(3,4-diOCH3—C6H3); (A);







oxalic acid (1:1)


432
B3
CH
2-butyl
H
CH2(3-OCH3-4-OH—C6H3)


433
B3
CH
CH2[N(CH3)2]
H
CH2(3,4-diCH3—C6H3)


434
B3
CH
CH2[N(CH3)2]
H
3,4-diOCH3—C6H3


435
B2
CH
CH2[N(CH3)2]
H
OC6H5


436
B9
CH
CH2[N(CH3)2]
H
4-methyl-1-piperazinyl


437
B2
N
CH(CH3)[N(CH3)2]
CH3
CH2(3,4-diOCH3—C6H3); (B)


438
B2
N
CH(CH3)[N(CH3)2]
CH3
CH2(3,4-diOCH3—C6H3); (A)


439
B2
CH
CH(CH3)[N(CH3)2]
CH3
CH2(3,4-diOCH3—C6H3); (A)
















TABLE 10













 










Co No
R1; R6; stereochemical descriptor



(Ex No)
if not racemic and/or addition salt







440 (B2)
4-Cl—C6H4; H



441 (B2)
3-Cl—C6H4; H



442 (B2)
3-F—C6H4; H



443 (B2)
4-F—C6H4; H



444 (B2)
C6H5; C6H5



445 (B2)
C6H5; CH3



446 (B2)
4-F—C6H4; CH3



447 (B2)
4-Cl—C6H4; C6H5



448 (B2)
3-Cl—C6H4; CH3



449 (B2)
3-Cl—C6H4; C6H5



450 (B2)
4-F—C6H4; C6H5



451 (B2)
4-Cl—C6H4; CH3



452 (B2)
C6H5; C2H5



453 (B2)
C6H5; C3H7



454 (B2)
CH(CH3)2; C6H5



455 (B2)
CH(CH3)2; CH3; (E)



456 (B2)
CH(CH3)2; 2-CH3—C6H4



457 (B2)
CH(CH3)2; C2H5



458 (B10)
CH(CH3)2; CH3; (+)-[A-(E)]



459 (B10)
CH(CH3)2; CH3; (−)-[B-(E)]



460 (B2)
C2H5; CH3; (E)



461 (B2)
CH(CH3)2; F; (E)



462 (B2)
C4H9; CH3; (E)



463 (B2)
cyclohexyl; CH3; (E)



464 (B2)
CH(CH3)2; C3H7; (E)



465 (B2)
CH(CH3)2; C4H9; (E)



466 (B2)
CH3; CH3; (E)



467 (B2)
C3H7; CH3; (E)



468 (B2)
cyclohexyl; C6H5; (E)



469 (B2)
cyclopropyl; CH3; (E)



470 (B2)
cyclopentyl; CH3; (E)



471 (B3)
CH(CH3)2; CH(CH3)2; (E)



472 (B3)
CH(CH3)2; cyclopentyl; (E)



473 (B3)
CH(CH3)2; cyclohexyl; (E)



474 (B2)
CH2CH(CH3)2; CH3; (E)



475 (B2)
(CH2)2CH(CH3)2; CH3; (E)



476 (B2)
CH2C(CH3)3; CH3; (E);




hydrate (2:1)



477 (B2)
1,3-dioxan-5-yl; CH3; (E)



478 (B2)
CH(C2H5)2; CH3; (E)



479 (B2)
CH═CH—CH(CH3)2; CH3; (E, E)



480 (B2)
CH(CH3)C2H5; CH3; (E)



481 (B2)
C(CH3)3; CH3; (E)



482 (B2)
CH(CH3)C3H7; CH3; [A-(E)]



483 (B2)
CH(S—C6H5)CH3; CH3; (A)



484 (B2)
CH(S—C6H5)CH3; CH3; (B)



485 (B2)
CH(C6H5)2; CH3; (E)



486 (B2)
CH(C3H7)2; CH3; (E)



487 (B2)
CH(CH3)C5H11; CH3; [A-(E)]



488 (B2)
CH(CH3)C5H11; CH3; [B-(E)]



489 (B2)
CH(C6H5)CH3; CH3; [A-(E)]



490 (B2)
CH(C6H5)CH3; CH3; [B-(E)]



491 (B2)
5,5,8,8-tetramethyl-5,6,7,8-




tetrahydro-2-naphtalenyl; CH3; (E)



492 (B2)
CH(C2H5)C5H11; CH3; [A-(E)]



493 (B2)
CH(C2H5)C4H9; CH3; (E)



494 (B2)
CH(C2H5)C5H11; CH3; [B-(E)]



495 (B2)
CH[N(CH3)2]CH3; CH3; [A-(E)]



496 (B3)
CH[N(CH3)2]CH3; CH3, [B-(E)]



497 (B2)
C6H5; H



498 (B2)
H; H



499 (B2)
CH(CH3)2; H



500 (B2)
4-Br—C6H4; H



501 (B2)
4-CH3—C6H4; H



502 (B2)
CH(CH3)2; H; (E)



786 (B3)
2,5-diCl—C6H3; CH3; (E)

















TABLE 11













 









R1; R6; R7; stereochemical


Co No
descriptor if not racemic and/or


(Ex No)
addition salt





503 (B2)
C6H5; H; C6H5


504 (B2)
4-Cl—C6H4; H; C6H5


505 (B2)
3-Cl—C6H4; H; C6H5


506 (B2)
4-F—C6H4; H; C6H5


507 (B2)
4-Cl—C6H4; H; C2H5


508 (B2)
4-F—C6H4; H; CH3


509 (B2)
H; H; C6H5


510 (B2)
CH3; H; C6H5


511 (B2)
CH(CH3)2; H; C6H5


512 (B2)
4-Cl-C6H4; H; CH3


513 (B3)
4-Cl-C6H4; H; C4H9


514 (B3)
4-Cl-C6H4; H; cyclohexyl; (E + Z)


515 (B3)
4-Cl-C6H4; H; CH(CH3)2; (E + Z)


516 (B2)
4-Cl-C6H4; H; 3-pyridinyl


517 (B2)
4-F-C6H4; H; 3-pyridinyl


518 (B3)
CH(CH3)2; CH3; 3-thienyl; (E + Z)


519 (B3)
CH(CH3)2; CH3; C3H7; (E + Z)


520 (B3)
4-Cl-C6H4; H; 3,5-diCl-C6H3
















TABLE 12













 










Co No
R1; stereochemical descriptor if



(Ex No)
not racemic and/or addition salt







521 (B17)
CH(CH3)2



522 (B1)
3-Cl—C6H4



523 (B1)
3-F—C6H4



524 (B1)
3-CF3—C6H4



525 (B1)
cyclohexyl



526 (B17)
cyclopropyl



527 (B17)
cyclopentyl



528 (B17)
(CH2)2CH(CH3)2



529 (B17)
CH2C(CH3)3



530 (B17)
1,3-dioxan-5-yl



531 (B1)
CH(C2H5)2



532 (B17)
CH═CH—CH(CH3)2



533 (B1)
CH(CH3)C2H5



534 (B1)
C(CH3)3



535 (B1)
CH[N(CH3)2]CH3; hydrate (1:1)



536 (B1)
CH(CH3)(n-C3H7)



537 (B1)
1-(1-piperidinyl)ethyl



538 (B1)
CH(S—C6H5)CH3; (A + B)



539 (B1)
CH(O—C6H5)CH3



540 (B1)
CH(CH3)CH2CN



541 (B1)
CH(C6H5)2



542 (B1)
CH(C2H5)(n-C3H7)



543 (B1)
CH(n-C3H7)2



544 (B17)
CH(C6H5)CH3



545 (B17)
5,5,8,8-tetramethyl-5,6,7,8-




tetrahydro-2-naphtalenyl



546 (B17)
CH(CH3)(n-C5H11)



547 (B17)
CH(C2H5)(n-C5H11)



548 (B1)
CH2N(CH3)2



549 (B1)
CH(C2H5)(n-C4H9)



550 (B17)
1-(ethoxycarbonyl)ethyl



551 (B1)
CH[N(CH3)2]CH3; (A);




hydrate (1:1)



552 (B1)
CH[N(CH3)2]CH3; (B)



553 (B1)
CH(CH3)[CH2(C6H5)]



554 (B1)
CH[N(C2H5)2]CH3; (A)



555 (B1)
CH[N(C2H5)2]CH3; (B)



556 (B1)
CH[N(C2H5)2]CH3



557 (B1)
CH[N(CH3)2]C2H5; (A)



558 (B1)
CH[N(CH3)2]C2H5; (B)



559 (B1)
CH[N(CH3)2]C2H5



560 (B1)
(ethoxycarbonyl)methyl



561 (B17)
CH[N(CH3)(CH2—C6H5)]CH3



562 (B1)
CH[N(CH3)(n-C4H9)]CH3



563 (B1)
CH[N(CH3)[(CH2)2N(CH3)2]CH3



564 (B17)
1-(4-morpholinyl)ethyl



565 (B1)
CH[N(CH3)2]C2H5



566 (B1)
CH[N(CH3)(C2H5)]CH3



567 (B1)
1-methyl-3-piperidinyl



568 (B1)
1-methyl-2-piperidinyl; (A)



569 (B1)
1-(4-methyl-1-piperazinyl)ethyl



570 (B1)
CH[N(CH3)(n-C3H7)]CH3



571 (B1)
CH[N(CH3)(C2H5—C6H5)]CH3



572 (B1)
CH[N(CH2—C6H5)2]CH3



573 (B1)
CH[OC(═O)N(CH2—C6H5)2]CH3



787 (B17)
2,5-diCl-C6H3

















TABLE 13













 










Co No
R7; stereochemical descriptor if



(Ex No)
not racemic and/or addition salt







574 (B2)
CH3; (E)



575 (B3)
3-pyridinyl; (E)



576 (B3)
4-pyridinyl; (E)



577 (B2)
3-Cl—C6H4; (E)



578 (B2)
3-CF3—C6H4



579 (B2)
4-Cl—C6H4; (E)



580 (B2)
4-CF3—C6H4; (E)



581 (B2)
cyclohexyl; (E)



582 (B2)
4-OCH3—C6H4; (E)



583 (B2)
4-F—C6H4; (E)



584 (B2)
3-OCH3—C6H4; (E)



585 (B2)
2-F—C6H4; (E)



586 (B2)
3-F—C6H4; (E)



587 (B2)
(CH2)2C6H5; (E)



588 (B2)
CH(CH3)2; (E)



589 (B2)
CH2C6H5; (E)



590 (B2)
6-quinolinyl; (E)



591 (B2)
2-naphtalenyl; (E)



592 (B2)
4-quinolinyl; (E); hydrate (2:1)



593 (B2)
1-naphtalenyl; (E)



594 (B2)
2-furanyl; (E)



595 (B2)
2-thienyl; (E)



596 (B2)
3-thienyl; (E)



597 (B3)
H



598 (B2)
2(1H)-quinolinone-6-yl; (E);




hydrate (2:1)



599 (B2)
2-methyl-2H-benzotriazole-5-yl; (E)



600 (B2)
2-benzofuranyl; (E)



601 (B2)
5-methyl-2-furanyl; (E)



602 (B2)
1-methyl-1H-benzotriazole-6-yl; (E)



603 (B2)
2(1H)-quinolinone-4-yl; (E)



604 (B3)
2-pyridinyl; (E)



605 (B3)
1-methyl-2-pyrrolyl



606 (B2)
2,3,5,6-tetra(F)-4-(OC2H5)phenyl; (E)



607 (B2)
2,4-di(F)—C6H3; (E)



608 (B2)
3-Br-4-F—C6H3; (E)



609 (B2)
2-F-4-CF3—C6H3; (E)



610 (B3)
4-NO2—C6H4; (E)



611 (B16)
4-NH2—C6H4; (E)



612 (B3)
4-(NHC(═O)CH3)—C6H4; (E)

















TABLE 14













 










Co No
R1, R4; stereochemical descriptor if



(Ex No)
not racemic and/or addition salt







613 (B1)
3-CF3—C6H4; CH3



614 (B2)
3-CF3—C6H4; CH2C6H5



615 (B1)
3-F—C6H4; CH3



616 (B1)
3-F—C6H4; CH3



617 (B2)
3-CF3—C6H4; CH═CHC6H5; (E)



618 (B2)
3-F—C6H4; CH═CHC6H5; (E)



619 (B2)
3-F—C6H4; CH2C6H5



620 (B2)
3-F—C6H4; C(CH3)═CHC6H5; (E);




nitrate (1:1)



621 (B2)
CH(C2H5)2; 1,3-benzodioxolan-2-yl



622 (B1)
CH2C(CH3)3; CH3



623 (B2)
CH2C(CH3)3; CH2(4-Cl—C6H4)



624 (B2)
CH[C(═O)OC2H5]CH3;




CH2(4-Cl—C6H4)



625 (B1)
CH(CH3)C2H5; CH3



626 (B2)
CH(CH3)C2H5; CH2(4-Cl—C6H4)



627 (B1)
CH[N(CH3)2]CH3; CH3; (A)



628 (B2)
CH[N(CH3)2]CH3; CH2(4-Cl—C6H4);




(A)



629 (B3)
CH[N(CH3)2]CH3;




(CH2)2(3,4-diOCH3—C6H3); (A)



630 (B3)
CH[N(CH3)2]CH3;




CH2(3,4,5-triOCH3C6H2); (A)



631 (B15)
CH[N(CH3)2]CH3; CH3; (B)



632 (B2)
CH[N(CH3)2]CH3;




C(CH3)═CHC6H5; [A-(E)]



633 (B1)
CH(CH3)CH2C6H5; CH3



634 (B2)
CH(CH3)CH2C6H5; CH2(4-Cl—C6H4)



635 (B15)
1-(methyl-1-piperidinyl)ethyl; CH3



636 (B2)
1-(methyl-1-piperidinyl)ethyl;




CH2(4-Cl—C6H4)



637 (B1)
CH(CH3)(n-C3H7); CH3



638 (B2)
CH(CH3)(n-C3H7); CH2(4-Cl—C6H4)



639 (B3)
CH(CH3)(n-C3H7);




CH2(3,4-diOCH3—C6H3)



640 (B3)
CH(CH3)C2H5;




CH2(3,4-diOCH3—C6H3)



641 (B1)
C(CH3)3; CH3



642 (B3)
C(CH3)3; CH2(3,4-diOCH3—C6H3);




hydrate (1;1)



643 (B1)
CH(n-C3H7)2; CH3



644 (B2)
CH(n-C3H7)2; CH2(3,4-diOCH3—




C6H3)



645 (B1)
CH[N(CH3)2]C2H5; CH3; (A)



646 (B3)
CH[N(CH3)2]C2H5;




CH2(3,4-diOCH3—C6H3); (A)



647 (B1)
CH[N(C2H5)2]CH3; CH3; (A)



648 (B1)
CH[N(C2H5)2]CH3; CH3; (A + B)



649 (B3)
CH[N(C2H5)2]CH3;




CH2(3,4-diOCH3—C6H3); (A)

















TABLE 15













 








Co No
R4, Rb; stereochemical descriptor if


(Ex No)
not racemic and/or addition salt





650 (B2)
H; H


651 (B2)
H; 4-Cl


652 (B2)
H; 3-Cl


653 (B2)
H; 4-F


654 (B2)
H; 3-CF3


655 (B2)
C6H5; H


656 (B2)
H; 3-F


657 (B2)
CH3; H


658 (B2)
CH(CH3)2; H


659 (B2)
cyclopentyl; H


660 (B2)
C2H5; H


661 (B2)
cyclohexyl; H


662 (B2)
H; 4-OCH3


663 (B2)
H; 4-OC2H5


664 (B2)
H; 2-Cl


665 (B2)
H; 3-OCH3


666 (B3)
H; 4-CH3


667 (B3)
H; 3-OH


668 (B3)
H; 4-OH


669 (B3)
OH; 4-Cl


670 (B3)
OCH3; H; [R—(R*,R*)] + [R—(R*,S*)]
















TABLE 16













 













R1, R4; stereochemical



Co No
pyridinyl
descriptor if not racemic



(Ex No)
position
and/or addition salt







671 (B14)
3
CH(CH3)2; CH3



672 (B2)
3
C6H5; CH═CH—C6H5



673 (B12)
3
4-Cl—C6H4; CH3



674 (B2)
3
4-Cl—C6H4; CH═CH—C6H5



675 (B2)
3
C6H5; C(CH3)═CH—C6H5



676 (B2)
3
4-Cl—C6H4; CH═C(C6H5)2



677 (B3)
4
4-Cl—C6H4; CH═CC6H5)2



678 (B2)
3
3-F—C6H4; CH═CH—C6H5



679 (B2)
3
CH(CH3)2;





C(CH3)═CH—C6H5; (E)



680 (B3)
2
4-Cl—C6H4; CH═C(C6H5)2



681 (B2)
4
CH(CH3)2;





C(CH3)═CH—C6H5; (E)



682 (B2)
2
CH(CH3)2;





C(CH3)═CH—C6H5; (E)



683 (B3)
3
4-Cl—C6H4;





CH═CH(3-Cl—C6H4)2



684 (B3)
3
4-Cl—C6H4;





CH═C(C6H5)(3-Cl—C6H4)



685 (B2)
4
CH(CH3)2; CH2(4-Cl—C6H4)



686 (B3)
3
CH(CH3)2; CH2(4-Cl—C6H4)



687 (B2)
2
CH(CH3)2; CH2(4-Cl—C6H4)



688 (B13)
2
OH; CH3



689 (B13)
3
OH; CH3



690 (B31)
3
CH(CH3)2; NH(3-F—C6H4)



691 (B31)
2
CH(CH3)2; NH(3-F—C6H4)



692 (B31)
4
CH(CH3)2; NH(3-F—C6H4)



788 (B3)
4
H; CH═C(C6H5)(3-Cl—C6H4)



789 (B3)
4
CH(CH3)2;





CH═C(C6H5)(3-Cl—C6H4)



790 (B3)
4
cyclohexyl;





CH═C(C6H5)(3-Cl—C6H4)

















TABLE 17













 













R1, R4; stereochemical



Co No
methyl
descriptor if not racemic



(Ex No)
position
and/or addition salt







693 (B2)
5
4-Cl—C6H4;





CH═C(C6H5)(3-Cl—C6H4);





(E + Z)



694 (B1)
2
CH(CH3)2; CH3



695 (B2)
2
CH(CH3)2;





CH2(4-Cl—C6H4)

















TABLE 18













 

















Stereochemical


Co.




descriptor if not racemic


No.
Ex. No.
R1
R4
X
and/or addition salt





696
B31
CH(CH3)2
CH3
CH



697
B31
CH(CH3)2
C6H5
CH


698
B25
CH(CH3)2
C6H5C(═O)—
CH


699
B22a
CH(CH3)2
H
CH



B22b


700
B31
CH(CH3)2
2F—C6H4
CH


701
B31
CH(CH3)2
3F—C6H4
CH


702
B25
CH(C2H5)2
C6H5—C(═O)—
CH


703
B22a
CH(C2H5)2
H
CH


704
B27
CH(CH3)[N(CH3)2]
2-benzothiazolyl
CH
(A)


705
B27
CH(C2H5)2
2-benzothiazolyl
CH


706
B27
CH(C2H5)2
2-benzothiazolyl
N


791
B25
2,5-diCl—C6H3
C6H5—C(═O)—
CH


792
B22a
2,5-diCl—C6H3
H
H
















TABLE 19













 

















Stereochemical







descriptor if not


Co. No.
Ex. No.
(Ra)n
R1
X
racemic





707
B31
4-(O—C2H5)
CH(CH3)2
CH



708
B23
3,4-di(OCH3)
CH(CH3)2
CH


709
B31
2,5-di(F)
3-(CF3)—C6H4
CH


710
B31
2,5-di(F)
CH(C2H5)2
CH


711
B31
3-F
3-(CF3)—C6H4
N


712
B31
2,5-di(F)
CH(C2H5)2
N


713
B31
2-F
CH(C2H5)2
CH


714
B31
2-F
3-(CF3)—C6H4
CH


715
B31
2-F
CH(C2H5)2
N


716
B31
4-OCH3
3-(CF3)—C6H4
CH


717
B23
3,4-di(OCH3)
CH(CH3)[N(CH3)2]
N
(A)


718
B23
3,4-di(OCH3)
CH(C2H5)2
N


719
B23
3,4-di(OCH3)
CH(CH3)[N(CH3)2]
CH
(A)


720
B23
3,4-di(OCH3)
CH(CH3)[N(CH3)2]
N
(E)


721
B23
3,4-di(OCH3)
CH2—N(CH3)2
CH


722
B31
4-OCH3
CH(CH3)2
CH


723
B31
3-F
CH(C2H5)2
N


724
B31
3-F
CH(C2H5)2
CH


725
B31
3-F
CH(CH3)2
N


726
B31
2-F
CH(CH3)2
CH


727
B7
3-NH2
CH(CH3)2
CH


728
B31
2,5-di(F)
CH(CH3)2
CH


729
B31
3-F
3-(CF3)—C6H4
CH


730
B31
3-CF3
CH(CH3)2
CH


731
B31
3-F
4-Cl—C6H4
CH


732
B31
3,4-di(Cl)
CH(CH3)2
CH


733
B31
3-OCH3
CH(CH3)2
CH


734
B31
2,4-di(F)
CH(CH3)2
CH


735
B31
3-F
C6H5
CH


736
B31
3-CH3
CH(CH3)2
CH


737
B31
3-NO2
CH(CH3)2
CH


738
B31
3-Cl
CH(CH3)2
CH


739
B31
4-Cl
CH(CH3)2
CH


740
B31
4-F
CH(CH3)2
CH


741
B31
3-F
CH(CH3)2
CH


742
B31
H
CH(CH3)2
CH
















TABLE 20













 



















Stereochemical


Co. No.





descriptor if not


(Ex. No.)
R1
R2
R4
X
Het
racemic





743 (B29)
CH(CH3)2
H
NH2
N—C6H5
1H-1-imidazolyl



744 (B29)
CH(CH3)2
H
NH2
N-(3F-
1H-1-imidazolyl






C6H4)


745 (B2)
CH(CH3)2
CH(CH3)2
—CH2—(4-Cl—C6H4)
O
1,2,4-triazol-1-yl


746 (B31)
CH(CH3)2
CH(CH3)2
—NH—(3-F—C6H4)
O
1H-1-imidazolyl


747 (B1)
CH(CH3)2
CH(CH3)2
CH3
O
1,2,4-triazol-1-yl


748 (B1)
CH(CH3)2
H
CH3
O
1,2,4-triazol-4-yl


749 (B2)
CH(CH3)2
H
—C(CH3)═CH—C6H5
O
1,2,4-triazol-4-yl


750 (B1)
CH(CH3)2
CH(CH3)2
CH3
O
1H-1-imidazolyl


751 (B2)
CH(CH3)2
CH(CH3)2
—C(CH3)═CH—C6H5
O
1H-1-imidazolyl
(E)


752 (B17)
CH3
CH3
CH3
O
1H-1-imidazolyl


753 (B2)
CH3
CH3
—C(CH3)═CH—C6H5
O
1H-1-imidazolyl


754 (B1)
CH(CH3)2
C2H5
CH3
O
1H-1-imidazolyl


755 (B2)
CH(CH3)2
C2H5
(4-Cl—C6H4)—CH2—
O
1H-1-imidazolyl


756 (B1)
C2H5
C2H5
CH3
O
1H-1-imidazolyl


757 (B1)
CH(C2H5)2
CH(CH3)2
CH3
O
1H-1-imidazolyl


758 (B2)
CH(CH3)2
C2H5
—C(CH3)═CH—C6H5
O
1H-1-imidazolyl
(E)


759 (B1)
CH(CH3)2
CH3
CH3
O
1H-1-imidazolyl


760 (B1)
CH(CH3)2
n-C4H9
CH3
O
1H-1-imidazolyl


761 (B2)
CH(CH3)2
n-C4H9
—C(CH3)═CH—C6H5
O
1H-1-imidazolyl
(E)


762 (B2)
CH(CH3)2
CH(CH3)2
CH2—[3,4-di-
O
1H-1-imidazolyl





(OCH3)—C6H3]


763 (B2)
CH(CH3)2
CH(CH3)2
—CH2—(4-Cl—C6H4)
O
1H-1-imidazolyl


764 (B28)
CH(CH3)2
H
—CH2—(4-Cl—C6H4)
S
1H-1-imidazolyl


765 (B9)
CH(C2H5)2
n-C3H7
CH3
O
1H-1-imidazolyl


766 (B2)
CH(C2H5)2
n-C3H7
—CH2—(4-Cl—C6H4)
O
1H-1-imidazolyl


767 (B1)
CH(C2H5)2
C2H5
CH3
O
1H-1-imidazolyl


768 (B2)
CH(C2H5)2
C2H5
—CH2—(4-Cl—C6H4)
O
1H-1-imidazolyl


 


769 (B25)
OH
H
CH3
O






 


770 (B25)
OH
H
CH3
O






 


771 (B24)
OH
CH(CH3)—
CH3
O
1-methyl-5-




N(CH3)2


imidazolyl


772 (B24)
OH
CH(C2H5)2
CH3
O
1-methyl-5-







imidazolyl


773 (B31)
CH(CH3)2
H
—NH—(3-F—C6H4)
O
2-methyl-1-







imidazolyl


793 (B33)
4-Cl—C6H4
H
H
O
1-methyl-5-







imidazolyl


794 (B3)
4-Cl—C6H4
OH
CH(OH)(3-Cl—C6H4)
O
1-methyl-5-







imidazolyl


795 (B3)
4-Cl—C6H4
H
CH(OH)(3-Cl—C6H4)
O
1-methyl-5-







imidazolyl


796 (32)
2,5-diCl—
H
—S—CH3
NH
1H-1-imidazolyl



C6H3


797 (B29)
2,5-diCl—
H
—NH—CH3
NH
1H-1-imidazolyl
HCl (1:2)



C6H3
















TABLE 20













 









Co. No.




(Ex. No.)
R4
n





774 (B17)
—CH2-(4-Cl—C6H4)
3


775 (B17)
CH3
3


776 (B17)
CH3
4









Table 21 lists the experimental elemental analysis values for carbon, hydrogen and nitrogen of some of the compounds as prepared in the experimental part hereinabove.












TABLE 21







Comp






No.
C
H
N





















17
64.0
6.2
12.7



18
63.8
6.3
13.0



20
63.5
6.7
12.8



21
64.2
6.6
12.8



30
72.3
8.3
8.4



52
72.0
8.1
9.3



53
68.7
8.6
12.2



61
74.2
8.2
10.0



64
65.9
5.8
16.3



85
70.8
7.7
13.8



86
70.7
7.8
13.9



87
69.6
6.7
10.6



119
71.3
7.5
10.0



120
75.1
7.0
8.4



121
74.4
6.9
11.9



122
73.9
7.9
10.2



123
74.0
7.9
10.3



125
74.3
8.1
10.0



131
64.7
5.7
15.2



142
69.6
6.8
11.0



143
62.7
5.2
10.3



145
71.4
7.0
15.2



147
72.1
7.0
15.4



148
52.6
5.0
11.5



152
72.3
7.2
16.0



154
73.5
6.8
15.7



162
66.9
5.9
14.0



163
70.2
7.8
15.3



164
76.9
7.6
11.6



194
71.0
6.4
17.5



237
70.6
6.5
10.7



247
71.7
6.6
16.6



248
69.4
5.6
11.5



259
50.5
4.3
16.5



260
50.6
4.4
16.6



298
60.1
6.0
16.5



299
60.7
6.0
16.5



318
68.2
7.3
13.5



343
68.9
6.5
14.8



348
69.6
7.5
12.7



349
65.1
8.2
22.5



360
69.3
6.6
10.5



367
67.0
6.2
14.3



368
65.1
6.2
13.8



369
67.5
5.1
8.9



376
62.7
4.5
8.3



383
69.4
7.6
12.1



389
69.5
7.5
11.0



391
67.2
7.1
11.7



392
68.3
7.4
12.7



394
64.8
6.2
9.0



397
66.2
6.3
10.3



402
64.6
6.5
9.6



404
67.9
6.9
9.8



405
67.9
7.0
9.7



410
66.9
7.2
11.8



411
69.8
7.1
12.1



414
68.9
7.6
12.1



415
71.6
7.2
10.8



417
71.2
6.0
9.0



419
75.1
6.4
9.5



420
75.2
5.5
11.0



425
72.9
5.1
10.2



426
72.9
5.5
9.6



438
65.5
7.2
16.1



445
79.6
5.9
10.7



454
79.9
6.3
10.0



455
77.0
7.0
11.7



456
79.5
6.7
9.5



457
77.3
7.4
11.2



458
76.5
7.1
11.5



459
76.3
7.1
11.5



460
75.4
6.6
12.0



461
72.0
6.0
11.3



462
77.0
7.3
11.2



463
78.1
7.4
10.4



464
77.1
7.6
10.7



465
77.5
7.8
10.4



466
75.6
6.3
12.6



467
76.9
7.0
11.7



468
80.8
6.8
9.0



469
77.4
6.5
11.7



470
77.8
7.1
10.8



471
77.6
7.7
10.9



472
78.2
7.5
10.1



482
77.2
7.6
10.8



483
73.5
6.0
9.1



484
73.7
6.2
9.1



485
81.8
5.9
8.6



497
78.7
5.6
10.8



502
75.9
6.6
12.0



511
79.7
6.4
9.9



512
72.8
5.2
9.6



513
74.8
6.2
8.9



514
75.2
6.2
8.4



515
73.7
5.8
9.1



521
69.9
7.4
16.3



523
70.0
5.2
13.6



524
63.4
4.5
11.7



566
67.6
8.1
18.6



572
76.2
7.1
12.7



574
71.4
7.7
14.0



575
73.3
6.8
15.6



576
73.2
6.7
15.6



577
69.5
6.0
10.6



578
67.3
5.6
9.8



579
69.7
6.1
10.5



580
67.4
5.6
9.8



581
75.6
8.6
11.4



582
73.7
7.0
10.7



583
73.3
6.4
11.1



584
73.4
7.0
10.5



585
72.9
6.4
11.1



586
72.9
6.4
11.1



587
76.4
7.5
10.6



588
74.1
8.6
13.2



589
77.2
7.4
11.2



602
68.6
6.2
19.8



612
71.9
6.8
13.5



613
59.8
4.2
15.3



614
65.9
4.4
12.7



615
65.8
4.9
18.2



616
65.7
4.7
18.2



617
66.9
4.1
12.4



618
72.1
4.7
14.0



619
71.3
4.9
14.6



620
64.5
4.7
14.2



636
66.0
6.6
14.9



644
67.4
7.3
11.5



650
75.1
6.8
12.5



666
76.1
7.4
11.9



667
71.9
6.5
11.9



676
79.3
5.1
5.5



677
79.8
5.1
5.5



679
80.8
7.0
7.4



680
78.9
5.0
5.6



681
81.4
7.2
7.5



682
80.8
7.1
7.5



695
68.0
6.2
10.7



704
60.3
5.7
18.7



705
63.3
6.2
15.7



706
60.5
5.4
19.2



720
61.5
6.6
19.3



734
64.8
5.4
15.2



749
73.4
6.7
15.6



771
63.9
7.7
17.2



777
65.1
5.6
17.2



782
70.6
7.7
13.9



783
70.5
7.7
13.8



786
67.0
4.5
8.9



788
76.0
4.9
6.5



789
76.9
5.8
5.9



793
66.1
4.9
12.7



794
61.8
4.4
8.4



795
63.5
4.6
8.6



797
46.9
4.6
14.5










C. Pharmacological Examples

EXAMPLE C.1
Inhibition of Retinoic Acid (RA) Metabolism
MCF-7 human breast cancer cells were grown as stock cultures according to art-known protocols. One day before the experiment, RA is added to the stock cultures to stimulate RA-metabolism. At the start of the experiment, cell suspensions were incubated in a tissue culture medium containing 3H-RA as the substrate. Different concentrations of the test compound (dissolved in 1% DMSO) were added to the incubation mixtures, and at the end of the incubation, the unmetabolized RA is separated from its polar metabolites. The fraction containing the polar 3H-labelled metabolites was collected and counted in a scintillation counter. For each experiment, a control and a blank incubation were run in parallel. Table 22 list the IC50 value (defined as the concentration in M needed to reduce the amount of metabolites to 50% of the control).










TABLE 22







Co.
IC50



No.
(in M)



















1
1.38E−10



2
3.00E−11



4
2.11E−09



5
2.70E−10



6
1.65E−09



7
7.90E−10



8
9.37E−11



10
1.55E−09



11
2.63E−09



12
3.65E−11



13
3.57E−11



17
9.99E−10



18
8.72E−10



21
2.89E−09



22
1.04E−09



23
5.03E−10



24
1.37E−09



25
6.10E−08



26
2.01E−10



27
2.32E−10



28
2.76E−09



29
8.12E−09



30
2.58E−08



31
2.63E−09



32
6.97E−10



33
1.01E−09



34
1.03E−09



35
2.24E−09



36
1.43E−09



37
1.00E−09



38
1.04E−09



39
1.04E−10



41
1.98E−09



45
1.72E−10



46
1.95E−09



47
1.33E−09



48
5.69E−10



49
4.33E−10



50
7.44E−09



51
8.95E−10



52
9.07E−10



53
2.12E−09



54
4.86E−09



56
2.51E−11



58
<1.00E−11 



61
7.34E−10



63
6.70E−09



64
6.60E−09



65
3.79E−10



66
3.56E−10



67
3.34E−10



68
1.72E−09



69
2.50E−10



70
2.95E−10



71
2.62E−10



72
1.66E−09



73
4.63E−10



75
4.17E−10



76
5.88E−10



77
3.32E−10



78
2.27E−10



79
3.42E−11



80
4.83E−11



81
2.31E−10



82
1.16E−09



83
1.62E−10



84
1.74E−09



85
3.92E−09



86
4.97E−10



87
2.80E−10



88
1.48E−10



89
1.31E−10



90
2.36E−09



91
9.35E−10



92
2.21E−09



93
1.59E−09



94
1.06E−09



95
1.48E−09



96
1.09E−09



97
1.32E−09



98
1.64E−09



99
5.77E−09



102
6.78E−11



103
7.11E−09



104
4.07E−11



105
5.16E−11



106
1.69E−09



107
1.44E−09



108
2.34E−11



109
3.21E−10



110
9.53E−10



111
1.03E−09



112
9.89E−10



113
8.52E−10



115
8.17E−09



116
6.78E−10



117
2.55E−10



118
2.24E−09



119
9.40E−10



120
3.88E−09



121
9.14E−10



122
2.40E−09



123
2.47E−11



124
3.97E−11



125
1.94E−10



126
<1.00E−11 



127
2.85E−11



128
1.81E−11



129
2.36E−11



130
1.09E−11



131
4.10E−09



132
4.49E−09



133
4.56E−09



134
2.98E−09



135
1.43E−09



136
4.83E−09



137
1.85E−09



138
6.38E−09



139
1.75E−09



140
2.15E−08



141
1.31E−09



142
3.11E−08



143
4.08E−09



145
3.03E−09



147
3.30E−08



148
1.86E−09



151
2.11E−09



152
5.18E−09



154
4.14E−09



155
5.01E−08



156
3.10E−08



157
8.48E−08



158
>1.00E−07 



159
>1.00E−07 



160
8.65E−08



161
1.87E−09



162
2.88E−09



163
2.36E−09



164
8.15E−09



165
1.08E−08



166
1.75E−09



167
4.16E−09



168
2.36E−09



169
5.31E−10



170
1.22E−08



171
8.58E−08



172
3.41E−09



173
5.17E−09



174
1.60E−09



175
4.83E−09



176
1.87E−08



179
3.69E−08



180
5.69E−08



181
1.41E−08



182
1.31E−08



183
7.40E−09



184
5.15E−09



185
3.97E−08



186
>1.00E−07 



187
1.88E−08



189
>1.00E−07 



190
>1.00E−07 



191
>1.00E−07 



192
3.34E−09



193
1.21E−08



194
7.07E−09



195
3.51E−08



196
2.23E−08



197
5.61E−09



198
1.07E−08



199
7.82E−09



200
4.43E−08



201
3.58E−09



202
1.84E−09



203
2.28E−08



204
4.58E−09



205
1.17E−08



207
2.54E−08



208
6.43E−09



209
8.27E−09



210
2.90E−08



212
4.07E−09



213
2.07E−09



214
3.37E−09



215
3.60E−08



216
1.17E−08



217
5.14E−09



219
3.20E−09



220
1.48E−09



221
1.08E−09



222
3.32E−09



223
1.20E−09



224
4.73E−09



225
8.28E−08



226
1.69E−08



227
7.80E−09



228
7.30E−08



229
1.64E−09



230
3.89E−09



231
1.86E−09



232
1.51E−09



233
2.43E−09



234
3.01E−09



235
6.94E−09



236
9.84E−08



237
1.82E−08



238
>1.00E−07 



239
7.28E−10



240
1.34E−09



241
2.59E−09



242
2.82E−09



243
3.59E−08



244
2.30E−09



245
2.79E−09



246
2.10E−09



247
3.55E−08



248
1.79E−09



249
7.58E−08



250
1.49E−08



251
3.93E−09



252
2.59E−09



253
5.55E−09



254
6.47E−09



255
6.24E−09



256
3.20E−09



259
9.29E−09



260
2.43E−09



261
2.22E−09



262
7.48E−09



263
4.66E−09



264
2.71E−09



266
3.11E−08



267
7.75E−09



268
7.79E−09



269
2.66E−09



270
5.61E−09



271
2.45E−09



272
4.81E−09



273
5.27E−08



274
6.64E−09



275
4.28E−09



276
1.60E−08



277
1.17E−09



288
1.28E−09



289
5.07E−10



290
1.14E−09



291
4.23E−09



292
1.37E−10



293
6.53E−09



297
7.86E−10



299
7.72E−10



301
6.05E−09



303
3.26E−09



305
8.29E−11



306
1.26E−09



307
7.01E−10



309
3.65E−09



311
6.64E−10



313
2.00E−11



316
4.06E−09



330
1.82E−09



332
1.50E−09



336
1.91E−09



339
1.23E−09



346
2.04E−09



351
5.69E−09



352
2.57E−10



353
1.97E−09



355
>1.00E−07 



356
>1.00E−07 



357
>1.00E−07 



358
>1.00E−07 



359
6.25E−09



360
1.08E−09



361
>1.00E−07 



362
1.43E−08



363
1.42E−09



364
1.41E−09



365
1.08E−09



366
3.05E−09



367
1.25E−09



368
5.83E−10



369
8.22E−08



370
8.34E−08



371
3.59E−09



372
1.97E−09



376
<1.00E−10 



378
1.74E−09



383
7.29E−10



385
6.75E−09



388
8.29E−10



389
5.67E−11



393
9.55E−10



404
1.35E−09



405
3.68E−09



412
3.99E−09



413
5.27E−09



415
2.64E−09



416
3.67E−10



420
8.38E−08



421
>1.00E−07 



422
>1.00E−08 



423
4.08E−08



424
>1.00E−07 



425
3.81E−08



426
>1.00E−07 



427
8.34E−09



432
8.10E−10



435
2.80E−09



445
1.92E−07



454
5.25E−08



455
2.87E−09



456
1.40E−07



457
2.50E−08



458
3.22E−09



459
1.77E−08



460
3.63E−08



461
1.69E−08



462
>1.00E−06 



463
2.45E−08



464
1.49E−07



465
5.04E−08



466
>1.00E−06 



467
2.58E−09



468
>1.00E−07 



469
>1.00E−07 



470
1.87E−08



471
>1.00E−07 



472
9.51E−08



473
>1.00E−07 



474
1.59E−08



475
>1.00E−07 



476
3.55E−08



477
>1.00E−06 



478
1.63E−09



479
>1.00E−07 



480
4.25E−09



481
2.83E−09



482
1.95E−09



483
1.98E−08



484
3.43E−09



485
>1.00E−07 



486
2.77E−08



488
>1.00E−07 



489
>1.00E−07 



490
>1.00E−07 



491
1.84E−09



492
4.07E−09



493
8.77E−09



497
3.76E−08



502
3.29E−08



511
1.05E−08



512
6.16E−07



513
8.60E−07



514
>1.00E−06 



515
>1.00E−06 



516
>1.00E−06 



517
3.69E−08



518
>1.00E−07 



519
3.80E−09



524
>1.00E−06 



558
1.32E−09



574
1.78E−09



575
2.57E−08



576
2.01E−08



577
4.23E−08



578
7.67E−09



579
1.24E−08



580
3.13E−08



581
>1.00E−07 



582
1.58E−09



583
2.78E−09



584
6.51E−09



585
7.21E−09



586
3.74E−09



587
3.16E−08



588
4.88E−08



589
2.75E−09



590
2.78E−09



591
4.01E−08



592
4.15E−09



593
2.70E−09



594
4.81E−09



595
3.83E−09



596
7.92E−09



597
5.00E−09



598
2.39E−08



599
6.36E−09



600
3.67E−08



601
2.00E−08



602
2.57E−08



603
>1.00E−07 



604
2.89E−09



605
1.40E−08



606
1.36E−08



608
6.61E−09



609
1.09E−08



610
6.53E−09



611
3.42E−09



612
1.68E−08



613
1.80E−06



614
2.78E−07



615
>1.00E−06 



616
>1.00E−06 



617
1.51E−07



618
1.57E−08



619
3.57E−08



620
>1.00E−06 



621
1.25E−09



623
1.38E−09



639
1.68E−09



640
2.17E−09



642
1.16E−09



644
2.96E−10



645
8.02E−09



646
3.07E−09



649
7.32E−09



650
4.86E−09



651
1.05E−08



652
>1.00E−07 



653
1.34E−09



654
2.34E−09



655
1.61E−08



656
1.47E−09



657
5.36E−09



658
5.48E−09



659
>1.00E−07 



660
6.37E−09



661
3.40E−08



662
3.58E−10



663
1.95E−09



664
1.56E−09



665
5.91E−09



666
1.45E−08



667
1.57E−09



668
3.16E−09



669
8.66E−09



670
5.72E−09



679
>1.00E−06 



680
1.21E−08



681
>1.00E−06 



682
>1.00E−07 



685
9.08E−08



686
4.31E−08



687
>1.00E−07 



690
>1.00E−07 



691
>1.00E−07 



692
3.80E−08



693
>1.00E−07 



695
>1.00E−07 



696
8.07E−09



697
1.71E−08



698
3.96E−08



699
9.69E−09



700
1.20E−08



707
1.30E−08



708
1.61E−09



709
2.40E−09



710
1.88E−10



711
>1.00E−07 



712
4.30E−12



713
1.38E−09



715
1.54E−10



718
1.33E−10



722
4.14E−09



723
1.13E−09



724
1.18E−09



725
3.29E−09



726
3.71E−09



727
1.64E−09



728
1.41E−09



729
>1.00E−07 



730
1.59E−08



731
>1.00E−07 



732
1.93E−08



733
2.41E−09



734
2.25E−09



735
>1.00E−07 



736
7.45E−09



737
2.36E−09



738
2.03E−09



739
4.21E−08



740
1.29E−09



741
1.44E−09



742
2.61E−10



743
1.10E−08



744
>1.00E−07 



745
3.87E−09



746
>1.00E−07 



749
1.26E−07



751
6.70E−08



753
>1.00E−07 



755
4.35E−09



758
1.88E−09



761
>1.00E−07 



762
4.08E−08



763
5.62E−09



764
2.33E−08



772
1.46E−10



773
>1.00E−07 



774
5.27E−09



776
4.39E−09



778
7.59E−08



780
4.57E−09



781
3.24E−09



782
1.26E−09



783
3.98E−08










EXAMPLE C.2
Vaginal Keratinization Test on Ovariectomized Rats
Ovariectomized rats were injected subcutaneously with a sesame oil solution containing 100 μg of estradiol undecylate in a volume of 0.1 ml per 100 g body weight and control animals were injected with sesame oil. On day one, two and three, test animals were treated once daily with a per os dose of the test compound and control animals with the drug vehicle (PEG 200). One day after the last treatment, the animals were sacrificed and their vaginas were processed for histological evaluation according to the method described in J. Pharmacol. Exp. Ther. 261(2), 773-779 (1992). A dose at which 50% of the tested rats show complete suppression of the estradiol undecylate induced keratinization effects is defined as an active dose. Table 23 lists the lowest active dose (LAD in mg/kg) of the compounds of formula (I) which were tested.










TABLE 23







Co.
LAD



No.
(mg/kg)



















2
5.00



3
>2.50



4
0.60



5
>2.50



6
2.50



7
>2.50



8
>2.50



10
2.50



11
>2.50



13
>2.50



15
>2.50



18
2.50



20
2.50



21
5.00



22
2.50



23
2.50



24
2.50



25
10.00



26
5.00



27
5.00



28
2.50



29
5.00



30
>5.00



31
5.00



32
5.00



33
5.00



34
2.50



35
2.50



36
5.00



37
5.00



38
5.00



39
0.60



41
2.50



43
2.50



44
2.50



45
2.50



46
>2.50



47
2.50



48
2.50



49
2.50



50
2.50



52
2.50



53
>2.50



55
>2.50



56
>5.00



57
>5.00



58
5.00



59
>2.50



61
2.50



62
>5.00



63
>5.00



64
>5.00



65
5.00



66
2.50



67
2.50



68
5.00



69
2.50



70
5.00



71
>5.00



72
2.50



73
>2.50



74
2.50



75
2.50



76
>2.50



77
2.50



78
1.25



79
2.50



80
>2.50



81
2.50



82
2.50



83
>2.50



84
>2.50



85
2.50



86
2.50



87
1.25



88
2.50



89
2.50



90
2.50



91
2.50



92
5.00



93
2.50



94
5.00



95
5.00



96
2.50



97
2.50



98
5.00



99
2.50



102
5.00



103
>2.50



104
2.50



105
2.50



106
2.50



107
>2.50



109
2.50



110
>2.50



111
>2.50



112
2.50



113
>2.50



114
2.50



115
>2.50



116
2.50



117
>2.50



118
2.50



121
>2.50



122
>2.50



123
2.50



125
2.50



126
2.50



127
>2.50



128
5.00



129
2.50



130
5.00



131
5.00



132
5.00



133
>5.00



134
5.00



135
2.50



136
5.00



137
>5.00



138
>5.00



139
10.00



140
5.00



141
>10.00



142
5.00



143
10.00



148
>5.00



151
5.00



152
>5.00



154
5.00



155
>10.00



156
>10.00



157
>10.00



158
>10.00



159
>10.00



160
10.00



161
>2.50



162
>5.00



163
20.00



164
20.00



165
>20.00



166
5.00



167
10.00



168
10.00



169
10.00



170
10.00



171
>10.00



172
10.00



173
10.00



174
10.00



175
10.00



176
>10.00



178
>10.00



179
>10.00



180
>10.00



181
10.00



182
10.00



183
>10.00



184
>10.00



185
10.00



186
>10.00



187
>10.00



189
>10.00



190
>10.00



191
>10.00



192
>10.00



193
>10.00



194
10.00



195
>10.00



196
>10.00



197
>10.00



198
>10.00



199
>10.00



200
>10.00



201
>10.00



202
>10.00



203
>10.00



204
>10.00



205
>10.00



207
10.00



208
>10.00



209
5.00



210
20.00



212
20.00



213
20.00



214
20.00



215
20.00



216
20.00



217
10.00



219
20.00



220
20.00



221
10.00



222
20.00



223
5.00



224
>10.00



227
>10.00



228
>10.00



229
>10.00



230
>10.00



231
>10.00



232
>10.00



233
>10.00



234
10.00



235
5.00



236
5.00



237
5.00



238
5.00



239
10.00



240
10.00



241
10.00



242
>10.00



243
10.00



244
10.00



245
10.00



246
10.00



247
10.00



248
2.50



249
5.00



250
>10.00



251
10.00



252
>10.00



253
>5.00



254
>5.00



255
5.00



256
>2.50



261
>10.00



262
20.00



263
>10.00



264
>10.00



266
>10.00



267
>10.00



268
>10.00



269
>10.00



270
>10.00



271
10.00



272
>10.00



273
>10.00



274
>10.00



275
>10.00



276
>10.00



277
>5.00



278
2.50



279
2.50



280
>2.50



281
>2.50



283
2.50



284
2.50



285
>2.50



286
>2.50



287
>2.50



288
>2.50



289
>2.50



290
2.50



291
>2.50



292
>2.50



293
>2.50



294
>2.50



295
>2.50



297
>2.50



300
>2.50



301
>2.50



302
>2.50



304
>2.50



306
>2.50



307
>2.50



308
>2.50



309
>2.50



310
2.50



311
2.50



312
>2.50



313
2.50



314
>2.50



315
>2.50



316
5.00



317
>5.00



318
>2.50



319
>5.00



320
5.00



322
>2.50



324
>2.50



325
2.50



326
>2.50



327
>2.50



328
>2.50



329
>2.50



330
2.50



332
>2.50



333
>2.50



337
2.50



338
>2.50



339
>2.50



340
2.50



341
>2.50



342
>2.50



343
>2.50



346
>5.00



347
>5.00



348
>2.50



349
>2.50



350
>2.50



351
>5.00



352
>5.00



353
>5.00



354
>5.00



355
>10.00



356
>10.00



357
>10.00



358
>10.00



359
>10.00



360
2.50



361
10.00



362
10.00



363
>10.00



364
2.50



365
10.00



366
>10.00



367
2.50



368
2.50



369
10.00



370
>10.00



371
10.00



372
5.00



374
2.50



375
>5.00



376
2.50



378
2.50



379
>2.50



380
>2.50



381
>2.50



383
>2.50



384
>2.50



385
>2.50



386
>2.50



387
>2.50



389
>2.50



390
>2.50



391
>5.00



392
>5.00



393
5.00



394
>2.50



395
>5.00



396
>2.50



397
>2.50



398
>5.00



400
>2.50



401
>2.50



402
>5.00



403
>5.00



404
5.00



405
5.00



406
>5.00



407
>5.00



408
>5.00



409
5.00



410
>5.00



411
2.50



412
>2.50



413
5.00



414
5.00



416
>5.00



417
>5.00



419
>5.00



420
>20.00



421
>10.00



422
>10.00



423
20.00



424
>10.00



425
>10.00



426
>10.00



427
2.50



428
>2.50



429
>2.50



431
>2.50



432
>2.50



433
>2.50



434
>2.50



435
>2.50



436
>5.00



437
>2.50



438
>2.50



439
>2.50



445
>20.00



454
>20.00



455
2.50



456
>20.00



457
>20.00



458
5.00



459
20.00



460
>20.00



461
10.00



462
20.00



463
20.00



464
>20.00



465
>20.00



466
>20.00



467
>20.00



468
10.00



469
>10.00



470
>20.00



471
>10.00



472
>20.00



473
>10.00



474
>10.00



475
>10.00



476
>10.00



477
>10.00



478
2.50



479
>10.00



480
10.00



481
10.00



482
10.00



483
>5.00



484
>5.00



485
5.00



486
5.00



487
>5.00



489
2.50



490
2.50



492
>2.50



493
>2.50



494
>2.50



495
>2.50



497
>20.00



502
5.00



511
>20.00



512
>20.00



513
>20.00



514
>20.00



515
>20.00



518
>10.00



519
>10.00



521
10.00



524
20.00



532
>10.00



551
>2.50



552
>2.50



554
2.50



555
>2.50



557
>5.00



558
>5.00



560
>5.00



562
5.00



566
5.00



570
>5.00



572
>5.00



574
20.00



575
20.00



576
10.00



577
10.00



578
>10.00



579
10.00



580
10.00



581
20.00



582
>10.00



583
10.00



584
10.00



585
10.00



586
>10.00



587
>10.00



588
10.00



589
10.00



590
>10.00



591
>10.00



592
>10.00



593
>10.00



594
>10.00



595
10.00



596
10.00



597
>10.00



598
>10.00



599
>20.00



600
>10.00



601
10.00



602
>10.00



603
>10.00



604
>10.00



605
>10.00



606
>10.00



608
>10.00



609
10.00



610
>10.00



611
10.00



612
10.00



613
>20.00



614
>20.00



615
>20.00



618
>20.00



619
>20.00



621
1.25



623
>5.00



624
>2.50



626
2.50



627
>2.50



628
>2.50



629
>2.50



630
>2.50



631
>2.50



632
>2.50



636
2.50



638
>2.50



639
2.50



640
>2.50



642
2.50



644
2.50



645
>5.00



646
5.00



647
>5.00



649
5.00



650
10.00



651
5.00



652
10.00



653
5.00



654
5.00



655
>10.00



656
10.00



657
>10.00



658
>10.00



659
>10.00



660
>10.00



661
>10.00



662
5.00



663
2.50



664
5.00



665
2.50



666
2.50



667
5.00



668
5.00



669
5.00



670
>2.50



679
>20.00



680
>20.00



681
>20.00



682
>20.00



686
>10.00



690
>10.00



692
>10.00



695
>10.00



696
>10.00



697
10.00



698
20.00



700
5.00



704
>5.00



705
>5.00



706
5.00



707
5.00



708
>5.00



709
5.00



710
2.50



711
5.00



712
5.00



713
2.50



714
2.50



715
>2.50



716
>2.50



717
>2.50



718
2.50



720
>2.50



721
>2.50



722
5.00



723
5.00



724
2.50



725
5.00



726
5.00



727
>10.00



728
5.00



729
2.50



730
>10.00



732
>10.00



733
>10.00



734
10.00



735
10.00



736
>10.00



737
>10.00



738
10.00



739
>10.00



740
20.00



741
10.00



742
10.00



743
>10.00



745
>5.00



746
>5.00



749
>20.00



751
10.00



753
>10.00



754
10.00



758
>5.00



761
>5.00



762
>5.00



763
>5.00



764
>5.00



766
>2.50



768
>2.50



772
>5.00



773
>10.00



774
10.00



776
>20.00



778
5.00



782
2.50



783
5.00



784
>5.00



785
5.00










D. Composition Examples

The following formulations exemplify typical pharmaceutical compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention. “Active ingredient” (A.I.) as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
EXAMPLE D.1
Oral Solution
9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxy-benzoate were dissolved in 41 of boiling purified water. In 31 of this solution were dissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20 g of A.I. The latter solution was combined with the remaining part of the former solution and 12 11,2,3-propane-triol and 31 of sorbitol 70% solution were added thereto. 40 g of sodium saccharin were dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence were added. The latter solution was combined with the former, water was added q.s. to a volume of 201 providing an oral solution comprising 5 mg of A.I. per teaspoonful (5 ml). The resulting solution was filled in suitable containers.
EXAMPLE D.2
Oral Drops
500 g of the A.I. was dissolved in 0.51 of 2-hydroxypropanoic acid and 1.51 of the polyethylene glycol at 60 ̃80° C. After cooling to 30 ̃40° C. there were added 351 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of 1750 g of sodium saccharin in 2.51 of purified water and while stirring there were added 2.51 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of A.I. The resulting solution was filled into suitable containers.
EXAMPLE D.3
Capsules
20 g of A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose, 0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate were vigorously stirred together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules, each comprising 20 mg of A.I.
EXAMPLE D.4
Injectable Solution
0.5 mg A.I. 1, 50 mg glucose anhydrous and 0.332 ml concentrated hydrochloric acid were mixed with 0.8 ml water for injections. Sodium hydroxide was added until pH=3.2±0.1 and water was added to 1 ml. The solution was sterilized and filled in sterile containers.
EXAMPLE D.5
Film-Coated Tablets
Preparation of Tablet Core
A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinyl-pyrrolidone (Kollidon-K 90®) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose (Avicel®) and 15 g hydrogenated vegetable oil (Sterotex®). The whole was mixed well and compressed into tablets, giving 10,000 tablets, each comprising 10 mg of the active ingredient.
Coating
To a solution of 10 g methyl cellulose (Methocel 60 HG®) in 75 ml of denaturated ethanol there was added a solution of 5 g of ethyl cellulose (Ethocel 22 cps®) in 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension (Opaspray K-1-2109®) and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.
EXAMPLE D.6
2% Cream
75 mg stearyl alcohol, 2 mg cetyl alcohol, 20 mg sorbitan monostearate and 10 mg isopropyl myristate are introduced into a doublewall jacketed vessel and heated until the mixture has completely molten. This mixture is added to a separately prepared mixture of purified water, 200 mg propylene glycol and 15 mg polysorbate 60 having a temperature of 70 to 75° C. while using a homogenizer for liquids. The resulting emulsion is allowed to cool to below 25° C. while continuously mixing. A solution of 20 mg A.I., 1 mg polysorbate 80 and purified water and a solution of 2 mg sodium sulfite anhydrous in purified water are next added to the emulsion while continuously mixing. The cream, 1 g of the A.I. is homogenized and filled into suitable tubes.
EXAMPLE D.7
2% Topical Gel
To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified water is added 20 mg of A.I. while stirring. Hydrochloric acid is added until complete dissolution and then sodium hydroxide is added until pH 6.0. This solution is added to a dispersion of 10 mg carrageenan PJ in 50 mg propylene glycol while mixing. While mixing slowly, the mixture is heated to 50° C. and allowed to cool to about 35° C. whereupon 50 mg ethyl alcohol 95% (v/v) is added. The rest of the purified water q.s. ad 1 g is added and the mixture is mixed to homogenous.
EXAMPLE D.8
2% Topical Cream
To a solution of 200 mg hydroxypropyl β-cyclodextrine in purified water is added 20 mg of A.I. while stirring. Hydrochloric acid is added until complete dissolution and next sodium hydroxide is added until pH 6.0. While stirring, 50 mg glycerol and 35 mg polysorbate 60 are added and the mixture is heated to 70° C. The resulting mixture is added to a mixture of 100 mg mineral oil, 20 mg stearyl alcohol, 20 mg cetyl alcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having a temperature of 70° C. while mixing slowly. After cooling down to below 25° C., the rest of the purified water q.s. ad 1 g is added and the mixture is mixed to homogenous.
EXAMPLE D.9
2% Liposome Formulation
A mixture of 2 g A.I. microfine, 20 g phosphatidyl choline, 5 g cholesterol and 10 g ethyl alcohol is stirred and heated at 55-60° C. until complete dissolution and is added to a solution of 0.2 g methyl paraben, 0.02 g propyl paraben, 0.15 g disodium edetate and 0.3 g sodium chloride in purified water while homogenizing. 0.15 g Hydroxypropyl-methylcellulose in purified water ad 100 g is added and the mixing is continued until swelling is complete.

## Claims

1. A compound having the formula




a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein:
X represents —O—, —S— or —NR3—;
R1 represents hydrogen, hydroxy, C1-6alkyl or aryl;
R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; Het1; or C1-12alkyl substituted with one or two substituents selected from C3-7cycloalkyl, hydroxy, C1-4alkyloxy, cyano, amino, mono- and di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, di(arylC1-4alkyl)aminocarbonyloxy, (C1-4alkyl) (arylC1-4alkyl)amino, mono- and di(aryl)amino, (C1-4alkyl)(di(C1-4alkyl)-aminoC1-4alkyl)amino, pyrrolidinyl, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, morpholinyl, perhydro-azepinyl, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl, mono- and di(C1-4alkyl)aminocarbonyl, aryl, aryloxy or arylthio;
R3 represents hydrogen, C1-6alkyl, aryl, Het1 or C1-6alkyl substituted with aryl or Het1;
R4 represents hydrogen; hydroxy; mercapto; C1-6alkyloxy; C1-6alkylthio; aryloxy; arylthio; Het1-oxy; Het1-thio; C1-12alkyl; C1-12alkyl substituted with halo; C2-8alkenyl substituted with aryl; or —NR3R5 wherein R5 represents hydrogen, C1-6alkyl, aryl, Het1, (aryl or Het1)C1-6alkyl, (aryl or Het1)carbonyl or (aryl or Het1)C1-6alkyloxycarbonyl;
aryl represents indanyl, indenyl, naphtyl, 5,6,7,8-tetrahydro-2-naphtalenyl, phenyl; said indanyl, indenyl, naphtyl or phenyl may be substituted with one, two, three, four or five substituents each independently selected from hydroxy, halo, nitro, cyano, amino, azido, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, C1-6alkyl, polyhaloC1-6alkyl, hydroxyC1-6alkyl, phenyl, phenyloxy, phenylC1-6alkyloxy, pyridinylC1-6alkyloxy, C1-6alkyloxy, formyl, carboxyl and C1-6alkylcarbonyl; or two adjacent carbon atoms on said phenyl may be substituted by a single bivalent radical having the formula C1-12alkanediyl or polyhaloC1-12alkanediyl;
Het represents triazolyl which may optionally be substituted with amino, mercapto, C1-6alkyl, C1-6alkylthio or aryl; and
Het1 represents a monocyclic heterocycle selected from pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,3,4-triazolyl, 1,2,4-triazolyl, tetrahydrofuranyl, furanyl, thiolanyl, thienyl, dioxolanyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrahydropyranyl, pyranyl, morpholinyl and dioxanyl; each of said monocyclic heterocycles may be optionally substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl; or a bicyclic heterocycle selected from indolinyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, 2H-1-benzopyranyl, 3,4-dihydro-2H-1-benzopyranyl, benzthiazolyl, isoquinolinyl, quinolinyl, 3,4-dihydroquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, chromanyl, 1,4-benzodioxinyl, 1,4-benzoxathianyl, benzodioxanyl and benzodioxolanyl; each of said bicyclic heterocycles may be substituted with one or two substituents each independently selected from C1-4alkyl, hydroxy, amino, halo, aryl, arylcarbonyl or C1-4alkyloxycarbonyl;
with the proviso the N-[4-(2-ethyl-1-[1,2,4]triazol-1-yl-butyl)-phenyl]-acetamide is not included.

2. A compound as claimed in claim 1 wherein R1 represents hydrogen, hydroxy or C1-6alkyl; and R2 represents hydrogen; C1-12alkyl; C3-7cycloalkyl; C2-8alkenyl; aryl; Het1; or C1-12alkyl substituted with one or two substituents selected from hydroxy, C1-4alkyloxy, cyano, mono- and di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, di(arylC1-4alkyl)aminocarbonyloxy, (C1-4alkyl) (arylC1-4alkyl)amino, (C1-4alkyl)(di(C1-4alkyl)aminoC1-4alkyl)amino, piperidinyl, piperazinyl optionally substituted with C1-4alkyl, morpholinyl, C1-4alkyloxycarbonyl, aryl, aryloxy or arylthio.

3. A compound as claimed in claim 1 wherein R3 is hydrogen; X is O and R4 is C2-8alkenyl substituted with aryl.

4. A compound according to claim 3 wherein R4 is C2-8alkenyl substituted with phenyl, optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C1-6alkyloxy, or phenyloxy.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim 1.

6. A compound as claimed in claim 1 for use as a medicine.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) an effective amount of retinoic acid, a derivative thereof or a stereochemically isomeric form thereof, and (b) an effective amount of a compound of formula (I) as described in claim 1.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) an effective amount of calcitriol or a prodrug thereof, and (b) an effective amount of a compound of formula (I) as described in claim 1.

9. A product containing (a) a pharmaceutical composition containing an effective amount of retinoic acid, a derivative thereof or a sterochemically isomeric form thereof and a pharmaceutical acceptable carrier, and (b) a pharmaceutical composition containing an effective amount of a compound of formula (I) as described in claim 1 and a pharmaceutical acceptable carrier.

10. A product containing (a) a pharmaceutical composition containing an effective amount of calcitriol or a prodrug thereof and a pharmaceutical acceptable carrier, and (b) a pharmaceutical composition containing an effective amount of a compound of formula (I) as described in claim 1 and a pharmaceutical acceptable carrier.

11. A product containing a) a pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier; and b) a pharmaceutical composition comprising a pharmaceutically effective amount of an anti-neoplastic agent and a pharmaceutically acceptable carrier.