Patent EA-004037-B1 (EA)
Title: Modified aminoacids, pharmaceuticals on their base
Inventor: RUDOLF KLAUS
IPC: C07D419/12
Filed: 1997-09-08
Abstract: 1. Modified amino acid amides of general formula (I) wherein R denotes unbranched alkyl with 1-3 carbon atoms, which is substituted in the end by cycloalkyl group with 5-7 carbon atoms, by one or two phenyl groups, by a 1-naphthyl, 2-naphthyl or 4-biphenylyl group, said aromatic residue can be further substituted by fluoro, chloro or bromo, methyl, methoxy group, amino group, acetyl amino group, 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indole-3-yl, quinolinyl, or iso-quinolinyl; substituted or unsubstituted in nitrogen atom by methyl, or ethyl, unbranched alkylamino group with 1-4 carbon atoms, which is substituted in the end by cycloalkyl with 5-7 carbon atoms, phenyl, which cam be mono- or disubstituted by fluoro, chloro or bromo, methyl, nitro group, methoxy group, trifluomethyl, hydroxyl, amino group or acetyl amino group, wherein the substituents can be similar or different, 2-pyrrolyl, 3-pyrrolyl, pyridinyl, 1H-indole-3-yl, quinolinyl, or iso-quinolinyl, or the rest of formula (II) wherein p denotes the number 1 or 2, o denotes the number 2 or, if Y<1> and Y<2> are not simultaneously nitrogen atoms, o may also denote 1. Y<1> denotes the nitrogen atom if R<5> is a free pair of electrons, or the carbon atom, Y<2> is the nitrogen atom or the group CH-, R<5> is a free pair of electrons if Y<1> denotes the nitrogen atom or, if Y<1> denotes the carbon atom, R<5> denotes a hydrogen atom, a C1-2-alkyl group, cyano, or phenyl group, R<6> denotes the hydrogen atom or, provided that Y<1> is not a nitrogen atom, R<6> together with R<5> may denote an additional bond, R<7> denotes the hydrogen atom or, provided that Y<1> is not a nitrogen atom and R<5> and R<6> together constitute an additional bond, R<7> together with R<N> may also denote a 1,4-butadienylene group, R<N> denotes a hydrogen atom or a C1-3-alkyl group which may be mono- or disubstituted in the end by one or two phenyl or pyridinyl groups, substituents can be similar or different, or hydroxyl or methoxy group, phenyl, which can be mono- or disubstituted by fluoro, chloro or bromo, methyl, nitro group, methoxy group, ethoxy group, trifluomethyl, hydroxyl or cyano group, wherein substituents can be similar or different, substituted by methylenedioxy group phenyl, 2-pyridinyl, 4-pyridinyl, amino, benzoylamino, aminocarbonyl, methylaminocarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonylamino group, methylaminocarbonylamino group, N-(aminocarbonyl)-N-methylamino, N-(methylaminocarbonyl)-N-methylamino, N-(aminocarbonyl)-N-(4-fluophenyl)-amino group, N-(methylaminocarbonyl)-N-phenylamino, phenylaminocarbonylamino, [N-phenyl(methylamino)]carbonylamino, N-(phenylaminocarbonyl)-N-methylamino, N-(phenylaminocarbonyl)-N-phenylamino, benzoylaminocarbonylamino, N-(aminocarbonyl)-N-phenylamino group, unsubstituted or substituted in phenyl ring by aminocarbonylamino group or methylsulfonylamino group of phenylamino group, 1,3-dihydro-4-phenyl-2H-2-oxoimidazole-1-yl, 1,3-dihydro-4-(3-thienyl)-2H-2-oxoimidazole-1-yl, 1,3-dihydro-5-phenyl-2H-2-oxoimidazole-1-yl, 1,3-dihydro-2H-2-oxobenzimidazole-1-yl, 1,3,3a,4,5,6,7,7a-octahydro-2(2H)-oxobenzimidazole-1-yl, 1H-indole-3-yl, 2,4(1H,3H)-dioxoquinaziline-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-b]pyridine-3-yl, 1,3(2H)-dioxo-1H-isoindole-2-yl, 1H-benzimidazole-1-yl, 3,4-dihydro-2(1H)-oxoquinazoline-3-yl, 3,4-dihydro-2(1H)-oxoquinazoline-1-yl, 2(3H)-oxobenzoxazole-3-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-d]pyrimidine-3-yl, 2,3,4,5-tetrahydro-2(1H)-oxo-1,3-benzodiazepine-3-yl, 3,4-dihydro-2(1H)-oxopyrido[2,3-d]pyrimidine-3-yl, 2(1H)-oxoquinoxaline-3-yl, 3,4,4a,5,6,7,8,8a-octahydro-2(1H)-oxoquinaziline-3-yl, 1,1-dioxydo-3(4H)-oxo-1,2,4-benzothiadiazine-2-yl, 2,4(1H,3H)-dioxothieno[3,4-d]pyrimidine-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,4-d]pyrimidine-3-yl, 3,4-dihydro-2(1H)-oxothieno[3,2-d]pyrimidine-3-yl, 2,4-dihydro-5-phenyl-3(3H)-oxo-1,2,4-triazole-2-yl, 1,3-dihydro-5-methyl-4-phenyl-2(2H)-oxoimidazole-1-yl, 2,5-dioxo-4-phenyl-imidazolidine-1-yl, 2,5-dioxo-4-(phenylmethyl)imidazolidine-1-yl, 3,4-dihydro-2,2-dioxydo-2,1,3-benzothiadiazine-3-yl, 1,3-dihydro-4-(4-biphenylyl)-2(2H)-oxoimidazole-1-yl, 1,3-dihydro-4-(2-naphtyl)-2(2H)-oxoimidazole-1-yl, 1,3-dihydro-4,5-diphenyl-2(2h)-oxoimidazole-1-yl, 1,3-dihydro-2(2H)-oxoimidazo[4,5-c]quinoline-3-yl, 4-phenyl-2(1H)-oxopyrimidine-1-yl, 4-[3,4-dihydro-2(1H)-oxoquinazoline-3-yl]-1-piperidinyl, 3,4-dihydro-2(1H)-oxopyrido[3,4-d]pyrimidine-3-yl, 3,4-dihydro-2-(1H)-oxopyrido[4,3-d]pyrimidine-3-yl, or 2,3-dihydro-4(1H)-oxoquinazoline-3-yl, wherein over mentioned mono- and biheterocycles of one of nitrogen atoms can be substituted by methoxycarbonylmethyl, and/or over mentioned mono- or biheterocycles in carbonic skeleton and/or in phenyl groups included in this residue can be mono-, di-, or trisubstituted by fluoro, chloro or bromo, methyl, trifluomethyl, methoxy, hydroxyl, amino, nitro, phenyl, phenylmethyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, hydroxyethylaminocarbonyl, (4-morpholinyl)carbonyl, (1-piperidinyl)carbonyl or (4-methyl-1-piperazinyl)-carbonyl, wherein substituents can be similar or different and multiple substitution with help of said last three substituents is excluded, or if Y<1> is not a nitrogen atom and R<5> and R<6> together denote an additional bond, R<N> together with R<7> may also denote the 1,4-butadienylene group, or, if Y<1> is a carbon atom, R<N> together with R<5>, including Y<1>, also denotes a carbonyl group or a saturated or mono-unsaturated 5- or 6-membered 1,3-diaza-heterocycle which may optionally contain one carbonyl group neighboring with one of nitrogen atoms, one of the nitrogen atoms may be substituted by phenyl, or if it is unsaturated, may be benzofused at the double bond; X denotes an oxygen atom or 2 hydrogen atoms, Z denotes a methylene group or the group -NR<1>, wherein R<1> denotes a hydrogen atom or methyl, R<11> denotes a hydrogen atom, methoxycarbonyl, ethoxycarbonyl or methyl, n denotes the number 1 and m is 0; or n denotes the number 0 and m is 1; R<2> denotes a phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydro-1-naphthyl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl, 1-(1,1-dimethylethoxycarbonyl)-1H-indol-3-yl, 2-thienyl, 3-thienyl, thiazolyl, or alkylthiazolyl with 1-3 carbon atoms in alkyl part, pyridinyl or quinolinyl, whilst the above-mentioned phenyl and naphthyl residue can be mono-, di-, or trisubstituted by fluoro, chloro or bromo, branched or unbranched alkyl groups with atom quantity of up to 5, alkoxy groups with 1-3 carbon atoms, vinyl, allyl, trifluomethyl, methylsulfonyloxy, 2-(dimethylamino)ethoxygroup, hydroxyl, cyanogroup, nitro group, or aminogroup, tetrazolyl, phenyl, pyridinyl, thiazolyl or furyl, wherein the substituents can be similar or different and multiple substitution with help of said last five substituents is excluded, A denotes a bond or linked via the carbonyl group to NR<3>R<4> of general formula (I) divalent group of formula(III): wherein R<8>and R<9> together denote an n-propylene group or R<8> denotes a hydrogen atom or methyl and R<9> denotes a hydrogen atom or a unbranched C1-4-alkyl group which, if it is unbranched, may be substituted in the end by a amino, methylamino, dimethylamino, aminoiminomethylamino, or aminocarbonylamino, wherein in the above-mentioned substituents, hydrogen atom linked to nitrogen atom can be substituted by protective group, e.g. phenylmethoxycarbonyl or tret-butyloxycarbonyl, R<3> denotes a hydrogen atom or C1-4-alkyl, unsubstituted or substituted in the end by amino group, methylamino group, dimethylamino group, or 4-(1-piperidinyl)-1-piperidinyl, R<4> denotes a hydrogen, methyl or ethyl, R<3> and R<4> together with the enclosed nitrogen atom denote a group of general formula(V) wherein Y<3> denotes a carbon atom or, if R<12> denotes a free pair of electrons, may also be the nitrogen atom, r denotes the number 1, q denotes the number 1, R<10> denotes a hydrogen atom, alkyl, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonylamino, aminocarbonylalkyl, alkoxycarbonyl, alkoxycarbonylmethyl, carboxymethyl, carboxyl or, cycloalkyl with 4-7 carbon atoms in cycle, benzoil, pyridinylcarbonyl, phenyl, pyridinyl and diazinyl, which in carbonic skeleton can be substituted by fluoro, chloro or bromo, acetyl, methyl, ethyl, methoxy or dimethylaminoalkyl with 1-4 carbon atoms in alkyl part, unsubstituted of substituted in alkyl group by hydroxyl, linked via nitrogen atom 1,3-dihydro-2-oxo-2H-imidazolyl, which can be condensed by double bond with benzoyl or pyridine ring, 1-pyrrolidinyl, 1-piperidinyl, 4-(dimethylamino)-1-piperidinyl, 4-piperidinyl or 4-morpholinyl, wherein nitrogen atom 4-piperidinyl can be substituted by alkanoil or alkyl, correspondingly, with 1-7 carbon atoms, benzoyl, methylsulfonyl, 3-carboxypropionyl, cyclopropylmethyl, alkoxycarbonylmethyl, carboxymethyl or protective group, e.g. phenylmethoxycarbonyl or tret-butyloxycarbonyl, hexahydro-1H-1azepinyl, 8-methyl-8-azabicyclo[3,2,1]oct-3-yl, 4-alkyl-1-piperazinyl, hexahydro-4-alkyl-1H-1,4-diazepine-1-yl, 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl, or R<10> together with R<12> and Y<3> denotes a 5-membered aliphatic ring in which a methylene group may be replaced by an imino group or methylamino group, R<12> denotes a hydrogen atom, a C1-2-alkyl group, which may be substituted in the end by a 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, methoxycarbonyl, ethoxycarbonyl, cyano group, 4-morpholinyl- or hexahydro-1H-1-azepinyl group, a free pair of electrons, if Y<3> denotes a nitrogen atom, and R<13> and R<14> denote a hydrogen atom or, if Y<3> is a carbon atom, R<12> together with R<14> also denotes another carbon-carbon bond, wherein R<10> is as hereinbefore defined and R<13> denotes a hydrogen atom or if Y<3> is a carbon atom, R<12> together with R<14> also denotes another carbon-carbon bond and R<10> together with R<13> and