Patent EA-005288-B1 (EA)
Title: Carboxamide diazepin derivatives, preparation method, use as medicines, pharmaceutical compositions and use thereof
Inventor: BHATNAGAR NEERJA
IPC: C07D487/04
Filed: 2000-12-21
Abstract: 1. Compounds of formula (I): in which: R1 represents the -C(O)-R5, -SO2-R5 or -C(O)-NR6R5 radical in which R6 represents a hydrogen atom or a linear or branched alkyl radical containing at most 4 carbon atoms and R5 represents a linear or branched alkyl radical containing at most 6 carbon atoms, cycloalkyl radical containing at most 6 carbon atoms, phenyl, naphthyl or a monocyclic heterocyclic radical saturated or unsaturated with 5 or 6 members containing one or more identical or different heteroatoms chosen from O, N or S, the alkyl, phenyl and heterocyclic radicals as defined above for R1, being optionally substituted by one or more radicals chosen from the halogen atoms and the linear or branched alkyl or alkoxy radicals containing at most 4 carbon atoms, hydroxyl, acyl radicals containing at most 7 carbon atoms, trifluoromethyl, cyano, thienyl, phenyl, phenoxy and isoxazolyl radicals; R2 and R7 are such that either R7 represents a hydrogen atom and R2 is such that the group in the compounds of formula (I) represents a so-called natural or non-natural amino acid remainder of structure with the exception of aspartic acid, or R2 and R7 together with the nitrogen and carbon atoms to which they are linked form a ring in such a way that the group thus formed in the compounds of formula (I): represents so-called natural or non-natural amino acid remainder of structure: R3 represents the -CH-N2 radical or the -CH2-L-R4 radical in which L represents a single bond or a divalent radical chosen from -O-, -O-C(O)-, -NH- and -S-(CH2)n-, with n representing an integer from 0 to 6, and R4 represents a linear or branched alkyl radical containing at most 6 carbon atoms or a monocyclic or bicyclic carbocyclic or heterocyclic radical containing from 5 to 10 members, saturated or unsaturated, containing one or more identical or different heteroatoms chosen from O, N, NH or S and able to contain a -C(O) member, the alkyl, carbocyclic and heterocyclic radicals as defined above for R4, being optionally substituted by one or more radicals chosen from the halogen atoms; the hydroxyl; free, salified or esterified carboxy; -C(O)-NH2, -C(O)-NH(alkyl), -C(O)-N(alkyl)(alkyl), -NH-C(O)-(alkyl), -N(alkyl)-C(O)-(alkyl); thienyl; phenyl; alkylphenyl; alkyl and alkoxy radicals themselves optionally substituted by one or more radicals chosen from the acyl radicals containing at most 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals, it being understood that in the above radicals, the alkyl and alkoxy radicals are linear or branched and contain at most 4 carbon atoms, the * sign indicating the carbon atoms which can be in S or R configuration, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (I). 2. Compounds of formula (1) as defined in claim 1 in which R1 and R3 have the meanings indicated in claim 1 and R2 represents a so-called natural amino acid remainder with the exception of aspartic acid, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (I). 3. Compounds of formula (I) as defined in any one of claims 1 and 2 in which R1 and R3 have the meanings indicated in claim 1 or 2 and R2 and R7 are such that: either R7 represents a hydrogen atom and R2 represents a hydrogen atom or a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted by one or more radicals chosen from the amino; acylamino; NH-C(NH2)-NH-; mercapto; linear or branched alkylthio radical containing at most 4 carbon atoms; hydroxyl; linear or branched alkoxy radical containing at most 4 carbon atoms; imidazolyl; indolyl; phenyl radical itself optionally substituted by one or more radicals chosen from the halogen atoms, the hydroxyl radical, a linear or branched alkoxy radical containing at most 4 carbon atoms and the phenoxy radical itself optionally substituted by one or more radicals chosen from the iodine atoms and the hydroxyl radical; and the -C(O)-O-R8 radical in which R8 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 6 carbon atoms, or R2 and R7 together with the nitrogen and carbon atoms to which they are linked form a ring comprising 5 to 7 members optionally substituted by one or more hydroxyl or linear or branched alkoxy radicals containing at most 4 carbon atoms, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (I). 4. Compounds of formula (I) as defined in any one of claims 1 to 3 in which R1 and R3 have the meanings indicated in any one of claims 1 to 3, R2 and R7 are such that: either R7 represents a hydrogen atom and R2 has the meaning indicated in claim 3 or R2 and R7 together with the nitrogen and carbon atoms form a pyrrolidinyl ring optionally substituted by one or more hydroxyl or linear or branched alkoxy radicals containing at most 4 carbon atoms, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (I). 5. Compounds of formula (I) as defined in any one of claims 1 to 3 corresponding to formula (Ia): in which R1a represents the -C(O)-R5a, -SO2-R5a or -C(O)-NR6aR5a radical in which R6a represents a hydrogen atom or a linear or branched alkyl radical containing at most 4 carbon atoms and R5a represents a radical chosen from the linear or branched alkyl radicals containing at most 6 carbon atoms; cycloalkyl radical containing at most 6 carbon atoms; phenyl; naphthyl; furyl; morpholinyl; thienyl; pyridyl radicals; the alkyl, phenyl, thienyl and pyridyl radicals being optionally substituted by one or more radicals chosen from the halogen atoms and the linear or branched alkyl or alkoxy radicals containing at most 4 carbon atoms, hydroxyl, acyl radicals containing at most 7 carbon atoms, phenoxy, trifluoromethyl, cyano, thienyl, phenyl and isoxazolyl radicals; R2a has the meaning indicated in any one of claims 1 to 4 when R7 represents a hydrogen atom, R3a represents the -CH-N2 radical or the -CH2-La-R4a radical in which La represents a single bond or a divalent radical chosen from -O-, -O-C(O)- and -S-(CH2)na-, with na representing an integer from 0 to 3, and R4a represents a radical chosen from the linear or branched alkyl radicals containing at most 6 carbon atoms; phenyl; tetrazolyl; piperazinyl; piperidyl; pyridyl; benzothiazolyl; quinolyl; thiadiazolyl; pyrimidinyl; tetralone radicals; the alkyl, phenyl, tetrazolyl, piperazinyl and piperidyl radicals as defined above for R4a, being optionally substituted by one or more radicals chosen from the halogen atoms; the hydroxyl; free, salified or esterified carboxy radicals; -C(O)-NH2; -C(O)-NH(alkyl); -C(O)-N(alkyl)(alkyl); -NH-C(O)-(alkyl); -N(alkyl)-C(O)-(alkyl); thienyl; phenyl; alkylphenyl; alkyl and alkoxy radicals themselves optionally substituted by one or more radicals chosen from the acyl radicals containing at most 7 carbon atoms, cyano, -NH2, -NH(alkyl), -N(alkyl)(alkyl) and phenyl radicals, it being understood that in the above radicals, the alkyl and alkoxy radicals are linear or branched and contain at most 4 carbon atoms, said products of formula (Ia) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or mineral and organic bases of said products of formula (Ia). 6. Products of formula (I) as defined in any one of claims 1 to 5 corresponding to formula (Ib): in which: R1b represents the -C(O)-R5b, -SO2-R5b or -C(O)-NR6bR5b radical in which R6b represents a hydrogen atom or a methyl radical and R5b represents a radical chosen from the linear or branched alkyl radicals containing at most 4 carbon atoms optionally substituted by a thienyl; cyclohexyl; phenyl radical optionally substituted by a linear or branched alkoxy radical containing at most 4 carbon atoms, a phenoxy or trifluoromethyl; naphthyl; furyl; morpholinyl; thienyl radical optionally substituted by an isoxazolyl radical; pyridyl radical optionally substituted by a trifluoromethyl radical; R2b represents a hydrogen atom or a linear or branched alkyl radical containing at most 6 carbon atoms optionally substituted either by the phenyl radical itself optionally substituted by the hydroxyl or linear or branched alkoxy radicals containing at most 4 carbon atoms, or by the -C(O)-O-R8b radical in which R8b represents a linear or branched alkyl or alkenyl radical containing at most 6 carbon atoms,; R3b represents the -CH-N2 radical or the -CH2-Lb-R4b radical in which Lb represents a single bond or a divalent radical chosen from -O-, -O-C(O)- and -S-(CH2)nb-, with nb representing the integer 0 or 1, and R4b represents a radical chosen from the pyridyl; benzothiazolyl; quinolyl; thiadiazolyl; pyrimidinyl; tetralone; linear or branched alkyl radicals containing at most 4 carbon atoms optionally substituted by a free, salified or esterified carboxy or thienyl radical; phenyl optionally substituted by one or more radicals chosen from the halogen atoms, the free, salified or esterified carboxy radicals, the linear or branched alkyl and alkoxy radicals containing at most 4 carbon atoms, cyanoalkyl, alkylphenyl, -NH-C(O)-CH3, -C(O)-N(alkyl)(alkyl); tetrazolyl radicals optionally substituted by a phenyl radical; piperazinyl optionally substituted on the second nitrogen atom by a phenyl or linear or branched alkyl radical containing at most 4 carbon atoms themsel