Patent EA-004678-B1 (EA)
Title: New bicyclic amino-pyrazinone compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: DE NANTEUIL GUILLAUME
IPC: C07D487/04
Filed: 2001-12-14
Abstract: 1. Compounds of formula (I): wherein ( R1 represents a linear or branched (C1-C6)alkyl group optionally substituted by one or more identical or different groups selected from phenyl or pyridyl, ( is tetrahydropyrrol, ( n is an integer such that 1<=n<=6, ( R2 represents any of the following groups: wherein X represents a CH group or a nitrogen atom, R4 represents a hydrogen or halogen atom, R5 represents any one of the groups: RaNHCOHN- wherein Ra represents a hydrogen atom or a linear or branched C1-C6alkyl group, RbSO2NHCO(NH)p-, wherein Rb represents a linear or branched C1-C6alkyl group, p represents 0 or 1, HON(C(NH2)-, HN-C(NHOM)-, Rc-(CH2)m-Y- wherein: Y represents CH2, O, S or RaN, m represents an integer such that 0<=m<=3, Rc represents a saturated or unsaturated heterocycle having 5 or 7 ring members containing from 1 to 4 hetero atoms, selected from oxygen, nitrogen and sulphur, said heterocycle optionally containing at least one carbonyl function and optionally being substituted by one or more identical or different substituents selected from halogen atoms, linear or branched (C1-C6)alkoxy groups and amino groups(optionally substituted by one or two linear or branched (C1-C6)alkyl groups), their isomers, their N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base, there being understood by an "aryl group" phenyl, biphenyl or naphthyl, each of those groups optionally being substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl (optionally substituted by a hydroxy group, a carboxy group, an amino group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups) or a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), linear or branched (C1-C6)alkoxy, hydroxy, linear or branched (C1-C6)trihaloalkyl, linear or branched (C1-C6)trihaloalkoxy, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), linear or branched (C1-C6)alkylcarbonyloxy, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C1-C6)alkyl groups), there being understood by a "heteroaryl group" an aromatic mono- or bi-cyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl (optionally substituted by a hydroxy group, a carboxy group, an amino group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups) or a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)trihaloalkyl, phenyl, amino (optionally N-substituted by one or more linear or branched (C1-C6)alkyl groups), carboxymethoxy and carbamoylmethoxy (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), there being understood by a "cycloalkyl group" a saturated or unsaturated, mono- or bi-cyclic hydrocarbon group having from 3 to 12 ring members, wherein the ring may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, linear or branched (C1-C6)trihaloalkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups) and aryl, there being understood by a "heterocycloalkyl group" a saturated or unsaturated, mono- or bi-cyclic group having from 4 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heterocycle may optionally be substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, linear or branched (C1-C6)trihaloalkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), aryl and diarylmethyl. 2. Compounds of formula (I) according to claim 1, wherein n is 1. 3. Compounds of formula (I) according to claim 1, wherein R2 represents a group. 4. Compounds of formula (I) according to claim 1, wherein R2 represents a group wherein X represents a CH group or a nitrogen atom, R4 represents a hydrogen or halogen atom, R5 represents any one of the groups: RaNHCOHN- wherein Ra represents a hydrogen atom or a linear or branched C1-C6alkyl group, RbSO2NHCO(NH)p-, wherein Rb represents a linear or branched C1-C6alkyl group, p represents 0 or 1, HON(C(NH2)-, HN-C(NHOM)-, Rc-(CH2)m-Y- wherein: Y represents CH2, O, S or RaN, m represents an integer such that 0<=m<=3, Rc represents a saturated or unsaturated heterocycle having 5 or 7 ring members containing from 1 to 4 hetero atoms, selected from oxygen, nitrogen and sulphur, said heterocycle optionally containing at least one carbonyl function and optionally being substituted by one or more identical or different substituents selected from halogen atoms, linear or branched (C1-C6)alkoxy groups and amino groups(optionally substituted by one or two linear or branched (C1-C6)alkyl groups). 5. Compounds of formula (I) according to claim 1, wherein R2 represents a bycyclic system of formula wherein: X represents CH-group or a nitrogen atom, and B, together with the carbon atoms to which it is attached, forms an aryl or a saturated or unsaturated heterocycle having 5 or 7 ring members containing from 1 to 4 hetero atoms, selected from oxygen, nitrogen and sulphur, said heterocycle optionally containing at least one carbonyl function and optionally being substituted by one or more identical or different substituents selected from halogen atoms, linear or branched (C1-C6)alkyl groups, linear or branched (C1-C6)alkoxy groups and amino groups (optionally substituted by one or two (C1-C6)alkyl groups). 6. Compound of formula (1) according to claim 1, which is (6S)-N-{4-[amino(hydroxyimino)methyl]benzyl]-3-[2,2-diphenylethyl)amino-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-alpha]pyrazine-6-carboxamide, its isomers, its N-oxides rind pharmaceutically acceptable addition salts thereof with an acid and pharmaceutically acceptable addition salts thereof with an acid or a base. 7. Compound of formula (I) according to claim 1, which is (6S)-N-{4-[amino(hydroxyimino)methyl]benzyl}-4-oxo-3-{(2-(2-pyridyl)ethyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 8. Compound of formula (I) according to claim 1, which is (6S)-N-[2-({[amino(imino)methyl]amino}oxy)ethyl]-3-[(2,2-diphenylethyl)amino]-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 9. Compound of formula (I) according to claim 1, which is (6S)-4-oxo-N-[(3-oxo-3,4-dihydro-2H-benzoxazin-8-yl)methyl]-3-{[2-(2-pyridyl)ethyl]amino}-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 10. Compound of formula (I) according to claim 1, which is (6S)-4-oxo-3-{[2-(2-pyridyl)ethyl]amino}-N-[2-(2-pyridylmethoxy)benzyl]-4,6,7,S-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 11. Compound of formula (I) according to claim 1, which is (6S)-4-oxo-N-{2-[(2-oxo-3-pyrrolidinyl)oxy]benzyl}-3-{[2-(2-pyridyl)ethyl]ammo}-4,6,7,8-tetrahydropyrrolo[1,2-a] pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 12. Compound of formula (I) according to claim 1, which is (6S)-N-[2-(4,5-dihydro-1H-imidazol-2-ylmethoxy)benzyl]-4-oxo-3-{[2-(2-pyridyl)ethyl]amino}-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 13. Compound of formula (I) according to claim 1, which is (6S)-N[2-(1H-imidazol-2-ylmethoxy)benzyl]-4-oxo-3-{[2-(2-pyridyl)ethyl]amino}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 14. Compound of formula (I) according to claim 1, which is (6S)-N-[1H-indol-6-yl-methyl)-4-oxo-3-{[2-(2-pyridyl)ethyl]ammo}-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide, its isomers, its N-oxides and pharmaceutically acceptable addition salts thereof with an acid or a base. 15. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that a compound of formula (II): wherein A is as defined for formula (I), P1 represents an amino function-protecting group and Bn represents a benzyl group, is reduced using an appropriate reducing agent to yield a compound of formula (III): wherein A, P1 and Bn are as defined hereinbefore, the hydroxy function of which compound of formula (III) is converted into methoxy and then into a cyano function by conventional reactions of organic chemistry to yield, after deprotection of the amino function, a compound of formula (IV): wherein A and Bn are as defined hereinbefore, which compound of formula (IV) is reacted with oxalyl chloride to yield a compound of formula (V): wherein A and Bn are as defined hereinbefore, which compound of formula (V) is reacted with a compound of formula (VI): R1-NH2			 (VI) wherein R1 is as defined for formula (I), to yield a compound of formula (VII): wherein A, Bn and R1 are as defined hereinbefore, which compound of formula (VII) is then converted by catalytic hydrogenation into a compound of formula (VIII) : wherein A and R1 are as defined hereinbefore, which com