Patent EA-003209-B1 (EA)
Title: New bicyclic amino-pyrazinone compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: DE NANTEUIL GUILLAUMM
IPC: C07K5/078
Filed: 2000-06-14
Abstract: 1. Compound of formula (I): wherein: R<1> represents a hydrogen atom or a linear or branched (C1-C6)alkyl group (optionally substituted by one or more identical or different substituents selected from aryl, heteroaryl, cycloalkyl, heterocycloalkyl, carboxy, linear or branched (C1-C6)-alkoxycarbonyl, and carbamoyl groups), a hydroxy group, a cycloalkyl group, a heterocycloalkyl group or a group of formula (G): wherein A1 represents a single bond, while a ring containing A1 is a 5-membered ring, or -CH2-, -CH2-CH2- or -N(CH3)- groups or an oxygen or sulphur atom, and X1 and X2, which may be identical or different, each represent a carbon or nitrogen atom, R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, represents a saturated ring having from 4 to 7 ring members that may contain in addition to the nitrogen atom one or two hetero atoms selected from O and S, or -N(R2) groups, R2 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, n represents an integer wherein 1.<= n <= 6, Ar represents an aryl or heteroaryl group, their isomers, their N-oxydes and addition salts thereof with a pharmaceutically acceptable acid or base, "aryl group" is understood to mean phenyl, biphenylyl or naphthyl, each of those groups being optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C1-C6)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), linear or branched (C1-C6)alkoxy, hydroxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, trihalogenoalkoxy in which the alkyl moiety is linear or branched, ammo (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), linear or branched alkylcarbonyloxy group, carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C1-C6)alkyl groups), "heteroaryl group" is understood to mean a mono- or bi-cyclic aromatic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heteroaryl may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C1-C6)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), hydroxy, linear or branched (C1-C6)alkoxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, 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), "cycloalkyl group" is understood to mean a saturated or unsaturated mono- or bi-cyclic hydrocarbon group having from 3 to 12 ring members, it being understood that the ring system may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups) and aryl, and "heterocycloalkyl group" being understood to mean a saturated or unsaturated mono-or bi-cyclic group having from 4 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that the heterocycle may be optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), aryl and diarylmethyl. 2. Compound of formula (I) according to claim 1 wherein n is 1. 3. Compound of formula (I) according to claim 1 wherein represents a pyrrolidinyl group. 4. Compound of formula (I) according to any one of claims 1 to 3 wherein Ar represents a phenyl or pyridyl group, each of those groups being optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (C1-C6)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), linear or branched (C1-C6)alkoxy, hydroxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C1-C6)alkyl groups). 5. Compound of formula (I) according to claim 4 wherein Ar represents a pyridyl group optionally substituted by one or more halogen atoms and/or by one or more identical or different groups selected from linear or branched (Ci-C6)alkyl (optionally substituted by a hydroxy or carboxy group or by a carbamoyl group (itself optionally substituted by one or two linear or branched (C1-C6)alkyl groups)), linear or branched (C1-C6)alkoxy, hydroxy, trihalo-( C1-C6)alkyl in which the alkyl moiety is linear or branched, amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), carboxymethoxy and carbamoylmethoxy (optionally N-substituted by one or two linear or branched (C1-C6)alkyl groups). 6. Compound of formula (I) according to claim 1 which is (65)-N-[(6-amino-2-methyl-3-pyridyl)methyl]-4-oxo-3-(2-phenethylamino)-4,6,7,8-tetrahydropyrrolo[l,2-a]-pyrazine-6-carboxamide, its isomers and its addition salts with a pharmaceutically acceptable acid. 7. 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 to the methoxy function and then to the cyano function by conventional organic chemistry reactions, 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 to a compound of formula (VIII): wherein A and R1 are as defined hereinbefore, which compound of formula (VIII) is then converted by catalytic hydrogenation in an alkaline medium to a compound of formula (IX): wherein A and R1 are as defined hereinbefore, which compound of formula (IX) is reacted with a compound of formula (X): wherein n and Ar are as defined for formula (I), to yield, after deprotection where appropriate, a compound of formula (I), which compound of formula (I) is purified, if necessary, according to a conventional purification technique, separated, if desired, into its isomers according to a conventional separation technique, and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base. 8. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 6 in combination with one or more inert, non-toxic pharmaceutically acceptable carriers. 9. Pharmaceutical composition according to claim 8 for use as an inhibitor of trypsin-related serine proteases. 10. Pharmaceutical composition according to claim 9 for use as a thrombin.