Patent EA-002645-B1 (EA)
Title: New 2,3-methano-amino acid compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: DE NANTEUIL GUILLAUME
IPC: C07D221/04
Filed: 2000-04-27
Abstract: 1. Compound of formula (I):   wherein: n represents 2 or 3, R1 represents a (C3-C8)cycloalkyl group, an optionally substituted phenyl group or a linear or branched (C1-C6)alkyl group optionally substituted by one or more identical or different groups selected from halogen, (C3-C8)cycloalkyl and optionally substituted phenyl, R2 represents: - an amino group, - an amidino group optionally substituted by one or more identical or different groups selected from linear or branched (C1-C6)alkyl and hydroxy, - a guanidino group optionally substituted by a linear or branched (C1-C6)alkyl group,or - an isothioureido group optionally substituted by a linear or branched (C1-C6)alkyl group, Ar represents an aryl group or a monocyclic nitrogen-containing heteroaryl group, X1 represents a hydroxy group, an amino group or an -NHR3 group, R3 represents a propargyl group; an iminomethyl group, a linear or branched (C1-C6)alkylsulphonyl group, a linear or branched aryl(C1-C6)alkylsulphonyl group, a -CONR'3R''3 group or a linear or branched (C1-C6)alkyl group optionally substituted by: - a -CO2R'3 group, - a -CONR'3R''3 group, - a heterocyclic group, - an aminosulphonyl group, - an aryl group, or - a heteroaryl group, * R'3 and R"3, which may be identical or different, each represents a hydrogen atom, or a linear or branched (C1-C6)alkylsulphonyl group, an aryl group, a linear or branched (C1-C6)alkyl group (optionally substituted by a carboxy group, a linear or branched (C1-C6)alkoxycarbonyl group or a carbamoyl group) or form, with the nitrogen atom carrying them, a heterocyclic group, isomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid or base, on the understanding that the term "optionally substituted phenyl" means substituted by one or more identical of different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, linear or branched trihalo-(C1-C6)alkyl and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), the term "heterocyclic group" denotes a saturated or unsaturated, 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, it being understood that the heterocycle may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, oxo, hydroxy, linear or branched trihalo(C1-C6)alkyl groups and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), the term "aryl" means phenyl, biphenylyl or naphthyl, each of those groups being optionally 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 trihalo(C1-C6)alkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups) and carboxy, and the term "heteroaryl group" denotes an aromatic mono- or bicyclic group having from 5 to 12 ring members containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, it being understood that heteroaryl may be optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, trihalomethyl and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). 2. Compound of formula (I) according to Claim 1, wherein R1 represents a (C3-C8))cycloalkyl group or an optionally substituted linear or branched (C1-C6)alkyl group. 3. Compound of formula (I) according to Claim 1, wherein R2 represents an amino or amidino group. 4. Compound of formula (I) according to Claim 1, wherein Ar represents an optionally substituted phenyl group or an optionally substituted pyridyl group. 5. Compound of formula (I) according to Claim 1, wherein X1 represents an amino group or an -NHR3 group, wherein R3 represents a linear or branched aryl (C1-C6)alkylsulphonyl group or an optionally substituted, linear or branched (C1-C6)alkyl group. 6. Compound of formula (I) according to Claim 1, which is 1-[(2R)-3,3-diphenylalanyl]-N-(4-amidinobenzyl)-(2S,3R)-2,3-methano-prolinamide, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 7. Compound of formula (I) according to Claim 1, which is 1-[N-carboxymethyl-(2R)-cyclohexylglycyl]-N-(4-amidinobenzyl)-(2S,3R)-2,3-methanoprolinamide, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 8. Compound of formula (I) according to Claim 1, which is 1-[(2R)-3-cyclohexylalanyl]-N-[(6-amino-2-methyl-3-pyridyl)methyl]-(2S,3R)-2,3-methanohomoprolinamide,its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 9. Compound of formula (I) according to Claim 1, which is 1-[N-methyl-(2R)-3-cyclohexylalanyl]-N-[(6-amino-2-methyl-3-pyridyl)methyl]-(2S,3R)-2,3-methanohomoprolinamide, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to Claim 1, which is 1-[(2R)-3,3-diphenylalanyl]-N-(4-amidinobenzyl)-(2S,3R)-2,3-methanohomoprolinamide, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 11. Compound of formula (I) according to Claim 1, which is 1-[(2R)-3,3-dicyclohexylalanyl]-N-[(6-amino-2-methyl-3-pyridyl)methyl]-(2S,3R)-2,3-methanohomoprolinamide, its isomers, and also addition salts thereof with a pharmaceutically acceptable acid. 12. Process for the preparation of compounds of formula (I) according to Claim 1, characterized in that a compound of formula (II):   wherein n is as defined for formula (I) and Bn represents a benzyl group, is reacted  with a compound of formula (III):   wherein R1 is as defined for formula (I), X2 represents an oxygen atom or -NH-, and P1 represents an amino function-protecting or hydroxy function-protecting group, in the presence of a peptide coupling agent, to yield a compound of formula (IV):   wherein n, R1, X2, Bn and P1 are as defined hereinbefore, which compound of formula (IV) is then converted, by catalytic hydrogenation or by hydrolysis, into a compound of formula (V):   wherein n, R1, X2 and P1 are as defined hereinbefore, which compound of formula (V) is then subjected to reaction with a compound of formula (VI):   wherein Ar is as defined for formula (I) and R4 represents R2 or R2-P2, R2 being as defined for formula (I) and P2 representing an amino function-protecting group, in the presence of a peptide coupling agent, to yield a compound of formula (VII) :   wherein n, R1, R4, Ar, X2 and P1 are as defined hereinbefore, which compound of formula (VII) is then converted into a compound of formula (I) by one or more deprotection, alkylation or reductive animation reactions, which compound of formula (I) is purified, if necessary, according to a conventional purification technique, is separated, if desired, into its isomers according to a conventional separation technique, and is converted, if desired, into an addition salt with a pharmaceutically acceptable acid or base. 13. Pharmaceutical composition comprising as active ingredient a compound according to any one of Claims 1 to 11, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 14. Pharmaceutical composition according to Claim 13 for use as a trypsin-related serine protease inhibitor. 15. Pharmaceutical composition according to Claim 14 for use as a thrombin inhibitor.