Patent EA-004591-B1 (EA)
Title: NEW alpha-AMINO ACID SULPHONYL COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
Inventor: DE NANTEUIL GUILLAUME
IPC: A61P37/06
Filed: 2002-03-27
Abstract: 1. Compound of formula (I) : wherein: represents a 5-membered, nitrogen-containing heterocycle optionally substituted by a cyano group, R1 represents a hydrogen atom or a linear or branched (C1-C6)alkyl, linear or branched (C1-C6)acyl, prolyl, alanyl, histidylprolyl or phenylalanylprolyl group, Ak represents a linear or branched (C1-C6)alkylene chain or a heteroalkylene chain, X represents a single bond or a phenylene group optionally substituted by one or more identical or different groups selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy and linear or branched (C1-C6)polyhaloalkyl groups, R2 represents a linear or branched (C1-C6)alkyl group (optionally substituted by one or more identical or different groups selected from aryl, linear or branched (C1-C6)alkylsulphonyl, (C3-C7)cycloalkylsulphonyl, (C3-C7)cycloalkyl group and halogen atoms), a (C3-C10)cycloalkyl group, or -NR2aR2b, wherein R2a and R2b, which may be (the same or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group or together with the nitrogen atom carrying them, form a nitrogen-containing heterocycle, Y represents a group -NR3-, x R3 represents a hydrogen atom or a group selected from linear or branched (C1-C6) alkyl group, (C3-C7) cycloalkyl and aryl, x R4, R5 and R6, which may be the same or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, or R4 and R6, or R5 and R6, together with the atoms carrying them, form an imidazolidine or dihydrobenzimidazole ring, its optical isomers and addition salts thereof with a pharmaceutically acceptable acid, a nitrogen-containing heterocycle being understood to mean a saturated, monocyclic, 5- to 7-membered group containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms, and a heteroalkylene chain being understood to mean a linear or branched (C1-C6) alkylene chain wherein a -CH2 member has been replaced by an oxygen or sulphur atom. 2. Compound of formula (I) according to claim I, wherein represents a 1-pyrrolidinyl group optionally substituted by a cyano group, or a 1,3-thiazolidin-3-yl group optionally substituted by a cyano group. 3. Compounds of formula (I) according to either claim 1 or claim 2, wherein X represents a single bond. 4. Compound of formula (I) according to any of one claims 1 to 3, wherein the configuration a to the amide function is (S). 5. Compound of formula (I) according to any one of claims 1 to 4, wherein R2 represents a linear or branched (C1-C6)alkyl group and Y represents a group 6. Compound of formula (I) according to any one of claims 1 to 4, wherein R2 represents a (C3-C10)cycloalkyl group and Y represents an -NH- group. 7. Compound of formula (I) according to claim 1, which is (S)-1-[N<5>-{(imino)-(methylsulphonylamino)-methyl}-ornithyl]-pyrrolidine, its optical isomers and addition salts thereof with a pharmaceutically acceptable acid. 8. Compound of formula (I) according to claim 1, which is (S)-N-[4-amino-5-oxo-5-(1-pyrrolidinyl)-pentyl]-cyclohexanesulphonamide, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid. 9. Compound of formula (I) according to claim 1, which is (2S)-2-cyano-1-[N<5>-{(imino)-(methylsulphonylamino)-methyl}-(S)-ornihyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to claim 1, which is (2S)-2-cyano-1-[N<6>-{(imino)-(methylsulphonylamino)-methyl}-(S)-lysyl]-pyrrolidine, its optical isomers and also addition salts thereof with a pharmaceutically acceptable acid. 11. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that a compound of formula (fl) wherein Ak, X and Y are as defined for formula (I), R'1 represents a protecting group for the amino function, or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)acyl group, a prolyl group optionally protected by an amino-function-protecting group, an alanyl group optionally protected by an amino-function-protecting group, a histidylprolyl group optionally protected by an amino-function-protecting group, or a phenylalanylprolyl group optionally protected by an amino-function-protecting group, and P2 represents a hydrogen atom or a protecting group for the amino function, is reacted with a compound of formula (III): wherein is as defined for formula (I), under conventional conditions of peptide coupling, to yield, after deprotection - where necessary - of the group Y, the compound of formula (IV): wherein , Ak, X, Y and R'1 are as defined hereinbefore, winch is then reacted with a compound of formula (V): R2-SO2-Z1			(V), wherein R2 is as defined for formula (I) and Z1 represents a leaving group such as, for example, a halogen atom, to yield, after deprotection where necessary, the compound of formula (I), which is purified, where appropriate, according to a conventional purification technique, which is separated, if desired, into its optical isomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid. 12. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 10, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 13. Pharmaceutical composition according to claim 12 for use as a medicament as an inhibitor of dipeptidyl-peptidase IV, for use in the treatment of glucose intolerance and of disorders associated with hyperglycaemia such as type II diabetes or obesity, in the prevention of transplant rejection after transplantation, in the treatment of cancer and the prevention of cancerous metastases, in the treatment of AIDS and of periodontitis, and also in recovery of the intestine after resection. 14. Pharmaceutical composition according to claim 12 for use as an antidiabetic medicament.