Patent EA-004865-B1 (EA)
Title: NEW alpha-AMINO ACID COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Inventor: DE NANTEUIL G
IPC: A61K31/426
Filed: 2002-05-14
Abstract: 1. Compound of formula (I): wherein: represents a 5-membered nitrogen-containing heterocycle optionally substituted by a cyano group, Ak represents a linear or branched (C1-C6)alkylene chain, X represents a single bond or a phenylene group, R1 and R2, which may be identical or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, Y represents NR4 or CH-NO2, R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R3 represents: - a group selected from linear or branched (C1-C6)alkyl, nitro and cyano, when Y represents CH-NO2, or - a group selected from nitro and cyano, when Y represents NR4, its tautomers when they exist, its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid, with the exclusion of compounds wherein, simultaneously, represents an unsubstituted 5-membered nitrogen-containing heterocycle, Ak represents the group -(CH2)3-, X represents a single bond, Y represents NH and R3 represents the nitro group, it being understood that the term "5-membered nitrogen-containing heterocycle" is understood to mean a 5-membered saturated monocyclic group containing one, two or three hetero atoms, one of which hetero atoms is the nitrogen atom, and any additional hetero atoms present are selected from the atoms oxygen, nitrogen and sulphur. 2. Compound of formula (I) according to claim 1 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. Compound of formula (I) according to either claim 1 or claim 2 wherein the configuration alpha to the amide function is (S). 4. Compound of formula (I) according to any one of claims 1 to 3 wherein Ak represents the group (CH2)4. 5. Compound of formula (I) according to any one of claims 1 to 3 wherein represents a 1-pyrrolidinyl group substituted by a cyano group, or a 1,3-thiazolidin-3-yl group substituted by a cyano group, and Ak represents the group (CH2)3. 6. Compound of formula (I) according to any one of claims 1 to 5 wherein X represents a single bond. 7. Compound of formula (I) according to any one of claims 1 to 6 wherein Y represents a group NR4, wherein R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group. 8. Compound of formula (I) according to any one of claims 1 to 7 wherein R3 represents the nitro group. 9. Compound of formula (I) according to claim 1 which is N-{(4S)-4-amino-5-[(2S)-2-cyano-1-pyrrolidinyl]-5-oxopentyl}-N'-nitroguanidine, and its optical isomers, its tautomers, and addition salts thereof with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to claim 1 which is N-{(5S)-5-amino-6-[(2S)-2-cyano-1-pyrrolidinyl]-6-oxohexyl}-N'-nitroguanidine, and its optical isomers, its tautomers, and addition salts thereof with a pharmaceutically acceptable acid. 11. Compound of formula (I) according to claim 1 which is N-{(5S)-5-amino-6-(1,3-thiazolidin-3-yl)-6-oxohexyl-N'-nitroguanidine, and its optical isomers, its tautomers, and addition salts thereof with a pharmaceutically acceptable acid. 12. Process for the synthesis of compounds of formula (I) according to claim 1, characterised in that a compound of formula (II): wherein Ak and X are as defined for formula (I), P1 represents an amino-function-protecting group, and P2 represents an amino-function-protecting group other than P1, is reacted with a compound of formula (III): wherein is as defined for formula (I), under conventional peptide coupling conditions, to yield, after deprotection, a compound of formula (IV), wherein , P1, Ak and X are as defined hereinbefore, which is then converted, by conventional organic chemistry reactions, followed by a deprotection reaction, to a compound of formula (I), which is purified, if necessary, according to a conventional purification technique, separated, if desired, into its optical isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid. 13. Pharmaceutical composition comprising as active ingredient a compound according to any one of claims 1 to 11, in combination with one or more inert, non-toxic pharmaceutically acceptable carriers. 14. Pharmaceutical composition according to claim 13 for use as a medicament as a dipeptidyl peptidase IV inhibitor, for use in the treatment of glucose intolerance, and of disorders associated with hyperglycaemia, such as type II diabetes or obesity. 15. Pharmaceutical composition according to claim 14 for use as an antidiabetic medicament.