Patent EA-004955-B1 (EA)
Title: NEW CYCLIC alpha-AMINO-gamma-HYDROXYAMIDE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
Inventor: WIERZBICKI MICHEL
IPC: C07D295/18
Filed: 2002-06-17
Abstract: 1. Compound of formula (I): wherein: represents a saturated hydrocarbon ring having from 4 to 8 ring members, optionally substituted by one or more linear or branched (C1-C6)alkyl groups, R1 and R4, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)acyl group, R2 and R3, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, R5 and R6, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, or R5 and R6 together, with the nitrogen atom carrying them, form a nitrogen-containing heterocycle optionally substituted by one or more identical or different groups selected from the groups cyano, CO2R7 (wherein R7 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group), COR7 (wherein R7 is as defined hereinbefore), nitro, CONR8aR8b (wherein R8a and R8b, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group or R8a and R8b together form a nitrogen-containing heterocycle), S(O)nR9 (wherein n represents 1, 2 or 3, and R9 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group or an aryl group) and PO3R10aR10b (wherein R10a and R10b, which may be identical or different, each represents a hydrogen atom or a linear or branched (C1-C6)alkyl group), stereoisomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid, a nitrogen-containing heterocycle being understood as an optionally bridged, saturated mono- or bi-cyclic group having from 5 to 12 ring members and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom or atoms optionally present being selected from the atoms oxygen, nitrogen and sulphur, and an aryl group being understood as phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of those groups optionally being substituted by one or more identical or different atoms or groups selected from the halogen atoms and the groups linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)poly-haloalkyl, nitro and (C1-C2)alkylenedioxy. 2. Compound of formula (I) according to claim 1, wherein represents a hydrocarbon ring having 5 or 6 ring members, stereoisomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 3. Compound of formula (I) according to either claim 1 or claim 2, wherein R5 and R6 together form an optionally substituted nitrogen-containing heterocycle, stereoisomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 4. Compound of formula (I) according to claim 3, wherein R5 and R6 together form an optionally substituted pyrrolidine or an optionally substituted thiazolidine, stereoisomers thereof, and also addition salts thereof with a pharmaceutically acceptable acid. 5. Compound of formula (I) according to claim 1, which is (1R,2S,1'S)-2-[1'-amino-2'-oxo-2'-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1'R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid. 6. Compound of formula (I) according to claim 1, which is (1R*,2R*,1'R*)-2-[1'-amino-2'-oxo-2'-(1-pyrrolidinyl)ethyl]cyclopentanol, and also addition salts thereof with a pharmaceutically acceptable acid, there being understood by (1R*,2R*,1'R*) compound a racemic mixture of the 2 enantiomers having the absolute configurations (1R,2R,1'R) and (1S,2S,1'S). 7. Compound of formula (I) according to claim 1, which is (1R,2S,1'R)-2-[1'-amino-2'-oxo-2'-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S, 2R, 1'S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid. 8. Compound of formula (I) according to claim 1, which is (1R,2S,1'S)-2-[1'-amino-2'-oxo-2'-(1-pyrrolidinyl)ethyl]cyclopentanol, its (1S,2R,1'R) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid. 9. Compound of formula (I) according to claim 1, which is (1R,2S,1'R)-2-[1'-amino-2'-oxo-2'-(1-pyrrolidinyl)ethyl]cyclohexanol, its (1S,2R,1'S) enantiomer, and also addition salts thereof with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to claim 1, which is (1R,2S,1'R)-2-[1'-amino-2'-oxo-2'-(1,3-thiazolidin-3-yl)ethyl]cyclohexanol, its (1S,2R,1'S) enantiomer, 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 chloroacetyl chloride is reacted with a compound of formula (II): HNR5R6,		(II) wherein R5 and R6 are as defined for formula (I), to yield a compound of formula (III): wherein R5 and R6 are as defined hereinbefore, which is converted into an amine of formula (IV): wherein R5 and R6 are as defined hereinbefore, which is reacted with benzaldehyde to yield a compound of formula (V): wherein R5 and R6 are as defined hereinbefore, which is reacted with a compound of formula (VI): wherein , R2 and R3 are as defined for formula (I), to yield, after optional acylation of the hydroxy function, a compound of formula (VII), which is of the relative configuration trans: wherein , R1, R2, R3, R5 and R6 are as defined hereinbefore, which is converted by hydrolysis followed, if desired, by acylation of the amino function, to yield a compound of formula (Ia) of the relative configuration trans, a particular case of the compounds of formula (I): wherein , R1, R2, R3, R4 R5 and R6 are as defined hereinbefore, which is converted, if desired, into a compound of formula (Ib) of the relative configuration cis, a particular case of the compounds of formula (I): wherein , R1, R2, R3, R4 R5 and R6 are as defined hereinbefore, which compounds of formulae (Ia) and (Ib) are separated, if desired, into their isomers by conventional separation techniques, are purified, if necessary, by conventional methods of purification, and are converted, if desired, into addition salts 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 pharmaceutically acceptable, inert, non-toxic carriers. 13. Pharmaceutical composition according to claim 12 for use as a medicament in the treatment of glucose intolerance and of disorders associated with hyperglycaemia, such as type II diabetes or obesity. 14. Pharmaceutical composition according to claim 12 for use as an anti-diabetic medicament.