Patent EA-003426-B1 (EA)
Title: New benzenesulphonamide compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: LAVIELLE GILBERT
IPC: A61K31/4965
Filed: 2001-01-19
Abstract: 1. Benzenesulphonamide derivatives of compounds of formula (I): wherein: n is an integer of from 1 to 3 inclusive, m is an integer of from 0 to 6 inclusive, Ra represents a hydroxy-, linear or branched (C1-C6) alkoxy-, aryloxy- or arylalkyloxy group, R1 and R2 represent independently a hydrogen atom, a halogen atom, an alkyl group, a linear or branched (C1-C6)) alkoxy group, a hydroxy group or a linear or branched (C1-C6))perhaloalkyl group, R3 represents a hydrogen atom or an alkyl, arylalkyl, cycloalkylalkyl, aryl or cycloalkyl group, T1 represents an alkylene, 0-alkylene, alkylene-O- or C1-C3alkylene-O-C1-C3-alkylene group, G represents a G1- or G1-T2-A- group wherein: A represents an aryl group, T2 represents a bond or an alkylene, -O-alkylene, alkylene-O- or C1-C3alkylene-O- C1-C3alkylene group, G1 represents a -NR4R5 group wherein R4 and R5 represent independently a hydrogen atom, or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, cycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or G1 represents a heterocycloalkyl group of formula having from 5 to 7 ring members, wherein Y represents a nitrogen atom, an oxygen atom or a CH or CH2 group and R6 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted diarylalkyl, optionally substituted diarylalkenyl, optionally substituted (aryl)(hydroxy)alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl or optionally substituted heteroarylcarbonylalkyl group, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base, wherein: - the term "alkyl" denotes a linear or branched chain having from 1 to 6 carbon atoms, - the term "alkenyl" denotes a chain having from 2 to 6 carbon atoms and containing from 1 to 3 double bonds, - the term "alkylene" denotes a linear or branched divalent group containing from 1 to 6 carbon atoms, unless specified otherwise, - the term "cycloalkyl" denotes a saturated cyclic group containing from 3 to 8 carbon atoms, - the term "aryl" denotes a phenyl or naphthyl group, - the term "heteroaryl" denotes a mono- or bi-cyclic group having from 4 to 11 ring members that is unsaturated or partially saturated and contains from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur, - the terms "diarylalkyl" and "diarylalkenyl" denote, respectively, alkyl and alkenyl groups as defined hereinbefore, substituted by two identical or different aryl groups as defined hereinbefore, - the term "substituted" relating to aryl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, diarylalkyl, diarylalkenyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl and heteroarylcarbonylalkyl denotes that the groups in question are substituted in the aromatic moiety by one or more halogen atoms, alkyl groups, linear or branched (C1-C6)alkoxy groups, hydroxy groups, cyano groups, nitro groups or amino groups (optionally substituted by one or two alkyl groups), wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group. 2. Compounds of formula (I) according to claim 1, wherein n is 2, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, wherein m is 2, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, wherein R3 represents a hydrogen atom, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1, wherein Ra represents a hydroxy group, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, wherein G1 represents a heterocycloalkyl group of formula their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1, wherein n and m are each 2, Ra represents a hydroxy group, R2 and R3 each represents a hydrogen atom, R1 represents a halogen atom and G1 represents a heterocycloalkyl group of formula wherein Y represents a nitrogen atom or a -CH- or CH2- group and R6 is selected from the groups alkyl, arylcarbonyl, arylcarbonylalkyl, diarylalkenyl, (aryl)-(hydroxy)alkyl, aryl and heteroaryl, their enantiomers and diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compound of formula (I) according to claim 1, that is 3-(6-{[(4-chlorophenyl)-sulphonyl] amino}-3-{2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl}-5,6,7,8-tetrahydro-1 -naphthyl)propanoic acid. 9. Compound of formula (I) according to claim 1, which is 3-(6-{[(4-chlorophenyl)-sulphonyl] amino}-3-{[2-(4-methyl-1-piperazinyl) phenoxy] methyl}-5,6,7,8-tetrahydro-1-naphthyl) propanoic acid. 10. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that there is used as starting material a compound of formula (II): wherein n, m, R1, R2, R3 and T1 are as defined for formula (I), R'a represents a linear or branched (C1-C6)alkoxy group and X1 represents a leaving group, or which, when it is desired to obtain compounds of formula (I) wherein G represents a group G1-T2-A- as defined for formula (I), is treated in basic medium with a compound of formula HO-T2-A-GR, wherein T2 and A are as defined for formula (I) and GR represents a reactive group so selected that it can effect nucleophylic substitution of the leaving group X1 present in the substrate to yield a compound of formula (IV): wherein m, n, R'a, R1, R2, R3, T1, A and T2 are as defined hereinbefore, the hydroxy group of which is converted into a leaving group or into a halogen atom to yield a compound of formula (V): wherein m, n, R'a, R1, R2, R3, T1, A and T2 are as defined hereinbefore and X2 represents a leaving group, which compound of formula (V) is treated in basic medium with a compound of formula G1H,where G1 is as defined for formula (I), to yield a compound of formula (I/a): a particular case of the compounds of formula (I) wherein m, n, R'a, R1, R2, R3, T1, T2, A, and G1 are as defined hereinbefore, which compounds of formulae (I/a) may be subjected to hydrolysis of the ester function, in acid or basic medium according to the reactive groups present in the molecule, to yield a compound of formula (I/b): a particular case of the compounds of formula (I) wherein m, n, R1, R2, R3, and T1are as defined hereinbefore and G is as defined for formula (I), which compounds (Ia), (I/b) and (I/c) constitute the totality of the compounds of formula (I), and: - may, if necessary, be purified according to a conventional purification technique, - are optionally separated into their stereoisomers according to a conventional separation technique, - are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base, wherein, at any moment considered appropriate during the course of the process described above, the carboxylic ester function -COR'a may be hydrolyzed to the corresponding acid, which may be converted again to a different ester as required by the synthesis. 11. Pharmaceutical compositions comprising as active ingredient a compound according to any one of claims 1 to 9 in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. for use in the manufacture of medicaments useful as TXA2 receptor antagonist and 5-HT2 receptor antagonists. 12. Pharmaceutical compositions according to claim 11, comprising an active ingredient according to any one of claims 1 to 9 for use in the manufacture of medicaments useful in the treatment of atherothrombotic cardiovascular disorders, such as myocardial infarction, angina pectoris, cerebral vascular accidents, Raynaud's disease, and also asthma, bronchospasms, migraine and venous disorders.