Patent EA-003096-B1 (EA)
Title: New piperide-4-sulphonamide compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: PEGLION JEAN-LOUIS
IPC: A61P9/08
Filed: 2001-01-30
Abstract: 1. Compounds of formula (I):   wherein: R1 represents a hydrogen atom or a linear or branched C1-C6alkyl group, R2a and R2b, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched C1-C6alkyl group, a hydroxy group, a linear or branched C1-C6alkoxy group, a linear or branched C1-C6trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched C1-C6alkylamino group, and a di-C1-C6alkyl-amino group in which each alkyl moiety is linear or branched, R3 represents a hydrogen atom or a hydroxy group, X represents an oxygen atom or a methylene group, V represents a linear or branched C1-C6alkylene chain optionally containing one or more unsaturations and being optionally substituted by one or more identical or different groups selected from halogen atoms, hydroxy groups and linear or branched C1-C6alkoxy groups, U represents a bond or a linear or branched C1-C6alkylene chain, W represents a group selected from aryl and heteroaryl, each of those groups being optionally substituted by one or more identical or different groups selected from halogen atoms, linear or branched C1-C6alkyl groups, hydroxy groups, linear or branched C1-C6alkoxy groups, linear or branched C1-C6trihaloalkyl groups, oxo groups, cyano groups, nitro groups, amino groups, linear or branched C1-C6-alkylamino groups, di-C1-C6alkylamino groups in which each alkyl moiety is linear or branched, pyridyl groups, linear or branched C1-C6alkylcarbonyl groups, aminocarbonyl groups (the amino moiety being optionally substituted by one or two identical or different linear or branched C1-C6alkyl groups), linear or branched C1-C6alkoxycarbonyl groups, linear or branched C1-C6trihaloalkylcarbonyl groups, linear or branched C1-C6alkylsulphonyl groups, and linear or branched C1-C6-trihaloalkylsulphonyl groups, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: - "aryl group" is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl and indenyl, - "heteroaryl group" is understood to mean a monocyclic aromatic or bicyclic system having from 5 to 12 ring members and containing from 1 to 3 identical or different hetero atoms selected from oxygen, nitrogen and sulphur, and in the case of a bicyclic system one of the rings has an aromatic character, it being possible for the other ring to be aromatic or partially hydrogenated. 2. Compounds of formula (I) according to claim 1, characterised in that X represents an oxygen atom, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 3. Compounds of formula (I) according to claim 1, characterised in that R1 represents a hydrogen atom or a methyl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 4. Compounds of formula (I) according to any one of claims 1 to 3, characterised in that they represent compounds of formula (I/A):   wherein W, U, V, R2a and R2b are as defined for formula (I), their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 5. Compounds of formula (I) according to claim 1, characterised in that W represents an isoquinolin-5-yl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 6. Compounds of formula (I) according to claim 1, characterised in that W represents a 1,2,3,4-tetrahydro-isoquinolin-5-yl group optionally substituted in the 2-position by a group of formula -C(O)-A wherein A represents a group selected from linear or branched C1-C6alkyl, ammo (itself optionally substituted by one or two identical or different linear or branched C1-C6alkyl groups), linear or branched C1-C6alkoxy, trifluoromethyl, linear or branched C1-C6alkylsulphonyl, and trifluoromethylsulphonyl, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 7. Compounds of formula (I) according to claim 4, characterised in that they represent compounds of formula (I/A) as defined hereinbefore wherein U, V, R2a and R2b are as defined for formula (I) and W represents an isoquinolin-5-yl group, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 8. Compounds of formula (I) according to claim 4, characterised in that they represent compounds of formula (I/A) as defined hereinbefore wherein U, V, R2a and R2b are as defined for formula (I) and W represents a 1,2,3,4-tetrahydroisoquinolin-5-yl group optionally substituted in the 2-position by a group of formula -C(O)A wherein A is as defined hereinbefore, their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid. 9. Compounds of formula (I) according to claim 1 which are : -N-{1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}-(isoquinolin-5-yl)sulphonamide, -ethyl 5-{[({(1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl}-3,4-dihydro-2( 1 fl)-isoquinolinecarboxylate, -N-({2-[2-benzofuran-3-yl)ethyl]-4-hydroxy-4-piperidyl}ethyl)-5-isoquinoline-sulphonamide, -N-({1-[2-(benzoruran-3-yl)ethyl]-4-hydroxy-4-piperidyl}methyl)-N-methyl-2,l,3- benzoxadiazole-4-sulphonamide, and -isopropyl 5-{[({1-[2-(benzofuran-3-yl)ethyl]-4-piperidyl}methyl)-(methyl)amino]-sulphonyl} -3,4-dihydro-2(1N)-isoquinolinecarboxylate. 10. Process for the preparation of compounds of formula (I) according to claim 1, characterised in that there is used as starting material a compound of formula (II) :   wherein X, R2a and R2b are as defined for formula (I), V1 represents a bond or a linear or branched C1-C5alkylene chain optionally containing one or more unsaturations, R5 represents a hydrogen atom, a chlorine atom, a hydroxy group or a linear or branched C1-C6alkoxy group, which compounds of formula (II) are reacted: either with a compound of formula (III/A) :   to yield compounds of formula (IV):   wherein R2a, R2b, X and V1 are as defined hereinbefore, the ketal function of which compounds of formula (IV) is deprotected in accordance with conventional techniques of organic synthesis, and which are then reacted under conditions of reductive amination with a compound of formula (V) : R1'-NH2                          (V) wherein R1' represents a linear or branched (C1-C6)alkyl group, to yield compounds of formula (VI/A):   wherein R1', R2a, R2b, X and V1 are as defined hereinbefore, or with a compound of formula (III/B):   wherein Boc represents a /er/'butoxycarbonyl group, to yield compounds of formula (VII) :   wherein Boc, R2a, R2b, X and V1 are as defined hereinbefore, the terminal amine function of which compounds of formula (VII) is deprotected to yield compounds of formula (VI/B):   wherein R2a, R2b, V1 and X are as defined hereinbefore, the totality of the compounds of formulae (VI/A) and (VI/B) constituting the compounds of formula (VI):   wherein R1 is as defined for formula (I) and R2a, R2b, X and V1 are as defined hereinbefore, which compounds of formula (VI) are treated with one of the reducing agents currently used in organic synthesis to reduce amide functions, to yield compounds of formula (VIII):   wherein R1, V1, X, R2a and R2b, are as defined hereinbefore, which compounds of formula (VIII) are treated with a compound of formula (IX): W-SO2C1                          (IX) wherein W is as defined for formula (I), to yield compounds of formula (I/a), a particular case of the compounds of formula (I):   wherein W, R1, V1, X, R2a and R2b are as defined hereinbefore, or with a compound of formula (III/C) :   wherein U1 represents a bond or a linear or branched (C1-C5)alkylene chain, to yield compounds of formula (X):   wherein U1, V1, X, R2a and R2b are as defined hereinbefore, which compounds of formula (X) are treated with ammonium hydroxide or with a compound of formula (V) as defined hereinbefore in the presence of a coupling agent, such as dicyclo-hexylcarbodiimide, carbonyldiimidazole or 1,1,1,3,3,3-hexamethyldisylazane, to yield compounds of formula (XI) :   wherein R1 is as defined for formula (I), and U1, V1, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XI) are reduced in accordance with conventional conditions of organic synthesis, to yield compounds of formula (XII):   wherein U2 represents a linear or branched C1-C6alkylene chain, and R1, V1 X, R2and R2b are as defined hereinbefore, which compounds of formula (XII) are reacted with a compound of formula (IX), as described hereinbefore, to yield compounds of formula (I/b), a particular case of the compounds of formula (I):   wherein W, R1 U2 V1 X, R2and R2b are as defined hereinbefore, 4 m, the terminal carbonyl group of which compounds of formula (II), which group is substituted by a group R5's having the meanings of R5 as defined hereinbefore with the exception of the meaning "chorine atom", is reduced, the resulting hydroxy group of which is then replaced by a halogen atom, such as Cl, Br or I, using customary techniques of organic chemistry, to yield compounds of formula (II/B):   wherein X and V are as defined for formula (I) and Hal represents a halogen atom, which compound of formula (II/B) is added to a compound of formula (III/D):   wherein U2 is as defined hereinbefore, to yield compounds of formula (XIII) :   wherein U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIII) are treated with a reducing agent or with a strong alkaline base, to yield compounds of formula (XIV) :   wherein R1a represents a hydrogen atom or a methyl group, and U2, V, X, R2a and R2b are as defined hereinbefore, which compounds of formula (XIV) are treated with a compound of formula (IX), to yield com