Patent EA-005093-B1 (EA)
Title: Indolin-2-one derivatives, preparation and their use as ocytocin receptor ligands
Inventor: FOULON LOIC
IPC: A61P5/10
Filed: 2001-04-02
Abstract: 1. A compound in the form of pure enantiomer or a mixture of enantiomers of formula: in which: -R0 represents a group selected from: 1): in which: -Z1 represents a chloro, bromo, iodo or fluoro atom or a (C1-C4) alkyl, (C1-C4) alkoxy or trifluoromethyl group; -Z2 represents hydrogen, chloro, bromo, iodo or fluoro atom or (C1-C4) alkyl, (C3-C5) cycloalkyl, (C1-C4) alkoxy, (C3-C5)cycloalkoxy, or polyfluoro(C1-C4) alkyl group; -R5 represents T1, W, where T1 represents -(CH2)m, m may be equal 0 or 1, W represents a hydrogen atom, or a hydroxycarbonyl (or carboxyl), (C1-C4) alkoxycarbonyl, 1,3-dioxolan-2-yl, or 1,3-dioxan-2-yl group, or otherwise W represents a -NR6R7, in which R6 and R7 represent, independently of one another, a hydrogen atom, an (C1-C4) alkyl, an (C1-C4) alkylsulfonyl or a phenylsulfonyl group, in which the phenyl group may be mono, di- or trisubstituted by a Z5 substituent; or otherwise R6 and R7 form together with a nitrogen atom with they are bound a morpholinyl group, optionally substituted by a (C1-C4) alkyl group or oxo, or otherwise R6 and R7 form together with a nitrogen atom with they are bound a piperazinyl group, optionally substituted by a Z3 substituent in position 4, or otherwise R6 and R7 form together with a nitrogen atom with they are bound a pyrrolidinyl or piperidinyl group, wherein said pyrrolidinyl and piperidinyl groups may be optionally substituted by a Z4 substituent; or otherwise W represents a -NR8COR9 group, in which R8 represents a hydrogen atom or a (C1-C4) alkyl group and R9 represents a hydrogen atom, a (C1-C4) alkyl group, benzyl, pyridyl or phenyl group, said phenyl group may be mono, di- or trisubstituted by a Z5 substituent; or otherwise R9 represents -NR10R11, in which R10 and R11 represent, independently of one another, a hydrogen atom or a (C1-C4) alkyl group, or otherwise R10 and R11 form together with a nitrogen atom, with which they are bound, pyrrolidinyl, piperidinyl, or morpholinyl group, optionally substituted by a (C1-C4) alkyl group, or otherwise R9 represents a pyrrolidin-2-yl or 3 yl group, or piperidin-2-yl, 3-yl or 4-yl group, said pyrrolidinyl and piperidinyl groups being optionally substituted by a Z7 substituent; or otherwise R9 represents a ungroupe-T2-R12 or -T2-COR12, in which T2 represents- (CH2)n-, where n may be 1, 2, 3 and 4, and R12 represents a (C1-C4)alkoxy group or -NR10R11, where R10 and R11 are as defined above; or otherwise W represents a -CONR13R14 group, in which R13 represents a hydrogen atom, a (C1C4) alkyl group, (C3-C7) cycloalkyl, a mono- or polyfluoro(C1-C4) alkyl group, and R14 represents a hydrogen atom, a (C1-C4) alkyl group, a phenyl group, optionally substituted by a Z5, a -T4-R15 group, in which T 4 represents -(CH2)q-, where q is 1, 2, 3 or 4 and R15 represents a hydroxyl group, a (C1-C4) alkoxy group, (C1-C4)alkoxycarbonyl group, (C1-C4) alkoxycarbonylamino group, a phenyl group, optionally mono- or disubstituted by a Z5 substituent, a pyrid-2-ye, 3-yl or 4-yl groups, a -NR16R17 group, in which R16 and R17 represent, independently of one another, a hydrogen atom, or a(C1-C4) alkyl group, or otherwise R16 and R17 form with a nitrogen atom, to which they are bound, a morpholinyl group, optionally mono or disubstituted by a (C1-C4) alkyl group, or otherwise R16 and R17 form with a nitrogen atom, to which they are bound, a piperazinyl group, optionally substituted by a Z3 substituent in position 4, or otherwise R16 and R17 form with a nitrogen atom, to which they are bound, a pyrrolidinyl or piperidinyl groups, wherein said pyrrolidinyl and piperidinyl groups being optionally substituted by a Z 5 substituent and understood, that when g is 1, R15 is other than hydroxyl, (C1-C4)alkoxy, (C1-C4) alkoxycarbonylamino, -NR16R17; or otherwise R13 and R14 form with a nitrogen atom, to which they are bound, a morpholinyl group, optionally mono or disubstituted by a(C1-C4) alkyl group, a piperazinyl group, optionally substituted by a Z3 in position 4; or otherwise R13 and R14 form with a nitrogen atom, to which they are bound, a azetidinyl, pyrrolidinyl, piperidinyl or hexahydroazepinyl group, said pyrrolidinyl, piperidinyl and hexahydroazepinyl groups being optionally mono or disubstituted by Z8 substituent; or otherwise W represents a OR18 group, in which R18 represents a hydrogen atom or an (C1-C4) alkyl group, (C1-C4)alkoxy(C1-C4)alkyl group or -T3-R19 group, in which T3 represents -(CH2)p-, where p is 2, 3 and R19 is selected from a hydroxyl group, a triphenylmethoxy group or a -NR20R21 group, in which R20 represents a hydrogen atom or a (C1-C4) alkyl group and R21 represents a hydrogen atom, a (C1-C4)alkyl group, a tetrahydrofuranylmethyl or tetrahydropyranylmethyl group, or otherwise R20 and R21 R17 form with a nitrogen atom, to which they are bound, a morpholinyl group, optionally mono or disubstituted by a (C1-C4) alkyl group, a piperazinyl group, optionally substituted by a Z3 substituent in position 4, or otherwise R20 and R21 form with a nitrogen atom, to which they are bound, a pyrrolidinyl or piperidinyl group, said pyrrolidinyl and piperidinyl groups being optionally substituted by a Z5 substituent; -Z3 represents a (C1-C4) alkyl group, pyridyl, phenyl, a (C1-C4) alkylcarbonyl, (C1-C4) alkoxycarbonyl group; -Z4 represents an oxo, a fluorine atom, a hydroxyl, a (C1-C4) alkyl, a benzyl, an amino, a (C1-C4) alkylamino, an di(C1-C4) alkylamino, an (C1-C4) alkoxy, an (C1-C4) alkoxycarbonyl, an (C1-C4) alkoxycarbonylamino; -Z5 represents a chlorine, bromine, iodine or fluorine atom, a hydroxyl group, a (C1-C4)alkyl group or an (C1-C4)alkoxy group; -Z7 represents a fluorine atom, a hydroxyl group, an hydroxy(C1-C4) alkyl group, an (C1-C4) alkyl group, an (C1-C4) alkoxy group, an (C1-C4) alkylcarbonyl group; -Z8 represents a fluorine atom, a hydroxyl group, (C1-C4) alkyl, (C3-C6) cycloalkyl, benzyl, amino, (C1-C4) alkylamino, di(C1-C4) alkylamino, (C1-C4) alkoxycarbonyl, (C1-C4) alkoxycarbonylamino, (C3-C6) cycloalkoxy, hydroxycarbonyl, hydroxy(C1-C4) alkyl or (C1-C4) alkoxy(C1-C4) alkyl, (C1-C4)alkoxy group or a -CONR23R24 group, in which R23 and R24 represent, independently of one another, a hydrogen atom, an (C1-C4) alkyl, a mono or polyfluoro (C1-C4) alkyl or otherwise R23 and R24 form with a nitrogen atom, to which they are bound, a pyrrolidinyl or piperidinyl group, said pyrrolidinyl or piperidinyl groups being optionally substituted by a Z3 substituent or a difluoromethyliden; 2): -Z6 represents a chlorine atom or a (C1-C4) alkyl group or (C1-C4)alkoxy group; -R1 represents an (C1-C4) alkyl group, optionally comprising a double or a triple bond, a (C1-C4) alkoxycarbonyl group, a phenyloxycarbonyl group or a T1-R22 group, in which T1 is as defined above, and R22 represents a hydroxyl group or (C1-C4) alkoxy group; - R2 and R4 represent, independently of one another, a hydrogen, chlorine or fluorine atom, or an (C1-C4) alkyl group or (C1-C4) alkoxy group; -R3 represents a chlorine or fluorine atom, an (C1-C4) alkyl, (C1-C4) alkoxy, hydroxyl, (C1-C4) carbamoyl, (C1-C4) alkylcarbonylamino, nitro, cyano, trifluoromethyl, amino, (C3-C6) cycloalkylamino, (C1-C4)alkylamino, di(C1-C4) alkylamino, tri(C1-C4) alkylammonium A<->, wherein A<-> is an anion, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl or hexahydroazepin-1-yl; -X and Y represent, independently of one another, a hydrogen, chlorine, bromine, iodine or fluorine atom or an (C1-C4) alkoxy or trifluoromethoxy group and their pharmaceutically acceptable salts, solvates and hydrates thereof. 2. A compound in the form of pure enantiomer or a mixture of enantiomers of formula: in which: -R0 represents a group selected from: 1): in which: Z1, Z2, R1, R2, R3, R4, R5, Y and X are as defined for (I) and their pharmaceutically acceptable salts, solvates and hydrates thereof. 3. Compounds according to claim 2 of the formula: in which R1 represents a methyl or hydroxyl group, and R0, R2, R3, R4, Y and X are as defined for (I) in the form of pure enantiomers or a mixture of enantiomers, and their pharmaceutically acceptable salts, solvates and hydrates thereof. 4. Compounds according to claim 3 of the formula: in which R1 represents a methyl or hydroxyl group, and R0, R3, R4 X are as defined for (I) in the form of pure enantiomers or a mixture of enantiomers, and their pharmaceutically acceptable salts, solvates and hydrates thereof. 5. Compounds according to claim 4 of the formula: in which R1 represents a methyl or hydroxyl group, and R0 and R3 are as defined for (I) in the form of pure enantiomers or a mixture of enantiomers, and their pharmaceutically acceptable salts, solvates and hydrates thereof. 6. Compounds according to claim 5 of the formula: in which R1 represents a methyl or hydroxyl group, and R0 is as defined for (I) in the form of pure enantiomers or a mixture of enantiomers, and their pharmaceutically acceptable salts, solvates and hydrates thereof. 7. Compounds according to any one of claims 1-6, where R0 represents a group: in which Z1, Z2 and R5 are as defined for (I). 8. Compounds according to claim 7, where R0 represents a group: in which R5 is as defined for (I). 9. Compounds according to any one of claims 1-8, where R1 represents a methyl group. 10. Compounds according to claim 1 selected from: 5-Chloro-3-(2-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylindolin-2-one; 5-Chloro-3-(2-chlorophenyl)-1-[4-(isopropylamino)-2-methoxybenzyl]-3-methylindolin-2-one; N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}acetamide; N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] phenyl}-3-methylbutanamide; N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl} benzamide; N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl] phenyl} nicotinamide; N-{4-Chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxoindolin-3-yl]phenyl}-methoxyacetamide; 3