Claims
- 1. Compound of formula ##STR58## in which: R.sub.1 and R.sub.2 each independently represent a hydrogen; a hydroxyl; a halogen; a (C.sub.1 -C.sub.7)alkyl; a (C.sub.1 -C.sub.7)polyfluoroalkyl; a (C.sub.1 -C.sub.7)alkoxy; a (C.sub.1 -C.sub.7)-alkylthio; a (C.sub.1 -C.sub.7)polyfluoroalkoxy; a (C.sub.3 -C.sub.7)cycloalkyloxy; a (C.sub.3 -C.sub.7)cycloalkylthio; a cycloalkylmethoxy or a cycloalkyl-methylthio in which the cycloalkyl is C.sub.3 -C.sub.7 ; a phenoxy; a benzyloxy; a nitro; or a cyano;
- R.sub.3 and R.sub.4, each independently of one another, substitute the phenyl group one or a number of times and represent a hydrogen; a halogen; a (C.sub.1 -C.sub.7)alkyl; a (C.sub.2 -C.sub.7)alkenyl; a (C.sub.1 -C.sub.7)polyhaloalkyl; a phenyl or a benzyl; a cyano; a nitro; an --NR.sub.5 R.sub.6 group; a hydroxyamino; a hydroxyl; an OR.sub.7 group; an SR.sub.7 group; a --COOR.sub.8 group, a --CONR.sub.9 R.sub.10 group; or a --CSNR.sub.9 R.sub.10 group, at least one of the R.sub.3 and R.sub.4 radicals being other than hydrogen;
- R.sub.5 and R.sub.6 each independently represent a hydrogen; a (C.sub.1 -C.sub.7)alkyl; a (C.sub.2 -C.sub.7)alkenyl; a phenyl; a benzyl; a (C.sub.1 -C.sub.7)alkylcarbonyl; a (C.sub.1 -C.sub.7)alkylthiocarbonyl; a (C.sub.3 -C.sub.7)cycloalkylcarbonyl; a (C.sub.3 -C.sub.7)cycloalkylthiocarbonyl; a benzoyl; a thienylcarbonyl; a furylcarbonyl; a (C.sub.1 -C.sub.7)alkyloxycarbonyl; a phenoxycarbonyl; a benzyloxy-carbonyl; a carbamoyl or a thiocarbamoyl which is unsubstituted or substituted by R.sub.9 and R.sub.10 or alternatively R.sub.5 and R.sub.6 form, with the nitrogen atom to which they are bonded, a heterocyclic group chosen from the pyrrolidine, pyrroline, pyrrole, indoline, indole and piperidine groups;
- R.sub.7 represents a (C.sub.1 -C.sub.7)alkyl; a (C.sub.2 -C.sub.7)alkenyl; a phenyl; a benzyl; a (C.sub.3 -C.sub.7)cycloalkyl; a (C.sub.1 -C.sub.7)poly-fluoroalkyl; a formyl; a (C.sub.1 -C.sub.7)alkylcarbonyl; a benzoyl; or a benzylcarbonyl;
- R.sub.8 represents a hydrogen; a (C.sub.1 -C.sub.7)alkyl; a phenyl; or a benzyl;
- R.sub.9 and R.sub.10 each independently represent hydrogen; a (C.sub.1 -C.sub.7)alkyl; a (C.sub.1 -C.sub.7)polyfluoroalkyl; a (C.sub.2 -C.sub.7)alkenyl; a (C.sub.3 -C.sub.7)cycloalkyl optionally substituted by a hydroxy (C.sub.1 -C.sub.4)alkyl; a pyridyl; a phenyl; a thienyl; a furyl; or alternatively R.sub.9 and R.sub.10 form, with the nitrogen atom to which they are bonded, a heterocyclic group chosen from the pyrrolidine, piperidine and piperazine groups, which is unsubstituted or substituted by (C.sub.1 -C.sub.4)alkyls; and the (C.sub.4 -C.sub.7)azacycloalkyl groups;
- W represents a --CH.sub.2 -- or --SO.sub.2 -- group;
- Cy forms, with the carbon to which it is bonded, a non-aromatic, saturated or unsaturated C.sub.3 -C.sub.12 hydrocarbon ring which is optionally condensed or substituted by one or a number of (C.sub.1 -C.sub.7)alkyl groups, it being possible for the said groups to substitute the same carbon atom one or a number of times, or by a C.sub.3 -C.sub.6 spirocycloalkyl;
- T represents a (C.sub.1 -C.sub.4)alkylene which is optionally interrupted by a (C.sub.3 -C.sub.6)cycloalkylene, the said alkylenes optionally being substituted one or a number of times on the same carbon atom by a (C.sub.1 -C.sub.3)alkyl; or alternatively T represents a direct bond;
- Z represents an --NR.sub.11 R.sub.12 group; --.sup.+ NR.sub.11 R.sub.12 (C.sub.1 -C.sub.4)-alkyl (A.sup.-), (A.sup.-) being an anion; --N(O)R.sub.11 R.sub.12 ; a --COOR.sub.11 group; an --NR.sub.11 COR.sub.12 group; a benzyloxycarbonylamino; a --CONR.sub.11 R.sub.12 group; it being understood that when T represents a methylene or a direct bond, Z cannot be --NR.sub.11 R.sub.12 ; --.sup.+ NR.sub.11 R.sub.12 (C.sub.1 -C.sub.4)alkyl; --N(O)R.sub.11 R.sub.12 ; --NR.sub.11 COR.sub.12 ; a benzyloxycarbonylamino;
- R.sub.11 and R.sub.12 each independently represent hydrogen; a (C.sub.1 -C.sub.7)alkyl; a (C.sub.1 -C.sub.4)alkoxy; a (C.sub.3 -C.sub.7)cycloalkyl; a phenyl; a (C.sub.1 -C.sub.3)alkylenecycloalkyl, in which the cycloalkyl is C.sub.3 -C.sub.7, or a (C.sub.1 -C.sub.3)alkylenephenyl, it being possible for the said groups optionally to be mono- or polysubstituted by R.sub.13 ;
- or alternatively R.sub.11 and R.sub.12 optionally form, with the nitrogen atom to which they are bonded, a heterocycle chosen from azetidine, pyrrolidine, piperidine, piperazine, piperazinone, morpholine, morpholinone, thiomorpholine and hexahydroazepine heterocycles, which heterocycle is optionally mono- or polysubstituted by R.sub.13 ; or a thiomorpholine 1,1-dioxide or a thiomorpholine 1-oxide; or alternatively R.sub.12 represents a pyrrolidone or a piperidone;
- R.sub.13 represents a hydroxyl group; a (C.sub.1 -C.sub.4)alkyl; a (C.sub.1 -C.sub.4)alkoxy; a mercapto; a (C.sub.1 -C.sub.4)alkylthio; a (C.sub.1 -C.sub.4)-alkylsulphinyl; a (C.sub.1 -C.sub.4)alkylsulphonyl; a benzyloxy; a hydroxyalkyloxy; an --NR.sub.14 R.sub.15 group in which R.sub.14 and R.sub.15 each independently represent hydrogen or a (C.sub.1 -C.sub.4)alkyl or a (C.sub.1 -C.sub.4)alkyloxycarbonyl or a benzyloxycarbonyl; a carboxyl; a (C.sub.1 -C.sub.4)alkyloxycarbonyl, a phenoxycarbonyl, a benzyloxycarbonyl; a carbamoyl; an amidino; a guanidino; an imidazolyl; a thienyl; a pyridyl; an indolyl; or a tetrahydroisoquinolyl;
- the phenyl group, which is constituent of the R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 substituents, being unsubstituted, mono- or di-substituted by a (C.sub.1 -C.sub.7)alkyl, a (C.sub.1 -C.sub.7)alkoxy, a tri-fluoromethyl, a halogen or trisubstituted by a (C.sub.1 -C.sub.7)-alkyl, a (C.sub.1 -C.sub.7)alkoxy or a halogen; and its salts.
- 2. Compound according to claim 1 of formula: ##STR59## in which R.sub.1, R.sub.3, R.sub.4, W, T and Z are as defined for (I) in claim 1 or one of its salts, solvates or hydrates.
- 3. Compound according to claim 1 of formula: ##STR60## in which R.sub.1, R.sub.3, R.sub.4, T and Z are as defined for (I) in claim 1 or one of its salts, solvates or hydrates.
- 4. Compound according to claim 1 of formula: ##STR61## in which R.sub.1, R.sub.3 and R.sub.4 are as defined for (I) in claim 1, T represents a (C.sub.1 -C.sub.3)alkylene and Z represents an amino group, a 2-hydroxyethylamino, a 2-(2-hydroxy)ethyloxyethylamino, a morpholinyl or a carboxylic acid, and its salts, solvates or hydrates.
- 5. Compound according to claim 1 of formula: ##STR62## in which R.sub.1, T and Z are as defined for (I) in claim 1 or one of its salts, solvates or hydrates.
- 6. Compound according to claim 1, wherein it is one of the compounds below:
- 5-chloro-3-spiro-[4-(2-morpholinoethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzene-sulphonyl]indolin-2-one;
- 5-ethoxy-3-spiro-[4-(2-aminoethyloxy)cyclohexane]-1-[4-(4N-tert-butylcarbamoyl)-2-methoxybenzene-sulphonyl]indolin-2-one;
- 5-ethoxy-3-spiro-[4-(2-(N-methyl-N-(2-hydroxy-ethyl)amino)ethyloxy)-cyclohexane]-1-[4-(N-tert-butyl-carbamoyl)-2-methoxybenzenesulphonyl]indolin-2-one
- 5-ethoxy-3-spiro-[4-(2-morpholinoethyloxy)cyclo-hexane]-1-[4(N-tert-butylcarbamoyl)-2-methoxybenzyl]-indolin-2-one;
- 5-ethoxy-1-[4-(N-tert-butylcarbamoyl)-2-methoxy-benzenesulphonyl]-3-spiro-[4(2-morpholinoethyloxy)-cyclohexane]indolin-2-one;
- 5-ethoxy-3-spiro-(4-carboxymethyloxycyclohexane)-1-(4-N-tert-butylcarbamoyl-2-methoxybenzenesulphonyl)-indolin-2-one;
- 5-ethoxy-3-spiro-[4-(2-morpholinoethyloxy)cyclo-hexane]-1-[4-(N-tert-amylcarbamoyl)-2-methoxy-benzenesulphonyl]indolin-2-one;
- 5-ethoxy-3-spiro-[4(2-carboxyethyloxy cyclo-hexane]1-[4-(N-tert-amylcarbamoyl)-2-methoxybenzene-sulphonyl]indolin-2-one;
- 5-ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-benzenesulphonyl]-3-spiro-[4-(2-dimethylaminoethyloxy)-cyclohexane]indolin2-one;
- 5-Ethoxy-3-spiro-[(2-(4-ethoxypiperidino)-ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-(2-glycylaminoethyloxy)- cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxy-benzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-(2-(N,N-dimethylglycylamino)-ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Chloro-3-spiro-[4-(N-(3-dimethylaminopropyl)- carbamoylmethyloxy)-cyclohexane]-1-[4(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-(2-(4-dimethylaminobutyryl-amino)ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4(2-(2-hydroxyethylamino)-ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-2-(-L-.gamma.-glutamylamino)-ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-(2-(-L-pyroglutamylamino)-ethyloxy)cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- 5-Ethoxy-3-spiro-[4-(2-(2-(2-hydroxyethyloxy)-ethylamino)ethyloxy)-cyclohexane]-1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]indolin-2-one;
- or their pharmaceutically acceptable salts, solvates or hydrates.
- 7. Process for the preparation of a compound of formula (I) according to claim 1, wherein:
- (1) either when Z.dbd.NR.sub.11 R.sub.12, in which R11 and R12 are as defined for (1):
- (1a) when at least one of the R.sub.11 and R.sub.12 radicals is different from hydrogen, a compound of formula: ##STR63## in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, W, Cy and T are as defined for (I) and in which X is a halogen or a sulphonic acid derivative is reacted with a derivative of formula ZH in a solvent selected from dimethylformamide, tetrahydrofuran or acetonitrile, at temperatures of between 0.degree. and 120.degree. C.;
- (1b) when R.sub.11 and R.sub.12 .dbd.H, the compound (IA), in which X is an azido, is reduced to amino;
- (2) or, when Z.dbd.--COOH, a compound of formula: ##STR64## in which R.sub.1, R.sub.2, W, R.sub.3, R.sub.4 and Cy are as defined for (I) and T' represents T--CH.sub.2 --, is oxidized in an acid solvent at a temperature of between 0.degree. C. and 100.degree. C., alkali metal dichromates or alkali metal or alkaline-earth metal permanganates;
- (3) or a compound of formula: ##STR65## in which R.sub.1, R.sub.2, Cy, T and Z are as defined for (I), is reacted with a compound of formula: ##STR66## in which W, R.sub.3 and R.sub.4 are as defined for (I) and Hal represents a halogen atom, in an anhydrous solvent in the presence of a metal hydride or an alkali metal alkoxide at temperatures of between -40.degree. and 25.degree. C.;
- (4) or, when Z.dbd.--COOH, a compound of formula: ##STR67## in which R.sub.1, R.sub.2 and Cy are as defined above for (I) and T' represents T--CH.sub.2, is oxidized, then the acid thus obtained of formula: ##STR68## in which R.sub.1, R.sub.2, Cy and T are as defined above for (I), is subsequently optionally protected by a protective group for the carboxylic acid, in order to obtain the intermediate of formula: ##STR69## in which R.sub.1, R.sub.2, Cy and T are as defined for (I) and P represents a protective group chosen from an alkyl, a tert-butyl or a benzyl, and, finally, this compound (II"BP) is subjected to the action of a derivative of formula (2) in order to obtain, after deprotection, a compound (I); one of its quaternary ammoniums, oxides, sulphones or salts.
- 8. Pharmaceutical composition containing, as active principle, a compound of formula (I) according to claim 1 or one of its pharmaceutically acceptable salts, hydrates or solvates.
- 9. Pharmaceutical composition containing, as active principle, a compound of formula (I1.) according to claim 2 or one of its pharmaceutically acceptable salts, hydrates or solvates.
- 10. Pharmaceutical composition containing, as active principle, a compound of formula (I.2) according to claim 3 or one of its pharmaceutically acceptable salts, hydrates or solvates.
- 11. Pharmaceutical composition containing, as active principle, a compound of formula (I.3) according to claim 4 or one of its pharmaceutically acceptable salts, hydrates or solvates.
- 12. Pharmaceutical composition containing, as active principle, a compound of formula (I.4) according to claim 5 or one of its pharmaceutically acceptable salts, hydrates or solvates.
- 13. Pharmaceutical composition containing, as active principle, a compound according to claim 6.
- 14. Pharmaceutical composition according to claim 8 also containing another active principle.
- 15. Pharmaceutical composition according to claim 14, characterized in that the other active principle is a specific antagonist of the angiotensin II receptor.
- 16. Pharmaceutical composition according to claim 15, characterized in that the specific antagonist of the angiotensin II receptor is irbesartan.
- 17. Pharmaceutical composition containing a combination of 5ethoxy-1-[4(N-tert-butylcarbamoyl)-2-methoxybenzene-sulphonyl]-3spiro-[(2-morpholinoethyloxy)cyclohexane]-indolin-2-one and irbesartan.
- 18. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 1.
- 19. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 2.
- 20. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 3.
- 21. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 4.
- 22. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 5.
- 23. A method for the treatment of diseases in which the vasopressin and/or oxytocin receptor is involved which comprises administering to a patient in need of such treatment an effective amount of a compound according to claim 6.
Priority Claims (1)
Number |
Date |
Country |
Kind |
95 12533 |
Oct 1995 |
FRX |
|
Parent Case Info
This application if a 371 of PCT/FR96/01666 filed Oct. 24, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/FR96/01666 |
10/24/1996 |
|
|
4/17/1998 |
4/17/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/15556 |
5/1/1997 |
|
|
US Referenced Citations (5)
Number |
Name |
Date |
Kind |
5618833 |
Foulon et al. |
Apr 1997 |
|
5663431 |
Di Malta et al. |
Sep 1997 |
|
5686624 |
Di Malta et al. |
Nov 1997 |
|
5696145 |
Foulon et al. |
Dec 1997 |
|
5726322 |
Di Malta et al. |
Mar 1998 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
636609 |
Feb 1995 |
EPX |
636608 |
Feb 1995 |
EPX |
WO9315051 |
Aug 1993 |
WOX |