1,3-dihydro-2H-indol-2one derivatives, process for preparing them and pharmaceutical compositions containing them

1. A compound of formula:

in which:

R 1 represents a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical;

R 2 represents a hydrogen atom; a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical;

or R 2 is in position -6- of the indol-2-one ring and R 1 and R 2 together represent a divalent trimethylene radical;

R 3 represents a halogen atom; a hydroxyl; a (C 1 –C 4 )alkyl; a (C 1 –C 2 )alkoxy; a trifluoromethoxy radical;

R 4 represents a hydrogen atom; a halogen atom; a (C 1 –C 2 )alkyl; a (C 1 –C 2 )alkoxy;

or R 4 is in position -3- of the phenyl and R 3 and R 4 together represent a methylenedioxy radical;

R 5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C 1 –C 2 )alkoxy;

R 6 represents a hydrogen atom; a (C 1 –C 4 )alkyl; a group —(CH 2 )n-CO—R 9 ; a group —CO—(CH 2 )n-NR 10 R 11 ;

R 9 represents a hydroxyl; a (C 1 –C 4 )alkoxy; a group —NR 12 R 13 ;

R 10 and R 11 each independently represent a (C 1 –C 4 )alkyl;

or R 10 and R 11 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

R 12 represents a hydrogen or a (C 1 –C 4 )alkyl;

R 13 represents a (C 1 –C 4 )alkyl; a —C(CH 3 ) 2 CH 2 OH group; a —C(CH 3 )(CH 2 OH) 2 group; a —C(CH 2 OH) 3 group;

or R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

n is 1 or 2;

or an acid-addition salt thereof.

2. A compound of formula:

in which:

R 1 represents a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical;

R 2 represents a hydrogen atom; a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical;

or R 2 is in position -6- of the indol-2-one ring and R 1 and R 2 together represent a divalent trimethylene radical;

R 4 is in position -3- of the phenyl and R 3 and R 4 together represent a methylenedioxy radical;

R 5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C 1 –C 2 )alkoxy;

R6 represents a hydrogen atom; a (C 1 –C 4 alkyl; a group —(CH 2 )n-CO—R 9 ; a group —CO—(CH 2 )n-NR 10 R 11 ;

R 7 represents a (C 1 –C 4 )alkoxy;

R 8 represents a (C 1 –C 4 alkoxy;

R 9 represents a hydroxyl; a (C 1 –C 4 alkoxy; a group —NR 12 R 13 ;

R 10 and R11 each independently represent a (C 1 –C 4 )alkyl;

or R 10 and R 11 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

R 12 represents a hydrogen or a (C 1 –C 4 )alkyl;

R 13 represents a (C 1 –C 4 )alkyl; a —C(CH 3 ) 2 CH 2 OH group; a —C(CH 3 )(CH 2 OH) 2 group; a —C(CH 2 OH) 3 group;

or R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocylic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

n is 1 or 2; or

a solvate, hydrate or acid-addition salt thereof.

3. A compound according to claim 2 of formula:

in which:

the carbon atom bearing substituent OR 6 has the (R) configuration and the carbon atom in position 3 of the indol-2-one has either the (R) configuration or the (S) configuration.

4. A compound according to claim 3 in the form of the levorotatory isomer.

5. A compound according to claim 4 of formula (Ia) in which:

R 1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical;

R 2 represents a hydrogen atom or is in position -6- of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical on trifluoromethyl radical;

R 4 is in position -3- of the phenyl and, together with R 3 , represent a methylenedioxy radical;

R 5 represents a dimethylamino radical or a methoxy radical;

R 6 represents a hydrogen atom; a methyl radical; an ethyl radical; a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amimo]carbonylmethyl radical; a (1-piperazinyl)carbonylmethyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical;

R 7 is in position -2- of the phenyl and represents a methoxy radical; and

R 8 represents a methoxy radical.

6. A compound of formula:

in which:

R 1 represents a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical;

R 2 represents a hydrogen atom; a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 alkoxy; a trifluoromethyl radical;

or R 2 is in position -6- of the indol-2-one ring and R 1 and R 2 together represent a divalent trimethylene radical;

R 3 represents a halogen atom; a hydroxyl; a (C 1 –C 2 )alkyl; a (C 1 –C 2 )alkoxy; a trifluoromethoxy radical;

R 4 represents a hydrogen atom; a halogen atom; a (C 1 –C 2 )alkyl; a (C 1 –C 2 )alkoxy;

or R 4 is in position -3- of the phenyl and R 3 and R 4 together represent a methylenedioxy radical;

R 5 represents an azetidin-1-yl radical; or a (C 1 –C 2 )alkoxy;

R 6 represents a hydrogen atom; a (C 1 –C 4 )alkyl; a group —(CH 2 )n-CO—R 9 ; a group —CO—(CH 2 )n-NR 10 R 11 ;

R 7 represents a (C 1 –C 4 )alkoxy;

R 8 represents a (C 1 –C 4 alkoxy;

R 9 represents a hydroxyl; a (C 1 –C 4 )alkoxy; a group —NR 12 R 13 ;

R 10 and R 11 each independently represent a (C 1 –C 4 alkyl;

or R 10 and R 11 , together with the nitrogen atom to which they are attached, constitute a heterocylic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

R 12 represents a hydrogen or a (C 1 –C 4 alkyl;

R 13 represents a (C 1 –C 4 )alkyl; a —C(CH 3 ) 2 CH 2 OH group; a —C(CH 3 )(CH 2 OH) 2 group; a —C(CH 2 OH) 3 group;

or R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

n is 1 or 2; or

a solvate, hydrate or acid-addition salt thereof.

7. A compound according to claim 6 of formula:

in which:

the carbon atom bearing substituent OR 6 has the (R) configuration and the carbon atom in position 3 of the indol-2-one has either the (R) configuration or the (S) configuration.

8. A compound according to claim 7 , in the form of the levorotatory isomer.

9. Compound according to claim 8 in which:

R 1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical;

R 2 represents a hydrogen atom or is in position -6- of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical;

R 3 represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical;

R4 represents a hydrogen atom or is in position -3- or -4- of the phenyl and represents a fluorine atom or a methoxy radical;

or R 4 is in position -3- of the phenyl and, together with R3, represent a methylenedioxy radical;

R 5 represents a methoxy radical;

R 6 represents a hydrogen atom; a methyl radical; an ethyl radical; a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy -1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethyl radical; a (1-piperazinyl)carbonylmethyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical;

R 7 is in position -2- of the phenyl and represents a methoxy radical; and

R 8 represents a methoxy radical.

10. A compound of formula:

in which:

R 1 represents a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical;

R 2 represents a hydrogen atom; a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 )alkoxy; a trifluoromethyl radical;

or R 2 is in position -6- of the indol-2-one ring and R 1 and R 2 together represent a divalent trimethylene radical;

R 3 represents a halogen atom; a hydroxyl; a (C 1 –C 2 )alkyl; a (C 1 –C 2 )alkoxy; a trifluoromethoxy radical;

R 4 represents a hydrogen atom; a halogen atom; a (C 1 –C 4 )alkyl; a (C 1 –C 4 alkoxy;

or R 4 is in position -3- of the phenyl and R 3 and R 4 together represent a methylenedioxy radical;

R 5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C 1 –C 2 )alkoxy;

R 6 represents a group —(CH 2 )n-CO—R 9 ; or a group —CO—(CH 2 )n-NR 10 R 11 ;

R 7 represents a (C 1 –C 4 )alkoxy;

R 8 represents a (C 1 –C 4 )alkoxy;

R 9 represents a hydroxyl; a (C 1 –C 4 )alkoxy; a group —NR 12 R 13 ;

R 10 and R 11 each independently represent a (C 1 –C 4 )alkyl;

or R 10 and R 11 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

R 12 represents a hydrogen or a (C 1 –C 4 )alkyl;

R 13 represents a (C 1 –C 4 )alkyl; a —C(CH 3 ) 2 CH 2 OH group; a —C(CH 3 )(CH 2 OH) 2 group; a —C(CH 2 OH) 3 group;

or R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl;

n is 1 or 2; or

a solvate, hydrate or acid-addition salt thereof.

11. A compound according to claim 10 of formula:

in which:

the carbon atom bearing substituent OR 6 has the (R) configuration and the carbon atom in position 3 of the indol-2-one has either the (R) configuration or the (S) configuration.

12. A compound according to claim 11 in the form of the levorotatory isomer.

13. A compound according to claim 11 in which:

R 1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical;

R 2 represents a hydrogen atom or is in position -6- of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical;

R 3 represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical;

R 4 represents a hydrogen atom or is in position -3- or -4- of the phenyl and represents a fluorine atom or a methoxy radical;

or R 4 is in position -3- of the phenyl and, together with R 3 represent a methylenedioxy radical;

R 5 represents a dimethylamino radical or a methoxy radical;

R 6 represents a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethyl radical; a (1-piperazinyl)carbonylmethyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical;

R 7 is in position -2- of the phenyl and represents a methoxy radical; and

R 8 represents a methoxy radical.

14. (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer according to claim 5 .

15. (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidinecarboxamide levorotatory isomer according to claim 8 .

16. A compound according to claim 9 selected from the group consisting of:

Methyl (2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidinecarboxylate levorotatory isomer,

Methyl (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate, levorotatory isomer; and

Methyl (2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate, levorotatory isomer.

17. A compound according to claim 3 selected from the group consisting of:

tert-Butyl 2-[[(3R,5 S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate, levorotatory isomer;

2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetic acid, levorotatory isomer;

(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide, levorotatory isomer;

(2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamide, levorotatory isomer;

(2S,4R)-1-[[(2,4-Dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide, levorotatory isomer; and

(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl 3-(4-morpholinyl)propanoate, levorotatory isomer.

18. A process for the preparation of a compound of formula I or an acid-addition salt, solvate or hydrate thereof:

which comprises reacting a compound of formula II:

with a compound of formula III:

wherein in the above formulas

R 1 is halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, trifluoromethyl, or trifluoromethoxy;

R 2 is hydrogen, halogen, (C 1 –C 4 )alkyl, (C 1 –C 4 )alkoxy, or trifluoromethyl;

or R 2 is in position -6- of the indol-2-one ring and R 1 and R 2 together form a divalent trimethylene radical;

R 3 is halogen, hydroxyl, (C 1 –C 4 )alkyl, (C 1 –C 2 )alkoxy, or trifluoromethoxy;

R 4 is hydrogen, halogen, (C 1 –C 2 )alkyl, or (C 1 –C 2 )alkoxy;

or R 4 is in position -3- of the phenyl and R 3 and R 4 together form a methylenedioxy radical;

R 5 is ethylamino, dimethylamino, azetidin-1-yl, or (C 1 –C 2 )alkoxy;

R 6 is hydrogen, (C 1 –C 4 )alkyl, —(CH 2 )n-CO—R 9 , or —CO—(CH 2 )n-NR 10 R 11 ;

R 7 is (C 1 –C 4 )alkoxy;

R 8 is (C 1 –C 4 )alkoxy;

R 9 is hydroxyl, (C 1 –C 4 )alkoxy, or —NR 12 R 13 ;

R 10 and R 11 are each independently (C 1 –C 4 )alkyl;

or R 10 and R 11 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl and thiomorpholin-4-yl;

R 12 is hydrogen or (C 1 –C 4 )alkyl;

R 13 is (C 1 –C 4 )alkyl, —C(CH 3 ) 2 CH 2 OH, —C(CH 3 )(CH 2 OH) 2 , or —C(CH 2 OH) 3 ,

or R 12 and R 13 , together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl and thiomorpholin-4-yl;

n is 1 or 2; and

Hal is halogen.

19. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable excipient.

20. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition comprising a compound according to claim 10 and a pharmaceutically acceptable excipient.