N-(1H-indolyl)-1H-indole-2-carboxamide derivatives, their preparation and their therapeutic use

1. A compound of the formula (I)

in which

X 1 , X 2 , X 3 , X 4 , Z 1 , Z 2 , Z 3 , Z 4 and Z 5 represent, independently of one another, a hydrogen or halogen atom or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, cyano, C(O)NR 1 R 2 , nitro, NR 1 R 2 , C 1 -C 6 thioalkyl, —S(O)—(C 1 -C 6 )alkyl, —S(O) 2 —(C 1 -C 6 )alkyl, SO 2 NR 1 R 2 , NR 3 COR 4 , NR 3 SO 2 R 5 or aryl group;

X 5 represents a hydrogen or halogen atom or a C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl group;

R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 or 3 position by one or more groups chosen from the C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl groups;

R optionally being substituted in the 4, 5, 6 or 7 position by one or more groups chosen from halogen atoms or C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy groups;

Y represents a hydrogen atom or a C 1 -C 6 alkyl group;

n is equal to 0, 1, 2 or 3;

R 1 and R 2 represent, independently of one another, a hydrogen atom or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkyl or aryl group; or

R 1 and R 2 form, together with the nitrogen atom which carries them, an azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, piperazine or homopiperazine group, said group optionally being substituted by a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 )cycloalkyl(C 1 -C 3 )alkyl or aryl group;

R 3 and R 4 represent, independently of one another, a hydrogen atom or a C 1 -C 6 alkyl or aryl group; and

R 5 represents a C 1 -C 6 alkyl or aryl group;

or a salt thereof.

2. The compound of formula (I) according to claim 1 , wherein

X 1 , X 2 , X 3 , X 4 , Z 1 , Z 2 , Z 3 , Z 4 and Z 5 represent, independently of one another, a hydrogen or halogen atom or a C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, nitro, NR 1 R 2 , C 1 -C 6 thioalkyl, —S(O)—(C 1 -C 6 )alkyl, —S(O) 2 —(C 1 -C 6 )alkyl or aryl group;

X 5 represents a hydrogen atom or a C 1 -C 6 alkyl group;

R represents a 4-, 5-, 6- or 7-indolyl group,

R optionally being substituted in the 1, 2 or 3 position by one or more C 1 -C 6 alkyl groups;

Y represents a hydrogen atom;

n is equal to 0, 1, 2 or 3; and

R 1 and R 2 represent, independently of one another, a hydrogen atom;

or a salt thereof.

3. The compound of formula (I) according to claim 1 , wherein

R represents an indol-5-yl group

R optionally being substituted in the 1, 2 or 3 position by one or more groups chosen from C 1 -C 6 alkyl and C 1 -C 6 fluoroalkyl groups; and

R optionally being substituted in the 4, 6 or 7 position by one or more groups chosen from halogen atoms or C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy groups;

or a salt thereof.

4. The compound of formula (I) according to claim 1 , wherein X 2 or X 3 is other than a hydrogen atom;

or a salt thereof.

5. The compound of formula (I) according to claim 1 , wherein X 5 represents a hydrogen atom;

or a salt thereof.

6. The compound of formula (I) according to claim 1 , wherein Y represents a hydrogen atom;

or a salt thereof.

7. A process for the preparation of a compound of formula (I) according to claim 1 , comprising the steps of:

a) reacting a compound of formula (V)

in which R and Y are as defined in the formula (I) according to claim 1 , with trimethylaluminum in a solvent;

b) adding a solution of a compound of formula (IV)

in which X 1 , X 2 , X 3 , X 4 , X 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and n are as defined in the formula (I) according to claim 1 and A represents a C 1 -C 4 alkoxy group, to reaction mixture obtained in step a); and

c) refluxing said reaction mixture to obtain the compound of formula (I).

8. A process for the preparation of a compound of formula (I) according to claim 1 , comprising the steps of:

a) reacting a compound of general formula (IV)

in which X 1 , X 2 , X 3 , X 4 , X 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and n are as defined in the formula (I) according to claim 1 and A represents a hydroxyl group, with thionyl chloride at reflux of a solvent to form an acid chloride;

b) reacting so obtained acid chloride of formula (IV), in the presence of a base, with the amino-indole of formula (V),

in which R and Y are as defined in the formula (I) according to claim 1 to form the compound of formula (I).

9. A process for the preparation of a compound of formula (I) according to claim 1 , comprising the step of:

subjecting a compound of formula (IV),

in which X 1 , X 2 , X 3 , X 4 , X 5 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and n are as defined in the formula (I) according to claim 1 and A represents a hydroxyl group, and the aminoindole of formula (V),

in which R and Y are as defined in the general formula (I) according to claim 1 , to a coupling reaction in the presence of a coupling agent and a base in a solvent.

10. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a compound of formula (I) according to claim 2 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising a compound of formula (I) according to claim 3 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising a compound of formula (I) according to claim 4 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising a compound of formula (I) according to claim 5 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising a compound of formula (I) according to claim 6 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient.

16. A method of treating a disease selected from the group consisting of pain and irritation of the skin, eyes and mucous membrane, comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I) according to claim 1 .