Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics

1. A compound of formula I:

in which:

n represents a value from 1 to 6;

—(C)n- represents a C 1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C 1-3 monoalkylamino, C 2-6 dialkylamino and C 1-3 alkoxy;

R1 represents

a hydrogen atom, or

a C 1-6 alkyl group;

R2 represents

a hydrogen atom, or

a C 1-6 alkyl or C 3-6 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C 1-3 monoalkylamino, C 2-6 dialkylamino, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, a monocyclic heteroaryl, and an aryl; the aryl being optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C 1-3 monoalkylamino, C 2-6 dialkylamino, C 1-3 alkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy and a C 1-3 alkylidenedioxy group;

B represents NR3R4, wherein

R3 and R4 represent, independently of one another, a C 1-6 alkyl group, or a hydrogen atom; or

R3 and R4 together represent a C 1-6 alkylidene group, a C 2-8 alkenylidene group, a C 1-3 alkylidene-O—C 1-3 alkylidene group, or a C 1-3 alkylidene-N(R5)-C 1-3 alkylidene group where R5 represents a hydrogen atom, or a C 1-3 alkyl or C 1-6 alkylcarbonyl group, it being possible for these C 1-3 alkyl and C 1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C 1-3 alkoxy, nitro, cyano or amino group; or

B represents an aminocycle, linked via a carbon to the group —NR1-(C)n-, said aminocycle being selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine; the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents selected from a phenyl, a benzyl, a halogen, a hydroxyl, a nitro, cyano, amino, C 1-3 monoalkylamino, C 2-6 dialkylamino, C 1-3 alkyl and C 1-3 alkoxy group; the nitrogen atom being optionally substituted with a C 1-3 alkyl;

or a salt, a hydrate or a solvate thereof;

with the exclusion of the compound in which R 1 and R 2 represent hydrogen atoms, B represents a dimethylamino group and —(C)n- represents an ethylidene group.

2. A compound as claimed in claim 1 wherein:

n is equal to 2, 3 or 4; and

R1 represents a hydrogen atom or a C 1-2 alkyl group; and

R2 represents a hydrogen atom, or a C 1-4 alkyl or C 5-6 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a phenyl, a C 3-6 cycloalkyl, C 1 - 2 perhaloalkyl, C 1-3 haloalkyl and C 1-3 alkoxy; the phenyl being optionally substituted with 1 to 4 substituents selected from a halogen atom, hydroxyl, nitro, cyano, amino, C 1 - 3 monoalkylamino, C 2-6 dialkylamino, C 1-3 alkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy group and C 1-3 alkylidenedioxy; and

B represents NR3R4, wherein

R3 and R4 represent, independently of one another, a C 1-4 alkyl group; or

when R3 and R4 together represent a C 1-6 alkylidene group, a C 2-8 alkenylidene group, a C 1-3 alkylidene-O—C 1-3 alkylidene group or a C 1-3 alkylidene-N(R5)-C 1-3 alkylidene group, B represents a group:

 or B represents an aminocycle linked via a carbon to the group —NR1-(C)n, chosen from aziridine, azetidine, pyrrolidine, piperidine and morpholine;

 the groups R3, R4 and R5 and also the aminocycle being optionally substituted;

or a salt, a hydrate or a solvate thereof.

3. A compound as claimed in claim 2 , wherein, when B represents NR3R4 and R3 and R4 together form a C 1-6 alkylidene group, a C 2-8 alkenylidene group, a C 1-3 alkylidene-O—C 1-3 alkylidene group or a C 1-3 alkylidene-N(R5)—C 1-3 alkylidene group, or when B represents an aminocycle, then B is selected from the group consisting of:

or a salt, a hydrate or a solvate thereof.

4. A compound as claimed in claim 1 , selected from the group consisting of:

N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(diethylamino)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(diethylamino)propyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

2-benzyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

2-(cyclopropylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

2-(cyclohexylmethyl)-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-N-[3-(2-methylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(3,6-dihydropyridin-1(2H)-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(diethylamino)propyl]-2-isopropyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(diethylamino)propyl]-2-(2-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(diethylamino)propyl]-2-(3-thienylmethyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

2-cyclohexyl-N-[3-(diethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(2,5-dihydro-1H-pyrrol-1-yl)propyl]-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(4-benzylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-(3-pyrrolidin-1-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-(3-morpholin-4-ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

N-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

2-(cyclohexylmethyl)-N-(3-pyrrolidin-1ylpropyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(cyclopropylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-benzyl-N-[2-(1-methylpyrrolidin-2-yl)ethyl]1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(4-isopropylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(1,3-benzodioxo1-5-ylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(4-bromobenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(2,5-dimethoxybenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(2-methylbutyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

(+/−)-2-(3-methoxybenzyl)-)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; and

(+/−)-2-(3,5-dimethylbenzyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide;

or a salt, a hydrate or a solvate thereof.

5. The compound according to claim 1 which is (+)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.

6. The compound according to claim 1 which is (−)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.

7. A compound of formula I:

in which:

n represents a value from 1 to 6;

—(C)n- represents a C 1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C 1-3 monoalkylamino, C 2 - 6 dialkylamino and C 1-3 alkoxy;

R1 represents a hydrogen atom, or a C 1-6 alkyl group;

R2 represents a C 1-6 alkyl or C 3-6 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C 1 - 3 monoalkylamino, C 2-6 dialkylamino, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3 - 6 cycloalkyl, a monocyclic heteroaryl, and an aryl; the aryl being optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C 1 - 3 monoalkylamino, C 2-6 dialkylamino, C 1-3 alkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy and a C 1-3 alkylidenedioxy group;

B represents NR3R4, wherein R3 and R4 represent, independently of one another, a C 1-6 alkyl group, or a hydrogen atom; or R3 and R4 together represent a C 1-6 alkylidene group, a C 2-8 alkenylidene group, a C 1-3 alkylidene-O—C 1-3 alkylidene group, or a C 1-3 alkylidene-N(R5)-C 1-3 alkylidene group where R5 represents a hydrogen atom, or a C 1-3 alkyl or C 1-6 alkylcarbonyl group, it being possible for these C 1-3 alkyl and C 1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C 1-3 alkoxy, nitro, cyano or amino group;

or B represents an aminocycle, linked via a carbon to the group -NR1-(C)n-, said aminocycle being selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine;

the groups R3 and R4 and also the aminocycle being optionally substituted with 1 to 4 substituents selected from a phenyl, a benzyl, a halogen, a hydroxyl, a nitro, cyano, amino, C 1-3 monoalkylamino, C 2-6 dialkylamino, C 1-3 alkyl and C 1-3 alkoxy group; the nitrogen atom being optionally substituted with a C 1-3 alkyl;

or a salt, a hydrate or a solvate thereof.

8. The compound according to claim 7 which is (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.

9. The compound according to claim 7 which is (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt, solvate or hydrate thereof.

10. A compound selected from the group consisting of (+)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide and (−)-2-(cyclohexylmethyl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl] -1,2,3 ,4-tetrahydroisoquinoline-7-sulfonamide; or a salt of said compound; or a hydrate of said salt.

11. A pharmaceutical composition containing a compound of formula I, as claimed in claim 1 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

12. A pharmaceutical composition comprising a compound according to claim 2 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

13. A pharmaceutical composition comprising a compound according to claim 3 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

14. A pharmaceutical composition comprising a compound according to claim 4 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

15. A pharmaceutical composition comprising a compound according to claim 5 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

16. A pharmaceutical composition comprising a compound according to claim 6 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

17. A pharmaceutical composition comprising a compound according to claim 7 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

18. A pharmaceutical composition comprising a compound according to claim 8 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.

19. A pharmaceutical composition comprising a compound according to claim 9 , or a salt, solvate or hydrate thereof, and at least one pharmaceutical excipient.