IP Library › Granted Patent US 8,273,733

Granted Patent B2

US 8,273,733 · App. 12/901,063 · Granted Sep 25, 2012

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

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Quick Facts

Patent No.: US 8,273,733
App. No.: 12/901,063
Granted: Sep 25, 2012
Kind: B2

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Abstract

The disclosure relates to tetrahydroisoquinoline sulfonamide compounds of formula I: wherein R1, R2, n and B are as defined in the disclosure, their preparation and their use in therapies for the treatment of central nervous system diseases such as vigilance and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, attention disorders in hyperkinetic children, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety, sexual dysfunction, dizziness and travel sickness.

Claims (128)

1. A method for treating a pathology selected from the group consisting of obesity and diabetes, said method comprising administering to a patient in need thereof an effective amount of compound of formula I:

wherein:

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. The method according to claim 1 , wherein for the compound of formula I:

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 selected from:

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. The method according to claim 2 , wherein for the compound of formula I, 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 represents:

or a salt, a hydrate or a solvate thereof.

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

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

7. A method for treating a central nervous system disease selected from the group consisting of vigilance and sleep disorders, narcolepsy, Alzheimer's disease and other dementias, Parkinson's disease, attention disorders in hyperkinetic children, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety, sexual dysfunction, dizziness and travel sickness, said method comprising administering to a patient in need thereof an effective amount of compound of formula I:

wherein:

n represents a value from 1 to 6;

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

B represents NR3R4,

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

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.

8. The method according to claim 7 , wherein for the compound of formula I:

n is equal to 2, 3 or 4; and

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

B represents NR3R4, wherein R3 and R4 represent, independently of one another, a C 1-4 alkyl 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.

9. The method according to claim 8 , wherein for the compound of formula I, 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 represents:

or a salt, a hydrate or a solvate thereof.

10. The method according to claim 7 , wherein the compound is 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;