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

A compound of formula II:

• wherein Pg represents a trifluoroacetyl group;
• n represents a value from 1 to 6;
• —(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino and C1-3 alkoxy;
• R1 represents a hydrogen atom or a C1-6 alkyl group;
• B represents:
• NR3R4, where R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O—C1-3alkylidene group, or a C1-3 alkylidene-N(R5)—C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 alkoxy, nitro, cyano or amino group;
• or B represents an aminocycle, linked via a carbon atom to the group —NR1-(C)n-, said aminocycle being selected from aziridine, azetidine, pyrrolidine, piperidine and morpholine;
• wherein the groups R3 and R4 and also the aminocycle are optionally substituted with 1 to 4 substituents selected from a phenyl, a benzyl, a halogen, a hydroxyl, a nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl and C1-3 alkoxy group;
• and the nitrogen atom being optionally substituted with a C1-3 alkyl;
• or a salt thereof.

A process for preparing a compound of formula I:

• wherein n represents a value from 1 to 6;
• —(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino and C1-3 alkoxy;
• R1 represents a hydrogen atom, or a C1-6 alkyl group;
• R2 represents a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy and a C1-3 alkylidenedioxy group;
• B represents NR3R4, wherein
• R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom;
• or R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O—C1-3 alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl and C1-3 alkoxy group;
• the nitrogen atom being optionally substituted with a C1-3 alkyl;
• or a salt, a hydrate or a solvate thereof;
• said method comprising reductive aminating a compound of the formula
• wherein R1, n, —(C)n-, and B are as defined for the compound of formula I,
• with a compound of formula III:
• wherein, after the reaction, R6 and R7 together with carbonyl carbon form R2 as defined above for the compound of formula I.

A process for preparing a compound of formula I:

• wherein n represents a value from 1 to 6;
• —(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino and C1-3 alkoxy;
• R1 represents a hydrogen atom, or a C1-6 alkyl group;
• R2 represents a C1-6 alkyl or C3-6 cycloalkyl group optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy, C3-6 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl, C1-2 perhaloalkyl, C1-3 haloalkyl, C1-3 alkoxy and a C1-3 alkylidenedioxy group;
• B represents NR3R4, wherein
• R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom;
• or R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O—C1-3 alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl and C1-3 alkoxy group;
• the nitrogen atom being optionally substituted with a C1-3 alkyl;
• or a salt, a hydrate or a solvate thereof;
• said process comprising deprotecting a compound of formula II:
• wherein Pg is a protective group, and R1, n, —(C)n-, and B are as defined above for the compound of formula I, to form the compound of the formula:
• wherein R1, n, —(C)n-, and B are as defined above for the compound of formula I;
• and then reductive aminating said compound of the formula
• with a compound of formula III:
• wherein, after the reaction, R6 and R7 together with carbonyl carbon form R2 as defined above for the compound of formula I;
• to form the compound of formula I.

A process for preparing the compound of formula II:

• wherein
• Pg is a protective group;
• n represents a value from 1 to 6;
• —(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino and C1-3 alkoxy;
• R1 represents a hydrogen atom, or a C1-6 alkyl group;
• B represents NR3R4, wherein
• R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom;
• or R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O—C1-3alkylidene group, or a C1-3 alkylidene-N(R5)—C1-3alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl and C1-3 alkoxy group;
• the nitrogen atom being optionally substituted with a C1-3 alkyl;
• said method comprising reacting a compound of formula V:
• wherein R1, n, —(C)n-, and B are as defined for the compound of formula II;
• with a compound of formula IV:
• wherein Pg is as defined above for the compound of formula II.

A process for preparing a compound of formula II:

• wherein
• Pg is a protective group;
• n represents a value from 1 to 6;
• —(C)n- represents a C1-6 alkylidene group optionally substituted with 1 to 4 substituents selected from halogen, hydroxyl, nitro, cyano, amino, C1-3 monoalkylamino, C2-6 dialkylamino and C1-3 alkoxy;
• R1 represents a hydrogen atom, or a C1-6 alkyl group;
• B represents NR3R4, wherein
• R3 and R4 represent, independently of one another, a C1-6 alkyl group, or a hydrogen atom;
• or R3 and R4 together represent a C1-6 alkylidene group, a C2-8 alkenylidene group, a C1-3 alkylidene-O—C1-3 alkylidene group, or a C1-3 alkylidene-N(R5)-C1-3 alkylidene group where R5 represents a hydrogen atom, or a C1-3 alkyl or C1-6 alkylcarbonyl group, it being possible for these C1-3 alkyl and C1-6 alkylcarbonyl groups to be substituted with a halogen atom, or a hydroxyl, C1-3 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, C1-3 monoalkylamino, C2-6 dialkylamino, C1-3 alkyl and C1-3 alkoxy group;
• the nitrogen atom being optionally substituted with a C1-3 alkyl;
• said method comprising reacting a compound of formula VII:
• wherein Pg and R1 are as defined for the compound of formula II;
• with a compound of formula VIII:
• wherein n, —(C)n-, and B are as defined for the compound of formula II.