Isoquinoline and benzo[H] isoquinoline derivatives, preparation and therapeutic use thereof as antagonists of the histamine H3 receptor

1. A compound of formula (I):

wherein:

represents a 6-membered unsaturated carbocycle with double bonds which is optionally substituted by one or two substituents chosen, independently of one another, from a halogen atom, a hydroxyl, a nitro, cyano, C 1-2 perhaloalkyl or C 1-3 alkyl group or a phenyl;

1 is 0 to 2;

m is 0 to 2;

wherein the aminocycle comprising —(C) l —, —(C) m — and —NR1- forms a pyrrolidine;

n is 0 to 6;

—(C) l —, —(C) m — and —(C) n — represent, independently of one another, a —C x-z — alkylene group, optionally substituted by 1 to 4 substituents chosen from a halogen atom, a hydroxyl, nitro, cyano, amino, C 1-2 perhaloalkyl or C 1-3 alkyl group or a phenyl; and when l, m and n are 0, —(C) 0 — represents a bond;

R1 represents

a hydrogen atom,

a C 1-3 alkyl group,

a C 1-6 alkylcarbonyl,

a C 1-6 alkoxycarbonyl,

it being possible for each to be substituted by a halogen atom, a hydroxyl, C 1-3 alkoxy, nitro, cyano or amino group or aryl;

a C 1-3 alkylaryl group,

a monocyclic heteroaryl, and

an aryl;

the aryl and heteroaryl groups optionally being substituted by 1 to 4 substituents chosen 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 or C 1-3 alkoxy group or a alkylidenedioxy group; and

R2 represents

a C 1-6 alkyl group or a C 3-6 cycloalkyl group, each optionally being substituted by 1 to 4 substituents chosen 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 or C 3-6 cycloalkyl group, a monocyclic heteroaryl, a bicyclic heteroaryl or an aryl group itself optionally substituted by 1 to 4 substituents chosen 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 or C 1-3 alkoxy group or a C 1-3 alkylidenedioxy group,

or a salt thereof.

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

represents a 6-membered unsaturated carbocycle optionally substituted by 1 or 2 substituents chosen, independently of one another, from a halogen atom or a hydroxyl, nitro, cyano, C 1-2 perhaloalkyl or C 1-3 alkyl group;

l is 1 or 2;

m is 0 or 1;

wherein the aminocycle comprising —(C) l —, —(C) m — and —NR1- forms a pyrrolidine;

n is 0, 1, 2 or 3;

—(C) l — and —(C) m — form, together with the —NR1- group, an aminocycle bonded via a carbon to the —O—(C) n — group and, when m is 0, —(C) 0 — represents a bond;

—(C) n — represents a —C 0-3 — alkylene group optionally substituted by 1 to 4 substituents chosen from a halogen atom or a hydroxyl, nitro, cyano, amino or C 1-2 perhaloalkyl group; and, when n is 0, —(C) 0 — represents a bond; and

R1 represents

a hydrogen atom,

a C 1-3 alkyl group,

a C 1-6 alkylcarbonyl,

a C 1-6 alkoxycarbonyl;

C 1-3 alkylaryl,

a heteroaryl,

an aryl group;

the aryl and heteroaryl groups optionally being substituted by 1 to 4 substituents chosen from a halogen atom or a hydroxyl, cyano, amino, C 1-3 monoalkylamino, C 1-3 alkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl, C 1-3 alkoxy or C 1-3 alkylidenedioxy group,

or a salt thereof.

3. The compound of formula (I) according to claim 2 , wherein the aminocycle of which —(C) l —, —(C) m — and —NR1- form part and which is bonded via a carbon to the —O—(C) n — group is:

and wherein:

R2 represents

a C 1-4 alkyl or C 5-6 cycloalkyl group, each being optionally substituted by 1 to 4 substituents chosen from a phenyl, a monocyclic heteroaryl, a bicyclic heteroaryl or a C 3-6 cycloalkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl or C 1-3 alkoxy group; the phenyl and the heteroaryl optionally being substituted by 1 to 4 substituents chosen 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 or C 1-3 alkoxy group or a C 1-3 alkylidenedioxy group,

or a salt thereof.

4. The compound of formula (I) according to claim 1 , wherein the unsaturated carbocycle with double bonds is a phenyl, or a salt thereof.

5. The compound of formula (I) according to claim 1 , wherein R1 is chosen from benzyloxycarbonyl, benzyl, phenethyl, thienyl, furyl, pyrrolyl, phenyl or naphthyl,

or a salt thereof.

6. The compound of formula (I) according to claim 1 , wherein R2 represents a C 1-4 alkyl or C 5-6 cycloalkyl group, each optionally being substituted by a monocyclic heteroaryl chosen from thienyl, furyl, pyrrolyl, benzotriazolyl, or an aryl chosen from phenyl or naphthyl,

or a salt thereof.

7. The compound according to claim 1 , which is selected from the group consisting of:

2-isobutyl-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

2-(3-methylbutyl)-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

2-(cyclohexylmethyl)-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

2-(cyclohexylmethyl)-7-{2-[(2R)-1-methylpyrrolidin-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;

2-(cyclohexylmethyl)-7-{2-[(2S)-1-methylpyrrolidin-2-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline;

2-benzyl-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

2-butyl-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline;

7-[2-(1-methylpyrrolidin-2-yl)ethoxy]-2-propyl-1,2,3,4-tetrahydroisoquinoline;

or a salt thereof.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. A pharmaceutical composition comprising a compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

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

reacting a compound of formula (II):

wherein R2 and A are as defined in claim 1 , with a compound of formula (III):

wherein l, m, n, and R1 are as defined in claim 1 , and Y represents a halogen atom, hydroxy, or a pseudohalogen selected from the group consisting of mesylate, triflate, tosylate, brosylate and nosylate.

16. A process for the preparation of a compound of formula (I) according to claim 1 , in which R1, R2, l, m, n and the A ring are as defined in claim 1 comprising the step according to the following reaction:

comprising

reacting a phenol of formula (II), wherein R2 and the A ring are as defined in claim 1 , under nucleophilic substitution reaction conditions with an amine of formula (III), in which R1, l, m and n are as defined in claim 1 and Y represents a halogen atom, hydroxy, or a “pseudohalogen” selected from the group consisting of mesylate, triflate, tosylate, brosylate and nosylate.

17. The process according to claim 16 , wherein the compound of formula (II) is prepared by reductive amination by reacting a secondary amine of formula (IV), in which R2 represents H and Pg is a protecting group:

with an aldehyde or a ketone of formula (V): (R3R4C(O)), where after reaction, R3 and R4 together with the carbonyl carbon form R2, to form a compound of formula (VI):

wherein R2 represents a C 1-6 alkyl group or a C 3-6 cycloalkyl group, each optionally being substituted by 1 to 4 substituents chosen 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 or C 3-6 cycloalkyl group, a monocyclic heteroaryl, a bicyclic heteroaryl or an aryl group itself optionally substituted by 1 to 4 substituents chosen 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 or C 1-3 alkoxy group or a C 1-3 alkylidenedioxy group; and

deprotecting the compound of formula VI to form the compound of formula (II).

18. The process according to claim 16 , wherein the compound of formula (II) is prepared by nucleophilic substitution by reacting a compound of formula (VIa):

wherein R2 represents a benzotriazolylmethyl group and Pg is a protecting group, with a Grignard reagent of formula (VII) R5MgW, wherein W represents a halogen atom chosen from chlorine, iodine and bromine and R5 represents a C 1-5 alkyl, C 1-2 perhaloalkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl group, a monocyclic heteroaryl or an aryl group; to form a compound of formula (VIb) wherein R2 is —CH 2 R 5 :

deprotecting the compound of formula VIb to form the compound of formula (II).