1,2,4-triazole derivatives as sigma receptor inhibitors

1. A compound of formula (I):

wherein:

R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alcoxyl, substituted or unsubstituted C 1 -C 6 alkyl, cyano, NR a R b , NHCONR c , NHSO 2 R d , COOH, COOR e , wherein R a is hydrogen or C 1 -C 6 alkyl and R b , R c , R d and R e are independently a C 1 -C 6 alkyl;

R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cycloalkyl, heteroaryl and heterocyclyl;

R 5 and R 6 are independently a C 1 -C 6 alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group;

X is selected from the group consisting of —S—, —SO—, —SO 2 — and O; and

n is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8,

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof,

with the proviso that

R 4 is not cyclopropyl; and

when R 4 is hydrogen at least one of R 1 , R 2 and R 3 is not hydrogen.

2. The compound according to claim 1 wherein at least one of R 1 to R 3 is hydrogen.

3. The compound according to claim 1 wherein two of R 1 to R 3 are hydrogen or halogen.

4. The compound according to claim 1 wherein R 4 is a C 1 -C 6 alkyl.

5. The compound according to claim 1 wherein R 5 and R 6 are independently a C 1 -C 6 alkyl.

6. The compound according to claim 1 wherein R 5 and R 6 form, together with the nitrogen to which they are attached, a substituted or unsubstituted heterocyclyl group.

7. The compound according to claim 1 wherein n is 1, 2, 3, 4 or 5.

8. A compound according to claim 1 , selected from the group consisting of:

4-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio ethyl] morpholine;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1.2.4-triazole-3-yl-thioethyl] piperidine;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl-thio ethyl] pyrrolidine;

2-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl-thio]-N,N-diisopropyl ethanamine;

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3yl-thio]-N,N-diethyl ethanamine;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)ethyl] azepane;

4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)propyl] morpholine;

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)propyl]-4-pyrrolidine;

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)propyl]-4-phenylpiperidine;

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)butyl]-4-phenylpiperidine;

4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)butyl] morpholine;

1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl] piperidine;

4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl]morpholine;

1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl]pyrrolidine;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfinyl) ethyl] pyrrolidine;

4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfinyl)-ethyl]-morpholine;

2-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylsulfinyl]-N,N-diisopropylethanamine;

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylsulfinyl)butyl]-4-phenylpiperidine;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylsulfonyl] ethyl pyrrolidine;

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfonyl]-N,N-diethylethanamine;

4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfonyl)-butyl] morpholine;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy) ethyl] piperidine;

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy]-N,N-diethylethanamine;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy)ethyl] pyrrolidine;

4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy)ethyl] morpholine;

2-(5-methyl-1-phenyl-1H-1,2,4-triazo-3-yloxy)-N,N-diethyl ethanamine;

1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yloxy)ethyl] pyrrolidine;

4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yloxy)ethyl] morpholine;

1-[2-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yloxy)ethyl] piperidine;

4-[4-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yloxy)butyl] morpholine;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]-4-methylpiperidine;

4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-ylthio)ethyl] morpholine;

4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] morpholine;

N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]-N,N -diisopropylpropan-2-amine;

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] piperidine;

4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] morpholine;

4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] pyrrolidine;

2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio]-N,N-diethylethanamine;

4-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio]-N,N-diethylbutan-1-amine;

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)butyl] piperidine;

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)butyl] pyrrolidine;

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylsulfinyl]-N,N-diethylethanamine;

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfinyl)ethyl] pyrrolidine

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfinyl)ethyl] morpholine

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfinyl)ethyl]-N,N-diethylamine;

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfonyl)ethyl] pyrrolidine

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfonyl)ethyl]-N,N-diisopropilamine;

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-sulfonyl)ethyl]-N,N-diethylamine;

or a pharmaceutically acceptable salt, isomer, or solvate thereof.

9. The compound according to claim 1 which is an oxalic salt thereof.

10. A compound according to claim 1 selected from the group consisting of:

4-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio ethyl] morpholine oxalate;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1.2.4-triazole-3-yl-thio)ethyl] piperidine oxalate;

1-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl-thio ethyl] pyrrolidine oxalate;

2-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl-thio]-N,N-diisopropyl ethanamine oxalate;

2-[1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-yl-thio]-N,N-diethyl ethanamine oxalate;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)ethyl] azepane oxalate;

4-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio) propyl] morpholine oxalate;

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)propyl] pyrrolidine oxalate;

1-[3-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)propyl]-4-phenylpiperidine oxalate;

1-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)butyl]-4-phenylpiperidine oxalate;

4-[4-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl-thio)butyl] morpholine oxalate;

1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl] piperidine oxalate;

4-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl] morpholine oxalate;

1-[5-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)pentyl] pyrrolidine oxalate;

4-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-yloxy)ethyl] morpholine oxalate;

4-[2-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazole-3-ylthio) ethyl] morpholine hydrochloride;

1-[2-(1-(3,4-dichlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]-4-methyl piperidinium oxalate;

4-[2-(5-methyl-1-phenyl-1H-1,2,4-triazol-3-ylthio)ethyl]morpholinium oxalate;

4-[2-(1-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] morpholinium oxalate;

N-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]-N,N -diisopropylpropan-2-aminium oxalate;

1-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]piperidinium oxalate;

4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl] morpholinium oxalate;

4-[2-(1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio)ethyl]pyrrolidinium oxalate;

2-[1-(3-chlorophenyl)-5-methyl-1H-1,2,4-triazol-3-ylthio]-N,N-diethylethan aminium oxalate.

11. A process for the preparation of a compound of formula (I), as defined in claim 1 or a salt, stereoisomer, or solvate thereof, which comprises the alkylation of the corresponding 5-alkyl-1-aryl-1H-1,2,4-triazol-3-thiol/ol of formula (II):

with an alkylating agent,

wherein:

R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alcoxyl, substituted or unsubstituted C 1 -C 6 alkyl, cyano, NR a R b , NHCONR c , NHSO 2 R d , COOH, COOR e , wherein R a is hydrogen or C 1 -C 6 alkyl and R b , R c , R d and R e are independently a C 1 -C 6 alkyl;

R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocyclyl and heteroaryl; and

X is O or S,

with the proviso that:

R 4 is not cyclopropyl; and

when R 4 is hydrogen at least one of R 1 , R 2 and R 3 is not hydrogen.

12. The process according to claim 11 wherein the alkylating agent is a compound of formula (III):

wherein

Z is a halogen,

R 5 and R 6 are independently a C 1 -C 6 alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group, and

n is selected form 1, 2, 3, 4, 5, 6, 7 and 8.

13. The process according to claim 11 wherein the alkylating agent is a compound of formula (IV):

wherein Z is a halogen and n selected form 1, 2, 3, 4, 5, 6, 7 and 8.

14. The process according to claim 13 which further comprises the reaction of the compound obtained after the alkylation reaction with an amine NHR 5 R 6 , wherein R 5 and R 6 are independently a C 1 -C 6 alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group.

15. A process for the preparation of a compound of formula (I), as defined in claim 1 or a salt, stereoisomer, or solvate thereof, which comprises the reaction of the compound of formula (V):

wherein:

R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alcoxyl, substituted or unsubstituted C 1 -C 6 alkyl, cyano, NR a R b , NHCONR c , NHSO 2 R d , COOH, COOR e , wherein R a is hydrogen or C 1 -C 6 alkyl and R b , R c , R d and R e are independently a C 1 -C 6 alkyl;

R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocyclyl and heteroaryl;

X is O or S;

Z is a halogen;

n selected form 1, 2, 3, 4, 5, 6, 7 and 8,

with the proviso that:

R 4 is not cyclopropyl; and

when R 4 is hydrogen at least one of R 1 , R 2 and R 3 is not hydrogen, with an amine NHR 5 R 6 , wherein R 5 and R 6 are independently a C 1 -C 6 alkyl or form, together with the nitrogen atom to which they are attached, a substituted or unsubstituted heterocyclyl group.

16. The process according to claim 11 which further comprises the oxidation of the corresponding 3-(alkylthio)-1H-1,2,4-triazole obtained after any of the processes defined in claims 11 or 15 .

17. A compound of formula (V):

wherein:

R 1 , R 2 and R 3 are independently selected from hydrogen, halogen, hydroxyl, alcoxyl, substituted or unsubstituted C 1 -C 6 alkyl, cyano, NR a R b , NHCONR c , NHSO 2 R d , COOH, COOR e , wherein R a is hydrogen or C 1 -C 6 alkyl and R b , R c , R d and R e are independently a C 1 -C 6 alkyl;

R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, cycloalkyl, heterocyclyl and heteroaryl;

X is O or S;

Z is a halogen;

n selected form 1, 2, 3, 4, 5, 6, 7 and 8,

with the proviso that:

R 4 is not cyclopropyl; and

when R 4 is hydrogen at least one of R 1 , R 2 and R 3 is not hydrogen.

18. A pharmaceutical composition which comprises a compound as defined in claim 1 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

19. The compound according to claim 3 wherein the halogen is chloride.

20. The compound according to claim 4 wherein R 4 is methyl.

21. The compound according to claim 5 wherein the R 5 and R 6 are independently ethyl or isopropyl.

22. The compound according to claim 6 wherein the heterocyclylc group is selected from the group consisting of pyrrolidine, piperidine, azepane and morpholine.