Tricyclic triazolic compounds

1. A compound of formula (I):

wherein

R 1 is a H; a C 1-6 alkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a C 3-9 cycloalkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O, N or S and being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a 5 or 6-membered aryl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 haloalkoxy, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a 5 or 6-membered heteroaryl having at least one heteroatom selected from O, N or S and being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a —(C(R 4 ) 2 ) m —C 3-9 cycloalkyl, the cycloalkyl group being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a —(C(R 4 ) 2 ) m -heterocycloalkyl, the heterocycloalkyl group being a 5 or 6-membered ring having at least one heteroatom selected from O, N or S and being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a —(C(R 4 ) 2 ) m -aryl, the aryl group being a 5 or 6-membered ring optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1,3 -haloalkyl, trihaloalkyl or a hydroxyl group; or a —(C(R 4 ) 2 ) m -heteroaryl, the heteroaryl group being a 5 or 6-membered ring having at least one heteroatom selected from O, N or S and being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group;

R 2 is a 5 or 6-membered aryl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; or a substituted 5 or 6-membered heteroaryl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group;

R 3 is a H; a C 1-6 alkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; —(C(R 4 ) 2 ) m —C 3-9 cycloalkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a —SO 2 R 5 group; a —COR 6 group; a —CO 2 R 7 group; or a —(C(R 4 ) 2 ) m —CONR 8 R 9 ;

R 4 is H or a C 1-6 alkyl;

R 5 , R 6 and R 7 are a C 1-6 alkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group;

R 8 and R 9 independently represent a H, a C 1-6 alkyl; or a —(C(R 4 ) 2 ) m -aryl, the aryl group being a 5 or 6-membered ring optionally substituted by at least one substitutent selected from a 5 or 6-membered heterocycloalkyl, a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group;

Z is CH 2 or C═O and

n is 0 or, 1;

m is 0, 1 or 2;

or a pharmaceutically acceptable salt or isomer thereof.

2. A compound of claim 1 wherein R 1 is H; a C 1-6 alkyl optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a 5 or 6-membered heterocycloalkyl having at least one heteroatom selected from O, N or S and being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; a —(C(R 4 ) 2 ) m —C 3-9 cycloalkyl, the cycloalkyl group being optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group; or a —(C(R 4 ) 2 ) m -aryl, the aryl group being a 5 or 6-membered ring optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -alkyl, C 1-3 -haloalkoxy, C 1-3 -haloalkyl, trihaloalkyl or a hydroxyl group.

3. A compound of claim 1 , wherein R 1 is H, a C 1-6 alkyl or a group selected from:

wherein R a represents a hydrogen, a halogen, C 1-3 alkyl, or a trihaloalkyl.

4. A compound of claim 1 , wherein R 2 is a phenyl optionally substituted by at least one halogen atom.

5. A compound of claim 1 , wherein R 3 is a H; a C 1-6 alkyl; —(C(R 4 ) 2 ) m —C 3-9 cycloalkyl; a —SO 2 R 5 group; a —COR 6 group; or a —CO 2 R 7 group; wherein R 5 , R 6 and R 7 are C 1-6 alkyl.

6. A compound of claim 1 , wherein

R 1 is H, a C 1-6 alkyl or a group selected from:

wherein R a represents a hydrogen, a halogen, C 1-3 alkyl, or a trihaloalkyl;

R 2 is a phenyl optionally substituted by at least one halogen atom; and

R 3 is a H; a C 1-6 alkyl; —(C(R 4 ) 2 ) m —C 3-9 cycloalkyl; a —SO 2 R 5 group; a —COR 6 group; or a —CO 2 R 7 group; wherein R 5 , R 6 and R 7 are C 1-5 alkyl.

7. A compound of claim 1 , having the following formula:

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

(rac) (5a,8a-trans)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine, hydrochloride,

(rac)-(5a,8a-cis)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-4-one,

(rac) (5a,8a-cis)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine,

(rac) 1-((5a,8a-trans)-7-benzyl-3-phenyl-6,7,8,8a-tetrahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-5(5aH)-yl)ethanone hydrochloride,

(rac)-(5a,8a-cis)-7-benzyl-3-phenyl-5-propyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-4-one,

(rac)-(5a,8a-trans)-tert-butyl-3-phenyl-6,7,8,8a-tetrahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine-5(5aH)-carboxylate,

(rac)-(5a,8a-trans)-tert-butyl-7-(4-fluorobenzyl)-3-phenyl-6,7,8,8a-tetrahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine-5(5aH)-carboxylate, pq, 66

(rac) (5a,8a-trans)-7-(4-fluorobenzyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-7-benzyl-3-phenyl-5-propyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-3-phenyl-5-propyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-7-pentyl-3-phenyl-5-propyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-cis)-7-benzyl-5-methyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine,

(rac) (5a,8a-cis)-7-benzyl-3-phenyl-5-propyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine,

(rac) (5a,8a-cis)-7-pentyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine,

(5aS,8aR)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine,

(rac) (5a,8a-trans)-7-benzyl-5-methyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) 1-((5a,8a-trans)-7-benzyl-3-phenyl-6,7,8,8a-tetrahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-5(5aH)-yl)propan-1-one hydrochloride,

(rac) (5a,8a-trans)-7-(cyclopropyl-methyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-3-phenyl-7-(tetrahydro-2H-pyran-4-yl)-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-7-benzyl-5-(methylsulfonyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aS,8aS)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-7-benzyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aS,8aS)-7-(4-fluorobenzyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-7-(4-fluorobenzyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-7-(4-chlorobenzyl)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-3-phenyl-7-(4-(trifluoromethyl)benzyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-3-phenyl-7-((tetrahydro-2H-pyran-4-yl)methyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (5a,8a-trans)-7-benzyl-3-(2-fluorophenyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(5aR,8aR)-7-benzyl-3-(2-fluorophenyl)-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazine hydrochloride,

(rac) (6a,9a-cis)-8-benzyl-3-phenyl-4,5,6,6a,7,8,9,9a-octahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]diazepine hydrochloride,

(rac) (6a,9a-cis)-8-benzyl-3-phenyl-6-propyl-4,5,6,6a,7,8,9,9a-octahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]diazepine hydrochloride,

(rac) (6a,9a-cis)-8-benzyl-6-(cyclopropylmethyl)-3-phenyl-4,5,6,6a,7,8,9,9a-octahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]diazepine hydrochloride,

(rac) 1-((6a,9a-cis)-8-benzyl-3-phenyl-4,5,7,8,9,9a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]diazepin-6(6aH)-yl)propan-1-one hydrochloride,

(6aR,9aS)-8-benzyl-3-phenyl-4,5,6,6a,7,8,9,9a-octahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]diazepine hydrochloride,

(6aS,9aR)-8-benzyl-3-phenyl-4,5,6,6a,7,8,9,9a-octahydropyrrolo[3,4-b][1,2,3]triazolo [1,5-d][1,4]-diazepine hydrochloride,

(rac)-(5a,8a-cis)-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-4-one hydrochloride and

(rac)-(5a,8a-cis)-7-benzyl-5-methyl-3-phenyl-5,5a,6,7,8,8a-hexahydro-4H-pyrrolo[3,4-e][1,2,3]triazolo[1,5-a]pyrazin-4-one.

9. A method of treating a patient suffering from a sigma receptor mediated disease or condition selected from the group consisting of pain, anxiety, depression, schizophrenia, and stress, the method comprising administering to the patient in need of such a treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or isomer thereof.

10. The method of claim 9 , wherein the condition is pain, which is selected from the group consisting of neuropathic pain, inflammatory pain, and pain conditions involving allodynia and/or hyperalgesia.

11. The method of claim 9 , wherein the condition is selected from stress, cancer, depression, anxiety, and schizophrenia.

12. A process for the preparation of a compound of claim 1 which is of formula (l):

comprising the cycloaddition reaction in a non-polar solvent of a compound of formula (II):

13. A process for the preparation of a compound of claim 1 which is of formula (l):

comprising the reaction in an organic solvent of a compound of formula (Ic):

with a compound of general formula (IIIa) or (VIa):

wherein X is a suitable leaving group.

14. A process for the preparation of a compound of claim 1 which is of formula (I):

comprising the reaction in an organic solvent of a compound of formula (Id):

with a compound of formula (IIIb), (IV), (V) or (VIb):

wherein R′ stands for R 5 and R 6 and X is a suitable leaving group.

15. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salts or isomers thereof, and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.

16. The process of claim 13 , wherein X is halogen or sulfonate.

17. The process of claim 14 , wherein X is halogen or sulfonate.