Tricyclic triazolic compounds

Patent metadata

Field	Value
Publication number	US-9512142-B2
Application number	US-201414785128-A
Country	US
Kind code	B2
Filing date	Apr 21, 2014
Priority date	Apr 19, 2013
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The present invention relates to new tricyclic triazolic compounds having a great affinity for sigma receptors, especially sigma-1 receptors, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
R 1 is selected from:
a —(C(R 3 ) 2 ) m -aryl group in which the aryl group may be optionally substituted by at least one halogen atom;
a —(C(R 3 ) 2 ) m -heteroaryl group in which the heteroaryl group may be optionally substituted by at least one substituent selected from a halogen, C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -haloalcoxy or C 1-3 -haloalkyl and in which the heteroaryl group may optionally be condensed with an additional ring system;
a —(C(R 3 ) 2 ) n -heterocycloalkyl group, in which the heterocycloalkyl may be optionally substituted by at least one substituent selected from a halogen, C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -haloalcoxy or C 1-3 -haloalkyl and contains at least one oxygen atom;

R 2 is selected from:
a phenyl group optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkoxy, C 1-3 -haloalcoxy, C 1-3 -haloalkyl or a hydroxyl group;
a heteroaryl group optionally substituted by at least one substitutent selected from a halogen, C 1-3 -alkyl C 1-3 -alkoxy, C 1-3 haloalcoxy, C 1-3 -haloalkyl or a hydroxyl group;
a heterocycloalkyl group and being optionally substituted by at least one substituent selected from a halogen, C 1-3 -alkyl, C 1-3 -alkoxy, C 1-3 -haloalcoxy, C 1-3 -haloalkyl or a hydroxyl group;

R 3 is H or C 1-3 alkyl;
m is 1 to 3; and
n is 0 to 3;
with the proviso that when R 1 is a —(C(R 3 ) 2 ) m -aryl group, R 2 is not a phenyl group;
or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.

2. A compound according to claim 1 , wherein R 1 is a benzyl optionally substituted by at least one halogen; a —(C(R 3 ) 2 ) m -heteroaryl group in which the heteroaryl is a 5 or 6 membered heteroaryl radical containing from 1 to 3 heteroatoms selected from N or O and is optionally substituted by at least one substituent selected from a halogen, C 1-3 -alkyl, C 1-3 -alkoxy or C 1-3 -haloalkyl; or a —(C(R 3 ) 2 ) n -heterocycloalkyl group, in which the heterocycloalkyl group is a tetrahydropyranyl or as tetrahydrofuranyl group.

3. A compound according to claim 1 , wherein R 1 is selected from:

wherein R a represents a hydrogen, a halogen, C 1-3 alkyl, C 1-3 -alkoxy or C 1-3 haloalkyl, R b represents a hydrogen or a halogen and m and n are as defined in claim 1 .

4. A compound according to claim 1 , wherein R 2 is a phenyl optionally substituted by at least one substituent selected from a halogen or C 1-3 haloalkyl; a 5 or 6 membered heteroaryl radical containing from 1 to 3 N atoms and optionally substituted by at least one substituent selected from a halogen, C 1-3 -alkyl or C 1-3 -alkoxy; or a tetrahydropyranyl group.

5. A compound according to claim 1 , wherein R 2 is selected from:

wherein represents a hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl.

6. A compound according to claim 1 , wherein R 1 is selected from:

R 2 is selected from:

wherein R a represents a hydrogen, a halogen, C 1-3 alkyl, C 1-3 -alkoxy or C 1-3 haloalkyl, R b represents a hydrogen or a halogen, R c represents a hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and m and n are as defined in claim 1 .

7. A compound according to claim 1 , selected from the group consisting of:
(5aR,8aR)-3-(2-fluorophenyl)-7-(pyridin-3-ylmethyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aRS,8aRS)-3-(2-fluorophenyl)-7-(pyridin-4-ylmethyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aRS,8aRS)-3-(2-fluorophenyl)-7-(pyridin-2-ylmethyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(4-fluorophenyl)-7-(tetrahydro-2H-pyran-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(4-fluorophenyl)-7-(tetrahydro-2H-pyran-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2-fluorophenyl)-7-(tetrahydro-2H-pyran-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-(tetrahydro-2H-pyran-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(6-methoxypyridin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2-fluorophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-((6-fluoropyridin-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-((6-methoxypyridin-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2-fluorophenyl)-7-((6-methoxypyridin-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2-fluorophenyl)-7-(((R)-tetrahydrofuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-(((S)-tetrahydrofuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2-fluorophenyl)-7-(((S)-tetrahydrofuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2-fluorophenyl)-7-(((R)-tetrahydrofuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-7-((6-ethoxypyridin-3-yl)methyl)-3-(2-fluorophenyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-7-((6-ethoxypyridin-3-yl)methyl)-3-(2-fluorophenyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aRS,8aRS)-3-(4-fluorophenyl)-7-(furan-3-ylmethyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2,4-difluorophenyl)-7-((2,5-dimethylfuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-3-(2,4-difluorophenyl)-7-((2,5-dimethylfuran-3-yl)methyl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aR,8aR)-7-(4-fluorobenzyl)-3-(pyridin-2-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-7-(4-fluorobenzyl)-3-(pyridin-2-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aRS,8aRS)-7-(4-fluorobenzyl)-3-(pyridin-4-yl)-4,5a,6,7,8,8a-hexahydropyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine hydrochloride
(5aS,8aS)-3-(2,4-difluorophenyl)-7-(te

Assignees

• Esteve Labor Dr

Inventors

• Díaz-Fernández José-Luís
• Almansa-Rosales Carmen
• Cuevas-Cordobés Félix

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title