Tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives as cannabinoid CB1 receptor agonists
View Patent ↗The invention relates to tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative having the general Formula (I) wherein X is CH 2 , O or S; R represents 1-3 substituents independently selected from H, (C 1-4 )alkyl, (C 1-4 )alkyloxy and halogen; R 1 is (C 5-8 )cycloalkyl; R 2 is H or (C 1-4 )alkyl; R 3 , R 3 ′, R 4 ′ R 4 ′, R 5 , R 5 ′ and R 6 ′ are independently hydrogen or (C 1-4 )-alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; R 6 is hydrogen or (C 1-4 )alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; or R 6 forms together with R 7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R 7 forms together with R 6 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; or R 7 is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C 1-4 )alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.
1. A tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative having the general Formula I
wherein
X is CH 2 , O or S;
R represents 1-3 substituents independently selected from H, (C 1-4 )alkyl, (C 1-4 )alkyloxy and halogen;
R 1 is (C 5-8 )cycloalkyl;
R 2 is H or (C 1-4 )alkyl;
R 3 , R 3 ′, R 4 , R 4 ′, R 5 , R 5 ′ and R 6 ′ are independently hydrogen or (C 1-4 )alkyl, optionally substituted with (C 1-4 alkyloxy, OH or halogen;
R 6 is hydrogen or (C 1-4 alkyl, optionally substituted with (C 1-4 alkyloxy, OH or halogen; or
R 6 forms together with R 7 a 4-7 membered saturated heterocyclic ring having only carbons as additional ring members; or
R 7 is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C 1-4 )alkyloxy; or a pharmaceutically acceptable salt thereof.
2. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 1 , wherein R is H and R 1 is cyclopentyl or cyclohexyl.
3. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 1 , wherein X is CH 2 or O.
4. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 1 , wherein R, R 2 , R 3 , R 3 ′, R 4 ′, R 5 , R 5 ′ and R 6 ′ are H; R 4 , R 6 and R 7 are independently H or (C 1-4 )alkyl; or R 6 forms together with R 7 a 5- or 6-membered saturated heterocyclic ring having only carbons as additional ring members and R 4 is H or (C 1-4 alkyl.
5. A pharmaceutical composition comprising a tricyclic 1-[(indol-3-yl)-carbonyl]piperazine derivative of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier therefor.
6. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 2 , wherein X is CH 2 or O.
7. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 2 , wherein R, R 2 , R 3 , R 3 ′, R 4 ′, R 5 , R 5 ′ and R 6 ′ are H; R 4 , R 6 and R 7 are independently H or (C 1-4 alkyl; or R 6 forms together with R 7 a 5- or 6-membered saturated heterocyclic ring having only carbons as additional ring members and R 4 is H or (C 1-4 )alkyl.
8. The tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 3 , wherein R, R 2 , R 3 , R 3 ′, R 4 ′, R 5 , R 5 ′ and R 6 ′ are H; R 4 , R 6 and R 7 are independently H or (C 1-4 alkyl; or R 6 forms together with R 7 a 5- or 6-membered saturated heterocyclic ring having only carbons as additional ring members and R 4 is H or (C 1-4 )alkyl.
9. A method of treating pain in a patient in need of such treatment, comprising:
administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.