1-[(indol-3-yl)carbonyl]piperazine derivatives
View Patent ↗The present invention relates to 1-[(indol-3-yl)carbonyl]piperazine derivative according to the general formula I or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said 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. An 1-[(indol-3-yl)carbonyl]piperazine derivative having the general formula I
wherein
R represents 1-4 substituents independently selected from H, (C 1-4 )alkyl (optionally substituted with halogen), (C 1-4 )alkyloxy (optionally substituted with halogen), halogen, OH, NH 2 , CN and NO 2 ;
R 1 is (C 5-8 )cycloalkyl or (C 5-8 )cycloalkenyl;
R 2 is H, methyl or ethyl;
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, halogen or OH;
R 6 is hydrogen or (C 1-4 )alkyl, optionally substituted with (C 1-4 )alkyloxy, halogen or OH; 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 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 1 , wherein R 2 is H and R 1 is (C 5-8 )cycloalkyl.
3. The 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 2 , wherein R is (C 1-4 )alkyloxy or halogen.
4. The 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 3 , wherein R represents a methoxy group at the 7-position of the indole ring.
5. The 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 4 , wherein 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 and R 4 is H or (C 1-4 )alkyl.
6. The 1-[(indol-3-yl)carbonyl]piperazine derivative according to claim 1 , wherein the derivative is selected from the group consisting of
1-{[1-(cyclohexylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-3,5-dimethyl-4-ethylpiperazine;
1-{[1-(cyclohexylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-3,4,5-trimethylpiperazine;
(S)-1-{[1-(cyclohexylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-3,4-dimethylpiperazine;
(S)-2-{[1-(cyclohexylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-octahydro-2H-pyrido-[1,2-a]pyrazine;
(S)-2-{[1-(cyclohexylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-octahydro-2H-pyrrolo-[1,2-a]pyrazine; and
(S)-2-{[1-(cyclopentylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-octahydro-2H-pyrido-[1,2-a]pyrazine;
or a pharmaceutically acceptable salt thereof of each individual derivative.
7. A pharmaceutical composition, comprising:
the 1-[(indol-3-yl)carbonyl]piperazine derivative of claim 1 , and
a pharmaceutically acceptable carrier.
8. A method of treating pain in a patient in need thereof, comprising:
administering an effective amount of the derivative according to claim 1 .