Indole derivatives

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Quick Facts

Patent No.: US 7,655,645
App. No.: 12/031,851
Granted: Feb 2, 2010
Kind: B2

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Abstract

The invention relates to indole derivative having the general Formula I wherein A represents a 5-membered aromatic heterocyclic ring, wherein X 1 , X 2 and X 3 are independently selected from N, O, S and CH; Y represents CH 2 , O, S or SO 2 ; R 1 is H, (C 1-4 )-alkyl, (C 1-4 )alkyloxy, CN or halogen; R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 and R 5 ′ are independently hydrogen, (C 1-4 )alkyl (optionally substituted with OH) or CO—OR 8 ; or one pair of geminal substituents R 3 and R 3 ′ or R 5 and R 5 ′ together represent a keto group, and the others are all hydrogen or (C 1-4 )alkyl; or R 2 and R 5 together represent a methylene or an ethylene bridge, and R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′ and R 5 ′ are hydrogen; n is 1 or 2; R 6 is H, (C 1-4 )alkyl (optionally substituted with OH, (C 1-4 )alkyloxy, CO—NR 9 R 10 , CO—OR 11 or 1,2,4-oxadiazol-3-yl), SO 2 NR 12 R 13 or COOR 14 ; R 7 is H or halogen; R 8 is (C 1-4 )alkyl; R 9 and R 10 are independently hydrogen, (C 1-4 )alkyl or (C 3-7 )cycloalkyl, the alkyl groups being optionally substituted with OH or (C 1-4 )alkyloxy; R 11 is H or (C 1-4 )alkyl; R 12 and R 13 are independently H or (C 1-4 )alkyl; R 14 is (C 1-6 )alkyl; or a pharmaceutically acceptable salt thereof, as agonists of the cannabinoid CB1 receptor, which can be used in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

Claims (76)

1. An indole derivative having the general Formula I

wherein

A represents a 5-membered aromatic heterocyclic ring, wherein X 1 , X 2 and X 3 are independently selected from N, O, S and CH;

Y represents CH 2 , O, S or SO 2 ;

R 1 is H, (C 1-4 )alkyl (C 1-4 )alkyloxy, CN or halogen;

R 2 , R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′, R 5 and R 5 ′ are independently hydrogen, (C 1-4 )alkyl (optionally substituted with OH) or CO—OR 8 ; or

one pair of geminal substituents R 3 and R 3 ′ or R 5 and R 5 ′ together represent a keto group, and the others are all hydrogen or (C 1-4 )alkyl; or

R 2 and R 5 together represent a methylene or an ethylene bridge, and R 2 ′, R 3 , R 3 ′, R 4 , R 4 ′ and R 5 ′ are hydrogen;

n is 1 or 2;

R 6 is H, (C 1-4 )alkyl (optionally substituted with OH, (C 1-4 )alkyloxy, CO—NR 9 R 10 , CO—OR 11 or 1,2,4-oxadiazol-3-yl), SO 2 NR 12 R 13 or COOR 14 ;

R 7 is H or halogen;

R 8 is (C 1-4 )alkyl;

R 9 and R 10 are independently hydrogen, (C 1-4 )alkyl or (C 3-7 )cycloalkyl, the alkyl groups being optionally substituted with OH or (C 1-4 )alkyloxy;

R 11 is H or (C 1-4 )alkyl;

R 12 and R 13 are independently H or (C 1-4 )alkyl;

R 14 is (C 1-6 )alkyl;

or a pharmaceutically acceptable salt thereof.

2. The indole derivative of claim 1 , wherein the heterocyclic ring A represents 1,2,4-oxadiazole (X 1 is N, X 2 is O, X 3 is N) or 1,2,4-thiadiazole (X 1 is N, X 2 is S, X 3 is N).

3. The indole derivative of claim 1 , wherein R 1 is Cl and R 7 is H.

4. The indole derivative of claim 1 , wherein Y represents O.

5. The indole derivative of claim 1 , wherein R 6 is (C 1-4 )alkyl, substituted with CO—NR 9 R 10 or 1,2,4-oxadiazol-3-yl.

6. The indole derivative of claim 1 , wherein R 6 is CH 2 —CONH 2 .

7. The indole derivative according to claim 1 which is selected from the group consisting of

3-({5-[4-(carbamoylmethyl)-piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-({5-[4-(ethylcarbamoylmethyl)piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-({5-[4-sulfamoylpiperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-ethyl-3-({5-[4-(N-isopropylcarbamoylmethyl)piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-ethyl-3-({5-[4-(methoxycarbonylmethyl)piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

3-({5-[4-(carbamoylmethyl)piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-7-methoxy-1-(tetrahydropyran-4-yl)methyl-1H-indole;

3-({5-[4-(carbamoylmethyl)piperazin-1-yl]methyl}-[1,2,4]-thiadiazol-3-yl)-7-chloro-1-(1,1-dioxo-hexahydrothiopyran-4-yl)methyl-1H-indole;

3-({5-[4-(carbamoylmethyl)piperazin-1-yl]methyl}-[1,2,4]-oxadiazol-3-yl)-7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-chloro-3-({5-[4-([1,2,4]-oxadiazol-3-ylmethyl)piperazin-1-yl]methyl}-[1,2,4]-oxadiazol-3-yl)-1-(1,1-dioxo-hexahydrothiopyran-4-yl)methyl-1H-indole;

3-[5-[4-(tert-butoxycarbonyl)-cis-2,6-dimethylpiperazin-1-ylmethyl]-[1,2,4]-oxadiazol-3-yl]-7-chloro-1-[(tetrahydropyran-4-yl)methyl]-1H-indole;

3-({5-[4-(carbamoylmethyl)homopiperazin-1-ylmethyl]-[1,2,4]-oxadiazol-3-yl}-7-chloro-1-[(tetrahydropyran-4-yl)methyl]-1H-indole;

(S)-7-chloro-3-[5-[3-hydroxymethyl-4-(methylcarbamoylmethyl)piperazin-1-ylmethyl]-[1,2,4]-oxadiazol-3-yl]-1-[(tetrahydropyran-4-yl)methyl]-1H-indole; and

3-({4-[4-(carbamoylmethyl)piperazin-1-yl]methyl}-[1,3]-thiazol-2-yl)-7-chloro-1-(tetra-hydropyran-4-yl)methyl-1H-indole, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising an indole derivative of claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries.

9. The pharmaceutical composition of claim 8 , wherein an indole derivative is selected from the group consisting of