Indole derivatives

1. An indole having the general Formula I

wherein

A represents a 5-membered aromatic heterocyclic oxadiazole or thiadiazole ring, wherein

X 1 , X 2 and X 3 are independently selected from N, O, and S;

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

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

R 2 is H or (C 1-4 )alkyl; or

R 2 together with R 3 and the carbon and nitrogen atoms to which they are bonded form pyrrolidine;

R 3 is H, (C 1-6 )alkyl or (C 3-7 )cycloalkyl, the alkyl groups being optionally substituted with OH, (C 1-4 )alkyloxy, (C 1-4 )alkylthio, (C 1-4 )alkylsulfonyl, CO—NR 5 R 6 , CO—OR 7 , CN or halogen;

R 4 is CO—NR 5 R 6 , CO—OR S , SO 2 —R 8 , SO 2 —NR 9 R 10 , or CO—R 11 ; or

R 4 is (C 1-3 )alkyl, substituted with CO—NR 5 R 6 , CO—OR 7 , SO 2 —R 8 , SO 2 —NR 9 R 10 , NH—CO—R 11 , NH—SO 2 —R 12 , or two OH groups; and optionally further substituted with OH; or

R 4 together with R 3 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O, S and SO 2 , the ring being substituted with CO—NR 13 R 14 , CO—OR 7 , SO 2 —R 8 , SO 2 —NR 9 R 10 , NH—CO—R 11 or NH—SO 2 —R 12 ; or the ring being substituted with (C 1-3 )alkyl, substituted with NH—CO—R 11 or NH—SO 2 —R 12 ;

R 5 , when present, is H or (C 1-4 )alkyl, optionally substituted with OH, (C 1-4 )alkyloxy or CONR 7 R 8 ;

R 6 , when present, is H or (C 1-4 )alkyl; or

R 6 together with R 5 and the N to which they are bonded form a 4-8 membered ring optionally containing a further heteroatom selected from O, S and SO 2 , the ring being optionally substituted with OH;

R 7 , when present, is H or (C 1-4 )alkyl;

R 8 , when present, is (C 1-4 )alkyl or (C 3-7 )cycloalkyl, optionally substituted with OH or (C 1-4 )alkyloxy;

R 9 , when present, is H or (C 1-4 )alkyl, optionally substituted with OH or (C 1-4 )alkyloxy;

R 10 , when present, is H or (C 1-4 )alkyl;

R 11 , when present, is H or (C 1-4 )alkyl, optionally substituted with OH or (C 1-4 )alkyloxy;

R 12 , when present, is (C 1-4 )alkyl, optionally substituted with OH or (C 1-4 )alkyloxy;

R 13 , when present, is H or (C 1-4 )alkyl, optionally substituted with OH, (C 1-4 )alkyloxy or CONR 7 R 8 ;

R 14 , when present, is H or (C 1-4 )alkyl; or

R 14 together with the C atom to which the CO—NR 13 R 14 group is bonded form a 5- or 6-membered spiro-ring;

with the proviso that when Y is SO 2 ,

R 4 may further represent H, (C 1-6 )alkyl or (C 3-7 )cycloalkyl, the alkyl groups being optionally substituted with OH, (C 1-4 )alkyloxy, (C 1-4 )alkylthio, (C 1-4 )alkylsulfonyl, CN or halogen; or

R 3 together with R 4 and the N to which they are bonded may form a 4-8 membered ring optionally containing a further heteroatom selected from O, S and SO 2 the ring being optionally substituted with OH;

or a pharmaceutically acceptable salt thereof.

2. The indole of claim 1 , wherein

R, when present, is H;

Y is CH 2 , O or SO 2 ;

R 2 is H; or

R 2 together with R 3 and the carbon and nitrogen atoms to which they are bonded form a 5-membered ring.

3. The indole of claim 1 , wherein

X 1 is N or S;

X 2 is S, O, or N;

X 3 is N or O.

4. The indole of claim 3 , wherein

the heterocycle A is 1,2,4-oxadiazole (X 1 is N, X 2 is O, X 3 is N), 1,2,4-thiadiazole (X 1 is N, X 2 is 5, X 3 is N), thiazole (X 1 is S, X 2 is CR, X 3 is N) or 1,3,4-oxadiazole (X 1 is N, X 2 is N, X 3 is O).

5. The indole of claim 4 , wherein the heterocycle A is 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 5, X 3 is N).

6. The indole of claim 5 , wherein

R 3 is (C 1-6 )alkyl, optionally substituted with OH;

R 4 is SO 2 —R 8 ; or

R 4 is (C 1-3 ) alkyl, substituted with CO—NR 5 R 6 ; or

R 4 together with R 3 and the N to which they are bonded form a 6-membered ring, the ring being substituted with CO—NR 13 R 14 .

7. The indole of claim 1 which is selected from

7-Chloro-3-[(5-{[4-(N-methyl)carboxamido]piperidin-1-yl}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(1,1-dioxo-hexahydro-thiopyran-4-yl)methyl-1H-indole;

7-Chloro-3-[(5-{4-[(N-{2-hydroxy}ethyl)carboxamido]piperidin-1-yl}methyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-Chloro-3-[(5-{[N-(carboxamido)methyl]-N-methylamino}methyl)-([1,2,4]oxadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-Chloro-3-({5-[(N—{[N-(carboxamido)methyl]carboxamido}methyl)-N-methyl-amino]methyl}-[1,2,4]oxadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-Chloro-3-({5-[(N—{[N-(2-hydroxyethyl)]carboxamido}methyl)-N-methylamino]methyl}-[1,2,4]oxadiazol-3-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole;

7-Chloro-3-({5-[(N-{2-hydroxy}ethyl)-(N-{methylsulfonyl})amino]methyl}-([1,2,4]-thiadiazol-3-yl))-1-(tetrahydropyran-4-yl)methyl-1H-indole; and

7-Ethyl-3-[(5-{4-[(N-{2-hydroxy}ethyl)carboxamido]piperidin-1-yl}methyl)-([1,2,4]-thiadiazol-3-yl)]-1-(tetrahydropyran-4-yl)methyl-1H-indole;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising an indole of claim 1 in admixture with pharmaceutically acceptable auxiliaries.

9. A pharmaceutical composition comprising an indole of claim 5 in admixture with pharmaceutically acceptable auxiliaries.

10. A pharmaceutical composition comprising an indole of claim 6 in admixture with pharmaceutically acceptable auxiliaries.

11. A pharmaceutical composition comprising an indole of claim 7 in admixture with pharmaceutically acceptable auxiliaries.

12. A method of treatment of pain comprising:

administering to a patient in need thereof a therapeutically effective amount of an indole derivative of claim 1 .

13. The method according to claim 12 , wherein the pain is selected from the group consisting of peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

14. A method of treatment of pain comprising: administering to a patient in need thereof a therapeutically effective amount of an indole derivative of claim 5 .

15. A method of treatment of pain comprising: administering to a patient in need thereof a therapeutically effective amount of an indole derivative of claim 6 .

16. A method of treatment of pain comprising: administering to a patient in need thereof a therapeutically effective amount of an indole derivative of claim 7 .