Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders

Patent metadata

Field	Value
Publication number	US-9522133-B2
Application number	US-201514817455-A
Country	US
Kind code	B2
Filing date	Aug 4, 2015
Priority date	Jul 23, 2008
Publication date	Dec 20, 2016
Grant date	Dec 20, 2016

Abstract

The present invention relates to certain substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives of Formula (Ia) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 receptor-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, microbial infections or diseases and viral infections or diseases.

First claim

What is claimed is:

1. A process for preparing a composition comprising admixing a compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates and hydrates thereof:

and a pharmaceutically acceptable carrier; wherein:
m is 1;
n is 1 or 2;
Y is N or CR 1 ;
Z is N or CR 4 ;
R 1 , R 2 , and R 4 are each independently selected from the group consisting of H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylthio, carboxamide, cyano, C 3 -C 7 cycloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl and heterocyclyl, wherein said C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or two substituents selected from C 3 -C 7 cycloalkyl and halogen; and
R 3 is C 3 -C 7 cycloalkyl.

2. The process according to claim 1 , wherein n is 1.

3. The process according to claim 1 , wherein Y is CR 1 .

4. The process according to claim 3 , wherein R 1 is H or C 1 -C 6 haloalkyl.

5. The process according to claim 1 , wherein R 2 is selected from the group consisting of H, cyano, C 1 -C 6 haloalkoxy and C 1 -C 6 haloalkyl.

6. The process according to claim 1 , wherein Z is N.

7. The process according to claim 1 , wherein Z is CR 4 .

8. The process according to claim 7 , wherein R 4 is selected from the group consisting of H, cyano, C 1 -C 6 haloalkoxy and C 1 -C 6 haloalkyl.

9. The process according to claim 1 , wherein the compound is selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
Y is N or CR 1 ;
Z is N or CR 4 ;
R 1 is H or C 1 -C 6 haloalkyl;
R 2 is selected from the group consisting of H, cyano, C 1 -C 6 haloalkoxy and C 1 -C 6 haloalkyl;
R 3 is C 3 -C 7 cycloalkyl; and
R 4 is selected from the group consisting of H, cyano, C 1 -C 6 haloalkoxy and C 1 -C 6 haloalkyl.

10. The process according to claim 1 , wherein the compound is selected from compounds of Formula (Ik) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
Y is N or CR 1 ;
Z is N or CR 4 ;
R 1 is H or trifluoromethyl;
R 2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl;
R 3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl; and
R 4 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl.

11. The process according to claim 1 , wherein the compound is selected from compounds of Formula (Im) and pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
R 2 is selected from the group consisting of H, cyano, trifluoromethoxy and trifluoromethyl; and
R 3 is selected from the group consisting of cyclobutyl, cyclohexyl, cyclopentyl, and cyclopropyl.

12. The process according to claim 1 , wherein the compound is selected from the following compounds and pharmaceutically acceptable salts, solvates and hydrates thereof:
2-(7-(4-cyclohexyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
2-(7-(3-cyano-4-cyclohexylbenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3yl)acetic acid;
2-(7-((6-cyclopentyl-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
2-(7-(4-cyclobutyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; and
2-(7-(4-cyclopropyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

13. The process according to claim 1 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof:
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

14. The process according to claim 1 , wherein the compound is selected from the following compound and pharmaceutically acceptable salts, solvates and hydrates thereof:
(S)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

15. A process according to claim 1 , wherein the salt is selected from the following salt and pharmaceutically acceptable solvates and hydrates thereof:
L-Arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid.

16. The process according to claim 1 , wherein the composition is suitable for oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, subcutaneous, or intravenous administration; or suitable for administration by inhalation, insufflation or by a transdermal patch.

17. The process according to claim 1 , wherein the composition is suitable for oral administration.

18. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a diluent.

19. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises mannitol.

20. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a lubricant.

21. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises magnesium stearate.

22. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a tablet disintegrating agent.

23. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a diluent, a lubricant, and a tablet disintegrating agent.

24. The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises mannitol and magnesium stearate.

25. The process according to claim 13 , wherein the composition is suitable for oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, subcutaneous, or intravenous administration; or suitable for administration by inhalation, insufflation or by a transdermal patch.

26. The process according to claim 13 , wherein the composition is suitable for oral administration.

27. The process according to claim 13 , wherein the pharmaceutically acceptable carrier comprises a diluent.

28. The process according to claim 13 , wherein the pharmaceutically acceptable carrier comprises mannitol.

29. The process according to claim 13 , wherein the pharmaceutically acceptable carrier comprises a lubricant.

30. The process according to claim 13 , wherein the pharmaceutically acceptable carrier comprises magnesium stearate.

31. The process according to claim 13 , w

Assignees

• Arena Pharm Inc

Inventors

• Jones Robert M
• Buzard Daniel J
• Han Sangdon
• Kim Sun Hee
• Lehmann Juerg
• Ullman Brett
• Moody Jeanne V
• Zhu Xiuwen
• Stirn Scott

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title