Indole Compounds having sphingosine-1-phosphate (S1P) receptor antagonist

Abstract

The present invention provides novel compounds having the following general formula I

Description

Claims

1. A compound represented by the general formula I

2. The compound of claim 1 wherein said aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole,oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalene, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone, which aryl is unsubstituted or is substituted with one or two alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, hydroxyl, alkoxyl, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.

3. The compound of claim 2 wherein o is 1 and R3 is phenyl.

4. The compound of claim 3 wherein R1 is i-propyl.

5. The compound of claim 4 wherein p is 1 and R2 is hydroxy methyloxymethyloxy or dihydropyranyloxy.

6. The compound of claim 5 wherein B is selected from the group consisting of C═C(R5)2, C═O and C═NOR5.

7. The compound of claim 6 wherein Y is R6.

8. The compound of claim 7 wherein R6 is selected from the group consisting of methyl, n-propyl, and i-butyl.

9. The compound of claim 4 wherein Y is selected from the group consisting of phenyl and 2,5 difluoro phenyl.

10. The compound of claim 9 wherein p is 0 or p is 1 and R2 is selected from the group consisting of hydroxy and dihyropyranyloxy.

11. The compound of claim 10 wherein A1 and A2 are absent, B is C═O and X is ethyl or ethenyl.

12. The compound of claim 10 wherein A1 and A2 are absent, B is C2H4 and X is CH2.

13. The compound of claim 10 wherein A1 and A2 are absent, B is sulfonyl; and X is NH.

14. The compound of claim 10 wherein A1, A2 and B are absent and X is oxadiazolyl.

15. The compound of claim 10 wherein A1 is absent, B is C═O, X is NH and A2 is NH.

16. The compound of claim 1 selected from the group consisting of b 1-Benzyl-3-((3,5-difluorobenzylamino)methyl)-2-isopropyl-1H-indol-5-ol,(E)-1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxaldehyde, O-Benzyl Oxime,(E)-1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carbaldehyde, O-Phenyl Oxime,(E)-1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-phenylpropenone,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-phenylpropan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)butan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-methylbutan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-phenylethan-1-one,(E)-1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)prop-2-en-1-one and1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)propan-1-one.

17. A method of treating a disease or condition selected from the group consisting of glaucoma, dry eye, angiogenesis, cardiovascular conditions or diseases and wound healing which comprises administering to a patient in need thereof a compound represented by the general formula I

18. The method of claim 17 wherein said aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole,oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran, dihydrobenzothiophene, indene, benzofuran, benzothiophene, coumarin and coumarinone, which aryl is unsubstituted or is substituted with one or two alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, hydroxyl, alkoxyl, alkylcarbonyl, formyl, oxycarbonyl, carboxyl, alkyl carboxylate, alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.

19. The method of claim 18 wherein o is 1 and R3 is phenyl.

20. The method of claim 19 wherein R1 is i-propyl.

21. The method of claim 20 wherein p is 1 and R2 is hydroxyl, methyloxymethyloxy or dihydropyranyloxy.

22. The method of claim 21 wherein B is selected from the group consisting of C═C(R5)2, C═O and C═NOR5.

23. The method of claim 22 wherein Y is R6.

24. The method of claim 23 wherein R6 is selected from the group consisting of methyl, n-propyl, and i-butyl.

25. The method of claim 20 wherein Y is selected from the group consisting of phenyl and 2,5 difluoro phenyl.

26. The method of claim 25 wherein p is 0 or p is 1 and R2 is selected from the group consisting of hydroxyl and dihydropyranyloxy.

27. The method of claim 26 wherein A1 and A2 are absent, B is C═O and X is ethyl or ethenyl.

28. The method of claim 26 wherein A1 and R2 are absent, B is C2, H4 and X is CH2.

29. The method of claim 26 wherein A1 and A2 are absent, B is sulfonyl and X is NH.

30. The method of claim 26 wherein A1, A2 and B are absent and X is oxadiazoyl.

31. The method of claim 26 wherein A1 is absent, B is C=0, X is NH and A2 is NH.

32. The method of claim 17 wherein said compound is selected from the group consisting of 1-Benzyl-3-((3,5-difluorobenzylamino)methyl)-2-isopropyl-1H-indol-5-ol,(E)-1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxaldehyde, O-Benzyl Oxime,(E)-1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carbaldehyde, O-Phenyl Oxime,(E)-1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-phenylpropenone,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-phenylpropan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)butan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-methylbutan-1-one,1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-2-phenylethan-1-one,(E)-1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)prop-2-en-1-one and1-(1-Benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)-3-(3,4-difluorophenyl)propan-1-one.

33. A ligand for the S1P receptor comprising a 3-substitued N-benzyl indole having biological activity at said receptor wherein said 3-substituent is represented by the formula (R4), Y-A2-X—B-A1- wherein:R4 is independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, aryl, halo, C1 to C12 haloalkyl, hydroxy, C1 to C12 alkoxy, C1 to C12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, C1 to C12 alkyl carboxylate, C1 to C12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, sulfonyl,

34. A method for treating a disease or condition mediated by the S1P receptor which comprises administering to a patient in need thereof a therapeutically-effective amount of a compound of claim 33.