INDOLE-3-CARBOXYLIC ACID AMIDE, ESTER, THIOAMIDE AND THIOL ESTER COMPOUNDS BEARING ARYL OR HETEROARYL GROUPS HAVING SPHINGOSINE-1-PHOSPHATE (S1P) RECEPTOR ANTAGONIST BIOLOGICAL ACTIVITY

Abstract

The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1-phosphate receptor agonist and or antagonist biological activity:

Description

Claims

1. Compounds represented by the formula I having sphingosine-1-phosphate receptor agonist and or antagonist biological activity:

2. The compound of claim 1 wherein Z is O.

3. The compound of claim 2 wherein Y is a phenyl group, or a heterocyclic aryl group selected from the group consisting of pyridyl, thienyl, furyl, pyradizinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl.

4. The compound of claim 2 wherein each said aryl is independently selected from the group consisting of phenyl, 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, wherein said 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.

5. The compound of claim 2 wherein Y is phenyl.

6. The compound of claim 2 wherein A is CH2.

7. The compound of claim 6 wherein X is NH.

8. The compound of claim 7 wherein n is 0 or an integer of 1 or 2 and R4 is selected from the group consisting of methyl, methoxy, fluoro and chloro.

9. The compound of claim 8 wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl and i-propyl.

10. The compound of claim 6 wherein R3 is selected from the group consisting of methyl, butyl, phenyl, benzyl, pyridyl, furanylmethylenyl, thienyl and thienyl methylenyl.

11. The compound of claim 10 wherein p is 0 or p is 1 and R2 is selected from the group consisting of hydroxyl, methoxy, nitro, amino, acetamido and benzyloxy.

12. The compound of claim 11 wherein p is 1 and R2 is a 5-hydroxy group; R1 is selected from the group consisting of methyl, ethyl, i-propyl and phenyl; R3 is selected from the group consisting of benzyl, thienylmethylenyl and furanylmethylenyl; n is 1 or 2 and R4 is selected from the group consisting of methoxy and fluoro.

13. The compound of claim 2 selected from the group consisting of 1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,5-Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzylamide;1-Butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid,3,5-Difluoro-benzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3,5-Difluorobenzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid 3,5-Difluorobenzylamide;1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid. 3, 4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Fluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, Benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Methoxybenzylamide;1-Butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid,3-Methoxy-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Fluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Methylbenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Chlorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Chlorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 2-methoxybenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3,4-Difluoro-benzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3-Methoxy-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzamide;5-Hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic Acid 3,4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-pyridin-2-yl-1H-indole-3-carboxylic Acid 3,4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-yl-1H-indole-3-carboxylic Acid 3,4-Difluorobenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid 3,5 -Difluoro-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,5-difluorobenzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3-methoxybenzylamide; and1-Benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic Acid, 3,5-Difluoro-benzylamide.

14. The compound of claim 13 selected from the group consisting of 1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,5-Difluorobenzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid 3,5-Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Methoxybenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3,4-Difluoro-benzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid 3,5-Difluoro-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,5-difluorobenzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3-methoxybenzylamide; and1-Benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic Acid, 3,5-Difluoro-benzylamide.

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

16. The method of claim 12 wherein Z is O.

17. The method of claim 12 wherein Y is a phenyl group, or a heterocyclic aryl group selected from the group consisting of pyridyl, thienyl, furyl, pyradizinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl.

18. The method of claim 16 wherein each said aryl is independently selected from the group consisting of phenyl, 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, wherein said 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 16 wherein Y is phenyl.

20. The method of claim 16 wherein A is CH2.

21. The method of claim 20 wherein X is NH.

22. The method of claim 21 wherein n is 0 or an integer of 1 or 2 and R4 is selected from the group consisting of methyl, methoxy, fluoro and chloro.

23. The method of claim 22 wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl and i-propyl.

24. The method of claim 20 wherein R3 is selected from the group consisting of methyl, butyl, phenyl, benzyl, pyridyl, furanylmethylenyl, thienyl and thienyl methylenyl.

25. The method of claim 24 wherein p is 0 or p is 1 and R2 is selected from the group consisting of hydroxyl, methoxy, nitro, amino, acetamido and benzyloxy.

26. The method of claim 25 wherein p is 1 and R2 is a 5-hydroxy group; R1 is selected from the group consisting of methyl, ethyl, i-propyl and phenyl; R3 is selected from the group consisting of benzyl, thienylmethylenyl and furanylmethylenyl; n is 1 or 2 and R4 is selected from the group consisting of methoxy and fluoro.

27. The method of claim 16 wherein said compound is selected from the group consisting of 1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,5 -Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzylamide;1-Butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,5 -Difluoro-benzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3,5 -Difluorobenzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid 3,5-Difluorobenzylamide;1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid. 3,4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Fluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, Benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Methoxybenzylamide;1-Butyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3-Methoxy-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Fluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Methylbenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Chlorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 4-Chlorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 2-methoxybenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3,4-Difluoro-benzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3-Methoxy-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,4-Difluorobenzamide;5-Hydroxy-2-methyl-1-phenyl-1H-indole-3-carboxylic Acid 3,4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-pyridin-2-yl-1H-indole-3-carboxylic Acid 3,4-Difluoro-benzylamide;5-Hydroxy-2-methyl-1-thiophen-2-yl-1H-indole-3-carboxylic Acid 3,4-Difluorobenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid 3,5-Difluoro-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,5-difluorobenzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3 -methoxybenzylamide; and1-Benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic Acid, 3,5-Difluoro-benzylamide.

28. The method of claim 27 wherein Said compound is selected from the group consisting of 1-Benzyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid, 3,5-Difluorobenzylamide;1-Furan-2-ylmethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic Acid 3,5-Difluorobenzylamide;5-Hydroxy-2-methyl-1-thiophen-2-ylmethyl-1H-indole-3-carboxylic Acid, 3-Methoxybenzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid, 3,4-Difluoro-benzylamide;1-Benzyl-2-ethyl-5-hydroxy-1H-indole-3-carboxylic Acid 3,5-Difluoro-benzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3,5-difluorobenzylamide;1-Benzyl-5-hydroxy-2-isopropyl-1H-indole-3-carboxylic Acid, 3-methoxybenzylamide; and1-Benzyl-5-hydroxy-2-phenyl-1H-indole-3-carboxylic Acid, 3,5-Difluoro-benzylamide.