Cycloalkane-containing sphingosine 1-phosphate agonists
The present invention provides sphingosine-1-phosphate analogs that are potent, and selective agonists at one or more S1P receptors, specifically the S1P 1 receptor type, which alter lymphocyte trafficking. The compounds of the invention include compounds having a phosphate moiety as well as compounds with hydrolysis-resistant phosphate surrogates such as phosphonates, alpha-substituted phosphonates, and phosphothionates.
1. A method for treatment of a pathological condition or symptom in a mammal, wherein the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired, comprising administering to said mammal an effective amount of a compound having the formula:
wherein R 4 and R 7 are independently CH, or CH 2 ; R 5 is C, CH, or N, R 6 is CH, CH 2 , O, S or NR 3 ; wherein R 3 is hydrogen, or an (C 1 -C 10 ) alkyl group;
X is selected from hydroxyl, phosphate, phosphonate, alpha-substituted phosphonate;
R 1 is selected from the group consisting of hydrogen, halo, trifluoromethyl, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkyl substituted with halo, hydroxy-, (C 1 -C 10 ) alkoxy, or cyano; and
R 2 is selected from the group consisting of (C 1 -C 10 )alkyl, cycloalkyl substituted alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, aryl, alkyl substituted aryl, arylalkyl and aryl substituted arylalkyl; wherein one or more of the carbon atoms in the R 2 groups can be independently replaced with non-peroxide oxygen, sulfur or NR 8 ; wherein R 8 is hydrogen, or an (C 1 -C 10 ) alkyl group;
wherein the alkyl, alkenyl, and alkynyl groups in R 2 are optionally substituted with oxo; n is 0, 1, 2 or 3; and represents 1,2, or 3, optional double bonds; or
a pharmaceutically acceptable salt or ester thereof,
wherein the treatment of the pathological condition or symptom comprises altering lymphocyte trafficking.
2. The method of claim 1 , comprising administering to said mammal an effective amount of a compound having formula (II):
wherein X is selected from hydroxyl, phosphate, phosphonate, and alpha-substituted phosphonate;
wherein R 1 is selected from the group consisting of hydrogen, halogens, (C 1 -C 6 ) alkyl, and halo-, hydroxy-, alkoxy-, cyanosubstituted (C 1 -C 6 ) alkyl;
R 2 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkyl substituted aryl, alkyl substituted cycloalkyl, arylalkyl and arylalkyl substituted aryl; and n is 0, 1, 2 or 3; or
a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein R 1 is fluorine or chlorine.
4. The method of claim 1 , wherein X is hydroxy or OPO 3 H 2 .
5. The method of claim 1 , wherein X is hydroxy.
6. The method of claim 1 , wherein alpha-substituted phosphonate is —CHFPO 3 H 2 , —CF 2 PO 3 H 2 , —CHOHPO 3 H 2 , C═OPO 3 H 2 or —OPO 2 SH 2 .
7. The method of claim 6 , wherein alpha-substituted phosphonate is —CHFPO 3 H 2 , —CF 2 PO 3 H 2 , —CHOHPO 3 H 2 , or —C═OPO 3 H 2 .
8. The method of claim 1 , wherein R 2 is alkyl having 5, 6, 7, 8, or 9 carbon atoms.
9. The method of claim 1 , wherein R 2 is octyl.
10. The method of claim 1 , wherein n is 1 or 2.
11. The method of claim 1 , wherein R 2 group placed para to the cycloalkyl ring.
12. The method of claim 1 , wherein the cyclo group has the formula:
13. The method of claim 1 , wherein the R 1 group is ortho or meta to R 2 .
14. The method of claim 1 , wherein the R 2 group is para to the benzylic cycloalkyl group.
15. The method of claim 1 , wherein the compound has the formula:
16. The method of claim 1 , wherein the compound has the formula:
17. The method of claim 1 , wherein altering lymphocyte trafficking treats an autoimmune disease selected from the group consisting of uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel disease, or multiples sclerosis.
18. The method of claim 17 , wherein the autoimmune disease is multiple sclerosis.
19. The method of claim 1 , wherein altering lymphocyte trafficking provides prolonged allograft survival.