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. The compounds 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 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 hydroxyl, phosphate, phosphonate, or alpha-substituted phosphonate;
R 1 is hydrogen, halo, tri-fluoromethyl, (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 (C 1 -C 20 ) alkyl, cycloalkyl substituted alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl, alkyl substituted aryl, arylalkyl or 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.
2. The compound of claim 1 , having Formula (II):
wherein X is hydroxyl, phosphate, phosphonate, or alpha-substituted phosphonate;
wherein R 1 is hydrogen, halogens, (C 1 -C 6 ) alkyl, or halo-, hydroxy-, alkoxy-, cyano-substituted (C 1 -C 6 ) alkyl; R 2 is alkyl, alkenyl, alkynyl, alkyl substituted aryl, alkyl substituted cycloalkyl, arylalkyl or arylalkyl substituted aryl; and n is 0, 1, 2 or 3; or
a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 1 is fluorine or chlorine.
4. The compound of claim 1 , wherein X is OPO 3 H 2 .
5. The compound of claim 1 , wherein X is hydroxy.
6. The compound 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 compound 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 compound of claim 1 , wherein R 2 is alkyl having 5, 6, 7, 8, or 9 carbon atoms.
9. The compound of claim 8 , wherein R 2 is heptyl, octyl, nonyl, or —O-heptyl.
10. The compound of claim 9 , wherein R 2 is octyl.
11. The compound of claim 1 , wherein n is 1 or 2.
12. The compound of claim 1 , wherein the R 2 group is placed para to the cycloalkyl ring.
13. The compound of claim 1 , wherein the cyclo group has the formula:
14. The compound of claim 1 , wherein the R 1 group is ortho or meta to R 2 .
15. The compound of claim 1 , wherein the R 2 group is para to the cyclo group.
16. The compound of claim 1 , having the formula:
17. A pharmaceutical composition comprising a compound of clam 1 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 hydroxyl, phosphate, phosphonate, or alpha-substituted phosphonate;
R 1 is hydrogen, halo, tri-fluoromethyl, (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 (C 1 -C 20 ) alkyl, cycloalkyl substituted alkyl, (C 2 -C 20 ) alkenyl, (C 2 -C 20 ) alkynyl, aryl, alkyl substituted aryl, arylalkyl or 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 and a pharmaceutically acceptable excipient.
18. The composition of claim 17 , wherein the composition is in the form of a kit.
19. The compound of claim 16 , having the formula:
20. The composition of claim 17 , having a compound of formula (II):
wherein X is hydroxyl, phosphate, phosphonate, or alpha-substituted phosphonate;
wherein R 1 is hydrogen, halogens, (C 1 -C 6 ) alkyl, or halo-, hydroxy-, alkoxy-, cyano-substituted (C 1 -C 6 ) alkyl;
R 2 is alkyl, alkenyl, alkynyl, alkyl substituted aryl, alkyl substituted cycloalkyl, arylalkyl or arylalkyl substituted aryl; and n is 0, 1, 2 or 3; or
a pharmaceutically acceptable salt thereof.
21. The composition of claim 20 , wherein R 2 is alkyl having 5, 6, 7, 8, or 9 carbon atoms.
22. The composition of claim 21 , wherein R 2 is heptyl, octyl, nonyl, or —O-heptyl.
23. The composition of claim 22 , wherein R 2 is octyl.
24. The composition of claim 17 , wherein n is 1 or 2.
25. The composition of claim 23 , wherein compound has the formula:
26. The composition of claim 25 , wherein the compound has the formula: