Method for treatment of neuropathic pain
Compounds and methods useful for preventing and treating pain, e.g., neuropathic pain, in a subject in need thereof are provided. The compounds can be “S1P modulating” agents that are capable of inducing a detectable change in S1P receptor activity.
1. A method therapeutic treatment of neuropathic pain in a mammal, comprising administering to said mammal an effective amount of a compound having the formula:
wherein 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 2; and or
a pharmaceutically acceptable salt or ester thereof.
2. The method of claim 1 ,
wherein X is hydroxyl, phosphate, phosphonate, or alpha-substituted phosphonate;
R 1 is hydrogen, halo, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl substituted with halo, hydroxy-, (C 1 -C 6 ) alkoxy, or cyano; and
R 2 is alkyl, alkenyl, alkynyl, alkyl substituted aryl, alkyl substituted cycloalkyl, arylalkyl or arylalkyl substituted aryl; 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 4 , wherein X is OPO 3 H 2 .
6. The method of claim 4 , wherein X is hydroxy.
7. The method of claim 1 , wherein the 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 .
8. The method of claim 7 , wherein the alpha-substituted phosphonate is —CHFPO 3 H 2 , —CF 2 PO 3 H 2 , —CHOHPO 3 H 2 , or —C═OPO 3 H 2 .
9. The method of claim 1 , wherein R 1 is hydrogen.
10. The method of claim 1 , wherein R 2 is alkyl having 5, 6, 7, or 8 carbon atoms.
11. The method of claim 10 , wherein R 2 is heptyl, octyl, nonyl, or —O-heptyl.
12. The method of claim 11 , wherein R 2 is n-octyl.
13. The method of claim 1 , wherein the R 2 group is placed para to the cycloalkyl ring.
14. The method of claim 1 , wherein the cycloalkyl group has the formula:
15. The method of claim 1 , wherein the R 1 group is ortho or meta to R 2 .
16. The method of claim 1 , wherein the R 2 group is para to the benzylic cycloalkyl group.
17. The method of claim 1 , wherein the compound has the formula:
18. The method of claim 17 , wherein the compound has the formula: