Bicyclic sphingosine 1-phosphate analogs
Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.
1. A compound of formula I:
wherein
X 1 , Y 1 and Z 1 are independently CR a and CR a R b ;
R 1 is hydrogen, halo, (C 1 -C 10 )alkyl, (C 1 -C 10 )haloalkyl, or (C 1 -C 10 )alkoxy;
R 2 is hydrogen, halo, (C 1 -C 20 )alkyl, (C 1 -C 20 )alkoxy; (C 2 -C 26 )alkoxyalkyl; (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 30 )arylalkyl, (C 2 -C 10 )heterocyclic, and (C 5 -C 10 )heteroaryl;
represents one optional double bond; R 3 is hydrogen, (C 1 -C 10 )alkyl, hydroxy(C 1 -C 10 )alkyl, or (C 1 -C 10 )alkoxy;
R 4 is hydroxyl (—OH), phosphate (—OPO 3 H 2 ), phosphonate (—CH 2 PO 3 H 2 ), halophosphonate, or thiophosphonate;
R a , and R b are independently hydrogen, or (C 1 -C 10 )alkyl;
wherein the alkyl groups of R 1 are optionally substituted with 1, 2, 3, or 4 substituent groups where the substituent groups independently are halo, (C 1 -C 10 )alkoxy or cyano;
wherein any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, or heteroaryl groups of R 2 are optionally substituted with 1, 2, 3, or 4 substituent groups where the substituent groups independently are (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, or C 6 -aryl; or wherein one or more of the carbon atoms in the R 2 alkyl groups can be independently replaced with non-peroxide oxygen; or
a pharmaceutically acceptable salt or ester thereof.
2. The compound of claim 1 , wherein R 1 is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl substituted with, alkoxy or cyano, alkyl-substituted aryl, aryl-substituted alkyl, or aryl-substituted arylalkyl.
3. The compound of claim 2 , wherein R 1 is hydrogen, trifluoromethyl, or —CH 2 CF 3 .
4. The compound of claim 2 , wherein R 1 is benzyl, phenylethyl, or methyl benzyl.
5. The compound of claim 1 , wherein R 2 comprises —CH 2 —CH 2 —O—CH 2 —CH 2 —O—.
6. The compound of claim 1 , wherein R 2 is (C 1 -C 10 )alkyl, (C 2 -C 10 )alkenyl and (C 2 -C 14 )alkynyl, (C 1 -C 10 )alkoxy or (C 2 -C 16 )alkoxyalkyl.
7. The compound of claim 6 , wherein R 2 is (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy or (C 2 -C 12 )alkoxyalkyl.
8. The compound of claim 7 , wherein R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, or octoxy.
9. The compound of claim 1 , wherein each of X 1 , Y 1 and Z 1 is CH 2 .
10. The compound of claim 1 , wherein R 3 is hydrogen, methyl, hydroxymethyl, ethyl, hydroxyethyl, propyl, or isopropyl.
11. The compound of claim 10 , wherein R 3 is hydrogen, methyl, hydroxymethyl, ethyl, or hydroxyethyl.
12. The compound of claim 1 , having the formula
13. The compound of claim 1 , having the formula:
14. 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 of claim 1 ; and
wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, or altering of lymphocyte trafficking.
15. The method of claim 14 , wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, or multiple sclerosis.
16. The method of claim 15 , wherein the pathological condition or symptom is multiple sclerosis.
17. The method of claim 14 , wherein the treatment of a pathological condition is altering lymphocyte trafficking
18. The method of claim 17 , wherein altering lymphocyte trafficking provides prolonged allograft survival.
19. The method of claim 18 , wherein the allograft is for transplantation.
20. A method for treatment of a pathological condition or symptom in a mammal, wherein the activity of S1P lyase is implicated and inhibition of the S1P lyase is desired, comprising administering to said mammal an effective amount of a compound of claim 1 ; and
wherein the pathological condition or symptom is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, or altering of lymphocyte trafficking.