Aryl amide sphingosine 1-phosphate analogs
The present invention provides compounds that have antagonist activity at the S1P 1 and/or S1P 3 receptors. These compounds have enhanced selectivity and potency at the S1P 1 and/or S1P 3 receptors.
1. A compound having formula (I):
wherein X and Y taken together with the atom to which they are attached form a keto group;
R 1 is hydrogen, halo, tri-fluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkyl substituted with halo, hydroxy, alkoxy, or cyano;
R 2 is (C 1 -C 10 )alkyl, (C 3 -C 8 )-cycloalkyl substituted alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, alkyl substituted aryl, arylalkyl or aryl substituted arylalkyl; or
a pharmaceutically acceptable ester or salt thereof.
2. The compound of claim 1 wherein R 2 is ortho or meta to the amide.
3. The compound of claim 1 wherein R 2 is meta to the amide.
4. The compound of claim 1 wherein the R 2 alkyl groups have from 5-8 carbon atoms.
5. The compound of claim 1 having the formula:
6. The compound of claim 1 in the form of a pharmaceutically acceptable salt of a compound of formula 1.
7. The compound of claim 1 in the form of a pharmaceutically acceptable ester of a compound of formula 1.
8. The compound of claim 7 wherein the ester group is methyl, ethyl, propyl, benzyl, or has the formula
9. A pharmaceutical composition comprising a compound of claim 1 , having formula (I):
wherein X and Y taken together with the atom to which they are attached form a keto group;
R 1 is hydrogen, halo, tri-fluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkyl substituted with halo, hydroxy, alkoxy, or cyano;
R 2 is (C 1 -C 10 )alkyl, (C 3 -C 8 )-cycloalkyl substituted alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, alkyl substituted aryl, arylalkyl or aryl substituted arylalkyl; or a pharmaceutically acceptable ester or salt thereof; and
a pharmaceutically acceptable carrier.
10. A kit for administering at least one compound of claim 1 having formula (I):
wherein X and Y taken together with the atom to which they are attached form a keto group;
R 1 is hydrogen, halo, tri-fluoromethyl, (C 1 -C 6 )-alkyl, (C 1 -C 6 ) alkyl substituted with halo, hydroxy, alkoxy, or cyano;
R 2 is (C 1 -C 10 )alkyl, (C 3 -C 8 )-cycloalkyl substituted alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, alkyl substituted aryl, arylalkyl or aryl substituted arylalkyl; or a pharmaceutically acceptable ester or salt thereof;
to a patient in need thereof, said kit comprising a pharmaceutical composition comprising at least one compound having formula (I), an applicator, and instructional material for the use thereof.