Modulators of sphingosine phosphate receptors
Compounds of the following generic structure are provided: Such compounds activate a sphingosine-I-phosphate receptor of the subtype 1 (S1P1), and have utility in the treatment of malconditions mediated by S1P1 activation. More specifically, such compounds are beneficial in the treatment of, for example, multiple sclerosis, transplant rejection and/or adult respiratory syndrome.
1. A compound of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
2. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
3. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
4. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
5. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
6. The compound of claim 1 of the structure:
or a pharmaceutically acceptable salt or stereoisomer thereof.
7. The compound of claim 1 wherein the pharmaceutically acceptable salt is a hydrochloric acid salt.
8. The compound of claim 1 wherein the pharmaceutically acceptable salt is a maleic acid salt, tartaric acid salt, citric acid salt, glycolic acid salt, fumaric acid salt, or methanesulfonic acid salt.
9. The compound of claim 1 wherein the compound is in the form of a racemic mixture.
10. The compound of claim 1 wherein the compound is in the form of an isolated optical isomer.
11. The compound of claim 10 wherein the isolated isomer is at least about 90% by weight pure relative to its corresponding optical isomer.
12. The compound of claim 10 wherein the isolated isomer is at least 99% by weight pure relative to its corresponding optical isomer.
13. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier or diluent.
14. The composition of claim 13 wherein the composition is in oral solid dosage form.
15. The composition of claim 14 wherein the oral solid dosage form is a tablet or capsule.
16. A method of activation, agonism, inhibition or antagonism of a sphingosine-1-phosphate receptor subtype 1 comprising contacting the receptor subtype 1 with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
17. A method for treating a malcondition in a patient having said malcondition, comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient, wherein the malcondition is multiple sclerosis, transplant rejection or adult respiratory syndrome.
18. The method of claim 17 wherein the malcondition is transplant rejection.
19. The method of claim 17 wherein the malcondition is multiple sclerosis.
20. The method of claim 17 wherein the malcondition is adult respiratory syndrome.