Modulators of sphingosine phosphate receptors
Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.
1. A method of treatment of a malcondition in a patient having such malcondition, wherein the malcondition is multiple sclerosis, transplant rejection or adult respiratory distress syndrome, comprising administering to the patient an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof:
wherein
a dashed line signifies that a single bond or a double bond can be present, provided that there are two double bonds and three single bonds in the ring comprising A 1 , A 2 , and A 3 ;
A 1 and A 3 are N and A 2 is O;
L 1 and L 2 are each independently a bond;
J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, CF 3 , OCF 3 , R′, methylenedioxy, ethylenedioxy, N(R′) 2 , SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, OC(O)OR′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 NHC(O)R′, N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′) 2 , N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(OR′)R′, C(═NH)N(R′) 2 , C(O)N(OR′)R′, or C(═NOR′)R′, wherein R′ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;
R 5 a group of formula a-i
mono- or pluri-substituted with J, wherein a wavy line indicates a point of attachment;
R 6 is phenyl mono- or pluri-substituted with J.
2. The method of claim 1 wherein the malcondition is transplant rejection or adult respiratory distress syndrome.
3. The method of claim 1 wherein the malcondition is multiple sclerosis.