Prepn. of phenoxy-azetidine derivs. as sphingosine 1-phosphate receptor modulators for treatment of autoimmune, inflammatory, and ocular disorders, and other diseases.

Abstract

The invention relates to prepn. of phenoxy-azetidine derivs. and their use as sphingosine-1-phosphate (S1P) receptor modulators for the treatment of ocular, inflammatory, autoimmune, cardiac and other diseases relieved by S1P receptor modulation. Compds. of formula I wherein A and B are independently an (un)substituted C6-10 aryl, (un)substituted heterocycle, (un)substituted C3-8 cycloalkyl, etc.; R1-R10 are independently H, halo, OC1-8 alkyl, etc.; L1 is O, S, NH, etc.; L2 is O, S, CHR12; a is 1-6; R12 is H or C1-8 alkyl; and their pharmaceutical compns. are claimed and exemplified. Compd. II was prepd. via oxidn. of alc. intermediate III, followed by reaction of the aldehyde with azetidine carboxylic acid to give II. Invention compds. were evaluated for S1P1 receptor activity in the GTP gamma35S binding assay run in cells expressing human S1P1 with the most potent compd. which was II demonstrating an EC50 of 1.37 nM. [on SciFinder(R)]