Preparation of tetrahydropyridine derivatives as inhibitors of proinflammatory cytokine production and CRAC ion channels for treating inflammation and immune disorders

Abstract

The invention relates to certain compounds or pharmaceutically acceptable salts thereof, including derivatives of tetrahydropyridine, that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders. The compounds act by inhibiting the activity of CRAC ion channels (calcium-release activated calcium channels) and the production of proinflammatory cytokines. Synthetic procedures for preparing the compounds of the invention are exemplified. Example compound I was prepared in a multistep synthesis that involved formation of II from N-(5-bromopyrazin-2-yl)-2,6-difluorobenzamide, 4-methylpyridin-3-ylboronic acid, and benzyl bromide and conversion of II in 3 steps to I. In assays to measure IL-2 production by Jurkat cells, I had an IC50 between 50 and 100 nM. In assays that measured ICRAC current, I caused 70-100% inhibition at 500 nM.