Toshiyasu Takemoto

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.

CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had ∼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).

A catalytic asymmetric synthesis of cis-decalin derivatives via π-allylpalladium intermediates

The usefully functionalized cis-decalin derivative 6 has been synthesized in up to 83% ee through the π-allylpalladium intermediate starting with the prochiral allylic acetate 3.

Synthesis of cis-decalin derivative via π-allylpalladium intermediate and its transformation to usefully functionalized trans-decalin derivative

treatment of 15 or 16 with Pd(PPh3)4 (10 mol %) and NaH (1.2 equiv) afforded the cis-decalin derivative 18 stereoselectivity in high yield, which was effectively transformed into the usefully functionalized trans-decalin derivative 29.

A versatile method for the preparation of 2,2-disubstituted morpholine analogues

Abstract We describe a versatile synthetic method for the preparation of 2,2-disubstituted morpholine analogues. Iodoetherification of 1,1-disubstituted olefin with N -Boc-aminoethanol using NIS proceeded smoothly in a regioselective manner and the following cyclization was accomplished in good yield. We successfully applied this method for the preparation of the key intermediate 2 of tachykinin receptor antagonist.