225526-40-9Relevant academic research and scientific papers
Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist 'CJ-17,493'
Shishido, Yuji,Wakabayashi, Hiroaki,Koike, Hiroki,Ueno, Naomi,Nukui, Seiji,Yamagishi, Tatsuya,Murata, Yoshinori,Naganeo, Fumiharu,Mizutani, Mayumi,Shimada, Kaoru,Fujiwara, Yoshiko,Sakakibara, Ayano,Suga, Osamu,Kusano, Rinko,Ueda, Satoko,Kanai, Yoshihito,Tsuchiya, Megumi,Satake, Kunio
, p. 7193 - 7205 (2008/12/22)
A novel central nervous system (CNS) selective neurokinin-1 (NK1) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (Ki = 0.2 nM) for the human NK1 receptor in IM-9 cells, potent activity in the [Sar9, Met(O2)11]SP-induced gerbil tapping model (ED50 = 0.04 mg/kg, sc) and in the ferret cisplatin (10 mg/kg, ip)-induced anti-emetic activity model (vomiting: ED90 = 0.07 mg/kg, sc), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.
Process research and development of an NK-1 receptor antagonist. Enantioselective trifluoromethyl addition to a ketone in the preparation of a chiral isochroman
Caron, Stephane,Do, Nga M.,Sieser, Janice E.,Arpin, Patrice,Vazquez, Enrique
, p. 1015 - 1024 (2012/12/30)
CJ-17,493 (4) is a chiral NK-1 receptor antagonist. It was first prepared through a diastereoselective crystallization, then through chiral chromatography of a key intermediate, and ultimately via asymmetric synthesis. Multiple routes for the preparation of a key isochroman were demonstrated, and conditions for improved regioselectivity of a Friedel-Crafts acylation were identified. Cesium fluoride was found to be an acceptable initiator for the generation of a nucleophilic trifluoromethyl anion from CF3TMS. A cinchonine-derived catalyst was identified for the enantioselective addition of the trifluoromethyl group to the ketone, and it was found that the product of the addition would be converted directly to the isochroman by treatment with t-BuOK. A Duff reaction was used for the formylation, and the resulting aldehyde was coupled to amine 5 to afford CJ-17,493 (4).
