66192-25-4Relevant articles and documents
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.
Practical Asymmetric Synthesis of an Endothelin Receptor Antagonist
Song, Zhiguo J.,Zhao, Mangzhu,Desmond, Richard,Devine, Paul,Tschaen, David M.,Tillyer, Richard,Frey, Lisa,Heid, Richard,Xu, Feng,Foster, Bruce,Li, Jing,Reamer, Robert,Volante, Ralph,Grabowski, Edward J. J.,Dolling, Ulf H.,Reider, Paul J.,Okada, Shigemitsu,Kato, Yoshiaki,Mano, Eiichi
, p. 9658 - 9667 (2007/10/03)
An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported. The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleach-catalyzed oxidation by sodium chlorite (NaClO2) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.
