Synthesis and Biological Studies of a Novel CB1 Antagonist

This paper describes the synthesis, early process development, salt selection strategies and pre clinical evaluation of novel, potent and selective CB1 antagonist, 8-Chloro-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-6-oxa-1,2-diaza-benzo[e]azulene-3-carboxylic acid piperidin-1-ylamide 1. The CB1 antagonism of compound 1 is also confirmed by reversal of CB1 agonist-induced hypothermia in Swiss albino mice. The process for the preparation of the compound 1 as a crystalline solid is also described. The crystalline form of the compound is found to be low bioavailable, therefore attempts have been made to improve its bioavailability through polymorphic transformation and salt formation. None of the salts prepared were found to be suitable for further development. The amorphous form of the compound 1 is found to be better suited. In vivo efficacy study of the amorphous form of compound 1 in 5% sucrose solution intake model in female Zucker fa/fa rats at single oral dose of 10 mg/kg demonstrates better reduction in the sucrose solution consumption than the corresponding crystalline form. The plasma concentration Cmax at AUC exposure of the amorphous form of the compound 1 is significantly improved and better than the Cmax of the corresponding crystalline form of the compound 1. On the basis of the efficacy, pharmacokinetic and toxicological evaluations, the compound 1 in the amorphous form is selected as a pre-clinical lead candidate.