Hapten Synthesis for ( + )-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,ll-dimethyl-2,3,4,5-tetra-hydro-8//-pyrido[4,,3,:4,5]thieno[3,2-/]triazolo[4,3-a][l,4]diazepine (E6123)

Abstract

( + )-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,ll-dimethyl-2,3,4,5-tetrahydro-8//-pyrido[4 'x2018;,3/:4,5]thieno-[3,2-/]triazolo[4,3-a][l,4]diazepine (E6123) is a very potent platelet-activating factor (PAF) receptor antagonist and shows potent anti-PAF activities at the microgram level in a variety of animal models. In order to examine the pharmacokinetics of E6123 at low doses, establishment of a radioimmunoassay is required. On the basis of the metabolic pattern of E6123, we synthesized 6-{2-chloro-4-(3-carboxypropyl)phenyl}-3-cyclopropanecarbonyl-8,ll-dimethyl-2,3,4,5-tetrahydro-8//-pyrido[4 'x2018;,3,:4,5]thieno[3,2-/][l,2,4]triazolo[4,ia][l,4]diazepine 22 as a potential hapten. In the synthesis of 22, we developed butynyl carbamate as a piperidine ring ^-protecting group to prevent possible side reaction, namely oxidation of the methylene at position 2. This protecting group is stable under usual basic and acidic conditions. © 1992, The Pharmaceutical Society of Japan. All rights reserved.