Miyazawa S, Okano K, Kawahara T, Machida Y, Yamatsu I
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Chem Pharm Bull (Tokyo). 1992 Mar;40(3):762-5. doi: 10.1248/cpb.40.762.
(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4, 5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]triazolo[4,3-a] [1,4]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-8,11-dimethyl-2,3,4,5-tetrahydro-8H -pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 22 as a potential hapten. In the synthesis of 22, we developed butynyl carbamate as a piperidine ring N-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.
（+）-6-（2-氯苯基）-3-环丙烷甲酰基-8,11-二甲基-2,3,4,5-四氢-8H-吡啶并[4',3':4,5]噻吩并[3,2-f]三唑并[4,3-a][1,4]二氮杂卓（E6123）是一种非常有效的血小板活化因子（PAF）受体拮抗剂，在多种动物模型中，微克水平下即表现出强效的抗PAF活性。为了研究低剂量E6123的药代动力学，需要建立一种放射免疫测定法。基于E6123的代谢模式，我们合成了6-[2-氯-4-（3-羧丙基）苯基]-3-环丙烷甲酰基-8,11-二甲基-2,3,4,5-四氢-8H-吡啶并[4',3':4,5]噻吩并[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂卓22作为潜在的半抗原。在22的合成中，我们开发了丁炔基氨基甲酸酯作为哌啶环N-保护基，以防止可能的副反应，即2位亚甲基的氧化。该保护基在通常的碱性和酸性条件下稳定。
