Epstein J W, Brabander H J, Fanshawe W J, Hofmann C M, McKenzie T C, Safir S R, Osterberg A C, Cosulich D B, Lovell F M
J Med Chem. 1981 May;24(5):481-90. doi: 10.1021/jm00137a002.
A series of 1-aryl-3-azabicyclo[3.1.0]hexanes was synthesized by hydride reduction of 1-arylcyclopropanedicarboximides. Hydroxyphenyl analogues 20, 22, and 24 were prepared by EtSNa--DMF ether cleavage of the corresponding methoxyphenyl analogues 2m, 2n, and 23, respectively, with the secondary amines 20 and 22 going through the N-formyl intermediate 19 and 21. The p-ethoxy analogue 26 was obtained by O-ethylation of 19, followed by base hydrolysis of the amide 25. The greatest analgesic potency in mouse writhing and rat paw-pain assays was observed for para-substituted compounds. Bicifadine, 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane (2b), was the most potent member of the series and is presently undergoing clinical trials in man. Analgesic activity of 2b is limited to the (+) enantiomer 2v, which has the 1R,5S absolute configuration as determined by single-crystal X-ray analysis. The N-methyl analogue (27d) of 2b showed significant analgesic potency, whereas the N-allyl (27a), N-(cyclopropylmethyl) (27b), and N-(n-hexyl) (27c) analogues were inactive. Bicifadine (2b) showed a nonnarcotic profile different from analogous azabicycloalkane and 3-phenylpyrrolidine analgesics.
通过1-芳基环丙烷二甲酰亚胺的氢化物还原反应合成了一系列1-芳基-3-氮杂双环[3.1.0]己烷。分别通过EtSNa-DMF醚裂解相应的甲氧基苯基类似物2m、2n和23制备了羟基苯基类似物20、22和24，仲胺20和22经过N-甲酰基中间体19和21。对甲氧基类似物26是通过19的O-乙基化反应，随后酰胺25的碱水解反应得到的。在小鼠扭体试验和大鼠足痛试验中，对位取代的化合物表现出最大的镇痛效力。比西法定，即1-(4-甲基苯基)-3-氮杂双环[3.1.0]己烷(2b)，是该系列中效力最强的成员，目前正在进行人体临床试验。2b的镇痛活性仅限于(+)对映体2v，通过单晶X射线分析确定其具有1R,5S绝对构型。2b的N-甲基类似物(27d)显示出显著的镇痛效力，而N-烯丙基(27a)、N-(环丙基甲基)(27b)和N-(正己基)(27c)类似物无活性。比西法定(2b)显示出与类似的氮杂双环烷烃和3-苯基吡咯烷镇痛药不同的非麻醉性特征。
