抗孕激素活性甾族化合物:7α-和7β-甲基-A-环失碳双炔雄甾醇的合成
ANTIPROGESTATIONAL STEROIDS: SYNTHESIS OF 7α-AND 7β-METHYL-A-NOR-5α-ANDROSTANE-2α, 17α-DIETHYNYL-2β, 17β-DIOL
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摘要: 本文报道利用睾丸酮为原料,经脱氢和二甲基铜锂试剂甲基化,制备7-甲基睾丸酮。采用结晶法分离7α-和7β-异构体后,分别进行锂氨还原、氧化、环合及炔锂炔化等反应,合成7α-和7β-甲基-A-环失碳-2α,17α-双乙炔基-5α-雄甾-2β,17β-二醇(Ⅱa,和Ⅱb),经初步药理试验表明,Ⅱa对大鼠具有较强的抗孕激素活性,口服剂量在2.5 mg/kg时,能明显抑制假孕大鼠蜕膜瘤的生长。抗早孕最低口服有效剂量为3.5 mg/kg/4 d,Ⅱb则较弱。Abstract: Introducing a methyl group at the 7-position of steroids may increase the biological activity of the alkylated derivative compared to the corresponding parent compound. Considering the various antiprogestational agents such as RMI 12,936 which possesses this structural, feature, we introduced a 7-methyl group into Anordrin, an effective antifertility agent, to yield 7α- and 7β-methyl-A-nor-5α-androstane-2α, 17α-diethynyl-2β, 17β-diol. The synthesis was accomplished by six steps from testosterone as shown in scheme 1 with good yield.Preliminary pharmacological results indicate that Ⅱa exhibited significant inhibition on the decidual reaction in pseudopregnant rats at an oral dose of 2.5 mg/kg. It was shown to be effective in anti-implantation and termination of early pregnancy in female rats, when given orally at a dose of 2.5 mg/kg/d for 4 days and 3.5 mg/kg/d for 4 days respectively. Ⅱb at a dose 10 mg/kg/d for 4 days showed only 30-40% efficacy in termination of early pregnancy.
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