Stütz P L, Stadler P A, Vigouret J M, Jaton A
J Med Chem. 1978 Aug;21(8):754-7. doi: 10.1021/jm00206a007.
A new two-step sequence for the epimerization of methyl dihydrolysergate (5) at C-8 leading to methyl dihydroisolysergate (7) is presented. The latter compound was used as a starting material for the synthesis of various ergolines, of which (5R,8R,10R)-8-(cyanomethyl)-6-methylergoline (4) is a very strong and long-lasting central dopaminergic agent. Furthermore, it was found that some 8-(arylthiomethyl)-6-methyler-golenes are not able to induce apomorphine-like stereotyped behavior in normal rats but exhibit a remarkable activity in rats unilaterally lesioned by 6-OH-DA in the nigrostriatal region. Compound 4 and (5R,8R)-8-[(2-pyridyl)thiomethyl]-6-methylergolene (9) were further tested for their ability to inhibit ovum implantation and to depress serum prolactin levels in rats. Their potency was evaluated in comparison with (5R,8S,10R)-8-(cyanomethyl)-6-methylergolines (2a and 2b) and 2-bromo-alpha-ergocryptine (1) as standards.
本文介绍了一种新的两步反应序列，用于使甲基二氢麦角酰二乙胺（5）在C-8位发生差向异构化，生成甲基二氢异麦角酰二乙胺（7）。后一种化合物被用作合成各种麦角灵的起始原料，其中（5R,8R,10R）-8-（氰基甲基）-6-甲基麦角灵（4）是一种非常强效且持久的中枢多巴胺能药物。此外，还发现一些8-（芳基硫甲基）-6-甲基麦角灵在正常大鼠中不能诱导阿扑吗啡样刻板行为，但在黑质纹状体区域单侧注射6-羟基多巴胺损伤的大鼠中表现出显著活性。对化合物4和（5R,8R）-8-[(2-吡啶基)硫甲基]-6-甲基麦角灵（9）抑制大鼠卵子着床和降低血清催乳素水平的能力进行了进一步测试。与（5R,8S,10R）-8-（氰基甲基）-6-甲基麦角灵（2a和2b）以及2-溴-α-麦角隐亭（1）作为标准品相比，评估了它们的效力。
