Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man.
Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man.
复制标题
4-羟基普萘洛尔硫酸盐的合成，这是人体中一种主要的非β-阻断性普萘洛尔代谢物。
DOI：
10.1021/jm00383a023
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发表时间：
1985
影响因子：
7.3
通讯作者：
Knapp,DR
中科院分区：
文献类型：
--
作者：
OatisJr,JE;Walle,T;Daniell,HB;Gaffney,TE;Knapp,DR
4'-羟基普萘洛尔硫酸酯(8)最近被确定为普萘洛尔（Inderal）的主要代谢物。为了确定其结构，进一步研究其性质和生物活性，我们以1,4 -萘醌(1)为原料合成了8。与碘化苄还原烷基化得到4-（苄氧基）萘酚(3)。硫酸和氯硫酸在iV/ v -二甲苯胺中得到1 -（苯氧基）-4-萘酚硫酸钾(4)。催化加氢，与[[[（三氟甲基）磺酰基]氧]甲基]氧环烷(6)烷基化，并在异丙胺中活化得到8。外消旋8被发现比外消旋心得安在狗身上作为3-肾上腺素能受体阻断剂的效力低100-1000倍。虽然对前萘洛尔代谢的广泛研究已经进行了15年以上，但直到最近才澄清了该药物处置的主要部分。不可提取的心得洛尔代谢产物（不是葡萄糖醛酸酯）的发现，现在可以解释实验动物和人体中缺失的那部分剂量。这些代谢物的主要成分是4'-羟基心得安的硫酸盐缀合物，约占剂量的20%。通过酶解和各种光谱技术（包括快速原子轰击质谱）对其进行了鉴定。由于硫酸4/羟基心得安有一个完整的侧链，因此存在它可能具有/3受体阻断特性的可能性，正如先前报道的4'-羟基心得安和其他一些环羟基化代谢物一样。5,6为了确认该代谢物的结构，测定其生物活性，并在药物配置研究中使用，我们制备了4'-
4'-Hydroxypropranolol sulfate (8) was recently identified as a major metabolite of propranolol (Inderal). In order to confirm the structure and to further study disposition and biological activity, we have synthesized 8 with use of 1, 4-naphthoquinone (1) as the starting material. Reduction and alkylationwith benzyl iodide gave 4-(benzyloxy) naphthol (3). Sulfation and chlorosulfuric acid in iV/V-dimethylaniline gave potassium l-(benzyloxy)-4-naphthol sulfate (4). Catalytic hydrogenation, alkylation with [[[(trifluoromethyl) sulfonyl] oxy] methyl] oxirane (6), and animation in isopropylamine gave 8. Racemic 8 was found to be 100-1000times less potent than racemic propranolol as a/3-adrenergic receptor blocking agent in the dog.Although extensive studies of the metabolism of pro-pranolol have been in progress over 15 years/only recently has a major part of the disposition of the drug been clarified. The finding of nonextractable propranolol me-tabolites, which are not glucuronides, can now account for the missing fraction of the dose both in laboratory animals2 and in man. 3 A major component of these metabolites is a sulfate conjugate of 4'-hydroxypropranolol, accounting for about 20% of the dose. It was identified by enzymatic hydrolysis and various spectroscopic techniques, including fast atom bombardment mass spectrometry. 4 As 4/-hydroxypropranolol sulfate has an intact side chain, the possibility existed that it might have/3-receptor blocking properties, as previously reported for 4'-hydroxypropranolol and several other ring hydroxylated metabolites. 5, 6 For confirmation of the structure of this metabolite, determination of its biological activity, and use in drug dispositionstudies, we have prepared 4'-