RING-HYDROXYLATED PROPRANOLOL - SYNTHESIS AND BETA-RECEPTOR ANTAGONIST AND VASODILATING ACTIVITIES OF THE 7 ISOMERS
RING-HYDROXYLATED PROPRANOLOL - SYNTHESIS AND BETA-RECEPTOR ANTAGONIST AND VASODILATING ACTIVITIES OF THE 7 ISOMERS
复制标题
DOI：
10.1021/jm00135a014
复制
发表时间：
1981-01-01
影响因子：
7.3
通讯作者：
WALLE, T
中科院分区：
文献类型：
--
作者：
OATIS, JE;RUSSELL, MP;WALLE, T
普萘洛尔（Inderal；1）在人体中广泛代谢。具有药理学意义的代谢物包括环羟基化普萘洛尔 (1a-g)。为了鉴定这些环氧化产物并研究羟基位置对生物活性的影响，合成了所有 7 种异构体。除了1b和1g之外，所需的化合物通过用环氧氯丙烷将相应的甲氧基-1-萘酚烷基化并且将所得环氧化物与异丙胺反应来制备。甲基在稠合吡啶盐酸盐中裂解得到1a,c-f。 1g通过用环氧氯丙烷直接烷基化1,8-萘二醇(17)，然后与异丙胺反应来制备。通过用Cl气处理2-萘酚(9)，然后用烯丙基氧化钠处理所得的1,1-二氯萘-2(1H)-酮(10)来合成1b。羟基官能团的乙酰化和烯丙基的环氧化，然后与异丙胺反应，得到3''-羟基-4''-氯普萘洛尔(15)。脱氯得到1b。所有外消旋羟基化普萘洛尔在麻醉狗中产生β-阻断和直接血管舒张。效力强烈依赖于羟基的位置，即，作为β-受体拮抗剂，1e的效力是1的4倍，而1a、1b和1g的效力均显着低于1。对于直接血管舒张，1a和1g与1等效，而1b-f的效力较低。将化合物的效力与其 1-辛醇/pH 7.4 缓冲液分配系数进行比较；直接血管舒张效力随着亲脂性的增加而增加，而β-肾上腺素能拮抗剂的效力下降。
Propranolol (Inderal; 1) is extensively metabolized in man. Metabolites of pharmacological interest include ring-hydroxylated propranolols (1a-g). To identify these ring-oxidized products and to study the effect of hydroxyl position on biological activity, all 7 isomers were synthesized. With the exception of 1b and 1g, the desired compounds were prepared by alkylation of the respective methoxy-1-naphthols with epichlorohydrin and reaction of the resulting epoxide with isopropylamine. Cleavage of the methyl group in fused pyridine hydrochloride afforded 1a,c-f. The 1g was prepared by the direct alkylation of 1,8-naphthalenediol (17) with epichlorohydrin, followed by reaction with isopropylamine. The 1b was synthesized by treating 2-naphthol (9) with Cl gas and then treating the resulting 1,1-dichloronaphthalen-2(1H)-one (10) with sodium allyl oxide. Acetylation of the hydroxy function and epoxidation of the allyl group, followed by reaction with isopropylamine, gave 3''-hydroxy-4''-chloropropranolol (15). Dechlorination gave 1b. All of the racemic hydroxylated propranolols produced .beta.-blockade and direct vasodilation in anesthetized dogs. The potency is strongly dependent upon the position of the hydroxyl group, i.e., 1e is 4 times as potent as 1 as a .beta.-receptor antagonist, whereas 1a, 1b and 1g are all significantly less potent than 1. For direct vasodilation 1a and 1g are equipotent to 1, while 1b-f are less potent. The potencies of the compounds were compared with their 1-octanol/pH 7.4 buffer distribution coefficients; the direct vasodilating potency increased with increasing lipophilicity, while the .beta.-adrenergic antagonist potency decreased.