Synthesis of N-isobutylnoroxymorphone from naltrexone by a selective cyclopropane ring opening reaction

被引：17

作者：

Fujii, Hideaki ^{[1
]}

Osa, Yumiko ^{[1
]}

Ishihara, Marina ^{[1
]}

Hanamura, Shinichi ^{[1
]}

Nemoto, Toru ^{[1
]}

Nakajima, Mayumi ^{[2
]}

Hasebe, Ko ^{[2
]}

Mochizuki, Hidenori ^{[2
]}

Nagase, Hiroshi ^{[1
]}

机构：

[1] Kitasato Univ, Sch Pharm, Minato Ku, Tokyo 1088641, Japan

[2] Toray Industries Ltd, Pharmaceut Res Labs, Kanagawa 2488555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 18期

关键词：

hydrogenolysis; platinum (IV) oxide; opioid; cyclopropylcarbinyl cation;

D O I：

10.1016/j.bmcl.2008.08.019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Selective ring opening reaction of the N-cyclopropylmethyl group in naltrexone (1d) was effected in the presence of platinum (IV) oxide and hydrobromic acid under a hydrogen atmosphere at rt to selectively afford N-isobutyl derivative 10. The binding affinity of N-i-Bu derivative 10 for opioid receptors was 11 17 times less than that of the corresponding N-CPM compound, naltrexone (1d). However, compound 10 showed dose-dependent analgesic effects. Contrary to expectations based on previous structure-activity relationship studies for a series of N-substituted naltrexone derivatives that compound 10 would be an opioid antagonist, 10 showed dose-dependent analgesia in the mouse acetic acid writhing test (ED50: 5.05 mg/kg, sc), indicating it was an opioid agonist. This finding may have a great influence on the drug design of opioid agonists. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4978 / 4981

页数：4

共 22 条

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