Synthesis and Biological Evaluation of 14‐Alkoxymorphinans. Part 9. 14‐O‐ethyl‐5‐methylnaltrexone, and opioid antagonist with unusual selectivity

Abstract

14-0-Ethyl-5-methylnaloxone (7) and 14-0-ethyl-5-methylnaltrexone (8) have been prepared starting from 14-0-ethyl-5-methyloxycodone (9) in several steps. Both, 7 and 8, were found to be opioid antagonists in vitro and in vivo. Compound 7 exhibited some selectivity forp opioid receptors, whereas compound 8 did not show selectivity for any of the receptor types. In the AcOH-writhing antagonism test, 8 was not able to antagonize morphineinduced antinociception, but antagonized fentanyl-and sufentanil-induced antinociception.

Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22. Influence of the 14-Alkoxy Group and the Substitution in Position 5 in 14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities

“…Prior to 14-O-allylation, the 3-OH and 6-keto groups were protected. First, ketal 12 was formed, which was 3-O-benzylated (13) and further 14-O-allylated with allyl bromide in N,N-dimethylformamide (DMF) in the presence of NaH as base to give compound 14. Acid hydrolysis with HCl/MeOH yielded compound 6 (Scheme 1).…”

“…The N-phenylethyl derivative 11 was prepared from 14-ethoxy-substituted N-nor morphinan 24 13 by Nalkylation with 2-phenylethyl bromide (24) followed by ether cleavage of 25 with 48% HBr.…”

A Novel Method for the Introduction of a 5β-Methyl Group into 4,5α-Epoxymorphinan-6-onesvia the Enol Ether

“…17-(Cyclopropylmethyl)-4,5a-epoxy-3-hydroxy-14b-methoxy-5b-methylmorphinan-6-one (5a) and 17-(Cyclopropylmethyl)-4,5a-epoxy-3-hydroxy-14b-methoxy-2,5b-dimethylmorphinan-6-one (6). A soln.…”

“…Here we describe a method of preparing 14b-alkoxy-17-(cyclopropylmethyl)-5b-methylmorphinan-6-ones starting from naltrexone (1). Thus 5b,14-O-dimethylnaltrexone (5a) as well as the more potent 14-O-ethyl-5b-methylnaltrexone (5b), which are opioid antagonists with unusual properties [5] [6] and from which the highly selective d-opioid antagonists 7a and 7b (HS 378) [7] [8] are synthesized, were prepared in only three steps instead of eight [1 ± 4].…”

β-Phenylethylamines and the isoquinoline alkaloids

“…Oxidation of this with phenylselenium chloride and hydrogen peroxide gave the enone [( 201), R = CO,Me], which was converted into the N-methyl analogue [(201), R = Re]. Reductive fission of this carbinolamine ether by zinc and acid was accompanied by addition of the liberated amine to the enone to produce (202), which was reduced to (203), and this gave /3-thebainone (204) on hydrolysis and dehydration.212 Since this was converted into its C-14 epimer, thebainone, during Gates's synthesis of morphine, this constitutes a new total synthesis of this alkaloid.…”