The analgesic properties of some 14-substituted derivatives of codeine and codeinone

Abstract

The effects of 14‐hydroxylation and subsequent 14‐acylation on the toxicity and analgesic activity of codeine, codeine‐6‐acetate, codeinone, and Δ7‐deoxycodeine have been examined in rats and mice. Acute toxicity was reduced in each instance by the introduction of a 14‐hydroxy group and was not generally enhanced by its esterification. 14‐Acetoxycodeine was approximately equal to morphine in potency and esterification at the 14‐position of hydroxycodeine with other straight chain aliphatic acids containing up to 5 carbon atoms failed to enhance analgesic potency further. 14‐Benzoylation of either 14‐hydroxycodeine or 14‐hydroxycodeinone had little effect on analgesic activity but the introduction of a methylene group between the carboxyl group and the phenyl ring enhanced potency considerably in each case. Increasing the number of carbon atoms from 2 to 5 in the 14‐acyl groups of esters of 14‐hydroxycodeinone and 14‐hydroxy‐Δ7‐deoxycodeine led to a gradual increase in analgesic activity. In rats the n‐valeryl ester of 14‐hydroxy‐Δ7‐deoxycodeine was estimated to have 75 times the potency of morphine.

The toxicity of some of the newer narcotic analgesics

“…However no details of their toxicity or side-effect liability are yet available. Esterification of the 1Chydroxy group of oxycodone has been shown to produce an increase in analgesic potency in mice with a marked reduction in acute toxicity when compared with the parent compound (Buckett, Farquharson & Haining, 1964), but no clinical data are yet available. This is derived from morphine by N-demethylation and has been demonstrated to occur in the liver and brain of rats following the injection of morphine (Misra, Mule & Woods, 1961;Milthers, 1962) and it has been suggested as the active metabolite of morphine (Beckett, Casy & Harper, 1956).…”