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

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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.

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