Codeine esters

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

In the United Kingdom, diamorphine is controlled as a Class A drng, nnder Part 1 of Schednle 2 of the Misnse of Drugs Act, 1971, as is its precursor, morphine. Codeine is controlled as a Class B drug. In addition, the prodncts fonnd as imparities from diamorphine prodnction, namely 3-monoacetyhnorphine and 6-monoacetylmorphine, are controlled as esters of morphine, while acetylcodeine is controlled as an ester of codeine. In the United States, heroin (diamorphine) is controlled as a Schednle I narcotic. 

Codeine phosphate in a paracetamol-codeine effervescent tablet was found to react at room temperature with the citric acid constituents to form citrate esters of codeine. The esterification was confirmed in a solid-state reaction at an elevated temperature. Tartaric acid also yielded an ester with codeine phosphate in a similar non-solvolytic reaction. 

The biological properties of narco tine have been reviewed (1). The antitussive activity of narcotine once more was a subject of many papers (259-271) and the question of this property, when compared with that of codeine, still remains unclear. Codeine is said to be superior in this respect to narcotine (272) but, according to other authors (273, 274), narcotine has some advantage over codeine. The antitussive activity of different stereoisomers of narcotine have also been studied (271). Narcotine-V-oxide showed an increased antitussive activity (271, 275, 276) and narcotine resinate was recommended as a long-acting antitussive (277, 278), as were the esters of 6-hydroxymethylnarcotine (279). The phar-... 

The asymmetric total synthesis of (+)-codeine, the unnatural enantiomer, was accomplished by J.D. White and coworkers using an intramolecular carbenoid insertion as the key step. The first stereogenic center that directed all subsequent stereochemical events was installed by the asymmetric hydrogenation of an alkylidene succinate that was obtained using the Stobbe condensation. Dimethyl succinate and isovanillin were reacted in the presence of excess sodium methoxide at reflux and the resulting reaction mixture was acidified to obtain the monomethyl ester. 

The alcoholic hydroxyl group of codeine can be acetylated by glacial acetic acid or acetic anhydride [226] to give acetylcodeine, the nitrogen ring being stable [227], Numerous other esters have been prepared 1223, 228-33],... 

Desoxycodeine-E [xxx] pan be prepared by the lithium aluminium hydride reduction of codeine [n] p-toluenesulphonyl ester [17-18], Its structure is shown to be [xxx] by hydrogenation of the base to dihydrodesoxycodeine-D [xiii], degradation of the methiodide to desoxy-a-codeimethine [xxix], and isomerization of the latter to desoxy-/3-codeimethine [xxvin], production of cyanonordesoxy codeine-E [xxxi] by the action of cyanogen bromide on the base, and by the facts that desoxycodeine-E is neither a phenol nor an enol ether [17]. Desoxycodeine-E can be demethylated to desoxymorphine-E [62]. 

A very different type of reaction is represented by the conjugation of xenobiotic alcohols with fatty acids, yielding highly lipophilic metabolites accumulating in tissues. Thus, ethanol and haloethanols form esters with palmitic acid, oleic acid, linoleic acid, and lin-olenic acid enzymes catalyzing such reactions are cholesteryl ester synthase (EC 3.1.1.13) and fatty-acyl-ethyl-ester synthase (EC 3.1.1.67) (71). Larger xenobiotics such as tet-rahydrocannabinols and codeine are also acy-... 

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