Codeine derivatives

Morphine is glucuronidated in the liver at the phenolic hydroxyl group (C3). Protection of that group with a methyl group, as occurs in codeine and other codeine derivatives such as oxycodone, renders the molecule less susceptible to glucuronidation and decreases the first-pass effect in the liver. It is for this reason that codeine and its derivatives retain activity following oral... 

Optical rotatory dispersion003 146 characteristics of (-)-levorphanol and (-)-morphine have been compared. The negative Cotton effects of each compound were attributed to the phenolic chromophores, and this afforded strong evidence for the configurations at C-9, C-13, and C-14 being identical in each. Circular dichroism(104) studies on other morphinan and codeine derivatives supported this conclusion. 

Conorfone is an opioid analgesic, a codeine derivative, with mixed agonist-antagonist activity (SED-11, 150). It has adverse effects similar to those of codeine, bnt canses more drowsiness (1). 

The methyl ethers of [xiv], [xxiv], [xxrx], and [xxxi] have been obtained by degradation of the corresponding (/(-codeine derivatives, [xiv], [xxix], and [xxxi] methyl ethers are reduced to hexahydro-e-codeimethine methyl ether, whilst the ether of [xxiv] is reduced to tetrahydro-e-codeimethine-A methyl ether [67]. 

The synthesis and agonist activity of some 14.beta.-substituted morphine and codeine derivatives... 

The metabolic pathways in plants and living organisms were studied by means of tritium-labeled morphine (508, 509). The use of unnaturally tritium-labeled codeine derivatives showed that P. somniferum is able to... 

Oxycontin and Vicodin, both codeine derivatives, along with Demerol, are among the most commonly abused prescription drugs. 

As 1-bromocodeine is readily prepared in multigram quantities, Davies and colleagues reported a procedure for its modification [96]. By palladium-catalyzed carbonylation reactions, codeines and morphines were elaborated. Wentland s team studied the carbonylative functionalization of 3-triflate substituted codeine derivatives and the biological activities of the products [97, 98]. 

Kirby et al. (1972) showed that Papaver somniferum was capable of converting unnatural precursors to unnatural alkaloids. Various O-demethylated codeine derivatives were converted to unnatural derivatives of morphine. One unnatural conversion which was more efficient... 

Aberrant Biosynthesis of Unnatural Alkaloids.—Kirby S has demonstrated that the opium poppy Papaver somniferum) is capable of carrying out transformations of unnatural precursors to unnatural alkaloids. The 0natural conversion of codeine into morphine by feeding to the plant a mixture of a [2- H]codeine derivative and [N-methyl- C]codeine. One unnatural transformation which was more efficient than the natural one was the conversion of dihydrodeoxycoddne (10) into di-hydrodeoxymorphine (11) (Scheme 4). Kirby concluded that neither the 6-hydroxy-group nor the 7,8-double bond in codeine is important for binding to the enzyme responsible for demethylation of the 3-methoxy-group of codeine. 

The Opiates. The International Narcotics Control Board—Vienna, tracks the tick production of narcotic dmgs and annually estimates world requkements for the United Nations. Thek most recent pubHcation (100) points out that more than 95% of the opium for Hcit medical and scientific purposes is produced by India and, in a declining trend, only about 600 t was utilized in 1988. This trend appears to be due to the fact that the United States, the largest user of opium for alkaloid extraction, reduced the amount of opium being imported from about 440 t in 1986 to 249 t in 1987 and 224 t in 1988. The United States used about 48 t of morphine (2, R = H) in 1988, most (about 90%) being converted to codeine (2, R = CH3) and the remainder being used for oral adrninistration to the terminally ill (about 2 t) and for conversion to other materials of minor commercial import which, while clearly alkaloid-derived, are not naturally occurring. 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

The processes used in the manufacture of morphine are believed to be still based on that described by the Scottish chemist Gregory,in 1833, with improvements devised by Anderson. A description has been published by Schwyzer, who also deals with the manufactme of codeine, narcotine, cotarnine, and the commercially important morphine derivatives, diamorphine (diacetylmorphine), and ethylmorphine (morphine ethyl ether). More recently Barbier has given an account of processes, based on long experience in the preparation of alkaloids from opium. Kanewskaja has described a process for morphine, narcotine, codeine, thebaine and papaverine, and the same bases are dealt with by Chemnitius, with the addition of narceine, by Busse and Busse, and by Dott. It is of interest to note that a number of processes for the extraction and separation of opium alkaloids have been protected by patent in Soviet Russia. ... 

In the strict sense, opiates are drugs which are derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non-peptidic structures. The old term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, pqrtidic or non-peptidic, that produces morphine-like effects through an action on opioid receptors. 

Opioids. Reactions to morphine, codeine phosphate, meperidine, fentanyl and its derivatives are uncommon. Because of their direct histamine-releasing properties, especially regarding morphine and codeine, distinction between anaphylaxis and non-immune-mediated histamine release is not always easy. Only 12 cases were recorded in the last 2 years epidemiologic survey in France, 9 of them being related to morphine administration [9]. 

Rice, K.C. (1980) Synthetic Opium Alkaloids and Derivatives. A Short Total Synthesis of (ib)-Dihydrothebainone, ( )-Dihydrocodeinone, and ( )-Nordihydrocodemone as an Approach to a Practical Synthesis of Morphine, Codeine, and Congeners. Journal of Organic Chemistry, 45, 3135-3137. 

When Montgomery and I published our article, we thought we had disproven another theory of placebo effects - the theory that placebo effects are produced by the release of endorphins in the brain. In 1978 researchers at the University of California in San Francisco discovered that when placebos reduce pain, they may stimulate the release of endorphins.18 Endorphins, the existence of which had only been discovered a few years earlier, are opioids that are produced naturally by the brain. Just like the opiates that are derived from opium - morphine and codeine, for example - endorphins reduce the sensation of pain. The University of California researchers reasoned that if placebos can mimic the effects of opiate drugs, maybe they do so by stimulating the release of the brain s endogenous opioids. 

However, the affinity of 43 was higher than that of the allylic derivative 72 and near to that of codeine, though 5-fold less (74). Recently, some naturally occurring hasubanan alkaloids have been submitted to screening for antitumor activity, but the results, as far as we know, remain obscure. 

All opiate derivatives are associated with constipation, but the degree of intestinal inhibitory effects seems to differ between agents. Orally administered opiates appear to have greater inhibitory effect than parenterally administered agents oral codeine is well known as a potent antimotility agent. 

---