Morphine substitution

Paper electrophoresis for the determination of some synthetic morphine substitutes in chemicotoxicological analysis... 

A patient with acute myeloid leukaemia started treatment with a 4-day course of busulfan 1 mg/kg four times daily followed by cyclophosphamide for 2 days before bone marrow transplantation. At the time he was also receiving ketobemidone 1 g daily for a rectal fissure. Busulfan plasma levels after the first dose were elevated (AUC increased by about one-third). Later, when the dose of ketobemidone was reduced and morphine substituted, busulfan levels decreased. The authors suggest that ketobemidone should not be used with high-dose busulfan unless monitoring is possible dose adjustments may be required to prevent busulfan toxicity. An alternative analgesic should be considered. 

Methadone Methadone was first synthesized as a morphine substitute and possesses many of that drag s pharmacological properties. It is mainly excreted in mine in imchanged form (5%-50% of a dose) or is metabolized by A-demethylation with spontaneoirs cycfization of the resirlting metabolite to 2-ethyfidene-l,5-dimethyl-3,3-dipher5flpyrrofidine (EDDP) (3%-25% of a dose). 

The first reaction was involved in a synthesis of morphine, the starting ketone being made by reduction of a substituted naphthalene O. Amer. Chem. Soc., 1950, 72, 3704). No doubt an epoxide could have been used as the electrophile. 

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

Codeine, like morphine, is isolated from the opium poppy. However, the low yield of 0.7—2.5% does not provide sufficient material to meet commercial demands. The majority of marketed codeine is prepared by methylating the phenolic hydroxyl group of morphine. Morphine yields from opium poppy are 4—21%. When prescribed for cough, the usual oral dose is 10—20 mg, three to four times daily. At these doses, adverse side effects are very few. Although the abuse potential for codeine is relatively low, the compound can substitute for morphine in addicts (47). 

In an effort to more closely mimic the aromatic substitution pattern found in morphine (see A) the pethidine analog containing the m-hydroxy group was prepared as well. Thus, in a synthesis analogous to that used to prepare the parent compound, double alkylation of m-methoxyphenylacetonitrile with the chloroamine. 

Still other halo-substituted compounds are providing important leads to new medicines. The compound epihatidine, for instance, has been isolated from the skin of Ecuadorian frogs and found to be more than 200 times as potent as morphine at blocking pain in animals. 

In Entry 9, the initial reaction involves 5-exo addition of the aryl radical to the more-substituted end of the cyclohexene double bond, followed by a 6-endo addition to the phenylthiovinyl group. The reaction is completed by elimination of the phenylthio radical. The product is an intermediate in the synthesis of morphine. 

Analogs 11-13 are representative of new morphinan-derived zwitter-ions. The orally active 14-substituted ether (11) is 10-fold more potent than 2 in reversing morphine-induced decrease in GI motility in rat [41]. 

Somewhat more effective catalysts are obtained by replacing BINAP with TolBINAP, which is 2,2 -bis(di-p-tolylphosphino)-l,l -binaphthyl.4 The presently preferred catalysts are complexes of Ru(OCOCF3)2 with (R)- or (S)-TolBINAP, obtained by treatment of Ru(OAc)2TolBINAP with 2 equiv. of trifluoroacetic acid. Such catalysts promote hydrogenation of typical enamides in 98% ee and 98% yield. This reaction can be used to provide asymmetric synthesis of isoquinoline alkaloids as well as of morphinans used as substitutes for morphine. 

Opioids are sedating and cause a reduction in processing speed in clinical populations (e.g.. Digit Symbol Substitution Test) (Wood et al. 1998). However, a study in healthy subjects did not confirm these effects on digit substitution (Walker and Zacny 1998). Improvements are seen in choice reaction time after morphine administration (Hanks et al. 1995). Deficits have been reported in early-stage visual processing (O Neill et al. 1995 Hanks et al. 1995). By comparison, morphine s cognitive effects are lesser than those of lorazepam, but milder than hydromorphone (Rapp et al. 1996 Hanks et al. 1995). 

Table 3.9. ANTAGONIST ACTIVITY OE C-I4 BETA-SUBSTITUTED MORPHINE...

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