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C2H5 3137

Methadone is a synthetic opioid that acts on the ^-receptors and is both qualitatively and quantitatively analogous to morphine. The principal difference lies in its higher efficacy when taken orally, and its long-lasting effect. Other than its use as a strong analgesic, it is used in treating drug addiction, since it replaces other agonists on the receptor. Synonyms for this drug are fizepton, methenone, dolofin, and others.

Meperidine: Meperidine, the ethyl ester of 1-methyl-4-phenylpiperidine-4-carboxylic acid (3.1.39), is a synthetic opioid analgesic. Its synthesis is accomplished by the alkyla-tion of benzyl cyanide using N,N-to-(2-chlorethyl)-N-methylamine in the presence of sodium amide, which forms 1-methyl-4-phenyl-4-cyanopiperidine (3.1.38), and its subsequent acidic ethanolysis into meperidine [30-32].

ch3 ch3

ch3 ch3

Meperidine is related to analgesics of the phenylpiperidine series. These compounds are also agonists, although they significantly differ from morphine in terms of structure. This drug also exhibits anticholinergic activity. Like morphine, it causes histamine release and spasm of the smooth muscles. It is practically inactive upon oral administration. Most of the pharmacological properties and administration indications are similar to those of morphine; however, this drug lacks antitussive properties. During parenteral administration, activity is basically one-eighth that of morphine. Meperidine is widely used in premedical and stabilizing anesthesia. It is preferred for use in obstetrical practice due to the quick onset of analgesia and its short-lasting action. The most frequently used synonyms are pethidine, dolantin, and demerol.

Promedol: Promedol, 1,2,5-trimethyl-4-phenyl-4-propionyloxypiperidine (3.1.45), is also related to analgesics belonging to the phenylpiperidine series, and in its own way represents a "reversed" meperidine; it differs from meperidine in that the carbonyl group is joined to the fourth position of the piperidine ring through oxygen instead of through a carbon atom. Synthesis of this compound pretty much differs from the synthesis of meperidine and is based on using of 1,2,5-trimethylpeperidin-4-one. This product comes from dimethylvinylethynylcarbinol (3.1.40), a condensation product of vinylacetylene with acetone in the Favorskii reaction, which undergoes dehydration into vinylisopropenylacetylene (3.1.41). The triple bond in vinylisopropenylacetylene is hydrated in dilute sulfuric acid in methanol and in the presence of mercury (II) sulfate (Kucherov reaction). This results in vinylisopropenylketone (3.1.42), primarily in the form of methoxy derivatives, which are products of addition of methanol to activated double bonds, and the reaction of heterocy-clization with methylamine to form 1,2,5-trimethylpiperidin-4-one (3.1.43). This undergoes a reaction with phenyllithium to form 1,2,5-trimethyl-4-phenylpiperidin-4-ol (3.1.44). Esterfication of this compound with propionyl chloride gives promedol [33].

C-C=C—ch=CH2 -» H2C=C-C=C—CH=CH2 —-,»H2C=C-C-CH=CH—ch3 -«.

C-C=C—ch=CH2 -» H2C=C-C=C—CH=CH2 —-,»H2C=C-C-CH=CH—ch3 -«.

Promedol is quickly absorbed and displays strong analgesic action during both parenteral and oral administration. It gives less respiratory suppression than morphine. It also displays antispasmodic effects on smooth muscle. It is used as a pain-relieving agent during surgical intervention, trauma, and diseases that are accompanied by painful sensations. A synonym for this drug is trimeperidine.

Loperamide: Loperamide, 1-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-a, a-diphenyl-1-piperidinebutyramide (3.1.55), proposed here as an analgesic, is synthesized by the alky-lation of 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) using N,N-dimethyl(3,3-diphenyltetrahydro-2-furylidene)ammonium bromide (3.1.54) in the presence of a base. The 4-(4-chlorophenyl)-4-hydroxypiperidine (3.1.50) is synthesized by reacting 1-benzylpiperidine-4-one (3.1.48) with 4-chlorophenylmagnesiumbromide, followed by debenzylation of the product (3.1.49) by hydrogenation using a palladium on carbon catalyst.

The starting 1-benzylpiperidin-4-one (3.1.48) is synthesized by Dieckmann intermolecular condensation of N-benzyl-N,N-to-(/¡-carboethoxyethyl)amine (3.1.46), which is easily formed by reaction of benzylamine with ethyl acrylate to give 1-benzyl-3-carboethoxy-piperidine-4-one (3.1.47) followed by acidic hydrolysis and thermal decarboxylation.

/==\ /=\ CH2-CH2—COOC2H5 C2H5ONa ^ h— CH2-NH2 + 2 H2C=CH-COOC2H5 -*- h— CH2-N( -»N-' CH2—CH2—COOC2H5

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