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Medicinal Chemistry of 2,2,4-Substituted Morpholines

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We have designed a number of 2-hydroxy (alkoxy)-2-aryl-4-alkyl-(5,6-alkyl)-morpholines with interesting biological activities, i.e. sympathomimetic, analgesic, drug metabolizing enzyme modulating ability, antioxidant potential, anti-inflammatory and anti-dyslipidemic properties.

They are synthesised by reaction of the proper 2-aminoethanol with aryl-bromomethyl-ketone. The intermediate hydroxyaminoketone is spontaneously cyclised to form the tetrahydro-1,4-oxazine ring. The produced 2-hydroxy substituted morpholines form the 2-alkoxy derivatives. The 2-hydroxy or 2-alkoxy-1,4-oxazine derivatives can lose water or alcohol, to give styrene-type products. The conditions for oxazine ring formation and water or alcohol abstraction are investigated. Ionisation constants and partition coefficients have been determined and related to structure and activity.

The biological activities of these compounds are quite interesting: The 2-phenyl analogues acquire the structural requirements for sympathomimetic amines, and present a structure related to the pethidine-type analgesics. Indeed, they show central dopaminergic and analgesic, antagonized by naloxone, activities. They also affect drug metabolising enzymes.

The 2- phenyl and especially the 2-biphenyl derivatives are good antioxidants, also possessing anti-inflammatory and immunomodulating action. The later class of compounds reduces remarkably plasma triglycerides, total cholesterol and LDL-cholesterol in hyperlipidemic rats. Since NO plays a multiple role in atheromatosis and inflammation, some 2- nitroxy-alkoxy derivatives are synthesized and their NO-liberating ability assessed. These nitric esters are also found to be potent hypolipidemic-hypocholesterolemic agents. In a mechanism elucidation attempt, it is indicated that these derivatives may act as squalene synthase inhibitors.

Keywords: Adjuvant Induced Disease; Al-cohol; Alzheimer's disease; Coronary heart disease; Lipophilicity; Medicinal Chemistry; Morpholines; Naloxone; Reactive oxygen species; adrenergic; alkoxyls; analgesics; anti-dyslipidemic; anti-inflammatory; antioxidants; arthritis; athe-rosclerosis; atherosclerosis; cholesterol; dyslipidemia; high performance liquid chromatography; histaminergic; hypocholesterolemic; inflammation; injection; piloerection; piperidine; proliferation; pyrrolidine; structure/activity relationships; suppression; synthesis; thin layer chromatography; triglyceride; tumour; xenobiotic

Document Type: Research Article


Publication date: October 1, 2010

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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