Abstract
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: Morpholines, synthesis, structure/activity relationships, analgesics, antioxidants, inflammation, dyslipidemia, atherosclerosis, Medicinal Chemistry, anti-inflammatory, anti-dyslipidemic, athe-rosclerosis, adrenergic, histaminergic, tumour, Alzheimer's disease, Al-cohol, alkoxyls, pyrrolidine, piperidine, Lipophilicity, high performance liquid chromatography, thin layer chromatography, injection, Naloxone, piloerection, suppression, Adjuvant Induced Disease, arthritis, Reactive oxygen species, Coronary heart disease, proliferation, cholesterol, triglyceride, xenobiotic, hypocholesterolemic
Current Medicinal Chemistry
Title: Medicinal Chemistry of 2,2,4-Substituted Morpholines
Volume: 17 Issue: 29
Author(s): E. A. Rekka and P. N. Kourounakis
Affiliation:
Keywords: Morpholines, synthesis, structure/activity relationships, analgesics, antioxidants, inflammation, dyslipidemia, atherosclerosis, Medicinal Chemistry, anti-inflammatory, anti-dyslipidemic, athe-rosclerosis, adrenergic, histaminergic, tumour, Alzheimer's disease, Al-cohol, alkoxyls, pyrrolidine, piperidine, Lipophilicity, high performance liquid chromatography, thin layer chromatography, injection, Naloxone, piloerection, suppression, Adjuvant Induced Disease, arthritis, Reactive oxygen species, Coronary heart disease, proliferation, cholesterol, triglyceride, xenobiotic, hypocholesterolemic
Abstract: 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.
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Cite this article as:
A. Rekka E. and N. Kourounakis P., Medicinal Chemistry of 2,2,4-Substituted Morpholines, Current Medicinal Chemistry 2010; 17 (29) . https://dx.doi.org/10.2174/092986710793176276
DOI https://dx.doi.org/10.2174/092986710793176276 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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