Medicinal chemistry of 2,2,4-substituted morpholines.
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.
Rekka
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EA
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki, Greece. rekka@pharm.auth.gr
Kourounakis
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PN
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical; D006949:Hyperlipidemias / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D013329:Structure-Activity Relationship
D000700:Analgesics; D000975:Antioxidants; D000960:Hypolipidemic Agents; D009025:Morpholines; D009569:Nitric Oxide