THE SYNTHESIS OF 2-ALKYLAMINO-DIHYDROXY-3, 4-DIHYDROQUINAZOLINES AS DOPAMINE ANALOGUES
Abstract
A review of the structure-activity relationships of various dopamine analogues is presented. Based upon a consideration of their geometry and functional properties several compounds are proposed which should possess dopamine like activity. Specifically, the 2-alkylamino-6,7-dihydroxy and 2-alkylamino-5,6-dihydroxy-3,4-dihydroquinazolines are proposed as guanidine-contained congeners of the highly active 2-alkylamino-6,7-dihydroxy and 2-alkylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalenes. In addition, the parent 2-alkylamino-3,4-dihydroquinazolines are predicted to have significant cardiovascular activity. The synthesis of the dihydroxy derivatives was carried out using a convergent synthetic scheme. The key step was the reaction of an appropriately substituted dimethoxyisatoic anhydride with an N-alkyl-substituted isothiourea to give an N-alkylamino-dimethoxyquinazolin-(1H)-4-one. The synthesis of the unsubsituted parent compounds was accomplished using a divergent synthetic scheme. The critical step involved the reaction of 2-methylthio-3,4-dihydroquinazoline with an appropriately substituted amine to give the 2-alkylamino-3,4-dihydroquinazoline. The 2-alkylamino-3,4-dihydroquinazolines were shown to decrease blood pressure in anesthetized rats through an alpha-adrenergic blocking mechanism. The 6,7-dihydroxy derivatives were found to antagonize the vasodilation caused by dopamine in the renal artery of the dog.
Degree
Ph.D.
Subject Area
Organic chemistry
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