Synthesis of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine, beta-adrenergic affinity, inotropic, chronotropic and coronary vasodilating activities

A series of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vas odilating activities in the canine heart, affinity to beta(1)-adrenergic re ceptor in turkey erythrocytes and affinity to the beta(2)-adrenergic recept or in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2- hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the beta(1) receptor than propranolol and 7-(3-tert-butylamino- 2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the beta(2) receptor and furthermore 4 386-fold mor e potent selectivity to the beta(2) receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H- 1,4-benzoxazine showed 1.1-fold more potent affinity to the beta(1) recepto r than propranolol and also 1 147-foId more potent selectivity to the beta( 1) receptor. With a few exceptions, negative inotropic and chronotropic act ions of these compounds were dependent on the size of the 4-substituent obe ying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the be nzoyl substituent conferred even stronger negative actions in the 6-oxyprop anolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to beta(1)-adrenoceptor nor coronary vasodilator acti on related with affinity to beta(2)-adrenoceptor were observed. 4-acetyl-7- [3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxaz ine exerted potent positive inotropic, chronotropic and coronary vasodilati ng actions. The inotropic and chronotropic actions of the latter compound m ay be attributed to the release of intrinsic catecholamines, as concluded b y the absence of beta(1)-adrenoceptor affinity and disappearance of activit y in the presence of a beta-blocker. (C) 1999 Editions scientifiques et med icales Elsevier SAS.