2-(Isoxazolylethenyl)phenoxypropanolamines: a new class of beta-receptor antagonists with antihypertensive activity.

The synthesis of a series of (E)-1-amino-3-[2-(2-isoxazolylethenyl)phenoxyl-2-propanols is described. These compounds were found to have beta- and alpha-adrenergic blocking properties, as well as hypotensive and antihypertensive properties. The beta-adrenoceptor antagonism of all these compounds was more pronounced than their alpha-sympatholytic and hypotensive activity. 3a was 16 times more potent than labetalol in beta-adrenergic receptor blockade and was effective in lowering blood pressure in acute trials on spontaneously hypertensive rats at a dosage of 15 mg/kg. Structure-activity considerations showed that antihypertensive potency was more sensitive to structural variations than beta-adrenoceptor antagonistic activity. However, in general, those compounds having the most potent beta-adrenoceptor blocking activity also lowered blood pressure most effectively.

[New beta-sympatholytic agents. Synthesis and pharmacological activity of isomeric benzthiazole and benzoxazole derivates (author's transl)]. / Neue beta-Sympatholytika: Synthesen und pharmakologische Wirkung isomerer Benzthiazol- und Benzoxazol-Derivate.

The synthesis and comparative pharmacological studies concerning structure-activity relationship of new benzothiazole, benzisothiazole, benzoxazole, and benisoxazole derivatives with beta-sympatholytic activity are reported. Most of the 4-benzisothiazole derivatives studied strongly act on cardiac beta 1-receptors in rats in situ (2.6-8.3 times propranolol). On the other hand derivatives of 4-benzisoxazole and 5-benzisothiazole are less potent. A strong decrease in activity was observed going from the benzisothiazoles and benzisoxazoles to the isomeric benzthiazoles and benzoxazoles. The active substances also block vascular beta 2-receptors. In the most cases they have little intrinsic adrenergic activity. The observed tendency concerning beta 1-selectivity in rats could not be confirmed in cats. The most potent 4-benzisothiazole derivatives in rats show also - beside some minor differences - very good beta-sympatholytic activity in cats after i.v. as well as after i.d. administration. Similar to the results in rats and cats the 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole (LU 24329) was found to possess a high activity in conscious dogs by oral or i.v. application. Both in dogs (i.v.) and in isolated perfused guinea pig hearts LU 24329 is eleven times more active than propranolol in blocking beta 1-receptors. A negative inotropic effect as an expression of non-specific membrane-stabilizing action of LU 24329 is also demonstrated in guinea pig hearts. The effective concentration is 4650 times higher than that effective on beta 1-adrenoceptors. The active compounds have a moderate acute toxicity. The LD50 values in mice after i.p. administration are ranging from 55-174% of the propranolol toxicity.