3-Amino-2H-1,2,4-benzothiadiazine-1,1-dioxides with antihypertensive and possibly diabetogenic activity (author's transl)

Wollweber,Horstmann,Stoepel,Garthoff,Puls,Krause,Thomas

, p. 279 - 288 (2007/10/02)

By reaction of dialkylaminoalkylamines or omega-amino-alkylethers with 2H-1,2,4-benzothiadiazine-1,1-dioxides bearing a group in the 3-position labile towards nucleophilic substitution (Cl, CH3S, CH3CO2), the corresponding 3-substituted amino-2H-1,2,4-benzothiadiazine-1,1-dioxides are obtained. A series of these compounds exerts an antihypertensive effect in the renally hypertonic rat after oral administration and in the "two-kidney hypertensive dog" after parenteral administration. Two compounds (1 and 4) were studied thoroughly in comparison to diazoxide (16) and the known piperazino compound (17). At 10 mg/kg in the rat, diazoxide causes a marked reduction of water and electrolyte excretion but at this dosage 1 and 4 are neither diuretic nor antidiuretic. In the hyperglycaemia test on normal rats at a dosage 30--100 times that required for an antihypertensive effect, 1 and 4 show after 300 mg/kg no hyperglycaemic effect and after 1000 mg/kg p.o. a very weak one. 17 has a weak hyperglycaemic effect at 300 mg/kg diazoxide a strong one. However, intensive glucose loading studies on diabetic rats (reduced glucose-tolerance) and on metabolically healthy rats with glucose loading showed that compounds 1 and 4 as well as the piperazine derivative 17 inhibit insulin release, albeit in higher doses than does diazoxide. In animals with insulin resistance a diabetic metabolic condition occurs with high blood-sugar levels. Owing to this possible diabetogenic activity, testing and application of 1, 4 and the known 7-chloro-3-(4-methyl-1-piperazinyl)-2H-1,2,4-benzothiadiazine-1,1-dioxide for blood-sugar lowering activity to human volunteers is not considered appropriate.