Wollweber H, Horstmann H, Stoepel K, Garthoff B, Puls W, Krause H P, Thomas G
Arzneimittelforschung. 1981;31(2):279-88.
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.
通过二烷基氨基烷基胺或ω-氨基烷基醚与在3位带有对亲核取代不稳定的基团（Cl、CH₃S、CH₃CO₂）的2H-1,2,4-苯并噻二嗪-1,1-二氧化物反应，可得到相应的3-取代氨基-2H-1,2,4-苯并噻二嗪-1,1-二氧化物。这些化合物中的一系列在口服给药后对肾性高血压大鼠以及在肠胃外给药后对“双肾高血压犬”具有降压作用。与二氮嗪（16）和已知的哌嗪化合物（17）相比，对两种化合物（1和4）进行了深入研究。在大鼠中，二氮嗪以10 mg/kg的剂量可导致水和电解质排泄显著减少，但在此剂量下，1和4既不是利尿剂也不是抗利尿剂。在对正常大鼠进行的高血糖测试中，以降压作用所需剂量的30 - 100倍给药时，1和4在300 mg/kg时未显示高血糖作用，口服1000 mg/kg时作用非常微弱。17在300 mg/kg时有微弱的高血糖作用，二氮嗪则有强烈的高血糖作用。然而，对糖尿病大鼠（糖耐量降低）和葡萄糖负荷的代谢健康大鼠进行的强化葡萄糖负荷研究表明，化合物1和4以及哌嗪衍生物17抑制胰岛素释放，尽管所需剂量高于二氮嗪。在具有胰岛素抵抗的动物中会出现血糖水平高的糖尿病代谢状况。由于这种可能的致糖尿病活性，不认为对1、4和已知的7-氯-3-(4-甲基-1-哌嗪基)-2H-1,2,4-苯并噻二嗪-1,1-二氧化物进行人体志愿者降血糖活性测试和应用是合适的。
