6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide derivatives were synthesized and characterized as activators of adenosine 5'-triphosphate (ATP) sensitive potassium (K(ATP)) channels in the beta-cells by measuring effects on membrane potential and insulin release in vitro. The effects on vascular tissue in vitro were measured on rat aorta and small mesenteric vessels. Selected compounds were characterized as competitive inhibitors of [(3)H]glibenclamide binding to membranes of HEK293 cells expressing human SUR1/Kir6.2 and as potent inhibitors of insulin release in isolated rat islets. 6-Chloro-3-(1-methylcyclobutyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (54) was found to bind and activate the SUR1/Kir6.2 K(ATP) channels in the low nanomolar range and to be at least 1000 times more potent than the reference compound diazoxide with respect to inhibition of insulin release from rat islets. Several compounds, e.g., 3-propylamino- (30), 3-isopropylamino- (34), 3-(S)-sec-butylamino- (37), and 3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (53), which were found to be potent and beta-cell selective activators of K(ATP) channels in vitro, were found to inhibit insulin secretion in rats with minimal effects on blood pressure and to exhibit good oral pharmacokinetic properties.

中文翻译：

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6-氯-3-烷基氨基-4H-噻吩并[3,2-e] -1,2,4-噻二嗪1,1-二氧化物衍生物有效地和选择性地激活了胰腺β细胞的ATP敏感性钾通道。

合成了6-氯-3-烷基氨基-4H-噻吩并[3,2-e] -1,2,4-噻二嗪1,1-二氧化物衍生物，并将其表征为5'-三磷酸腺苷（ATP）敏感钾的活化剂（通过测量体外对膜电位和胰岛素释放的影响，在β细胞中通过K（ATP））通道。在大鼠主动脉和肠系膜小血管上测量了对体外血管组织的影响。选定的化合物被表征为[（3）H] glibenclamide与表达人SUR1 / Kir6.2的HEK293细胞膜结合的竞争性抑制剂，以及在离体大鼠胰岛中胰岛素释放的有效抑制剂。发现6-氯-3-（1-甲基环丁基）氨基-4H-噻吩并[3,2-e] -1,2,4-噻二嗪1,1-二氧化物（54）结合并激活SUR1 / Kir6。2 K（ATP）通道在低纳摩尔范围内，在抑制大鼠胰岛中胰岛素释放方面，其效力比参考化合物二氮嗪高至少1000倍。几种化合物，例如3-丙基氨基-（30），3-异丙基氨基-（34），3-（S）-仲丁基氨基-（37）和3-（1-甲基环丙基）氨基-4H-噻吩并[3 ，2-2-e] -1,2,4-噻二嗪1,1-二氧化物（53）被认为是有效的，体外K（ATP）通道的β细胞选择性激活剂被发现抑制胰岛素分泌。大鼠对血压的影响最小，并表现出良好的口服药代动力学特性。