苯乙脒,2,6-二氯-a-羟基- | 194086-61-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 中文名称: 苯乙脒,2,6-二氯-a-羟基-
• 英文名称: 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide
• 英文别名: 3,6-Dichloro-4h-thieno[3,2-e][1,2,4]thiadiazine 1,1-dioxide
• CAS: 194086-61-8
• 化学式: C₅H₂Cl₂N₂O₂S₂
• 分子量: 257.121
• InChiKey: NZHOYUFGQJNYSD-UHFFFAOYSA-N

物化性质

• 熔点：
  >240 °C (decomp)
• 沸点：
  455.6±55.0 °C(Predicted)
• 密度：
  2.16±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  95.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  苯乙脒,2,6-二氯-a-羟基- 以 盐酸 、 1-甲基环丙胺 、 乙酸乙酯 为溶剂， 以26%的产率得到6-氯-3-((1-甲基环丙基)氨基)-4H-噻吩并(3,2-e)-1,2,4-噻二嗪 1,1-二氧化物
  参考文献：
  名称：

  Fused 1,2,4-thiadiazine derivatives, their preparation and use

  摘要：

  本发明涉及通式为4H-噻吩[3,2-e]-1,2,4-噻二嗪衍生物的化合物，其中X、Y、R1、R2和R3在描述中有定义，描述了这些化合物的组合物和制备方法。这些化合物在治疗中枢神经系统、心血管系统、肺部系统、消化系统和内分泌系统疾病中具有用途。

  公开号：

  US06329367B1
• 作为产物：
  描述：

  6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide 在 磷酸 、 吡啶盐酸盐 、 三氯氧磷 作用下， 反应 15.0h， 以73%的产率得到苯乙脒,2,6-二氯-a-羟基-
  参考文献：
  名称：

  6-Chloro-3-alkylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-Dioxide Derivatives Potently and Selectively Activate ATP Sensitive Potassium Channels of Pancreatic β-Cells

  摘要：

  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 [H-3]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 KATP 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.

  DOI：

  10.1021/jm0208121

文献信息

• Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their
  申请人：Novo Nordisk A/S

  公开号：US05889002A1

  公开（公告）日：1999-03-30

  1,2,4-Thiadiazine and 1,4-thiazine derivatives represented by the formula ##STR1## wherein A, B, D, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined in the description, compositions thereof and methods for preparing the compounds are described. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinologic system.

  1,2,4-噻二嗪和1,4-噻嗪衍生物，其代表性结构式如上，其中A、B、D、R1、R2、R3和R4在描述中有定义，以及它们的组合物和制备方法被描述。这些化合物在治疗中枢神经系统疾病、心血管系统疾病、肺系统疾病、胃肠系统疾病和内分泌系统疾病方面具有用途。
• New 3-Alkylamino-4<i>H</i>-thieno-1,2,4-thiadiazine 1,1-Dioxide Derivatives Activate ATP-Sensitive Potassium Channels of Pancreatic Beta Cells
  作者：Flemming E. Nielsen、Søren Ebdrup、Anette Frost Jensen、Lars Ynddal、Thora B. Bodvarsdottir、Carsten Stidsen、Anne Worsaae、Harrie C. M. Boonen、Per O. G. Arkhammar、Tinna Fremming、Philip Wahl、Hanne T. Kornø、J. Bondo Hansen

  DOI：10.1021/jm060042j

  日期：2006.7.1

  Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K(ATP) channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues

  化合物1a（NN414）是Kir6.2 / SUR1 K（ATP）通道的有效开启剂。化合物1a抑制胰岛素在体外和体内的释放，并在临床前动物模型中保留β细胞功能，这表明该化合物可用于治疗或预防1型和2型糖尿病。介绍了1a的晶体结构和会聚合成，以及一系列1a的新类似物。有几种化合物，例如6-氯-3-（1-甲基-1-苯乙基）氨基-4H-噻吩并[3,2-e] -1,2,4-噻二嗪1,1-二氧化物（1h）。被发现是有效的Kir6.2 / SUR1 K（ATP）通道的开放剂，并且能够抑制葡萄糖从大鼠胰岛中体外（EC（50）= 0.04 +/- 0.01μM）和静脉内或静脉注射后体内释放的胰岛素口服给予高胰岛素肥胖的Zucker大鼠（ED（50）= 4.0 mg / kg）。
• Fused 1,2,4-Thiadiazine derivatives, their preparation and use
  申请人：NOVO NORDISK A/S

  公开号：EP1338600A1

  公开（公告）日：2003-08-27

  The present invention relates to 4H-thieno[3,2-e]-1,2,4-thiadiazine derivatives, compositions thereof and methods for preparing the compounds. The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.

  本发明涉及4H-噻吩[3,2-e]-1,2,4-噻二嗪衍生物、其组成物及制备该化合物的方法。该化合物在治疗中枢神经系统、心血管系统、肺系统、胃肠系统和内分泌系统疾病方面具有用途。
• Synthesis of carbon-14 and stable isotope labelled NN414: a potent potassium channel opener
  作者：Steen K. Johansen、Jesper B. Kristensen、Lars K. Müller、Claus U. Jessen、Christian Foged

  DOI：10.1002/jlcr.805

  日期：2004.2

  Currently, NN414, a potent β-cell selective potassium channel opener, is undergoing clinical trials for the treatment of type 2 diabetes. Here, we report the synthesis of carbon-14 and stable isotope labelled NN414 for use in metabolic studies and as an internal standard in pharmacokinetic assays, respectively. The carbon-14 labelling was performed in two steps starting from an advanced intermediate. This provided [14C]NN414 in 60% overall radiochemical yield with a specific activity of 58mCi/mmol. The stable isotope labelling was accomplished from benzyl tert-butyl malonate in eight steps using [13C,2H3]iodomethane and [2H2]dibromomethane as the source of carbon-13/deuterium. The synthetic sequence, which included a Mannich reaction followed by deamination, a Simmons–Smith-type cyclopropanation and a modified Curtius reaction, provided [13C,2H5]NN414 in 8.6% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.

  目前，NN414是一种有效的β细胞选择性钾通道开放剂，正在进行治疗2型糖尿病的临床试验。在这里，我们报告了碳 14 和稳定同位素标记的 NN414 的合成，分别用于代谢研究和药代动力学测定中的内标。碳 14 标记从高级中间体开始分两步进行。这提供了总放射化学产率为 60% 且比活性为 58mCi/mmol 的 [14C]NN414。使用[13C,2H3]碘甲烷和[2H2]二溴甲烷作为碳13/氘源，通过八个步骤从丙二酸叔丁基苄酯完成稳定同位素标记。合成序列包括曼尼希反应、随后脱氨、西蒙斯-史密斯型环丙烷化和改进的库尔蒂斯反应，以 8.6% 的总产率提供 [13C,2H5]NN414。版权所有 © 2004 约翰·威利父子有限公司
• [EN] POLYMORPHIC FORMS OF A 4H-THIENO[3,2-E]-1,2,4-THIADIAZINE 1,1-DIOXIDE DERIVATIVE<br/>[FR] FORMES POLYMORPHIQUES D'UN DERIVE DE 4H-THIENO[3,2-E]-1,2,4-THIADIAZINE 1,1-DIOXYDE
  申请人：NOVO NORDISK AS

  公开号：WO2004005299A1

  公开（公告）日：2004-01-15

  The present invention relates to novel polymorphic/pseudopolymorphic forms of 6-Chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide or mix-tures thereof, their preparation and their use as therapeutic agents.

  本发明涉及6-氯-3-(1-甲基环丙基)氨基-4H-噻吩[3,2-e]-1,2,4-噻二嗪1,1-二氧化物或其混合物的新颖多形/伪多形形式，它们的制备和作为治疗剂的用途。