7-fluoro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide | 228253-48-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻二嗪
• 英文名称: 7-fluoro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
• 英文别名: 7-fluoro-3-methylsulfanyl-4H-1lambda6,2,4-benzothiadiazine 1,1-dioxide；7-fluoro-3-methylsulfanyl-4H-1λ6,2,4-benzothiadiazine 1,1-dioxide
• CAS: 228253-48-3
• 化学式: C₈H₇FN₂O₂S₂
• 分子量: 246.286
• InChiKey: TZRIPIICOWWICP-UHFFFAOYSA-N

物化性质

• 熔点：
  265-268 °C
• 沸点：
  426.6±47.0 °C(Predicted)
• 密度：
  1.63±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  92.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  7-fluoro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 在 溴 、 sodium carbonate 、 sodium hydroxide 作用下， 以 水 为溶剂， 反应 0.5h， 以83%的产率得到7-fluoro-3-(methylsulfinyl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide
  参考文献：
  名称：

  发现具有抗癌活性的卤代苯并噻二嗪衍生物**

  摘要：

  线粒体呼吸复合物 II (CII)，也称为琥珀酸脱氢酶，在线粒体代谢中起关键作用。已知但效力低的 CII 抑制剂对癌细胞具有选择性细胞毒性，包括基于苯并噻二嗪的抗低血糖二氮嗪。在此，我们首次研究了苯并噻二嗪衍生物对CII抑制的构效关系及其对癌细胞的影响。与二氮嗪相比，CII 抑制增加了 15 倍，尽管其 IC 50值为微摩尔。新衍生物的细胞毒性评估导致鉴定出比二氮嗪具有更大抗肿瘤作用的化合物，其中最有效的化合物具有 IC 50在三阴性乳腺癌细胞模型中为 2.93±0.07 μM，对非恶性细胞具有高选择性，是临床药物 5-氟尿嘧啶的两倍多。没有发现细胞毒性和 CII 抑制之间的相关性，因此表明该支架的作用机制尚未明确。本文描述的衍生物代表了用于三阴性乳腺癌治疗发现的有价值的热门化合物。

  DOI：

  10.1002/cmdc.202000729
• 作为产物：
  描述：

  4-氟苯胺 在 吡啶 、 aluminum (III) chloride 、 tetraphosphorus decasulfide 、 碳酸氢钠 作用下， 以 甲醇 、 硝基甲烷 、 水 为溶剂， 反应 2.0h， 生成 7-fluoro-3-methylsulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
  参考文献：
  名称：

  发现具有抗癌活性的卤代苯并噻二嗪衍生物**

  摘要：

  线粒体呼吸复合物 II (CII)，也称为琥珀酸脱氢酶，在线粒体代谢中起关键作用。已知但效力低的 CII 抑制剂对癌细胞具有选择性细胞毒性，包括基于苯并噻二嗪的抗低血糖二氮嗪。在此，我们首次研究了苯并噻二嗪衍生物对CII抑制的构效关系及其对癌细胞的影响。与二氮嗪相比，CII 抑制增加了 15 倍，尽管其 IC 50值为微摩尔。新衍生物的细胞毒性评估导致鉴定出比二氮嗪具有更大抗肿瘤作用的化合物，其中最有效的化合物具有 IC 50在三阴性乳腺癌细胞模型中为 2.93±0.07 μM，对非恶性细胞具有高选择性，是临床药物 5-氟尿嘧啶的两倍多。没有发现细胞毒性和 CII 抑制之间的相关性，因此表明该支架的作用机制尚未明确。本文描述的衍生物代表了用于三阴性乳腺癌治疗发现的有价值的热门化合物。

  DOI：

  10.1002/cmdc.202000729

文献信息

• [EN] HALOGENATED BENZOTHIADIAZINES FOR THE TREATMENT OF CANCER<br/>[FR] BENZOTHIADIAZINES HALOGÉNÉES POUR LE TRAITEMENT DU CANCER
  申请人：UNIV NEBRASKA

  公开号：WO2021236818A1

  公开（公告）日：2021-11-25

  Provided herein are compounds and methods for modulating the mitochondrial respiratory complex II (CII) and vascular endothelial growth factor (VEGF) pathways. More particularly, provided are inhibitors of the mitochondrial respiratory complex II (CII) and vascular endothelial growth factor (VEGF) pathways and the uses of such inhibitors in regulating diseases and disorders, e.g., to treat cancer.

  本文提供了一些化合物和方法，用于调节线粒体呼吸链复合物II（CII）和血管内皮生长因子（VEGF）通路。更具体地，提供了线粒体呼吸链复合物II（CII）和血管内皮生长因子（VEGF）通路的抑制剂，以及这些抑制剂在调节疾病和紊乱方面的用途，例如治疗癌症。
• Toward Tissue-Selective Pancreatic B-Cells K_ATP Channel Openers Belonging to 3-Alkylamino-7-halo-4<i>H</i>-1,2,4-benzothiadiazine 1,1-Dioxides
  作者：Pascal de Tullio、Bénédicte Becker、Stéphane Boverie、Michael Dabrowski、Philip Wahl、Marie-Hélène Antoine、Fabian Somers、Sophie Sebille、Raogo Ouedraogo、John Bondo Hansen、Philippe Lebrun、Bernard Pirotte

  DOI：10.1021/jm021117w

  日期：2003.7.1

  3-(Alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides were synthesized, and their activity on rat-insulin-secreting cells and rat aorta rings was compared to that of the K-ATP channel activators diazoxide and pinacidil. Structure-activity relationships indicated that an improved potency and selectivity for the pancreatic tissue was obtained by introducing a fluorine atom in the 7-position and a short linear (preferably ethyl) or cyclic (preferably cyclobutyl) hydrocarbon chain on the nitrogen atom in the 3-position. By contrast, strong myorelaxant activity was gained by the introduction of a halogen atom different from the fluorine atom in the 7-position and a bulky branched alkylamino chain in the 3-position. Thus, 3-(ethylamino)-7-fluoro-4H-1,2,4-benzothiadiazine 1,1-dioxide (11) expressed a marked inhibitory activity on pancreatic B-cells (IC50 = 1 muM) associated with a weak vasorelaxant effect (ED50 > 300 muM), whereas 7-chloro-3-(1,1-dimethylpropyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide (27), which was only slightly active on insulin-secreting cells (IC50 > 10 muM), was found to be very potent on vascular smooth muscle cells (ED50 = 0.29 muM). Radioisotopic and electrophysiological. investigations performed with 7-chlorinated, 7-iodinated, and 7-fluorinated 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides confirmed that the drugs activated K-ATP channels. The present data revealed that subtle structural modifications of 3-(alkylamino)-7-halo-4H-1,2,4-benzothiadiazine 1,1-dioxides can generate original compounds activating K-ATP channels and exhibiting different in vitro tissue selectivity profiles.
• Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4<i>H</i>-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism Stability
  作者：Pascal de Tullio、Anne-Catherine Servais、Marianne Fillet、Florian Gillotin、Fabian Somers、Patrice Chiap、Philippe Lebrun、Bernard Pirotte

  DOI：10.1021/jm200786z

  日期：2011.12.22

  Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent K-ATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic tissue (compared to vascular smooth muscle tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a K-ATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.
• Synthesis and evaluation of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives as KATP channel agonists
  作者：Andrew J Peat、Claire Townsend、Jennings F Worley, III、Scott H Allen、Dulce Garrido、Robert J Mertz、Jeffrey L Pfohl、Christopher M Terry、Jim F Truax、Robert L Veasey、Stephen A Thomson

  DOI：10.1016/s0960-894x(02)00617-0

  日期：2002.10

  A series of 7-substituted-3-cyclobutylamino-4H-1,2,4-benzothiadiazine-1,1-dioxide derivatives has been synthesized and evaluated as K-ATP channel agonists using the inside-out excised patch clamp technique. The most active compounds were similar to20-fold more potent than diazoxide in opening K-ATP channels. A linear relationship exists between the potency of the compound and the sigma value of the 7-substituent with electron-withdrawing groups exhibiting higher activity. These compounds may be useful in modulating insulin release from pancreatic beta-cells and in diseases associated with hyperinsulinemia. (C) 2002 Elsevier Science Ltd. All rights reserved.
• Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation
  作者：Bader I. Huwaimel、Sravan Jonnalagadda、Shirisha Jonnalagadda、Fatema T. Zahra、Alessio Nocentini、Claudiu T. Supuran、Constantinos M. Mikelis、Paul C. Trippier

  DOI：10.1016/j.bmc.2022.116805

  日期：2022.8