7-chloro-4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide | 1204572-58-6

• 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-chloro-4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide
• 英文别名: 7-Chloro-4-cyclopropyl-2,3-dihydro-1lambda6,2,4-benzothiadiazine 1,1-dioxide；7-chloro-4-cyclopropyl-2,3-dihydro-1λ6,2,4-benzothiadiazine 1,1-dioxide
• CAS: 1204572-58-6
• 化学式: C₁₀H₁₁ClN₂O₂S
• 分子量: 258.729
• InChiKey: VESNDZCNBSTVHA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  57.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-chloro-4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide 、 碘甲烷 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 生成 7-chloro-4-cyclopropyl-2-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide
  参考文献：
  名称：

  单，二和三烷基取代的7-氯-3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物的合成与药理作用与X射线结构分析相结合以了解意外情况AMPA受体的结构-活性关系

  摘要：

  2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA）型离子型谷氨酸受体的正构构调节剂是用于治疗神经系统疾病（例如阿尔茨海默氏病）的有前途的化合物。在这里，我们报告一系列单，二或三烷基取代的7-氯-3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物的合成和药理学评估，其中包括总共16个新的调制器。三取代的化合物7b，7d和7e表现出有效的活性（EC 2x= 2.7–4.3μM；在体外细胞荧光测定（FLIPR）中作为AMPA受体增强剂的，负责AMPA介导的应答增加2倍的化合物的浓度。与先前描述的4-单烷基取代的苯并噻二二嗪二氧化物相反，4-环丙基化合物7f的效力明显较低（EC 2x = 60μM），其中环丙基是取代基的最佳选择。7b将其与GluA2配体结合结构域一起进行X射线结构分析。我们提出了这种新的单，二和三烷基取代的1,2,4-苯并噻二嗪1,1-二氧化物化合物系

  DOI：

  10.1021/acschemneuro.5b00318
• 作为产物：
  描述：

  2-氯-5-硝基苯胺 在 盐酸 、 sodium tetrahydroborate 、 sodium nitrite 作用下， 以 1,4-二氧六环 、 水 、 异丙醇 为溶剂， 反应 27.25h， 生成 7-chloro-4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide
  参考文献：
  名称：

  Synthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold

  摘要：

  Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a K-d of 0.35 mu M (Delta H = -7.5 kcal/mol and -T Delta S = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.

  DOI：

  10.1021/jm4012092

文献信息

• Cycloalkylated benzothiadiazines, a process for their preparation and pharmaceutical compostions containing them
  申请人：FRANCOTTE Pierre

  公开号：US20100009974A1

  公开（公告）日：2010-01-14

  Compounds of formula (I): wherein: R Cy represents an unsubstituted or substituted cycloalkyl group or cycloalkylalkyl group, R 1 , R 2 , R 3 and R 4 , which may be the same or different, each represent a hydrogen or halogen atom or a nitro group; a cyano group; a hydroxy group; an alkoxy group; an alkyl group; an unsubstituted or substituted amino group; a carboxy group; an alkoxycarbonyl group; an aryloxycarbonyl group; an unsubstituted or substituted aminocarbonyl group. Medicinal products containing the same which are useful in treating or preventing conditions treatable by an AMPA receptor modulator.

  式（I）的化合物：其中：RCy表示未取代或取代的环烷基或环烷基烷基，R1、R2、R3和R4，可以相同也可以不同，每个代表氢或卤素原子或硝基团；氰基；羟基；烷氧基；烷基；未取代或取代的氨基团；羧基；烷氧羰基；芳基氧羰基；未取代或取代的氨基羰基。含有这些化合物的药物产品，可用于治疗或预防通过AMPA受体调节剂可治疗的疾病。
• Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4-dihydro-2<i>H</i>-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
  作者：Anja Probst Larsen、Pierre Francotte、Karla Frydenvang、Daniel Tapken、Eric Goffin、Pierre Fraikin、Daniel-Henri Caignard、Pierre Lestage、Laurence Danober、Bernard Pirotte、Jette Sandholm Kastrup

  DOI：10.1021/acschemneuro.5b00318

  日期：2016.3.16

  4-monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The

  2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA）型离子型谷氨酸受体的正构构调节剂是用于治疗神经系统疾病（例如阿尔茨海默氏病）的有前途的化合物。在这里，我们报告一系列单，二或三烷基取代的7-氯-3,4-二氢-2 H -1,2,4-苯并噻二嗪1,1-二氧化物的合成和药理学评估，其中包括总共16个新的调制器。三取代的化合物7b，7d和7e表现出有效的活性（EC 2x= 2.7–4.3μM；在体外细胞荧光测定（FLIPR）中作为AMPA受体增强剂的，负责AMPA介导的应答增加2倍的化合物的浓度。与先前描述的4-单烷基取代的苯并噻二二嗪二氧化物相反，4-环丙基化合物7f的效力明显较低（EC 2x = 60μM），其中环丙基是取代基的最佳选择。7b将其与GluA2配体结合结构域一起进行X射线结构分析。我们提出了这种新的单，二和三烷基取代的1,2,4-苯并噻二嗪1,1-二氧化物化合物系
• Nouveaux dérivés de benzothiadiazines cycloalkylées, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
  申请人：Les Laboratoires Servier

  公开号：EP2147915B1

  公开（公告）日：2010-09-15
• US7741320B2
  申请人：——

  公开号：US7741320B2

  公开（公告）日：2010-06-22
• Synthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2<i>H</i>-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold
  作者：Ann-Beth Nørholm、Pierre Francotte、Lars Olsen、Christian Krintel、Karla Frydenvang、Eric Goffin、Sylvie Challal、Laurence Danober、Iuliana Botez-Pop、Pierre Lestage、Bernard Pirotte、Jette S. Kastrup

  DOI：10.1021/jm4012092

  日期：2013.11.14

  Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a K-d of 0.35 mu M (Delta H = -7.5 kcal/mol and -T Delta S = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.