3,4-dimethyl-6-(3,5-bis(trifluoromethyl)-phenyl)isoxazolo[3,4-d]pyridazin-7(6H)-one | 263890-16-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3,4-dimethyl-6-(3,5-bis(trifluoromethyl)-phenyl)isoxazolo[3,4-d]pyridazin-7(6H)-one
• 英文别名: 6-[3,5-Bis(trifluoromethyl)phenyl]-3,4-dimethyl-[1,2]oxazolo[3,4-d]pyridazin-7-one
• CAS: 263890-16-0
• 化学式: C₁₅H₉F₆N₃O₂
• 分子量: 377.246
• InChiKey: ZBSIEGTZMUSKIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  26
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  58.7
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  3,4-dimethyl-6-(3,5-bis(trifluoromethyl)-phenyl)isoxazolo[3,4-d]pyridazin-7(6H)-one 、 alkaline earth salt of/the/ methylsulfuric acid 以 四氢呋喃 为溶剂， 生成 6-(3,5-bistrifluoromethylphenyl)-4-methyl-3-(1,3-diphenylpropan-2-yl)-isoxazolo[3,4-d]pyridazin-7(6H)-one
  参考文献：
  名称：

  异恶唑并[3,4-d]哒嗪酮的横向金属化对代谢型谷氨酸受体选择性正调节剂的命中先导开发

  摘要：

  异恶唑并[3,4-d]哒嗪酮 ([3,4-d]s) 先前已被证明对代谢型谷氨酸受体 (mGluR) 亚型 2 和 4 具有选择性正向调节作用，而与 mGluR1a、mGluR5 没有功能性交叉反应，或 mGluR8。正如同源模型所表明的，制备了额外的类似物以进入更多的变构口袋并实现更高的结合亲和力。生成了两组不同的类似物。一种使用完全形成的[3,4-d]和带有或不带有卤素的N6-芳基。它们在异恶唑的 C3 处成功进行了选择性横向金属化和亲电猝灭 (LM&EQ)。在第二组类似物中，通过 4-苯乙酰基-3-乙氧羰基-5-甲基异恶唑与相应的肼缩合，在 [3,4-d] 环的 C4 位引入苯基，生成 3 ,4-ds 2b 和 2j 至 2n。

  DOI：

  10.3390/molecules28196800
• 作为产物：
  描述：

  3,5-双(三氟甲基)苯肼 、 4-乙酰基-5-甲基异恶唑-3-甲酸乙酯 以96%的产率得到3,4-dimethyl-6-(3,5-bis(trifluoromethyl)-phenyl)isoxazolo[3,4-d]pyridazin-7(6H)-one
  参考文献：
  名称：

  Isoxazole analogues bind the System xc- transporter: Structure–activity relationship and pharmacophore model

  摘要：

  Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System x(c)(-). Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System x(c)(-), the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y' = 3,5-(CF3)(2), which both inhibited glutamate uptake by the System x(c)(-) transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.11.001

文献信息

• Isoxazole analogues bind the System xc- transporter: Structure–activity relationship and pharmacophore model
  作者：Sarjubhai A. Patel、Trideep Rajale、Erin O’Brien、David J. Burkhart、Jared K. Nelson、Brendan Twamley、Alex Blumenfeld、Monika I. Szabon-Watola、John M. Gerdes、Richard J. Bridges、Nicholas R. Natale

  DOI：10.1016/j.bmc.2009.11.001

  日期：2010.1

  Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System x(c)(-). Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System x(c)(-), the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y = Y' = 3,5-(CF3)(2), which both inhibited glutamate uptake by the System x(c)(-) transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. (C) 2009 Elsevier Ltd. All rights reserved.
• The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors
  作者：Christina A. Gates、Donald S. Backos、Philip Reigan、Nicholas R. Natale

  DOI：10.3390/molecules28196800

  日期：——

  Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR1a, mGluR5, or mGluR8. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of

  异恶唑并[3,4-d]哒嗪酮 ([3,4-d]s) 先前已被证明对代谢型谷氨酸受体 (mGluR) 亚型 2 和 4 具有选择性正向调节作用，而与 mGluR1a、mGluR5 没有功能性交叉反应，或 mGluR8。正如同源模型所表明的，制备了额外的类似物以进入更多的变构口袋并实现更高的结合亲和力。生成了两组不同的类似物。一种使用完全形成的[3,4-d]和带有或不带有卤素的N6-芳基。它们在异恶唑的 C3 处成功进行了选择性横向金属化和亲电猝灭 (LM&EQ)。在第二组类似物中，通过 4-苯乙酰基-3-乙氧羰基-5-甲基异恶唑与相应的肼缩合，在 [3,4-d] 环的 C4 位引入苯基，生成 3 ,4-ds 2b 和 2j 至 2n。