4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene | 1156499-64-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶吡嗪类
• 英文名称: 4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene
• 英文别名: 7-chloro-12-methoxy-5-(trifluoromethyl)-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene
• CAS: 1156499-64-7
• 化学式: C₁₁H₆ClF₃N₄O
• 分子量: 302.643
• InChiKey: LBIRMOOKAZUPCH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  52.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene 在 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 、 甲苯 为溶剂， 反应 6.0h， 生成 3-(2-Chlorophenyl)-12-methoxy-7-methyl-5-(trifluoromethyl)-2,4,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10,12-hexaene
  参考文献：
  名称：

  Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors

  摘要：

  The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound I and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

  DOI：

  10.1021/jm2009138
• 作为产物：
  描述：

  8-methoxy-3-trifluoromethyl-5H-2,5,9,9b-tetraaza-cyclopenta[a]naphthalen-4-one 在 三氯氧磷 作用下， 反应 3.0h， 以99%的产率得到4-chloro-8-methoxy-3-trifluoromethyl-2,5,9,9b-tetraaza-cyclopenta[a]naphthalene
  参考文献：
  名称：

  Pyrido[3,2-E]Pyrazines, Process For Preparing The Same, And Their Use As Inhibitors Of Phosphodiesterase 10

  摘要：

  这项发明涉及吡啶并[3,2-e]吡嗪化合物，涉及其制备方法，包括这些化合物的药物组成物以及这些化合物的药用，这些化合物是磷酸二酯酶10的抑制剂，作为治疗中枢神经系统疾病、肥胖和代谢紊乱的活性化合物。

  公开号：

  US20090143361A1

文献信息

• [EN] PYRIDO[3,2-E]PYRAZINES, PROCESS FOR PREPARING THE SAME, AND THEIR USE AS INHIBITORS OF PHOSPHODIESTERASE 10<br/>[FR] PYRIDO[3,2-E]PYRAZINES, LEUR PROCÉDÉ DE PRÉPARATION, ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PHOSPHODIESTÉRASE 10
  申请人：WYETH CORP

  公开号：WO2009070583A1

  公开（公告）日：2009-06-04

  The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical compositions which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating central nervous system disorders, obesity, and metabolic disorders.