tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate | 1065112-78-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吖庚因类
• 英文名称: tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate
• 英文别名: tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydropyrimido[4,5-d]azepine-7-carboxylate
• CAS: 1065112-78-8
• 化学式: C₂₂H₃₀N₄O₂
• 分子量: 382.506
• InChiKey: QWHFUISZKATKKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  67.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate 在 盐酸 、 二乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 正庚烷 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 N-methyl-2-(1-phenylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine
  参考文献：
  名称：

  Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5-d]azepines as Potent 5-Hydroxytryptamine 2C (5-HT_2C) Receptor Agonists with Exquisite Functional Selectivity over 5-HT_2A and 5-HT_2B Receptors

  摘要：

  A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.

  DOI：

  10.1021/jm5003292
• 作为产物：
  描述：

  α-甲基苯腈 在 吡啶 、 三甲基铝 、 sodium methylate 、 氯化铵 作用下， 以 甲醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 87.0h， 生成 tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate
  参考文献：
  名称：

  Multiparameter Optimization in CNS Drug Discovery: Design of Pyrimido[4,5-d]azepines as Potent 5-Hydroxytryptamine 2C (5-HT_2C) Receptor Agonists with Exquisite Functional Selectivity over 5-HT_2A and 5-HT_2B Receptors

  摘要：

  A series of 4-substituted pyrimido[4,5-d]azepines that are potent, selective 5-HT2C receptor partial agonists is described. A rational medicinal chemistry design strategy to deliver CNS penetration coupled with SAR-based optimization of selectivity and agonist potency provided compounds with the desired balance of preclinical properties. Lead compounds 17 (PF-4479745) and 18 (PF-4522654) displayed robust pharmacology in a preclinical canine model of stress urinary incontinence (SUI) and no measurable functional agonism at the key selectivity targets 5-HT2A and 5-HT2B in relevant tissue-based assay systems. Utilizing recent advances in the structural biology of GPCRs, homology modeling has been carried out to rationalize binding and agonist efficacy of these compounds.

  DOI：

  10.1021/jm5003292
• 作为试剂：
  描述：

  tert-butyl 2-(1-phenylethyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate 、 甲胺 在 tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate 、 crude material 、 ethyl acetate dichloromethane 作用下， 以 乙腈 为溶剂， 反应 20.0h， 以to yield the desired product as a white crystalline solid (89 mg, 90% yield)的产率得到tert-butyl 4-(methylamino)-2-(1-phenylethyl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine-7-carboxylate
  参考文献：
  名称：

  Pyrimido [4,5-D] azepine derivatives as 5-HT2c agonists

  摘要：

  本发明提供一种式子(I)的化合物或其药学上可接受的盐，其中变量R1、R2、R3a、R3b、R3b、R3d和R100的定义如本文所述。本发明还涉及包含式子(I)化合物的药物组合物以及使用式子(I)化合物或包含式子(I)化合物的药物组合物治疗5-HT2c受体介导的疾病的方法。

  公开号：

  US07928099B2

文献信息

• Pyrimido [4,5-D] Azepine Derivatives As 5-HT2C Agonists
  申请人：Andrews Mark

  公开号：US20100113422A1

  公开（公告）日：2010-05-06

  The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt thereof wherein the variables R 1 , R 2 , R 3a , R 3b , R 3b , R 3d , and R 100 are as defined herein. The invention is also directed to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a 5-HT 2c receptor-mediated disorders with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I).

  本发明提供了式（I）的化合物：或其药学上可接受的盐，其中变量R1、R2、R3a、R3b、R3b、R3d和R100如本文所定义。本发明还涉及包括式（I）化合物的制药组合物，以及使用式（I）的化合物或包括式（I）的制药组合物治疗5-HT2c受体介导的疾病的方法。
• WO2008/117169
  申请人：——

  公开号：——

  公开（公告）日：——
• PYRIMIDO [4, 5-D]AZEPINE DERIVATIVES AS 5-HT2C AGONISTS
  申请人：Pfizer Limited

  公开号：EP2139896A1

  公开（公告）日：2010-01-06
• US7928099B2
  申请人：——

  公开号：US7928099B2

  公开（公告）日：2011-04-19
• [EN] PYRIMIDO [4, 5-D] AZEPINE DERIVATIVES AS 5-HT2C AGONISTS<br/>[FR] DÉRIVÉS PYRIMIDO [4,5-D] AZÉPINE COMME ANTAGONISTES DU 5-HT2C
  申请人：PFIZER LTD

  公开号：WO2008117169A1

  公开（公告）日：2008-10-02

  [EN] The present invention relates to compounds of formula (I): wherein R¹, R², R^3a,^{R3b, R3c, R3d and R100 are as defined in the specification. These compounds act as 5-HT_2C agonists.
  [FR] La présente invention concerne des composés de formule (I) : R1, R2, R3a,R3b, R3c, R3d et R100 étant tels que définis dans la spécification. Ces composés agissent comme des antagonistes du 5-HT_2C.}