tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl malonate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl malonate
• 英文别名: 1-O-tert-butyl 3-O-[1-[4-[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3-yl]-2-methoxyphenoxy]-2-methylpropan-2-yl] propanedioate
• 化学式: C₃₀H₃₁ClN₂O₇S
• 分子量: 599.104
• InChiKey: JXUKSIUZLZCUAG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  132
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl malonate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以91%的产率得到3-(1-(4-(6-(4-Chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yloxy)-3-oxopropanoic acid
  参考文献：
  名称：

  Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate

  摘要：

  Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

  DOI：

  10.1021/jm500026w
• 作为产物：
  描述：

  1-(2-methoxy-4-nitrophenoxy)-2-methylpropan-2-ol 在 4-二甲氨基吡啶 、 palladium 10% on activated carbon 、 氢气 、 N,N'-二异丙基碳二亚胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、413.7 kPa 条件下， 反应 41.0h， 生成 tert-butyl 1-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-2-methylpropan-2-yl malonate
  参考文献：
  名称：

  Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate

  摘要：

  Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

  DOI：

  10.1021/jm500026w

文献信息

• Non-basic melanin concentrating hormone receptor-1 antagonists
  申请人：Washburn N. William

  公开号：US20070093509A1

  公开（公告）日：2007-04-26

  The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

  本申请提供了按照公式I提供的化合物，包括所有立体异构体、溶剂合物、前药和药学上可接受的形式。此外，本申请提供了含有至少一种按照公式I的化合物和可选的至少一种额外治疗剂的制药组合物。最后，本申请提供了通过给予按照公式I的化合物的治疗有效剂量来治疗患有MCHR-1调节的疾病或疾病，例如肥胖症、糖尿病、抑郁症或焦虑症的患者的方法。
• Substituted thieno[3,2-d]pyrimidinones as MCHR1 antagonists and methods for using them
  申请人：Washburn William N.

  公开号：US08618115B2

  公开（公告）日：2013-12-31

  The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.

  本申请提供了公式I所示的化合物，包括所有立体异构体、溶剂化物、前药和药学上可接受的形式。此外，本申请还提供了含有至少一种公式I化合物和可选的至少一种其他治疗剂的药物组合物。最后，本申请提供了通过给患有MCHR-1调节性疾病或疾病的患者以公式I化合物的治疗有效剂量来治疗患者的方法，例如肥胖症、糖尿病、抑郁症或焦虑症。
• THIENOPYRIMIDINONE DERIVATIVES AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS
  申请人：Bristol-Myers Squibb Company

  公开号：EP1948665B1

  公开（公告）日：2013-02-27
• [EN] NON-BASIC MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANTAGONISTES DU RECEPTEUR 1 DE L'HORMONE DE CONCENTRATION DE LA MELANINE NON BASIQUES
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2007050726A2

  公开（公告）日：2007-05-03

  [EN] The present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formula I. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-1 modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I.
  [FR] L'invention concerne des composés comprenant tous les stéréoisomères, les solvates, les promédicaments et leurs formes pharmaceutiquement acceptables de formule (I). L'invention concerne, de plus, des compositions pharmaceutiques contenant au moins un composé de formule (I) et éventuellement au moins un agent thérapeutique supplémentaire. Enfin, l'invention concerne des méthodes pour traiter un patient souffrant d'une maladie ou des troubles modulés par la MCHR-1, tels que l'obésité, le diabète, la dépression ou l'anxiété comprenant l'administration d'une dose à efficacité thérapeutique du composé de formule (I).
• Identification of a Nonbasic Melanin Hormone Receptor 1 Antagonist as an Antiobesity Clinical Candidate
  作者：William N. Washburn、Mark Manfredi、Pratik Devasthale、Guohua Zhao、Saleem Ahmad、Andres Hernandez、Jeffrey A. Robl、Wei Wang、James Mignone、Zhenghua Wang、Khehyong Ngu、Mary Ann Pelleymounter、Daniel Longhi、Rulin Zhao、Bei Wang、Ning Huang、Neil Flynn、Anthony V. Azzara、Joel C. Barrish、Kenneth Rohrbach、James J. Devenny、Suzanne Rooney、Michael Thomas、Susan Glick、Helen E. Godonis、Susan J. Harvey、Mary Jane Cullen、Hongwei Zhang、Christian Caporuscio、Paul Stetsko、Mary Grubb、Brad D. Maxwell、Hong Yang、Atsu Apedo、Brian Gemzik、Evan B. Janovitz、Christine Huang、Lisa Zhang、Chris Freeden、Brian J. Murphy

  DOI：10.1021/jm500026w

  日期：2014.9.25

  Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).