tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethylcarbamate | 1104606-06-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethylcarbamate
• 英文别名: (R)-tert-butyl (1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-2-(1H-indol-3-yl)ethyl)carbamate；tert-Butyl (1R)-2-(1H-indol-3-yl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-ethylcarbamate；tert-butyl N-[(1R)-1-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-2-(1H-indol-3-yl)ethyl]carbamate
• CAS: 1104606-06-5
• 化学式: C₂₄H₂₅FN₄O₂
• 分子量: 420.487
• InChiKey: WCUACAOOMLDOLB-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  82.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethylcarbamate 在 吡啶 、 titanium(IV) isopropylate 、 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 (R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1,1-diphenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
  参考文献：
  名称：

  The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes

  摘要：

  A structure-activity relationship study of the imidazolyl-beta-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.

  DOI：

  10.1021/ml300063m
• 作为产物：
  描述：

  BOC-D-色氨酸 在 ammonium acetate 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 4.5h， 生成 tert-butyl (1R)-2-(1H-indol-3-yl)-1-(4-(4-fluorophenyl)-1H-imidazol-2-yl)ethylcarbamate
  参考文献：
  名称：

  生长抑素受体拮抗剂的路线开发和多千克GMP传递

  摘要：

  描述了MK-4256首次GMP交付的多公斤级路线开发和演示。聚合路线的关键方面包括区域选择性绿色碘化，一锅法合成恶二唑，有效的酮Pictet-Spengler反应以及通过结晶的非对映异构体升级，从而提供6 kg的API。回收程序可以从Pictet-Spengler反应中，从富含不需要的非对映异构体的非对映异构体混合物中增加所需非对映异构体的收率。

  DOI：

  10.1021/op300128c

文献信息

• Route Development and Multikilogram GMP Delivery of a Somatostatin Receptor Antagonist
  作者：Rebecca T. Ruck、Mark A. Huffman、Gavin W. Stewart、Ed Cleator、Wynne V. Kandur、Mary M. Kim、Dalian Zhao

  DOI：10.1021/op300128c

  日期：2012.8.17

  Route development and demonstration on multikilogram scale for the first GMP delivery of MK-4256 are described. Key aspects of the convergent route include a regioselective green iodination, one-pot oxadiazole synthesis, and an efficient ketone Pictet–Spengler reaction with diastereomeric upgrade via crystallization to afford 6 kg of API. A recycle procedure augmented the yield of desired diastereomer

  描述了MK-4256首次GMP交付的多公斤级路线开发和演示。聚合路线的关键方面包括区域选择性绿色碘化，一锅法合成恶二唑，有效的酮Pictet-Spengler反应以及通过结晶的非对映异构体升级，从而提供6 kg的API。回收程序可以从Pictet-Spengler反应中，从富含不需要的非对映异构体的非对映异构体混合物中增加所需非对映异构体的收率。
• BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS
  申请人：Dobbelaar Peter H.

  公开号：US20100184758A1

  公开（公告）日：2010-07-22

  Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.

  结构式I的β-咔啉衍生物是生长抑素亚型受体3（SSTR3）的选择性拮抗剂，可用于治疗2型糖尿病以及通常与该疾病相关的病症，包括高血糖、胰岛素抵抗、肥胖、脂质异常和高血压。这些化合物还可用于治疗抑郁症和焦虑症。
• OXADIAZOLE BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS
  申请人：DU WU

  公开号：US20100184799A1

  公开（公告）日：2010-07-22

  Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.

  结构式I的β-咔唑啉衍生物是生长抑素亚型受体3（SSTR3）的选择性拮抗剂，可用于治疗2型糖尿病以及通常与该疾病相关的病症，包括高血糖、胰岛素抵抗、肥胖、脂质代谢异常和高血压。这些化合物也可用于治疗抑郁症和焦虑症。
• Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes
  作者：Shrenik K. Shah、Shuwen He、Liangqin Guo、Quang Truong、Hongbo Qi、Wu Du、Zhong Lai、Jian Liu、Tianying Jian、Qingmei Hong、Peter Dobbelaar、Zhixiong Ye、Edward Sherer、Zhe Feng、Yang Yu、Frederick Wong、Koppara Samuel、Maria Madiera、Bindhu V. Karanam、Vijay B. Reddy、Stan Mitelman、Sharon X. Tong、Gary G. Chicchi、Kwei-Lan Tsao、Dorina Trusca、Yue Feng、Margaret Wu、Qing Shao、Maria E. Trujillo、George J. Eiermann、Cai Li、Michele Pachanski、Guillermo Fernandez、Donald Nelson、Patricia Bunting、Pierre Morissette、Sylvia Volksdorf、Janet Kerr、Bei B. Zhang、Andrew D. Howard、Yun-Ping Zhou、Alexander Pasternak、Ravi P. Nargund、William K. Hagmann

  DOI：10.1021/ml500514w

  日期：2015.5.14

  The imidazolyl-tetrahydro-beta-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (17e, MK-1421).
• The Discovery of MK-4256, a Potent SSTR3 Antagonist as a Potential Treatment of Type 2 Diabetes
  作者：Shuwen He、Zhixiong Ye、Quang Truong、Shrenik Shah、Wu Du、Liangqin Guo、Peter H. Dobbelaar、Zhong Lai、Jian Liu、Tianying Jian、Hongbo Qi、Raman K. Bakshi、Qingmei Hong、James Dellureficio、Alexander Pasternak、Zhe Feng、Reynalda deJesus、Lihu Yang、Mikhail Reibarkh、Scott A. Bradley、Mark A. Holmes、Richard G. Ball、Rebecca T. Ruck、Mark A. Huffman、Frederick Wong、Koppara Samuel、Vijay B. Reddy、Stan Mitelman、Sharon X. Tong、Gary G. Chicchi、Kwei-Lan Tsao、Dorina Trusca、Margaret Wu、Qing Shao、Maria E. Trujillo、George J. Eiermann、Cai Li、Bei B. Zhang、Andrew D. Howard、Yun-Ping Zhou、Ravi P. Nargund、William K. Hagmann

  DOI：10.1021/ml300063m

  日期：2012.6.14

  A structure-activity relationship study of the imidazolyl-beta-tetrahydrocarboline series identified MK-4256 as a potent, selective SSTR3 antagonist, which demonstrated superior efficacy in a mouse oGTT model. MK-4256 reduced glucose excursion in a dose-dependent fashion with maximal efficacy achieved at doses as low as 0.03 mg/kg po. As compared with glipizide, MK-4256 showed a minimal hypoglycemia risk in mice.