1-methyl-pyrazol-4-yl 5-methyl-1,2,4-oxadiazol-3-yl ketone | 1104240-73-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-methyl-pyrazol-4-yl 5-methyl-1,2,4-oxadiazol-3-yl ketone
• 英文别名: (5-methyl-1,2,4-oxadiazol-3-yl)(1-methyl-1H-pyrazol-4-yl)methanone；(5-Methyl-1,2,4-oxadiazol-3-yl)-(1-methylpyrazol-4-yl)methanone
• CAS: 1104240-73-4
• 化学式: C₈H₈N₄O₂
• 分子量: 192.177
• InChiKey: DETCVBORVXOTOL-UHFFFAOYSA-N

物化性质

• 沸点：
  374.9±34.0 °C(Predicted)
• 密度：
  1.46±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  73.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-methyl-pyrazol-4-yl 5-methyl-1,2,4-oxadiazol-3-yl ketone 、 在 硅酸四乙酯 、 sodium acetate 作用下， 以 二甲基亚砜 、 甲苯 、 乙腈 为溶剂， 反应 40.0h， 以42.4%的产率得到MK-4256
  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
• 作为产物：
  描述：

  1-甲基-4-碘-吡唑 、 N-methoxy-N-methyl-5-methyl-1,2,4-oxadiazole-3-carboxamide 在 异丙基氯化镁 作用下， 以 四氢呋喃 为溶剂， 反应 2.17h， 以88.4%的产率得到1-methyl-pyrazol-4-yl 5-methyl-1,2,4-oxadiazol-3-yl ketone
  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

• [EN] TRIAZOLE BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS<br/>[FR] DÉRIVÉS DE LA BÊTA CARBOLINE TRIAZOLE CONSTITUANT DES COMPOSÉS ANTIDIABÉTIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010051177A1

  公开（公告）日：2010-05-06

  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、脂质紊乱和高血压。这些化合物还可用于治疗抑郁症和焦虑症。
• 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。
• TRIAZOLE BETA CARBOLINE DERIVATIVES AS ANTI-DIABETIC AGENTS
  申请人：Guo Liangqin

  公开号：US20110201615A1

  公开（公告）日：2011-08-18

  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。
• 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.
• SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists
  作者：Shuwen He、Peter H. Dobbelaar、Liangqin Guo、Zhixiong Ye、Jian Liu、Tianying Jian、Quang Truong、Shrenik K. Shah、Wu Du、Hongbo Qi、Raman K. Bakshi、Qingmei Hong、James D. Dellureficio、Edward Sherer、Alexander Pasternak、Zhe Feng、Mikhail Reibarkh、Melissa Lin、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、Guillermo Fernandez、Donald Nelson、Patricia Bunting、Janet Kerr、Patrick Fitzgerald、Pierre Morissette、Sylvia Volksdorf、George J. Eiermann、Cai Li、Bei B. Zhang、Andrew D. Howard、Yun-Ping Zhou、Ravi P. Nargund、William K. Hagmann

  DOI：10.1016/j.bmcl.2016.02.022

  日期：2016.3

  MK-4256, a tetrahydro-beta-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-beta-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability. (C) 2016 Elsevier Ltd. All rights reserved.