ethyl (4-methylcyclohexanecarbonyl)acetate | 220203-27-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: ethyl (4-methylcyclohexanecarbonyl)acetate
• 英文别名: ethyl (4-methylcyclohexylcarbonyl)acetate；Ethyl 3-(4-methylcyclohexyl)-3-oxopropanoate
• CAS: 220203-27-0
• 化学式: C₁₂H₂₀O₃
• 分子量: 212.289
• InChiKey: JUFQIGGRYLOFSX-UHFFFAOYSA-N

物化性质

• 沸点：
  285.5±13.0 °C(Predicted)
• 密度：
  1.007±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (4-methylcyclohexanecarbonyl)acetate 在 sodium hydroxide 、 potassium tert-butylate 作用下， 以 甲醇 为溶剂， 反应 15.17h， 生成 5-(4-Methyl-cyclohexyl)-5-oxo-pentanoic acid
  参考文献：
  名称：

  4-(trans-4-Methylcyclohexyl)-4-Oxobutyric Acid (JTT-608). A New Class of Antidiabetic Agent

  摘要：

  During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined th at the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.

  DOI：

  10.1021/jm9804228
• 作为产物：
  描述：

  4-甲基环己烷甲酸 、 ethyl potassium malonate 在 N,N'-羰基二咪唑 、 magnesium chloride 作用下， 以 四氢呋喃 为溶剂， 生成 ethyl (4-methylcyclohexanecarbonyl)acetate
  参考文献：
  名称：

  Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity

  摘要：

  Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ETA and ETB receptors. The ETA receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ETB receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ETA-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ETA-selective, ETB-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ETA selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00022-x

文献信息

• THERAPEUTIC AGENT FOR DIABETES
  申请人：Japan Tobacco Inc.

  公开号：EP0885869A1

  公开（公告）日：1998-12-23

  A therapeutic agent for diabetes, which comprises a compound of the formula [I] wherein Xis a group of the formula wherein R4 and R5 are the same or different and each is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, and R6 is a hydrogen atom or an amino-protecting group; R1 is an optionally substituted alkyl having 1 to 5 carbon atoms, an optionally substituted alkenyl having 2 to 6 carbon atoms and the like, R2 is a hydrogen atom, an optionally substituted alkyl having 1 to 5 carbon atoms and the like, R2' is a hydrogen atom, and R3 is an optionally substituted alkyl having 1 to 5 carbon atoms and the like, a prodrug thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof. The compound of the present invention shows superior blood sugar decreasing action on the state of hyperglycemia, but does not affect the blood sugar when it is in the normal range or in the hypoglycemic state, which means that it is free of serious side effects such as hypoglycemia. Therefore, the compound of the present invention is useful as a therapeutic drug for diabetes and also useful as a preventive of the chronic complications of diabetes.

  用于治疗糖尿病的疗法剂，包括公式[I]的化合物 其中 X是公式的组 其中R4和R5相同或不同，每个都是氢原子，可选地取代的具有1至5个碳原子的烷基等等，R6是氢原子或氨基保护基团；R1是具有1至5个碳原子的可选取代烷基，具有2至6个碳原子的可选取代烯基等等，R2是氢原子，具有1至5个碳原子的可选取代烷基等等，R2'是氢原子，R3是具有1至5个碳原子的可选取代烷基等等，其前药，药用可接受盐，水合物和溶剂化物。 本发明的化合物在血糖升高状态下表现出优越的降血糖作用，但在正常范围或低血糖状态下不影响血糖，这意味着它没有低血糖等严重副作用。因此，本发明的化合物作为治疗糖尿病的药物很有用，也用作预防糖尿病慢性并发症。
• 4-(<i>trans</i>-4-Methylcyclohexyl)-4-Oxobutyric Acid (JTT-608). A New Class of Antidiabetic Agent
  作者：Hisashi Shinkai、Hidekazu Ozeki、Takahisa Motomura、Takeshi Ohta、Noboru Furukawa、Itsuo Uchida

  DOI：10.1021/jm9804228

  日期：1998.12.1

  During an investigation of drugs for improving the beta-cell response to glucose, we found that 4-cyclohexyl-4-oxobutyric acid selectively improved glucose-stimulated insulin release and glucose tolerance in both normal and diabetic rats. A series of 4-cycloalkyl-4-oxobutyric acids and related compounds were synthesized and evaluated for their effects on the glucose tolerance test and fasting euglycemia. This study elucidated the structural requirements for drug activity and determined th at the optimum compound was 4-(trans-4-methylcyclohexyl)-4-oxobutyric acid 7 (JTT-608). This compound improved glucose tolerance from an oral dose of 3 mg/kg and did not change fasting euglycemia even at an oral dose of 30 mg/kg. Selective improvement of glucose-induced insulin secretion was observed in studies using neonatal streptozotocin rats (nSTZ rats) and perfused pancreases isolated from nSTZ rats.
• Discovery of a series of pyrrolidine-based endothelin receptor antagonists with enhanced ETA receptor selectivity
  作者：Steven A Boyd、Robert A Mantei、Andrew S Tasker、Gang Liu、Bryan K Sorensen、Kenneth J Henry Jr、Thomas W von Geldern、Martin Winn、Jinshyun R Wu-Wong、William J Chiou、Douglas B Dixon、Charles W Hutchins、Kennan C Marsh、Bach Nguyen、Terry J Opgenorth

  DOI：10.1016/s0968-0896(99)00022-x

  日期：1999.6

  Endothelins, ET-1, ET-2, and ET-3 are potent vasoconstricting and mitogenic 21-amino acid bicyclic peptides, which exert their effects upon binding to the ETA and ETB receptors. The ETA receptor mediates vasoconstriction and smooth muscle cell proliferation, and the ETB receptor mediates different effects in different tissues, including nitric oxide release from endothelial cells, and vasoconstriction in certain vascular cell types. Selective antagonists of endothelin receptor subtypes may prove useful in determining the role of endothelin in various tissue types and disease states, and hence as therapeutic agents for such diseases. The pyrrolidine carboxylic acid A-127722 has been disclosed as a potent and ETA-selective antagonist, and is currently undergoing clinical trials. In our efforts to find antagonists with altered selectivity (ETA-selective, ETB-selective, or nonselective), we investigated the SAR of the 2-substituent on the pyrrolidine. Compounds with alkyl groups at the 2-position possessed ETA selectivity improved over A-127722 (1400-fold selective), with the best of these compounds showing nearly 19,000-fold selectivity. (C) 1999 Elsevier Science Ltd. All rights reserved.