[(3R)-4-(4-chlorobenzyl)-7-fluoro-5-acetyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-3-yl]acetic acid | 794535-36-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-acetyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-3-yl]acetic acid
• 英文别名: 2-[(3R)-5-acetyl-4-[(4-chlorophenyl)methyl]-7-fluoro-2,3-dihydro-1H-cyclopenta[b]indol-3-yl]acetic acid
• CAS: 794535-36-7
• 化学式: C₂₂H₁₉ClFNO₃
• 分子量: 399.849
• InChiKey: YYAWOSLKARYYMV-CQSZACIVSA-N

物化性质

• 沸点：
  632.0±55.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Predicted)

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：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  59.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-acetyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-3-yl]acetic acid 在 重水 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 生成 、 、 2-[(3R)-4-[(4-chlorophenyl)methyl]-7-fluoro-5-(2,2,2-trideuterioacetyl)-2,3-dihydro-1H-cyclopenta[b]indol-3-yl]acetic acid
  参考文献：
  名称：

  Base-catalyzed deuterium and tritium labelling of 1-biphenyl-4-ylpropane-1,2-dione and deuteration of aryl methyl ketones

  摘要：

  我们在温和的条件下开发了一种合成方法和碱催化交换反应，用于对碱敏感的 1-联苯-4-基丙烷-1,2-二酮甲基的氘化和随后的氚化，如图 1 所示。以 Et3N 为碱基，甲基的氘化率为 88.9%，氚化后的比放射性为 119 mCi/mmol。交换范围扩大到甲基芳基酮 2-4。Copyright © 2004 John Wiley & Sons, Ltd. All Rights Reserved.

  DOI：

  10.1002/jlcr.879
• 作为产物：
  描述：

  在 palladium diacetate 、 tris(dibenzylideneacetone)dipalladium (0) 吡啶 、 盐酸 、 sodium hydroxide 、 三苯胂 、 (S)-(-)-1-(1-naphthyl)ethylamine salt 、 四丁基氯化铵 、 sodium hydride 、 溶剂黄146 、 pyridinium hydrobromide perbromide 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.5h， 生成 [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-acetyl-1,2,3,4-tetrahydrocyclopenta-[b]indol-3-yl]acetic acid
  参考文献：
  名称：

  Discovery of a Potent and Selective Prostaglandin D₂ Receptor Antagonist, [(3R)-4-(4-Chloro- benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic Acid (MK-0524)

  摘要：

  The discovery of the potent and selective prostaglandin D-2 (PGD(2)) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13)is presented. Initial lead antagonists 6and 7were found to be potent and selective DP antagonists (DP K-i = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (C-max = 1100 mu M for 6and 3900 mu M for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6and 7with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.

  DOI：

  10.1021/jm0603668

文献信息

• Niacin Receptor Agonists, Compositions Containing Such Compounds and Methods of Treatment
  申请人：Raghavan Subharekha

  公开号：US20090062269A1

  公开（公告）日：2009-03-05

  The present invention encompasses compounds of Formula I: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating atherosclerosis, dyslipidemias and the like. Pharmaceutical compositions and methods of use are also included.

  本发明涵盖了Formula I的化合物，以及其药用盐和水合物，可用于治疗动脉粥样硬化、血脂异常等疾病。药物组合物和使用方法也包括在内。
• Fused pyrazole derivatives and methods of treatment of metabolic-related disorders thereof
  申请人：Boatman Douglas P.

  公开号：US20070073062A1

  公开（公告）日：2007-03-29

  The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.

  本发明涉及公式（Ia）的某些融合吡唑衍生物及其药学上可接受的盐，其表现出有用的药理特性，例如作为RUP25受体的激动剂。本发明还提供了包含本发明化合物的药物组合物，以及使用本发明化合物和组合物治疗代谢相关疾病的方法，包括血脂异常、动脉粥样硬化、冠心病、胰岛素抵抗、2型糖尿病、X综合症等。此外，本发明还提供了将本发明化合物与其他活性剂（例如属于α-葡萄糖苷酶抑制剂、醛糖还原酶抑制剂、双胍类、HMG-CoA还原酶抑制剂、角鲨烷合成抑制剂、菸酸类、LDL降解增强剂、血管紧张素转化酶（ACE）抑制剂、胰岛素分泌增强剂、DP受体拮抗剂等）组合使用的方法。
• Method of Treating Atherosclerosis, Dyslipidemias and Related Conditions
  申请人：Waters M. Gerard

  公开号：US20070244107A1

  公开（公告）日：2007-10-18

  A method of treating atherosclerosis, dyslipidemia and related conditions is disclosed wherein a compound of formula I: or a pharmaceutically acceptable salt or solvate thereof is administered to the patient in combination with a DP receptor antagonist. The DP receptor antagonist is administered to reduce, prevent or eliminate flushing that may otherwise occur.

  揭示了一种治疗动脉粥样硬化、血脂异常及相关疾病的方法，其中给患者以公式I的化合物或其药学上可接受的盐或溶剂的组合，同时与DP受体拮抗剂一起给予。DP受体拮抗剂被用于减少、预防或消除可能发生的潮红。
• FUSED PYRAZOLE DERIVATIVES AND METHODS OF TREATMENT OF METABOLIC-RELATED DISORDERS THEREOF
  申请人：Boatman P. Douglas

  公开号：US20090258892A1

  公开（公告）日：2009-10-15

  The present invention relates to certain fused pyrazole derivatives of Formula (Ia), and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists for the RUP25 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of metabolic-related disorders, including dyslipidemia, atherosclerosis, coronary heart disease, insulin resistance, type 2 diabetes, Syndrome-X and the like. In addition, the present invention also provides for the use of the compounds of the invention in combination with other active agents such as those belonging to the class of α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, HMG-CoA reductase inhibitors, squalene synthesis inhibitors, fibrates, LDL catabolism enhancers, angiotensin converting enzyme (ACE) inhibitors, insulin secretion enhancers, DP receptor antagonists, and the like.

  本发明涉及公式（Ia）的某些融合吡唑衍生物及其药学上可接受的盐，其具有有用的药理特性，例如作为RUP25受体激动剂。本发明还提供了包含该化合物的制药组合物，并且提供了使用该化合物和组合物治疗代谢相关疾病的方法，包括脂质代谢异常、动脉硬化、冠心病、胰岛素抵抗、2型糖尿病、X综合症等。此外，本发明还提供了将该化合物与其他活性剂（例如属于α-葡萄糖苷酶抑制剂、醛糖还原酶抑制剂、双胍类、HMG-CoA还原酶抑制剂、角鲨烷合成抑制剂、纤维酸类、LDL降解增强剂、血管紧张素转换酶（ACE）抑制剂、胰岛素分泌增强剂、DP受体拮抗剂等类别）组合使用的用途。
• Niacin receptor agonists, compositions containing such compounds and methods of treatment
  申请人：Imbriglio Jason E.

  公开号：US20090054423A1

  公开（公告）日：2009-02-26

  The present invention encompasses compounds of Formula I: as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating dyslipidemias. Pharmaceutical compositions and methods of use are also included.

  本发明涵盖了I式化合物，以及其药学上可接受的盐和水合物，用于治疗血脂异常。此外，还包括药物组合物和使用方法。