5-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-1-yl)nicotinic acid | 1418274-27-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环丁烷
• 英文名称: 5-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-1-yl)nicotinic acid
• 英文别名: 5-[3-[2-Chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-3-carboxylic acid；5-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-3-carboxylic acid
• CAS: 1418274-27-7
• 化学式: C₂₈H₂₂Cl₃N₃O₅
• 分子量: 586.859
• InChiKey: RECGOOIVMAFZGM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  39
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-溴烟酸甲酯 在 正丁基锂 、 palladium diacetate 、 caesium carbonate 、 戴斯-马丁氧化剂 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 28.0h， 生成 5-(3-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-3-hydroxyazetidin-1-yl)nicotinic acid
  参考文献：
  名称：

  Novel substituted isoxazole FXR agonists with cyclopropyl, hydroxycyclobutyl and hydroxyazetidinyl linkers: Understanding and improving key determinants of pharmacological properties

  摘要：

  Several isoxazole-containing series of FXR agonists have been published over the last 15 years, subsequent to the prototypical amphiphilic 'hammerhead'-type structure that was originally laid out by GW4064, the first potent synthetic FXR agonist. A set of novel compounds where the hammerhead is connected to the terminal carboxylic acid-bearing aryl or heteroaryl moiety by either a cyclopropyl, a hydroxycyclobutyl or a hydroxyazetidinyl linker was synthesized in order to improve upon the ADME properties of such isoxazoles. The resulting compounds all demonstrated high potencies at the target receptor FXR but with considerable differences in their physicochemical and in vivo profiles. The structure-activity relationships for key chemical features that have a major impact on the in vivo pharmacology of this series are discussed. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.05.070

文献信息

• Novel FXR (NR1H4) binding and activity modulating compounds
  申请人：Phenex Pharmaceuticals AG

  公开号：EP2545964A1

  公开（公告）日：2013-01-16

  The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of the NR1H4 receptor (FXR). The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds. wherein R is selected from the group consisting of COOR6, CONR7R8, tetrazolyl, SO2NR7R8, C1-6 alkyl, SO2-C1-6 alkyl and H, with R6 independently selected from the group consisting of H or C1-6 alkyl, and R7 and R8 independently from each other selected from the group consisting of H, C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkylene-R9, SO2-C1-6 alkyl, wherein R9 is selected from the group consisting of COOH, OH and SO3H; A is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of OH, O-C1-6 alkyl, O-halo-C1-6 alkyl, C1-6 alkyl, halo-C1-6 alkyl, C3-6 cycloalkyl and halogen; Q is selected from the group consisting of phenyl, pyridyl, thiazolyl, thiophenyl, pyrimidyl, each optionally substituted with one or two groups independently selected from the group consisting of C1-6 alkyl, halo-C1-6 alkyl, halogen and CF3; Y is selected from N or CH; Z is selected from wherein X= CH, N, NO.

  本发明涉及与NR1H4受体（FXR）结合并作为NR1H4受体（FXR）激动剂的化合物。该发明还涉及利用这些化合物制备用于治疗疾病和/或病况的药物，通过这些化合物结合所述核受体来实现，并涉及一种合成这些化合物的方法。其中R从COOR6，CONR7R8，四唑基，SO2NR7R8，C1-6烷基，SO2-C1-6烷基和H组成的群体中选择，R6独立地从H或C1-6烷基组成的群体中选择，R7和R8相互独立地从H，C1-6烷基，卤代C1-6烷基，C1-6烷基烯基-R9，SO2-C1-6烷基中选择，其中R9从COOH，OH和SO3H组成的群体中选择；A从苯基，吡啶基，嘧啶基，吡唑基，吲哚基，噻吩基，苯并噻吩基，吲哚啉基，苯并异噁唑基，苯并呋喃基，苯并三唑基，呋喃基，苯并噻唑基，噻唑基，氧代二唑基中选择，每种基可选择地被一个或两个基独立地从OH，O-C1-6烷基，O-卤代C1-6烷基，C1-6烷基，卤代C1-6烷基，C3-6环烷基和卤素取代；Q从苯基，吡啶基，噻唑基，噻吩基，嘧啶基中选择，每种基可选择地被一个或两个基独立地从C1-6烷基，卤代C1-6烷基，卤素和CF3中选择；Y从N或CH中选择；Z从中选择其中X= CH，N，NO。
• NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS
  申请人：Kinzel Olaf

  公开号：US20140221659A1

  公开（公告）日：2014-08-07

  The present invention relates to compounds which bind to the NR1H4 receptor (FXR) and act as agonists of FXR. The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

  本发明涉及结合NR1H4受体（FXR）并作为FXR激动剂的化合物。该发明还涉及利用这些化合物制备药物以治疗疾病和/或病况，通过这些化合物结合所述核受体，并涉及这些化合物的合成过程。
• NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING AZOLES
  申请人：Gilead Sciences, Inc.

  公开号：EP3246070A1

  公开（公告）日：2017-11-22

  The present invention relates to compounds which bind to the NR1 H4 receptor (FXR) and act as agonists of FXR. The invention further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and/or conditions through binding of said nuclear receptor by said compounds and to a process for the synthesis of said compounds.

  本发明涉及与 NR1 H4 受体（FXR）结合并作为 FXR 激动剂的化合物。本发明还涉及化合物的用途，即通过所述化合物与所述核受体结合制备治疗疾病和/或病症的药物，以及所述化合物的合成工艺。
• A FARNESOID X RECEPTOR AGONSITS FORUSE AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS INFECTION
  申请人：INSERM (Institut National de la Santé et de la Recherche Médicale)

  公开号：EP3711762A1

  公开（公告）日：2020-09-23

  The present invention relates to methods and pharmaceutical compositions for the treatment of hepatitis B virus infection. In particular, the present invention relates to farnesoid X receptor (FXR) agonists for use in a method for the treatment of hepatitis B virus infection in a subject in need thereof.

  本发明涉及治疗乙型肝炎病毒感染的方法和药物组合物。特别是，本发明涉及法尼类固醇 X 受体（FXR）激动剂，用于治疗有需要的受试者的乙型肝炎病毒感染的方法。
• FXR agonists and methods for making and using
  申请人：Salk Institute for Biological Studies

  公开号：US10077268B2

  公开（公告）日：2018-09-18

  Novel FXR agonists are disclosed, embodiments of a method of making the same, and of a composition comprising them are disclosed herein. Also disclosed are embodiments of a method of treating or preventing a metabolic disorder in a subject, comprising administering to a subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and treating or preventing a metabolic disorder in the subject. Additionally disclosed are embodiments of a method of treating or preventing inflammation in an intestinal region of a subject, comprising administering to the subject (e.g., via the gastrointestinal tract) a therapeutically effective amount of one or more of the disclosed compounds, thereby activating FXR receptors in the intestines, and thereby treating or preventing inflammation in the intestinal region of the subject.

  本文公开了新型 FXR 激动剂、其制造方法的实施方案以及包含它们的组合物。还公开了一种治疗或预防受试者代谢紊乱的方法的实施方案，包括向受试者施用（例如通过胃肠道）治疗有效量的一种或多种已公开化合物，从而激活肠道中的 FXR 受体，治疗或预防受试者的代谢紊乱。此外，还公开了一种治疗或预防受试者肠道区域炎症的方法的实施方案，该方法包括向受试者施用（例如，经由胃肠道）治疗有效量的一种或多种所公开化合物，从而激活肠道中的FXR受体，进而治疗或预防受试者肠道区域的炎症。