isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate | 99438-50-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate
• 英文别名: (1S,3S)-isopropyl 3-hydroxycyclohexanecarboxylate；propan-2-yl (1S,3S)-3-hydroxycyclohexane-1-carboxylate
• CAS: 99438-50-3
• 化学式: C₁₀H₁₈O₃
• 分子量: 186.251
• InChiKey: DBBXNLQKVHOCBM-IUCAKERBSA-N

物化性质

• 沸点：
  262.8±33.0 °C(Predicted)
• 密度：
  1.067±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate 在 chromium(VI) oxide 、 硫酸 、 hydroxide 作用下， 以 丙酮 为溶剂， 生成 (1R)3-氧代环己烷甲酸乙酯
  参考文献：
  名称：

  化学酶促合成构象刚性的谷氨酸类似物

  摘要：

  通过微生物步骤和标准化学方法的结合，由相应的3-酮-环烷基羧酸酯合成了环己烷和谷氨酸的环戊烷衍生的类似物的所有立体异构体。

  DOI：

  10.1016/s0040-4039(00)82278-9
• 作为产物：
  描述：

  1-bromocyclohexanecarbonyl chloride 在 chromium(VI) oxide 、 sodium tetrahydroborate 、 Geotrichum candidum 、 乙酸酐 作用下， 以 喹啉 、 甲醇 、 乙醇 、 二氯甲烷 、 溶剂黄146 为溶剂， 反应 75.0h， 生成 isopropyl (1S,3S)-3-hydroxycyclohexane-1-carboxylate
  参考文献：
  名称：

  Chemoenzymatic synthesis of enantiopure isopropyl (3R)- and (3S)-3-hydroxycyclohex-1-ene-1-carboxylates and their reduction to isomers of isopropyl 3-hydroxy-cyclohexane-1-carboxylate

  摘要：

  Reduction of an alpha,beta-unsaturated cyclic ketone with Geotrichum candidum affords the corresponding (S)-allylic alcohol, while enantiospecific oxidation of the corresponding racemic alcohols leases the (R)-enantiomer unchanged, giving access to both enantiomeric forms. Subsequent chemical reduction of the double bond of these homochiral allylic alcohol allows all isomers of the corresponding cyclohexanols to be obtained. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0957-4166(02)00152-0

文献信息

• [EN] CYCLOHEXYL ACID TRIAZOLE AZINES AS LPA ANTAGONISTS<br/>[FR] AZINES TRIAZOLES D'ACIDE CYCLOHEXYLE UTILISÉES EN TANT QU'ANTAGONISTES DE LPA
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2019126093A1

  公开（公告）日：2019-06-27

  The present invention provides compounds of Formula (I): Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

  本发明提供了化合物的结构式（I）：结构式（I）或其立体异构体、互变异构体或药学上可接受的盐或溶剂，其中所有变量如本文所定义。这些化合物是选择性LPA受体抑制剂。
• [EN] ISOXAZOLE O-LINKED CARBAMOYL CYCLOHEXYL ACIDS AS LPA ANTAGONISTS<br/>[FR] ACIDES CARBAMOYLE CYCLOHEXYLIQUES À LIAISON O ISOXAZOLE UTILISÉS EN TANT QU'ANTAGONISTES DE LPA
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2019126084A1

  公开（公告）日：2019-06-27

  The present invention provides compounds of Formula (Ia) or (Ib) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein wherein X1, X2, X3, and X4 are each independently CR6 or N; provided that no more than two of X1, X2, X3, or X4 are N; L is C1-4 alkylene substituted with 0 to 4 R7; R1 is (-CH2)aR9; a is an integer of 0 or 1; R2 is each independently halo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxy, alkoxyalkyi, haloalkoxyallcyl, or haloalkoxy; n is an integer of 0, 1, or 2; R3 is hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxyalkyi, haloalkoxyalkyl, alkoxy, or haloalkoxy, and the alkyl, by itself or as part of other moiety, is optionally substituted with deuterium partially or fully; R4 is C1-10 alkyl, C1-10 deuterated alkyl, C1-10 haloalkyi, C1-10 alkenyl, C3-8 cycloalkyl, 6 to 10-membered aryl, 3 to 8-membered heterocyclyl, -(C1-6 alkylene)-(C3-8 cycloalkyl), -(C1-6 alkylene)-(6 to 10-membered aryl), -(C1-6 alkylene)-(3 to 8-membered heterocyclyl), or -(C1-6 alkylene)-(5 to 6-membered heteroaryl); wherein each of the alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R8; or alternatively, R3 and R4, taken together with the N atom to which they are attached, form a 4 to 9-membered heterocyclic ring moiety which is substituted with 0 to 3 R; R5 and R6 are each independently hydrogen, halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R7 is halo, oxo, cyano, hydroxyl, amino, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R8 are each independently deuterium, halo, hydroxyl, amino, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C2-6 alkenyl, C2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl; or alternatively, two R8, taken together with the atoms to which they are attached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic ring each of which is independently substituted with 0 to 3 R12; R9 is selected from -CN, -C(O)OR10, -C(O)NR11aR11b, -CO-NH-CO-Re, -CO-NH-SO2-Re, -CO-NH-SO-Re, -SO2-OH, -SO2-NH-CO-Re, -P(O)(OH)2, tetrazol-5-yl, -CH2-CO-NH-CO-Re, -CH2-CO-NH-SO2-Re, CH2-CO-NH-SO-Re, -CH2-SO2-OH, -CH2-SO2-NH-CO-Re, -CH2-P(O)(OH)2, tetrazol-5-ylmethylene; Re is C1-6 alkyl, C3 -6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R10 is hydrogen or C1-10 alkyl; and R11a and R11b are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and R12 is halo, cyano, hydroxyl, amino, C1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl. These compounds are selective LPA receptor inhibitors.

  本发明提供了式(Ia)或(Ib)的化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂，其中X1、X2、X3和X4分别独立地为CR6或N；但X1、X2、X3或X4中不超过两个为N；L为C1-4烷基，其上取代有0至4个R7；R1为(-CH2)aR9；a为0或1的整数；R2分别为卤素、氰基、羟基、氨基、C1-6烷基、C3-6环烷基、C4-6杂环烷基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基、烷氧基烷基、卤代烷氧基烷基或卤代烷氧基；n为0、1或2的整数；R3为氢、C1-6烷基、C1-6氘代烷基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基烷基、烷氧基或卤代烷氧基，烷基本身或作为其他基团的一部分，可以部分或完全地被氘取代；R4为C1-10烷基、C1-10氘代烷基、C1-10卤代烷基、C1-10烯基、C3-8环烷基、6至10成员芳基、3至8成员杂环烷基、-(C1-6烷基)-(C3-8环烷基)、-(C1-6烷基)-(6至10成员芳基)、-(C1-6烷基)-(3至8成员杂环烷基)或-(C1-6烷基)-(5至6成员杂芳基)；其中烷基、烷基烯烃、烷烃、芳基、杂环烷基和杂芳基中的每一个，本身或作为其他基团的一部分，可以独立地被0至3个R8取代；或者，R3和R4，与它们连接的N原子一起，形成一个取代有0至3个R的4至9成员杂环基团；R5和R6分别独立地为氢、卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基烷基、烷氧基或卤代烷氧基；R7为卤素、氧、氰基、羟基、氨基、C1-6烷基、C3-6环烷基、C4-6杂环烷基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基烷基、烷氧基或卤代烷氧基；R8分别独立地为氘、卤素、羟基、氨基、氰基、C1-6烷基、C1-6氘代烷基、C2-6烯基、C2-6炔基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基烷基、烷氧基、卤代烷氧基、苯基或5至6成员杂芳基；或者，两个R8，与它们连接的原子一起，形成一个取代有0至3个R12的3至6成员碳环基或3至6成员杂环基；R9从-CN、-C(O)OR10、-C(O)NR11aR11b、-CO-NH-CO-Re、-CO-NH-SO2-Re、-CO-NH-SO-Re、-SO2-OH、-SO2-NH-CO-Re、-P(O)(OH)2、四唑-5-基、- -CO-NH-CO-Re、- -CO-NH-SO2-Re、 -CO-NH-SO-Re、- -SO2-OH、- -SO2-NH-CO-Re、-CH2-P(O)(OH)2、四唑-5-基亚甲基中选择；Re为C1-6烷基、C3-6环烷基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基或卤代烷氧基；R10为氢或C1-10烷基；R11a和R11b分别独立地为氢、C1-6烷基、C3-6环烷基、C4-6杂环烷基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基、烷氧基或卤代烷氧基；R12为卤素、氰基、羟基、氨基、C1-6烷基、烷基氨基、卤代烷基、羟基烷基、氨基烷基、烷氧基烷基、卤代烷氧基、烷氧基或卤代烷氧基、苯基或5至6成员杂芳基。这些化合物是选择性的LPA受体抑制剂。
• 溶血磷脂酸受体拮抗剂及其制备方法
  申请人：武汉朗来科技发展有限公司

  公开号：CN111434655A

  公开（公告）日：2020-07-21

  本发明属于药物化学技术领域，具体涉及一种溶血磷脂酸受体拮抗剂及其制备方法。申请人惊奇地发现，本发明的化合物具有高的LPAR1拮抗活性和选择性，且毒性低、代谢稳定性好，具有良好的药物开发前景，可以用于预防或治疗与LPAR1相关的疾病或病症。申请人还意外地发现，本发明部分化合物的IC50值可以低至300nM以下，甚至50nM以下。并且，本发明的化合物都具有较好的安全性，其CC50范围可高达200μM以上。此外，本发明的化合物在人、大鼠、小鼠中都具有较好的代谢稳定性，这样优异的抑制活性对于它们作为LPAR1抑制剂应用于上述疾病或病症而言是令人非常期待的。此外，本发明化合物的制备方法简单，反应条件温和，产品收率高，适于工业化生产。
• Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA₁) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases
  作者：Peter T. W. Cheng、Robert F. Kaltenbach、Hao Zhang、Jun Shi、Shiwei Tao、Jun Li、Lawrence J. Kennedy、Steven J. Walker、Yan Shi、Ying Wang、Suresh Dhanusu、Ramesh Reddigunta、Selvakumar Kumaravel、Sutjano Jusuf、Daniel Smith、Subramaniam Krishnananthan、Jianqing Li、Tao Wang、Rebekah Heiry、Chi Shing Sum、Stephen S. Kalinowski、Chen-Pin Hung、Ching-Hsuen Chu、Anthony V. Azzara、Milinda Ziegler、Lisa Burns、Bradley A. Zinker、Stephanie Boehm、Joseph Taylor、Julia Sapuppo、Kathy Mosure、Gerry Everlof、Victor Guarino、Lisa Zhang、Yanou Yang、Qian Ruan、Carrie Xu、Atsu Apedo、Sarah C. Traeger、Mary Ellen Cvijic、Kimberley A. Lentz、Giridhar Tirucherai、Lakshmi Sivaraman、Jeffrey Robl、Bruce A. Ellsworth、Glenn Rosen、David A. Gordon、Matthew G. Soars、Michael Gill、Brian J. Murphy

  DOI：10.1021/acs.jmedchem.1c01256

  日期：2021.11.11

  The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1Kb of 6.9 nM. The structure–activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its ph

  氧环己酸 BMS-986278 ( 33 ) 是一种有效的溶血磷脂酸受体 1 (LPA 1 ) 拮抗剂，人类 LPA 1 K b为 6.9 nM。讨论了从 LPA 1拮抗剂临床化合物 BMS-986020 ( 1 )开始的构效关系 (SAR) 研究，最终发现了33。详细的体外和体内临床前药理学概况33，以及它的药代动力学/代谢特征，进行了描述。基于其在啮齿动物慢性肺纤维化模型中的体内功效以及在多个临床前物种中优异的整体 ADME（吸收、分布、代谢、排泄）特性，33 项已进入临床试验，包括正在进行的 2 期临床试验。肺纤维化 (NCT04308681)。
• [EN] CYCLOHEXYL ACID PYRAZOLE AZOLES AS LPA ANTAGONISTS<br/>[FR] ACIDES PYRAZOLES AZOLES CYCLOHEXYLIQUES UTILISÉS EN TANT QU'ANTAGONISTES DE LPA
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2019126103A1

  公开（公告）日：2019-06-27

  The present invention provides compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

  本发明提供了式（I）的化合物或其立体异构体、互变异构体或药学上可接受的盐或溶剂，其中所有变量如本文所定义。这些化合物是选择性LPA受体抑制剂。