benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl)carbamate | 1004536-68-8

• 分子结构分类: 有机化合物 - 苯类化合物
• 英文名称: benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl)carbamate
• 英文别名: Benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-ylcarbamate；benzyl N-[(3S)-1-[(1S,2R,4R)-2-acetamido-4-aminocyclohexyl]-2-oxopyrrolidin-3-yl]carbamate
• CAS: 1004536-68-8
• 化学式: C₂₀H₂₈N₄O₄
• 分子量: 388.467
• InChiKey: NJSKUWQRGSSYLN-XDNAFOTISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl)carbamate 在 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 三乙酰氧基硼氢化钠 、 sodium cyanoborohydride 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 异丙醇 为溶剂， 60.0 ℃ 、101.33 kPa 条件下， 反应 18.5h， 生成 BMS-741672
  参考文献：
  名称：

  Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

  摘要：

  We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

  DOI：

  10.1021/acsmedchemlett.8b00439
• 作为产物：
  描述：

  tert-butyl (1R,2S,5R)-2-((S)-2-(((benzyloxy)carbonyl)amino)-4-(iododimethyl-λ4-sulfanyl)butanamido)-7-oxo-6 azabicyclo[3.2.1]octane-6-carboxylate 在 lithium hydroxide monohydrate 、 碘苯二乙酸 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙腈 为溶剂， 反应 18.33h， 生成 benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl)carbamate
  参考文献：
  名称：

  Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

  摘要：

  We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

  DOI：

  10.1021/acsmedchemlett.8b00439

文献信息

• CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
  申请人：Carter Percy H.

  公开号：US20080027080A1

  公开（公告）日：2008-01-31

  This invention relates generally to modulators of chemokine receptor activity having unexpected combination of desirable pharmacological properties. Pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases, particularly diabetes, Crohn's disease, atherosclerosis, and multiple sclerosis, along with methods of preparing compounds and intermediates therefor. Metabolites of active compounds are also provided herein, pharmaceutical compositions and use thereof are also provided.

  这项发明涉及具有意想不到的理想药理特性组合的趋化因子受体活性调节剂。包含这些化合物的药物组合物，以及将其用作治疗和预防炎症、过敏、自身免疫、代谢、癌症和/或心血管疾病的药剂，特别是糖尿病、克罗恩病、动脉粥样硬化和多发性硬化症，以及制备化合物和中间体的方法。此外，还提供了活性化合物的代谢产物，以及药物组合物和其使用方法。
• MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY CRYSTALLINE FORMS AND PROCESS
  申请人：Duncia John V.

  公开号：US20080027084A1

  公开（公告）日：2008-01-31

  The present invention provides a novel antagonist or partial agonists/antagonist of MCP-1 receptor activity: N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4 -ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide: wherein R 1 , R 8 , R 9 , R 10 , and are as described herein. Compounds that are useful intermediates of the process are also provided herein.

  本发明提供了一种新型的MCP-1受体活性的拮抗剂或部分激动剂/拮抗剂：N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺，或其药学上可接受的盐、溶剂化物或前药，具有意想不到的理想药理特性的组合。本发明还提供了该化合物的晶体形式。含有该化合物的制药组合物以及将其作为治疗炎症性疾病、过敏、自身免疫、代谢、癌症和/或心血管疾病的药物的使用方法也是本发明的目标。本公开还提供了制备式(I)化合物的方法，包括N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺：其中R1、R8、R9、R10如本文所述。本文还提供了该过程有用的中间体化合物。
• MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY, CRYSTALLINE FORMS AND PROCESS
  申请人：Duncia John V.

  公开号：US20100113489A1

  公开（公告）日：2010-05-06

  The present invention provides a novel antagonist or partial agonists/antagonist of MCP-1 receptor activity: N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin- 4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide: wherein R 1 , R 8 , R 9 , R 10 , and are as described herein. Compounds that are useful intermediates of the process are also provided herein.

  本发明提供了一种MCP-1受体活性的新型拮抗剂或部分激动剂/拮抗剂：N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺，或其药学上可接受的盐、溶剂化合物或前药，具有意外的理想药理特性组合。本发明还提供了该化合物的晶体形式。本发明还旨在提供含有该化合物的制药组合物，并将其用作治疗炎症性疾病、过敏、自身免疫、代谢、癌症和/或心血管疾病的药物。本公开还提供了一种制备式(I)化合物，包括N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺的方法：其中R1，R8，R9，R10和如本文所述。本文还提供了该过程有用的中间体化合物。
• Substituted pyrrolidine-2-one compounds
  申请人：Bristol-Myers Squibb Company

  公开号：US08049019B2

  公开（公告）日：2011-11-01

  The present invention provides a novel antagonist or partial agonists/antagonist of MCP-1 receptor activity: N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino) pyrrolidin-1-yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide: wherein R1, R8, R9, R10, and are as described herein. Compounds that are useful intermediates of the process are also provided herein.

  本发明提供了一种新型的MCP-1受体活性拮抗剂或部分激动剂/拮抗剂：N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺，或其药学上可接受的盐、溶剂合物或前药，具有意想不到的理想药理特性的组合。本发明还提供了该化合物的晶体形式。本发明还提供了含有该化合物的药物组合物以及将其用作治疗炎症性疾病、过敏、自身免疫、代谢、癌症和/或心血管疾病的药物的方法。本公开还提供了制备式(I)化合物的方法，包括N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺：其中R1、R8、R9、R10如本文所述。本文还提供了该过程有用的中间体化合物。
• N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino) pyrrolidin-1-yl)cyclohexyl)acetamide and other modulators of chemokine receptor activity, crystalline forms and process
  申请人：Bristol-Myers Squibb Company

  公开号：US07629351B2

  公开（公告）日：2009-12-08

  The present invention provides a novel antagonist or partial agonists/antagonist of MCP-1 receptor activity: N-((1R,2S,5R)-5-tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide, or a pharmaceutically acceptable salt, solvate or prodrug, thereof, having an unexpected combination of desirable pharmacological characteristics. Crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of using the same as agents for the treatment of inflammatory diseases, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases is also an objective of this invention. The present disclosure also provides a process for preparing compounds of Formula (I), including N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide: wherein R1, R8,R9, R10, and are as described herein. Compounds that are useful intermediates of the process are also provided herein.

  本发明提供了一种新型的MCP-1受体活性的拮抗剂或部分激动剂/拮抗剂：N-((1R,2S,5R)-5-叔丁基氨基)-2-((S)-2-氧代-3-(6-(三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺，或其药学上可接受的盐、溶剂合物或前药，具有意想不到的理想药理特性组合。本发明还提供了该化合物的晶体形式。本发明还旨在提供含有该化合物的制药组合物以及将其用作治疗炎症性疾病、过敏、自身免疫、代谢、癌症和/或心血管疾病的药剂的方法。本公开还提供了一种制备式(I)化合物的方法，包括N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-2-氧代-3-(6-三氟甲基)喹唑啉-4-基氨基)吡咯烷-1-基)环己基)乙酰胺：其中R1、R8、R9、R10如本文所述。本文还提供了该过程的有用中间体化合物。