benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate | 1004758-01-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate
• 英文别名: benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate；benzyl N-[(3S)-1-[(1S,2R,4R)-2-acetamido-4-[methyl(propan-2-yl)amino]cyclohexyl]-2-oxopyrrolidin-3-yl]carbamate
• CAS: 1004758-01-3
• 化学式: C₂₄H₃₆N₄O₄
• 分子量: 444.574
• InChiKey: GLMYZBAHHPSYME-MBDNFAEBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  91
• 氢给体数：
  2
• 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-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate 在 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 异丙醇 、 乙腈 为溶剂， 17.0~25.0 ℃ 、308.18 kPa 条件下， 反应 14.5h， 生成 BMS-741672
  参考文献：
  名称：

  CCR2拮抗剂的立体选择性本体合成BMS-741672：通过顺序异构不对称加氢组装顺式（S，R，R）-1,2,4-三氨基环己烷（TACH）核

  摘要：

  报道了立体化学复杂的CCR2拮抗剂BMS-741672的简明本体合成。一个独特的结构特征是手性全顺式1,2,4-三氨基环己烷（TACH）核，它是通过连续的立体控制的异种氢化反应组装而成的：由（S）-α-指导的有效Pt催化还原的β-烯氨基酯。甲基苄基胺作为一种低成本的手性模板，以及还原胺化3,4-顺式二取代的环己酮在硫化的Pt / C引入叔胺，设置在清一色第三立体中心顺环己烷核。回收非均相催化剂。酯水解产生作为其Na盐分离的γ-氨基酸。一个具有挑战性的库尔提斯反应在C-2引入剩余的C-N键通过基本的存在的强烈影响叔胺，提供了stereoelectronically高度活化的异氰酸酯。需要详细的机械和工艺知识，以便能够用酒精（t- BuOH）进行干净捕集，同时避免形成副产物，尤其是不寻常的氨基甲酰基磷酸酯。脱保护，N-乙酰化和未催化的S N将Ar与已知的4-氯喹唑啉偶联提供最终产物。所得的12

  DOI：

  10.1021/acs.oprd.6b00282
• 作为产物：
  描述：

  1,4-环己二酮单乙二醇缩酮 在 titanium(IV) isopropylate 、 盐酸 、 叠氮磷酸二苯酯 、 10% Pt/activated carbon 、 palladium 10% on activated carbon 、 氢气 、 sodium hydride 、 1-羟基苯并三唑 、 caesium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 、 1,2-二氯乙烷 、 丙酮 、 乙腈 为溶剂， 80.0 ℃ 、344.75 kPa 条件下， 反应 245.5h， 生成 benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate
  参考文献：
  名称：

  [EN] CYTOTOXICITY TARGETING CHIMERAS FOR CCR2-EXPRESSING CELLS
  [FR] CHIMÈRES CIBLANT LA CYTOTOXICITÉ POUR DES CELLULES EXPRIMANT CCR2

  摘要：

  The present disclosure relates to heterobifunctional molecules, referred to as cytotoxicity targeting chimeras (CyTaCs) or antibody recruiting molecules (ARMs) that are able to simultaneously bind a target cell-surface protein as well as an exogenous antibody protein. The present disclosure also relates to agents capable of binding to a receptor on a surface of a pathogenic cell and inducing the depletion of the pathogenic cell in a subject for use in the treatment of cancer, inflammatory diseases, autoimmune diseases, viral infection, or bacterial infection. Formula (I)

  公开号：

  WO2023161881A1

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：Yang G. Michael

  公开号：US20080027083A1

  公开（公告）日：2008-01-31

  The present invention provides a novel antagonist or partial agonists/antagonists of MCP-1 receptor activity: N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-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-(isopropyl(methyl)amino)-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-(异丙基(甲基)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。本发明还提供了所述晶体形式。本发明还提供了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/或心血管疾病的药物的方法。本公开还提供了制备式(I)化合物的过程，包括N-((1R,2S,5R)-5-(异丙基(甲基)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等如本文所述。本文还提供了该过程的有用中间体化合物。
• Modulators of chemokine receptor activity, crystalline forms and process
  申请人：Bristol-Myers Squibb Company

  公开号：US07671062B2

  公开（公告）日：2010-03-02

  The present invention provides a novel antagonist or partial agonists/antagonists of MCP-1 receptor activity: N-((1R,2S,5R)-5-(isopropyl(methyl)amino)-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-(isopropyl(methyl)amino)-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-(异丙基(甲基)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-(异丙基(甲基)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。
• Cyclic derivatives as modulators of chemokine receptor activity
  申请人：Bristol-Myers Squibb Company

  公开号：US07687508B2

  公开（公告）日：2010-03-30

  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.

  本发明涉及调节趋化因子受体活性的调节剂，具有意外的理想药理特性的组合。本发明还涉及含有这些调节剂的药物组合物，并将其作为治疗和预防炎症、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、动脉硬化和多发性硬化症的药剂，以及制备化合物和中间体的方法。本发明还提供了活性化合物的代谢产物，提供了药物组合物及其使用方法。
• Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672
  作者：Michael G. Yang、Zili Xiao、Robert J. Cherney、Andrew J. Tebben、Douglas G. Batt、Gregory D. Brown、Jing Chen、Mary Ellen Cvijic、Marta Dabros、John V. Duncia、Michael Galella、Daniel S. Gardner、Purnima Khandelwal、Soo S. Ko、Mary F. Malley、Ruowei Mo、Jian Pang、Anne V. Rose、Joseph B. Santella、Hong Shi、Anurag Srivastava、Sarah C. Traeger、Bei Wang、Songmei Xu、Rulin Zhao、Joel C. Barrish、Sandhya Mandlekar、Qihong Zhao、Percy H. Carter

  DOI：10.1021/acsmedchemlett.8b00439

  日期：2019.3.14

  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.