rac-(3S,4R)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: rac-(3S,4R)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine
• 英文别名: 1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine；rac-(3R,4S)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine；(±)-(3R,4S)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine；(3R,4S)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine；trans-4-(4-bromophenyl)-1-(phenylmethyl)-3-pyrrolidinamine；(3S,4R)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine
• 化学式: C₁₇H₁₉BrN₂
• 分子量: 331.255
• InChiKey: JORFOQFEPOWZMD-DLBZAZTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  29.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  rac-(3S,4R)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine 在 1-氯乙基氯甲酸酯 、 三乙胺 作用下， 以 乙醇 、 1,2-二氯乙烷 为溶剂， 反应 2.0h， 生成 tert-butyl (4-(4-bromophenyl)pyrrolidin-3-yl)carbamate
  参考文献：
  名称：

  Are We There Yet? Applying Thermodynamic and Kinetic Profiling on Embryonic Ectoderm Development (EED) Hit-to-Lead Program

  摘要：

  It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (k(off)) of the lead compounds were observed as the program progressed. Analysis of the kinetic data indicated that compound cellular activity correlated with both K-i; and k(off). Our analysis revealed that ITC data should be interpreted in the context of chiral purity of the compounds. The thermodynamic signatures of the EED aminopyrrolidine compounds were found to be mainly enthalpy driven with improved enthalpic contributions as the program progressed. Our study also demonstrated that significant challenges still exist in utilizing kinetic and thermodynamic parameters for hit selection.

  DOI：

  10.1021/acs.jmedchem.7b00576
• 作为产物：
  描述：

  rac-(3S,4R)-1-benzyl-3-(4-bromophenyl)-4-nitropyrrolidine 在 Raney nickel 作用下， 以 四氢呋喃 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 2.2h， 生成 rac-(3S,4R)-1-benzyl-4-(4-bromophenyl)pyrrolidin-3-amine
  参考文献：
  名称：

  氨基吡咯烷的SAR通过EED结合作为PRC2复合物的有效和新型蛋白质-蛋白质相互作用抑制剂。

  摘要：

  本文中，我们公开了一系列二甲基氨基吡咯烷的SAR研究，最近我们报道了它通过破坏EED / H3K27me3结合而成为PRC2复合物的新型抑制剂。筛选命中1的吲哚和苄基部分的修饰提供了具有实质上改善的结合和细胞活性的类似物。这项工作最终鉴定了化合物2，这是我们的纳摩尔概念验证（PoC）抑制剂，可在小鼠异种移植模型中提供对靶标肿瘤生长的抑制作用。还讨论了结合在EED活性位点上的几种抑制剂的X射线晶体结构。

  DOI：

  10.1016/j.bmcl.2017.02.030

文献信息

• [EN] COMPOSITIONS AND METHODS FOR INHIBITING PROTEIN EMBRYONIC ECTODERM DEVELOPMENT ACTIVITY AND TREATING DISEASE<br/>[FR] COMPOSITIONS ET PROCÉDÉS POUR L'INHIBITION DE L'ACTIVITÉ DE DÉVELOPPEMENT D'ECTODERME EMBRYONNAIRE DE PROTÉINE ET DE TRAITEMENT D'UNE MALADIE
  申请人：EXO THERAPEUTICS INC

  公开号：WO2021195183A1

  公开（公告）日：2021-09-30

  The invention provides compounds that are inhibitors of the protein embryonic ectoderm development (EED), pharmaceutical compositions, their use in modulating the activity of EED, and their use in the treatment of medical disorders, such as cancer. The invention further provides methods of treating medical disorders, such as cancer, and covalently modifying and/or modulating the activity of EED, using an agent that reacts with, and forms a covalent bond to, cysteine324 of EED.

  这项发明提供了抑制蛋白胚胎外胚层发育（EED）的化合物，药物组合物，它们在调节EED活性中的应用，以及它们在治疗癌症等医学疾病中的应用。该发明还提供了治疗医学疾病（如癌症）的方法，并利用一种与EED的半胱氨酸324发生反应并形成共价键的试剂，对EED进行共价修饰和/或调节活性。
• 4-Aryl Pyrrolidines as Novel Orally Efficacious Antimalarial Agents. Part 2: 2-Aryl-<i>N</i>-(4-arylpyrrolidin-3-yl)acetamides
  作者：Marvin J. Meyers、Jianguang Liu、Zhijun Liu、Hongwei Ma、Linglin Dai、Dickson Adah、Siting Zhao、Xiaofen Li、Xiaorong Liu、Yongzhi Lu、Yanhui Huang、Zhengchao Tu、Xiaoping Chen、Micky D. Tortorella

  DOI：10.1021/acsmedchemlett.9b00123

  日期：2019.6.13

  Plasmodium demands identification of new drugs with novel chemotypes and mechanisms of action. As a follow up to our evaluation of 4-aryl-N-benzylpyrrolidine-3-carboxamides as novel pyrrolidine-based antimalarial agents, we describe herein the structure–activity relationships of the reversed amide homologues 2-aryl-N-(4-arylpyrrolidin-3-yl)acetamides. Unlike their carboxamide homologues, acetamide pyrrolidines

  疟疾是由疟原虫寄生虫感染引起的，每年造成数十万人死亡。疟原虫的新抗药性菌株的出现要求鉴定具有新化学型和作用机理的新药物。作为我们对4-芳基-N-苄基吡咯烷-3-羧酰胺作为新型吡咯烷基抗疟剂的评估的后续措施，我们在此描述了反向酰胺同系物2-芳基-N-（4-芳基吡咯烷酮）的结构-活性关系-3-基）乙酰胺。不同于其酰胺酰胺同系物，乙酰胺吡咯烷不需要第三手性中心即可成为P的有效抑制剂。恶性疟并且在疟疾的小鼠模型中具有良好的药代动力学特性和改善的口服功效。化合物（-）-32a（CWHM-1552）在恶性疟原虫3D7分析中的体外IC 50为51 nM ，体内ED 90 <10 mg / kg / day和ED 99为30 mg / kg /鼠P. chabaudi模型中的一天。值得注意的是，此乙酰胺系列（3 S，4 R）与同源羧酰胺系列测定的结果相反。此类先导化合物对hERG通道具有适度的亲和力，并抑制CYP
• INDANE INHIBITORS OF EED AND METHODS OF THEIR USE
  申请人：AbbVie Inc.

  公开号：US20170320880A1

  公开（公告）日：2017-11-09

  Compounds having a structure of Formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein A 1 , A 2 , A 3 , A 4 , A 5 , n, and m are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various EED-related conditions or diseases, including cancer, by administration of such compounds are also provided.

  提供具有下列化学式（I）结构、立体异构体、互变异构体或药学上可接受的盐的化合物，其中A1、A2、A3、A4、A5、n和m的定义如本文所述。同时提供包含这些化合物的制药组合物和通过给予这些化合物治疗各种与EED相关的疾病或状况，包括癌症的方法。
• [EN] COMPOUNDS WHICH POTENTIATE GLUTAMATE RECEPTOR AND USES THEREOF IN MEDICINE<br/>[FR] COMPOSÉS POTENTIALISATEURS DE RÉCEPTEUR DE GLUTAMATE ET UTILISATIONS DE CEUX-CI EN MÉDECINE
  申请人：GLAXO GROUP LTD

  公开号：WO2006015827A1

  公开（公告）日：2006-02-16

  Compounds of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, are disclosed: wherein R1 is C1-6alkyl, haloC1-6alkyl, C2-6alkenyl, amino, monoC1-4alkylamino or diC1-4alkylamino; B is -N(R4)- or -0-; A and D, which may be the same or different, are -C(R5)2-; each R2, which may be the same or different, is C1-6alkyl, halogen, haloCl-­6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro or amino; n is 0, 1 or 2; R3 is C1-6alkyl, haloCl-6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, amino, -(CH2)pNR3aSO2R3b,-(CH2)pNR3a(C=O)R3b, -(CH2)pNR3a(C=O)N(R3c)2, -(CH2)p(C=O)R3d, -(CH2)pSO2R3e, phenyl or heterocyclyl, wherein when R3 is phenyl or heterocyclyl, it is optionally substituted by one or more groups independently selected from: C1-6alkyl, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, amino, -(CH2)pNR3aSO2R3b, -(CH2)pNR3a(C=O)R3b, -(CH2)pNR3a(C=O)N(R3c)2 -(CH2)p(C=O)R3d and -(CH2)pSO2R3e; where R3a and each R3c, which may be the same or different, is hydrogen or C1-6alkyl; R3b and R3e are C1-6alkyl or haloCl-6alkyl; R3d is C1-6alkyl, C1-4alkoxy or haloC1-6alkyl; or R3a and R3b, or R3a and R3c, together with the interconnecting atoms, may form a 5- or 6-membered ring; and p is 0, 1, or 2; R4 is carbocyclyl or carbocyclylC1-4alkyl, wherein the carbocyclyl group of either is optionally substituted by one or more groups independently selected from C1-6alkyl and halogen; or R4 is hydrogen, C1-6alkyl, haloC1-6alkyl, C1-6alkylcarbonyl, Cl-6alkylsulfonyl or C1-6alkylaminocarbonyl; each R5, which may be the same or different, is hydrogen, C1-­6alkyl or halogen; and R6 is hydrogen or fluorine. Methods of preparation of the compounds, and uses thereof in medicine, for example treatment of schizophrenia, are also disclosed.

  公开了化合物(I)的配方或其药学上可接受的盐、溶剂化物或前药，其中R1是C1-6烷基、卤代C1-6烷基、C2-6烯基、氨基、单C1-4烷基氨基或双C1-4烷基氨基；B是-N（R4）-或-0-；A和D，可以相同也可以不同，是-C（R5）2-；每个R2，可以相同也可以不同，是C1-6烷基、卤素、卤代C1-6烷基、C1-4烷氧基、卤代C1-4烷氧基、氰基、硝基或氨基；n为0、1或2；R3是C1-6烷基、卤代C1-6烷基、C1-4烷氧基、卤代C1-4烷氧基、氰基、硝基、氨基、-(CH2)pNR3aSO2R3b、-(CH2)pNR3a（C=O）R3b、-(CH2)pNR3a（C=O）N（R3c）2、-(CH2)p（C=O）R3d、-(CH2)pSO2R3e、苯基或杂环基，其中当R3是苯基或杂环基时，它可以选择性地被一个或多个独立选择的基团取代，这些基团包括C1-6烷基、卤素、C1-6烷基、卤代C1-6烷基、C1-4烷氧基、卤代C1-4烷氧基、氰基、硝基、氨基、-(CH2)pNR3aSO2R3b、-(CH2)pNR3a（C=O）R3b、-(CH2)pNR3a（C=O）N（R3c）2、-(CH2)p（C=O）R3d和-(CH2)pSO2R3e；其中R3a和每个R3c，可以相同也可以不同，是氢或C1-6烷基；R3b和R3e是C1-6烷基或卤代C1-6烷基；R3d是C1-6烷基、C1-4烷氧基或卤代C1-6烷基；或R3a和R3b，或R3a和R3c，连同连接的原子，可以形成5-或6-成员环；p为0、1或2；R4是碳环基或碳环基C1-4烷基，其中任意一个的碳环基可以选择性地被一个或多个独立选择的基团取代，这些基团包括C1-6烷基和卤素；或R4是氢、C1-6烷基、卤代C1-6烷基、C1-6烷基羰基、C1-6烷基磺酰基或C1-6烷基氨基羰基；每个R5，可以相同也可以不同，是氢、C1-6烷基或卤素；R6是氢或氟。还公开了化合物的制备方法以及它们在医学上的用途，例如治疗精神分裂症。
• Compounds Which Potentiate Glutamate Receptor and Uses Thereof in Medicine
  申请人：Thewlis Michael Kevin

  公开号：US20070270471A1

  公开（公告）日：2007-11-22

  This case discloses compounds of formula (I) wherein R 1 is C 1-6 alkyl, haloC 1-6 alkyl, C 2-6 alkenyl, amino, monoC 1-4 alkylamino or diC 1-4 alkylamino; B is —N(R 4 )— or —O—; A and D, which may be the same or different, are —C(R 5 ) 2 —; each R 2 , which may be the same or different, is C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, cyano, nitro or amino; n is 0, 1 or 2; R 3 is C 1-6 alkyl, haloC 1-6 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, cyano, nitro, amino, —(CH 2 ) p NR 3a SO 2 R 3b , —(CH 2 ) p NR 3a (C═O)R 3b , —(CH 2 ) p NR 3a (C═O)N(R 3c ) 2 , —(CH 2 ) p (C═O)R 3d , —(CH 2 ) p SO 2 R 3e , phenyl or heterocyclyl, wherein when R 3 is phenyl or heterocyclyl, it is optionally substituted by one or more groups independently selected from: C 1-6 alkyl, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, cyano, nitro, amino, —(CH 2 ) p NR 3a SO 2 R 3b , —(CH 2 ) p NR 3a (C═O)R 3b , —(CH 2 ) p NR 3a (C═O)N(R 3c ) 2 , —(CH 2 ) p (C═O)R 3d and —(CH 2 ) p SO 2 R 3e ; where R 3a and each R 3c , which may be the same or different, is hydrogen or C 1-6 alkyl; R 3b and R 3e are C 1-6 alkyl or haloC 1-6 alkyl; R 3d is C 1-6 alkyl, C 1-4 alkoxy or haloC 1-6 alkyl; or R 3a and R 3b , or R 3a and R 3c , together with the interconnecting atoms, may form a 5- or 6-membered ring; and p is 0, 1, or 2; R 4 is carbocyclyl or carbocyclylC 1-4 alkyl, wherein the carbocyclyl group of either is optionally substituted by one or more groups independently selected from C 1-6 alkyl and halogen; or R 4 is hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylsulfonyl or C 1-6 alkylaminocarbonyl; each R 5 , which may be the same or different, is hydrogen, C 1-6 alkyl or halogen; and R 6 is hydrogen or fluorine.

  该案例揭示了公式（I）化合物，其中R1是C1-6烷基，卤代C1-6烷基，C2-6烯基，氨基，单个C1-4烷基氨基或双个C1-4烷基氨基; B是—N（R4）—或—O—; A和D，可以相同也可以不同，是—C（R5）2—; 每个R2，可以相同也可以不同，是C1-6烷基，卤素，卤代C1-6烷基，C1-4烷氧基，卤代C1-4烷氧基，氰基，硝基或氨基; n为0,1或2; R3是C1-6烷基，卤代C1-6烷基，C1-4烷氧基，卤代C1-4烷氧基，氰基，硝基，氨基，—（CH2）pNR3aSO2R3b，—（CH2）pNR3a（C═O）R3b，—（CH2）pNR3a（C═O）N（R3c）2，—（CH2）p（C═O）R3d，—（CH2）pSO2R3e，苯基或杂环基，其中当R3为苯基或杂环基时，它可以选择性地被一个或多个基团独立地选自：C1-6烷基，卤素，C1-6卤代烷基，C1-4烷氧基，卤代C1-4烷氧基，氰基，硝基，氨基，—（CH2）pNR3aSO2R3b，—（CH2）pNR3a（C═O）R3b，—（CH2）pNR3a（C═O）N（R3c）2，—（CH2）p（C═O）R3d和—（CH2）pSO2R3e;其中R3a和每个R3c，可以相同也可以不同，是氢或C1-6烷基; R3b和R3e是C1-6烷基或卤代C1-6烷基; R3d是C1-6烷基，C1-4烷氧基或卤代C1-6烷基; 或者R3a和R3b，或者R3a和R3c，连通的原子一起可以形成一个5-或6-成员环; p为0,1或2; R4是碳环基或碳环基C1-4烷基，其中任一碳环基可以选择性地被一个或多个基团独立地选自C1-6烷基和卤素; 或者R4是氢，C1-6烷基，卤代C1-6烷基，C1-6烷基羰基，C1-6烷基磺酰基或C1-6烷基氨基羰基; 每个R5，可以相同也可以不同，是氢，C1-6烷基或卤素; 而R6是氢或氟。