methyl 2-fluoro-4-(piperazin-1-yl)benzoate | 234082-13-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: methyl 2-fluoro-4-(piperazin-1-yl)benzoate
• 英文别名: methyl 2-fluoro-4-piperazin-1-ylbenzoate
• CAS: 234082-13-4
• 化学式: C₁₂H₁₅FN₂O₂
• 分子量: 238.262
• InChiKey: ZPIJTNXEKLSQBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  41.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 2-fluoro-4-(piperazin-1-yl)benzoate 在 N-甲基吗啉 、 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 33.5h， 生成 tert-butyl (2S)-benzenesulfonylamino-3-[2-fluoro-4-{4-(pyrimidin-2-yl)piperazin-1-yl}benzoylamino]propionate
  参考文献：
  名称：

  Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 1: Design and synthesis of a lead compound exhibiting αvβ3/αIIbβ3 dual antagonistic activity

  摘要：

  In order to generate novel compounds with integrin alpha(v)beta(3)-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta(3) antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta(3)/alpha(IIb)beta(3) dual antagonist. Structureactivity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2005.10.060
• 作为产物：
  描述：

  哌嗪 、 2,4-二氟苯甲酸甲酯 在 二甲基亚砜 作用下， 生成 methyl 2-fluoro-4-(piperazin-1-yl)benzoate
  参考文献：
  名称：

  Phenylpiperazine derivatives as integrin &agr;v&bgr;3 antagonists

  摘要：

  本发明的一个目标是提供具有整合素αvβ3拮抗活性、GP IIb/IIIa拮抗活性和/或人类血小板聚集抑制活性的化合物，以及用于治疗整合素αvβ3介导疾病和抑制血小板聚集的治疗剂。根据本发明的衍生物是由以下式（I）表示的化合物或其药学上可接受的盐或溶剂：其中A代表含有两个氮原子等的五至七元杂环环；X和Z代表CH或氮原子；R4和R5代表烷基、卤素等；Q代表>C=O、>CH2等；R6代表H、烷基、芳基烷基等；R7代表H、炔基等；R8代表H、取代氨基等；R9代表H或烷基；m为0至5；n为0至4；p为2或3；q为0或1。

  公开号：

  US06451800B1

文献信息

• [EN] NOVEL AGENTS TARGETING CYP51<br/>[FR] NOUVEAUX AGENTS CIBLANT CYP51
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2015048306A1

  公开（公告）日：2015-04-02

  The invention provides inhibitors of a sterol C14-demethylase, a new series of 4- aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) developed using structure-based drug design as well as structure -property relationship (SPR) analyses. The screening hit starting point, LP 10 (KD < 42 nM; EC50 of 0.65 μΜ), has been optimized to give the potential leads that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts. Many of the optimized compounds have improved microsome stability, and most are selective against the T. cruzi CYP51 relative to human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 μΜ). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of several compounds of the invention with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis. Orally active compounds and their cyclodextrin complexes have been shown to be effective against Chagas-infected mice.

  该发明提供了一种甾醇C14-去甲基酶的抑制剂，这是一种新系列基于4-氨基吡啶的首选抑制剂，通过基于结构的药物设计以及结构-性质关系（SPR）分析来瞄准Trypanosoma cruzi CYP51（TcCYP51）而开发的。筛选起始点LP 10（KD < 42 nM；EC50为0.65 μΜ）已经经过优化，产生了具有低纳摩尔级别结合亲和力和对在人类肌细胞培养的T. cruzi游离体的显著活性的潜在首选抑制剂。许多经过优化的化合物具有改善的微粒体稳定性，大多数相对于人类CYPs 1A2、2D6和3A4对T. cruzi CYP51具有选择性（在1 μΜ下<50%的抑制）。提出了改善微粒体稳定性和抑制剂对人类代谢CYP酶的选择性的理由。此外，通过X射线结构分析表征了该发明的几种化合物与T. brucei CYP51（TbCYP51）同源物的结合方式。口服活性化合物及其环糊精复合物已被证明对克氏病感染的小鼠有效。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR<br/>[FR] COMPOSÉS ET MÉTHODES POUR LA DÉGRADATION CIBLÉE DU RÉCEPTEUR DES ANDROGÈNES
  申请人：ARVINAS OPERATIONS INC

  公开号：WO2021127443A1

  公开（公告）日：2021-06-24

  This disclosure pertains to compounds, the preparation thereof, and the use of these compounds in the treatment of prostate cancer, including metastatic and/or castrate-resistant prostate cancer, in subjects in need thereof.

  这项披露涉及化合物、其制备以及在需要的受试者中治疗前列腺癌，包括转移性和/或去势抵抗性前列腺癌中使用这些化合物的用途。
• Phenylpiperazine derivatives as integrin &agr;v&bgr;3 antagonists
  申请人：Meiji Seika Kaisha, Ltd.

  公开号：US06451800B1

  公开（公告）日：2002-09-17

  An objective of the present invention is to provide compounds having integrin &agr;v&bgr;3 antagonistic activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity, and therapeutic agents for treating integrin &agr;v&bgr;3-mediated diseases and for inhibiting platelet aggregation. The derivatives according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof: wherein A represents a five- to seven-membered heterocyclic ring containing two nitrogen atoms or the like; X and Z represent CH or a nitrogen atom; R4 and R5 represent alkyl, halogen or the like; Q represents >C=O, >CH2 or the like; R6 represents H, alkyl, aralkyl or the like; R7 represents H, alkynyl or the like; R8 represents H, substituted amino or the like; R9 represents H or alkyl; m is 0 to 5; n is 0 to 4; p is 2 or 3; and q is 0 or 1.

  本发明的一个目标是提供具有整合素αvβ3拮抗活性、GP IIb/IIIa拮抗活性和/或人类血小板聚集抑制活性的化合物，以及用于治疗整合素αvβ3介导疾病和抑制血小板聚集的治疗剂。根据本发明的衍生物是由以下式（I）表示的化合物或其药学上可接受的盐或溶剂：其中A代表含有两个氮原子等的五至七元杂环环；X和Z代表CH或氮原子；R4和R5代表烷基、卤素等；Q代表>C=O、>CH2等；R6代表H、烷基、芳基烷基等；R7代表H、炔基等；R8代表H、取代氨基等；R9代表H或烷基；m为0至5；n为0至4；p为2或3；q为0或1。
• [EN] RAPIDLY ACCELERATING FIBROSARCOMA PROTEIN DEGRADING COMPOUNDS AND ASSOCIATED METHODS OF USE<br/>[FR] COMPOSÉS DE DÉGRADATION DE PROTÉINE DE FIBROSARCOME RAPIDEMENT ACCÉLÉRÉ ET LEURS PROCÉDÉS D'UTILISATION
  申请人：ARVINAS OPERATIONS INC

  公开号：WO2022047145A1

  公开（公告）日：2022-03-03

  Bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (Raf, such as c-Raf, A-Raf, and/or B-Raf), are described herein. In particular, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds Raf, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本文描述了作为快速加速纤维肉瘤（Raf，如c-Raf、A-Raf和/或B-Raf）调节剂的双功能化合物。具体来说，本公开的异双功能化合物在一端含有结合到cereblon E3泛素连接酶的部分，另一端含有结合Raf的部分，使目标蛋白质靠近泛素连接酶以实现目标蛋白质的降解（和抑制）。本公开的异双功能化合物表现出与目标蛋白质的降解/抑制相关的广泛的药理活性。由于目标蛋白质异常调节导致的疾病或疾病可以通过本公开的化合物和组合物进行治疗或预防。
• PHENYLPIPERAZINE DERIVATIVES AS INTEGRIN ALPHAvBETA3 ANTAGONISTS
  申请人：Meiji Seika Kaisha, Ltd.

  公开号：EP1057818A1

  公开（公告）日：2000-12-06

  An objective of the present invention is to provide compounds having integrin αvβ3 antagonistic activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity, and therapeutic agents for treating integrin αvβ3-mediated diseases and for inhibiting platelet aggregation. The derivatives according to the present invention are compounds represented by formula (I) or pharmaceutically acceptable salts or solvates thereof: wherein A represents a five- to seven-membered heterocyclic ring containing two nitrogen atoms or the like; X and Z represent CH or a nitrogen atom; R4 and R5 represent alkyl, halogen or the like; Q represents >C=O, >CH2 or the like; R6 represents H, alkyl, aralkyl or the like; R7 represents H, alkynyl or the like; R8 represents H, substituted amino or the like; R9 represents H or alkyl; m is 0 to 5; n is 0 to 4; p is 2 or 3; and q is 0 or 1.

  本发明的目的是提供具有整合素αvβ3拮抗活性、GPⅡb/Ⅲa拮抗活性和/或人体血小板聚集抑制活性的化合物，以及治疗整合素αvβ3介导的疾病和抑制血小板聚集的治疗剂。根据本发明的衍生物是式 (I) 所代表的化合物或其药学上可接受的盐或溶液： 其中 A 代表含有两个氮原子或类似物的五至七元杂环；X 和 Z 代表 CH 或氮原子；R4 和 R5 代表烷基、卤素或类似物；Q 代表 >C=O、>CH2 或类似物；R6 代表 H、烷基、芳烷基或类似物；R7 代表 H、炔基或类似物；R8 代表 H、取代氨基或类似物；R9 代表 H 或烷基；m 为 0 至 5；n 为 0 至 4；p 为 2 或 3；q 为 0 或 1。