2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile | 1818885-54-9

• 英文名称: 2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile
• 英文别名: 4-((1r,3r)-3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-chlorobenzonitrile；2-Chloro-4-[trans-3-amino-2,2,4,4-tetramethylcyclobutoxy]benzonitrile；4-(3-amino-2,2,4,4-tetramethylcyclobutyl)oxy-2-chlorobenzonitrile
• CAS: 1818885-54-9
• 化学式: C₁₅H₁₉ClN₂O
• 分子量: 278.782
• InChiKey: ZMQAQKRIAFCCDB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  59
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险性防范说明：
  P264,P280,P302+P352,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险性描述：
  H315,H319

反应信息

• 作为反应物：
  描述：

  2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile 在 铁粉 、 sodium cyanoborohydride 、 potassium carbonate 、 溶剂黄146 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 t-butyl 2-((5-(2-((1r,3r)-3-(3-chloro-4-cyanophenyloxy)-2,2,4,4-tetramethylcyclobutyl)-1-isoindoline-5-amino)pentane)oxy)acetate
  参考文献：
  名称：

  EP3957633

  摘要：

  公开号：
• 作为产物：
  描述：

  2-氯-4-氟苯腈 在 盐酸 、 sodium hydride 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 生成 2-chloro-4-(trans-3-amino-2,2,4,4-tetramethylcyclobutoxy)benzonitrile
  参考文献：
  名称：

  Systematic Structure Modifications of Imidazo[1,2-a]pyrimidine to Reduce Metabolism Mediated by Aldehyde Oxidase (AO)

  摘要：

  N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy] 2,2,4,4-tetramethylcyclobutyl}imidazo [1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.

  DOI：

  10.1021/jm2010942

文献信息

• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF ANDROGEN RECEPTOR
  申请人：Arvinas, Inc.

  公开号：US20180099940A1

  公开（公告）日：2018-04-12

  The present disclosure relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present disclosure is directed to compounds, which contain on one end a cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds Androgen Receptor, such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present disclosure exhibits a broad range of pharmacological activities associated with compounds according to the present disclosure, consistent with the degradation/inhibition of Androgen Receptor.

  本公开涉及双功能化合物，其用于降解和（抑制）雄激素受体。具体而言，本公开涉及包含一端结合到E3泛素连接酶的谷氨酰腺苷环配体，另一端结合到雄激素受体的部分的化合物，使得雄激素受体与泛素连接酶靠近，以实现雄激素受体的降解（和抑制）。本公开展示了与根据本公开涉及的化合物相关的广泛的药理活性范围，与雄激素受体的降解/抑制一致。
• CEREBLON LIGANDS AND BIFUNCTIONAL COMPOUNDS COMPRISING THE SAME
  申请人：Arvinas, Inc.

  公开号：US20180215731A1

  公开（公告）日：2018-08-02

  The description relates to cereblon E3 ligase binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.

  该描述涉及cereblon E3连接酶结合化合物，包括包含相同成分的双功能化合物，这些化合物作为靶向泛素化的调节剂具有实用价值，尤其是抑制剂，可降解和/或以其他方式抑制根据本公开的双功能化合物。特别是，该描述提供了化合物，其一端含有与cereblon E3泛素连接酶结合的配体，另一端含有与目标蛋白结合的部分，使目标蛋白位于泛素连接酶附近以降解（和抑制）该蛋白。可以合成表现出广泛药理活性的化合物，与几乎所有类型的靶向多肽的降解/抑制一致。
• 一类作为蛋白降解剂的化合物及其制备方法和医药用途
  申请人：江西济民可信集团有限公司

  公开号：CN113582974B

  公开（公告）日：2022-05-17

  本发明公开了一类作为蛋白降解剂的化合物及其制备方法和医药用途，具体地，本发明公开了式(Ⅰ)所示化合物及其药效上可接受的盐，以及该化合物作为雄激素受体(AR)、雌激素受体(ER)、含溴结构域蛋白质、TANK结合激酶等降解的应用。
• [EN] COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF THE ANDROGEN RECEPTOR<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION CIBLÉE DU RÉCEPTEUR DES ANDROGÈNES
  申请人：ARVINAS INC

  公开号：WO2016118666A1

  公开（公告）日：2016-07-28

  The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) Androgen Receptor. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds Androgen Receptor such that Androgen Receptor is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of Androgen Receptor. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of Androgen Receptor.

  本发明涉及双功能化合物，其可用于降解和（抑制）雄激素受体。具体而言，本发明涉及含有一端与泛素连接酶结合的VHL配体，另一端含有与雄激素受体结合的部分的化合物，使得雄激素受体与泛素连接酶靠近以实现雄激素受体的降解（和抑制）。本发明展示了与根据本发明的化合物相关的广泛的药理活性，与雄激素受体的降解/抑制一致。
• [EN] ANDROGEN RECEPTOR PROTEIN DEGRADERS<br/>[FR] AGENTS DE DÉGRADATION DE PROTÉINE DE RÉCEPTEUR DES ANDROGÈNES
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2022011205A1

  公开（公告）日：2022-01-13

  The present disclosure provides compounds represented by Formula I: A-L-B1 and the salts or solvates thereof, wherein A, L, and B1 are as defined in the specification. Compounds having Formula I are androgen receptor degraders useful for the treatment of cancer and other diseases.

  本公开提供由式I表示的化合物：A-L-B1及其盐或溶剂合物，其中A、L和B1如规范中所定义。具有式I的化合物是雄激素受体降解剂，用于治疗癌症和其他疾病。