(R)-2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione | 1584154-99-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: (R)-2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione
• 英文别名: 2-[2-[(2R)-oxiran-2-yl]ethyl]isoindole-1,3-dione
• CAS: 1584154-99-3
• 化学式: C₁₂H₁₁NO₃
• 分子量: 217.224
• InChiKey: KPQFNAHIBWPUSX-MRVPVSSYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  49.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione 在 二乙胺基三氟化硫 作用下， 以 二氯甲烷 、 异丙醇 为溶剂， 反应 24.0h， 生成 (R)-2-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-fluorobutyl)isoindoline-1,3-dione
  参考文献：
  名称：

  Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  摘要：

  The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin- I -yl) -3-hydroxybutyl)1H-indole-2carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutylproduct (8).

  DOI：

  10.1021/ml500006v
• 作为产物：
  描述：

  N-(3,4-环氧基丁基)邻苯二甲酰亚胺 在 (R,R)-N,N′-bis(3,5-di-tertbutylsalicylidene)-1,2-cyclohexanediaminocobalt(III) acetate 作用下， 以 四氢呋喃 为溶剂， 反应 72.5h， 以30%的产率得到(R)-2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione
  参考文献：
  名称：

  Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

  摘要：

  The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin- I -yl) -3-hydroxybutyl)1H-indole-2carboxamide ((R)-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). (R)-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than (R)-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutylproduct (8).

  DOI：

  10.1021/ml500006v

文献信息

• Investigation of Novel Primary and Secondary Pharmacophores and 3-Substitution in the Linking Chain of a Series of Highly Selective and Bitopic Dopamine D₃ Receptor Antagonists and Partial Agonists
  作者：Anver Basha Shaik、Vivek Kumar、Alessandro Bonifazi、Adrian M. Guerrero、Sophie L. Cemaj、Alexandra Gadiano、Jenny Lam、Zheng-Xiong Xi、Rana Rais、Barbara S. Slusher、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.9b00607

  日期：2019.10.24

  with a 3-F in the linker between the primary pharmacophore (PP) and secondary pharmacophore (SP). Among the 3-F-compounds, 9b demonstrated the highest D3R binding affinity (Ki = 0.756 nM) and was 327-fold selective for D3R over D2R. In addition, modification of the PP or SP with a 3,4-(methylenedioxy)phenyl group was also examined. Further, an enantioselective synthesis as well as chiral HPLC methods were

  多巴胺 D 3受体 (D 3 R) 在包括物质使用障碍 (SUD) 在内的神经精神疾病中起关键作用。最近，我们报道了一系列N- (3-羟基-4-(4-苯基哌嗪-1-基)丁基)-1 H-吲哚-2-甲酰胺类似物作为高亲和力和选择性的 D 3 R 先导分子用于治疗阿片类药物使用障碍 (OUD)。进一步优化导致一系列类似物在主要药效团 (PP) 和次要药效团 (SP) 之间的接头中用 3-F 代替 3-OH。在 3-F 化合物中，9b表现出最高的 D 3 R 结合亲和力（K i= 0.756 nM)，对 D 3 R的选择性比对 D 2 R的选择性高 327 倍。此外，还检查了用 3,4-(亚甲二氧基)苯基对 PP 或 SP 的修饰。此外，还开发了对映选择性合成和手性 HPLC 方法，以得到四种先导化合物的对映纯R - 和S - 对映异构体。脱靶结合亲和力、功能功效和代谢谱揭示了 D 3 R 选择性
• [EN] DOPAMINE D3 RECEPTOR SELECTIVE ANTAGONISTS/PARTIAL AGONISTS; METHOD OF MAKING; AND USE THEREOF<br/>[FR] ANTAGONISTES/AGONISTES PARTIELS SÉLECTIFS DU RÉCEPTEUR D3 DE LA DOPAMINE ; PROCÉDÉ DE PRÉPARATION ; ET UTILISATION ASSOCIÉE
  申请人：US HEALTH

  公开号：WO2017160552A1

  公开（公告）日：2017-09-21

  Disclosed herein novel dopamine D3 receptor selective antagonists/partial agonists compounds with high affinity and metabolic stability useful for the treatment of psychiatric and neurological disorders and as research and diagnostic tools. Also disclosed are methods of making the compounds.

  本文披露了一种新型多巴胺D3受体选择性拮抗剂/部分激动剂化合物，具有高亲和力和代谢稳定性，可用于治疗精神疾病和神经系统疾病，并作为研究和诊断工具。还披露了制备这些化合物的方法。
• TRICYCLIC COMPOUND DERIVATIVES USEFUL IN THE TREATMENT OF NEOPLASTIC DISEASES, INFLAMMATORY DISORDERS AND IMMUNOMODULATORY DISORDERS
  申请人：GREGOR Vlad Edward

  公开号：US20140228350A1

  公开（公告）日：2014-08-14

  Provided are compounds of the formula (I): or a stereoisomer, tautomer, salt, hydrate or prodrug thereof that modulate tyrosine kinase activity, compositions comprising the compounds and methods of their use.

  提供的化合物公式(I)或其立体异构体、互变异构体、盐、水合物或前药，可调节酪氨酸激酶活性，包括该化合物的组合物和使用方法。
• Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof
  申请人：THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：US11299476B2

  公开（公告）日：2022-04-12

  Disclosed herein novel dopamine D3 receptor selective antagonists/partial agonists compounds with high affinity and metabolic stability useful for the treatment of psychiatric and neurological disorders and as research and diagnostic tools. Also disclosed are methods of making the compounds.

  本披露内容涉及一种新型的高亲和力和代谢稳定的大麻素D3受体选择性拮抗剂/部分激动剂化合物，这些化合物可用于治疗精神和神经系统疾病，以及作为研究和诊断工具。同时，本披露还涉及制备这些化合物的方法。
• Dopamine D3 receptor selective antagonists/partial agonists and uses thereof
  申请人：THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

  公开号：US11337971B2

  公开（公告）日：2022-05-24

  Disclosed herein are novel methods of treating pain in a patient in need thereof by providing to the patient a selective dopamine D3 receptor antagonist/partial agonist which when used with an opioid analgesic, can mitigate the development of opioid dependence, by preventing the need for dose escalation while either maintaining the opioid analgesic effect or providing analgesia with a lower dose of the opioid. In addition, the D3 antagonists/partial agonists described herein may be used to augment the effectiveness of current Medication Assisted Treatment regimens (e.g. methadone or buprenorphine) for the treatment of opioid use disorders.

  本文公开了治疗有需要的患者疼痛的新方法，通过向患者提供选择性多巴胺 D3 受体拮抗剂/部分激动剂，当与阿片类镇痛药一起使用时，可以通过防止剂量升级的需要，同时保持阿片类镇痛效果或以较低剂量的阿片类药物提供镇痛效果，从而减轻阿片类药物依赖性的发展。此外，本文所述的 D3 拮抗剂/部分激动剂可用于增强当前药物辅助治疗方案（如美沙酮或丁丙诺啡）治疗阿片类药物使用障碍的效果。