6-(4-chlorobenzoyl)-4-(3-bromo-phenyl)-1-methyl-1H-quinolin-2-one | 501421-82-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 英文名称: 6-(4-chlorobenzoyl)-4-(3-bromo-phenyl)-1-methyl-1H-quinolin-2-one
• 英文别名: 4-(3-Bromophenyl)-6-(4-chlorobenzoyl)-1-methylquinolin-2(1H)-one；4-(3-bromophenyl)-6-(4-chlorobenzoyl)-1-methylquinolin-2-one
• CAS: 501421-82-5
• 化学式: C₂₃H₁₅BrClNO₂
• 分子量: 452.735
• InChiKey: HOBHZKNTZMLGCV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  6-(4-chlorobenzoyl)-4-(3-bromo-phenyl)-1-methyl-1H-quinolin-2-one 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 正丁基锂 、 三乙胺 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 25.0h， 生成 (R,S)-6-[(4-chlorophenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-(3-hydroxy-3-methylbutyn-1-yl)-phenyl)-1-methyl-1H-quinolin-2-one
  参考文献：
  名称：

  合成法呢基转移酶抑制剂候选药物的简化工艺

  摘要：

  作为快节奏肿瘤学项目的一部分，喹啉酮 1 被发现并开发为一种有效的法尼基转移酶抑制剂，用于治疗癌症。最初的合成受到冗长的线性序列和后期色谱分辨率的影响，被认为不适合大规模生产。在研究解决这些问题的替代路线的同时，原始合成得到了不断改进和精简。这种启用的路线提供了支持早期毒理学和临床研究所需的药物物质的及时生产。对该过程进行了多次迭代，由于这些改进，开发了一种有效的四步序列，用于从容易获得的外包中间体 5 以 26% 的总产率合成 d-酒石酸喹啉酮 2，包括一个经典的决议。该合成的关键特征包括卡斯特罗-史蒂文斯偶联、咪唑格氏加成以及伴随的经典分辨率/最终...

  DOI：

  10.1021/op049935g
• 作为产物：
  描述：

  4-氯-4-硝基苯甲酮 在 盐酸 、 4-二甲氨基吡啶 、 titanium(III) chloride 、 苄基三乙基氯化铵 、 对甲苯磺酸 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 62.0h， 生成 6-(4-chlorobenzoyl)-4-(3-bromo-phenyl)-1-methyl-1H-quinolin-2-one
  参考文献：
  名称：

  合成法呢基转移酶抑制剂候选药物的简化工艺

  摘要：

  作为快节奏肿瘤学项目的一部分，喹啉酮 1 被发现并开发为一种有效的法尼基转移酶抑制剂，用于治疗癌症。最初的合成受到冗长的线性序列和后期色谱分辨率的影响，被认为不适合大规模生产。在研究解决这些问题的替代路线的同时，原始合成得到了不断改进和精简。这种启用的路线提供了支持早期毒理学和临床研究所需的药物物质的及时生产。对该过程进行了多次迭代，由于这些改进，开发了一种有效的四步序列，用于从容易获得的外包中间体 5 以 26% 的总产率合成 d-酒石酸喹啉酮 2，包括一个经典的决议。该合成的关键特征包括卡斯特罗-史蒂文斯偶联、咪唑格氏加成以及伴随的经典分辨率/最终...

  DOI：

  10.1021/op049935g

文献信息

• QUINOLINONE FARNESYL TRANSFERASE INHIBITORS FOR THE TREATMENT OF SYNUCLEINOPATHIES AND OTHER INDICATIONS
  申请人：Lansbury, JR. Peter T.

  公开号：US20090253655A1

  公开（公告）日：2009-10-08

  Novel quinolinone farnesyl transferase inhibitors are provided. These new compounds are useful in the treatment or prevention of synucleinopathies, such as Parkinson's Disease, Diffuse Lewy Body Disease, multiple system atrophy, and disorders of brain iron concentration including pantothenate kinase-associated neurodegeneration (e.g., PANK1), or other neurodegenerative/neurological diseases. Provided compounds are also useful in the treatment of proliferative diseases such as cancer, and in the treatment of neurological diseases, such as cognitive impairment, depression, and anxiety. The treatment including administering to a subject a therapeutically effective amount of an inventive farnesyl transferase inhibitor compound.

  提供了新型喹诺酮法尼西基转移酶抑制剂。这些新化合物在治疗或预防突触核蛋白病（如帕金森病、弥漫性莱维小体病、多系统萎缩和脑铁浓度紊乱疾病，包括泛酰辅酶A激酶相关的神经退行性疾病（例如PANK1）或其他神经退行性/神经系统疾病方面具有用处。提供的化合物还可用于治疗癌症等增生性疾病，以及治疗认知障碍、抑郁症和焦虑等神经系统疾病。治疗包括向受试者施用一种创新的法尼西基转移酶抑制剂化合物的治疗有效剂量。
• TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR
  申请人：LANSBURY, JR. PETER T.

  公开号：US20110060005A1

  公开（公告）日：2011-03-10

  Methods and pharmaceutical compositions comprising a low dose of a farnesyl transferase inhibitor useful in the treatment of proteinopathies and mitochondrial disorders are provided. These low doses are below the doses used in oncological treatments for which these compounds were initially designed. The treatment includes administering to a subject an amount of a farnesyl transferase inhibitor, wherein the amount administered is sufficient to stimulate mitophagy in said subject. Treatments in accordance with the present invention may also include an acetylcholinesterase inhibitor, an activator of neurotrophic receptors, an NMDA anatagonist, an amyloid deposit inhibitor, an antipsychotic agent, an antidepressant, an anxiolytic, or an antioxidant.

  本发明提供了一种低剂量法尼酰转移酶抑制剂的方法和制药组合物，用于治疗蛋白质病和线粒体疾病。这些低剂量低于最初设计这些化合物用于肿瘤治疗的剂量。该治疗方法包括向受试者施用足够的法尼酰转移酶抑制剂，以刺激该受试者的线粒体自噬。根据本发明的治疗方法还可以包括乙酰胆碱酯酶抑制剂、神经营养因子受体激活剂、NMDA拮抗剂、淀粉样沉积抑制剂、抗精神病药物、抗抑郁药、抗焦虑药或抗氧化剂。
• TREATMENT OF PROTEINOPATHIES USING A FARNESYL TRANSFERASE INHIBITOR
  申请人：Lansbury, JR. Peter T.

  公开号：US20110294794A1

  公开（公告）日：2011-12-01

  Methods and pharmaceutical compositions comprising a low dose of a farnesyl transferase inhibitor useful in the treatment of proteinopathies are provided. These low doses are below the doses used in oncological treatments for which these compounds were initially designed. The treatment includes administering to a subject in need thereof a therapeutically effective amount of a farnesyl transferase inhibitor, wherein the amount is effective to inhibit the farnesylation of a non-Ras FTase substrate involved in the autophagy pathway without substantially affecting the farnesylation of Ras or other oncology related substrates. Treatments in accordance with the present invention may also include an acetylcholinesterase inhibitor, an activator of neurotrophic receptors, an NMDA anatagonist, an amyloid deposit inhibitor, an antipsychotic agent, an antidepressant, an anxiolytic, or an antioxidant.

  本发明提供了一种低剂量法尼醇转移酶抑制剂及其制药组合物，用于治疗蛋白病。这些低剂量低于最初设计这些化合物用于肿瘤治疗所使用的剂量。治疗包括向需要治疗的受体中注射治疗有效量的法尼醇转移酶抑制剂，其中该量能够有效抑制参与自噬通路的非Ras FTase底物的法尼酰化，而不会对Ras或其他与肿瘤相关的底物的法尼酰化产生明显影响。按照本发明的治疗方法还可以包括乙酰胆碱酯酶抑制剂、神经营养因子受体激活剂、NMDA拮抗剂、淀粉样沉积抑制剂、抗精神病药物、抗抑郁药物、抗焦虑药物或抗氧化剂。
• Enantiomers of 6-[(4-chloro-phenyl)- hydroxy-(3-methyl-3h-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1- methyl-1h-quinolin-2-one and salts thereof, useful in the treatment of cancer
  申请人：Pfizer Inc.

  公开号：US20030114487A1

  公开（公告）日：2003-06-19

  This invention relates to the enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-y)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl) -phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and said prodrugs, that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. The invention also relates to processes for the production of enantiomerically pure or optically enriched (+)- or (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl )-phenyl]-1 -methyl-1H-quinol in-2-one enantiomers from a mixture containing two enantiomers using continuous chromatography. The invention further relates to the L-(+)-tartaric acid or (S)-(−)-1 1'-binapthyl-2,2'-diyl hydrogenphosphate salts of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one.

  本发明涉及 6-[(4-氯-苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3-羟基-3-甲基-丁-1-炔基)-苯基&rsqb；-1-甲基-1H-喹啉-2-酮、其原药，以及所述化合物和所述原药的药学上可接受的盐和溶液，可用于治疗哺乳动物的过度增殖性疾病，如癌症。本发明还涉及生产对映体纯的或光学富集的(+)-或(-)-6-[(4-氯苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基&rsqb；-4-[3-(3-羟基-3-甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮对映体。本发明还涉及 L-(+)-酒石酸或(S)-(-)-1 1'-联萘-2,2'-二基磷酸氢盐的(+)-6-&lsqb；(4-氯苯基)-羟基-(3-甲基-3H-咪唑-4-基)-甲基]-4-[3-(3-羟基-3-甲基-丁-1-炔基)-苯基]-1-甲基-1H-喹啉-2-酮的磷酸氢盐。
• Enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one and salts thereof, useful in the treatment of cancer
  申请人：Pfizer Inc.

  公开号：US20040192727A1

  公开（公告）日：2004-09-30

  This invention relates to the enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof, and pharmaceutically acceptable salts and solvates of said compounds and said prodrugs, that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. The invention also relates to processes for the production of enantiomerically pure or optically enriched (+)- or (−)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one enantiomers from a mixture containing two enantiomers using continuous chromatography. The invention further relates to the L-(+)-tartaric acid or (S)-(−)-1,1′-binapthyl-2,2′-diyl hydrogenphosphate salts of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one.