(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine | 195987-42-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine
• 英文别名: (3R)-4-(benzenesulfonyl)-3-benzyl-1-(1H-imidazol-5-ylmethyl)-3,5-dihydro-2H-1,4-benzodiazepine-7-carbonitrile
• CAS: 195987-42-9
• 化学式: C₂₇H₂₅N₅O₂S
• 分子量: 483.594
• InChiKey: RHXLRBJBYOPEAL-RUZDIDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (R)-7-bromo-2,3,4,5-tetrahydro-3-(phenylmethyl)-1H-1,4-benzodiazepine-2,5-dione 在 N-甲基吡咯烷酮 、 硼烷四氢呋喃络合物 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 80.5h， 生成 (R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine
  参考文献：
  名称：

  Discovery of (R)-7-Cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a Farnesyltransferase Inhibitor with Potent Preclinical Antitumor Activity

  摘要：

  Continuing structure-activity studies were performed on the 2,3,4,5-tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepine farnesyltransferase (FT) inhibitors. These studies demonstrated that; a 3(R)-phenylmethyl group, a hydrophilic 7-cyano group, and a 4-sulfonyl group bearing a variety of substituents provide low;nanomolar FT inhibitors with cellular activity at concentrations below 100 nM. Maximal in vivo activity in the mutated K-Ras bearing HCT-116 human colon tumor model was achieved with analogues carrying hydrophobic side chains such as propyl, phenyl, or thienyl attached to the N-4 sulfonyl group. Several such compounds achieved curative efficacy when given orally in this model. On the basis of its excellent preclinical antitumor activity and promising pharmacokinetics, compound 20 (BMS-214662, (R)-7-cyano-2;3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)- -1H-1,4-benzodiazepine) has been advanced into human clinical trials.

  DOI：

  10.1021/jm000248z

文献信息

• Synergistic methods and compositions for treating cancer
  申请人：——

  公开号：US20020002162A1

  公开（公告）日：2002-01-03

  The present invention provides a synergistic method for the treatment of cancer which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of: (1) at least agent selected from the group consisting of cytotoxic agents and cytostatic agents, and (2) a compound of formula I 1 or a pharmaceutically acceptable salt thereof. The present invention further provides a pharmaceutical composition for the synergistic treatment of cancer which comprises at least one agent selected from the group consisting of antiproliferative cytotoxic agents and antiproliferative cytostatic agents, a compound of formula I, and a pharmaceutically acceptable carrier.

  本发明提供了一种治疗癌症的协同方法，其包括向需要该方法的哺乳动物物种施用以下的协同、治疗有效量：(1) 选择自细胞毒性剂和细胞增殖抑制剂组的至少一种药剂，和(2) 公式I的化合物或其药学上可接受的盐。本发明还提供了一种用于协同治疗癌症的药物组合物，其包括至少一种选择自抗增殖细胞毒性剂和抗增殖细胞增殖抑制剂组的药剂，公式I的化合物和药学上可接受的载体。
• Methods for the treatment of synucleinopathies
  申请人：Lansbury T. Peter

  公开号：US20050272722A1

  公开（公告）日：2005-12-08

  Methods are provided of treating synucleinopathies, such as Parkinson's Disease, Diffuse Lewy Body Disease and Multiple System Atrophy, comprising administering to a synucleinopathic subject a farnesyl transferase inhibitor compound.

  提供了一种治疗突触核蛋白病的方法，例如帕金森病、弥漫性Lewy体病和多系统萎缩症，包括向突触核蛋白病患者施用一种法尼酰转移酶抑制剂化合物。
• Process for the preparation of 3,7-disubstituted-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine compounds
  申请人：——

  公开号：US20030162965A1

  公开（公告）日：2003-08-28

  Methods for the synthesis of benzodiazepine compounds having farnesyl protein transferase inhibitory activity.

  合成具有法尼酰蛋白转移酶抑制活性的苯二氮平类化合物的方法。
• [EN] INHIBITORS OF FARNESYL PROTEIN TRANSFERASE<br/>[FR] INHIBITEURS DE LA FARNESYL-TRANSFERASE
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：WO1997030992A1

  公开（公告）日：1997-08-28

  (EN) This invention relates to compounds that inhibit farnesyl-protein transferase and ras protein farnesylation, thereby making them useful as anti-cancer agents. The compounds are also useful in the treatment of diseases, other than cancer, associated with signal transduction pathways operating through ras and those associated with proteins other than ras that are also post-translationally modified by the enzyme farnesyl protein transferase. The compounds may also act as inhibitors of other prenyl transferases, and thus be effective in the treatment of diseases associated with other prenyl modifications of proteins.(FR) La présente invention concerne des composés inhibant la farnésyl-transférase et la farnésylation de la protéine Ras, ce qui en fait d'utiles agents anticancéreux. Ces composés conviennent également particulièrement au traitement de maladies autres que le cancer, associées aux canaux de transduction de signaux par la protéine Ras, et de maladies associées à des protéines autres que les protéines Ras qui subissent une modification post-translationnelle sous l'effet de la farnésyl-transférase. Ces composés se comportent également comme inhibiteurs d'autres prényl-transférases, et peuvent de ce fait convenir au traitement d'affections associées à d'autres modifications prényl des protéines.

  （中文翻译）本发明涉及抑制法尼醇-蛋白质转移酶和ras蛋白质法尼醇化的化合物，因此使它们成为有用的抗癌剂。这些化合物还适用于治疗与ras信号转导途径以及其他被酶法尼醇蛋白质转移酶后翻译修饰的蛋白质相关的疾病，除了癌症。这些化合物还可以作为其他异戊二烯基转移酶的抑制剂，因此在治疗与其他蛋白质的异戊二烯基修饰相关的疾病方面也很有效。
• Production of tertiary amines by reductive amination
  申请人：——

  公开号：US20020169313A1

  公开（公告）日：2002-11-14

  A process for the production of tertiary amines by reductive amination of carbonyl compounds with secondary amines in the presence of a water scavenger, preferably trifluoroacetic acid anhydride, is disclosed. This process has applications in the preparation of imidazole-containing benzodiazepines, which are inhibitors of farnesyl protein transferase.

  本发明涉及一种通过还原胺化法在次级胺的存在下，采用水清除剂（优选三氟乙酸酐）来制备三级胺的方法。该方法适用于制备含咪唑的苯二氮平类化合物，其为法尼酰基蛋白转移酶的抑制剂。