(R)-7-Cyano-1,2,3,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1,4-benzodiazepine

• 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-1,2,3,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1,4-benzodiazepine
• 英文别名: (3R)-3-benzyl-1-(1H-imidazol-5-ylmethyl)-2,3,4,5-tetrahydro-1,4-benzodiazepine-7-carbonitrile
• 化学式: C₂₁H₂₁N₅
• 分子量: 343.431
• InChiKey: HTEGPLHGRBAKJT-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  67.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-7-Cyano-1,2,3,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-1,4-benzodiazepine 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 (R)-3-Benzyl-4-(2-dimethylamino-ethanesulfonyl)-1-(3H-imidazol-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carbonitrile
  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
• 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 、 盐酸 、 硼烷四氢呋喃络合物 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 48.5h， 生成 (R)-7-Cyano-1,2,3,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4H-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

• 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。
• [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。
• 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。
• Inhibitors of farnesyl protein transferase
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP1481975A1

  公开（公告）日：2004-12-01

  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.

  本发明涉及抑制法尼基蛋白转移酶和 ras 蛋白法尼基化，从而使其可用作抗癌剂的化合物。除癌症外，这些化合物还可用于治疗与通过 ras 运作的信号转导通路有关的疾病，以及与同样经法尼基蛋白转移酶翻译后修饰的 ras 以外的蛋白质有关的疾病。这些化合物还可以作为其他前炔基转移酶的抑制剂，从而有效治疗与蛋白质的其他前炔基化修饰有关的疾病。
• INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0892797A1

  公开（公告）日：1999-01-27