(R)-2,3,4,5-Tetrahydro-4-(phenylsulfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine-7-carbonitrile | 195985-69-4

• 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)-2,3,4,5-Tetrahydro-4-(phenylsulfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine-7-carbonitrile
• 英文别名: (R)-7-cyano-2,3,4,5-tetrahydro-3-(phenylmethyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine；(3R)-4-(benzenesulfonyl)-3-benzyl-1,2,3,5-tetrahydro-1,4-benzodiazepine-7-carbonitrile
• CAS: 195985-69-4
• 化学式: C₂₃H₂₁N₃O₂S
• 分子量: 403.505
• InChiKey: FEJHSDQBQCVYPE-OAQYLSRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  81.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-咪唑甲醛 、 (R)-2,3,4,5-Tetrahydro-4-(phenylsulfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine-7-carbonitrile 在 溶剂黄146 、 三乙酰氧基硼氢化钠 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 1.0h， 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
• 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 、 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 79.5h， 生成 (R)-2,3,4,5-Tetrahydro-4-(phenylsulfonyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine-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

文献信息

• 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。
• 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。
• PROCESS FOR THE PREPARATION OF 3,7-DISUBSTITUTED-2,3,4,5- TETRAHYDRO-1H-1,4-BENZODIAZEPINE COMPOUNDS
  申请人：Bristol-Myers Squibb Company

  公开号：EP1443936A2

  公开（公告）日：2004-08-11
• EP1443936A4
  申请人：——

  公开号：EP1443936A4

  公开（公告）日：2006-01-11
• US6011029A
  申请人：——

  公开号：US6011029A

  公开（公告）日：2000-01-04