(3R)-1-(2-fluorophenyl)-3-(2-indolylcarbonylamino)-3,4,6,7-tetrahydropyrrolo<3,2,1-jk><1,4>benzodiazepin-4(3H)-one | 167820-10-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3R)-1-(2-fluorophenyl)-3-(2-indolylcarbonylamino)-3,4,6,7-tetrahydropyrrolo<3,2,1-jk><1,4>benzodiazepin-4(3H)-one
• 英文别名: N-[(3R)-1-(2-Fluorophenyl)-4-oxo-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]-1H-indole-2-carboxamide；N-[(11R)-9-(2-fluorophenyl)-12-oxo-1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7,9-tetraen-11-yl]-1H-indole-2-carboxamide
• CAS: 167820-10-2
• 化学式: C₂₆H₁₉FN₄O₂
• 分子量: 438.461
• InChiKey: WKJDXKWFGJWGAS-DEOSSOPVSA-N

物化性质

• 沸点：
  759.3±60.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.6
• 氢给体数：
  2
• 氢受体数：
  4

制备方法与用途

生物活性

CHEMBL333994 是一种有效的口服缩胆囊素 A (CCK-A) 拮抗剂，其 IC50 值为 0.67 nM。

靶点

IC50: 0.67 nM (CCK-A)

反应信息

• 作为产物：
  描述：

  2-氟苯腈 在 Ru-carbon 吡啶 、 三氯化铝 、 O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 potassium tert-butylate 、 氢气 、 三氯化硼 、 N,N-二异丙基乙胺 、 亚硝酸异戊酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 生成 (3R)-1-(2-fluorophenyl)-3-(2-indolylcarbonylamino)-3,4,6,7-tetrahydropyrrolo<3,2,1-jk><1,4>benzodiazepin-4(3H)-one
  参考文献：
  名称：

  Synthesis and structure–activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1- hi ]indoles: novel PDE4 inhibitors

  摘要：

  A novel series of benzodiazepine derivatives have been discovered as inhibitors of PDE4 enzymes. We have found that our compounds are selective versus other PDE enzymes, and that the activity can be modulated by specific structural modifications. One compound exhibited a strong eosinophilic infiltration inhibiting action on sensitized Brown-Norway rats (compound 9, 5.1 mg/kg p.o.), moreover this compound is not emetic at 3 mg/kg i.v. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(99)00573-9

文献信息

• Studies on a Novel, Potent and Orally Effective Cholecystokinin A Antagonist, FK-480. Synthesis and Structure-Activity Relationships of FK-480 and Related Compounds.
  作者：Yoshinari SATOH、Teruaki MATSUO、Hajime SOGABE、Harunobu ITOH、Toshiji TADA、Takayoshi KINOSHITA、Keizou YOSHIDA、Takao TAKAYA

  DOI：10.1248/cpb.42.2071

  日期：——

  We prepared various novel tricyclic 1, 4-benzodiazepine derivatives as cholecystokinin (CCK) A antagonists, which were evaluated preliminarily for inhibition of <125>I-CCK-8 binding to rat pancreatic membranes in vitro and inhibiting effect on CCK-8-induced inhibition of charcoal meal gastric emptying in mice. On the basis of structure-activity relationship (SAR) studies, as well as the stability and availability of the starting materials of those compounds, (S)-N-[1-(2-fluorophenyl)-3, 4, 6, 7-tetrahydro-4-oxo-pyrrolo[3, 2, 1-jk][1, 4]benzodiazepin-3-yl]-1H-indole-2-carboxamide (9f, FK-480) was selected as a candidate compound for further evaluation. The absolute configuration of the precursor of FK-480, (3S)-amino-1, 4-benzodiazepine derivative ((S)-8a, R1=F) was determined by an X-ray crystallographic study of its ureido derivative with (S)-α-methylbenzyl isocyanate.FK-480 is now undergoing clinical studies for the treatment of chronic pancreatitis.

  我们制备了多种新型三环1,4-苯并二氮杂䓬衍生物作为胆囊收缩素（CCK）A受体拮抗剂，并初步评估了它们对<125>I-CCK-8与大鼠胰腺膜体外结合的抑制作用以及对CCK-8诱导的小鼠活性炭餐胃排空的抑制作用。基于构效关系（SAR）研究以及这些化合物的起始原料的稳定性和可获得性，我们选择了(S)-N-[1-(2-氟苯基)-3,4,6,7-四氢-4-氧代-吡咯并[3,2,1-jk][1,4]苯并二氮杂䓬-3-基]-1H-吲哚-2-甲酰胺（9f, FK-480）作为候选化合物进行进一步评估。通过与(S)-α-甲基苄基异氰酸酯的脲基衍生物的X射线晶体学研究，确定了FK-480前体(3S)-氨基-1,4-苯并二氮杂䓬衍生物（(S)-8a, R1=F）的绝对构型。FK-480目前正在进行治疗慢性胰腺炎的临床研究。
• Tricyclic compounds, processes for their preparation and pharmaceutical compositions comprising them
  申请人：FUJISAWA PHARMACEUTICAL CO., LTD.

  公开号：EP0360079B1

  公开（公告）日：1994-02-02
• US4981847A
  申请人：——

  公开号：US4981847A

  公开（公告）日：1991-01-01
• US5155101A
  申请人：——

  公开号：US5155101A

  公开（公告）日：1992-10-13
• US5248679A
  申请人：——

  公开号：US5248679A

  公开（公告）日：1993-09-28