2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole | 1022249-15-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole
• 英文别名: 2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-1-methyl-7-pentan-3-ylbenzimidazole
• CAS: 1022249-15-5
• 化学式: C₂₀H₂₁BrCl₂N₂O
• 分子量: 456.21
• InChiKey: INUDDVORWHQJQY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.8
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  27
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole 在 正丁基锂 、 1-羟基-1H-苯并三唑铵盐 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.25h， 生成 3-chloro-4-((4-chloro-7-(1-ethylpropyl)-1-methyl-1Hbenzimidazol-2-yl)oxy)-5-methylbenzamide
  参考文献：
  名称：

  Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

  摘要：

  Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 mu L/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering win vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 mu L/min/mg) than compound 1. Compound 24d demonstrated potent CRF1 binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CREI receptor. Orally administered compound 24d (6-24 mu mol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.11.011
• 作为产物：
  描述：

  2-氯-3-硝基苯甲酸甲酯 在 盐酸 、 N-氯代丁二酰亚胺 、 偶氮二异丁腈 、 palladium 10% on activated carbon 、 氢气 、 lithium 、 potassium carbonate 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 乙醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 106.0h， 生成 2-(4-bromo-2-chloro-6-methylphenoxy)-4-chloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole
  参考文献：
  名称：

  Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist

  摘要：

  Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 mu L/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering win vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 mu L/min/mg) than compound 1. Compound 24d demonstrated potent CRF1 binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CREI receptor. Orally administered compound 24d (6-24 mu mol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.11.011

文献信息

• BENZIMIDAZOLE COMPOUNDS
  申请人：Aso Kazuyoshi

  公开号：US20100056515A1

  公开（公告）日：2010-03-04

  There is provided a compound of the formula (I): wherein R 1 is an optionally substituted C 1-10 alkyl; R 2 is H, or a C 1-6 alkyl which may be substituted with 1 to 3 substituents; R 3 is a 5- or 6-membered aromatic group which may be substituted with 1 to 5 substituents, wherein the 5- or 6-membered aromatic group may be fused with a 5- or 6-membered ring which may be substituted with 1 to 3 C 1-6 alkyls; R 4 is a hydrogen, a halogen, a hydroxy, a cyano, a C 1-6 alkyl or a C 1-6 alkoxy; Z is —O—, —S—, —SO—, —SO 2 —, or —NR 5 — wherein R 5 is a hydrogen or a C 1-6 alkyl; or a salt thereof or a prodrug thereof, which have CRF receptor antagonist activity and use thereof.

  提供了一个式子(I)的化合物： 其中，R1是可选取代的C1-10烷基；R2是氢，或者是一个C1-6烷基，该烷基可以用1至3个取代基取代；R3是一个5-或6-成员芳香基团，可以用1至5个取代基取代，其中5-或6-成员芳香基团可以与一个5-或6-成员环融合，该环可以用1至3个C1-6烷基取代；R4是氢、卤素、羟基、氰基、C1-6烷基或C1-6烷氧基；Z是-O-、-S-、-SO-、-SO2-或-NR5-，其中R5是氢或C1-6烷基；或其盐或前药，具有CRF受体拮抗活性和使用方法。
• WO2008/51533
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] BENZIMIDAZOLE COMPOUNDS<br/>[FR] COMPOSÉS DE BENZIMIDAZOLE
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2008051533A2

  公开（公告）日：2008-05-02

  [EN] There is provided a compound of the formula (1) wherein R¹ is an optionally substituted C_1-10 alkyl; R² is H, or a C_1-6 alkyl which may be substituted with 1 to 3 substituents; R³ is a 5- or 6-membered aromatic group which may be substituted with 1 to 5 substituents, wherein the 5- or 6-membered aromatic group may be fused with a 5- or 6- membered ring which may be substituted with 1 to 3 C_1-6 alkyls; R⁴ is a hydrogen, a halogen, a hydroxy, a cyano, a C_1-6 alkyl or a C_1-6 alkoxy; Z is -O-, -S-, -SO-, -SO₂-, or - NR⁵- wherein R⁵ is a hydrogen or a C_1-6 alkyl; or a salt thereof or a prodrug thereof, which have CRF receptor antagonist activity and use thereof.
  [FR] L'invention concerne un composé de la formule (I) dans laquelle : R¹ est C_1-10 alkyle éventuellement substitué; R² est H, ou un C_1-6 alkyle qui peut être substitué par 1 à 3 substituants ; R³ est un groupe aromatique à 5 ou 6 éléments qui peut être substitué par 1 à 5 substituants, le groupe aromatique à 5 ou 6 éléments pouvant être fusionné avec un anneau à 5 ou 6 éléments qui peut être substitué par 1 à 3 C_1-6 alkyles; R⁴ représente hydrogène, un halogène, un hydroxy, un cyano, un C_1-6 alkyle ou un C_1-6 alcoxy; et Z représente -O-, -S-, -SO-, -SO₂-, ou - NR⁵-, R⁵ représentant hydrogène ou un C_1-6 alkyle. L'invention concerne également un sel de ce composé, ou un pro-médicament de celui-ci, possédant une activité antagoniste de récepteur de CRF, ainsi que leur utilisation.
• Discovery of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole, a novel CRF1 receptor antagonist
  作者：Michiyo Mochizuki、Takuto Kojima、Katsumi Kobayashi、Etsuo Kotani、Yuji Ishichi、Naoyuki Kanzaki、Hideyuki Nakagawa、Teruaki Okuda、Yohei Kosugi、Takahiko Yano、Yuu Sako、Maiko Tanaka、Kazuyoshi Aso

  DOI：10.1016/j.bmc.2016.11.011

  日期：2017.3

  Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF1) receptor (IC50 = 9.5 nM) and in vitro antagonistic activity (IC50 = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 mu L/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure-activity relationship (SAR) studies considering win vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 mu L/min/mg) than compound 1. Compound 24d demonstrated potent CRF1 binding inhibitory activity (IC50 = 4.1 nM), in vitro antagonistic activity (IC50 = 44 nM), and slow dissociation from the CREI receptor. Orally administered compound 24d (6-24 mu mol/kg) showed ex vivo CRF1 receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF1 receptor antagonists and the pharmacological profiles of compound 24d. (C) 2016 Elsevier Ltd. All rights reserved.