methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate | 851889-13-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate
• 英文别名: methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate；methyl 1-methyl-2-oxo-1,3-dihydro-1H-benzimidazole-7-carboxylate；methyl 1-methyl-2-oxo-1,3-dihydro-2H-benzimidazole-7-carboxylate；methyl 3-methyl-2-oxo-1H-benzimidazole-4-carboxylate
• CAS: 851889-13-9
• 化学式: C₁₀H₁₀N₂O₃
• 分子量: 206.201
• InChiKey: YPYNRANLVWDZPD-UHFFFAOYSA-N

物化性质

• 密度：
  1.288±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate 在 盐酸 、 N-氯代丁二酰亚胺 、 偶氮二异丁腈 、 lithium 、 potassium carbonate 、 三氯氧磷 作用下， 以 四氢呋喃 、 四氯化碳 、 乙醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 97.0h， 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
• 作为产物：
  描述：

  2-氯-3-硝基苯甲酸甲酯 在 palladium on activated charcoal 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate
  参考文献：
  名称：

  发现四唑酰胺-苯并咪唑-2-酮作为新型 4-羟基苯基丙酮酸双加氧酶抑制剂

  摘要：

  4-羟基苯丙酮酸双加氧酶（HPPD，EC 1.13.11.27）因其独特的生物学功能而成为最有价值的除草剂靶标之一。为了寻找具有良好生物学性能的 HPPD 抑制剂，我们采用基于结构的药物设计策略设计并合成了一系列新型四唑酰胺-苯并咪唑-2-酮类化合物。合成的化合物中，1-(2-氯苄基)-3-甲基-N- (1-甲基-1H-四唑-5-基)-2-氧代-2,3-二氢-1H-苯并[ d] ]咪唑-4-甲酰胺， 25 ，IC 50 = 10 nM，被认为是最出色的 HPPD 抑制剂，其对拟南芥HPPD ( At HPPD) 的抑制效力比甲基磺草酮 (IC 50 = 363 nM) 增加了 36 倍以上）。我们的At HPPD- 25配合物表明，四唑环上的一个氮原子和酰胺基上的氧原子与金属离子形成了经典的二齿螯合相互作用，苯并咪唑-2-一环与金属离子形成了紧密的π-π堆积相互作用。 Phe381和Phe

  DOI：

  10.1021/acs.jafc.3c06798

文献信息

• [EN] THIAZOLE DERIVATIVES AS PROTEIN KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE THIAZOLE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：SCHERING CORP

  公开号：WO2009058728A1

  公开（公告）日：2009-05-07

  The present invention relates to novel Thiazole Derivatives, compositions comprising the Thiazole Derivatives, and methods for using the Thiazole Derivatives for treating or preventing a proliferative disorder, an anti-proliferative disorder, inflammation, arthritis, a central nervous system disorder, a cardiovascular disease, alopecia, a neuronal disease, an ischemic injury, a viral infection, a fungal infection, or a disorder related to the activity of a protein kinase.

  本发明涉及新型噻唑衍生物，包含该噻唑衍生物的组合物，以及使用该噻唑衍生物治疗或预防增生性疾病、抗增生性疾病、炎症、关节炎、中枢神经系统疾病、心血管疾病、脱发、神经疾病、缺血性损伤、病毒感染、真菌感染或与蛋白激酶活性相关的疾病的方法。
• Process Development of a CRF₁ Receptor Antagonist Based on the Selective Chlorination of a Benzimidazolone via Chlorine Migration
  作者：Yasuhiro Sawai、Osamu Yabe、Keiichiro Nakaoka、Tomomi Ikemoto

  DOI：10.1021/acs.oprd.6b00389

  日期：2017.2.17

  (pentan-3-yl)-1H-benzo[d]imidazole 1, a novel corticotropin-releasing factor 1 (CRF1) receptor antagonist, has been developed. The key chemical transformations were (1) a novel regioselective chlorination at the 4-position of a benzimidazolone intermediate with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione in the presence of sodium tertiary butoxide via a chlorine migration mechanism (N-3 to C-4) and

  实用合成4-氯-2-（2,4-二氯-6-甲基苯氧基）-1-甲基-7-（戊烷-3-基）-1 H-苯并[ d ]咪唑1（一种新型促肾上腺皮质激素-已经开发了释放因子1（CRF 1）受体拮抗剂。关键的化学转化是（1）在存在钠的情况下，用1,3,5-三氯-1,3,5-三嗪烷-2,4,6-三酮在苯并咪唑酮中间体的4位上进行新的区域选择性氯化反应叔丁醇通过氯的迁移机理（N -3到C -4）和（2）在存在p的情况下，苄基叔醇的一锅，三步脱羟基顺序（脱水，异构化和氢化）-甲苯磺酸和Pd催化剂。残局也进行了优化，以提高质量和产量。从可商购的材料开始的无色谱六步工艺提供15％的总收率和大于99％的纯度。
• Nitrogen-containing fused heterocyclic compounds
  申请人：Gyorkos Charles Albert

  公开号：US20070135452A1

  公开（公告）日：2007-06-14

  There is provided a CRF receptor antagonist comprising a compound of the formula (I): wherein, ring A is a 5-membered ring represented by the formula (A′): wherein X is a carbon and X 1 is an oxygen, a sulfur or —NR 5 —, or formula (A″): wherein X is a nitrogen and R 6 is an optionally substituted hydrocarbyl, R 1 is an amino substituted by two optionally substituted hydrocarbyl groups, R 2 is an phenyl, Y 1 is CR 3a or a nitrogen, y 2 is CR 3b or a nitrogen and Y 3 is CR 3c or a nitrogen, provided that one or less of Y 1 , Y 2 , and Y 3 is nitrogen, W is a bond, —(CH 2 )n-, and Z is a bond, —NR 4 —, etc.; or a salt thereof or a prodrug thereof.

  提供了一种CRF受体拮抗剂，包括式(I)的化合物：其中，环A是由式(A')表示的5元环：其中X是碳，X1是氧、硫或—NR5—，或由式(A'')表示的环：其中X是氮，R6是可选取代的烃基，R1是氨基，由两个可选取代的烃基基团取代，R2是苯基，Y1是CR3a或氮，y2是CR3b或氮，Y3是CR3c或氮，但Y1、Y2和Y3中至多一个是氮，W是键，—(CH2)n—，Z是键，—NR4—等；或其盐或前药。
• 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。
• Fused Heterocyclic Compounds
  申请人：Aso Kazuyoshi

  公开号：US20090312383A1

  公开（公告）日：2009-12-17

  There is provided a CRF receptor antagonist comprising a compound of the formula (I): wherein R 1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl; R 2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or —NR 3 — (wherein R 3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); Y 1 , Y 2 and Y 3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y 1 , Y 2 and Y 3 is nitrogen; and Z is a bond, —CO—, oxygen, sulfur, —SO—, —SO 2 —, —NR 4 —, —NR 4 -alk-, —CONR 4 — or —NR 4 CO— (wherein alk is an optionally substituted C 1-4 alkylene and R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl); or a salt thereof or a prodrug thereof.

  提供了一种CRF受体拮抗剂，其包括式(I)的化合物：其中，R1是可选取代的烃基、可选取代的C-连接杂环基、可选取代的N-连接杂芳基、氰或酰基；R2是可选取代的环烃基或可选取代的杂环基；X是氧、硫或—NR3—（其中，R3是氢、可选取代的烃基或酰基）；Y1、Y2和Y3分别是可选取代的碳或氮，但其中一个或少于一个是氮；Z是键、—CO—、氧、硫、—SO—、—SO2—、—NR4—、—NR4-alk-、—CONR4—或—NR4CO—（其中，alk是可选取代的C1-4烷基，R4是氢、可选取代的烃基或酰基）；或其盐或前药。