7-(4-chloro-3-methoxyphenyl)-2-([[4-(2-[2-[2-(dimethylamino)ethoxy]ethoxy] ethoxy)-2,6-difluorophenyl]methyl]sulfanyl)-1-(4-fluorophenyl)-7-methyl-4,5,6,7-tetrahydro-1H-1,3-benzodiazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 7-(4-chloro-3-methoxyphenyl)-2-([[4-(2-[2-[2-(dimethylamino)ethoxy]ethoxy] ethoxy)-2,6-difluorophenyl]methyl]sulfanyl)-1-(4-fluorophenyl)-7-methyl-4,5,6,7-tetrahydro-1H-1,3-benzodiazole
• 英文别名: 2-[2-[2-[4-[[7-(4-chloro-3-methoxyphenyl)-1-(4-fluorophenyl)-7-methyl-5,6-dihydro-4H-benzimidazol-2-yl]sulfanylmethyl]-3,5-difluorophenoxy]ethoxy]ethoxy]-N,N-dimethylethanamine
• 化学式: C₃₆H₄₁ClF₃N₃O₄S
• 分子量: 704.253
• InChiKey: ASSHMONQQUUFEV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  48
• 可旋转键数：
  16
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  83.3
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  5-溴-2-氯苯甲醚 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-溴代丁二酰亚胺(NBS) 、 sodium azide 、 palladium 10% on activated carbon 、 potassium tert-butylate 、 氢气 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 溶剂黄146 、 三乙胺 、 sodium iodide 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 反应 59.5h， 生成 7-(4-chloro-3-methoxyphenyl)-2-([[4-(2-[2-[2-(dimethylamino)ethoxy]ethoxy] ethoxy)-2,6-difluorophenyl]methyl]sulfanyl)-1-(4-fluorophenyl)-7-methyl-4,5,6,7-tetrahydro-1H-1,3-benzodiazole
  参考文献：
  名称：

  Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes

  摘要：

  We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGRS. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGRS (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)(0-120 min) in oral glucose tolerance tests (OGTT).

  DOI：

  10.1021/acsmedchemlett.7b00116

文献信息

• [EN] TETRAHYDRO-BENZOIMIDAZOLYL MODULATORS OF TGR5<br/>[FR] MODULATEURS TÉTRAHYDRO-BENZOIMIDAZOLYLES DE TGR5
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2015160772A1

  公开（公告）日：2015-10-22

  The present invention comprises compounds of Formula (I). wherein: R1, R2, R3, R4, R5, R6, R7, R8, X, Z1and Z2 are defined in the specification.

  本发明包括式（I）的化合物。其中：R1、R2、R3、R4、R5、R6、R7、R8、X、Z1和Z2在规范中定义。
• TETRAHYDRO-BENZOIMIDAZOLYL MODULATORS OF TGR5
  申请人：Janssen Pharmaceutica NV

  公开号：US20170029381A1

  公开（公告）日：2017-02-02

  The present invention comprises compounds of Formula (I). wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Z 1 and Z 2 are defined in the specification.
• Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes
  作者：Xuqing Zhang、Mark Wall、Zhihua Sui、Jack Kauffman、Cuifen Hou、Cailin Chen、Fuyong Du、Thomas Kirchner、Yin Liang、Dana L. Johnson、William V. Murray、Keith Demarest

  DOI：10.1021/acsmedchemlett.7b00116

  日期：2017.5.11

  We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGRS. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGRS (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)(0-120 min) in oral glucose tolerance tests (OGTT).