methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate
• 英文别名: Methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate；methyl 1-(cyclopropylmethyl)-2-(9-ethylcarbazol-3-yl)benzimidazole-5-carboxylate
• 化学式: C₂₇H₂₅N₃O₂
• 分子量: 423.514
• InChiKey: HIJRXRGAZYBOEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  49
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 20.0h， 以73%的产率得到1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylic acid
  参考文献：
  名称：

  Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis

  摘要：

  The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising antiinflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

  DOI：

  10.1021/acs.jmedchem.8b01862
• 作为产物：
  描述：

  3,4-二氨基苯甲酸甲酯 在 sodium metabisulfite 、 sodium hydride 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.5h， 生成 methyl 1-(cyclopropylmethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate
  参考文献：
  名称：

  Identification of a Benzimidazolecarboxylic Acid Derivative (BAY 1316957) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis

  摘要：

  The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising antiinflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.

  DOI：

  10.1021/acs.jmedchem.8b01862

文献信息

• NOVEL BENZIMIDAZOLE DERIVATIVES AS EP4 ANTAGONISTS
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160214977A1

  公开（公告）日：2016-07-28

  The present invention relates to novel benzimidazole derivatives of the general formula (I), processes for their preparation and their use for the production of pharmaceutical compositions for the treatment of diseases and indications that are connected with the receptor EP4.

  本发明涉及通式(I)的新型苯并咪唑衍生物，其制备方法以及它们用于制备治疗与EP4受体相关的疾病和适应症的药物组合物的用途。
• NEUARTIGE BENZIMIDAZOLDERIVATE ALS EP4-ANTAGONISTEN
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：EP2928884B1

  公开（公告）日：2017-05-24
• US9708311B2
  申请人：——

  公开号：US9708311B2

  公开（公告）日：2017-07-18
• Identification of a Benzimidazolecarboxylic Acid Derivative (<b>BAY 1316957</b>) as a Potent and Selective Human Prostaglandin E2 Receptor Subtype 4 (hEP4-R) Antagonist for the Treatment of Endometriosis
  作者：Stefan Bäurle、Jens Nagel、Olaf Peters、Nico Bräuer、Antonius ter Laak、Cornelia Preusse、Antje Rottmann、Dieter Heldmann、Ulrich Bothe、Thorsten Blume、Ludwig Zorn、Daryl Walter、Thomas M. Zollner、Andreas Steinmeyer、Gernot Langer

  DOI：10.1021/acs.jmedchem.8b01862

  日期：2019.3.14

  The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients are primarily driven by hormone-dependent and inflammatory processes-the latter being frequently associated with severe, acute, and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising antiinflammatory and antinociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful structure-activity relationship investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific, and selective hEP4-R antagonist with excellent drug metabolism and pharmacokinetics properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patient's quality of life.