4-(piperazin-1-ylmethyl)benzonitrile dihydrochloride | 333993-01-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(piperazin-1-ylmethyl)benzonitrile dihydrochloride
• 英文别名: 4-(Piperazin-1-ylmethyl)benzonitrile hydrochloride；4-(piperazin-1-ylmethyl)benzonitrile;hydrochloride
• CAS: 333993-01-4
• 化学式: C₁₂H₁₅N₃*2ClH
• mdl: MFCD09455661
• 分子量: 274.193
• InChiKey: VMFGYJPRGXNTTJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.23
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.416
• 拓扑面积：
  39.1
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(piperazin-1-ylmethyl)benzonitrile dihydrochloride 在 盐酸 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 1.5h， 生成 4-({4-[5-({1-[(5-methoxypyrazin-2-yl)methyl]piperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]-piperazin-1-yl}methyl)benzonitrile ditosylate
  参考文献：
  名称：

  Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity

  摘要：

  This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.

  DOI：

  10.1248/cpb.c20-00015
• 作为产物：
  描述：

  1-Boc-4-(4-氰基苄基)哌嗪 在 盐酸 作用下， 以 氯仿 、 乙酸乙酯 为溶剂， 反应 72.0h， 以8.0 g的产率得到4-(piperazin-1-ylmethyl)benzonitrile dihydrochloride
  参考文献：
  名称：

  Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity

  摘要：

  This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-({4-[5-({1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.

  DOI：

  10.1248/cpb.c20-00015

文献信息

• PHARMACEUTICAL COMPOSITION HAVING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE COMPONENT
  申请人：Astellas Pharma Inc.

  公开号：EP3231425A1

  公开（公告）日：2017-10-18

  To provide a pharmaceutical composition for treating multiple myeloma. [Solution] After investigating compounds having a mitochondrial Complex I inhibitory effect, the present inventor completed the present invention by confirming that the bicyclic nitrogen-containing aromatic heterocyclic amide compounds of the present invention have a mitochondrial Complex I inhibitory effect, and that these compounds have a growth inhibition effect on multiple myeloma.

  提供一种用于治疗多发性骨髓瘤的药物组合物。【解决方案】在调查具有线粒体复合物I抑制作用的化合物后，本发明人通过确认本发明的双环氮杂芳香杂环酰胺化合物具有线粒体复合物I抑制作用，并且这些化合物对多发性骨髓瘤具有生长抑制作用，完成了本发明。
• PHARMACEUTICAL COMPOSITION HAVING BICYCLIC NITROGEN-CONTAINING AROMATIC HETROCYCLIC AMIDE COMPOUNDS AS ACTIVE INGREDIENT
  申请人：Astellas Pharma Inc.

  公开号：EP3231426A1

  公开（公告）日：2017-10-18

  [Problem] To provide a pharmaceutical composition for treating various cancers in which mitochondrial complex I is involved, in particular, colon cancer, leukemia and/or malignant lymphoma. [Solution] With the invention of creating pharmaceutical compositions for treating various cancers, the inventors confirmed, on the basis of the result of intensive investigation, that pharmaceutical compositions, which contain specific bicyclic nitrogen-containing aromatic heterocyclic amide compounds having an AMPK activation effect and mitochondrial complex I is involved, in particular, colon cancer, leukemia and/or malignant lymphoma; thereby completing the present invention.

  【问题】提供一种用于治疗涉及线粒体复合物I的各种癌症，特别是结肠癌、白血病和/或恶性淋巴瘤的药物组合物。【解决方案】通过创造用于治疗各种癌症的药物组合物的发明，发明人根据深入调查的结果确认，包含具有AMPK激活作用和涉及线粒体复合物I的特定双环氮杂芳香杂环酰胺化合物的药物组合物，特别是用于治疗结肠癌、白血病和/或恶性淋巴瘤；从而完成了本发明。
• Novel Indirect AMP-Activated Protein Kinase Activators: Identification of a Second-Generation Clinical Candidate with Improved Physicochemical Properties and Reduced hERG Inhibitory Activity
  作者：Kazuyuki Kuramoto、Yuki Sawada、Tomohiro Yamada、Takeyuki Nagashima、Kei Ohnuki、Takashi Shin

  DOI：10.1248/cpb.c20-00015

  日期：2020.5.1

  This study reports the synthesis and evaluation of novel indirect AMP-activated protein kinase (AMPK) activators. The series of compounds selectively inhibited cell growth in several human breast cancer cell lines by activating AMPK. We performed back-up medicinal chemistry synthetic research on ASP4132, a previously reported as a compound for clinical development that acts as an indirect AMPK activator. This led to the successful identification of 4-(4-[5-(1-[(5-ethoxypyrazin-2-yl)methyl]-4-fluoropiperidin-4-yl}methoxy)-3-methylpyridine-2-carbonyl]piperazin-1-yl}methyl)benzonitrile succinate (27b), a potent, highly aqueous soluble and metabolically stable compound in human hepatocytes. Compound 27b also showed weaker human Ether-a-go-go Related Gene (hERG) inhibitory activity than that of compound 13 and ASP4132. Therefore, 27b was a promising AMPK activator and a second-generation clinical candidate for treatment for human cancer.