tert-butyl 4-(2-cyanobenzylidene)piperidine-1-carboxylate | 888729-73-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 4-(2-cyanobenzylidene)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-[(2-cyanophenyl)methylidene]piperidine-1-carboxylate
• CAS: 888729-73-5
• 化学式: C₁₈H₂₂N₂O₂
• 分子量: 298.385
• InChiKey: NIBRGKLFPWAKHN-UHFFFAOYSA-N

物化性质

• 熔点：
  109-111 °C
• 沸点：
  160-170 °C(Press: 1.4 Torr)
• 密度：
  1.12±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  53.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(2-cyanobenzylidene)piperidine-1-carboxylate 在 palladium on activated charcoal sodium hydroxide 、 氢气 、 双氧水 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 为溶剂， 反应 13.0h， 生成 tert-butyl 4-(2-carbamoylbenzyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

  摘要：

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

  DOI：

  10.1021/jm051034q
• 作为产物：
  描述：

  2-氰基溴苄 在 15-冠醚-5 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 25.5h， 生成 tert-butyl 4-(2-cyanobenzylidene)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity

  摘要：

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-{3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.

  DOI：

  10.1021/jm051034q

文献信息

• [EN] NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS<br/>[FR] DÉRIVÉS HÉTÉROCYCLIQUES AZOTÉS ET LEUR APPLICATION DANS DES MÉDICAMENTS
  申请人：SUNSHINE LAKE PHARMA CO LTD

  公开号：WO2015090232A1

  公开（公告）日：2015-06-25

  The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, IPF, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.

  本发明涉及医学领域，提供了新颖的含氮杂环化合物，其制备方法以及作为药物的用途，特别是用于治疗和预防组织纤维化。本文还提供了包含这些含氮杂环化合物的药用可接受组合物，以及这些组合物在治疗人类或动物组织纤维化方面的用途，特别是用于人类或动物肾间质纤维化、肾小球硬化、肝纤维化、肺纤维化、IPF、腹膜纤维化、心肌纤维化、皮肤纤维化、术后粘连、良性前列腺增生、骨骼肌纤维化、硬皮病、多发性硬化、胰腺纤维化、肝硬化、肌肉肉瘤、神经纤维瘤、肺间质纤维化、糖尿病肾病、阿尔茨海默病或血管纤维化。
• NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
  申请人：Sunshine Lake Pharma Co., Ltd.

  公开号：EP3083584A1

  公开（公告）日：2016-10-26
• NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN THE TREATMENT OF TISSUE FIBROSIS
  申请人：Sunshine Lake Pharma Co., Ltd.

  公开号：EP3083584B1

  公开（公告）日：2018-02-21
• US9902712B2
  申请人：——

  公开号：US9902712B2

  公开（公告）日：2018-02-27
• Discovery of a Piperidine-4-carboxamide CCR5 Antagonist (TAK-220) with Highly Potent Anti-HIV-1 Activity
  作者：Shinichi Imamura、Takashi Ichikawa、Youichi Nishikawa、Naoyuki Kanzaki、Katsunori Takashima、Shinichi Niwa、Yuji Iizawa、Masanori Baba、Yoshihiro Sugihara

  DOI：10.1021/jm051034q

  日期：2006.5.1

  We incorporated various polar groups into previously described piperidine-4-carboxamide CCR5 antagonists to improve their metabolic stability in human hepatic microsomes. Introducing a carbamoyl group into the phenyl ring of the 4-benzylpiperidine moiety afforded the less lipophilic compound 5f, which possessed both high metabolic stability and good inhibitory activity of HIV-1 envelope-mediated membrane fusion (IC50 = 5.8 nM). Further optimization to increase potency led to the discovery of 1-acetyl-N-3-[4-(4-carbamoylbenzyl) piperidin-1-yl]propyl}-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide (5m, TAK-220), which showed high CCR5 binding affinity (IC50 = 3.5 nM) and potent inhibition of membrane fusion (IC50 = 0.42 nM), as well as good metabolic stability. Compound 5m strongly inhibited the replication of CCR5-using HIV-1 clinical isolates in human peripheral blood mononuclear cells (mean EC50 = 1.1 nM, EC90 = 13 nM) and exhibited a good pharmacokinetic profile in monkeys (BA = 29%). This compound has been chosen as a clinical candidate for further development.