1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide | 333985-70-9

• 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: 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide
• CAS: 333985-70-9
• 化学式: C₁₈H₂₄Cl₂N₂O₂
• 分子量: 371.307
• InChiKey: JWWHICDGXIDOEK-UHFFFAOYSA-N

物化性质

• 熔点：
  113-114 °C(Solv: ethyl acetate (141-78-6); ethyl ether (60-29-7))
• 沸点：
  552.3±50.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide 在 potassium iodide N-甲基吗啉 、 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 、 三氟乙酸 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 26.0h， 生成 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(3-exo-(2-phenylacetamido)-8-azabicyclo[3.2.1]oct-8-yl)propyl)-4-piperidinylcarboxamide
  参考文献：
  名称：

  AMIDE COMPOUNDS, THEIR PHARMACEUTICAL COMPOSITIONS, THEIR PREPARATION METHOD AND THEIR USES

  摘要：

  本发明涉及制药化学领域，揭示了由式I代表的8-(3-氨丙基)-3-外消旋-8-氮杂双环[3.2.1]辛烷-3-氨基酰胺化合物，以及药物组合物、制备方法和使用方法。这些化合物或其药用可接受盐可用作CCR5的拮抗剂，用于制备治疗由CCR5介导的疾病的药物，特别是HIV感染、哮喘、类风湿性关节炎、自身免疫疾病和慢性阻塞性肺病（COPD）的药物。

  公开号：

  US20110251192A1
• 作为产物：
  描述：

  N-(3-氯-4-甲基苯基)甲酰胺 在 盐酸 、 caesium carbonate 作用下， 以 N-甲基吡咯烷酮 、 异丙醇 、 丙酮 为溶剂， 反应 29.0h， 生成 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide
  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
• 作为试剂：
  描述：

  1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide 、 4-(4-哌啶基甲基)-苯甲酰胺盐酸盐 在 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)piperidine-4-carboxamide 作用下， 以72的产率得到1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide
  参考文献：
  名称：

  J. Med. Chem. 2006, 49, 2784-2793

  摘要：

  DOI：

文献信息

• Cyclic amine compounds as CCR5 antagonists
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US06562978B1

  公开（公告）日：2003-05-13

  A compound of formula (I) (wherein R1 is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2 is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1 and R2 may combine to each other together with A to form a heterocyclic group which may be substituted; A is N or N+—R5.Y−(R5 is a hydrocarbon group; Y− is a counter anion); R3 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; n is 0 or 1; R4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo; G1 is a bond, CO or SO2; G2 is CO, SO2, NHCO, CONH or OCO; J is methine or a nitrogen atom; and each of Q and R is a bond or a divalent C1-3 aliphatic hydrocarbon which may be substituted; provided that J is methine when G2 is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo group(s) when G1 is a bond) or a salt thereof has a potent CCR5 antagonistic activity and can be advantageously used for the treatment or prevention of infectious disease of various HIV in human (e.g. AIDS).

  式（I）的化合物（其中R1是氢原子，可能被取代的碳氢基团，可能被取代的非芳香杂环基团，R2是可能被取代的碳氢基团，可能被取代的非芳香杂环基团，或R1和R2可以彼此结合与A一起形成可能被取代的杂环基团；A是N或N+—R5.Y−（R5是碳氢基团；Y−是一个对离子）；R3是可能被取代的环烃基团或可能被取代的杂环基团；n为0或1；R4是氢原子，可能被取代的碳氢基团，可能被取代的杂环基团，可能被取代的烷氧基团，可能被取代的芳基氧基团，或可能被取代的氨基团；E是可能被除氧以外的基团取代的二价脂肪族碳氢基团；G1是键，CO或SO2；G2是CO，SO2，NHCO，CONH或OCO；J是亚甲基或氮原子；Q和R中的每一个是键或可能被取代的二价C1-3脂肪族碳氢基团；条件是当G2为OCO时J为亚甲基，当另一个为键时Q和R中的一个不是键，当G1为键时Q和R中的每一个都不被氧基取代）或其盐具有强大的CCR5拮抗活性，并可优势用于治疗或预防人类体内各种HIV引起的传染病（例如艾滋病）。
• Heterocylic antiviral compounds
  申请人：Lemoine Remy

  公开号：US20070191335A1

  公开（公告）日：2007-08-16

  Chemokine receptor antagonists, in particular, 3,7-diazabicyclo[3.3.0]octane compounds according to formula (I) wherein R 1 -R 3 R 6c and X 1 are as defined herein are antagonists of chemokine CCR5 receptors which are useful for treating or preventing an human immunodeficiency virus (HIV-1) infection, or treating AIDS or ARC. The invention further provides methods for treating diseases that are alleviated with CCR5 antagonists. The invention includes pharmaceutical compositions and methods of using the compounds for the treating diseases mediated by the CCR5 receptor.

  足迹化学受体拮抗剂，特别是根据式(I)的3,7-二氮杂双环[3.3.0]辛烷化合物，其中R1-R3R6c和X1如本文所定义，是足迹化学CCR5受体的拮抗剂，可用于治疗或预防人类免疫缺陷病毒（HIV-1）感染，或治疗艾滋病或ARC。该发明还提供了用于治疗通过CCR5拮抗剂缓解的疾病的方法。该发明包括药物组合物和使用这些化合物治疗通过CCR5受体介导的疾病的方法。
• Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors
  作者：Ming-xin Dong、Lu Lu、Haitao Li、Xiaohua Wang、Hong Lu、Shibo Jiang、Qiu-yun Dai

  DOI：10.1016/j.bmcl.2012.03.019

  日期：2012.5

  A series of novel 1,4-disubstituted piperidine/piperazine derivatives were designed, synthesized and evaluated for their in vitro activities against HIV-1 Bal (R5) infection in CEMX174 5.25M7 cells. A majority of these compounds showed potent anti-HIV-1 activities with IC at nanomolar levels. -(4-Fluoro-benzyl)piperazine analog hydrochloride exhibited potency against HIV-1 activity similar to that of

  设计、合成了一系列新型 1,4-二取代哌啶/哌嗪衍生物，并评估了它们在 CEMX174 5.25M7 细胞中抗 HIV-1 Bal (R5) 感染的体外活性。大多数这些化合物显示出有效的抗 HIV-1 活性，IC 为纳摩尔水平。 -(4-氟苄基)哌嗪类似物盐酸盐表现出与 TAK-220 盐酸盐相似的抗 HIV-1 活性，但它具有更好的水溶性（25°C 磷酸钠缓冲液中 25mg/ml）和口服生物利用度(56%) 高于 TAK-220 盐酸盐（溶解度为 2mg/ml，口服生物利用度为 1.4%）。这些结果表明，盐酸盐可以作为开发新的抗 HIV-1 疗法或治疗和预防 HIV-1 感染的杀菌剂的更好先导物。
• 一种氨基丙基取代托烷胺类化合物、其药物组 合物及其制备方法和用途
  申请人：中国科学院上海药物研究所

  公开号：CN106977511B

  公开（公告）日：2019-04-12

  本发明属于药物化学领域，公开了如下通式(Ⅰ)所示的8‑(3‑氨基丙基)‑3‑外向‑8‑氮杂双环[3.2.1]辛烷‑3‑氨基酰胺类化合物、其药物组合物和用途。该类化合物或其药学上可接受的盐可作为CCR5的拮抗剂，用于制备治疗由CCR5介导的疾病的药物，从而用于制备治疗HIV感染、哮喘、类风湿性关节炎、自身免疫性疾病和慢性梗阻性肺病(COPD)的药物。
• A “Two-Birds-One-Stone” Approach toward the Design of Bifunctional Human Immunodeficiency Virus Type 1 Entry Inhibitors Targeting the CCR5 Coreceptor and gp41 N-Terminal Heptad Repeat Region
  作者：Chao Wang、Xinling Wang、Huan Wang、Jing Pu、Qing Li、Jiahui Li、Yang Liu、Lu Lu、Shibo Jiang

  DOI：10.1021/acs.jmedchem.1c00781

  日期：2021.8.12

  Previous studies have reported the stepwise nature of human immunodeficiency virus type 1 (HIV-1) entry and the pivotal role of coreceptor CCR5 and the gp41 N-terminal heptad repeat (NHR) region in this event. With this in mind, we herein report a dual-targeted drug compound featuring bifunctional entry inhibitors, consisting of a piperidine-4-carboxamide-based CCR5 antagonist, TAK-220, and a gp41

  先前的研究报告了 1 型人类免疫缺陷病毒 (HIV-1) 进入的逐步性质以及辅助受体 CCR5 和 gp41 N 端七肽重复 (NHR) 区域在该事件中的关键作用。考虑到这一点，我们在此报告了一种具有双功能进入抑制剂的双靶向药物化合物，由基于哌啶-4-甲酰胺的 CCR5 拮抗剂 TAK-220 和 gp41 NHR 靶向融合抑制肽 C34 组成。所得嵌合体是通过将两个药效团与聚乙二醇间隔物连接起来而构建的。一种嵌合体 CP12TAK 表现出异常有效的抗病毒活性，分别是其母体抑制剂 C34 和 TAK-220 的 40 倍和 306 倍。除了 R5-tropic 病毒，CP12TAK 还强烈抑制 X4-tropic HIV-1 毒株的感染。这些数据为 CP12TAK 作为一种新型抗 HIV-1 药物的进一步开发提供了希望。结果表明，该策略可以扩展到针对其他包膜病毒感染的疗法的设计。