1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide | 333994-00-6

• 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-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide
• 英文别名: TAK-220；TAK220；1-acetyl-N-[3-[4-(4-carbamoylbenzyl)-1-piperidyl]propyl]-N-(3-chloro-4-methylphenyl)-4-piperidine carboxamide；1-acetyl-N-[3-[4-[(4-carbamoylphenyl)methyl]piperidin-1-yl]propyl]-N-(3-chloro-4-methylphenyl)piperidine-4-carboxamide
• CAS: 333994-00-6
• 化学式: C₃₁H₄₁ClN₄O₃
• 分子量: 553.145
• InChiKey: ASSJTMUEFHUKMJ-UHFFFAOYSA-N

物化性质

• 熔点：
  166-167 °C(Solv: ethyl acetate (141-78-6); ethanol (64-17-5))
• 沸点：
  757.8±60.0 °C(Predicted)
• 密度：
  1.208±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  87
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

生物活性

TAK-220 是一种选择性的、可口服的 CCR5 拮抗剂，能够抑制 RANTES 和 MIP-1α 与 CCR5 结合，其 IC50 值分别为 3.5 nM 和 1.4 nM。然而，它对 CCR1、CCR2b、CCR3、CCR4 或者 CCR7 没有作用。TAK-220 还能够选择性地抑制 HIV-1，在外周单核细胞中，其 EC50 值分别为 1.2 nM (HIV-1 KK)、0.72 nM (HIV-1 CTV)、1.7 nM (HIV-1 HKW)、1.7 nM (HIV-1 HNK)、0.93 nM (HIV-1 HTN) 和 0.55 nM (HIV-1 HHA)，EC90 值分别为 12 nM (HIV-1 KK)、5 nM (HIV-1 CTV)、12 nM (HIV-1 HKW)、28 nM (HIV-1 HNK)、15 nM (HIV-1 HTN) 和 4 nM (HIV-1 HHA)。

靶点

指标	值
RANTES	3.5 nM
MIP-1α	1.4 nM
HIV-1 KK	1.2 nM (EC50), 12 nM (EC90)
HIV-1 CTV	0.72 nM (EC50), 5 nM (EC90)
HIV-1 HKW	1.7 nM (EC50), 12 nM (EC90)
HIV-1 HNK	1.7 nM (EC50), 28 nM (EC90)
HIV-1 HTN	0.93 nM (EC50), 15 nM (EC90)
HIV-1 HHA	0.55 nM (EC50), 4 nM (EC90)

体外研究

TAK-220 是一种选择性的 CCR5 拮抗剂，其在 CHO 细胞中对 RANTES 和 MIP-1α 的 IC50 值分别为 3.5 nM 和 1.4 nM。它不会影响与 CCR1、CCR2b、CCR3、CCR4 或者 CCR7 的结合。TAK-220 可以与 CCR5 结合但不与 RANTES 结合，并且可以抑制由 CCR5 引发的 Ca2+ 信号传导。TAK-220 还能够抑制 R5 HIV-1 (JR-FL) 包膜介导的膜融合，其 IC50 值为 0.42 nM，但不会改变 X4 HIV-1 (HXB2) 包膜介导的膜融合。TAK-220 还能选择性地抑制 HIV-1，EC50 值分别为 1.2 nM (HIV-1 KK)、0.72 nM (HIV-1 CTV)、1.7 nM (HIV-1 HKW)、1.7 nM (HIV-1 HNK)、0.93 nM (HIV-1 HTN) 和 0.55 nM (HIV-1 HHA)，EC90 值分别为 12 nM (HIV-1 KK)、5 nM (HIV-1 CTV)、12 nM (HIV-1 HKW)、28 nM (HIV-1 HNK)、15 nM (HIV-1 HTN) 和 4 nM (HIV-1 HHA)，都在外周血单核细胞中测定。TAK-220 对 R5 突变株表现出很强的抑制活性，其 IC50 值分别为 3.12 nM 对 HIV-1 R5-08、13.47 nM 对 HIV-1 R5-06 和 2.26 nM 对 HIV-1 R5-18。在未感染的外周血单核细胞中，TAK-220 的浓度超过 100 nM 并没有表现出毒性。

反应信息

• 作为产物：
  描述：

  N-(3-氯-4-甲基苯基)甲酰胺 在 盐酸 、 potassium carbonate 、 caesium carbonate 作用下， 以 N-甲基吡咯烷酮 、 N,N-二甲基甲酰胺 、 异丙醇 、 丙酮 为溶剂， 反应 44.0h， 生成 1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide
  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

• 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）。
• [EN] THERAPEUTIC COMPOUNDS<br/>[FR] COMPOSÉS THÉRAPEUTIQUES
  申请人：UNIV MINNESOTA

  公开号：WO2016138142A1

  公开（公告）日：2016-09-01

  and salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods using a compound of formula I.

  其中的盐也被披露。还披露了包括I式化合物的药物组合物，用于制备I式化合物的过程，用于制备I式化合物的有用中间体以及使用I式化合物的治疗方法。
• [EN] CYCLIC AMINE COMPOUNDS AS CCR5 ANTAGONISTS<br/>[FR] COMPOSES D'AMINE CYCLIQUE UTILISES COMME ANTAGONISTES DE CCR5
  申请人：TAKEDA CHEMICAL INDUSTRIES LTD

  公开号：WO2001025200A1

  公开（公告）日：2001-04-12

  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 R?1 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 SO¿2; G?2 is CO, SO¿2?, 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 G?1¿ 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).

  化合物式为（I）（其中R1是氢原子，可被取代的碳氢基团，可被取代的非芳香杂环基团，R2是可被取代的碳氢基团，可被取代的非芳香杂环基团，或R1和R2可以与A一起结合形成可被取代的杂环基团；A是N或N+ -R5 • Y-（R5是碳氢基团；Y-是反离子）；R3是可被取代的环烃基团或可被取代的杂环基团；n为0或1；R4是氢原子，可被取代的碳氢基团，可被取代的杂环基团，可被取代的烷氧基，可被取代的芳氧基，或可被取代的氨基，E是可被除氧基以外的基取代的二价脂肪烃基团；G1是键，CO或SO2；G2是CO，SO2，NHCO，CONH或OCO；J是甲基或氮原子；Q和R中的每一个都是一个键或一个可被取代的二价C1-3脂肪基团；前提是当G2是OCO时，J是甲基，当另一个是键时，其中一个不是键，当G1是键时，Q和R中的每一个都没有被氧基团取代）或其盐具有强效的CCR5拮抗活性，并可用于人类各种HIV感染疾病（例如艾滋病）的治疗或预防。
• Process for preparation of benzylpiperidine compounds
  申请人：Miki Shokyo

  公开号：US20060094877A1

  公开（公告）日：2006-05-04

  According to the process as shown in the following scheme having a step for reacting Compound (I) with Compound (II) to produce Compound (III), benzylpiperidine compounds useful as synthesis starting materials of pharmaceutical agents, agricultural chemicals and the like can be produced conveniently by a short step: wherein R 1 is a hydrogen atom or an amino-protecting group, R 2 is a hydrogen atom, a hydrocarbon group optionally having substituents, an alkoxy group optionally having substituents or a heterocyclic group optionally having substituents, and R 3 is a lower alkyl group.

  根据下图所示的过程，其中包含将化合物（I）与化合物（II）反应以产生化合物（III）的步骤，可以通过简短的步骤方便地生产用作制药剂、农业化学品等综合起始材料的苯甲基哌啶化合物：其中R1是氢原子或氨基保护基，R2是氢原子、烃基（可选取代基）、烷氧基（可选取代基）或杂环基（可选取代基），R3是较低的烷基基团。
• Use of compounds having ccr antagonism
  申请人：Tsuchimori Noboru

  公开号：US20050245537A1

  公开（公告）日：2005-11-03

  It is intended to provide preventives/remedies for graft-versus-host disease and/or rejection in organ or bone marrow transplantation, rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic cerebral cell injury, myocardial infarction, chronic nephritis and arteriosclerosis. The above object can be achieved by preventives/remedies for graft-versus-host disease and/or rejection in organ or bone marrow transplantation, rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic cerebral cell injury, myocardial infarction, chronic nephritis and arteriosclerosis characterized by containing a specific compound having a CCR (CC chemokine receptor) antagonism.

  本发明旨在为移植手术中的移植物抗宿主病和/或排斥反应、类风湿性关节炎、自身免疫疾病、过敏性疾病、缺血性脑细胞损伤、心肌梗死、慢性肾炎和动脉硬化提供预防和治疗措施。上述目标可以通过包含具有CCR（CC趋化因子受体）拮抗作用的特定化合物的移植物抗宿主病和/或排斥反应、类风湿性关节炎、自身免疫疾病、过敏性疾病、缺血性脑细胞损伤、心肌梗死、慢性肾炎和动脉硬化的预防和治疗措施来实现。