4-(3-benzyl-1-ethyl-pyrazol-5-yl)piperidine | 301219-18-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-(3-benzyl-1-ethyl-pyrazol-5-yl)piperidine
• 英文别名: 4-(5-Benzyl-2-ethylpyrazol-3-yl)piperidine
• CAS: 301219-18-1
• 化学式: C₁₇H₂₃N₃
• 分子量: 269.39
• InChiKey: ABVPBLJJVGVAJR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  29.8
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(3-benzyl-1-ethyl-pyrazol-5-yl)piperidine 在 palladium on activated charcoal 氢气 、 三乙酰氧基硼氢化钠 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 1,2-二氯乙烷 为溶剂， 生成 (R)-{(3S,4S)-3-[4-(5-Benzyl-2-ethyl-2H-pyrazol-3-yl)-piperidin-1-ylmethyl]-4-phenyl-pyrrolidin-1-yl}-cyclohexyl-acetic acid
  参考文献：
  名称：

  Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

  摘要：

  Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.12.004
• 作为产物：
  描述：

  tert-butyl 4-(3-oxo-4-phenylbutyryl)piperidine-1-carboxylate 在 苯甲醚 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 4-(3-benzyl-1-ethyl-pyrazol-5-yl)piperidine
  参考文献：
  名称：

  Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

  摘要：

  Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.12.004

文献信息

• Modulators of CCR5 chemokine receptor activity
  申请人：——

  公开号：US20020193407A1

  公开（公告）日：2002-12-19

  Compounds of Formula I: 1 (wherein R 1 , R 2 , R 3 , R 4 , Q, and X are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

  化合物的化学式I： 1 （其中R 1 ，R 2 ，R 3 ，R 4 ，Q和X在此处定义）已被描述。这些化合物是CCR5趋化因子受体活性的调节剂。这些化合物在预防或治疗HIV感染以及治疗艾滋病方面是有用的，可以作为化合物或药学上可接受的盐，或作为药物组成部分，可选地与其他抗病毒药物，免疫调节剂，抗生素或疫苗组合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
  申请人：——

  公开号：US20040002504A1

  公开（公告）日：2004-01-01

  The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: 1 wherein, generally, Q is 2 R 1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C 1-4 alkyl or halogen, such as methyl, fluorine or bromine; R 2 is hydrogen or C 1-4 alkyl such as methyl; R 3 is phenyl; R 4 is hydrogen; R 5 is hydrogen or C 1-6 alkylcarbonyl such as methylcarbonyl; X is —SO 2 — or —C(O)N(R 2 )SO 2 — where R 2 is preferably hydrogen; Y is a bond, CH 2 or Z 1 where Z 1 is —N(R f )— in which R f is C 1-6 alkylcarbonyl such as ethylcarbonyl; and R 6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C 1-6 alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.

  本发明提供了一种治疗患有疾病（如精神分裂症）的受试者的方法，其中该疾病的治疗需要使用NK-3拮抗剂，包括向该受试者施用化合物I的治疗有效量： 1 其中，通常情况下， Q是 2 R 1 是苄基、苯基、噻吩或咪唑基，可选择地用C 1-4 烷基或卤素（如甲基、氟或溴）取代； R 2 是氢或C 1-4 烷基，如甲基； R 3 是苯基； R 4 是氢； R 5 是氢或C 1-6 烷基羰基，如甲基羰基； X是—SO 2 —或—C(O)N(R 2 )SO 2 —，其中R 2 最好是氢； Y是键、CH 2 或Z 1 ，其中Z 1 是—N(R f )—，其中R f 是C 1-6 烷基羰基，如乙基羰基；以及 R 6 是苯基、吡唑基、吡啶基、嘧啶基或苯并咪唑基，可选择地用来自C 1-6 烷基和苄基的一个或两个基团取代，如甲基、乙基和苄基； 或其药学上可接受的盐。
• Pyrrolidine modulators of CCR5 chemokine receptor activity
  申请人：——

  公开号：US20020094989A1

  公开（公告）日：2002-07-18

  Pyrrolidine compounds of Formula I: 1 (wherein 1 , R 2 , R 3 , R 4 , R 5 ,R 6a , R 6b , R 7 and R 8 are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

  Pyrrolidine化合物的化学式I： 1 （其中 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6a ，R 6b ，R 7 和R 8 在此定义）已被描述。这些化合物是CCR5趋化因子受体活性的调节剂。这些化合物可用于预防或治疗HIV感染和治疗艾滋病，作为化合物或药学上可接受的盐，或作为药物组成部分，可选择与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment
  作者：Min Shu、Jennifer L Loebach、Kerry A Parker、Sander G Mills、Kevin T Chapman、Dong-Ming Shen、Lorraine Malkowitz、Martin S Springer、Sandra L Gould、Julie A DeMartino、Salvatore J Siciliano、Jerry Di Salvo、Kathy Lyons、James V Pivnichny、Gloria Y Kwei、Anthony Carella、Gwen Carver、Karen Holmes、William A Schleif、Renee Danzeisen、Daria Hazuda、Joseph Kessler、Janet Lineberger、Michael D Miller、Emilio A Emini

  DOI：10.1016/j.bmcl.2003.12.006

  日期：2004.2

  Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable

  在我们的苄基吡唑系列CCR5拮抗剂中，广泛的SAR研究表明，苄基苯基上的亲脂性和亲水性取代基均可提高抗病毒效力。然而，通常仅通过更多的亲脂取代观察到药代动力学特征的改善。在这方面，4-联苯（51）表现最好。高度亲脂性取代基赋予这些CCR5拮抗剂不良的离子通道活性。烷氧基取代基提供了抗病毒活性，药代动力学参数和选择性之间的良好平衡。与母体化合物9相比，包含3，4-二甲氧基取代基的化合物42b和42d被认为是最有希望的改进。它们显示出改进的抗病毒活性，同时保留了良好的药代动力学特性和选择性。
• Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds
  作者：Dong-Ming Shen、Min Shu、Christopher A. Willoughby、Shrenik Shah、Christopher L. Lynch、Jeffrey J. Hale、Sander G. Mills、Kevin T. Chapman、Lorraine Malkowitz、Martin S. Springer、Sandra L. Gould、Julie A. DeMartino、Salvatore J. Siciliano、Kathy Lyons、James V. Pivnichny、Gloria Y. Kwei、Anthony Carella、Gwen Carver、Karen Holmes、William A. Schleif、Renee Danzeisen、Daria Hazuda、Joseph Kessler、Janet Lineberger、Michael D. Miller、Emilio A. Emini

  DOI：10.1016/j.bmcl.2003.12.005

  日期：2004.2

  Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-

  在我们的吡唑化合物先导化合物1中烷基乙酸部分和吡咯烷上的苯基进行修饰，得到异丙基化合物9。该化合物是有效的CCR5拮抗剂，对HIV-1表现出良好的体外抗病毒活性，出色的选择性和良好的口服性三种动物的生物利用度。在该研究过程中，发现了一种新的方法，该方法使用三氟甲磺酸银从吡咯烷和α-溴-α-α，二烷基乙酸制备α-（吡咯烷-1-基）-α，α-二烷基乙酸。这使我们能够首次制备诸如24和25之类的化合物。还没有发现新型的Pd介导的α-（吡咯烷-1-基）乙酸的N-去烷基化反应。