tert-butyl 4-(3-cyanobenzyl)piperidine-1-carboxylate | 584555-72-6

• 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: tert-butyl 4-(3-cyanobenzyl)piperidine-1-carboxylate
• 英文别名: tert-butyl 4-[(3-cyanophenyl)methyl]piperidine-1-carboxylate
• CAS: 584555-72-6
• 化学式: C₁₈H₂₄N₂O₂
• 分子量: 300.401
• InChiKey: IDBFAPGXZVDSFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 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-(3-cyanobenzyl)piperidine-1-carboxylate 在 盐酸 、 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.0h， 生成 N-[3-[4-[(3-carbamoylphenyl)methyl]-1-piperidyl]propyl]-N-(3,4-dichlorophenyl)-1-methylsulfonyl-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
• 作为产物：
  描述：

  3-氰基苄基溴 在 15-冠醚-5 、 氢气 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 、 mineral oil 为溶剂， 反应 0.5h， 生成 tert-butyl 4-(3-cyanobenzyl)piperidine-1-carboxylate
  参考文献：
  名称：

  [EN] NITROGENOUS HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN DRUGS
  [FR] DÉRIVÉS HÉTÉROCYCLIQUES AZOTÉS ET LEUR APPLICATION DANS DES MÉDICAMENTS

  摘要：

  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。

  公开号：

  WO2015090232A1

文献信息

• [EN] PIPERIDINE AND PIPERAZINE DERIVATIVES POSSESSING AFFINITY AT 5HT-1 TYPE RECEPTORS<br/>[FR] DERIVES DE PIPERIDINE ET DE PIPERAZINE POSSEDANT UNE AFFINITE POUR LES RECEPTEURS DE TYPE 5HT-1
  申请人：GLAXO GROUP LTD

  公开号：WO2003068236A1

  公开（公告）日：2003-08-21

  Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed:wherein A is optionally substituted phenyl, indolyl, quinolinyl, quinazolinyl, indazolyl or isoquinolinyl; X is carbon, Y is CH and is a double bond; or X is CH, Y is CH2 or oxygen and is a single bond; or X is nitrogen, Y is CH2 and is a single bond; R1 is halogen, cyano, nitro, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, C3-7 heterocyclylC1-6 alkyl, C3-7 heterocyclyl C1-6 alkoxy; a is 0, 1, 2, 3 or 4; R2 is either: halogen, -CN, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl or an optionally substituted C-linked 3-7 membered heterocyclic group; or a group -(Z)b-B wherein: (i) Z is oxygen, CH2, C=O, SO2 or C=N-OR3 wherein R3 is hydrogen or C1-6 alkyl; b is 1, 2, or 3; and B is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxy or NR4R5 wherein R4 and R5 are independently hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkanoyl, fluoroC1-6 alkanoyl, C1-6 alkylsulfonyl, fluoroC¿1-6 alkylsulfonyl, carbamoyl or C1-6 alkylcarbamoyl, or R4 and R5, together with the nitrogen atom to which they are attached, form part of an optionally substituted 3 to 7 membered heterocyclic group; or (ii) Z is oxygen, CH or CH2, b is 1, and B forms the rest of an aryl or a C3-7 heterocyclic group fused to the phenyl ring; excluding 1-[2-[2-(phenylmethyl)phenoxy]ethyl]-4-[(2,3,4-trimethoxyphenyl)methyl]-piperazine and pharmaceutically acceptable salts thereof, and N-[4-[2-[4-[(3,4-dimethoxyphenyl)methyl]-1-piperazinyl]ethoxy]phenyl]-ethanesulfonamide and pharmaceutically acceptable salts thereof. Methods of preparing the compounds and uses of the compounds in therapy, in particular for CNS disorders such as depression and anxiety, are also disclosed.

  公开了公式（I）的化合物及其药学上可接受的盐：其中A是可选择取代的苯基、吲哚基、喹啉基、喹唑啉基、吲唑基或异喹啉基；X是碳，Y是CH且为双键；或X是CH，Y是CH2或氧且为单键；或X是氮，Y是 且为单键；R1是卤素、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-7杂环基C1-6烷基、C3-7杂环基C1-6烷氧基；a为0、1、2、3或4；R2为：卤素、-CN、可选择取代的C3-7环烷基、可选择取代的芳基或可选择取代的C-连接的3-7成员杂环基；或者为一个组-(Z)b-B，其中：（i）Z为氧、 、C=O、SO2或C=N-OR3，其中R3为氢或C1-6烷基；b为1、2或3；B为氢、C1-6烷基、C3-7环烷基、C1-6烷氧基或NR4R5，其中R4和R5独立地为氢、C1-6烷基、C3-7环烷基、C1-6烷酰基、氟代C1-6烷酰基、C1-6烷基磺酰基、氟代C¿1-6烷基磺酰基、氨基或C1-6烷基氨基；或R4和R5连同它们所连接的氮原子形成可选择取代的3至7成员杂环基的一部分；或（ii）Z为氧、CH或 ，b为1，B形成与苯环融合的芳基或C3-7杂环基的其余部分；不包括1-[2-[2-(苯甲基)苯氧基]乙基]-4-[(2,3,4-三甲氧基苯基)甲基]-哌嗪和药学上可接受的盐，以及N-[4-[2-[4-[(3,4-二甲氧基苯基)甲基]-1-哌嗪基]乙氧基]苯基]-乙烷磺酰胺和药学上可接受的盐。还公开了制备这些化合物的方法以及这些化合物在治疗中的用途，特别是用于中枢神经系统疾病如抑郁症和焦虑症。
• Piperidine and piperazine derivatives possessing affinity at 5ht-1 type receptors
  申请人：Flynn F. Sean

  公开号：US20050176724A1

  公开（公告）日：2005-08-11

  Compounds of formula (I) and pharmaceutically acceptable salts thereof are disclosed: wherein A is optionally substituted phenyl, indolyl, quinolinyl, quinazolinyl, indazolyl or isoquinolinyl; X is carbon, Y is CH and ═ is a double bond; or X is CH, Y is CH 2 or oxygen and ═ is a single bond; or X is nitrogen, Y is CH 2 and ═ is a single bond; R 1 is halogen, cyano, nitro, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 3-7 heterocyclylC 1-6 alkyl, C 3-7 heterocyclyl C 1-6 alkoxy; a is 0, 1, 2, 3 or 4; R2 is either: halogen, —CN, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl or an optionally substituted C-linked 3-7 membered heterocyclic group; or a group -(Z)b-B wherein: (i) Z is oxygen, CH 2 , C═O, SO 2 or C═N—OR3 wherein R3 is hydrogen or C 1-6 alkyl; b is 1, 2, or 3; and B is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy or NR4R5 wherein R4 and R5 are independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkanoyl, fluoroC 1-6 alkanoyl, C 1-6 alkylsulfonyl, fluoroC 1-6 alkylsulfonyl, carbamoyl or C 1-6 alkylcarbamoyl, or R4 and R5, together with the nitrogen atom to which they are attached, form part of an optionally substituted 3 to 7 membered heterocyclic group; or (ii) Z is oxygen, CH or CH 2 , b is 1, and B forms the rest of an aryl or a C 3-7 heterocyclic group fused to the phenyl ring; excluding 1-[2-[2-(phenylmethyl)phenoxy]ethyl]-4-[(2,3,4-trimethoxyphenyl)methyl]-piperazine and pharmaceutically acceptable salts thereof, and N-[4-[2-[4-[(3,4-dimethoxyphenyl)methyl]-1-piperazinyl]ethoxy]phenyl]-ethanesulfonamide and pharmaceutically acceptable salts thereof. Methods of preparing the compounds and uses of the compounds in therapy, in particular for CNS disorders such as depression and anxiety, are also disclosed.

  本文披露了公式(I)的化合物及其药学上可接受的盐：其中A是可选取代的苯基、吲哚基、喹啉基、喹唑啉基、吲唑基或异喹啉基；X为碳，Y为CH，═为双键；或X为CH，Y为CH2或氧，═为单键；或X为氮，Y为 ，═为单键；R1为卤素、氰基、硝基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C3-7杂环烷基C1-6烷基、C3-7杂环烷基C1-6烷氧基；a为0、1、2、3或4；R2为：卤素、-CN、可选取代的C3-7环烷基、可选取代的芳基或可选取代的C-连接的3-7环成员杂环基；或一个-(Z)b-B基团，其中：(i)Z为氧、 、C═O、SO2或C═N—OR3，其中R3为氢或C1-6烷基；b为1、2或3；B为氢、C1-6烷基、C3-7环烷基、C1-6烷氧基或NR4R5，其中R4和R5独立地为氢、C1-6烷基、C3-7环烷基、C1-6烷酰基、氟代C1-6烷酰基、C1-6烷基磺酰基、氟代C1-6烷基磺酰基、氨基或C1-6烷基氨基；或R4和R5与它们所连接的氮原子一起构成可选取代的3到7环成员杂环基的一部分；或(ii)Z为氧、CH或 ，b为1，B为连接到苯环或C3-7杂环基的其余部分的芳基或C3-7杂环基；不包括1-[2-[2-(苯甲基)苯氧基]乙基]-4-[(2,3,4-三甲氧基苯基)甲基]-哌嗪和其药学上可接受的盐，以及N-[4-[2-[4-[(3,4-二甲氧基苯基)甲基]-1-哌嗪基]乙氧基]苯基]-乙烷磺酰胺和其药学上可接受的盐。本文还披露了制备这些化合物的方法以及这些化合物在治疗中的应用，特别是在中枢神经系统疾病如抑郁症和焦虑症中的应用。
• PIPERIDINE AND PIPERAZINE DERIVATIVES POSSESSING AFFINITY AT 5HT-1 TYPE RECEPTORS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1476161A1

  公开（公告）日：2004-11-17
• 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