Cyclo-(Gly-Pip) | 37043-04-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌嗪基哌啶类
• 英文名称: Cyclo-(Gly-Pip)
• 英文别名: cyclo-(Pip-Gly)；3,6,7,8,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione；hexahydro-pyrido[1,2-a]pyrazine-1,4-dione；Hexahydro-1H-pyrido[1,2-a]pyrazine-1,4(6H)-dione；3,6,7,8,9,9a-hexahydro-2H-pyrido[1,2-a]pyrazine-1,4-dione
• CAS: 37043-04-2
• 化学式: C₈H₁₂N₂O₂
• mdl: MFCD10574833
• 分子量: 168.195
• InChiKey: YXBLPNSWHUPKPH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  Cyclo-(Gly-Pip) 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 生成 八氢吡啶并[1,2-a]吡嗪
  参考文献：
  名称：

  构象受限的N- [2-（3,4-二氯苯基）乙基] -N-甲基-2-（1-吡咯烷基）乙基胺的合成和评价。2.哌嗪，双环胺，桥联双环胺和其他化合物。

  摘要：

  作为我们先前研究（J. Med。Chem。1992，35，4334-4343）的继续，我们构象限制了sigma-受体配体2-（1-吡咯烷基）-N- [2-（3,4-二氯苯基）乙基] -N-甲基乙胺（1）掺入一系列同源的哌嗪3-9和均哌嗪10和11中，二氮杂双环壬烷和癸烷，桥头双环辛烷和壬烷以及其他其他化合物。使用[3H]（+）-喷他佐辛在豚鼠脑膜sigma 1位点获得sigma-受体结合亲和力。研究表明，在哌嗪中发现的氮孤对取向提供最强的结合相互作用。其他氮孤对取向或代表1 [不可能的交错构象的化合物，如4- [2-（3,4-二氯苯基）乙基] -1,4-二氮杂双环[3.2]。2] nonane（16）]显示非常弱的sigma相互作用。比较1的不同N-取代同系物与1- [2-（3,4-二氯苯基）乙基] -4-烷基哌嗪的结合数据表明，1的两个氮原子彼此相反。就其对空间体积的敏感性而言。1,4-二氮杂双环[4

  DOI：

  10.1021/jm00068a007
• 作为产物：
  描述：

  在 三乙胺 作用下， 以 甲醇 为溶剂， 反应 1.0h， 生成 Cyclo-(Gly-Pip)
  参考文献：
  名称：

  构象受限的N- [2-（3,4-二氯苯基）乙基] -N-甲基-2-（1-吡咯烷基）乙基胺的合成和评价。2.哌嗪，双环胺，桥联双环胺和其他化合物。

  摘要：

  作为我们先前研究（J. Med。Chem。1992，35，4334-4343）的继续，我们构象限制了sigma-受体配体2-（1-吡咯烷基）-N- [2-（3,4-二氯苯基）乙基] -N-甲基乙胺（1）掺入一系列同源的哌嗪3-9和均哌嗪10和11中，二氮杂双环壬烷和癸烷，桥头双环辛烷和壬烷以及其他其他化合物。使用[3H]（+）-喷他佐辛在豚鼠脑膜sigma 1位点获得sigma-受体结合亲和力。研究表明，在哌嗪中发现的氮孤对取向提供最强的结合相互作用。其他氮孤对取向或代表1 [不可能的交错构象的化合物，如4- [2-（3,4-二氯苯基）乙基] -1,4-二氮杂双环[3.2]。2] nonane（16）]显示非常弱的sigma相互作用。比较1的不同N-取代同系物与1- [2-（3,4-二氯苯基）乙基] -4-烷基哌嗪的结合数据表明，1的两个氮原子彼此相反。就其对空间体积的敏感性而言。1,4-二氮杂双环[4

  DOI：

  10.1021/jm00068a007

文献信息

• [EN] 1-[(INDOL-3-YL)CARBONYL] PIPERAZINE DERIVATIVES<br/>[FR] DERIVES DE 1-[(INDOL-3-YL)CARBONYL] PIPERAZINE
  申请人：AKZO NOBEL NV

  公开号：WO2004000832A1

  公开（公告）日：2003-12-31

  The present invention relates to 1-[(indol-3-yl)carbonyl]piperazine derivative according to the general formula (I), wherein R represents 1-4 substituents independently selected from H, (C1-4)alkyl (optionally substituted with halogen), (C 1-4)alkyloxy (optionally substituted with halogen), halogen, OH, NH2, CN and NO2; R1 is (C5-8)cycloalkyl or (C5-8)cycloalkenyl; R2 is H, methyl or ethyl; R3, R3', R4' R4', R5, R5' and R6' are independently hydrogen or (C1-4)alkyl, optionally substituted with (C1-4)alkyloxy, halogen or OH; R6 is hydrogen or (C1-4)alkyl, optionally substituted with (C1-4)alkyloxy, halogen or OH; or R6 forms together with R7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R7 forms together with R6 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; or R7 is H, (C1-4)alkyl or (C3-5)cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C1-4)alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.

  本发明涉及根据通式（I）的1-[(indol-3-yl)carbonyl]哌嗪衍生物，其中R代表独立选择的1-4个取代基，包括H，（C1-4）烷基（可选择用卤素取代），（C1-4）烷氧基（可选择用卤素取代），卤素，羟基，氨基，氰基和硝基；R1为（C5-8）环烷基或（C5-8）环烯基；R2为H，甲基或乙基；R3，R3'，R4'，R4'，R5，R5'和R6'独立地为氢或（C1-4）烷基，可选择用（C1-4）烷氧基，卤素或羟基取代；R6为氢或（C1-4）烷基，可选择用（C1-4）烷氧基，卤素或羟基取代；或R6与R7一起形成一个含有O和S等进一步杂原子的4-7元饱和杂环；R7与R6一起形成一个含有O和S等进一步杂原子的4-7元饱和杂环；或R7为H，（C1-4）烷基或（C3-5）环烷基，烷基基团可选择用羟基，卤素或（C1-4）烷氧基取代；或其药学上可接受的盐。该发明还涉及包含所述1-[(indol-3-yl)carbonyl]哌嗪衍生物的药物组合物，并且涉及在治疗疼痛方面使用这些衍生物，如围手术疼痛，慢性疼痛，神经病性疼痛，癌症疼痛以及与多发性硬化症相关的疼痛和痉挛。
• 1-[(Indol-3-yl)carbonyl]piperazine derivatives
  申请人：Cowley Martin Phillip

  公开号：US20050250760A1

  公开（公告）日：2005-11-10

  The present invention relates to 1-[(indol-3-yl)carbonyl]piperazine derivative according to the general formula I or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.

  本发明涉及一种符合通式I的1-[(indol-3-yl)carbonyl]piperazine衍生物，或其药学上可接受的盐。本发明还涉及包含上述1-[(indol-3-yl)carbonyl]piperazine衍生物的药物组合物，以及利用这些衍生物治疗疼痛，例如围手术期疼痛、慢性疼痛、神经病理性疼痛、癌症疼痛以及与多发性硬化相关的疼痛和痉挛。
• Tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives as cannabinoid cb1 receptor agonists
  申请人：Adam-Worrall Julia

  公开号：US20070088025A1

  公开（公告）日：2007-04-19

  The invention relates to tricyclic 1-[(in-dol-3-yl)carbonyl]piperazine derivative having the general Formula (I) wherein X is CH 2 , O or S; R represents 1-3 substituents independently selected from H, (C 1-4 )alkyl, (C 1-4 )alkyloxy and halogen; R 1 is (C 5-8 )cycloalkyl; R 2 is H or (C 1-4 )alkyl; R 3 , R 3 ′, R 4 ′, R 4 ′, R 5 , R 5 ′ and R 6 ′ are independently hydrogen or (C 1-4 )-alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; R 6 is hydrogen or (C 1-4 )alkyl, optionally substituted with (C 1-4 )alkyloxy, OH or halogen; or R 6 forms together with R 7 a 4-7 membered saturated heterocyclic ring, optionally containing a further heteroatom selected from O and S; R 7 forms together with R 6 a 4-7 membered saturated heterocydic ring, optionally containing a further heteroatom selected from O and S; or R 7 is H, (C 1-4 )alkyl or (C 3-5 )cycloalkyl, the alkyl groups being optionally substituted with OH, halogen or (C 1-4 )alkyloxy; or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions comprising said tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives, and to the use of these derivatives in the treatment of pain, such as peri-operative pain, chronic pain neuropathic pain, cancer pain, and pain and spasticity associated with multiple sclerosis.

  本发明涉及三环1-[(吲哚-3-基)羰基]哌嗪衍生物，其具有通式（I），其中X为CH2、O或S；R代表1-3个取自H、（C1-4）烷基、（C1-4）烷氧基和卤素的取代基；R1为（C5-8）环烷基；R2为H或（C1-4）烷基；R3、R3'、R4'、R4'、R5、R5'和R6'独立地为氢或（C1-4）烷基，可选地被（C1-4）烷氧基、OH或卤素取代；R6为氢或（C1-4）烷基，可选地被（C1-4）烷氧基、OH或卤素取代；或R6与R7形成4-7成员饱和杂环环，可选地包含进一步的选自O和S的杂原子；R7与R6a形成4-7成员饱和杂环环，可选地包含进一步的选自O和S的杂原子；或R7为H、（C1-4）烷基或（C3-5）环烷基，烷基基团可选地被OH、卤素或（C1-4）烷氧基取代；或其药学上可接受的盐。本发明还涉及含有上述三环1-[(吲哚-3-基)羰基]哌嗪衍生物的制药组合物，以及在治疗疼痛，如围手术期疼痛、慢性疼痛、神经病性疼痛、癌症疼痛和与多发性硬化症相关的疼痛和痉挛中使用这些衍生物的用途。
• New Serotonin 5-HT_1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage
  作者：Isabel Marco、Margarita Valhondo、Mar Martı́n-Fontecha、Henar Vázquez-Villa、Joaquı́n Del Rı́o、Anna Planas、Onintza Sagredo、José A. Ramos、Iván R. Torrecillas、Leonardo Pardo、Diana Frechilla、Bellinda Benhamú、Marı́a L. López-Rodrı́guez

  DOI：10.1021/jm2007886

  日期：2011.12.8

  We report the synthesis of new compounds 4 35 based on structural modifications of different moieties of previously described lead UCM-2550. The new nonpiperazine derivatives, representing second-generation agonists, were assessed for binding affinity, selectivity, and functional activity at the 5-HT1A receptor (5-HT1AR). Computational beta(2)-based homology models of the ligand receptor complexes were used to explain the observed structure affinity relationships. Selected candidates were also evaluated for their potential in vitro and in vivo neuroprotective properties. Interestingly, compound 26 (2-6-[(3,4:-dihydro-2H-chromen-2-ylmethyl)amino]hexyl}-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione) has been characterized as a high-affinity and potent 5-HT1AR agonist (K-i, = 5.9 nM, EC50 = 21.8 nM) and exhibits neuroprotective effect in neurotoxicity assays in primary cell cultures from rat hippocampus and in the MCAO model of focal cerebral ischemia in rats.
• Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity:  Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties
  作者：María L. López-Rodríguez、M. José Morcillo、Esther Fernández、Esther Porras、Luis Orensanz、M Eugenia Beneytez、Jorge Manzanares、Jose Angel Fuentes

  DOI：10.1021/jm000929u

  日期：2001.1.1

  In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT1A and alpha (1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH2)(3)-, -(CH2)(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT1A and alpha (1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural-networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT1A: K-i = 27 nM; alpha (1): K-i > 1000 nM). This derivative displays affinity for the dopamine D-2 receptor (K-i = 22 nM) and is selective versus all other receptors examined (5-HT2A, 5-HT3, 5-HT4 and Bz; K-i > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and; as an antagonist in the dopamine D-2 receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT1A/D-2 antagonist properties and this derivative could be useful as a pharmacological tool.