(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl)-methanone

• 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: (4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl)-methanone
• 英文别名: (4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanone；(4-benzyl-piperidin-1yl)-(6-hydroxy-1H-benzoimidazol-2-yl)-methanone；(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl)methanone
• 化学式: C₂₀H₂₁N₃O₂
• 分子量: 335.406
• InChiKey: BOZSYJQUWROAKM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  69.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-甲氧基-2-硝基苯胺 在 palladium on activated charcoal 氢溴酸 、 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 58.17h， 生成 (4-benzylpiperidin-1-yl)-(6-hydroxy-1H-benzimidazol-2-yl)-methanone
  参考文献：
  名称：

  Benzimidazole-2-carboxamides as novel NR2B selective NMDA receptor antagonists

  摘要：

  A novel series of benzimidazole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of some structural elements, like H-bond donor groups placed on the benzimidazole skeleton and the substitution pattern of the piperidine ring, on the biological activity was studied. Compound 6a showed excellent analgetic activity in the mouse formalin test following po administration. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.06.002

文献信息

• Selective NR1/2B <i>N</i>-Methyl-<scp>d</scp>-aspartate Receptor Antagonists among Indole-2-carboxamides and Benzimidazole-2-carboxamides
  作者：István Borza、Éva Bozó、Gizella Barta-Szalai、Csilla Kiss、Gábor Tárkányi、Ádám Demeter、Tamás Gáti、Viktor Háda、Sándor Kolok、Anikó Gere、László Fodor、József Nagy、Kornél Galgóczy、Ildikó Magdó、Béla Ágai、József Fetter、Ferenc Bertha、György M. Keserü、Csilla Horváth、Sándor Farkas、István Greiner、György Domány

  DOI：10.1021/jm060420k

  日期：2007.3.1

  (4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.

  (4-苄基哌啶-1-基)-(6-羟基-1H-吲哚-2-基)-甲酮(6a)是从(E)-1-(4-苄基哌啶-1-基)-3-(4-羟基苯基)丙烯酮(5)中鉴定出的一种强效的NMDA受体NR2B亚基选择性拮抗剂。为了建立结构-活性关系(SAR)并尝试改善先导化合物的ADME性质，制备并测试了一系列化合物。多种衍生物在结合和功能性测定中均显示出低纳摩尔的活性。在环磷酰胺诱导的小鼠痛觉过敏模型中，6a和(4-苄基哌啶-1-基)-[5(6)-羟基-1H-联吡啶-2-基]-甲酮(60a)在口服给药后与Besonprodil(2)具有相同的活性。基于一系列吲哚-和联吡啶-2-羧酰胺的结合数据，开发了一种CoMSIA模型。
• Amide derivatives as NMDA receptor antagonists
  申请人：RICHTER GEDEON VEGYESZETI GYAR RT.

  公开号：US20030199552A1

  公开（公告）日：2003-10-23

  New Formula (I) compounds are disclosed having NR2B selective NMDA receptor antagonist activity 1 wherein one of the neighboring R 1 , R 2 , R 3 and R 4 groups is OH or NH2 and the others are each hydrogen , or two of the neighboring R 1 , R 2 R 3 and R 4 groups in given case together with one or more identical or different additional hetero atom and —CH═ and/or —CH 2 — groups forms a 5-6 membered homo- or heterocyclic ring, preferably pyrrole, pyrazole, imidazole, oxazole, oxo-oxazolidine, or 3-oxo-1,4-oxazine ring, and the other two of R 1 , R 2 , R 3 and R 4 groups are is hydrogen atoms, R 5 and R 6 together with the nitrogen between them form a saturated or unsaturated, 4-6 membered heterocyclic ring, which is substituted by hydroxy group, and/or in given case phenyl or phenoxy, phenyl-(C 1 -C 4 alkyl), phenyl-(C 1 -C 4 alkoxy), phenoxy-(C 1 -C 4 alkyl), anilino, phenyl-(C 1 -C 4 alkylamino), [phenyl-(C 1 -C 4 alkyl)]-amino, benzoyl, hydroxy-diphenylmethyl, C 1 -C 4 alkoxycarbonyl-phenoxymethyl or benzhydrylidene group, optionally substituted on the aromatic ring by one or more halogen atom, cyano or hydroxy group, C 1 -C 4 alkyl or C 1 -C 4 alkoxy group, X is independently oxygen, —NH— or a CH2 group, Y is independently a nitrogen atom or a —CH— group, and the salts thereof formed with acids and bases.

  揭示了具有NR2B选择性NMDA受体拮抗活性的新配方(I)化合物，其中相邻的R1、R2、R3和R4基团中的一个是OH或NH2，其他基团均为氢，或者在某些情况下，相邻的R1、R2、R3和R4基团中的两个与一个或多个相同或不同的额外杂原子和—CH和/或—CH2—基团一起形成5-6元素的同源或异源环，优选为吡咯、吡唑、咪唑、噁唑、噁唑烷酮或3-氧代-1,4-噁唑环，并且R1、R2、R3和R4中的另外两个基团是氢原子，R5和R6与它们之间的氮原子一起形成饱和或不饱和的、4-6元素的杂环，该环被羟基取代，或者在某些情况下为苯基或苯氧基、苯基-(C1-C4烷基)、苯基-(C1-C4氧基)、苯氧基-(C1-C4烷基)、苯胺基、苯基-(C1-C4烷基氨基)、[苯基-(C1-C4烷基)]-氨基、苯甲酰基、羟基-二苯甲基、C1-C4烷氧羰基-苯氧基甲基或苯甲亚乙基基团取代的芳环，该芳环上可以进一步取代一个或多个卤素原子、氰基或羟基、C1-C4烷基或C1-C4氧基基团，X独立地为氧、—NH—或CH2基团，Y独立地为氮原子或—CH—基团，以及与酸和碱形成的盐。
• [EN] NEW HETEROCYCLIC CARBOXYLIC ACID AMIDE DERIVATIVES<br/>[FR] NOUVEAUX DERIVES AMIDES D'ACIDE CARBOXYLIQUE HETEROCYCLIQUE
  申请人：RICHTER GEDEON VEGYESZET

  公开号：WO2006010969A1

  公开（公告）日：2006-02-02

  The invention relates to new heterocyclic carboxylic acid amide derivatives of formula (I) - wherein the meaning of X is hydrogen or halogen atom, hydroxy, cyano, C1-C4 alkylsulfonamido optionally substituted by a halogen atom or halogen atoms, C1-C4 alkanoylamido optionally substituted by a halogen atom or halogen atoms, arylsulfonamido groups, is -CH= group or -N= atom, Z is one or more hydrogen or halogen atom, C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, trifluoromethoxy group and to the salts thereof, which are antagonists of NMDA receptor or are intermediates for preparing thereof.

  该发明涉及公式（I）的新杂环羧酸酰胺衍生物，其中X的含义是氢或卤素原子，羟基，氰基，C1-C4烷基磺酰胺（可选择地由卤素原子或卤素原子取代），C1-C4烷酰胺（可选择地由卤素原子或卤素原子取代），芳基磺酰胺基团，-CH=基团或-N=原子，Z是一个或多个氢或卤素原子，C1-C4烷基，C1-C4烷氧基，氰基，三氟甲基，三氟甲氧基团及其盐，这些衍生物是NMDA受体的拮抗剂或用于其制备的中间体。
• [EN] AMIDE DERIVATIVES AS NMDA RECEPTOR ANTAGONISTS<br/>[FR] DERIVES AMIDIQUES COMME ANTAGONISTES DU RECEPTEUR NMDA
  申请人：RICHTER GEDEON VEGYESZET

  公开号：WO2002034718A1

  公开（公告）日：2002-05-02

  The invention relates to new NR2B selective NMDA receptor antagonist carboxylic acid amide derivatives of formula (I) as well as the recemates, optical antipodes and the salts thereof formed with acids and bases. Fruthermore objets of the present invention are the pharmaceutical compositions containing compounds of formula (I) or the salts thereof as active ingredients, as well as the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the method of treatments with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament. The new carboxylic acid amide derivatives of formula (I) of the present invention are highly effective and selective antagonists of NMDA receptor, and moreover most of the compounds are selective antagonist of NR2B subtype of NMDA receptor.

  本发明涉及公式（I）的新型NR2B选择性NMDA受体拮抗剂羧酸酰胺衍生物，以及与酸和碱形成的外消旋体，光学对映体和其盐。此外，本发明的目标是含有公式（I）化合物或其盐作为活性成分的制药组合物，以及公式（I）化合物的合成，以及含有这些化合物的药物的化学和制药制造，以及使用这些化合物的治疗方法，即向待治疗的哺乳动物（包括人类）施用本发明的化合物的有效量/量，作为药物或单独使用。本发明的新型羧酸酰胺衍生物的公式（I）是高效和选择性的NMDA受体拮抗剂，而且大多数化合物是NMDA受体NR2B亚型的选择性拮抗剂。
• AMIDE DERIVATIVES AS NMDA RECEPTOR ANTAGONISTS
  申请人：RICHTER GEDEON VEGYESZETI GYAR R.T.

  公开号：EP1328514A1

  公开（公告）日：2003-07-23