4-phenyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)piperidine | 269084-96-0

• 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-phenyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)piperidine
• CAS: 269084-96-0
• 化学式: C₂₂H₂₇N
• 分子量: 305.463
• InChiKey: DHMDOIVYRXIWRW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  5,6,8,9-四氢-苯并环庚烯-7-酮 在 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 30.0h， 生成 4-phenyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)piperidine
  参考文献：
  名称：

  Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines

  摘要：

  Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)(3) led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by S(N)2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (K-i = 2.3 nM and 2.9 nM, respectively). With respect to selectivity against the PCP binding site, sigma(1) and sigma(2) receptors the phenylpiperazine 6f is the most promising GluN2B antagonist. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.10.004

文献信息

• Novel compounds
  申请人：SmithKline Beecham SpA

  公开号：US20040024218A1

  公开（公告）日：2004-02-05

  Compounds of formula I, or a salt thereof or a hydrate thereof, as follows: 1 wherein X and Y are selected independently from hydrogen and aryl, which aryl is unsubstituted or substituted one or more times by hydroxy, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, aryl, heterocyclyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, arylC 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkoxy or halo, which alkyl or alkoxy groups are unsubstituted or substituted one or more times by halo; m and n are independently 0 to 3, provided that m and n are not both 0; A represents a single bond or is —(CR pa R pb ) p — wherein p is 1-3 and R pa and R pb are selected independently from hydrogen, C 1-6 alkyl, C 1-6 alkoxy and halo, which alkyl or alkoxy groups are independently substituted one or more times by halo; B represents a C 4-8 saturated or unsaturated ring, which ring is unsubstituted or substituted one or more times by C 1-6 alkyl, C 1-6 alkoxy, aryl, aryloxy, hydroxy, oxo, halo, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, and C 1-6 alkylamido, which C 1-6 alkyl or C 1-6 alkoxy groups are unsubstituted or substituted one or more times by halo, which aryl group is unsubstituted or substituted one or more times by aryl, heterocyclyl, aryloxy, arylC 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, arylC 1-6 alkyl, hydroxy, C 1-6 alkenoxy, C 1-6 alkoxy, halo, or C 1-6 alkyl, which C 1-6 alkyl may be substituted one or more times by halo, and which aryl group is linked to said ring by a single bond or is benzo-condensed therewith are ligands of the ORL-1 receptor.

  式I的化合物，或其盐或水合物，如下所示：其中X和Y分别选择自氢和芳基，所述芳基未取代或被羟基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、芳基、杂环烷基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、芳基C1-6烷氧基、C1-6烷基、C1-6烷氧基或卤素取代一次或多次，其中烷基或烷氧基基团未取代或被卤素取代一次或多次；m和n独立地为0到3，但要求m和n不能同时为0；A代表单键或为—(CRpaRpb)p—，其中p为1-3且Rpa和Rpb独立选择自氢、C1-6烷基、C1-6烷氧基和卤素，其中烷基或烷氧基基团独立地被卤素取代一次或多次；B代表C4-8饱和或不饱和环，所述环未取代或被C1-6烷基、C1-6烷氧基、芳基、芳氧基、羟基、氧代、卤素、氨基、C1-6烷基氨基、二(C1-6烷基)氨基和C1-6烷酰胺取代一次或多次，其中C1-6烷基或C1-6烷氧基基团未取代或被卤素取代一次或多次，所述芳基未取代或被芳基、杂环烷基、芳氧基、芳基C1-6烷氧基、氨基、C1-6烷基氨基、二(C1-6烷基)氨基、芳基C1-6烷基、羟基、C1-6烯氧基、C1-6烷氧基、卤素或C1-6烷基取代一次或多次，所述C1-6烷基可能被卤素取代一次或多次，所述芳基通过单键与所述环相连或与之苯并结合的化合物是ORL-1受体的配体。
• N-SUBSTITUTED AZACYCLES, THEIR PREPARATION AND THEIR USE AS ORL-1 RECEPTOR LIGANDS
  申请人：Smithkline Beecham S.p.A.

  公开号：EP1129072A2

  公开（公告）日：2001-09-05
• US6969724B2
  申请人：——

  公开号：US6969724B2

  公开（公告）日：2005-11-29
• [EN] NOVEL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS
  申请人：SMITHKLINE BEECHAM SPA

  公开号：WO2000027815A2

  公开（公告）日：2000-05-18

  Compounds of formula (I) or a salt thereof or a hydrate thereof, as follows: wherein X and Y are selected independently from hydrogen and aryl, which aryl is unsubstituted or substituted one or more times by hydroxy, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, aryl, heterocyclyl, amino, C1-6alkylamino, di(C1-6alkyl)amino, arylC1-6alkoxy, C1-6alkyl, C1-6alkoxy or halo, which alkyl or alkoxy groups are unsubstituted or substituted one or more times by halo; m and n are independently 0 to 3, provided that m and n are not both 0; A represents a single bond or is -(CRpa Rpb)p- wherein p is 1-3 and Rpa and Rpb are selected independently from hydrogen, C1-6alkyl, C1-6alkoxy and halo, which alkyl or alkoxy groups are independently substituted one or more times by halo; B represents a C4-8 saturated or unsaturated ring, which ring is unsubstituted or substituted one or more times by C1-6alkyl, C1-6alkoxy, aryl, aryloxy, hydroxy, oxo, halo, amino, C1-6alkylamino, di(C1-6alkyl)amino, and C1-6alkylamido, which C1-6alkyl or C1-6alkoxy groups are unsubstituted or substituted one or more times by halo, which aryl group is unsubstituted or substituted one or more times by aryl, heterocyclyl, aryloxy, arylC1-6alkoxy, amino, C1-6alkylamino, di(C1-6alkyl)amino, arylC1-6alkyl, hydroxy, C1-6alkenoxy, C1-6alkoxy, halo, or C1-6, which C1-6alkyl may be substituted one or more times by halo, and which aryl group is linked to said ring by a single bond or is benzo-condensed therewith are ligands of the ORL-1 receptor.
• Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines
  作者：Sandeep Gawaskar、Dirk Schepmann、Alessandro Bonifazi、Bernhard Wünsch

  DOI：10.1016/j.bmc.2014.10.004

  日期：2014.12

  Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)(3) led to the secondary amines 6a-d, cis-6h and trans-6i. The tertiary amines 6e-g were obtained by S(N)2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (K-i = 2.3 nM and 2.9 nM, respectively). With respect to selectivity against the PCP binding site, sigma(1) and sigma(2) receptors the phenylpiperazine 6f is the most promising GluN2B antagonist. (C) 2014 Elsevier Ltd. All rights reserved.