octahydro-4,7-ethano-cyclobuta[f]isoindole-1,3-dione | 4960-04-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: octahydro-4,7-ethano-cyclobuta[f]isoindole-1,3-dione
• 英文别名: 4-Azatetracyclo[5.4.2.02,6.08,11]tridecane-3,5-dione
• CAS: 4960-04-7
• 化学式: C₁₂H₁₅NO₂
• 分子量: 205.257
• InChiKey: MWTNVBHCPXCHMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.83
• 拓扑面积：
  46.2
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  octahydro-4,7-ethano-cyclobuta[f]isoindole-1,3-dione 在 sodium hydride 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-[4-[4-(6-Chloropyrazin-2-yl)piperazin-1-yl]butyl]-4-azatetracyclo[5.4.2.02,6.08,11]tridecane-3,5-dione
  参考文献：
  名称：

  Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies

  摘要：

  A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.

  DOI：

  10.1021/jm00402a023

文献信息

• Fused bicyclic imides with psychotropic activity
  申请人：AMERICAN HOME PRODUCTS CORPORATION

  公开号：EP0220873A1

  公开（公告）日：1987-05-06

  There are disclosed compounds of the formula wherein R represents formula III or represents -CHR1-CHR2-wherein R1 and R2 taken together represent formula II or IV with the proviso that the sum of o and p in formula III and in formula IV where Y is -(CH2)0- is not zero; R3 is unsubstituted or substituted phenyl, 2-pyridinyl, 2-pyrimidinyl, 2-pyrazinyl or 3-pyridazinyl, where the substituents are selected from the group lower alkyl, lower alkoxy, halo, cyano, nitro and trifluoromethyl, with the proviso that when R1 and R2 taken together represent formula II in which X is O,methylene or dimethylene, R3 is other than unsubstituted or substituted phenyl, 2-pyridinyl or 2-pyrimidinyl; Y is -(CH2)0- or vinylene; X is lower alkylene, vinylene or O; m is 2-4; n is 1 - 3; o is 0 - 3; p is 0 - 4; .... represents a single or double bond; and the pharmaceutically acceptable salts thereof and their use as antipsychotic/ anxiolytic agents having a low liability for extrapyramidal side effects.

  公开了如下式的化合物 其中 R 代表式 III 或代表 -CHR1-CHR2- 其中 R1 和 R2 合在一起代表式 II 或 IV 但在式 III 和 Y 为-(CH2)0-的式 IV 中，o 和 p 之和不为零；R3 为未取代或取代的苯基、2-吡啶基、2-嘧啶基、2-吡嗪基或 3-哒嗪基，其中取代基选 自低级烷基、低级烷氧基、卤代、氰基、硝基和三氟甲基，但当 R1 和 R2 合在一起代表式 II（其中 X 为 O、亚甲基或二亚甲基）时，R3 不是未取代或取代的苯基、2-吡啶基或 2-嘧啶基； Y 是-(CH2)0-或亚乙烯； X 是低级亚烷基、亚乙烯基或 O； m 是 2-4； n 是 1 - 3 o 是 0 - 3 p 为 0 - 4； .... 代表单键或双键；及其药学上可接受的盐类，以及它们作为抗精神病药/抗焦虑药的用途，具有较低的锥体外系副作用。
• ABOU-GHARBIA, MAGID;PATEL, USHA R.;WEBB, MICHAEL B.;MOYER, JOHN A.;ANDREE+, J. MED. CHEM., 31,(1988) N 7, 1382-1392
  作者：ABOU-GHARBIA, MAGID、PATEL, USHA R.、WEBB, MICHAEL B.、MOYER, JOHN A.、ANDREE+

  DOI：——

  日期：——
• Polycyclic aryl- and heteroarylpiperazinyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies
  作者：Magid Abou-Gharbia、Usha R. Patel、Michael B. Webb、John A. Moyer、Terrance H. Andree、Eric A. Muth

  DOI：10.1021/jm00402a023

  日期：1988.7

  A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.