2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocycloheptindole | 147213-06-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocycloheptindole
• 英文别名: (10S*)-2-fluoro-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole；2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole；5-fluoro-9,15-diazatetracyclo[10.2.1.02,10.03,8]pentadeca-2(10),3(8),4,6-tetraene
• CAS: 147213-06-7
• 化学式: C₁₃H₁₃FN₂
• 分子量: 216.258
• InChiKey: BHBOTTMNPGXYAZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  27.8
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocycloheptindole 生成 (+)-2-fluoro-5,6,7,8,9,10-hexahydro-7(S),10(R)-iminocycloheptindole
  参考文献：
  名称：

  解析的5,6,7,8,9,10-六氢-7,10-亚氨基环庚[b]吲哚的D2 / 5-HT2亲和力比：对潜在的非典型抗精神病药设计的对映选择性方法。

  摘要：

  通过拆分2-氟-5,6,7,8,9,10获得了一些N-取代的5,6,7,8,9,10-六氢-7,10-亚氨基环庚[b]吲哚的对映异构体-六氢-7,10-亚氨基环庚[b]吲哚和5,6,7,8,9,10-六氢-7,10-亚氨基环庚[b]吲哚，然后进行N-烷基化。评价了这些以及外消旋体对5-HT 2和D 2受体的亲和力。那些具有7S，10R立体化学的化合物一直被5-HT2和D2受体识别为eutomer。2-氟-11- [4-（4-氟苯基）-4-氧丁基] -5,6,7,8,9,10-六氢-7S，10 R-亚氨基环庚[b]吲哚[（7S，10R） -8]对5-HT2受体的亲和力最高（Ki = 0.80 nM），而其异构体（7R，10S）-8是此类桥联的伽马咔啉中最具选择性的成员（D2 / 5-HT2 = 562）。

  DOI：

  10.1021/jm00073a005
• 作为产物：
  描述：

  tropinone 在 potassium carbonate 、 溶剂黄146 、 锌 作用下， 生成 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocycloheptindole
  参考文献：
  名称：

  Bridged .gamma.-carbolines and derivatives possessing selective and combined affinity for 5-HT2 and D2 receptors

  摘要：

  A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and 6,7,8,9,10,11-hexahydro-7,-11-imino-5H-cyclooct[b]indoles was prepared. Structural modifications of the lead compound, 11-[4-(4-fluorobenzoyl)propyl]-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole (5, K(i) = 0.82 nM vs [H-3]ketanserin) enabled the identification of the functionality necessary for high affinity at serotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety, were essential for high affinity. Variations of the length of the side chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo binding studies were performed on selected members in this series. The most potent member, 2-fluoro-11-[4-(4-fluorobenzoyl)butyl]-5,6,7,8,9,-10-hexahydro-7,10-iminocyclohept[b]indole (36) had an ED50 of <1 mg/kg at the 5-HT2 and D2 receptors following oral administration.

  DOI：

  10.1021/jm00062a023

文献信息

• [EN] 1, 3, 4, 5-TETRAHYDRO-2H-PYRIDO[4,3-B]INDOLE DERIVATIVES FOR THE TREATMENT, ALLEVIATION OR PREVENTION OF DISORDERS ASSOCIATED WITH TAU AGGREGATES LIKE ALZHEIMER'S DISEASE<br/>[FR] DÉRIVÉS DE 1,3,4,5-TÉTRAHYDRO-2H-PYRIDO[4,3-B]INDOLE POUR LE TRAITEMENT, LE SOULAGEMENT OU LA PRÉVENTION DE TROUBLES ASSOCIÉS À DES AGRÉGATS DE TAU COMME LA MALADIE D'ALZHEIMER
  申请人：AC IMMUNE SA

  公开号：WO2019134978A1

  公开（公告）日：2019-07-11

  The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

  本发明涉及一类新化合物，可用于治疗、缓解或预防与Tau蛋白聚集相关的一组疾病和异常，包括但不限于神经原纤维缠结（NFTs），如阿尔茨海默病（AD）。
• 5,6,7,8,9,10-hexahydro-7
  申请人：Scios Nova Inc.

  公开号：US05250537A1

  公开（公告）日：1993-10-05

  5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indole, 6,7,8,9,10,11-hexahydro-7,11-imino-5H-cyclooct[b]indole and substituted derivatives are effective in the treatment of psychoses with limited liability to produce concomitant adverse extrapyramidal symptoms. These compounds are also useful for treating other central nervous system and cardiovascular disorders.

  5,6,7,8,9,10-六氢-7,10-亚胺基环庚[b]吲哚、6,7,8,9,10,11-六氢-7,11-亚胺基-5H-环辛[b]吲哚及其取代衍生物在治疗精神病方面具有有效性，且具有产生伴随不良锥体外系症状的有限责任。这些化合物也可用于治疗其他中枢神经系统和心血管疾病。
• Compounds for the treatment, alleviation or prevention of disorders associated with Tau aggregates
  申请人：AC Immune SA

  公开号：US10633383B2

  公开（公告）日：2020-04-28

  The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

  本发明涉及新型化合物，可用于治疗、缓解或预防与 Tau（微管蛋白相关单位）蛋白聚集有关的一组疾病和异常，包括但不限于神经纤维缠结（NFT），如阿尔茨海默病（AD）。
• Synthesis and in vitro evaluation of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: high-affinity ligands for the N,N'-di-o-tolylguanidine-labeled .sigma. binding site
  作者：Richard E. Mewshaw、Ronald G. Sherrill、Rose M. Mathew、Carl Kaiser、Michael A. Bailey、E. William Karbon

  DOI：10.1021/jm00055a005

  日期：1993.2

  A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclo[b]indoles substituted at the 5 and/or 11 positions was synthesized from tropinone. Affinity for sigma binding sites was determined using [H-3]-N,N'-di-o-tolylguanidine ([H-3]DTG) and [H-3]-(+)-3-(3-hydroxyphenyl)-N-1-propylpiperidine ([H-3]-(+)-3-PPP) and for the dopamine D2 receptor labeled with [H-3]sulpiride. Nearly all compounds studied in this series possessed a higher affinity for [H-3]DTG than [H-3]-(+)-PPP-labeled sigma sites, suggesting that [H-3]DTG and [H-3]-(+)-3-PPP radioligands label pharmacologically distinct sigma binding sites, as reported previously. Substitution at the 11 position with side chains containing a four-carbon tether resulted in compounds having the highest affinity for the [H-3]DTG-labeled a site. The most potent and selective member of this series was 11-[4-(2-furanyl)butyl]-5,6,7,8,9, 10-hexahydro-7,10-iminocyclohept[b]indole(40). Enantioselectivity was investigated by preparing the (+)- and (-)-isomers of 40. These studies revealed that (+)-40 was more potent at the [H-3]-DTG-labeled sigma site whereas (-)-40 had a higher affinity at sigma sites labeled with [H-3]-(+)-PPP. Racemic 40 was observed to possess a higher affinity than either of its respective enantiomers at both the [H-3]DTG- and [H-3]-(+)-3-PPP-labeled sites, suggesting an allosteric interaction.
• Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library
  作者：Ruwei Yao、Anders A. Jensen、Hogan P. Bryce-Rogers、Katrine Schultz-Knudsen、Libin Zhou、Nicklas P. Hovendal、Henrik Pedersen、Mariusz Kubus、Trond Ulven、Luca Laraia

  DOI：10.1021/acs.jmedchem.3c01059

  日期：2023.8.24