(RS)-4-[N-(tert-butyloxycarbonyl)methylamino]-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole | 182317-21-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (RS)-4-[N-(tert-butyloxycarbonyl)methylamino]-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole
• 英文别名: (R,S)-4-(N-tert-butyloxycarbonyl-N-methylamino)-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole；4-(N-tert-butyloxycarbonyl-N-methylamino)-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole；tert-butyl N-methyl-N-(3-oxo-4,5,6,7-tetrahydro-1,2-benzoxazol-4-yl)carbamate
• CAS: 182317-21-1
• 化学式: C₁₃H₂₀N₂O₄
• 分子量: 268.313
• InChiKey: ZVUOYGWTWXPECF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (RS)-4-[N-(tert-butyloxycarbonyl)methylamino]-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 在 盐酸 、 potassium carbonate 、 sodium iodide 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 122.0h， 生成 4-[(4,4-diphenyl-but-3-enyl)-methyl-amino]-4,5,6,7-tetrahydro-benzo[d]isoxazol-3-ol; hydrochloride
  参考文献：
  名称：

  Selective inhibitors of GABA uptake: synthesis and molecular pharmacology of 4-N-methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol analogues

  摘要：

  A series of lipophilic diaromatic derivatives of the glia-selective GABA uptake inhibitor (R)-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol [(R)-exo-THPO, 4] were synthesized via reductive amination of 3-ethoxy-4,5,6,7-tetrahydrobenzo[d]isoxazol-4-one (9) or via N-alkylation of O-alkylatedracemic 4. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation or primary cultures of mouse cortical neurons and glia cells (astrocytes), as well as HEK cells transfected with cloned mouse GABA transporter subtypes (GAT1-4). The activity against isoniazid-induced convulsions in mice after subcutaneous administration of the compounds was determined. All of the compounds were potent inhibitors of synaptosomal uptake the most potent compound being (RS)-4-[N-(1,1-diphenylbut-1-4-en-yl)amino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (17a, IC50 = 0.14 muM). The majority of the compounds showed a weak preference for glial, as compared to neuronal, GABA uptake. The highest degree of selectivity was 10-fold corresponding to the glia selectivity of (R)-N-methyl-exo-THPO (5). All derivatives showed a preference for the GAT1 transporter, as compared with GAT2-4, with the exception of (RS)-4-[N-[1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl]-N-methylamino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (28d), which quite surprisingly turned out to be more potent than GABA at both GAT1 and GAT2 subtypes. The GAT1 activity was shown to reside in (R)-28d whereas (R)-28d and (S)-28d contributed equally to GAT2 activity. This makes (S)-28d a GAT2 selective compound, and (R)-28d equally effective in inhibition of GAT1 and GAT2 mediated GABA transport. All compounds tested were effective as anticonvulsant reflecting that these compounds have blood-brain barrier permeating ability. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2004.10.029
• 作为产物：
  描述：

  3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one 在 sodium hydroxide 、 3 A molecular sieve 、 氢溴酸 、 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 为溶剂， 反应 21.83h， 生成 (RS)-4-[N-(tert-butyloxycarbonyl)methylamino]-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole
  参考文献：
  名称：

  神经胶质GABA摄取的选择性抑制剂：3-羟基-4-氨基-4,5,6,7-四氢-1,2-苯并恶唑（exo-THPO）和类似物的对映异构体的合成，绝对立体化学和药理作用。

  摘要：

  3-甲氧基-4,5,6,7-四氢-1,2-苯并恶唑-4-酮（20a）或相应的3-乙氧基类似物（20b）和3-氯-4,5,6,7 -四氢-1,2-苯并噻唑-4（51）是通过区域选择性铬酸氧化相应的双环四氢苯（19a，b和50）合成的，它们用作合成目标两性离子3-异恶唑的关键中间体8-15和3-异噻唑16和17。这些反应序列涉及不同的还原过程。鉴于（RS）-4-氨基-3-羟基-4,5,6,7-四氢-1,2-苯并恶唑（8，exo-THPO）是通过肟22a或22b的铝汞齐还原合成的，化合物9通过还原胺化获得11-13和15-17。通过N-Boc保护的伯胺25的N-乙基化合成化合物10。通过由伯胺23b和（R）-α-甲氧基苯基乙酰氯合成并随后通过制备型HPLC分离的非对映酰胺32和33，以高对映体纯度（ee≥99.1％）获得8的对映体。由仲胺27类似地制备9的对映异构体。基于X射线晶体学分析，肟22a的构型显示为E，（-）-8

  DOI：

  10.1021/jm9904452

文献信息

• 4-aminotetrahydrobenzisoxazole or -isothiazole compounds
  申请人：H. Lundbeck A/S

  公开号：US05998613A1

  公开（公告）日：1999-12-07

  The present invention relates to novel 4-aminotetrahydrobenzisoxazoles or 4-aminotetrahydrobenziothiazoles having gamma-aminobutanoic acid (GABA)-uptake inhibiting activity and thus useful in the treatment of analgesia, psychosis, convulsions, anxiety, epileptic disorders or muscular and movement disorders, such as spastic disorders or symptoms in Huntington's disease or Parkinson disease.

  本发明涉及具有γ-氨基丁酸（GABA）摄取抑制活性的新型4-氨基四氢苯并异噁唑或4-氨基四氢苯并噻唑，因此在治疗疼痛、精神病、抽搐、焦虑、癫痫性疾病或肌肉和运动障碍方面具有用处，如在亨廷顿病或帕金森病中的痉挛障碍或症状。
• 4-AMINOTETRAHYDROBENZISOXAZOLE OR -ISOTHIAZOLE COMPOUNDS
  申请人：H. LUNDBECK A/S

  公开号：EP0812318B1

  公开（公告）日：2006-02-08
• US5998613A
  申请人：——

  公开号：US5998613A

  公开（公告）日：1999-12-07
• US6174909B1
  申请人：——

  公开号：US6174909B1

  公开（公告）日：2001-01-16
• Selective Inhibitors of Glial GABA Uptake:  Synthesis, Absolute Stereochemistry, and Pharmacology of the Enantiomers of 3-Hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (<i>exo</i>-THPO) and Analogues
  作者：Erik Falch、Jens Perregaard、Bente Frølund、Birgitte Søkilde、Anders Buur、Lene M. Hansen、Karla Frydenvang、Lotte Brehm、Tina Bolvig、Orla M. Larsson、Connie Sanchez、Harold S. White、Arne Schousboe、Povl Krogsgaard-Larsen

  DOI：10.1021/jm9904452

  日期：1999.12.1

  was more pronounced for 9, which showed IC(50) values of 40 and 500 microM as an inhibitor of glial and neuronal GABA uptake, respectively. These effects of 8 and 9 proved to be enantioselective, (R)-(-)-8 and (R)-(+)-9 being the active inhibitors of both uptake systems. The selectivity of 9 as a glial GABA uptake inhibitor was largely lost by replacing the N-methyl group of 9 by an ethyl group, compound

  3-甲氧基-4,5,6,7-四氢-1,2-苯并恶唑-4-酮（20a）或相应的3-乙氧基类似物（20b）和3-氯-4,5,6,7 -四氢-1,2-苯并噻唑-4（51）是通过区域选择性铬酸氧化相应的双环四氢苯（19a，b和50）合成的，它们用作合成目标两性离子3-异恶唑的关键中间体8-15和3-异噻唑16和17。这些反应序列涉及不同的还原过程。鉴于（RS）-4-氨基-3-羟基-4,5,6,7-四氢-1,2-苯并恶唑（8，exo-THPO）是通过肟22a或22b的铝汞齐还原合成的，化合物9通过还原胺化获得11-13和15-17。通过N-Boc保护的伯胺25的N-乙基化合成化合物10。通过由伯胺23b和（R）-α-甲氧基苯基乙酰氯合成并随后通过制备型HPLC分离的非对映酰胺32和33，以高对映体纯度（ee≥99.1％）获得8的对映体。由仲胺27类似地制备9的对映异构体。基于X射线晶体学分析，肟22a的构型显示为E，（-）-8