tert-butyl (1S,5R)-3-(4-bromophenyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate | 851527-76-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: tert-butyl (1S,5R)-3-(4-bromophenyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate
• CAS: 851527-76-9
• 化学式: C₁₆H₂₁BrN₂O₂
• 分子量: 353.259
• InChiKey: YMPRECSZKNYVRU-FZMZJTMJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl (1S,5R)-3-(4-bromophenyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate 在 盐酸 作用下， 以 甲醇 、 水 为溶剂， 生成
  参考文献：
  名称：

  Design of a New Histamine H₃ Receptor Antagonist Chemotype: (3aR,6aR)-5-Alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, Synthesis, and Structure−Activity Relationships

  摘要：

  A new histamine H-3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based oil a previously identified conessine-based H3R. antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H-3 K-i of 0.54 nM, rat H-3 K-i of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).

  DOI：

  10.1021/jm900480x
• 作为产物：
  描述：

  (1S,5R)-3,6-二氮杂双环[3.2.0]庚烷-6-羧酸叔丁酯 、 1,4-二溴苯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 生成 tert-butyl (1S,5R)-3-(4-bromophenyl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate
  参考文献：
  名称：

  Design of a New Histamine H₃ Receptor Antagonist Chemotype: (3aR,6aR)-5-Alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, Synthesis, and Structure−Activity Relationships

  摘要：

  A new histamine H-3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based oil a previously identified conessine-based H3R. antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H-3 K-i of 0.54 nM, rat H-3 K-i of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).

  DOI：

  10.1021/jm900480x

文献信息

• Substituted Diazabicycloalkane Derivates
  申请人：Frost Jennifer M.

  公开号：US20080275048A1

  公开（公告）日：2008-11-06

  Compounds of formula (I) Z-Ar 1 —Ar 2 (I) wherein Z is a diazabicyclic amine, Ar 1 is a 5- or 6-membered aromatic ring, and Ar 2 is selected from the group consisting of an unsubstituted or substituted 5- or 6-membered heteroaryl ring; unsubstituted or substituted bicyclic heteroaryl ring; 3,4-(methylenedioxy)phenyl; carbazolyl; tetrahydrocarbazolyl; naphthyl; and phenyl; wherein the phenyl is substituted with 0, 1, 2, or 3 substituents in the meta- or para-positions. The compounds are useful in treating conditions or disorders prevented by or ameliorated by α7 nAChR ligands. Also disclosed are pharmaceutical compositions comprising compounds of formula (I) and methods for using such compounds and compositions.

  化合物的公式为（I）Z-Ar1—Ar2（I），其中Z是一种二氮杂双环胺，Ar1是一种5或6成员芳香环，而Ar2则选自未取代或取代的5或6成员杂芳基环；未取代或取代的双环杂芳基环；3,4-（亚甲氧基）苯基；咔唑基；四氢咔唑基；萘基；和苯基；其中苯基在间位或对位上取代有0、1、2或3个取代基。这些化合物在治疗由α7 nAChR配体预防或改善的疾病或疾病方面是有用的。此外，还披露了包含公式（I）化合物的制药组合物以及使用这些化合物和组合物的方法。
• US7872010B2
  申请人：——

  公开号：US7872010B2

  公开（公告）日：2011-01-18
• Design of a New Histamine H₃ Receptor Antagonist Chemotype: (3a<i>R</i>,6a<i>R</i>)-5-Alkyl-1-aryl-octahydropyrrolo[3,4-<i>b</i>]pyrroles, Synthesis, and Structure−Activity Relationships
  作者：Chen Zhao、Minghua Sun、Youssef L. Bennani、Thomas R. Miller、David G. Witte、Timothy A. Esbenshade、Jill Wetter、Kennan C. Marsh、Arthur A. Hancock、Jorge D. Brioni、Marlon D. Cowart

  DOI：10.1021/jm900480x

  日期：2009.8.13

  A new histamine H-3 receptor (H3R) antagonist chemotype 1 was designed by combining key pharmacophoric elements from two different precursor structural series and then simplifying and optimizing the resulting combined structural features. First, analogues were made based oil a previously identified conessine-based H3R. antagonist series. While the first analogues 11 and 15 showed no antagonistic activity to H3R, the mere addition of a key moiety found in the reference compound 7 (ABT-239) elevated the series to high potency at H3R. The hybrid structure (16b) was judged too synthetically demanding to enable an extensive SAR study, thus forcing a strategy to simplify the chemical structure. The resulting (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrrole series proved to be highly potent, as exemplified by 17a having a human H-3 K-i of 0.54 nM, rat H-3 K-i of 4.57 nM, and excellent pharmacokinetics (PK) profile in rats (oral bioavailability of 39% and t(1/2) of 2.4 h).