(1R,2S,4S,5R,6S)-5-[6-[(3-bromophenyl)methylamino]-2-chloropurin-9-yl]-N,8,8-trimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxamide | 793695-98-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: (1R,2S,4S,5R,6S)-5-[6-[(3-bromophenyl)methylamino]-2-chloropurin-9-yl]-N,8,8-trimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxamide
• CAS: 793695-98-4
• 化学式: C₂₃H₂₄BrClN₆O₃
• 分子量: 547.839
• InChiKey: LEIFMPOBIWSIQY-OUDIDXKTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,2S,4S,5R,6S)-5-[6-[(3-bromophenyl)methylamino]-2-chloropurin-9-yl]-N,8,8-trimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxamide 在 甲醇 、 水 、 三氟乙酸 作用下， 反应 3.0h， 以70%的产率得到(1'S,2'R,3'S,4'R,5'S)-4'-[6-(3-bromobenzylamino)-2-chloropurin-9-yl]-2',3'-dihydroxybicyclo[3.1.0]hexane-1'-carboxylic acid methyl amide
  参考文献：
  名称：

  [EN] PURINE DERIVATIVES AS A3 AND A1 ADENOSINE RECEPTOR AGONISTS
  [FR] DERIVES DE PURINE COMME AGONISTES DU RECEPTEUR D'ADENOSINE A3 ET A1

  摘要：

  揭示了一种公式为[N-甲烷卡巴腺嘌呤核苷]的高效A3腺苷受体激动剂，包括这种核苷的制药组合物，以及这些核苷的使用方法，其中R1-R6如规范中所定义。这些核苷被考虑用于治疗多种疾病，例如炎症、心肌缺血、中风、哮喘、糖尿病和心律失常。该发明还提供了既是A1受体又是A3受体激动剂的化合物，用于心脏保护。

  公开号：

  WO2006031505A1
• 作为产物：
  描述：

  ethyl (1'S,2'R,3'S,4'R,5'S)-4'-(2,6-dichloropurin-9-yl)-2',3'-O-(isopropylidene)bicyclo[3.1.0]hexane-1'-carboxylate 在 三乙胺 作用下， 以 甲醇 、 水 为溶剂， 反应 3.0h， 生成 (1R,2S,4S,5R,6S)-5-[6-[(3-bromophenyl)methylamino]-2-chloropurin-9-yl]-N,8,8-trimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxamide
  参考文献：
  名称：

  (N)-Methanocarba 2,N⁶-Disubstituted Adenine Nucleosides as Highly Potent and Selective A₃ Adenosine Receptor Agonists

  摘要：

  A series of ring-constrained (N)-methanocarba-5 '-uronamide 2,N-6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5 '-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5 '-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A(3)AR agonists. Selected compounds were compared in binding to the rat A(3)AR to assess their viability for testing in rat disease models. The N-6-(3-chlorobenzyl) and N-6-(3-bromobenzyl) analogues displayed K-i values at the human A(3)AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N-6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A(3)AR was the following (fold): the N-6-(2,2-diphenylethyl) analogue 34 (1900), the N-6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N-6-(2,5-dichlorobenzyl) and N-6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N-6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A(2A) and A(2B)ARs. The (N)-methanocarba-5 '-uronamide analogues were full agonists at the A(3)AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 mu M. The N-6-(2,2-diphenylethyl) derivative was an A(3)AR agonist in the (N)-methanocarba-5 '-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.

  DOI：

  10.1021/jm049580r

文献信息

• [EN] PURINE DERIVATIVES AS A3 AND A1 ADENOSINE RECEPTOR AGONISTS<br/>[FR] DERIVES DE PURINE COMME AGONISTES DU RECEPTEUR D'ADENOSINE A3 ET A1
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2006031505A1

  公开（公告）日：2006-03-23

  Disclosed are (N)-methanocarba adenine nucleosides of the formula: [Formula] as highly potent A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R1-R6 are as defined in the specification. These nucleosides are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias. The invention also provides compounds that are agonists of both A1 and A3 adenosine receptors for use in cardioprotection.

  揭示了一种公式为[N-甲烷卡巴腺嘌呤核苷]的高效A3腺苷受体激动剂，包括这种核苷的制药组合物，以及这些核苷的使用方法，其中R1-R6如规范中所定义。这些核苷被考虑用于治疗多种疾病，例如炎症、心肌缺血、中风、哮喘、糖尿病和心律失常。该发明还提供了既是A1受体又是A3受体激动剂的化合物，用于心脏保护。
• (<i>N</i>)-Methanocarba 2,<i>N</i>⁶-Disubstituted Adenine Nucleosides as Highly Potent and Selective A₃ Adenosine Receptor Agonists
  作者：Susanna Tchilibon、Bhalchandra V. Joshi、Soo-Kyung Kim、Heng T. Duong、Zhan-Guo Gao、Kenneth A. Jacobson

  DOI：10.1021/jm049580r

  日期：2005.3.1

  A series of ring-constrained (N)-methanocarba-5 '-uronamide 2,N-6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5 '-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5 '-N-methylamide. The compounds, mainly 2-chloro-substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A(3)AR agonists. Selected compounds were compared in binding to the rat A(3)AR to assess their viability for testing in rat disease models. The N-6-(3-chlorobenzyl) and N-6-(3-bromobenzyl) analogues displayed K-i values at the human A(3)AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N-6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A(3)AR was the following (fold): the N-6-(2,2-diphenylethyl) analogue 34 (1900), the N-6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N-6-(2,5-dichlorobenzyl) and N-6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N-6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700-900). Typically, even greater selectivity ratios were obtained in comparison with the A(2A) and A(2B)ARs. The (N)-methanocarba-5 '-uronamide analogues were full agonists at the A(3)AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 mu M. The N-6-(2,2-diphenylethyl) derivative was an A(3)AR agonist in the (N)-methanocarba-5 '-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A(3)AR affinity in the 9-riboside series, including those that reduce intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.