(1'S,2'R,3'S,4'R,5'S)-4'-[6-chloro-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester | 793695-77-9

• 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: (1'S,2'R,3'S,4'R,5'S)-4'-[6-chloro-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester
• 英文别名: (1'S,2'R,3'S,4'S,5'S)-4'-[6-chloro-2-iodo-purin-9-yl]-2',3'-O-isopropylidene-bicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester；(1'R,2'R,3'S,4'R,5'S)-4'-(6-chloro-2-iodopurin-9-yl)-2',3'-O-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester；ethyl (1R,2S,4S,5R,6S)-5-(6-chloro-2-iodopurin-9-yl)-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carboxylate
• CAS: 793695-77-9
• 化学式: C₁₇H₁₈ClIN₄O₄
• 分子量: 504.712
• InChiKey: SXSNTNLNLFTKLT-YMSDUSNHSA-N

物化性质

• 沸点：
  597.9±60.0 °C(Predicted)
• 密度：
  2.10±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  88.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1'S,2'R,3'S,4'R,5'S)-4'-[6-chloro-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester 在 三乙胺 作用下， 以 甲醇 为溶剂， 生成 (1'S,2'R,3'S,4'S,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodopurin-9-yl]-2',3'-O-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid N-methylamine
  参考文献：
  名称：

  基于结构的设计、点击化学合成和高选择性 A3 腺苷受体激动剂的体内活性†

  摘要：

  ( N )-methanocarba 腺苷 5'-uronamides 的 2-芳基乙炔基衍生物是选择性 A 3 AR（腺苷受体）激动剂。在这里，我们用 1,2,3-三唑-1-基连接体代替刚性的线性乙炔基，以消除其潜在的代谢负担。使用 A 3 AR的混合分子模型（基于 A 2A AR 激动剂结合结构）将含有可能的短连接体部分的核苷对接在腺嘌呤 C2 位置，正确预测三唑将保持 A 3 AR 选择性，因为它能够适应受体中的狭窄裂缝。合成了具有各种N 6和 C2-芳基三唑基取代的类似物，并对其结合（ K i at hA 3 AR 0.3–12 nM）和体内特征进行了表征，以证明控制慢性神经性疼痛（慢性缩窄性损伤）的功效。在N 6 -甲基衍生物中， 9 (MRS7116)中的末端嘧啶-2-基基团增加了体内作用持续时间（3 小时时疼痛保护 36%）。N 6 -乙基 5-氯噻吩-2-基类似物15 (M

  DOI：

  10.1039/c4md00571f
• 作为产物：
  描述：

  2-碘-6-氯嘌呤 、 乙基(1S,2R,3S,4S,5S)-2,3-O-(异亚丙基)-4-羟基双环[3.1.0]己烷羧酸酯 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 10.17h， 以54%的产率得到(1'S,2'R,3'S,4'R,5'S)-4'-[6-chloro-2-iodopurin-9-yl]-2',3'-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid ethyl ester
  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

文献信息

• Evidence for the Interaction of A₃ Adenosine Receptor Agonists at the Drug-Binding Site(s) of Human P-glycoprotein (ABCB1)
  作者：Biebele Abel、Dilip K. Tosh、Stewart R. Durell、Megumi Murakami、Shahrooz Vahedi、Kenneth A. Jacobson、Suresh V. Ambudkar

  DOI：10.1124/mol.118.115295

  日期：2019.8

  interaction of some A3 adenosine receptor agonists that are being developed for the treatment of chronic diseases, including rheumatoid arthritis, psoriasis, chronic pain, and hepatocellular carcinoma. Biochemical assays of the ATPase activity of P-gp and by photolabeling P-gp with its transport substrate [125I]-iodoarylazidoprazosin led to the identification of rigidified (N)-methanocarba nucleosides (i.e

  P-糖蛋白（P-gp）是一种多药转运蛋白，在肾脏，肠，肝脏的胆小管膜，血脑屏障和肾上腺的上皮细胞腔表面表达。该转运蛋白利用ATP水解的能量从细胞中排出各种结构不同的疏水和两亲化合物，包括抗癌药。在这方面，了解药物实体在发展中与P-gp的相互作用是重要的，在美国食品药品管理局现行指南中强烈建议使用。在这里，我们测试了一些A3腺苷受体激动剂的P-gp相互作用，这些激动剂正在开发用于治疗慢性疾病，包括类风湿性关节炎，牛皮癣，慢性疼痛和肝细胞癌。对P-gp ATPase活性进行生化分析，并通过用其运输底物[125I]-碘代芳基叠氮吡嗪对P-gp进行光标记，鉴定出了刚性的（N）-甲氨基甲酸核苷（即，化合物3作为刺激物，化合物8作为P-gp ATPase活性的部分抑制剂）。化合物8显着抑制人P-gp介导的硼二吡咯亚甲基（BODIPY）-维拉帕米转运（IC50 2.4±0.6 µM）；但是，P-gp不能
• Purine (<i>N</i>)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A₃ Adenosine Receptor Agonists
  作者：Dilip K. Tosh、Antonella Ciancetta、Eugene Warnick、Robert O’Connor、Zhoumou Chen、Elizabeth Gizewski、Steven Crane、Zhan-Guo Gao、John A. Auchampach、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1021/acs.jmedchem.5b01998

  日期：2016.4.14

  C6-Me and C6-styryl derivatives had unexpectedly high A3AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A3AR Ki values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A3AR (MRS7220, Ki

  缺乏环外胺的嘌呤（N）-甲氨基甲酰基5'-N-烷基尿嘧啶核苷A3腺苷受体（A3AR）激动剂是Sonogashira偶联过程中发生意外反应并随后发生氨解的结果。由于初始的C6-Me和C6-苯乙烯基衍生物具有出乎意料的高A3AR亲和力，因此制备了缺少环外胺的其他刚性核苷类似物。其中，C6-Me-（2-苯基乙炔基）和C2-（5-氯噻吩基乙炔基）类似物特别有效，人A3AR Ki值分别为6和42 nM。此外，C2-（5-氯噻吩基）-6-H类似物在A3AR（MRS7220，Ki 60 nM）处具有强效和选择性，并且还可以完全逆转小鼠坐骨神经机械性异常性疼痛（体内3μmol/ kg，口服）。可以通过同源建模和这些超修饰核苷的对接来合理化缺乏C6 H键供体，同时保持A3AR亲和力和功效。该模型表明，稳定特征的适当组合可以部分弥补环外胺的缺乏，而环外胺是在A3AR结合位点识别的其他重要因素。
• [EN] A3 ADENOSINE RECEPTOR AGONISTS<br/>[FR] AGONISTES DU RÉCEPTEUR DE L'ADÉNOSINE A3
  申请人：US HEALTH

  公开号：WO2015080940A1

  公开（公告）日：2015-06-04

  Disclosed are compounds of the formula (I) and (II) which are A3 adenosine receptor agonists, pharmaceutical compositions comprising such compounds, and a method of use of these compounds, wherein X, Y, Z, R2-R6, and R103-R106 are as defined in the specification. These compounds are selective to the A3 receptor, and are contemplated for use in the treatment or prevention of a number of diseases or conditions, for example, neuropathic pain.

  揭示了公式(I)和(II)的化合物，这些化合物是A3腺苷受体激动剂，包括这些化合物的药物组合物，以及使用这些化合物的方法，其中X、Y、Z、R2-R6和R103-R106如规范中所定义。这些化合物对A3受体具有选择性，可用于治疗或预防多种疾病或症状，例如神经病性疼痛。
• Structure activity relationships of 5-HT2B and 5-HT2C serotonin receptor antagonists: N6, C2 and 5′-Modified (N)-methanocarba-adenosine derivatives
  作者：Dilip K. Tosh、Maggie M. Calkins、Marko S. Ivancich、Hailey A. Bock、Ryan G. Campbell、Sarah A. Lewicki、Eric Chen、Zhan-Guo Gao、John D. McCorvy、Kenneth A. Jacobson

  DOI：10.1016/j.ejmech.2023.115691

  日期：2023.11

  (N)-Methanocarba adenosine derivatives were structurally modified to target 5-HT2B serotonin receptors as antagonists, predominantly containing branched N6-alkyl groups. N6-Dicycloalkyl-methyl groups, including their asymmetric variations, as well as 2-iodo, were found to generally favor 5-HT2Rs, while only N6-dicyclohexyl-methyl derivative 35 showed weak 5-HT2AR affinity (Ki 3.6 μM). The highest 5-HT2BR

  （N）-甲烷氨基甲酸腺苷衍生物在结构上被修饰为靶向 5-HT2B 5-羟色胺受体作为拮抗剂，主要包含支链 N6-烷基。发现 N6-二环烷基甲基，包括它们的不对称变体，以及 2-碘，通常有利于 5-HT2Rs，而只有 N6-二环己基甲基衍生物 35 表现出弱的 5-HT2AR 亲和力 （K 3.6 μM）。最高的 5-HT2BR 亲和力为 K 11-23 nM（N6-二环丙基-甲基-2-碘 11,2-氯-5′-脱氧-5′-甲基硫代 15 和 N6-（（R）-环丁基-环丙基-甲基）-2-碘 43）和 K 73 nM，在 5-HT2CR 下为 36。腺嘌呤核苷及其相应的刚性 （N）-甲烷氨基甲酸酯衍生物的直接比较 （参见 51 和 MRS8099 45） 表明与双环系统的多倍亲和力增强。化合物 43、45 和 48 在 Gq 介导的钙通量测定中是功能性 5-HT2BR （KB 2–3 nM） 和
• (<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.