1-(6-氯-9H-嘌呤-9-基)-1-脱氧-N-甲基-2,3-O-异亚丙基-beta-D-呋喃核糖酰胺 | 152918-47-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 中文名称: 1-(6-氯-9H-嘌呤-9-基)-1-脱氧-N-甲基-2,3-O-异亚丙基-beta-D-呋喃核糖酰胺
• 英文名称: 2',3'-isopropylidene-1-(6-chloro-9H-purin-9-yl)-1-deoxy-N-methyl-β-D-ribofuranosiduronamide
• 英文别名: 2',3'-O-isopropylidene-6-chloropurine-5'-N-methyluronamide；6-chloropurine-2',3'-O-isopropylidene-N-methyluronamide；2,3-O-isopropylidene-1-(6-chloropurin-9-yl)-1-deoxy-N-methyl-β-D-ribofuranuronamide；2',3'-O-isopropylidene-6-chloropurine-5'-methyluronamide；1-(6-Chloro-9H-purin-9-yl)-1-deoxy-N-methyl-2,3-O-isopropylidene-beta-D-ribofuranuronamide；(3aR,4R,6S,6aS)-4-(6-chloropurin-9-yl)-N,2,2-trimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxole-6-carboxamide
• CAS: 152918-47-3
• 化学式: C₁₄H₁₆ClN₅O₄
• 分子量: 353.765
• InChiKey: VXKQFHVZIXOPJH-LOKDSWTASA-N

物化性质

• 密度：
  1.74

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  1-(6-氯-9H-嘌呤-9-基)-1-脱氧-N-甲基-2,3-O-异亚丙基-beta-D-呋喃核糖酰胺 在 盐酸 、 三乙胺 作用下， 以 乙醇 为溶剂， 反应 20.0h， 生成 N6-(3-碘苄基)腺苷-5'-N-甲基糖酰胺
  参考文献：
  名称：

  Structure-Activity Relationships of N6-Benzyladenosine-5'-uronamides as A3-Selective Adenosine Agonists

  摘要：

  Adenosine analogues modified at the 5'-position as uronamides and/or as N-6-benzyl derivatives were synthesized. These derivatives were examined for affinity in radioligand binding assays at the newly discovered rat brain A(3) adenosine receptor and at rat brain A(1) and Az, receptors. 5'Uronamide substituents favored AS selectivity in the order N-methyl > N-ethyl approximate to unsubstituted carboxamide > N-cyclopropyl. 5'-(N-Methylcarboxamido)-N-6-benzyladenosine was 37-56-fold more selective for Ag receptors. Potency at A(3) receptors was enhanced upon substitution of the benzyl substituent with nitro and other groups. 5'-N-Methyluronamides and N-6-(3-substituted-benzyl) adenosines are optimal for potency and selectivity at A(3) receptors. A series of 3-(halobenzyl)5'-N-ethyluronamide derivatives showed the order of potency at A(1) and A(2)a receptors of I similar to Br > Cl > F. At A(3) receptors the 3-F derivative was weaker than the other halo derivatives. 5'-N-Methyl-N-6- (3-iodobenzyl) adenosine displayed a K-i value of 1.1 nM at A(3) receptors and selectivity versus A(1) and A(2a), receptors of 50-fold. A series of methoxybenzyl derivatives showed that a C-methoxy group best favored A(3) selectivity. A 4-sulfobenzyl derivative was a specific ligand at A(3) receptors of moderate potency. An aryl amino derivative was prepared as a probe for radioiodination and receptor cross-linking.

  DOI：

  10.1021/jm00031a014
• 作为产物：
  描述：

  2',3'-O-异丙叉肌苷 在 chromium(VI) oxide 、 氯化亚砜 、 溶剂黄146 、 N,N-二甲基甲酰胺 作用下， 以 氯仿 为溶剂， 反应 54.33h， 生成 1-(6-氯-9H-嘌呤-9-基)-1-脱氧-N-甲基-2,3-O-异亚丙基-beta-D-呋喃核糖酰胺
  参考文献：
  名称：

  N6-Substituted N-alkyladenosine-5'-uronamides: bifunctional ligands having recognition groups for A1 and A2 adenosine receptors

  摘要：

  The coronary vasoactivity of N-ethyl-1'-deoxy-1'-(6-amino-9H-purin-9-yl)-beta-D-ribofuranuronamide (NECA, 1) is over 2 orders of magnitude greater than that of adenosine, and the vasoactivity of certain N6-substituted adenosines is as much as 1 order of magnitude greater. Such results suggest that a combination of appropriate modifications at N6 and C-5' might additively augment the agonist potency of adenosine. At low temperatures 1-deoxy-1-(6-chloro-9H-purin-9-yl)-2',3'-O-isopropylidene- beta-D-ribofuranosyl chloride (5), obtained in three steps from inosine, reacts with amines to yield uronamides. The subsequent reaction of such uronamides with amines at elevated temperatures displaces the purine 6-chloro group to yield, after deblocking, N-alkyl(or aryl)-N6-alk(ar)yl-adenosine-5'-uronamides. At the coronary artery A2 receptor the potency of N6-modified analogues of 1 is similar to that of the N6-substituted adenosine, rather than equal to or greater than 1. As agonists in the A2 receptor-mediated stimulation of adenylate cyclase in plasma membranes of PC12 pheochromocytoma cells or human platelets, N6-substituted analogues of 1 are intermediate between the high potency of 1 and the lower potency of the N6-substituted adenosines. At the A1 receptor of rat brain the potency of an N6-substituted analogue of 1 is often greater than that of the corresponding N6-substituted adenosine. At all four receptors, replacing the ethyl group of N-ethyl-N6-3-pentyladenosine-5'-uronamide by larger alkyl groups reduces potency; amides of secondary amines are inactive or have only marginal activity. Analogues of 1 containing a chiral center in the N6 substituent retain the stereoselectivity characteristic of each of the four receptors. Thus, at either A1 or A2 adenosine receptors, adenosine analogues interact with both the N6 and the C-5' receptor regions. However, the effects of N6 and C-5' modifications on potency are less than additive, evidence that the interaction of a substituent with its receptor region influences the interaction of other substituents with their respective receptor regions.

  DOI：

  10.1021/jm00159a020

文献信息

• N6-Substituted Adenosine Receptor Agonists. Synthesis and Pharmacological Activity as Potent Antinociceptive Agents
  作者：Timur Gungor、Patrice Malabre、Jean-Marie Teulon、Francoise Camborde、Joelle Meignen、Francoise Hertz、Angela Virone-Oddos、Francois Caussade、Alix Cloarec

  DOI：10.1021/jm00051a007

  日期：1994.12

  N6-(indol-3-yl)alkyl derivatives of adenosine were synthesized. The adenosine receptor affinity and the antinociceptive activity of these compounds were assessed in binding studies and the phenylbenzoquinone-induced writhing test. Most of these analogues exhibited a potent analgesic activity without side effects. Among them, compound 3c (UP 202-32) bound to A1 (Ki = 110 nM) and A2 (Ki = 350 nM) adenosine receptors

  合成了腺苷的新型N6-（吲哚-3-基）烷基衍生物。在结合研究和苯基苯醌诱导的扭体试验中评估了这些化合物的腺苷受体亲和力和抗伤害感受活性。这些类似物中的大多数表现出有效的镇痛活性而没有副作用。其中，化合物3c（UP 202-32）以特定方式与A1（Ki = 110 nM）和A2（Ki = 350 nM）腺苷受体结合，因为它不与许多其他受体（尤其是阿片样物质结合位点）相互作用。苯基苯醌试验（ED50 = 3.3 mg / kg口服）中的抗伤害感受活性被8-环戊基茶碱拮抗，表明腺苷能机制是该化合物观察到的镇痛作用的基础。
• The synthesis of a series of adenosine A₃receptor agonists
  作者：Kenneth J. Broadley、Erica Burnell、Robin H. Davies、Alan T. L. Lee、Stephen Snee、Eric J. Thomas

  DOI：10.1039/c6ob00244g

  日期：——

  N-methyl-β-D-ribofuranuronamides that were characterised by 2-dialkylamino-7-methyloxazolo[4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised. This work involved the synthesis of 2-dialkylamino-5-aminomethyl-7-methyloxazolo[4,5-b]pyridines and analogues that were coupled with the known 1′-(6-chloropurin-9-yl)-1′-

  一系列的1'-（6-氨基嘌呤-9-基）-1'-脱氧-N-甲基-β - D-核呋喃核糖酰胺，其特征为2-二烷基氨基-7-甲基恶唑并[4,5- b ]吡啶-已经合成了用于筛选为选择性腺苷A 3受体激动剂的感兴趣的N 6上的5-基甲基取代基。这项工作涉及与已知的1'-（6-氯嘌呤-9-基）-1'-脱氧偶联的2-二烷基氨基-5-氨基甲基-7-甲基恶唑并[4,5- b ]吡啶和类似物的合成。- ñ -甲基- β- d -ribofuranuronamide。通过2,4-二甲基吡啶N的区域选择性官能化合成恶唑并[4,5- b ]吡啶-氧化物。发现这些反应的区域选择性取决于与2-二甲基氨基-5,7-二甲基恶唑并[4,5- b ]吡啶-N-氧化物在与三氟乙酸反应时在7-甲基上进行区域选择性官能化的杂环的性质。与4，6-二甲基-3-羟基吡啶-N-氧化物与乙酸酐的反应相反，后者导致6-甲基官能化。为了优化对A
• The synthesis of highly potent, selective, and water-soluble agonists at the human adenosine A3 receptor
  作者：Michael P. DeNinno、Hiroko Masamune、Lois K. Chenard、Kenneth J. DiRico、Cynthia Eller、John B. Etienne、Jeanene E. Tickner、Scott P. Kennedy、Delvin R. Knight、Jimmy Kong、Joseph J. Oleynek、W. Ross Tracey、Roger J. Hill

  DOI：10.1016/j.bmcl.2006.01.088

  日期：2006.5

  Using a combination of parallel and directed synthesis, the discovery of a highly potent and selective series of adenosine A3 agonists was achieved. High aqueous solubility, required for the intended parenteral route of administration, was achieved by the presence of one or two basic amine functional groups.

  使用平行和定向合成的组合，发现了高效和选择性系列的腺苷A3激动剂。预期的肠胃外给药途径所需的高水溶性是通过存在一个或两个碱性胺官能团实现的。
• Synthesis and evaluation of new N6-substituted adenosine-5′-N-methylcarboxamides as A3 adenosine receptor agonists
  作者：Shane M. Devine、Alison Gregg、Heidi Figler、Kate McIntosh、Vijay Urmaliya、Joel Linden、Colin W. Pouton、Paul J. White、Steven E. Bottle、Peter J. Scammells

  DOI：10.1016/j.bmc.2010.03.047

  日期：2010.5

  A number of N6-substituted adenosine-5′-N-methylcarboxamides were synthesised and their pharmacology, in terms of their receptor affinity, selectivity and cardioprotective effects, were explored. The first series of compounds, 4a–4f and 5a–5f, showed modest receptor affinity for the A3AR with Ki values in the low to mid μM range. However, the incorporation of a 4-(2-aminoethyl)-2,6-di-tert-butylphenol

  合成了许多N 6-取代的腺苷-5'- N-甲基羧酰胺，并就其受体亲和力，选择性和心脏保护作用探讨了其药理作用。第一系列的化合物，4A - 4F和5A - 5F显示出适度的受体的亲和力的A 3 AR与ķ我在低位μM中间范围的值。但是，在N 6位（在化合物4g和5g中）引入4-（2-氨基乙基）-2,6-二叔丁基苯酚基团可以显着改善与K i值分别为30和9 nM。当引入功能化的接头时，亲和力和选择性都得到了改善。所述Ñ 6 -苯基系列，化合物7A - 7D，表明低到中纳摩尔亲和力受体（ķ我 = 2.3-45.0纳米），与图7B显示用于A 109倍的选择性3 AR（Vs的1）。所述Ñ 6 -苄基系列图9a - 9c中也被证明是有效的和选择性阿3 AR激动剂和较长链长的接头13在A是不能容忍的3 AR，无需取消亲和力或选择性。通过模拟的局部缺血细胞培养测定法证明了心脏保护作用，其中7b，7c，9a，9b和9c均在100
• WO2008/111082
  申请人：——

  公开号：——

  公开（公告）日：——