6-chloro-N-phenyl-9H-purin-2-amine | 114300-74-2

• 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: 6-chloro-N-phenyl-9H-purin-2-amine
• 英文别名: 9H-Purin-2-amine, 6-chloro-N-phenyl-；6-chloro-N-phenyl-7H-purin-2-amine
• CAS: 114300-74-2
• 化学式: C₁₁H₈ClN₅
• 分子量: 245.671
• InChiKey: XIJHMCHYHSKERV-UHFFFAOYSA-N

物化性质

• 熔点：
  155-160 °C
• 沸点：
  356.0±52.0 °C(Predicted)
• 密度：
  1.56±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-N-phenyl-9H-purin-2-amine 在 sodium hydroxide 、 sodium hydride 作用下， 反应 51.0h， 生成 2-苯胺基-9-(4-羟基丁基)-3H-嘌呤-6-酮
  参考文献：
  名称：

  Synthesis, Properties, and Pharmacokinetic Studies of N2-Phenylguanine Derivatives as Inhibitors of Herpes Simplex Virus Thymidine Kinases

  摘要：

  Two series of selective inhibitors of herpes simplex virus types 1 and 2 (HSV1,2) thymidine kinases (TK) have been developed as potential treatment of recurrent virus infections. Among compounds related to the potent base analog N-2-[m-(trifluoromethyl)phenyl]guanine (mCF(3)PG), none was a more potent inhibitor than mCF(3)PG itself. Compounds related to the nucleoside N-2-phenyl-2'-deoxyguanosine (PhdG), but with alkyl, hydroxyalkyl, and related substituents at the 9-position in place of the glycosyl group of PhdG, retained significant but variable inhibitory potencies against the HSV TKs. The most potent inhibitor of HSV1 TK among 9-substituted derivatives, 9-(4-hydroxybutyl)-N-2-phenylguanine (HBPG), was a competitive inhibitor with respect to the substrate thymidine but was not itself a substrate for the enzyme. Water solubilities and 1-octanol:water partition coefficients for the 9-substituted N-2-phenylguanines were linearly but oppositely related to the sum of hydrophobic fragmental constants (Sigma f) of the 9-substituents. Four of the inhibitors were given as solutions to mice by iv and ip routes, and the time course of their plasma concentrations was determined by HPLC analysis of the parent compounds. HBPG was completely absorbed by the ip route, and the plasma concentration could be prolonged by use of suspension formulations. HBPG is a candidate for animal trials of the ability of TK inhibitors to prevent recurrent herpes virus infections.

  DOI：

  10.1021/jm00001a010
• 作为产物：
  描述：

  2-溴次黄嘌呤 在 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 2,2,2-三氟乙醇 为溶剂， 反应 25.0h， 生成 6-chloro-N-phenyl-9H-purin-2-amine
  参考文献：
  名称：

  2-芳氨基-6-乙炔基嘌呤是 Nek2 激酶的半胱氨酸靶向不可逆抑制剂

  摘要：

  人们对与疾病状态有关的酶的共价抑制剂重新产生了兴趣，从而提供了几种针对与癌症相关的蛋白激酶的药物。我们现在报告了 6-乙炔基嘌呤的设计、合成和生物学评价，6-乙炔基嘌呤通过捕获靠近该蛋白激酶催化结构域的半胱氨酸残基 (Cys22) 来充当 Nek2 的共价抑制剂。对与 Nek2 复合的非共价抑制剂 3-((6-环己基甲氧基-7 H-嘌呤-2-基)氨基)苯甲酰胺的晶体结构的检查表明，用乙炔基取代烷氧基放置了炔烃的末端接近Cys22并且处于与迈克尔加成的立体电子学要求兼容的位置。制备了一系列 6-乙炔基嘌呤并建立了抑制 Nek2 的结构活性关系 (SAR)。 6-乙炔基-N-苯基-7 H-嘌呤-2-胺 [IC 50 0.15 μM (Nek2)] 和 4-((6-乙炔基-7 H-嘌呤-2-基)氨基)苯磺酰胺 (IC 50 0.14)选择 Nek2 的抑制模式来确定 Nek2 的抑制模式，该抑制模式具有时间依赖性，不能通过添加

  DOI：

  10.1039/d0md00074d

文献信息

• Drugs to prevent recurrent herpes virus infections
  申请人：University of Massachusetts Medical Center

  公开号：US05646155A1

  公开（公告）日：1997-07-08

  N.sup.2 -substituted alkylguanine and N.sup.2 -substituted phenylguanine compounds which prevent recurrent herpes simplex infections are disclosed. By virtue of their ability to inhibit herpes virus thymidine kinase in vivo, such compounds will prevent, reduce the frequency of, or reduce the severity of recurring HSV infections in humans. The N.sup.2 -alkylguanine compounds are of the formula: ##STR1## where R.sub.1 is a normal or branched chain C.sub.n H.sub.2n+1 (where n is 1-12); R.sub.2 is H, 2-deoxyribofuranosyl, (CH.sub.2).sub.n OH (where n is 2-5), CH.sub.2 CH(OH)CH.sub.2 OH, (CH.sub.2).sub.n --COOH (where n is 1-4), CH.sub.2 CH(OH)CH.sub.2 --O--COR.sub.4, (CH.sub.2).sub.n --O--COR.sub.4 (where n is 2-5), or (CH.sub.2).sub.n CO--OR.sub.4 (where n is 1-4); R.sub.4 is CH.sub.3, CH.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 NH.sub.2, CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 or CH.sub.2 CH.sub.2 CO.sub.2 H; and R.sub.3 is OH, H, Cl or NH.sub.2, or a tautomer or a pharmaceutically acceptable salt thereof. The N.sup.2 -substituted phenylguanine compounds are of similar structure, where R.sub.1 is a phenyl or a phenyl substituted at the 3 and 4 positions with an H, a hydrophobic or electron extracting group, or a CH.sub.2 CH.sub.3.

  揭示了防止复发的单纯疱疹病毒感染的N.sup.2-取代烷基鸟嘌呤和N.sup.2-取代苯基鸟嘌呤化合物。由于它们在体内能够抑制单纯疱疹病毒胸苷激酶，这些化合物将防止、减少或减轻人类复发性HSV感染的频率或严重程度。N.sup.2-烷基鸟嘌呤化合物的结构如下：其中R.sub.1是正常或支链C.sub.n H.sub.2n+1（其中n为1-12）；R.sub.2是H、2-去氧核糖呋喃糖基、（CH.sub.2).sub.n OH（其中n为2-5）、CH.sub.2 CH(OH)CH.sub.2 OH、（CH.sub.2).sub.n --COOH（其中n为1-4）、CH.sub.2 CH(OH)CH.sub.2 --O--COR.sub.4、（CH.sub.2).sub.n --O--COR.sub.4（其中n为2-5）或（CH.sub.2).sub.n CO--OR.sub.4（其中n为1-4）；R.sub.4是CH.sub.3、CH.sub.2 CH.sub.3、CH.sub.2 CH.sub.2 NH.sub.2、CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2或CH.sub.2 CH.sub.2 CO.sub.2 H；R.sub.3是OH、H、Cl或NH.sub.2，或其互变异构体或药学上可接受的盐。N.sup.2-取代苯基鸟嘌呤化合物具有类似结构，其中R.sub.1是苯基或在3和4位置用H、疏水性或电子提取基团或CH.sub.2 CH.sub.3取代的苯基。
• Cyclin-Dependent Kinase (CDK) Inhibitors: Structure–Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines
  作者：Christopher R. Coxon、Elizabeth Anscombe、Suzannah J. Harnor、Mathew P. Martin、Benoit Carbain、Bernard T. Golding、Ian R. Hardcastle、Lisa K. Harlow、Svitlana Korolchuk、Christopher J. Matheson、David R. Newell、Martin E. M. Noble、Mangaleswaran Sivaprakasam、Susan J. Tudhope、David M. Turner、Lan Z. Wang、Stephen R. Wedge、Christopher Wong、Roger J. Griffin、Jane A. Endicott、Céline Cano

  DOI：10.1021/acs.jmedchem.6b01254

  日期：2017.3.9

  Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 44(6-([1,1'-bipheny1]-3-y1)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 mu M) but was similar to 2000-fold less active toward CDK1 (IC50 86 mu M). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.
• N2-Phenyldeoxyguanosine: a novel selective inhibitor of herpes simplex thymiding kinase
  作者：Federico Focher、Catherine Hildebrand、Stephen Freese、Giovanni Ciarrocchi、Timothy Noonan、Stefano Sangalli、Neal Brown、Silvio Spadari、George Wright

  DOI：10.1021/jm00403a004

  日期：1988.8

  A series of N2-substituted guanine derivatives was screened against mammalian thymidine kinase and the thymidine kinase encoded by type I herpes simplex virus to examine their capacity to selectivity inhibit the viral enzyme. Several bases, nucleosides, and nucleotides displayed selective activity. The mechanism of action of the most potent derivative, N2-phenyl-2'-deoxyguanosine (PhdG) was studied in detail. PhdG (a) inhibited the viral enzyme competitively with respect to the substrates thymidine and deoxycytidine, (b) was completely resistant to phosphorylation, (c) displayed limited toxicity for the HeLa cell lines employed as hosts for viral infection, and (d) selectively inhibited viral thymidine kinase function in intact cultured cells. The results indicate that the PhdG drug prototype has potential as a selective anti-herpes agent and as a novel molecular probe of the structure and function of herpes simplex thymidine kinase.
• Inhibition of Herpes Simplex Virus Thymidine Kinases by 2-Phenylamino-6-oxopurines and Related Compounds:  Structure−Activity Relationships and Antiherpetic Activity in Vivo
  作者：Andrzej Manikowski、Annalisa Verri、Andrea Lossani、Bryan M. Gebhardt、Joseph Gambino、Federico Focher、Silvio Spadari、George E. Wright

  DOI：10.1021/jm049059x

  日期：2005.6.1

  Derivatives of the herpes simplex thymidine kinase inhibitor HBPG [2-phenylamino-9-(4-hydroxybutyl)-6-oxopurine] have been synthesized and tested for inhibitory activity against recombinant enzymes (TK) from herpes simplex types 1 and 2 (HSV-1, HSV-2). The compounds inhibited phosphorylation of [H-3]thymidine by both enzymes, but potencies differed quantitatively from those of HBPG and were generally greater for HSV-2 than HSV-1 TKs. Changes in inhibitory potency were generally consistent with the inhibitor/substrate binding site structure based on published X-ray structures of HSV-1 TK. In particular, several 9-(4-aminobutyl) analogues with bulky tertiary amino substituents were among the most potent inhibitors. Variable substrate assays showed that the most potent compound, 2-phenylamino-9-[4-(1-decahydroquinolyl)butyl]-6-oxopurine, was a competitive inhibitor, with K-i values of 0.03 and 0.005 mu M against HSV-1 and HSV-2 TKs, respectively. The parent compound HBPG was uniquely active in viral infection models in mice, both against ocular HSV-2 reactivation and against HSV-1 and HSV-2 encephalitis. In assays lacking [H-3]thymidine, HBPG was found to be an efficient substrate for the enzymes. The ability of the TKs to phosphorylate HBPG may relate to its antiherpetic activity in vivo.
• FOCHER, FEDERICO;HILDEBRAND, CATHERINE;FREESE, STEPHEN;CIARROCCHI, GIOVAN+, J. MED. CHEM., 31,(1988) N 8, C. 1496-1500
  作者：FOCHER, FEDERICO、HILDEBRAND, CATHERINE、FREESE, STEPHEN、CIARROCCHI, GIOVAN+

  DOI：——

  日期：——