4,8-bis(benzylamino)-2,6-dichloropyrimido[5,4-d]pyrimidine | 94542-24-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4,8-bis(benzylamino)-2,6-dichloropyrimido[5,4-d]pyrimidine
• 英文别名: 2,6-dichloro-4,8-dibenzylaminopyrimido[5,4-d]pyrimidine；N,N'-dibenzyl-2,6-dichloro-pyrimido[5,4-d]pyrimidine-4,8-diamine；N⁴,N⁸-dibenzyl-2,6-dichloro-pyrimido[5,4-d]pyrimidine-4,8-diyldiamine；N⁴,N⁸-Dibenzyl-2,6-dichlor-pyrimido[5,4-d]pyrimidin-4,8-diyldiamin；2,6-Dichloro-4,8-di-(benzylamino)pyrimidopyrimidine；4-N,8-N-dibenzyl-2,6-dichloropyrimido[5,4-d]pyrimidine-4,8-diamine
• CAS: 94542-24-2
• 化学式: C₂₀H₁₆Cl₂N₆
• 分子量: 411.293
• InChiKey: YXUVICSSVPNGJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4,8-bis(benzylamino)-2,6-dichloropyrimido[5,4-d]pyrimidine 在 palladium on activated charcoal 氢氧化钾 、 氢气 作用下， 以 四氢呋喃 为溶剂， 75.0 ℃ 、275.79 kPa 条件下， 反应 26.0h， 生成 4,8-bis(benzylamino)-2-(2-hydroxyethylamino)pyrimido[5,4-d]pyrimidine
  参考文献：
  名称：

  2,4,6,8-四氯嘧啶[5,4- d ]嘧啶的受控逐步转化为2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶

  摘要：

  为了合理合成2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶，需要嘌呤 模拟物，连续的亲核取代 2,4,6,8-四氯嘧啶[5,4- d ]嘧啶已被调查。已经设计出反应条件，以产生2,4,6,8-四取代的嘧啶并[5,4- d ]嘧啶，其取代方式表示为abab（与亲核试剂1在C-4和C-8处反应，随后与亲核试剂2反应）在C-2和C-6处）或abac（在C-4和C-8与亲核试剂1反应，在C-2与亲核试剂2反应，在C-6与亲核试剂3反应）或abcd（在C-4与亲核试剂1反应），C-8的亲核试剂2，C-2的亲核试剂3和C-6的亲核试剂4）。使用低温，相对稀释的溶液，并小心添加胺亲核试剂可以控制关​​键的第一步。产生abcd图案的第三步产生了两种区域异构体，它们的结构特征是1 H NMR以及晶体结构分析。选择的2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶经测试为抑制剂 细胞周期蛋白依赖性激酶1复合物（细胞周期蛋白B

  DOI：

  10.1039/b102224p
• 作为产物：
  描述：

  5-氨基乳清酸 在 五氯化磷 、 ammonium chloride 、 potassium carbonate 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 反应 16.33h， 生成 4,8-bis(benzylamino)-2,6-dichloropyrimido[5,4-d]pyrimidine
  参考文献：
  名称：

  2,4,6,8-四氯嘧啶[5,4- d ]嘧啶的受控逐步转化为2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶

  摘要：

  为了合理合成2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶，需要嘌呤 模拟物，连续的亲核取代 2,4,6,8-四氯嘧啶[5,4- d ]嘧啶已被调查。已经设计出反应条件，以产生2,4,6,8-四取代的嘧啶并[5,4- d ]嘧啶，其取代方式表示为abab（与亲核试剂1在C-4和C-8处反应，随后与亲核试剂2反应）在C-2和C-6处）或abac（在C-4和C-8与亲核试剂1反应，在C-2与亲核试剂2反应，在C-6与亲核试剂3反应）或abcd（在C-4与亲核试剂1反应），C-8的亲核试剂2，C-2的亲核试剂3和C-6的亲核试剂4）。使用低温，相对稀释的溶液，并小心添加胺亲核试剂可以控制关​​键的第一步。产生abcd图案的第三步产生了两种区域异构体，它们的结构特征是1 H NMR以及晶体结构分析。选择的2,4,6,8-四取代的嘧啶[5,4- d ]嘧啶经测试为抑制剂 细胞周期蛋白依赖性激酶1复合物（细胞周期蛋白B

  DOI：

  10.1039/b102224p

文献信息

• Pyrimidopyrimidine compounds
  申请人：Newcastle University Ventures Limited

  公开号：US06297250B1

  公开（公告）日：2001-10-02

  A range of dipyridamole analogues useful for inhibiting transport of nucleosides or purines across cell membranes, thereby to potentiate the activity of various cytotoxic antitumor drugs, is disclosed. These analogues comprise compounds having general structural formula (I) or pharmaceutically acceptable salts thereof; wherein R1 is chloro and R3 is diethanolamino, or R1 and R3 are identical and are selected from allyl, halo, diethanolamino, solketalo and a group having the formula: —O—Rz or —NHRz, Rz being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and R2 and R4 are identical and are selected from piperidino, N-tetrahydroisoquinolyl, and a benzylamino group having structural formula (II) wherein R5 is H, or an optionally substituted alkyl or benzyl group, and R6 and R7 represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NRxRy where Rx and Ry each represent hydrogen or alkyl, subject to the provisos that (a) if R1 and R3 are both chloro or diethanolamino, R2 and R4 are not both benzylamino, i.e. R2 and R4 do not correspond to structure II with R5, R6 and R7 each being hydrogen, and (b) if R2 and R4 are both piperidino, R1 and R3 are not both chloro, diethanolamino, solketalo or (2,3-dimethoxy)propoxy

  本发明揭示了一系列二吡啶酮类似物，用于抑制核苷或嘌呤在细胞膜上的转运，从而增强各种细胞毒性抗肿瘤药物的活性。这些类似物包括具有一般结构式（I）或其药学上可接受的盐的化合物；其中R1为氯，R3为二乙醇胺基，或者R1和R3相同且选自烯丙基，卤素，二乙醇胺基，索尔凯托洛和具有公式的基团：—O—Rz或—NHRz，其中Rz选自烷基，羟基烷基，烷氧基烷基，双烷氧基烷基和2-氧代烷基，其中每个烷基和/或烷氧基具有少于六个碳原子，且R2和R4相同且选自哌啶基，N-四氢异喹啉基和苄基氨基基团，其结构式为（II），其中R5为H，或者是一个可选的取代烷基或苄基基团，R6和R7代表H或芳香核中的可选取代基，选自卤素，烷基，烷氧基，羟基，三氟甲基，偶氮基，氰基，硝基，羧基，羧酸酯，氨基或取代氨基NRxRy，其中Rx和Ry各代表氢或烷基，但须符合以下规定：（a）如果R1和R3都是氯或二乙醇胺基，则R2和R4不会同时是苄基氨基，即R2和R4不会对应于结构式II，其中R5，R6和R7各自是氢；（b）如果R2和R4都是哌啶基，则R1和R3不会同时是氯，二乙醇胺基，索尔凯托洛或（2,3-二甲氧基）丙氧基。
• Resistance-Modifying Agents. 11. Pyrimido[5,4-<i>d</i>]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein
  作者：Nicola J. Curtin、Hannah C. Barlow、Karen J. Bowman、A. Hilary Calvert、Richard Davison、Bernard T. Golding、Bing Huang、Peter J. Loughlin、David R. Newell、Peter G. Smith、Roger J. Griffin

  DOI：10.1021/jm040772w

  日期：2004.9.1

  The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of H-3-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.
• Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer
  作者：Antonella Virgilio、Daniela Spano、Veronica Esposito、Valeria Di Dato、Giuseppe Citarella、Natascia Marino、Veronica Maffia、Daniela De Martino、Pasqualino De Antonellis、Aldo Galeone、Massimo Zollo

  DOI：10.1016/j.ejmech.2012.08.020

  日期：2012.11

  The human (h)-prune protein is a member of the DHH protein superfamily and it has a cAMP phosphodiesterase activity. Its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and a high degree of lymph-node metastasis. One mechanism by which h-prune stimulates cell motility and metastasis processes is through its phosphodiesterase activity, which can be suppressed by dipyridamole, a pyrimido[5,4-d]pyrimidine analogue. To obtain new and more potent agents that have high specificity towards inhibition of this h-prune activity, we followed structure activity-relationship methodologies starting from dipyridamole and synthesised eight new pyrimido pyrimidine derivatives. We analysed these newly generated compounds for specificity towards h-prune activities in vitro in cellular models using scintillation proximity assay for cAMP-PDE activity, cell index in cell proliferation assays and transwell methodology for two-dimensional cell migration in a top-down strategy of selection. Our findings show that two pyrimido[5,4-d]pyrimidine compounds are more effective than dipyridamole in two highly metastatic cellular models of breast cancer in vitro. Future studies will assess their therapeutic effectiveness against breast and other cancers where there is over-expression of h-prune, and in ad-hoc, proof of concept, animal models. (C) 2012 Elsevier Masson SAS. All rights reserved.
• US6232312B1
  申请人：——

  公开号：US6232312B1

  公开（公告）日：2001-05-15
• US6297250B1
  申请人：——

  公开号：US6297250B1

  公开（公告）日：2001-10-02