2,6-dichloro-4,8-di-(N-1,2,3,4-tetrahydroisoquinolyl)pyrimido[5,4-d]pyrimidine | 95489-20-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2,6-dichloro-4,8-di-(N-1,2,3,4-tetrahydroisoquinolyl)pyrimido[5,4-d]pyrimidine
• 英文别名: 2,6-dichloro-4,8-bis-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrimido[5,4-d]pyrimidine；2,6-Dichloro-4,8-di-(N-1,2,3,4-tetrahydroisoquinolyl)pyrimidopyrimidine；2,6-dichloro-4,8-bis(3,4-dihydro-1H-isoquinolin-2-yl)pyrimido[5,4-d]pyrimidine
• CAS: 95489-20-6
• 化学式: C₂₄H₂₀Cl₂N₆
• 分子量: 463.369
• InChiKey: PQIRVVBVUYALSL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  32
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  58
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,6-dichloro-4,8-di-(N-1,2,3,4-tetrahydroisoquinolyl)pyrimido[5,4-d]pyrimidine 、 二乙醇胺 以17%的产率得到2-[[6-[Bis-(2-hydroxy-ethyl)-amino]-4,8-bis-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrimido[5,4-d]pyrimidin-2-yl]-(2-hydroxy-ethyl)-amino]-ethanol
  参考文献：
  名称：

  Resistance-Modifying Agents. 11. Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein

  摘要：

  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.

  DOI：

  10.1021/jm040772w
• 作为产物：
  描述：

  1,5-dihydropyrimido[5,4-d]pyrimidine-2,4,6,8-(3H,7H)-tetrone 在 sodium hydroxide 、 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 8.33h， 生成 2,6-dichloro-4,8-di-(N-1,2,3,4-tetrahydroisoquinolyl)pyrimido[5,4-d]pyrimidine
  参考文献：
  名称：

  Resistance-Modifying Agents. 11. Pyrimido[5,4-d]pyrimidine Modulators of Antitumor Drug Activity. Synthesis and Structure−Activity Relationships for Nucleoside Transport Inhibition and Binding to α₁-Acid Glycoprotein

  摘要：

  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.

  DOI：

  10.1021/jm040772w

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。
• US6297250B1
  申请人：——

  公开号：US6297250B1

  公开（公告）日：2001-10-02
• 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.