<6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl>methyl 2,2-dimethylpropanoate | 106585-53-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: <6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl>methyl 2,2-dimethylpropanoate
• 英文别名: 6-(Bromomethyl)-3,4-dihydro-4-oxo-3-<(pivaloyloxy)methyl>quinazoline；2,2-dimethylpropanoic acid, [6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl]methyl ester；6-Bromomethyl-3,4-dihydro-4-oxo-3-((pivaloyl)oxy)methylquinazoline；[6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl]methyl 2,2-dimethylpropanoate；[6-(bromomethyl)-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate
• CAS: 106585-53-9
• 化学式: C₁₅H₁₇BrN₂O₃
• 分子量: 353.216
• InChiKey: SSZQKNKMABBMEA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  59
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  <6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl>methyl 2,2-dimethylpropanoate 在 sodium hydroxide 、 cesium bicarbonate 、 氰基磷酸二乙酯 、 三乙胺 、 三氟乙酸 作用下， 以 乙醇 、 水 为溶剂， 反应 58.0h， 生成 2-desamino-5,8-dideaza-10-oxafolic acid
  参考文献：
  名称：

  Comparison of the biological effects of selected 5,8-dideazafolate analogs with their 2-desamino counterparts

  摘要：

  Three new 5,8-dideaza analogues of folic acid devoid of an amino group at position 2 have been prepared by using synthetic routes patterned after earlier methodologies. They were 2-desamino-5,8-dideazaisofolic acid, 2b, 2-desamino-10-thia-5,8-dideazafolic acid, 2c, and 2-desamino-10-oxa-5,8-dideazafolic acid, 2d. These compounds were found to be 4-6-fold more cytoxic toward L1210 leukemia cells than their 2-NH2 counterparts and to be poor inhibitors of mammalian thymidylate synthase. However, they were only 1.5-3-fold less inhibitory toward dihydrofolate reductase than the analogous compounds containing a 2-NH2 group. The known thymidylate synthase inhibitors 2-desamino-10-propargyl-5,8-dideazafolic acid and 10-propargyl-5,8-dideazafolic acid were included in this study for purposes of comparison.

  DOI：

  10.1021/jm00124a019
• 作为产物：
  描述：

  4-羟基-6-甲基喹唑啉 在 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 作用下， 以 四氯化碳 为溶剂， 反应 2.83h， 生成 <6-(bromomethyl)-4-oxo-3(4H)-quinazolinyl>methyl 2,2-dimethylpropanoate
  参考文献：
  名称：

  Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency

  摘要：

  The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid state by intermolecular hydrogen bonding. In examining this moiety we have removed the 2-amino group and now report on 2-desamino-10-propargyl-5,8-dideazafolic acid (8e) and four analogues with H, Me, Et, and allyl at N10. 3,4-Dihydro-4-oxo-6-methylquinazoline was solubilized by alkylating the lactam nitrogen with chloromethyl pivalate. Reaction with N-bromosuccinimide gave the corresponding 6-bromomethyl compound, which was coupled with diethyl N-(4-aminobenzoyl)-L-glutamate or the appropriate N-substituted derivative thereof. The quinazoline N3 nitrogen and carboxyl groups in the product were simultaneously deprotected by cold alkali in the final step to give the desired five antifolates. These were tested against L1210 TS and it was found that removal of the 2-amino group caused a slight (3-9-fold) loss of TS inhibition. 8e was only 8-fold a lesser TS inhibitor than the parent drug. Inhibition of rat liver dihydrofolate reductase was reduced by over 1 order of magnitude for three compounds tested. All five analogues were more cytotoxic to L1210 cells in culture than their 2-amino counterparts; 8e was 8.5-fold more active with an ID50 of 0.4 microM. This remarkable result probably owes to increased cellular penetration. 8e was 5-fold more soluble than 1 at pH 5.0 and greater than 340-fold more soluble at pH 7.4.

  DOI：

  10.1021/jm00124a018

文献信息

• Substituted quinazolinones as anticancer agents
  申请人：Warner-Lambert Company

  公开号：US04857530A1

  公开（公告）日：1989-08-15

  Novel 6-substituted-4(3H)-quinazolinones are described as well as methods for the preparation and pharmaceutical composition of same, which inhabit the enzyme thymidylate synthase (TS) and are thus useful as anticancer agents.

  描述了一种新型的6-取代-4(3H)-喹唑啉酮，以及其制备和药物组合物的方法，这些化合物抑制了酶胸苷酸甲基化酶(TS)，因此可用作抗癌药物。
• Potent inhibition of thymidylate synthase by two series of nonclassical quinazolines
  作者：Dennis J. McNamara、Ellen M. Berman、David W. Fry、Leslie M. Werbel

  DOI：10.1021/jm00169a040

  日期：1990.7

  OCF3 greater than or equal to F. The 2-desamino target compounds 13a-c,k also exhibited significant, although diminished, TS inhibition. Both series were growth inhibitory to cells in tissue culture and this inhibition could be reversed by thymidine alone, indicating that the primary target was TS. None of the compounds was a potent inhibitor of dihydrofolate reductase. These studies indicate that the

  描述了两个系列的非经典胸苷酸合酶（TS）抑制剂的合成和生物学活性。第一个是一系列10-炔丙基-5,8-二叠氮基水杨酸衍生物（10a-j），第二个是一系列类似的2-desamino衍生物（13a-c，k），两者在其上均具有更亲脂的取代基苯环比经典抗叶酸剂的CO-谷氨酸盐高。化合物10a-j通常以各种方式处理N- [6-（溴甲基）-3,4-二氢-4-氧代-2-喹唑啉基] -2,2-二甲基丙酰胺（6），以直接的方式制备。苯基取代的N-炔丙基苯胺（8），然后脱保护。由[6-（溴甲基）-4-氧代-3（4H）-喹唑啉基] 2，2-二甲基丙酸甲酯（11）类似地制备化合物13a-c，k。测试了这些化合物对纯化的L1210 TS的抑制作用以及对L1210细胞的体外抑制作用。这些非经典类似物中的几种达到了含有谷氨酸的TS抑制剂10-炔丙基-5,8-二氮杂az酸（1，CB3717）的TS抑制能力。2-氨基目标化合物10a-j通常是L1210
• Anti-cancer quinazoline derivatives
  申请人：National Research Development Corporation

  公开号：US05236927A1

  公开（公告）日：1993-08-17

  A compound of formula I: ##STR1## wherein R is hydrogen; oran alkyl, alkenyl or alkynyl group of up to 6 carbon atoms; nis O; 1 or 2; Z represents --CH.dbd.CH-- or --S--; each X independently represents halogeno, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, nitro or trifluoromethyl; and Y represents a group of formula: ##STR2## or a pharmaceutically acceptable salt or ester thereof.

  化合物I的化学式为：##STR1## 其中R为氢；或具有最多6个碳原子的烷基、烯基或炔基；n为O；1或2；Z代表--CH.dbd.CH--或--S--；每个X独立地代表卤素、C.sub.1-C.sub.4烷基、C.sub.1-C.sub.4烷氧基、硝基或三氟甲基；Y代表以下式的基团：##STR2## 或其药学上可接受的盐或酯。
• Inhibition of mammalian folylpolyglutamate synthetase and human dihydrofolate reductase by 5,8-dideaza analogs of folic acid and aminopterin bearing a terminal L-ornithine
  作者：Shirish A. Patil、Barry Shane、James H. Freisheim、Shyam K. Singh、John B. Hynes

  DOI：10.1021/jm00127a026

  日期：1989.7

  8-dideazapteroyl)-L-ornithine (3f) was identified as the most potent inhibitor of mammalian folylpolyglutamate synthetase reported thus far (Ki congruent to 2 nM). Its 4-oxy counterpart, N alpha-(5-chloro-5,8-dideazapteroyl)-L-ornithine, was only 5-fold less inhibitory than 3f toward folylpolyglutamate synthetase but was found to be a much weaker inhibitor of dihydrofolate reductase than 3f.

  通过使用多步合成序列，制备了含有末端L-鸟氨酸残基的6种新的叶酸和氨基蝶呤5,8-dideaza类似物。每种都被评估为猪肝叶酰聚谷氨酸合成酶和人二氢叶酸还原酶的抑制剂。包括2、4、5和10位的结构修饰，以帮助定义此类化合物的结构活性关系。化合物Nα-（4-氨基-4-脱氧-5-氯-5,8-二氮杂叠氮酰基）-L-鸟氨酸（3f）被确定为迄今为止报道的哺乳动物叶酰聚谷氨酸合成酶的最强抑制剂（Ki相当于2 nM）。它的4-氧对应物Nα-（5-氯-5,8-二氮杂叠氮酰基）-L-鸟氨酸对叶酰聚谷氨酸合成酶的抑制作用仅比3f低5倍，但发现它是比二氢叶酸还原酶弱得多的抑制剂。 3楼
• Quinazoline antifolate thymidylate synthase inhibitors: 2'-Fluoro-N10-propargyl-5,8,-dideazafolic acid and derivatives with modifications in the C-2 position
  作者：Ann L. Jackman、Peter R. Marsham、Timothy J. Thornton、Joel A. M. Bishop、Brigid M. O'Connor、Leslie R. Hughes、A. Hilary Calvert、Terence R. Jones

  DOI：10.1021/jm00173a025

  日期：1990.11

  L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates. Compared with their non-fluorinated parent compounds, the 2'-fluoro analogues were all approximately 2-fold more potent as TS inhibitors. Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and

  描述了2'-氟-10-炔丙基-5,8-二氮杂萘甲酸及其2-脱氨基，2-脱氨基-2-羟甲基和2-脱氨基-2-甲氧基类似物的合成。通常，合成途径包括将N- [2-氟-4-（丙-2-炔氨基）苯甲酰基二乙基]谷氨酸与适当的6-（溴甲基）喹唑啉偶联，然后用弱碱脱保护。测试了这四种化合物以及2-desamino-2-methyl类似物对L1210胸苷酸合酶（TS）的活性。还检查了它们对L1210细胞系和两种突变L1210细胞系（过度产生二氢叶酸还原酶（DHFR）的L1210：R7A和抑制还原叶酸摄取的L1210：1565）生长的抑制作用。与非氟化母体化合物相比，2' -氟类似物作为TS抑制剂的效力均高约2倍。同样，它们还显示出对L1210细胞生长的抑制作用得到改善（1.5-5倍），并且通过与胸腺嘧啶核苷共同孵育而阻止了这种活性。它们都保留或改善了对L1210：R7A和L1210：1565细胞系的活性。