N-(4-(N-((3,4-dihydro-4-oxo-6-quinazolinyl)methyl) ethylamino)benzoyl)-L-glutamic acid | 106585-68-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(4-(N-((3,4-dihydro-4-oxo-6-quinazolinyl)methyl) ethylamino)benzoyl)-L-glutamic acid
• 英文别名: (2S)-2-[[4-[ethyl-[(4-oxo-3H-quinazolin-6-yl)methyl]amino]benzoyl]amino]pentanedioic acid
• CAS: 106585-68-6
• 化学式: C₂₃H₂₄N₄O₆
• 分子量: 452.467
• InChiKey: BCAXXUAMVUQADK-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4-羟基-6-甲基喹唑啉 在 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 、 calcium carbonate 作用下， 以 四氯化碳 、 乙醇 、 水 、 二甲胺 为溶剂， 反应 49.83h， 生成 N-(4-(N-((3,4-dihydro-4-oxo-6-quinazolinyl)methyl) ethylamino)benzoyl)-L-glutamic acid
  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

• Anti-cancer quinazoline derivatives
  申请人：BRITISH TECHNOLOGY GROUP LIMITED

  公开号：EP0204529A2

  公开（公告）日：1986-12-10

  Quinazoline derivatives of the formula wherein R is 1) hydrogen or 2) a straight or branched chain saturated or unsaturated hydrocarbon group, or 3) a straight or branched chain saturated or unsaturated hydrocarbon group which is substituted by at least one heteroatom, the or each heteroatom being halogeno when R is a C, hydrocarbon group, by a saturated carbocyclic group or by a group containing at least one heteroatom, the or each heteroatom being 0, N or S when R contains a cyclic group; n is 0,1 or 2; Z represents -CH=CH- or-O-or-S-; X or, when n is an integer of at least 2, each X independently, represents a halogeno, C1-C4 alkyl, aryl or aralkyl group or a group including at least one heteroatom and Y represents a group of formula: or where m ≥1 (poly-L-glutamic acid residues) or or or a pharmaceutically acceptable salt or ester thereof are good inhibitors of thymidylate synthase but have reduced hepatic toxicity compared to their 2-amino quinazolinyl analogues. This renders compounds of formula I of value as anti-tumour agents. Compounds of formula I can be prepared by condensing appropriately substituted 6-halomethyl or sul- phonylmethyl quinazolines with appropriating substituted p-amino benzoyl-, furoyl- or thienylcarbonyl aspartates, glutamates, alanines or amino butyric acids and removing the protecting groups.

  式中的喹唑啉衍生物 其中 R 是 1) 氢 或 2) 直链或支链饱和或不饱和烃基，或 3) 被至少一个杂原子取代的直链或支链饱和或不饱和烃基，当 R 为 C、烃基时，该杂原子或每个杂原子为卤代；当 R 含有环状基团时，该杂原子或每个杂原子为 0、N 或 S；n 为 0、1 或 2；Z 代表-CH=CH- 或-O-或-S-；X 或，当 n 为至少 2 的整数时，每个 X 独立地代表卤素、C1-C4 烷基、芳基或芳烷基或包含至少一个杂原子的基团，Y 代表式中的一个基团： 或 其中 m ≥1（多 L-谷氨酸残基）或 或 或其药学上可接受的盐或酯是胸腺嘧啶酸合成酶的良好抑制剂，但与 2-氨基喹唑啉类似物相比，肝毒性较低。这使得式 I 化合物具有抗肿瘤剂的价值。通过将适当取代的 6-卤甲基或砜甲基喹唑啉与适当取代的对氨基苯甲酰、呋喃基或噻吩基羰基天冬氨酸、谷氨酸、丙氨酸或氨基丁酸缩合并除去保护基团，可制备式 I 化合物。
• US5236927A
  申请人：——

  公开号：US5236927A

  公开（公告）日：1993-08-17
• Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency
  作者：Terence R. Jones、Timothy J. Thornton、Anthony Flinn、Ann L. Jackman、D. R. Newell、A. Hilary Calvert

  DOI：10.1021/jm00124a018

  日期：1989.4

  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.