N-(4-{N-[(3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-prop-2-ynylamino}benzoyl)-L-glutamic acid | 106585-65-3

• 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]-prop-2-ynylamino}benzoyl)-L-glutamic acid
• 英文别名: (S)-2-(4-(((4-oxo-3,4-dihydroquinazolin-6-yl)methyl)(prop-2-ynyl)amino)benzamido)pentanedioic acid；(2S)-2-[[4-[(4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoyl]amino]pentanedioic acid
• CAS: 106585-65-3
• 化学式: C₂₄H₂₂N₄O₆
• 分子量: 462.462
• InChiKey: AOGOUTMDEVCZHA-FQEVSTJZSA-N

物化性质

• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-(4-{N-[(3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-prop-2-ynylamino}benzoyl)-L-glutamic acid 在 diethyl cyanophosphoridate 、 Tris buffer (tris(hydroxymethyl)aminomethane, ZnCl₂, aq. HCl, pH 7.3) 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (S)-2-[(S)-4-tert-Butoxycarbonyl-4-((S)-4-tert-butoxycarbonyl-4-{4-[(4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-butyrylamino)-butyrylamino]-pentanedioic acid di-tert-butyl ester
  参考文献：
  名称：

  Syntheses and thymidylate synthase inhibitory activity of the poly-.gamma.-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates

  摘要：

  Thirteen poly-gamma-glutamates derived from several novel antifolates have been synthesized by a convergent route. The syntheses of poly-gamma-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid (8) (ICI D1694), 2-desamino-N10-propargyl-5,8-dideazafolic acid (6), 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (7), 2-desamino-2-methyl-N10-propargyl-2'-fluoro-5,8-dideazafolic acid (9), and 2-desamino-2-methyl-4-chloro-N10-propargyl-2'-fluoro-3,5,8-trideazafolic acid (11) are described. A key step in the route involves coupling of an alpha-tert-butyl-protected poly-gamma-glutamate of the required chain length to the appropriate 5,8-dideazapteroic acid, obtained by carboxypeptidase G2 cleavage of the parent monoglutamate, if available, or by chemical synthesis. Deprotection with trifluoroacetic acid in the final step gave the desired poly-gamma-glutamyl antifolates as their trifluoroacetate salts. As inhibitors of thymidylate synthase, these polyglutamates were more potent in every case than the corresponding non-polyglutamylated drug.

  DOI：

  10.1021/jm00083a008
• 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 39.33h， 生成 N-(4-{N-[(3,4-dihydro-4-oxo-6-quinazolinyl)methyl]-prop-2-ynylamino}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：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.

  公式I的化合物：##STR1## 其中R为氢；或者是由最多6个碳原子的烷基，烯基或炔基组成的基团；n为O；1或2；Z代表--CH.dbd.CH--或--S--；每个X分别代表卤素，C.sub.1-C.sub.4烷基，C.sub.1-C.sub.4烷氧基，硝基或三氟甲基；而Y代表下列公式的基团：##STR2## 或其药学上可接受的盐或酯。
• ——
  作者：JONES T. R.、 JACKMAN A. L.、 NEWELL D. R.

  DOI：——

  日期：——
• US5236927A
  申请人：——

  公开号：US5236927A

  公开（公告）日：1993-08-17