3,4-dihydro-6-methyl-4-oxo-3-<(pivaloyloxy)methyl>quinazoline | 106585-52-8

• 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: 3,4-dihydro-6-methyl-4-oxo-3-<(pivaloyloxy)methyl>quinazoline
• 英文别名: 3,4-Dihydro-6-methyl-4-oxo-3-((pivaloyl)oxy)methyl-quinazoline；3,4-dihydro-6-methyl-4-oxo-3-[(pivaloyloxy)methyl]quinazoline；(6-Methyl-4-oxoquinazolin-3-yl)methyl 2,2-dimethylpropanoate
• CAS: 106585-52-8
• 化学式: C₁₅H₁₈N₂O₃
• 分子量: 274.32
• InChiKey: BZAAFJBIUTUSKM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  20
• 可旋转键数：
  4
• 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：

  3,4-dihydro-6-methyl-4-oxo-3-<(pivaloyloxy)methyl>quinazoline 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 四氯化碳 为溶剂， 反应 0.33h， 以76.3%的产率得到<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
• 作为产物：
  描述：

  2-氨基-5-甲基苯甲酸 在 sodium hydride 作用下， 反应 4.5h， 生成 3,4-dihydro-6-methyl-4-oxo-3-<(pivaloyloxy)methyl>quinazoline
  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.

  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。
• JONES, TERENCE R.;THORNTON, TIMOTHY J.;FLINN, ANTHONY;JACKMAN, ANN L.;NEW+, J. MED. CHEM., 32,(1989) N, C. 847-852
  作者：JONES, TERENCE R.、THORNTON, TIMOTHY J.、FLINN, ANTHONY、JACKMAN, ANN L.、NEW+

  DOI：——

  日期：——
• ——
  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
• 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.