N-<4--N-prop-2-ynylamino>-2-fluorobenzoyl>-L-glutamic acid | 112887-67-9

• 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-prop-2-ynylamino>-2-fluorobenzoyl>-L-glutamic acid
• 英文别名: p-[ N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-o-fluorobenzoyl-L-glutamic acid；N-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-o-fluorobenzoyl-L-glutamic acid；2-{2-Fluoro-4-[(4-hydroxy-2-methyl-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-pentanedioic acid；(2S)-2-[[2-fluoro-4-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoyl]amino]pentanedioic acid
• CAS: 112887-67-9
• 化学式: C₂₅H₂₃FN₄O₆
• 分子量: 494.479
• InChiKey: ZALTVGFCLRNRRP-NRFANRHFSA-N

物化性质

• 熔点：
  228-230 °C
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  148
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-<4--N-prop-2-ynylamino>-2-fluorobenzoyl>-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-{2-fluoro-4-[(4-hydroxy-2-methyl-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-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：

  6-溴甲基-3,4-二氢-2-甲基-喹唑啉-4-酮 在 sodium hydroxide 、 calcium carbonate 作用下， 以 乙醇 、 N,N-二甲基乙酰胺 为溶剂， 反应 29.0h， 生成 N-<4--N-prop-2-ynylamino>-2-fluorobenzoyl>-L-glutamic acid
  参考文献：
  名称：

  喹唑啉抗叶酸胸苷酸合酶抑制剂：C2-甲基系列中的苯甲酰基环修饰。

  摘要：

  描述了在对氨基苯甲酰基环中具有取代基的九种新的2-甲基-10-炔丙基喹唑啉抗叶酸酯的合成。通常，合成路线涉及将合适的环取代的N- [4-（丙-2-炔丙基氨基）苯甲酰基]苯甲酰基] -L-谷氨酸与6-（溴甲基）-3,4-二氢-2-甲基- 4-氧代喹唑啉，然后用中性碱脱保护。测试了这些化合物作为部分纯化的L1210胸苷酸合酶（TS）的抑制剂。还检查了它们对培养物中L1210细胞生长的抑制作用。与母体化合物1a相比，2'-氟类似物2a在两个系统中均显示出增强的效力，而3'-氟类似物3a对L1210细胞显示出增强的生长抑制特性，尽管分离的酶的抑制剂较弱。氯，羟基，甲氧基，该酶也很好地耐受2'-位的硝基取代基和硝基取代基，但是不能增强生长抑制作用。该系列被扩展以覆盖2'-氟，3'-氟，2'-氯，2'-甲基，2'-氨基，2'-甲氧基和2'-硝基衍生物的类似物，其在烷基上具有修饰的烷基取代基。 N10。

  DOI：

  10.1021/jm00173a026

文献信息

• MARSHAM, PETER R.;JACKMAN, ANN L.;OKIDFIELD, JOHN;HUGHES, LESLIE R.;THORN+, J. MED. CHEM. , 33,(1990) N1, C. 3072-3078
  作者：MARSHAM, PETER R.、JACKMAN, ANN L.、OKIDFIELD, JOHN、HUGHES, LESLIE R.、THORN+

  DOI：——

  日期：——
• US4992550A
  申请人：——

  公开号：US4992550A

  公开（公告）日：1991-02-12
• US5081124A
  申请人：——

  公开号：US5081124A

  公开（公告）日：1992-01-14
• US5187167A
  申请人：——

  公开号：US5187167A

  公开（公告）日：1993-02-16
• 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
  作者：Graham M. F. Bisset、Krzysztof Pawelczak、Ann L. Jackman、A. Hilary Calvert、Leslie R. Hughes

  DOI：10.1021/jm00083a008

  日期：1992.3

  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.