4--N-prop-2-ynylamino>benzoic acid, trifluoroacetate salt | 138899-84-0

• 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: 4--N-prop-2-ynylamino>benzoic acid, trifluoroacetate salt
• 英文别名: 4--N-prop-2-ynylamino>benzoic acid trifluoroacetate salt；4--N-prop-2-ynylamino>benzoic acid trifluoroacetate；4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]benzoic acid, trifluoroacetate salt；2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazapteroic acid trifluoroacetate salt；4-{N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino}benzoic acid trifluoroacetate；4-[[(3,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]-2-propyn-1-ylamino]benzoic acid 2,2,2-trifluoroacetate；4-[(2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]benzoic acid;2,2,2-trifluoroacetic acid
• CAS: 138899-84-0
• 化学式: C₂HF₃O₂*C₂₀H₁₇N₃O₃
• 分子量: 461.397
• InChiKey: WBKZHYRUXFUSMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  33.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  123.59
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  4--N-prop-2-ynylamino>benzoic acid, trifluoroacetate salt 在 叠氮磷酸二苯酯 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 以82%的产率得到4--N-prop-2-ynylamino>benzoylazide
  参考文献：
  名称：

  喹唑啉抗叶酸胸苷酸合酶抑制剂：取代C2-甲基系列中的谷氨酸。

  摘要：

  强大的胸苷酸​​合酶（TS）抑制剂N- [4- [N-[（3,4-二氢-2-甲基-4-氧代-6-喹唑啉基）甲基] -N-prop的一系列类似物的合成描述了-2-炔基氨基]苯甲酰基] -L-谷氨酸（ICI 198583，1），其中谷氨酸残基已被其他α-氨基酸取代。这些类似物大多数是通过将4-（丙-2-炔氨基）苯甲酸叔丁酯（37）与6-（溴甲基）-3,4-二氢-2-甲基-4-氧代喹唑啉（34）偶联而制得的通过将叔丁酯脱保护成该酸并将叠氮化物介导的偶联成适当的氨基酸或氨基酸酯。在氨基酸酯与酰叠氮不反应的情况下，使用修饰形式，其中喹唑啉酮部分被保护为其3-（新戊酰氧基）甲基衍生物。这允许生成对氨基苯甲酸酯单元的更具反应性的酰氯。通常，这些修饰产生的化合物与分离的TS抑制剂具有与1等效的效价，除非氨基酸缺乏亲脂性的α-取代基。这些化合物似乎需要减少的叶酸载体（RFC）才能转运到细胞中，但是由于它们不

  DOI：

  10.1021/jm00006a019
• 作为产物：
  描述：

  6-溴甲基-3,4-二氢-2-甲基-喹唑啉-4-酮 在 calcium carbonate 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 17.17h， 生成 4--N-prop-2-ynylamino>benzoic acid, trifluoroacetate salt
  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

文献信息

• Synthesis of novel quinazoline-based antifolates with modified glutamate side chains as potential inhibitors of thymidylate synthase and antitumour agents
  作者：Vassilios Bavetsias、Graham M.F. Bisset、Rosemary Kimbell、F.Thomas Boyle、Ann L. Jackman

  DOI：10.1016/s0040-4020(97)00851-x

  日期：1997.9

  7-dimethyl-4-oxo-6-quinazolinyl)-methyl]-N-prop-2-ynylamino]-2-fluorobenzoic acid (24), and finally removal of the protecting groups. The resulting quinazoline-based antifolates with modified glutamate side chains, and in particular, the tetrazole derivatives 26 and 29 displayed potent TS and L1210 cell growth inhibitory activities (e.g., for 26: TS IC50 = 2.4 nM, L1210 IC50 = 1.3 μM).

  合成了几种新型的抗叶酸剂，它们是2-脱氨基-2-甲基-N 10-炔丙基-5,8-二氮杂壬酸的衍生物，作为胸苷酸合酶（TS）的抑制剂和抗肿瘤剂。这是通过首先开发通往关键中间体Glu-Ome-γ-ψ[CSNH] Glu（OEt）-OEt（8），Glu-OBu t -γ -ψ[CH 2 NH] Glu（OBu t）-的途径来完成的将OBu t（16），Glu-OMe-γ-ψ[CN 4 ] Gly-OMe（23）及其2,5-二取代的区域异构体（22），然后将DEPC偶联至4- [ N- [3,4-二氢-2-甲基-4-氧代-6-喹唑啉基）-甲基] -N-丙-2-炔基氨基]苯甲酸（9）或4- [ N -[（3,4-二氢-2,7-二甲基-4-氧代-6-喹唑啉基）-甲基] -N-丙-2-炔基氨基] -2-氟苯甲酸（24），最后除去保护基。所得的具有修饰的谷氨酸侧链的基于喹唑啉的抗叶酸剂，尤其是四唑衍生物2
• Quinazoline Antifolate Thymidylate Synthase Inhibitors:  γ-Linked <scp>l</scp>-<scp>d</scp>, <scp>d</scp>-<scp>d</scp>, and <scp>d</scp>-<scp>l</scp> Dipeptide Analogues of 2-Desamino-2-methyl-<i>N</i>¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)^,
  作者：Vassilios Bavetsias、Ann L. Jackman、Rosemary Kimbell、William Gibson、F. Thomas Boyle、Graham M. F. Bisset

  DOI：10.1021/jm950471+

  日期：1996.1.1

  The syntheses of gamma-linked L-D, D-D, and D-L dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) are described. The general methodology for the synthesis of these molecules involved the preparation of the dipeptide derivatives employing solution phase peptide synthesis followed by condensation of the dipeptide free bases with the appropriate pteroic acid analogue

  描述了γ-连接的2-脱氨基-2-甲基-N10-炔丙基-5,8-二氮杂萘甲酸的LD，DD和DL二肽类似物的合成（ICI 198583）。合成这些分子的通用方法包括采用溶液相肽合成法制备二肽衍生物，然后通过氰基磷酸二乙酯（DEPC）活化将二肽游离碱与适当的蝶酸类似物缩合。在最后一步中，通过三氟乙酸（TFA）水解除去叔丁酯。ZL-Glu-OBut-γ-D-Ala-OBut例如是由N-（苄氧羰基）-L-谷氨酸的α-叔丁基和D-丙氨酸的叔丁基通过异丁基-混合酸酐偶联制备的。通过催化氢解除去Z-基团，并通过DEPC偶联将所得的二肽游离碱与2-脱氨基-2-甲基-N10-炔丙基-5,8-二脱氮杂戊酸缩合。最后，通过TFA水解除去叔丁酯，得到ICI198583-γ-D-Ala。测试这些化合物作为胸苷酸合酶和L1210细胞生长的抑制剂。发现与γ-连接的LD二肽具有良好的酶和生长抑制活性，最好的例子是Glu-γ-D-Glu衍生物35（Ki
• The Synthesis and Thymidylate Synthase Inhibitory Activity of L-.gamma.-L-Linked Dipeptide and L-.gamma.-Amide Analogs of 2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)
  作者：Graham M. F. Bisset、Vassilios Bavetsias、Timothy J. Thornton、Krzysztof Pawelczak、A. Hilary Calvert、Leslie R. Hughes、Ann L. Jackman

  DOI：10.1021/jm00046a014

  日期：1994.9

  Sixteen gamma-linked dipeptide and four L-Glu-gamma-amide analogues of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid (ICI 198583) have been synthesized and evaluated as inhibitors of thymidylate synthase (TS). Z-blocked L-Glu-gamma-L-linked dipeptides and L-Glu-gamma-amides were prepared by condensing alpha-tert-butyl-N-(benzyloxycarbonyl)-L-glutamic acid with the appropriate tert-butyl-protected L-amino acid or amine. The Z group was removed by catalytic hydrogenolysis, and the resulting dipeptides or L-Glu-gamma-amides were condensed with the appropriate pteroic acid analogue trifluoroacetate salt using diethyl cyanophosphoridate as coupling reagent. Deprotection with trifluoroacetic acid in the final step gave the desired quinazoline gamma-linked dipeptides and L-Glu-gamma-amides as their trifluoroacetate salts. Nearly all the dipeptide analogues were potent inhibitors of TS, the best being ICI 198583-gamma-L-2-aminoadipate (IC50 = 2 nM). Several of these dipeptides were found to be susceptible to enzymatic hydrolysis in mice. The quinazoline monocarboxylate L-Glu-gamma-amides, lacking an alpha'-carboxyl group, are less active against TS and L1210 cell growth but are also not susceptible to enzymatic hydrolysis in mice.
• Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-<i>N</i>¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)
  作者：Vassilios Bavetsias、Ann L. Jackman、Jonathan H. Marriott、Rosemary Kimbell、William Gibson、F. Thomas Boyle、Graham M. F. Bisset

  DOI：10.1021/jm960878u

  日期：1997.5.1

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.
• HUGHES, LESLIE RICHARD
  作者：HUGHES, LESLIE RICHARD

  DOI：——

  日期：——