4-[1-(2,4-Diaminopteridin-6-yl)butan-2-yl]benzoic acid | 80576-81-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 4-[1-(2,4-Diaminopteridin-6-yl)butan-2-yl]benzoic acid
• CAS: 80576-81-4
• 化学式: C₁₇H₁₈N₆O₂
• 分子量: 338.369
• InChiKey: YQGAPVSWXCFUHZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  141
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-[1-(2,4-Diaminopteridin-6-yl)butan-2-yl]benzoic acid 在 N-甲基吗啉 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 30.0h， 生成 (S)-2-((S)-4-Carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[1-(2,4-diamino-pteridin-6-ylmethyl)-propyl]-benzoylamino}-butyrylamino)-butyrylamino]-butyrylamino}-butyrylamino)-pentanedioic acid
  参考文献：
  名称：

  10-脱氮杂min蝶呤和10-乙基-10-脱氮杂min蝶呤的聚-γ-谷氨酰基代谢产物的合成和生物学评估。

  摘要：

  实验性抗癌药物10-脱氮杂min蝶呤（10-DAAM）和10-乙基-10-脱氮杂min蝶呤（10-EDAAM）的一系列聚-γ-谷氨酰基代谢物的化学合成已通过固相程序进行。合成产物与正常小鼠组织产生的放射性标记的10-DAAM和10-EDAAM的聚-γ-谷氨酰胺代谢物在[（二乙氨基）乙基]纤维素柱上的洗脱体积以及人血浆叶酰聚谷氨酸水解酶的水解敏感性有关。 。在组织中检测到谷氨酸链长度最多为四个谷氨酸残基的聚-γ-谷氨酰基代谢物。用甲氨蝶呤（MTX）敏感和耐MTX的干酪乳杆菌和粪链球菌菌株评估抗叶酸活性。一般来说，抑制力随Glu链长度的增加而降低。但是，有两个例外。在10-DAAM中添加一个Glu残基可增强其对耐MTX干酪乳杆菌的效力，在10-EDAAM中添加一个Glu残基可增强对MTX敏感性干酪乳杆菌的效力。如先前对于MTX聚谷氨酸盐所示，聚谷氨酰化极大地增强了10-DAAM和10-EDAA

  DOI：

  10.1021/jm00396a029
• 作为产物：
  描述：

  4-(p-carbomethoxyphenyl)-1-phthalimido-3-buten-2-one 在 吡啶 、 盐酸 、 甲醇 、 sodium hydroxide 、 potassium permanganate 、 sodium dithionite 、 盐酸羟胺 、 一水合肼 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 、 三氟乙酸 为溶剂， 反应 118.83h， 生成 4-[1-(2,4-Diaminopteridin-6-yl)butan-2-yl]benzoic acid
  参考文献：
  名称：

  Folate analogs. 24. Syntheses of the antitumor agents 10-deazaaminopterin (10-DAAM) and 10-ethyl-10-deazaaminopterin (10-EDAAM)

  摘要：

  DOI：

  10.1021/jo00211a019

文献信息

• Synthesis and antitumor activity of 10-alkyl-10-deazaminopterins. A convenient synthesis of 10-deazaminopterin
  作者：J. I. DeGraw、V. H. Brown、H. Tagawa、R. L. Kisliuk、Y. Gaumont、F. M. Sirotnak

  DOI：10.1021/jm00352a026

  日期：1982.10

  Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the

  大规模合成有效的抗肿瘤药10-脱氮蝶呤的要求导致了该化合物及其10-烷基类似物的简便合成的发展。用3-甲氧基烯丙基氯将适当的对烷基苯甲酸的二异丙基氨基锂锂生成的二价阴离子烷基化。在pH 7-8下将所得的4-（对羧基苯基）-1-甲氧基-1-丁烯溴化，得到2-溴-4-（对羧基苯基）丁醛。与2,4,5,6-四氨基嘧啶缩合，然后原位氧化所得的二蝶啶，得到结晶的10-烷基-10-脱氮基-4-氨基-4-脱氧蝶酸。通过混合酸酐法将蝶酸与谷氨酸二乙酯偶联，然后在室温下皂化，以得到目标10-脱氮蝶呤类化合物。10-烷基化合物作为叶酸依赖性细菌的生长抑制剂与10-脱氮蝶呤大致相等。它们抑制干酪乳杆菌和L1210衍生的二氢叶酸还原酶的能力也相似。体外转运特性提示10-烷基类似物的治疗指数得到改善。相对于小鼠中的L1210，在LD10剂量下，寿命延长百分比为+ 151％（甲氨蝶呤），+ 178％（10-脱氮蝶呤），+
• Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10-dideazaaminopterin and an alternative synthesis of 10-ethyl-10-deazaaminopterin (edatrexate)
  作者：J. R. Piper、C. A. Johnson、G. M. Otter、F. M. Sirotnak

  DOI：10.1021/jm00094a011

  日期：1992.8

  -5,10-dideazapteroic acid methyl ester (9a) and 4-amino-4-deoxy-10-ethyl-10-deazapteroic acid methyl ester (9b). This route to 9b intersects reported synthetic approaches leading to 10-ethyl-10-deazaaminopterin (10-EDAM, edatrexate), an agent now in advanced clinical trials. Thus the Wittig approach affords an alternative synthetic route to 10-EDAM. Remaining steps were ester hydrolysis of 9a,b to

  先前的发现表明5,10-二叠氮杂氨基蝶呤的5,10-二烷基取代的衍生物值得研究，因为潜在的抗叶酸药物提示了10-乙基-5-甲基-5,10-二氮杂氨基蝶呤的合成（12a）。合成路线12a的关键步骤是将6-（溴甲基）-2,4-二氨基-5-甲基吡啶并[2,3-d]嘧啶（7a）衍生的三丁基膦与4-丙酰基苯甲酸甲酯进行Wittig缩合。使用由6-（溴甲基）-2,4-哌啶二胺（7b）制备的三丁基膦烷开发了Wittig缩合反应的条件。每个维蒂希产品8a和8b以75-80％的产率获得。8a和8b在它们的9,10-双键处氢化，得到4-氨基-4-脱氧-10-乙基-5-甲基-5，10-二脱氮杂戊酸甲酯（9a）和4-氨基-4-脱氧-10-乙基-10-脱氮杂戊酸甲酯（9b）。据报道，这种通向9b的途径与合成方法有关，可导致10-乙基-10-deazaaminopterin（10-EDAM，edatrexate），该
• [EN] DEAZAAMINOPTERINS
  申请人：SOUTHERN RESEARCH INSTITUTE

  公开号：WO1993013102A1

  公开（公告）日：1993-07-08

  (EN) 5,10-Diakyl substituted 5,10-dideazaaminopterin and a cyclized derivative thereof are disclosed as potent antineoplastic agents. Also disclosed in an improved process for preparation of 10-ethyl-10-deazaaminopterin using the intermediate methyl 4-[[2-(2,4-diamino-6-pteridinyl)-1-ethyl]ethenyl]benzoate.(FR) On décrit la 5,10-didéazaaminoptérine substituée par 5,10-diakyle ainsi qu'un dérivé cyclisé de celle-ci comme agents antinéoplastiques puissants. On décrit également un procédé perfectionné de préparation de 10-éthyle-10-déazaaminoptérine à l'aide de l'intermédiaire méthyle-4-[[2-(2,4-diamino-6-ptéridinyle)-1-éthyle]éthényle]benzoate.

  5,10-丁基取代的5,10-二羟基异 rigsineopsin及其环化衍生物被披露为强效的抗肿瘤剂。此外，还披露了一种优化了的合成10-乙基-10-二羟基异 rigsineopsin的方法，使用中间体甲苯4-[[2-(2,4-二氨基-6-pteridinyl)-1-乙基]乙烯基]苯zoate。
• Folate analogs. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase
  作者：Ann Abraham、J. J. McGuire、John Galivan、Zenia Nimec、R. L. Kisliuk、Y. Gaumont、M. G. Nair

  DOI：10.1021/jm00105a035

  日期：1991.1

  Five analogues of methotrextate (MTX), 10-deazaaminopterin (10-DAM), and 10-ethyl-10-deazaaminopterin (10-EDAM) in which the glutamate moiety was replaced by either a gamma-methyleneglutamate or beta-hydroxyglutamate were synthesized and evaluated for their antifolate activity. These analogous are 4-amino-4-deoxy-N-10-methylpteroyl-beta-hydroxyglutamic acid (1), 4-amino-4-deoxy-10-deazapteroyl-beta-hydroxyglutamic acid (2), 4-amino-4-deoxy-N-10-methylpteroyl-gamma-methyleneglutamic acid (3, MMTX), 4-amino-4-deoxy-10-deazapteroyl-gamma-methyleneglutamic acid (4, MDAM), and 4-amino-4-deoxy-10-ethyl-10-deazapteroyl-gamma-methyleneglutamic acid (5, MEDAM). None of these compounds were metabolized to the respective polyglutamate derivative as judged by their inability to serve as substrates for CCRF-CEM human leukemia cell folypolyglutamate synthetase (FPGS) in vitro. All compounds inhibited recombinant human-dihydrofolate reductase (DHFR) at nearly equivalent magnitude as MTX. Growth-inhibition studies with H35 hepatoma, Manca human lymphoma, and CCRF-CEM human leukemia cells established greater cytotoxic effects with compounds 3-5 than with compounds 1 and 2. Gamma-Methyleneglutamate derivatives 3-5 were transported to H35 hepatoma cells better than MTX or beta-hydroxyglutamate derivatives 1 and 2. Compound 3 was 2.5 times better than MTX in competing with folinic acid transport in H35 hepatoma cells. Compound 1 did not have a significant inhibitory effect on folinic acid transport even at 50-mu-M under identical conditions. The IC50 for compound 1 against H35-hepatoma cell growth was 8.5-fold higher than MTX. Compounds with the gamma-methyleneglutamate moiety (3-5) exhibited almost equal or lower IC50 values than MTX against the growth of CCRF-CEM human leukemia cells. These studies show that on continuous exposure, the non-poly glutamylatable inhibitors DHFR (3-5) can exhibit superior antifolate activity compared to the polyglutamylatable methotrexate, presumably due to their enhanced transport to these cell lines. Compounds 3-5 appear to be excellent models to study the role of polyglutamylation of antifolates in antitumor activity and host toxicity.
• Analogues of the Potent Nonpolyglutamatable Antifolate <i>N</i>^α-(4-Amino-4-deoxypteroyl)-<i>N</i>^δ-hemiphthaloyl-<scp>l</scp>-ornithine (PT523) with Modifications in the Side Chain, <i>p</i>-Aminobenzoyl Moiety, or 9,10-Bridge:  Synthesis and in Vitro Antitumor Activity
  作者：Andre Rosowsky、Joel E. Wright、Chitra M. Vaidya、Ronald A. Forsch、Henry Bader

  DOI：10.1021/jm990630f

  日期：2000.4.1

  Seven N-alpha-(4-amino-4-deoxypteroyl)-N-sigma-hemiphtha (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. in growth assays against cultured CCRF-CEM human leukemic cells exposed to drug for 72 h, the IC50 values of analogues in which N-10 was replaced by CH2 and CHMe were found to be 0.55 +/- 0.07 and 0.63 +/- 0.08 nM, and thus these analogues are more potent than 1 (IC50 = 4.4 +/- 1.0 nM) or 2 (IC50 = 1.5 +/-: 0.39 nM). The 10-ethyl-10-deaza analogue of 2 (IC50 = 1.2 +/- 0.25 nM) was not statistically different from 2 but was more potent than edatrexate, the 10-ethyl-10-deaza analogue of 1, which had an IC50 of 3.3 +/- 0.36 nM. In contrast, the analogue of 2 with both an ethyl and a CO2Me group at the 10-position had an IC50 of 54 +/- 4.9 nM, showing this modification to be unfavorable. The 4-amino-1-naphthoic acid analogue of 2 had an IC50 Of 1.2 +/- 0.22 nM, indicating that replacement of the p-aminobenzoic acid (pABA) moiety does not diminish cytotoxicity. The analogues in which the (CH2)(3) Side chain was replaced by slightly longer CH2SCH2 and (CH2)(2)-SCH2 groups gave IC50 values of 4.4 +/- 1.1 and 5.0 +/- 0.56 nM and thus were somewhat less potent than the parent molecule. However the analogues in which the aromatic COOH group was at the meta and para positions of the phthaloyl ring had IC50 values of 7.5 +/- 0.47 and 55 +/- 0.07 nM, confirming the low potency we had previously observed with these compounds against other cell lines. Overall, the results in this study support the conclusion that, while the position of the phthaloyl COOH group and the length of the amino acid side chain in 2 are important determinants of cytotoxic potency, changes in the pABA region and 9,10-bridge are well-tolerated and can even increase potency.