amino-4-deoxy-10-ethyl-10-deazapteroic acid | 142721-22-0

• 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: amino-4-deoxy-10-ethyl-10-deazapteroic acid
• 英文别名: methyl 4-<1-<(2,4-diamino-6-pteridinyl)methyl>propyl>benzoate；methyl 4-amino-4-deoxy-10-ethyl-10-deazapteroate；Methyl 4-[1-(2,4-diaminopteridin-6-yl)butan-2-yl]benzoate
• CAS: 142721-22-0
• 化学式: C₁₈H₂₀N₆O₂
• 分子量: 352.396
• InChiKey: LFXXEKISORVSHJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  130
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  amino-4-deoxy-10-ethyl-10-deazapteroic acid 在 sodium hydroxide 作用下， 以 二甲基亚砜 为溶剂， 反应 29.0h， 以77%的产率得到4-[1-(2,4-Diaminopteridin-6-yl)butan-2-yl]benzoic acid
  参考文献：
  名称：

  10-乙基-5-甲基-5,10-二氮杂氨基蝶呤的合成和抗叶酸评估，以及10-乙基-10-脱氮杂min蝶呤（edatrexate）的替代合成。

  摘要：

  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

  DOI：

  10.1021/jm00094a011
• 作为产物：
  描述：

  methyl 4-<2-(2,4-diamino-6-pteridinyl)-1-ethylethenyl>benzoate 在 platinum(IV) oxide 氢气 作用下， 以 溶剂黄146 为溶剂， 反应 18.0h， 以73%的产率得到amino-4-deoxy-10-ethyl-10-deazapteroic acid
  参考文献：
  名称：

  10-乙基-5-甲基-5,10-二氮杂氨基蝶呤的合成和抗叶酸评估，以及10-乙基-10-脱氮杂min蝶呤（edatrexate）的替代合成。

  摘要：

  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

  DOI：

  10.1021/jm00094a011

文献信息

• [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。
• 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.
• Synthesis and biological activity of resolved carbon-10 diastereomers of 10-methyl- and 10-ethyl-10-deazaminopterin
  作者：J. I. DeGraw、P. H. Christie、H. Tagawa、R. L. Kisliuk、Y. Gaumont、F. A. Schmid、F. M. Sirotnak

  DOI：10.1021/jm00156a026

  日期：1986.6

  Synthesis and evaluation of the antitumor drugs 10-methyl- and 10-ethyl-10-deazaminopterin (15a,b) were previously reported for the diastereomeric mixtures, lacking resolution at the C-10 position. In order to assess biological properties of the individual diastereomers, the C-10 isomers of 4-amino-4-deoxy-10-methyl- and 10-ethyl-10-deazapteroic acids (13a,b) were prepared by total synthesis. Coupling with L-glutamate afforded the appropriate diastereomers of the title compounds. Biochemical, transport, and cell growth inhibitory properties in L1210 cells and folate-dependent bacteria were measured. Differences were generally less than 2-fold between diastereomeric pairs, but a factor of 3 was noted for d,L-15b vs. l,L-15b in inhibition of DHFR from L1210 cells and in cytotoxicity toward L1210 cells. An in vivo comparison of the isomers of 15b with racemic compound against L1210 in mice did not show a significant efficacy difference (ILS) among the compounds. However, d,L-15b showed an acute toxicity about 2.5 times that of l,L-15b.
• J. Med. Chem. 1992, 35, 3002-3006
  作者：

  DOI：——

  日期：——
• DEGRAW, JOSEPH I.;CHRISTIE, PAMELA H.;SIROTNAK, FRANCIS M.
  作者：DEGRAW, JOSEPH I.、CHRISTIE, PAMELA H.、SIROTNAK, FRANCIS M.

  DOI：——

  日期：——