2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-4-methylene-pentanedioic acid | 131216-21-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-4-methylene-pentanedioic acid
• 英文别名: 2-[[4-[2-(2,4-diaminopteridin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid
• CAS: 131216-21-2
• 化学式: C₂₁H₂₁N₇O₅
• 分子量: 451.442
• InChiKey: QCLDSHDOWCMFBV-UHFFFAOYSA-N

物化性质

• 熔点：
  291-295 °C
• 密度：
  1.495±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  207
• 氢给体数：
  5
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  4-methylene-DL-glutamic acid hydrochloride 在 N-甲基吗啉 、 sodium hydroxide 、 氯化亚砜 作用下， 以 乙腈 为溶剂， 反应 57.0h， 生成 2-{4-[2-(2,4-Diamino-pteridin-6-yl)-ethyl]-benzoylamino}-4-methylene-pentanedioic acid
  参考文献：
  名称：

  Folate analogs. 34. Synthesis and antitumor activity of non-polyglutamylatable inhibitors of dihydrofolate reductase

  摘要：

  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.

  DOI：

  10.1021/jm00105a035

文献信息

• CRYSTALLINE SALT FORMS OF ANTIFOLATE COMPOUNDS AND METHODS OF MANUFACTURING THEREOF
  申请人：Pimplaskar Harish K.

  公开号：US20090253719A1

  公开（公告）日：2009-10-08

  The present invention provides methods of preparing antifolate compounds. The inventive methods can particularly be use for preparing compounds exhibiting improved bioavailability, making the compound particularly useful in pharmaceutical compositions. The compounds prepared according to the inventive methods are useful in the treatment of multiple conditions, including abnormal cell proliferation, inflammatory diseases, asthma, and arthritis.

  本发明提供了制备抗叶酸化合物的方法。本发明的方法特别适用于制备具有改善生物利用度的化合物，使该化合物特别适用于制药组合物。根据本发明方法制备的化合物在治疗多种疾病方面有用，包括异常细胞增殖、炎症性疾病、哮喘和关节炎。
• ENZYME INHIBITING COMPOUNDS
  申请人：Roberts Michael J.

  公开号：US20110112126A1

  公开（公告）日：2011-05-12

  The present invention is directed to compounds that are specifically structured to provide enzyme inhibition. In specific embodiments, the enzyme inhibiting compounds exhibit antifolate activity. Particularly, the inventive compounds are formed of an antifolate residue that is active in inhibiting one or more of TS, DHFR, GAR, FPGS, and AICAR Tfase. The enzyme inhibiting compounds are useful in a variety of methods of treatment, including treating abnormal cell proliferation and treating inflammation.

  本发明涉及一种具有特定结构以提供酶抑制作用的化合物。在具体实施例中，这些酶抑制化合物表现出抗叶酸活性。特别地，本发明的化合物由一个抗叶酸残基形成，该残基在抑制TS、DHFR、GAR、FPGS和AICAR Tfase中的一个或多个方面具有活性。这些酶抑制化合物在多种治疗方法中有用，包括治疗异常细胞增殖和治疗炎症。
• MEDICINAL COMPOSITIONS CONTAINING ANTI-Fas ANTIBODY
  申请人：Sankyo Company, Limited

  公开号：EP1180369A1

  公开（公告）日：2002-02-20

  The present invention provides a novel pharmaceutical composition containing an anti-Fas antibody which is useful as an agent for prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis. More particularly, the present invention provides a pharmaceutical composition containing an anti-human Fas antibody having apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients. According to the present invention, the amount of the anti-Fas antibody to be used can be reduced in an agent for prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis, and thereby, the possibility that the patient becomes tolerant to anti-Fas antibody as a result of the production of antibodies against the anti-Fas antibody in the patient's body or the like can be decreased, and thus there can be provided a pharmaceutical composition of the present invention useful as an excellent agent for prophylaxis and/or treatment which can be used for a long time.

  本发明提供了一种含有抗 Fas 抗体的新型药物组合物，该药物组合物可用于预防和/或治疗自身免疫性疾病或类风湿性关节炎。 更具体地说，本发明提供了一种药物组合物，它含有一种具有诱导细胞凋亡活性的抗人 Fas 抗体和一种具有叶酸拮抗剂活性或二氢叶酸还原酶抑制活性的化合物作为活性成分。 根据本发明，在预防和/或治疗自身免疫性疾病或类风湿性关节炎的药剂中，可以减少抗 Fas 抗体的用量，从而降低患者因体内产生抗 Fas 抗体的抗体等而对 Fas 抗体产生耐受性的可能性，因此可以提供本发明的药物组合物，该药物组合物可作为预防和/或治疗的优良药剂长期使用。
• Pharmaceutical compositions containing anti-fas antibody
  申请人：SANKYO COMPANY, LIMITED

  公开号：US20020103212A1

  公开（公告）日：2002-08-01

  A pharmaceutical composition containing an anti-human Fas antibody having apoptosis inducing activity and a compound having a folate antagonist activity or a dihydrofolate reductase inhibiting activity, as active ingredients for the prophylaxis and/or treatment of an autoimmune disease or rheumatoid arthritis. According to the present invention, the amount of the anti-Fas antibody to be used can be reduced and thereby the possibility that a patient may become tolerant to anti-Fas antibody as a result of the production of antibodies against the anti-Fas antibody in the patient's body or the like can be decreased, and thus is provided a pharmaceutical composition which can be used for a long time.

  一种药物组合物，含有一种具有诱导细胞凋亡活性的抗人 Fas 抗体和一种具有叶酸拮抗剂活性或二氢叶酸还原酶抑制活性的化合物作为活性成分，用于预防和/或治疗自身免疫性疾病或类风湿性关节炎。根据本发明，可以减少抗 Fas 抗体的用量，从而降低患者因体内产生抗 Fas 抗体的抗体等而对 Fas 抗体产生耐受性的可能性，因此提供了一种可以长期使用的药物组合物。
• Combinations of antibodies selective for a tumor necrosis factor-related apoptosis-inducing ligand receptor and other therapeutic agents
  申请人：——

  公开号：US20030133932A1

  公开（公告）日：2003-07-17

  An antibody of the invention interacts with human DR5 or with human DR4 to produce agonistic or antagonistic effects downstream of the receptor including inhibition of cell proliferation and apoptosis. Methods and uses for the antibodies, optionally in combination with various therapeutic agents, are detailed, including treatment of apoptosis-related disease and treatment of dysregulated cell growth.

  本发明的抗体与人类 DR5 或人类 DR4 相互作用，在受体下游产生激动或拮抗作用，包括抑制细胞增殖和凋亡。详细介绍了抗体的方法和用途，可选择与各种治疗剂结合使用，包括治疗细胞凋亡相关疾病和治疗细胞生长失调。