5-甲氧基-2,4-二氨基喹唑啉 | 27018-21-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: 5-甲氧基-2,4-二氨基喹唑啉
• 英文名称: 2,4-diamino-5-methoxyquinazoline
• 英文别名: 5-methoxy-2,4-diaminoquinazoline；5-methoxyquinazoline-2,4-diamine；2,4-diaminoquinazoline；5-methoxy-quinazoline-2,4-diamine；5-Methoxy-2,4-chinazolindiamin
• CAS: 27018-21-9
• 化学式: C₉H₁₀N₄O
• 分子量: 190.205
• InChiKey: FYEWYRWGCVGNJW-UHFFFAOYSA-N

物化性质

• 熔点：
  208-209 °C
• 沸点：
  484.8±53.0 °C(Predicted)
• 密度：
  1.372±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  87
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090
• 危险性防范说明：
  P261,P271,P280,P261,P271,P280
• 危险性描述：
  H315,H319,H335
• 储存条件：
  室温

反应信息

• 作为产物：
  描述：

  2,6-二氟苯腈 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基乙酰胺 为溶剂， 反应 18.17h， 生成 5-甲氧基-2,4-二氨基喹唑啉
  参考文献：
  名称：

  USE OF A QUINAZOLINE COMPOUND IN PREPARING A MEDICAMENT AGAINST FLAVIVIRIDAE VIRUS

  摘要：

  本发明揭示了一种使用式I的喹唑啉化合物，其中2,4-二氨基喹唑啉作为母核，用于制备治疗由黄病毒科感染引起的疾病的药物，特别是用于对抗丙型肝炎病毒感染和登革热病毒感染的用途。

  公开号：

  US20130261139A1

文献信息

• [EN] SMALL MOLECULE INHIBITORS OF DIHYDROFOLATE REDUCTASE<br/>[FR] INHIBITEURS À PETITES MOLÉCULES DE LA DIHYDROFOLATE RÉDUCTASE
  申请人：CIDARA THERAPEUTICS INC

  公开号：WO2016201219A1

  公开（公告）日：2016-12-15

  The disclosure relates to compositions and methods for the treatment of fungal, bacterial, and parasitic infections and inhibition of fungal, bacterial, and parasitic growth. In particular, such compositions include dihydrofolate reductase (DHFR) inhibitors that are able to bind to DHFR and inhibit its function, resulting in inhibition of DNA biosynthesis and reduced cell division. The disclosure features DHFR inhibitors having a diaminoquinazoline scaffold.

  该披露涉及用于治疗真菌、细菌和寄生虫感染以及抑制真菌、细菌和寄生虫生长的组合物和方法。具体来说，这些组合物包括能够结合到二氢叶酸还原酶（DHFR）并抑制其功能的DHFR抑制剂，从而抑制DNA合成和减少细胞分裂。该披露涉及具有二氨基喹唑啉骨架的DHFR抑制剂。
• Dicyclic and Tricyclic Diaminopyrimidine Derivatives as Potent Inhibitors of <i>Cryptosporidium parvum</i> Dihydrofolate Reductase: Structure-Activity and Structure-Selectivity Correlations
  作者：Richard G. Nelson、Andre Rosowsky

  DOI：10.1128/aac.45.12.3293-3303.2001

  日期：2001.12

  A structurally diverse library of 93 lipophilic di- and tricyclic diaminopyrimidine derivatives was tested for the ability to inhibit recombinant dihydrofolate reductase (DHFR) cloned from human and bovine isolates of Cryptosporidium parvum (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153–165, 1996). In parallel, the library was also tested against human DHFR and, for comparison, the enzyme from Escherichia coli . Fifty percent inhibitory concentrations (IC ₅₀ s) were determined by means of a standard spectrophotometric assay of DHFR activity with dihydrofolate and NADPH as the cosubstrates. Of the compounds tested, 25 had IC ₅₀ s in the 1 to 10 μM range against one or both C. parvum enzymes and thus were not substantially different from trimethoprim (IC ₅₀ s, ca. 4 μM). Another 25 compounds had IC ₅₀ s of <1.0 μM, and 9 of these had IC ₅₀ s of <0.1 μM and thus were at least 40 times more potent than trimethoprim. The remaining 42 compounds were weak inhibitors (IC ₅₀ s, >10 μM) and thus were not considered to be of interest as drugs useful against this organism. A good correlation was generally obtained between the results of the spectrophotometric enzyme inhibition assays and those obtained recently in a yeast complementation assay (V. H. Brophy et al., Antimicrob. Agents Chemother. 44:1019–1028, 2000; H. Lau et al., Antimicrob. Agents Chemother. 45:187–195, 2001). Although many of the compounds in the library were more potent than trimethoprim, none had the degree of selectivity of trimethoprim for C. parvum versus human DHFR. Collectively, the results of these assays comprise the largest available database of lipophilic antifolates as potential anticryptosporidial agents. The compounds in the library were also tested as inhibitors of the proliferation of intracellular C. parvum oocysts in canine kidney epithelial cells cultured in folate-free medium containing thymidine (10 μM) and hypoxanthine (100 μM). After 72 h of drug exposure, the number of parasites inside the cells was quantitated by indirect immunofluorescence microscopy. Sixteen compounds had IC ₅₀ s of <3 μM, and five of these had IC ₅₀ s of <0.3 μM and thus were comparable in potency to trimetrexate. The finding that submicromolar concentrations of several of the compounds in the library could inhibit in vitro growth of C. parvum in host cells in the presence of thymidine (dThd) and hypoxanthine (Hx) suggests that lipophilic DHFR inhibitors, in combination with leucovorin, may find use in the treatment of intractable C. parvum infections.

  摘要 对 93 种亲脂性二环和三环二氨基嘧啶衍生物的结构多样性文库进行了测试，以检测其抑制从人和牛分离的副隐孢子虫中克隆的重组二氢叶酸还原酶（DHFR）的能力。 副猪隐孢子虫 (J. R. Vásquez et al., Mol. Biochem. Parasitol. 79:153-165, 1996)。与此同时，该文库还针对人类 DHFR 进行了测试，并与来自 大肠杆菌 .五成抑制浓度（IC 50 s）是通过以二氢叶酸和 NADPH 为共底物的 DHFR 活性标准分光光度法测定的。在测试的化合物中，25 个化合物的 IC 50 在 1 至 10 μM 范围内，对一种或两种 C. parvum 因此与三甲氧苄啶（IC 50 s，约为 4 μM）没有本质区别。另外 25 种化合物的 IC 50 s 为 1.0 μM，其中 9 种化合物的 IC 50 为 0.1 μM，因此药效至少是三甲氧苄啶的 40 倍。其余 42 种化合物为弱抑制剂（IC 50 s，>10 μM），因此不被认为是对这种生物有用的药物。分光光度法酶抑制测定的结果与最近在酵母互补测定中获得的结果之间通常具有良好的相关性（V. H. Brophy 等人，Antimicrob.Agents Chemother.44:1019-1028, 2000; H. Lau et al.Agents Chemother.45:187-195, 2001).虽然文库中的许多化合物都比三甲氧苄氨嘧啶更有效，但没有一种化合物具有三甲氧苄氨嘧啶对副猪嗜血杆菌的选择性。 副猪嗜血杆菌 对人类 DHFR 的选择性。总之，这些检测结果构成了目前最大的亲脂性抗酚化合物潜在抗隐孢子虫药物数据库。该化合物库中的化合物还作为细胞内副猪嗜血杆菌增殖抑制剂进行了测试。 副猪嗜血杆菌 卵囊在含有胸苷（10 μM）和次黄嘌呤（100 μM）的无叶酸培养基中培养的犬肾上皮细胞中的增殖抑制剂。药物暴露 72 小时后，通过间接免疫荧光显微镜对细胞内的寄生虫数量进行量化。16种化合物的IC 50 为 <3 μM，其中五个化合物的 IC 50 s 为 <0.3 μM，因此其效力与三甲曲沙相当。研究发现，库中几种亚摩尔浓度的化合物可抑制副嗜血杆菌的体外生长。 副猪嗜血杆菌 在胸苷（dThd）和次黄嘌呤（Hx）存在的宿主细胞中的体外生长。 C. parvum 感染。
• S_NAr reaction in aqueous medium in the presence of mixed organic and inorganic bases
  作者：Nilesh B. Shelke、Ramrao Ghorpade、Ajay Pratap、Vijay Tak、B. N. Acharya

  DOI：10.1039/c5ra03510d

  日期：——

  N-Arylation of amines with fluorobenzonitriles in aqueous medium is described. A mixture of N,N-diisopropylethyl amine and Na₂CO₃ (1 : 1) is found to achieve maximum conversion by refluxing for 3 hours in water.

  在水介质中描述了氨基与氟苯甲腈的N-芳基化反应。发现在水中回流3小时的条件下，N,N-二异丙基乙基胺和Na2CO3（1：1）混合物可实现最大转化率。
• Formulations for hydrophobic pharmaceutical agents
  申请人：——

  公开号：US20010012844A1

  公开（公告）日：2001-08-09

  The present invention features formulations, including liquid, semi-solid or solid pharmaceutical formulations, that improve the oral bioavailability of hydrophobic pharmaceutical agents, such as quinazoline-, nitrothiazole-, and indolinone-based compounds. Also featured are formulations for parenteral delivery of such hydrophobic pharmaceutical agents, as well as methods of making and using both types of formulations.

  本发明涉及包括液体、半固体或固体制剂的配方，可以提高疏水性药物，如喹唑啉、硝基噻唑和吲哚酮类化合物的口服生物利用度。还包括适用于静脉注射递送这些疏水性药物的配方，以及制备和使用这两种类型配方的方法。
• Methods of modulating serine/threonine protein kinase function with quinazoline-based compounds
  申请人：——

  公开号：US20010014679A1

  公开（公告）日：2001-08-16

  The present invention is directed in part towards methods of modulating the function of serine/threonine protein kinases with quinazoline-based compounds. The methods incorporate cells that express a serine/threonine protein kinase, such as RAF. In addition, the invention describes methods of preventing and treating serine/threonine protein kinase-related abnormal conditions in organisms with a compound identified by the invention. Furthermore, the invention pertains to quinazoline compounds and pharmaceutical compositions comprising these compounds.

  本发明部分涉及使用基于喹唑啉的化合物调节丝氨酸/苏氨酸蛋白激酶功能的方法。该方法包括表达丝氨酸/苏氨酸蛋白激酶（例如RAF）的细胞。此外，本发明还描述了使用本发明所确定的化合物预防和治疗有关丝氨酸/苏氨酸蛋白激酶的异常情况的方法。此外，本发明还涉及喹唑啉化合物和包含这些化合物的制药组合物。