3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one | 196195-12-7

• 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: 3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one
• 英文别名: 6-methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one；[6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate
• CAS: 196195-12-7
• 化学式: C₂₂H₃₁N₃O₆
• 分子量: 433.505
• InChiKey: GWDIZSRFDFBVCH-UHFFFAOYSA-N

物化性质

• 沸点：
  590.4±60.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  89.9
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one 在 盐酸 、 氯化亚砜 、 氨 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 异丙醇 为溶剂， 反应 1.5h， 生成 4-(4-benzofuranylamino)-6-methoxy-7-(3-morpholinopropoxy)quinazoline
  参考文献：
  名称：

  Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src

  摘要：

  Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.

  DOI：

  10.1021/jm030317k
• 作为产物：
  描述：

  4-(3-羟丙基)吗啉 、 7-羟基-6-甲氧基-3-((特戊酰氧基)甲基)-3,4-二氢喹唑啉-4-酮 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以100%的产率得到3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one
  参考文献：
  名称：

  Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src

  摘要：

  Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.

  DOI：

  10.1021/jm030317k

文献信息

• Substituted anilino-quinazoline (or quinoline) compounds and use thereof
  申请人：Astrazeneca AB

  公开号：US06593333B1

  公开（公告）日：2003-07-15

  The invention concerns amide derivatives of Formula (I), wherein: G is N or CH; R1 is a group such as hydroxy, halo, trifluoromethyl, C1-6alkyl and C1-6alkoxy; each of R2 and R3 is hydrogen, halo, C1-6alkyl, C2-6alkenyl or C2-6alkynyl; R4 is a group such as hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy and C3-7cycloalkyl, or R4 is of the Formula (IC): —K—J, wherein J is aryl, heteroaryl or heterocyclyl and K is a bond or a group such as oxy and imino, R5 is a group such as hydrogen, halo and trifluoromethyl: m is 1-3 and q is 0-4; or pharmaceutically acceptable salts or in vivo cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

  该发明涉及式（I）的酰胺衍生物，其中：G为N或CH；R1为羟基、卤素、三氟甲基、C1-6烷基和C1-6烷氧基等基团；R2和R3中的每一个为氢、卤素、C1-6烷基、C2-6烯基或C2-6炔基；R4为氢、羟基、C1-6烷基、C1-6烷氧基和C3-7环烷基等基团，或R4为式（IC）中的基团：—K—J，其中J为芳基、杂芳基或杂环烷基，K为键或氧基、亚胺基等基团；R5为氢、卤素和三氟甲基等基团；m为1-3，q为0-4；或其药学上可接受的盐或体内可水解酯；其制备方法，含有它们的药物组合物以及它们在治疗由细胞因子介导的疾病或医疗状况中的用途。
• Substituted anilino-quinoline compounds and use thereof
  申请人：ASTRAZENECA AB

  公开号：US20030216417A1

  公开（公告）日：2003-11-20

  The invention concerns amide derivatives of Formula (I), wherein: G is N or CH; R 1 is a group such as hydroxy, halo, trifluoromethyl, C 1-6 alkyl and C 1-6 alkoxy; each of R 2 and R 3 is hydrogen, halo, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; R 4 is a group such as hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-7 cycloalkyl, or R 4 is of the Formula (IC): —K-J, wherein J is aryl, heteroaryl or heterocyclyl and K is a bond or a group such as oxy and imino, R 5 is a group such as hydrogen, halo and trifluoromethyl; m is 1-3 and q is 0-4; or pharmaceutically acceptable salts or in vivo cleavable esters thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.

  本发明涉及公式（I）的酰胺衍生物，其中：G为N或CH；R1为羟基、卤素、三氟甲基、C1-6烷基和C1-6烷氧基等基团；R2和R3中的每一个是氢、卤素、C1-6烷基、C2-6烯基或C2-6炔基；R4为氢、羟基、C1-6烷基、C1-6烷氧基和C3-7环烷基等基团，或者R4为公式（IC）中的基团：—K-J，其中J为芳基、杂芳基或杂环基，K为键或氧和亚胺等基团；R5为氢、卤素和三氟甲基等基团；m为1-3，q为0-4；或其药学上可接受的盐或体内可水解的酯。本发明还涉及制备这些化合物的方法、含有它们的制药组合物以及它们在治疗由细胞因子介导的疾病或医疗情况中的用途。
• US6184225
  申请人：——

  公开号：——

  公开（公告）日：——
• US06184225B2
  申请人：——

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• QUINAZOLINE DERIVATIVES AS VEGF INHIBITORS
  申请人：ZENECA LIMITED

  公开号：EP0880508A1

  公开（公告）日：1998-12-02