4-[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]benzoic acid | 451471-51-5

• 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: 4-[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]benzoic acid
• 英文别名: 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoic acid；4-{[1-Methyl-2,4-Dioxo-6-(3-Phenylprop-1-Yn-1-Yl)-1,4-Dihydroquinazolin-3(2h)-Yl]methyl}benzoic Acid；4-[[1-methyl-2,4-dioxo-6-(3-phenylprop-1-ynyl)quinazolin-3-yl]methyl]benzoic acid
• CAS: 451471-51-5
• 化学式: C₂₆H₂₀N₂O₄
• 分子量: 424.456
• InChiKey: FLTYDFYSVZBKOB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  77.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]benzoic acid 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 1-羟基苯并三唑 、 C.I.酸性橙108 在 diethyl ether ethyl acetate 、 氯化钠 、 magnesium sulfate 、 乙酸乙酯 、 盐酸 作用下， 以 N,N-二甲基甲酰胺 、 水 为溶剂， 反应 16.0h， 生成 2-dimethylamino-ethyl 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]-benzoate
  参考文献：
  名称：

  Alkynylated fused ring pyrimidine compounds

  摘要：

  从式（I）的化合物中选择一个，其中W1代表O，S或—NR3，其中R3代表氢，烷基，OH或CN；W2代表从氢，CF3，NH2，单烷基氨基，双烷基氨基，烷基，烯基，炔基，芳基，芳基烷基，环烷基烷基，杂环中选择的基团，这些基团可以被取代，或W1和W2共同形成式为—N═X4—W3—的基团，如描述中所定义，X1、X2和X3代表N或C，可以被取代，n为0至8，Z代表—CR12R13，其中R12和R13如描述中所定义，A代表一个环系统，基团R2代表氢或如描述中所定义的各种化学基团，q为0至7；R1代表氢，烷基，烯基，炔基或一个环系统，以及其光学异构体，N-氧化物和与药学上可接受的酸或碱形成的加合物，以及含有它们的药物制剂可作为第13型基质金属蛋白酶的特异性抑制剂。

  公开号：

  US20030130278A1
• 作为产物：
  描述：

  N-甲基蒽 在 N-甲基吗啉 、 copper(l) iodide 、 四(三苯基膦)钯 、 碘 、 sodium acetate 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 sodium iodide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 4-[1-methyl-2,4-dioxo-6-(3-phenylprop-1-yn-1-yl)-1,4-dihydro-2H-quinazolin-3-ylmethyl]benzoic acid
  参考文献：
  名称：

  An efficient synthesis of isotope-labeled PD0331179 and its labeled metabolite

  摘要：

  4-[1-甲基-2,4-二氧-6-(3-苯基-丙-1-炔基)-1,4-二氢-2H-喹唑啉-3-基甲基]-苯甲酸，PD0331179，正在作为基质金属蛋白酶-13的抑制剂进行研究。14C标记和2H标记的PD0331179及其2H标记代谢物（PD0335699）是支持其临床前和临床研究所需的。以[14C]苯甲酸为起始材料高效制备了[14C] 3-苯基-1-三甲基/三苯基硅基炔，并将其作为合成[14C] PD0331179的关键标记试剂。开发了一种芳基碘化物与三烷基硅基炔的一锅耦合反应，以提高合成效率。这些合成的具体细节已报告。版权 © 2012 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.2963

文献信息

• Matrix metalloproteinase inhibitors
  申请人：——

  公开号：US20030078276A1

  公开（公告）日：2003-04-24

  Compounds are provided that bind allosterically to the catalytic domain of MMP-13 and comprise a hydrophobic group, first and second hydrogen bond acceptors and at least one, and preferably both, of a third hydrogen bond acceptor and a second hydrophobic group. Cartesian coordinates for centroids of the above features are defined in the specification. When the ligand binds to MMP-13, the first, second and third (when present) hydrogen bond acceptors bond respectively with Thr245, Thr 247 and Met 253, the first hydrophobic group locates within the S1′ channel of MMP-13 and the second hydrophobic group (when present) is relatively open to solvent. The compounds specifically inhibit the matrix metalloproteinase-13 enzyme and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.

  提供了一些与MMP-13的催化结构域发生变构结合的化合物，包括一个疏水基团，第一和第二氢键受体，以及至少一个，最好是两个，第三氢键受体和第二疏水基团。上述特征的质心的笛卡尔坐标在说明书中定义。当配体与MMP-13结合时，第一、第二和第三（存在时）氢键受体分别与Thr245、Thr247和Met253结合，第一个疏水基团位于MMP-13的S1'通道内，第二疏水基团（存在时）相对于溶剂是开放的。这些化合物特异性地抑制基质金属蛋白酶-13酶，因此可用于治疗由组织分解引起的疾病，如心脏病、多发性硬化症、关节炎、动脉粥样硬化和骨质疏松症。
• Combination of an allosteric inhibitor of matrix metalloproteinase-13 with a selective inhibitor of cyclooxygenase-2 that is not celecoxib or valdecoxib
  申请人：——

  公开号：US20040034085A1

  公开（公告）日：2004-02-19

  This invention provides a combination, comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention further provides a combination, comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with an NSAID, or a pharmaceutically acceptable salt thereof. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with an NSAID, or a pharmaceutically acceptable salt thereof. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with an NSAID, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention combinations may also be further combined with other pharmaceutical agents depending on the disease being treated.

  本发明提供了一种组合物，包括MMP-13的变构抑制剂或其药学上可接受的盐，以及选择性COX-2抑制剂或其药学上可接受的盐，但不包括Celecoxib或Valdecoxib。本发明还提供了一种治疗对MMP-13和环氧合酶-2抑制敏感的疾病的方法，包括向患有此类疾病的患者投与包含MMP-13的变构抑制剂或其药学上可接受的盐和选择性COX-2抑制剂或其药学上可接受的盐的发明组合物。本发明还提供了一种制药组合物，包括MMP-13的变构抑制剂或其药学上可接受的盐，选择性COX-2抑制剂或其药学上可接受的盐，但不包括Celecoxib或Valdecoxib，以及药学上可接受的载体、稀释剂或赋形剂。本发明还提供了一种组合物，包括MMP-13的变构抑制剂或其药学上可接受的盐，以及NSAID或其药学上可接受的盐。本发明还提供了一种治疗对MMP-13和环氧合酶-2抑制敏感的疾病的方法，包括向患有此类疾病的患者投与包含MMP-13的变构抑制剂或其药学上可接受的盐和NSAID或其药学上可接受的盐的发明组合物。本发明的组合物也可以根据所治疾病进一步与其他药物组合使用。
• Combination of an allosteric alkyne inhibitor of matrix metalloproteinase-13 with a selective inhibitor of cyclooxygenase-2 that is not celecoxib or valdecoxib
  申请人：——

  公开号：US20040019055A1

  公开（公告）日：2004-01-29

  The invention provides a combination, comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with a selective inhibitor of COX-2, or a pharmaceutically acceptable salt thereof, that is not celecoxib or valdecoxib, and a pharmaceutically acceptable carrier, diluent, or excipient. This invention also provides a combination comprising an NSAID, or a pharmaceutically acceptable salt thereof, and an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with an NSAID, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-1 or cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with an NSAID, or a pharmaceutically acceptable salt thereof. The invention combinations may also be further combined with other pharmaceutical agents depending on the disease being treated.

  本发明提供了一种组合物，包括MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐，与COX-2的选择性抑制剂或其药学上可接受的盐的组合物，但不包括Celecoxib或Valdecoxib。本发明还提供了一种治疗对MMP-13和环氧合酶-2抑制有反应的疾病的方法，包括向患有此类疾病的患者施用本发明组合物，包括MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐，与COX-2的选择性抑制剂或其药学上可接受的盐的组合物，但不包括Celecoxib或Valdecoxib。本发明还提供了一种药物组合物，包括本发明组合物，包括MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐，与COX-2的选择性抑制剂或其药学上可接受的盐的组合物，但不包括Celecoxib或Valdecoxib，以及药学上可接受的载体、稀释剂或赋形剂。本发明还提供了一种组合物，包括NSAID或其药学上可接受的盐，以及MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐。本发明还提供了一种药物组合物，包括本发明组合物，包括MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐，与NSAID或其药学上可接受的盐的组合物，以及药学上可接受的载体、稀释剂或赋形剂。本发明还提供了一种治疗对MMP-13和环氧合酶-1或环氧合酶-2抑制有反应的疾病的方法，包括向患有此类疾病的患者施用本发明组合物，包括MMP-13的变构异构烯烃抑制剂或其药学上可接受的盐，与NSAID或其药学上可接受的盐的组合物。本发明的组合物也可以根据所治疾病进一步与其他药物组合使用。
• Method of determining potential allosterically-binding matrix metalloproteinase inhibitors
  申请人：Andrianjara Charles

  公开号：US20050004126A1

  公开（公告）日：2005-01-06

  Compounds are provided that bind allosterically to the catalytic domain of MMP-13 and comprise a hydrophobic group, first and second hydrogen bond acceptors and at least one, and preferably both, of a third hydrogen bond acceptor and a second hydrophobic group. Cartesian coordinates for centroids of the above features are defined in the specification. When the ligand binds to MMP-13, the first, second and third (when present) hydrogen bond acceptors bond respectively with Thr245, Thr 247 and Met 253, the first hydrophobic group locates within the S1′ channel of MMP-13 and the second hydrophobic group (when present) is relatively open to solvent. The compounds specifically inhibit the matrix metalloproteinase-13 enzyme and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.

  提供了一种与MMP-13催化域发生变构作用的化合物，其中包括一个疏水基团、第一和第二氢键受体以及至少一个第三氢键受体和第二个疏水基团，最好是两者都有。上述特征的笛卡尔坐标在说明书中有定义。当配体与MMP-13结合时，第一、第二和第三（存在时）氢键受体分别与Thr245、Thr 247和Met 253结合，第一疏水基团位于MMP-13的S1'通道内，第二疏水基团（存在时）相对于溶剂较为开放。这些化合物特异性地抑制了基质金属蛋白酶-13酶，因此可用于治疗由组织分解引起的疾病，如心脏病、多发性硬化症、关节炎、动脉粥样硬化和骨质疏松症。
• Alkynylated quinazoline compounds
  申请人：Gaudilliere Bernard

  公开号：US06962922B2

  公开（公告）日：2005-11-08

  A compound selected from those of formula (I): wherein W 1 represents O, S, or —NR 3 in which R 3 represents hydrogen, alkyl, OH or CN; W 2 represents a group selected from hydrogen, CF 3 , NH 2 , monoalkylamino, dialkylamino, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkylalkyl, heterocycle, these groups being optionally substituted, or W 1 and W 2 form together a group of formula —N═X 4 —W 3 — as defined in the description, X 1 , X 2 and X 3 represent N or C optionally substituted, n is 0 to 8, Z represents —CR 12 R 13 , wherein R 12 and R 13 are as defined in the description, A represents a ring system, the groups R 2 represent hydrogen or various chemical groups as defined in the description, q is 0 to 7; R 1 represents hydrogen, alkyl, alkenyl, alkynyl, or a ring system, and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix metalloprotease.

  从式（I）中选择的化合物： 其中，W1表示O、S或—NR3，其中R3表示氢、烷基、羟基或氰基；W2表示从氢、CF3、NH2、单烷基氨基、二烷基氨基、烷基、烯基、炔基、芳基、芳基烷基、环烷基烷基、杂环等选择的基团，这些基团可以选择性地被取代，或者W1和W2组成一个式为—N═X4—W3—的基团，其中X1、X2和X3表示N或C，可以选择性地被取代，n为0至8，Z表示—CR12R13，其中R12和R13如说明中所定义，A表示一个环系，基团R2表示氢或如说明中所定义的各种化学基团，q为0至7；R1表示氢、烷基、烯基、炔基或一个环系，以及其光学异构体、N-氧化物和与药学上可接受的酸或碱形成的加合盐，以及含有它们的药物制剂，用作特异性抑制剂13型基质金属蛋白酶。