3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester | 448964-76-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并嘧啶酮衍生物
• 英文名称: 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester
• 英文别名: pyridin-4-ylmethyl 3-benzyl-2,4-dioxo-1H-thieno[2,3-d]pyrimidine-6-carboxylate
• CAS: 448964-76-9
• 化学式: C₂₀H₁₅N₃O₄S
• 分子量: 393.423
• InChiKey: SLHZBCGNQXCJPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  117
• 氢给体数：
  1
• 氢受体数：
  6

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。
• Fused pyrimidinone matrix metalloproteinase inhibitors
  申请人：——

  公开号：US20030004172A1

  公开（公告）日：2003-01-02

  Selective MMP-13 inhibitors are fused pyrimidinones of the formula 1 or a pharmaceutically acceptable salt thereof, wherein: W, together with the carbon atoms to which it is attached, form a 5-membered ring diradical 2 X is O, S, SO, SO 2 , NR 5 , or CH 2 ; 3 B is O or NR 5 ; or A and B are taken together to form —C≡C—; R 1 , R 4 , and R 5 are hydrogen, alkyl, alkenyl, alkynyl, (CH 2 ) n aryl, (CH 2 ) n cycloalkyl, C 1 -C 6 alkanoyl, or (CH 2 ) n heteroaryl; R 2 and R 3 are hydrogen, alkyl, alkenyl, alkynyl CN, NO 2 , NR 4 R 5 , (CH 2 ) n cycloalkyl, (CH 2 ) n aryl, or (CH 2 ) n heteroaryl; R 2 may further be halo; n is an integer of from 0 to 5; and R 4 and R 5 when taken together with a nitrogen to which they are both attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing O, S, or N, and substituted or unsubstituted; with the proviso that R 1 and R 3 are not both selected from hydrogen and C 1 -C 6 alkyl.

  选择性MMP-13抑制剂是具有以下结构的嘧啶酮类化合物或其药用盐： 其中： W与其连接的碳原子一起形成一个5元环二自由基； X为O、S、SO、SO2、NR5或CH2； B为O或NR5； 或A和B结合形成—C≡C—； R1、R4和R5为氢、烷基、烯基、炔基、( )n芳基、( )n环烷基、C1-C6烷酰基或( )n杂环芳基； R2和R3为氢、烷基、烯基、炔基、CN、NO2、NR4R5、( )n环烷基、( )n芳基或( )n杂环芳基；R2还可以是卤素； n为0到5的整数； R4和R5与它们都连接的氮一起形成含碳原子且可选择含有O、S或N的3-8元环，可以是取代或未取代的； 但要注意R1和R3不同时选择自氢和C1-C6烷基。
• 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。
• 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。
• Combination of an allosteric inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib
  申请人：——

  公开号：US20040034086A1

  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, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, 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. This invention also provides a pharmaceutical composition, comprising the invention combination and a pharmaceutically acceptable carrier, diluent, or excipient. The invention combination 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的异位抑制剂或其药学上可接受的盐与塞来昔布或其药学上可接受的盐或缬癸昔布或其药学上可接受的盐。本发明还提供了一种治疗对抑制 MMP-13 和环氧合酶-2 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的组合物。本发明还提供了一种药物组合物，包括本发明组合物和药学上可接受的载体、稀释剂或赋形剂。本发明组合物还可根据治疗的疾病进一步与其他药剂组合。