公开(公告)号：US07402586B2

公开(公告)日：2008-07-22

申请号：US11254086

申请日：2005-10-19

申请人： Tianbao Lu ,  Bruce Tomczuk ,  Thomas P. Markotan ,  Colleen Siedem

发明人： Tianbao Lu ,  Bruce Tomczuk ,  Thomas P. Markotan ,  Colleen Siedem

IPC分类号： C07D239/54 ,  A61K31/513

CPC分类号： C07D213/74 ,  C07D213/75 ,  C07D401/12 ,  C07D409/12 ,  C07K5/06139

摘要： Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: wherein X is O or NR9 and Het, R1, R7, R8, R12—R15, Ra, Rb, Rc, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

摘要翻译： 描述了氨基胍和烷氧基胍化合物，包括式VII的化合物：其中X是O或NR 9和Het，R 1，R 7， R 8，R 12，R 15，R 12，R 12，R 12， 说明书中描述的R，Z和n以及其抑制蛋白水解酶如凝血酶的水合物，溶剂合物或其药学上可接受的盐。 还描述了制备这些化合物的方法。 本发明的化合物是蛋白酶的有效抑制剂，特别是胰蛋白酶样丝氨酸蛋白酶，如胰凝乳蛋白酶，胰蛋白酶，凝血酶，纤溶酶和因子Xa。 某些化合物通过直接，选择性抑制凝血酶表现出抗血栓形成活性。 本发明包括用于抑制血小板损失，抑制血小板聚集体形成，抑制纤维蛋白形成，抑制血栓形成和抑制哺乳动物栓塞形成的组合物，其包含本发明化合物在药学上可接受的载体中。 本发明化合物的其它用途是作为凝血剂或者物理上连接于用于血液收集，血液循环和血液储存（例如导管，血液透析机，采血注射器和管）中使用的装置的制造中使用的材料的抗凝剂， 血线和支架。 另外，化合物可以被可检测地标记并用于血栓的体内成像。

公开(公告)号：US20060211719A1

公开(公告)日：2006-09-21

申请号：US11254086

申请日：2005-10-19

申请人： Tianbao Lu ,  Bruce Tomczuk ,  Thomas Markotan ,  Colleen Siedem

发明人： Tianbao Lu ,  Bruce Tomczuk ,  Thomas Markotan ,  Colleen Siedem

IPC分类号： A61K31/513 ,  C07D403/02

CPC分类号： C07D213/74 ,  C07D213/75 ,  C07D401/12 ,  C07D409/12 ,  C07K5/06139

摘要： Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: wherein X is O or NR9 and Het, R1, R7, R8, R12-R15, Ra, Rb, Rc, Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

摘要翻译： 描述了氨基胍和烷氧基胍化合物，包括式VII的化合物：其中X是O或NR 9和Het，R 1，R 7， R 8，R 12，R 15，R 12，R 12，R 12， 说明书中描述的R，Z和n以及其抑制蛋白水解酶如凝血酶的水合物，溶剂合物或其药学上可接受的盐。 还描述了制备这些化合物的方法。 本发明的化合物是蛋白酶的有效抑制剂，特别是胰蛋白酶样丝氨酸蛋白酶，如胰凝乳蛋白酶，胰蛋白酶，凝血酶，纤溶酶和因子Xa。 某些化合物通过直接，选择性抑制凝血酶表现出抗血栓形成活性。 本发明包括用于抑制血小板损失，抑制血小板聚集体形成，抑制纤维蛋白形成，抑制血栓形成和抑制哺乳动物栓塞形成的组合物，其包含本发明化合物在药学上可接受的载体中。 本发明化合物的其它用途是作为凝血剂或者物理上连接于用于血液收集，血液循环和血液储存（例如导管，血液透析机，采血注射器和管）中使用的装置的制造中使用的材料的抗凝剂， 血线和支架。 另外，化合物可以被可检测地标记并用于血栓的体内成像。