公开(公告)号：US06730783B2

公开(公告)日：2004-05-04

申请号：US10419972

申请日：2003-04-22

申请人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan

发明人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan

IPC分类号： A61K31255

CPC分类号： C07C309/73 ,  C07C309/75 ,  C07C309/76 ,  C07C309/77 ,  C07C311/16 ,  C07C311/17 ,  C07C311/18 ,  C07C311/19 ,  C07C311/21 ,  C07C317/14 ,  C07C323/66 ,  C07C2601/02 ,  C07C2601/14 ,  C07D211/96 ,  C07D213/42 ,  C07D213/74 ,  C07D215/36 ,  C07D217/02 ,  C07D217/22 ,  C07D239/42 ,  C07D295/13 ,  C07D295/26 ,  C07D307/66

摘要： Aminoguanidine and alkoxyguanidine compounds, including compounds of the formula: wherein X is O or NR9 and R1-R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present 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, or are intermediates useful for forming compounds having antithrombotic activity. 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.

摘要翻译： 氨基胍和烷氧基胍化合物，包括下式的化合物：其中X是O或NR 9和R 1 -R 4，R 6 -R 9，R 11，R 12， 说明书中列出的R a，R b，R c，Y，Z，n和m以及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是 描述。 还描述了制备式I化合物的方法。本发明的新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，例如胰凝乳蛋白酶，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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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。

公开(公告)号：US06706765B2

公开(公告)日：2004-03-16

申请号：US10359078

申请日：2003-02-06

申请人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan ,  Thomas P. Stagnaro

发明人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan ,  Thomas P. Stagnaro

IPC分类号： A61K3118

CPC分类号： C07C309/73 ,  C07C309/75 ,  C07C309/76 ,  C07C309/77 ,  C07C311/16 ,  C07C311/17 ,  C07C311/18 ,  C07C311/19 ,  C07C311/21 ,  C07C317/14 ,  C07C323/66 ,  C07C2601/02 ,  C07C2601/14 ,  C07D211/96 ,  C07D213/42 ,  C07D213/74 ,  C07D215/36 ,  C07D217/02 ,  C07D217/22 ,  C07D239/42 ,  C07D295/13 ,  C07D295/26 ,  C07D307/66

摘要： Aminoguanidine and alkoxyguanidine compounds, including compounds of the formula: wherein X is O or NR9 and R1-R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present 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, or are intermediates useful for forming compounds having antithrombotic activity. 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.

摘要翻译： 氨基胍和烷氧基胍化合物，包括下式的化合物：其中X是O或NR 9和R 1 -R 4，R 6 -R 9，R 11，R 12， 说明书中列出的R a，R b，R c，Y，Z，n和m以及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是 描述。 还描述了制备式I化合物的方法。本发明的新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，例如胰凝乳蛋白酶，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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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。

公开(公告)号：US06417161B1

公开(公告)日：2002-07-09

申请号：US09296296

申请日：1999-04-22

申请人： Tianbao Lu ,  Bruce E. Tomczuk ,  Thomas P. Markotan ,  Richard M. Soll

发明人： Tianbao Lu ,  Bruce E. Tomczuk ,  Thomas P. Markotan ,  Richard M. Soll

IPC分类号： A61K3805

CPC分类号： C07K5/06078 ,  A61K38/00 ,  C07D207/16 ,  C07K5/0222

摘要： The present invention is directed to aminoguanidine and alkoxyguanidine compounds, including compounds of Formula I: wherein X is O or NR19 and A1, A2, R7-R10, R18, Ra, Rb, Rc, n and m 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 the compounds of Formula I. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. 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. 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.

摘要翻译： 本发明涉及氨基胍和烷氧基胍化合物，包括式I化合物：其中X是O或NR19，并且A1，A2，R7-R10，R18，Ra，Rb，Rc，n和m在说明书中阐述， 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。 还描述了制备式I化合物的方法。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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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。 本发明化合物的其它用途是作为抗凝剂，其嵌入或用于制造用于采血，血液循环和血液储存中的装置的材料中物理连接。

公开(公告)号：US06344466B2

公开(公告)日：2002-02-05

申请号：US09796319

申请日：2001-02-28

申请人： Richard M. Soll ,  Tianbao Lu ,  Bruce E. Tomczuk ,  Thomas P. Markotan ,  Colleen Siedem

发明人： Richard M. Soll ,  Tianbao Lu ,  Bruce E. Tomczuk ,  Thomas P. Markotan ,  Colleen Siedem

IPC分类号： A61K31445

CPC分类号： C07D213/40 ,  C07C279/00 ,  C07D211/16 ,  C07D211/62 ,  C07D213/74 ,  C07D217/06 ,  C07D295/192

摘要： The present invention is directed to aminoguanidine and alkoxyguanidine compounds, including compounds of Formula I: wherein X is O or NH, L is —O— or —SO2—, and R1-R4, R9-R19, Ra, Rb, Rc, Y, Z, n and m 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 the compounds of Formula I. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. 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. 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.

摘要翻译： 本发明涉及氨基胍和烷氧基胍化合物，包括式I化合物：其中X为O或NH，L为-O-或-SO 2 - ，R 1 -R 4，R 9 -R 19，R a，R b，R c，Y ，Z，n和m在说明书中列出，以及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。 还描述了制备式I化合物的方法。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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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。 本发明化合物的其它用途是作为抗凝剂，其嵌入或用于制造用于采血，血液循环和血液储存中的装置的材料中物理连接。

公开(公告)号：US06326492B1

公开(公告)日：2001-12-04

申请号：US09578487

申请日：2000-05-26

申请人： Aihua Wang ,  Tianbao Lu ,  Bruce E. Tomczuk ,  Richard M. Soll ,  John Spurlino ,  Roger Bone

发明人： Aihua Wang ,  Tianbao Lu ,  Bruce E. Tomczuk ,  Richard M. Soll ,  John Spurlino ,  Roger Bone

IPC分类号： C07D26502

CPC分类号： C07D413/12 ,  C07D413/14

摘要： Described are compounds of the Formula VII: wherein Het, R1, R7 and A 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： 描述了式VII的化合物：其中Het，R 1，R 7和A在本说明书中列出，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连接于制造用于血液收集，血液循环和血液储存中的装置的材料的抗凝剂，例如导管，血液透析机，采血注射器和管， 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：US06281206B1

公开(公告)日：2001-08-28

申请号：US09502005

申请日：2000-02-11

申请人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

发明人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

IPC分类号： A61K31445

CPC分类号： C07D295/195 ,  C07C309/73 ,  C07C311/21 ,  C07D211/22 ,  C07D211/26

摘要： Amidino and benzamidino compounds, including compounds of the formula: wherein R1-R4, R6-R9, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit a number of proteolytic enzymes are described. Also described are methods for preparing the compounds of Formula I.

公开(公告)号：US06414020B2

公开(公告)日：2002-07-02

申请号：US09851123

申请日：2001-05-09

申请人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

发明人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

IPC分类号： A61K31155

CPC分类号： C07D295/195 ,  C07C309/73 ,  C07C311/21 ,  C07D211/22 ,  C07D211/26

摘要： Amidino and benzamidino compounds, including compounds of the formula: wherein R1-R4, R6-R9, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit a number of proteolytic enzymes are described. Also described are methods for preparing the compounds of Formula I.

摘要翻译： 脒基和苯甲脒基化合物，包括下式的化合物：其中R1-R4，R6-R9，Y，Z，n和m在本说明书中列出，以及其水合物，溶剂合物或其药学上可接受的盐，其抑制数目 的蛋白水解酶。 还描述了制备式I化合物的方法。

公开(公告)号：US06235778B1

公开(公告)日：2001-05-22

申请号：US08979234

申请日：1997-11-26

申请人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan ,  Thomas P. Stagnaro

发明人： Bruce E. Tomczuk ,  Richard M. Soll ,  Tianbao Lu ,  Cynthia L. Fedde ,  Carl R. Illig ,  Thomas P. Markotan ,  Thomas P. Stagnaro

IPC分类号： A61K31255

CPC分类号： C07C309/73 ,  C07C309/75 ,  C07C309/76 ,  C07C309/77 ,  C07C311/16 ,  C07C311/17 ,  C07C311/18 ,  C07C311/19 ,  C07C311/21 ,  C07C317/14 ,  C07C323/66 ,  C07C2601/02 ,  C07C2601/14 ,  C07D211/96 ,  C07D213/42 ,  C07D213/74 ,  C07D215/36 ,  C07D217/02 ,  C07D217/22 ,  C07D239/42 ,  C07D295/13 ,  C07D295/26 ,  C07D307/66

摘要： Aminoguanidine and alkoxyguanidine compounds, including compounds of the formula: wherein X is O or NR9 and R114 R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and mare set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula I. The novel compounds of the present 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, or are intermediates useful for forming compounds having antithrombotic activity. 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.

摘要翻译： 氨基胍和烷氧基胍化合物，包括下式的化合物：其中X是O或NR9，R114R4，R6-R9，R11，R12，Ra，Rb，Rc，Y，Z，n和母本也在说明书中列出 描述了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。 还描述了制备式I化合物的方法。本发明的新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，例如胰凝乳蛋白酶，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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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连接于制造用于血液收集，血液循环和血液储存中的装置的材料的抗凝剂，例如导管，血液透析机，采血注射器和管， 血线和支架。

公开(公告)号：US6133315A

公开(公告)日：2000-10-17

申请号：US270734

申请日：1999-03-16

申请人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

发明人： Tianbao Lu ,  Bruce E. Tomczuk ,  Carl R. Illig ,  Richard M. Soll

IPC分类号： C07D295/14 ,  A61K31/00 ,  A61K31/18 ,  A61K31/24 ,  A61K31/445 ,  A61K31/495 ,  A61P1/00 ,  A61P1/18 ,  A61P7/00 ,  A61P7/02 ,  A61P9/00 ,  A61P9/10 ,  A61P29/00 ,  A61P43/00 ,  C07C309/73 ,  C07C311/21 ,  C07D211/22 ,  C07D211/26 ,  C07D211/28 ,  C07D295/195 ,  A61K31/155 ,  C07C257/14 ,  C07C311/46

CPC分类号： C07D295/195 ,  C07C309/73 ,  C07C311/21 ,  C07D211/22 ,  C07D211/26

摘要： Amidino and benzamidino compounds, including compounds of the formula: ##STR1## wherein R.sup.1 -R.sup.4, R.sup.6 -R.sup.9, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit a number of proteolytic enzymes are described. Also described are methods for preparing the compounds of Formula I.

公开(公告)号：US06635637B2

公开(公告)日：2003-10-21

申请号：US09919815

申请日：2001-08-02

申请人： Aihua Wang ,  Tianbao Lu ,  Bruce Edward Tomczuk ,  Richard M. Soll ,  John Curtis Spurlino ,  Roger Francis Bone

发明人： Aihua Wang ,  Tianbao Lu ,  Bruce Edward Tomczuk ,  Richard M. Soll ,  John Curtis Spurlino ,  Roger Francis Bone

IPC分类号： C07D26502

CPC分类号： C07D273/06 ,  C07D265/02

摘要： Cyclic oxyguanidine compounds, including compounds of Formulae I and II: wherein R1, R3-R6, R21-R26, L, Y, Z, and A are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formulae I and II. The novel compounds of the present 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, or are intermediates useful for forming compounds having antithrombotic activity. 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.

摘要翻译： 包括式I和II化合物的环状氧基胍化合物：其中R 1，R 3 -R 6，R 21 -R 26，L，Y，Z和A列于 描述了抑制蛋白水解酶如凝血酶的说明书以及其水合物，溶剂合物或其药学上可接受的盐。 还描述了制备式I和II化合物的方法。 本发明的新型化合物是蛋白酶，特别是胰蛋白酶样丝氨酸蛋白酶的有效抑制剂，例如胰凝乳蛋白酶，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，或者是用于形成具有抗血栓形成活性的化合物的中间体。 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。