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    Heteroaryl protease inhibitors and diagnostic imaging agents
    1.
    发明授权
    Heteroaryl protease inhibitors and diagnostic imaging agents 有权
    杂芳基蛋白酶抑制剂和诊断显像剂

    公开(公告)号：US06420397B1

    公开(公告)日：2002-07-16

    申请号：US09612591

    申请日：2000-07-07

    申请人： Wenxi Pan ,  Tianbao Lu ,  Richard M. Soll ,  Bruce E. Tomczuk

    发明人： Wenxi Pan ,  Tianbao Lu ,  Richard M. Soll ,  Bruce E. Tomczuk

    IPC分类号： A61K314412

    CPC分类号： C07D213/76 ,  C07D417/12

    摘要： Ketothiazole alkoxyguanidine and aminoguanidine analogs are described, including compounds of the Formula I: wherein X is O or NR9 and Het, A, R1, R7, R8, R12, R13, Ra, Rb, Rc, Z, m 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： 描述了酮噻唑烷氧基胍和氨基胍类似物，包括式I化合物：其中X是O或NR 9，并且阐述Het，A，R 1，R 7，R 8，R 12，R 13，R a，R b，R c，Z，m和n 在说明书中，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。

    Aminoguanidines and alkoxyguanidines as protease inhibitors
    2.
    发明授权
    Aminoguanidines and alkoxyguanidines as protease inhibitors 有权
    氨基胍和烷氧基胍作为蛋白酶抑制剂

    公开(公告)号：US06638931B1

    公开(公告)日：2003-10-28

    申请号：US09722363

    申请日：2000-11-28

    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 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。

    Aminoguanidines and alkoxyguanidines as protease inhibitors
    3.
    发明授权
    Aminoguanidines and alkoxyguanidines as protease inhibitors 有权
    氨基胍和烷氧基胍作为蛋白酶抑制剂

    公开(公告)号：US06518310B2

    公开(公告)日：2003-02-11

    申请号：US09809293

    申请日：2001-03-16

    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 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为O或NR 9，R 1 -R 4，R 6 -R 9，R 11，R 12，R a，R b，R c，Y，Z，n和m在说明书中阐述， 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。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。

    Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors
    4.
    发明授权
    Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors 有权
    苯甲酰胺和磺酰胺取代的氨基胍和烷氧基胍作为蛋白酶抑制剂

    公开(公告)号：US06344486B1

    公开(公告)日：2002-02-05

    申请号：US09283241

    申请日：1999-04-01

    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： A61K31165

    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。

    Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
    6.
    发明授权
    Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors 失效
    芳基磺酰氨基苯衍生物及其作为因子Xa抑制剂的用途

    公开(公告)号：US5741819A

    公开(公告)日：1998-04-21

    申请号：US488196

    申请日：1995-06-07

    申请人： Carl R. Illig ,  Richard M. Soll ,  Joseph M. Salvino ,  Bruce E. Tomczuk ,  Tianbao Lu ,  Nalin L. Subasinghe

    发明人： Carl R. Illig ,  Richard M. Soll ,  Joseph M. Salvino ,  Bruce E. Tomczuk ,  Tianbao Lu ,  Nalin L. Subasinghe

    IPC分类号： A61K31/18 ,  A61K31/195 ,  A61K31/245 ,  A61K31/27 ,  A61K31/435 ,  A61K31/44 ,  A61P25/00 ,  A61P29/00 ,  A61P35/00 ,  C07C311/21 ,  C07C311/44 ,  C07D213/40 ,  C07D453/02 ,  A61K31/24

    CPC分类号： C07D213/40 ,  C07C311/21 ,  C07C311/44 ,  C07D453/02

    摘要： The present invention is directed to non-peptidic factor Xa inhibitors which are useful for the treatment of arterial and venous thrombotic occlusive disorders, inflammation, cancer, and neurodegenerative diseases. The factor Xa inhibitors provide compounds of structure: ##STR1## or pharmaceutically acceptable salts thereof; wherein R.sup.1 is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R.sup.2 is one of hydrogen, alkyl, cycloalkyl or aryl; R.sup.3 is one of hydrogen, hydroxy or alkoxy; R.sup.4 is one of --NH.sub.2, phenyl or pyridyl, wherein said phenyl and said pyridyl are optionally substituted with one or two of halogen, hydroxy, hydroxyalkyl, alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl and/or dialkylaminoalkyl; X is one of --CH.sub.2 -- or --C(O)--; and n is from zero to eleven; provided that when R.sup.4 is --NH.sub.2, then R.sup.3 is hydrogen and n is other than zero; and also provided that when R.sup.3 is hydroxy or alkoxy, then R.sup.4 is other than --NH.sub.2, and n is other than zero.

    摘要翻译： 本发明涉及可用于治疗动脉和静脉血栓闭塞障碍，炎症，癌症和神经变性疾病的非肽因子Xa抑制剂。 因子Xa抑制剂提供以下结构的化合物：其中I或其药学上可接受的盐; 其中R 1是烷基，取代的烷基，环烷基，芳基，取代的芳基，杂芳基或取代的杂芳基; R2是氢，烷基，环烷基或芳基之一; R3是氢，羟基或烷氧基之一; R4是-NH2，苯基或吡啶基之一，其中所述苯基和所述吡啶基任选被一个或两个卤素，羟基，羟基烷基，烷氧基，氨基，单烷基氨基，二烷基氨基，氨基烷基，单烷基氨基烷基和/或二烷基氨基烷基取代。 X是-CH 2 - 或-C（O） - ; n为零至十一; 条件是当R4为-NH2时，则R3为氢，n为0以上。 并且还提供当R3是羟基或烷氧基时，则R4不是-NH2，n不为0。

    Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors
    7.
    发明授权
    Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors 有权

    公开(公告)号：US06274628B1

    公开(公告)日：2001-08-14

    申请号：US09283241

    申请日：1999-04-01

    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： A61K31165

    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.

    Amidino protease inhibitors
    8.
    发明授权
    Amidino protease inhibitors 有权
    脒基蛋白酶抑制剂

    公开(公告)号：US06225302B1

    公开(公告)日：2001-05-01

    申请号：US09631107

    申请日：2000-08-01

    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.

    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。