Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-29
2003-07-01
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253090, C514S254010, C514S254050, C514S349000, C514S345000, C514S383000, C514S424000, C546S188000, C546S207000, C546S210000, C546S223000, C546S229000, C546S232000, C548S566000, C548S570000
Reexamination Certificate
active
06586418
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to heteroaryl-phenyl substituted compounds that are inhibitors of trypsin-like serine protease enzymes, especially factor Xa or thrombin, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca
2+
and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin, inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa, thrombin, or both are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa, thrombin, or both inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel heteroaryl-phenyl substituted compounds that are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel compounds for use in therapy.
It is another object of the present invention to provide the use of novel compounds for the manufacture of a medicament for the treatment of thrombosis or a disease mediated by factor Xa.
REFERENCES:
patent: WO 9619483 (1996-06-01), None
patent: WO 9723212 (1997-07-01), None
patent: WO 9748706 (1997-12-01), None
patent: WO 9828326 (1998-07-01), None
patent: WO 9857937 (1998-12-01), None
J.E.Semple, 'Design & constrc. of novel Thrombin inhibit.,Bioorg. & Med. Chem.Ltrs. 8,2501-6(1996).*
Semple J.E.,Design & Construction od Novel Throm . . . ,Bioorg. & Med.Chem.Ltrs. 8,2501-6(1998).*
Bednar MM(PubMed Abstr.:11060682;also cited as Expert Opin Inverst Drugs,9/2, 355-69(2000).*
Turpie et al(PubMed Abstr.8578525;also cited as Throm. Haemost,74/1,565-71(1995).*
St-Denis, Y. et al., Potent Bicyclic Lactam Inhibitors of Thrombin: Part 1 P3 Modifications, Bioorganic and Medicinal Chemistry Letters. 1998, vol. 8, No. 22, pp 3193-3198.
Plummer, J.S. et al., Potent and Selective Bicyclic Lactam Inhibitors of Thrombin: Part 2 P1 Modifications, Bioorganic and Medicinal Chemistry Letters. 1998, vol. 8, No. 23, pp 3409-3414.
Plummer, J.S. et al., Potent and Selective Bicyclic Lactam Inhibitors of Thrombin: Part 3 P1' Modifications, Bioorganic and Medicinal Chemistry Letters. 1999, vol. 9, No. 6, pp 835-840.
Narasimhan, L.S. et al., Structural Basis of the Thrombin Selectivity of a Ligand That Contains the Constrained Arginine Mimic (2S)-2-Amino-(3S)-3-(1-carbamimidoyl-piperidin-3-yl)-propanoic Acid at P1. J. Med. Chem. 2000, 43, 361-368.
Pinto Donald J. P.
Quan Mimi L
Belfield Jing S.
Bristol--Myers Squibb Company
Patel Sudhaker B.
Raymond Richard L.
Vance David H.
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