Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-08
2004-09-14
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S277000, C514S345000, C546S216000, C546S223000, C546S242000, C546S244000
Reexamination Certificate
active
06790845
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to a novel class of fused heterocycles, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment of thromboembolic disorders.
BACKGROUND OF THE INVENTION
WO99/62904 illustrates Factor Xa inhibitors that incorporate a five-membered ring heterocycle such as the example shown below.
WO00/475631 describes Factor Xa inhibitors that are seven-membered ring lactams of the general structure shown below.
WO99/50257 provides compounds of the general formula shown below as inhibitors of Factor Xa.
None of the above references teaches or suggests the compounds of the present invention that are described in detail below.
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 (Elodi, S, Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation.
Thromb. Res.
1979, 15, 617-629), 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 are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel fused heterocycles 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 a novel method of treating a patient in need of thromboembolic disorder treatment, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
It is another object of the present invention to provide a novel method, comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a thromboembolic disorder.
It is another object of the present invention to provide novel fused heterocycles for use in therapy.
It is another object of the present invention to provide the use of novel fused heterocycles for the manufacture of a medicament for the treatment of a thromboembolic disorder.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that the presently claimed fused heterocyclic compounds, or pharmaceutically acceptable salt or prodrug forms thereof, are effective factor Xa inhibitors.
REFERENCES:
patent: CH583226 (1976-12-01), None
patent: 9824766 (1998-06-01), None
patent: WO 9950257 (1999-10-01), None
patent: WO 9962904 (1999-12-01), None
patent: 9962904 (1999-12-01), None
patent: WO 00/47563 (2000-08-01), None
PubMed Abstract 11060682, also cited as Expert Opin Investing Drugs, 9/2,355-69(2000).*
PubMed ASbstract 8578525, also cited as Thromb Haemost. 74/1,565-71(1995).*
CAPLUS DN 129:67702, also cited as WO9824766.
Jacobson Irina C.
Quan Mimi L.
Wexler Ruth R.
Belfield Jing S.
Bristol-Myers Squibb Pharma Company
Patel Sudhaker B.
Raymond Richard L.
Vance David H.
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