Benzoxazinoes/benzothiazinones as serine protease inhibitors

Details Benzoxazinoes/benzothiazinones as serine protease inhibitors Benzoxazinoes/benzothiazinones as serine protease inhibitors

2000-08-14

2003-01-21

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S224200, C514S225200, C514S225500, C514S225800, C514S226200, C514S052000, C514S105000

Reexamination Certificate

active

06509335

ABSTRACT:

FIELD OF THE INVENTION
In one aspect, this invention discloses benzoxazinone and benzothiazinone compounds which display inhibitory effects on serine proteases such as factor Xa, thrombin, and/or factor VIIa. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
BACKGROUND OF THE INVENTION
In economically developed countries, cardiovascular disease still represents a major cause of mortality. In particular, abnormal coagulation and inappropriate thrombus formation within blood vessels precipitates many acute cardiovascular disease states. While it has long been recognized that a variety of plasma proteins such as fibrinogen, serine proteases. and cellular receptors are involved in hemostasis, it is the abnormal regulation that has emerged as important contributing factors to cardiovascular disease. Thrombin can be considered the key or principal regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator in normal hemostasis. However, in some pathologic conditions, the former is amplified through catalytic activation of cofactors required for thrombin generation such as factor Xa. Factor Xa, as part of the prothrombinase complex composed of nonenzymatic cofactor Va, calcium ions, and a phospholipid membrane surface regulates the generation of thrombin from its zymogen prothrombin. Furthermore, the location of the prothrombinase complex at the convergence of both the intrinsic and extrinsic coagulation pathways suggests that inhibition of factor Xa, and hence thrombin generation, may be a viable approach to limiting the procoagulant activity of thrombin.
Indeed, ample evidence exists for the role of factor Xa inhibitors as anticoagulants. Antistasin, a potent inhibitor of blood coagulation factor Xa from the Mexican leech: Haementeria officinalis, displays antithrombotic activity in various models of arterial and venous thrombosis (Lapatto et al.,
Embo. J
., 1997:5151-5161). Other protein or polypeptide factor Xa inhibitors include recombinant tick anticoagulant peptide (rTAP), which is known to accelerate the recombinant tissue plasminogen activator mediated clot lysis and prevent acute reocclusion in the dog, hence indicating factor Xa inhibitors may be useful as an adjunct to thrombolytic therapy (Mellott et al.,
Fibrinolysis
, 1993:195-202). Furthermore, in a canine coronary artery electrolytic lesion model, rTAP was demonstrated to reduce thrombus mass and time to occlusion in the absence of dramatic hemodynamic or hemostatic changes indicating the primary role for factor Xa in the process of arterial thrombosis (Lynch et al.,
Thromb. Haemostasis
, 1995:640-645; Schaffer et al.,
Circulation,
1991:1741-1748). On the venous side, rTAP was also demonstrated to reduce fibrin deposition in a rabbit model of venous thrombosis while having little affect on systemic hemostatic parameters (Fioravanti et al.,
Thromb. Res
., 1993:317-324). In addition to these relatively high molecular weight proteins that are not suitable as oral antithrombotic agents, there also exist examples of low molecular weight factor Xa inhibitors. In particular Dx9065a, a low molecular weight synthetic factor Xa inhibitor, has also shown antithrombotic potential in various experimental thrombosis rat models. In both arteriovenous shunt and venous stasis models, inhibition of thrombus formation was achieved at doses that had little effect on APTT, indicating that DX9065a is effective in preventing thrombosis and hence has therapeutic antithrombotic potential (Wong et al.,
Thromb. Res
., 1996:117-126).
The majority of factor Xa inhibitors known to date have been previously summarized in two reviews (Edmunds et al.,
Annual Reports in Medicinal Chemistry
, 1996:51 and Kunitada and Nagahara,
Curr. Pharm. Des
., 1996:531-542). However, it is readily apparent that there still exists a need for more effective agents that regulate factor Xa proteolytic activity.
Some benzoxazinones and benzothiazinones have been reported and these compounds have displayed marked pharmacological activity:
Moriyama et al.,
Biol. Pharm. Bull
, 1997:701-703;
Gezginci et al.,
Farmaco
, 1997:255-256;
Sastry et al.,
Indian J. Chem., Sect. B,
1989:882-884;
U.S. Pat. No. 6,807,18;
Bomschein et al.,
Pharmazie
, 1977:695-697 and Pfeifer et al.,
Pharmazie
, 1977:587-592;
Japanese Application 60166674;
European Application 116368;
Japanese Application 01272524;
U.S. Pat. No. 4,786,635;
Fujita M. et al.,
J. Med Chem
., 1990:1898;
Japanese Application 03118380;
Japanese Application 09227561;
Shridhar et al.,
Indian J. Chem., Sect. B
, 1985;24B(12):1263-1267;
Bornschein et al.,
Pharmazie,
1977;32(11):695-697 and 1977;32(10):587-592;
Thuillier et al.,
Eur. J Med Chem.—Chim. Ther
., 1975;10(1):37-42;
German Patent 2044530; and
U.S. Pat. No. 3,401,166.
None of the above articles set forth above, however, disclose or suggest compounds set forth herein that are inhibitors of serine proteases involved in the blood coagulation cascade.
SUMMARY OF THE INVENTION
One object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards enzymes involved in the coagulation cascade and principally the target enzymes, factor Xa, thrombin, and factor VIIa.
A further object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards the target enzyme factor Xa and are provided for in a pharmacologically acceptable state.
Still a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof as anticoagulant and factor Xa inhibitory agents.
Yet a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof for therapeutic treatment of various thrombotic maladies.
A further object of the present invention is a process for the synthesis of these low molecular weight thrombin inhibitors. The enzyme inhibitors of the present invention are encompassed by the structure of general Formula
1
set forth below.
The present invention meets these objectives and provides for novel compounds that display antithrombotic activity. More specifically, the present invention provides for novel compounds that display antithrombotic activity via the inhibition of factor Xa as reflected in Formula 1, or pharmaceutically acceptable salts or prodrug forms thereof. The present invention also provides pharmaceutically acceptable compositions comprising the novel compounds or their salts or prodrug forms, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
Thus in a first embodiment. the present invention provides novel compounds of Formula 1:
or stereolsomers or pharmaceutically acceptable salt forms or prodrugs thereof, wherein:
A is selected from O, S, S(═O), S(═O)(═O), OCH
2
, CH
2
O, SCH
2
, S(═O)CH
2
, S(═O)(═O)CH
2
, CH
2
S, CH
2
S(═O), CH
2
S(═O)(═O);
B is selected from hydrogen, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R
1
and R
2
;
D is selected from H, (C
3-20
)alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R
1
and R
2
;
E is absent or selected from O, S, NH;
F is selected from N, NCH
2
, CH
2
N;
G is absent or selected from alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl, cycloalkyl interrupted by one or more heteroatoms;
J is absent or selected from aryl or heterocycle each optionally substituted with R
1
and R
2
;
K is absent or selected from an alkyl, alkyl interrupted by one or more heteroatoms,

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