Amidino protease inhibitors

Details Amidino protease inhibitors Amidino protease inhibitors

2000-02-11

2001-08-28

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S210010, C514S217120, C514S218000, C514S252120, C514S331000, C514S399000, C514S408000, C540S470000, C540S483000, C540S575000, C540S609000, C544S398000, C544S402000, C546S246000, C548S300100, C548S569000, C548S950000, C548S967000

Reexamination Certificate

active

06281206

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds that function as enzyme inhibitors, and particularly to a new class of non-peptide inhibitors of proteolytic enzymes.
2. Related Art
Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes; serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al.,
J. Biol. Chem.
257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implanted as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in
Enzyme Inhibitors as Drugs,
Sandler, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase, plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states. Cathepsin G is another human neutrophil serine protease. Compounds with the ability of inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Chymotrypsin and trypsin are digestive enzymes. Inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multifactorial protein, induces a number of effects on platelets, endothelial cells, smooth muscle cells, leukocytes, the heart, and neurons (Tapparelli et al.,
Trends in Pharmacological Sciences
14:366-376 (1993); Lefkovits and Topol,
Circulation
90(3):1522-1536 (1994); Harker,
Blood Coagulation and Fibrinolysis
5 (
Suppl
1):S47-S58 (1994)). Activation of the coagulation cascade through either the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage to vessel walls or tissue factor release) leads to a series of biochemical events that converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolytic cleavage of the cell surface thrombin receptor (Coughlin,
Seminars in Hematology
31(4):270-277 (1994)), and autoamplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myocardial infarction; unstable angina; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer's disease; and Down's syndrome.
Factor Xa is another serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase complex. This prothrombinase complex then converts prothrombin to thrombin (Claeson,
Blood Coagulation and Fibrinolysis
5:411-436 (1994); Harker,
Blood Coagulation and Fibrinolysis
5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa are thought to offer an advantage over agents that directly inhibit thrombin since direct thrombin inhibitors still permit significant new thrombin generation (Lefkovits and Topol,
Circulation
90(3):1522-1536 (1994); Harker,
Blood Coagulation and Fibrinolysis
5 (Suppl 1):S47-S58 (1994)).
A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian proteolytic disease states.
SUMMARY OF THE INVENTION
The present invention is directed to novel compounds having one of Formulae I-III (below). Also provided are processes for preparing compounds of Formulae I-III. 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 inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. Other compounds are inhibitors of trypsin and/or chymotrypsin, and are the therefore useful in treating pancreatitis. Also provided are methods of inhibiting or treating aberrant proteolysis in a mammal and methods of treating thrombosis, ischemia, stroke, restenosis or inflammation in a mammal by administering an effective amount of a compound of Formulae I-III. Further provided are pharmaceutical compositions comprising a compound of Formulae I-III and one or more pharmaceutically acceptable carriers or diluents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Compounds of the present invention include compounds having one of Formulae I-III:
or solvates, hydrates or pharmaceutically acceptable salts thereof; wherein:
Z is one of —NR
10
SO
2
—, —SO
2
NR
10
—, —NR
10
C(R
y
R
z
)—, —C(R
y
R
z
)NR
10
—, —OSO
2
—, —SO
2
O—, —OC(R
y
R
z
)—, —C(R
y
R
z
)O—, —NR
10
CO— or —CONR
10
—;
R
y
and R
z
are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
R
1
is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
R
2
, R
3
and R
4
are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamide, —CO
2
R
x
, —CH
2
OR
x
or —OR
x
, or when present on adjacent carbon atoms, R
2
and R
3
may also be taken together to form one of —CH═CH—CH═CH— or —(CH
2
)
q
—, where q is from 2 to 6, and R
4
is defined as above;
R
x
, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
Y is one of —O—, —NR
10
—, —S—, —CHR
10
— or a covalent bond;
W is N or CR
10
;
R
5
is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
R
6
, in each instance, is independently one of hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO
2
R
w
, where R
w
is alkyl or cycloalkyl;
R
7
and R
8
are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R
7
and R
8
are taken together to form —(CH
2
)
y
—, where y is zero, 1 or 2, with the proviso that when W is N,

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