Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-18
2001-12-11
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S023000, C514S252010, C514S307000, C514S454000, C514S533000, C514S613000, C536S017300, C536S018200, C544S359000, C544S386000, C546S146000, C549S388000, C560S020000, C560S024000, C560S051000
Reexamination Certificate
active
06329377
ABSTRACT:
FIELD OF THE INVENTION
Novel ketomethylene group-containing inhibitors of cysteine or serine proteases, methods for making these novel compounds, and methods for using the same are disclosed.
BACKGROUND OF THE INVENTION
Numerous cysteine and serine proteases have been identified in human tissues. A “protease” is an enzyme which degrades proteins into smaller components (peptides). The terms “cysteine protease” and “serine protease” refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and serine proteases. However, when present at elevated levels or when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
For example, calcium-activated neutral proteases (“calpains”)comprise a family of intracellular cysteine proteases which are ubiquitously expressed in mammalian tissues. Two major calpains have been identified; calpain I and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation. Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington's Disease, and epilepsy.
The lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. Interleukin-1&bgr; converting enzyme (“ICE”)is a cysteine protease which catalyzes the formation of interleukin-1&bgr;. Interleukin-1&bgr; is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS).
Cysteine proteases are also produced by various pathogens. The cysteine protease clostripain is produced by
Clostridium histolyticum
. Other proteases are produced by
Trypanosoma cruzi
, malaria parasites
Plasmodium falciparum
and
P.vinckei
and Streptococcus. Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes.
Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G. Specifically, thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, cystic fibrosis, and emphysema. Pancreatic elastase is implicated in pancreatitis. Chymase, an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease. Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung.
Given the link between cysteine and serine proteases and various debilitating disorders, compounds which inhibit these proteases would be useful and would provide an advance in both research and clinical medicine. The present invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention is directed to novel cysteine and serine protease inhibitors which contain a ketomethylene group adjacent to the P2 position. They are represented by the following Formula I:
wherein:
Q is aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring, alkoxy having from 1 to about 10 carbons, aralkyloxy having from about 7 to about 15 carbons, a carbohydrate moiety optionally containing one or more alkylated hydroxyl groups, xanthene-9-yl, CH(i-C
4
H
9
)NHCbz, CH
2
N(i-C
4
H
9
)Cbz, or Formula II or III:
Y has the formula:
wherein:
R
1
and R
2
are independently H, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, or a natural or unnatural side chain of an L-amino acid, said alkyl and cycloalkyl groups being optionally substituted with one or more J groups;
J is halogen, lower alkyl, aryl, heteroaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, aralkoxycarbonyl, alkoxy, hydroxy, or carboxy; and
G is hydrogen, C(═O)NR
3
R
4
, C(═O)OR
3
or CH
2
R
5
;
wherein:
R
3
and R
4
are each independently hydrogen, alkyl having from 1 to about 10 carbons, said alkyl groups being optionally substituted with one or more J groups, aryl having from about 6 to about 14 carbons, and aralkyl having from about 7 to about 15 carbons; and
R
5
is halogen;
with the proviso that if G is hydrogen and Q is alkyl substituted with J, and said J is an &agr;-amino group, then the &agr;-amino nitrogen must be tertiary (that is, trisubstituted with other than hydrogen).
Preferred embodiments of the compounds of Formula I include those wherein R
2
is isobutyl, R
1
is isobutyl, benzyl, or ethyl, G is hydrogen, C(═O)NHC
2
H
5
, or CH
2
F, and Q is as previously defined.
The compounds of the invention are useful for the inhibition of cysteine and serine proteases. Beneficially, the compounds find utility in a variety of settings. For example, in a research arena, the claimed compounds can be used, for example, as standards to screen for natural and synthetic cysteine protease and serine protease inhibitors which have the same or similar functional characteristics as the disclosed compounds. In a clinical arena, our compounds can be used to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases. Accordingly, methods for using the subject compounds, such as methods for inhibiting serine proteases or cysteine proteases comprising contacting said proteases with an inhibitory amount of a compound of the invention are disclosed. Methodologies for making our ketomethylene group-containing inhibitors are also disclosed. These and other features of the compounds of the subject invention are set forth in more detail below.
DETAILED DESCRIPTION
Novel cysteine and serine protease inhibitors have been discovered which are represented by the general Formula I:
wherein:
Q is aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, alkyl having from 1 to about 10 carbons, said alkyl groups being optionally substituted with one or more J groups, heteroalkyl having from 2 to about 7 carbons, arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring, alkoxy having from 1 to about 10 carbons, aralkyloxy having from about 7 to about 15 carbons, a carbohydrate moiety optionally containing one or more alkylated hydroxyl groups, xanthene-9-yl, CH(i-C
4
H
9
)NHCbz, CH
2
N(i-C
4
H
9
)Cbz, or Formula II or III:
Y has the formula
wherein:
R
1
and R
2
are independently H, alkyl having from one
Cephalon Inc.
Shah Mukund J.
Truong Tamthom N.
Woodcock & Washburn LLP
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