Hydroxamate-containing cysteine and serine protease inhibitors

Details Hydroxamate-containing cysteine and serine protease inhibitors Hydroxamate-containing cysteine and serine protease inhibitors

1999-09-17

2004-02-03

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C530S331000, C562S553000

Reexamination Certificate

active

06686335

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel inhibitors of cysteine or serine proteases, referred to herein as hydroxamates. The present invention is also directed to methods for making these novel compounds, and methods for using the same.
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
Trpanosoma cruzi,
malaria parasites
Plasmodium falciparum
and
P.vinckei
and Streptocococcus. 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.
Hydroxamates which are structurally distinct from the compounds disclosed herein have been described as inhibitors of glycogen phosphorylase (International Patent Application Pub. No. WO 96/39385) and thrombin (U.S. Pat. No. 5,563,127).
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 referred to herein as hydroxamates. In preferred embodiments, the novel compounds are represented by the following Formula I:
wherein:
W is A—B—D;
A is aryl(CH
2
)
n
, heteroaryl(CH
2
)
n
, alkyl having from one to about 14 carbons, alkenyl having from two to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, said A group being optionally substituted with one or more J groups;
B is a bond or CO, SO, SO
2
, OCO, NR
5
CO, NR
5
SO
2
, or NR
5
SO;
D is a bond, an amino acid residue, or a peptide composed of 2 to about 5 amino acid residues, said amino acid residue(s) being independently defined by the formula —NH—**CH(R
6
)—CO—, in which ** denotes the &agr; carbon of an &agr;-amino acid residue possessing, when R
6
is other than hydrogen, the D-configuration, the L-configuration, or a mixture of D- and L-;
n is an integer from 0 to about 6;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are, independently, hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, said alkyl, and cycloalkyl groups being optionally substituted with one or more J groups; and
J is halogen, lower alkyl, aryl, heteroaryl, haloaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, amido, lower alkylamido, sulfonamido, lower alkyl sulfonamido, lower alkylsulfonyl, lower alkylsulfoxy, lower alkylthio, lower alkoxy, aryloxy, arylalkyloxy, hydroxy, carboxy, cyano, or nitro; and
* denotes the &agr; carbon of an &agr;-amino acid residue possessing, when R
2
is other than hydrogen, the D-configuration, the L-configuration, or a mixture of the D- and L-configurations.
In some preferred embodiments, R
1
is alkyl or alkyl substituted with J, wherein J is lower alkoxy. In more preferred embodiments, R
1
is benzyl, methoxymethyl, or butyl.
In further preferred embodiments, R
2
is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl. In more preferred embodiments, R
2
is isobutyl or benzyloxymethyl.
In further preferred embodiments, R
3
is H.
In some preferred embodiments, R
4
is alkyl, alkyl substituted with J, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl. More preferably, R
4
is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl)methyl, tert-butyl, or 4-methylcyclohexyl.
In some preferred embodiments, W is benzyloxycarbonyl, methanesulfonyl, benzoyl, tert-butoxycarbonyl, or benzyloxycarbonyl-leucyl.
In some preferred embodiments, R
3
is H, and R
1
is alkyl or alkyl substituted with J, wherein J is lower alkoxy.
In further preferred embodiments, R
3
is H, and R
2
is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl.
In still further preferred embodiments, R
3
is H, and R
4
is alkyl, alkyl substituted with J, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, alkyl, haloaryl, or heteroaryl.
In still further preferred embodiments, R
3
is H, R
1
is alkyl or alkyl substituted with J, wherein J is lower alkoxy, and R
2
is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl.
In still further preferred embodiments, R
3
is H, R
1
is alkyl or alkyl substituted with J, wherein J is lower alkoxy, and R
4
is alkyl, alkyl substituted with J, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl.
In further preferred embodiments, R
3
is H, R
1
is alkyl or alkyl substituted with J, wherein J is lower alkoxy, R
4
is alkyl, alkyl substituted with J, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl, and R
2
is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl.
In

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