Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine...

Details Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine... Peptidyl-2-amino-1-hydroxyalkanesulfonic acid cysteine...

1998-04-15

2002-02-19

Lukton, David (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S017400, C514S018700, C530S330000, C530S331000, C530S345000

Reexamination Certificate

active

06348448

ABSTRACT:

FIELD OF THE INVENTION
Peptidyl-2-amino-1-hydroxyalkanesulfonic acid inhibitors of cysteine proteases, methods for making these compounds, and methods for using the same are disclosed.
BACKGROUND OF THE INVENTION
Numerous cysteine proteases have been identified in human tissues. A “protease” is an enzyme which degrades proteins into smaller components (peptides). The term “cysteine protease” refers to proteases which are distinguished by presence therein of a cysteine 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 proteases. However, when present at elevated levels or when abnormally activated, cysteine proteases are 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 disease, amyotrophy, motor neuron damage, spinal cord trauma, traumatic brain injury, 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, spinal cord trauma, traumatic brain injury, hypoglycemia and epilepsy.
The lysosomal cysteine protease cathepsin B has been implicated in 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 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
. Viral cysteine proteases such as HAV C3 are essential for processing of picornavirus structural proteins and enzymes.
Given the link between cysteine proteases and various debilitating disorders, compounds which inhibit these proteases would be useful and would provide an advance in both research and clinical settings.
SUMMARY OF THE INVENTION
The present invention is directed to novel cysteine protease inhibitors which we refer to as peptidyl-2-amino-1-hydroxyalkanesulfonic acids. Exemplary compounds are represented by Formula I:
Constituent members and preferred embodiments are defined infra.
The compounds of the invention are useful for the inhibition of cysteine proteases. Beneficially, these compounds find utility in a variety of settings. For example, in a research arena, the subject compounds can be used as standards for screening in the discovery of agents for treating disorders associated with abnormal and/or aberrant activity of cysteine proteases. In a therapeutic arena, the compounds can be used to alleviate, mediate, reduce, and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases. One particular advantage of the subject compounds is that they have unexpectedly excellent solubility in aqueous media, approximately between 1 and 300 mg/mL. Thus, the compounds can be easily administered parenterally, for example intravenously, intrathecally or supradurally by bolus or infusion in the clinical or laboratory setting in media such as aqueous saline buffer.
Also disclosed are methodologies for making the peptidyl-2-amino-1-hydroxyalkanesulfonic acids. These and other features of the invention are set forth in more detail below.
DETAILED DESCRIPTION
Novel cysteine protease inhibitors have been discovered which are represented by Formula I:
wherein:
* denotes the &agr;-carbon of an &agr;-amino acid residue having the L configuration;
o denotes a carbon having either stereochemical configuration, or a mixture thereof;
A is selected from the group consisting of lower alkyl, aryl having from 6 to about 14 carbons, heterocyclyl having from about 5 to about 14 ring atoms, heterocycloalkyl having from about 5 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, and heteroarylalkyl, said alkyl, aryl, heterocyclyl, heterocycloalkyl, aralkyl and heteroarylalkyl groups being optionally substituted with J;
B is selected from the group consisting of C(═O), OC(═O), S(═O), S(═O)
2
, and NR
4
C(═O), where R
4
is H or lower alkyl;
each Aaa is independently an amino acid which optionally contains one or more blocking groups;
n is 0, 1, 2, or 3;
G is selected from the group consisting of H, C(═O)NR
5
R
6
, C(═O)OR
5
, CF
3
, CF
2
R
5
, P(═O) (R
5
) (OR
6
) and P(═O) (OR
5
) (OR
6
);
J is selected from the group consisting of halogen, lower alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, aryl substituted with aralkyloxy, C(═O)OR
7
, OC(═O)R
7
, NR
8
C(═O)OR
7
, OR
7
, CN, NO
2
, NR
7
R
8
, N═C(R
7
)R
8
, SR
7
, S(═O)R
7
, S(═O)
2
R
7
, and C(═NR
7
)NHR
8
;
R
5
and R
6
are independently selected from the group consisting of H, lower alkyl, aralkyl, heterocyclic, and heterocycloalkyl, said lower alkyl, aralkyl, heterocyclic, and heterocycloalkyl groups being optionally substituted with one or more hydroxy, alkoxy, aryloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, or halogen groups;
R
1
, R
2
, and R
3
, independently, are selected from the group consisting of H, lower alkyl, aryl, and heterocyclyl, said lower alkyl, aryl and heterocyclyl groups being optionally substituted with one or more J groups;
or R
2
and R
3
, may be taken together with the carbon and nitrogen atoms to which they are attached to form a 4-8 membered ring which is optionally substituted with one or more J groups;
R
7
and R
8
, independently, are selected from the group consisting of H, lower alkyl, aralkyl, heterocyclic, and heterocycloalkyl, said lower alkyl, aralkyl, heterocyclic, and heterocycloalkyl groups being optionally substituted with one or more hydroxy, alkoxy, aryloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, or halogen groups;
M is a pharmaceutically acceptable cation selected from the group consisting of sodium, lithium, potassium, calcium, magnesium, zinc, aluminum, ammonium, mono-, di-, tri-, or tetraalkylammonium, morpholinium, piperidinium, and megluminium; and
with the proviso that R
2
and R
3
taken together is other than —CH
2
—CH
2
—CH
2
.
In some preferred embodiments of the compounds of Formula I R
1
is lower alkyl or lower alkyl substituted with J.
In some preferred embodiments, J is cycloalkyl, aryl, or aryl substituted with aralkyloxy. In more preferred embodiments, R
1
is ethyl, isopropyl, benzyl, isobutyl, cyclohexylmethyl, or 4-benzyloxybenzyl.
In other preferred embodiments, R
2
is alkyl or cycloalkyl. In more preferred embodiments, R
2
is isobutyl, isopropyl, or cyclopentyl.
In some preferred embodiments, R
3
is H. In other preferred embodiments, R
2
and R
3
are taken together with the carbon and nitrogen atoms to which they are attached to form a 4-8 membered ring which is optionally substituted with one or more J groups.
In some preferre

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