Sulfamide and bis-sulfamide amino acid derivatives as...

Details Sulfamide and bis-sulfamide amino acid derivatives as... Sulfamide and bis-sulfamide amino acid derivatives as...

2000-04-19

2002-12-17

Weber, Jon P. (Department: 1651)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Hydrolase

C435S219000, C514S600000, C514S601000, C514S605000

Reexamination Certificate

active

06495358

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to acyclic sulfamides and bis-sulfamides useful as inhibitors of proteolytic enzymes. The invention further relates to general templates for use in designing combinatorial libraries, screening and identification of biologically active, peptidomimetic protease inhibitors. There are four classes of proteases: serine, cysteine, aspartic and metalloproteases.
Degenerative diseases associated with serine proteases such as human leukocyte elastase (HLE) include cystic fibrosis, chronic obstructive pulmonary disease (e.g., emphysema and asthma), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, chronic bronchitis, psoriasis, rheumatoid arthritis, pancreatitis, periodontal disease, and other inflammatory diseases
A variety of cyclic mechanism-based inhibitors of serine proteases are known. Exemplary protease inhibitors include sulfonyloxy derivatives of isothiazolidin-3-one 1,1-dioxides (Groutas et al.,
Biochemical and Biophysical Research Communications
1997(2):730 (December, 1993)), 1,2,5-thiadiazolidin-3-one 1,1-dioxides (Kuang et al.,
J. Am. Chem. Soc.
121:8128 (September 1999)) and 3-alkyl-N-hydroxysuccinimides (Groutas et al.,
J. Med. Chem.
32:1607 (1989)). These compounds react irreversibly with a variety of serine proteases via a sequence of steps involving binding of the inhibitor molecule to the active site of the enzyme, nucleophilic ring opening of the cyclic inhibitor, rearrangement of the ring-opened structure to provide a reactive intermediate, followed by irreversible reaction of the compound with a second site on the enzyme, resulting in enzyme deactivation.
Diseases associated with cysteine proteases include cancer metastasis, osteoporosis and osteoarthritis (McGrath et al.
Nature: Structural Biology
4(2):105 (1997)), bone resorption, muscular dystrophy, parasitic diseases (leishmaniasis, malaria) (Li et al.
Bioorg. Med. Chem.
4(9):1421 (1996); Rosenthal et al.
J. Clin. Invest.
91:1052 (1993)), inflammation, common cold (Webber et al.
J. Med. Chem.
39:5072 (1996)), and hepatitis A (Malcolm et al.
Biochemistry
34:8172 (1996)). Many known cysteine protease inhibitors are peptidyl aldehydes, halomethylketones and Michael acceptors (&agr;,&bgr;-unsaturated groups).
Matrix metalloproteinases (MMPs), such as collagenase, stromelysin and gelatinase, are involved in connective tissue breakdown. Metalloproteinase (MMP) inhibitors are of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example, multiple sclerosis, as well as management of angiogenesis-dependent diseases, proliferative retinopathies, neovascular glaucoma, ocular tumors, angiofibromas and hemangiomas. See, WO 95/35275, entitled “Metalloproteinase Inhibitors”. Many known metalloproteinases are characterized by the presence in the structure of a zinc(II) ion at the active site, and thus, most known MMP inhibitors typically include hydroxamic acid or carboxylic acid to bind zinc. For example, arylsulfonamide-substituted hydroxamic acids have been reported as matrix metalloproteinase inhibitors. See, U.S. Pat. No. 5,455,258 to MacPherson et al.
SUMMARY OF THE INVENTION
The present invention makes available a new class of compounds useful as protease inhibitors. The open sulfamide structure is anticipated to be more stable chemically than related closed ring structures, e.g., 1,2,5-thiadiazolidin-3-one 1,1-dioxides, yet show high inhibition of proteolytic activity.
The invention features a compound having the general formula I
and pharmaceutically acceptable salts thereof, wherein,
Z is a chemical species or R
1
capable of binding at a primary specificity site of a protease;
Y is a chemical species reactive to a specific class of protease;
each of R
2
, R
3
, R
5
and R
7
is independently selected from the group consisting hydrogen, alkyls, aryls, substituted aryls, alkylaryls and arylalkyls;
R
4
and R
6
are independently selected from the group consisting of:
(a) H, alkyl, aryl, arylalkyl, alkylaryl, substituted derivatives thereof, and R
i
;
(b) —C(O)OH and derivatives thereof, said derivatives selected from the group consisting of —C(O)OQ, —C(O)NR
Y
R
Z
, —C(O)[NHCHR
i(q)
C(O)]
q
OQ, and —C(O)[NHCHR
i(q)
C(O)]
q
NR
Y
R
Z
; and
(c) —CHR
i
NH
2
and derivatives thereof, said derivatives selected from the group consisting of —CHR
i
NHW, —CHR
i
NHC(O)OQ, —CHR
i
NHC(O)R, —CHR
i
NHC(O)NR
Y
R
Z
, —CHR
i
NHC(O)[NHCHR
i(q)
C(O)]
q
OQ, —CHR
i
NHSO
2
R, and —CHR
i
NH[C(O)CHR
i(r)
NH]
r
W,
where q and r independently are integers from 1 to 10 inclusive;
where J is a carboxyl protecting group;
where G is an amino protecting group;
where Q is H, R or J;
where W is H, R or G;
where each R
i
is independently selected from naturally or non-naturally occurring amino acid side chains;
where R is alkyl, aryl, substituted aryl, alkylaryl, arylalkyl, or heterocyclic radical; and
where each R
Y
and R
Z
is independently H, alkyl, aryl, substituted aryl, alkylaryl, arylalkyl, or heterocyclic radical.
In another aspect of the invention, a compound of the general formula III, is provided, and pharmaceutically acceptable salts thereof,
wherein
Z is a chemical species or R
i
capable of binding at a primary specificity site of a protease;
Y is a chemical species reactive to a specific class of protease;
R
30
is selected from the group consisting of hydrogen, alkyls, aryls, substituted aryls, alkylaryls or arylalkyls;
R
31
is selected from the group consisting of alkyl, aryl, arylalkyl, alkylaryl, substituted derivatives thereof, R
i
, —C(O)OQ, —C(O)NR
Y
R
Z
, —C(O)R, —SO
2
R —[C(O)CHR
i(r)
NH]
r
W, —C(O)[NHCHR
i(q)
C(O)]
q
OQ, and —C(O)[NHCHR
i(q)
C(O)]
q
NR
Y
R
Z
; and
R
32
is selected from the group consisting of alkyl, aryl, substituted aryl, arylalkyl, alkylaryl, R
i
; —CHR
i
C(O)O, —C(O)OQ, —C(O)NR
Y
R
Z
, —C(O)[NHCHR
i(q)
C(O)]
q
OQ, and —[C(O)CHR
i(r)
NH]
r
W;
where q and r independently are integers from 1 to 10 inclusive,
where Q is H, R or J, and J is a carboxyl protecting group,
where W is H, R or GI and G is an amino protecting group;
where each R
i
is independently selected from naturally or non-naturally occurring amino acid side chains,
where R is alkyl, aryl, substituted aryl, alkylaryl, arylalkyl, or heterocyclic radical, and
where each R
Y
and R
Z
is independently H, alkyl, aryl, substituted aryl, alkylaryl, arylalkyl, or heterocyclic radical.
In another aspect of the invention, a compound of the general formula IV is provided, and pharmaceutically acceptable salts thereof,
wherein
Z is a chemical species or R
i
capable of binding at a primary specificity site of a protease;
Y is a chemical species reactive to a specific class of protease;
R
30
is selected from the group consisting of hydrogen, alkyls, aryls, alkylaryls or arylalkyls;
R
34
is aryloxy, arylalkyl, —CHR
i
NHW or —NHCHR
i
C(O)OQ; and
R
35
is alkyl, aryl, alkylaryl, arylalkyl or amino acid side group, R
i
,
where Q is H, R or a carboxyl protecting group;
where W is H, R or an amino protecting group; and
where R is H, alkyl, aryl, substituted aryl, alkaryl, aralkyl, or heterocyclic radical.
In another aspect of the invention, a compound of the general formula V is provided and pharmaceutically acceptable salts thereof,
wherein
Z is a chemical species or R
i
capable of binding at a primary specificity site of a protease;
Y is a chemical species reactive to a specific class of protease;
R
30
is selected from the group consisting of hydrogen, alkyls, aryls, alkylaryls or arylalkyls;
R
36
is alkyl, aryl, alkylaryl, arylalkyl or amino acid side group, R
i
.;
R
34
is aryloxy, arylalkyl, —CHR
i
NHW or —NHCHR
i
C(O)OQ,
where Q is H, R or a carboxyl protecting group;
where W is H, R or an amino protecting group; and
where R is H, alkyl, aryl, substituted aryl, alkaryl, aralkyl, or heterocyclic radical.
In still another aspect of the invention, a compound having the general formula II, and pharmaceutically ac

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