Matrix metalloprotease inhibitors

Details Matrix metalloprotease inhibitors Matrix metalloprotease inhibitors

1999-12-21

2003-06-17

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S352000, C546S270400, C546S309000

Reexamination Certificate

active

06579890

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to compounds and their pharmaceutically acceptable salts, which inhibit matrix metalloproteases, and are therefore useful in the treatment of mammals having disease-states alleviated by the inhibition of such matrix metalloproteases.
BACKGROUND OF THE INVENTION
Matrix metalloproteases (“MMPs)” are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes, and cartilage. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal ulceration, and in complications of diabetes. MMP inhibition is, therefore, recognized as a good target for therapeutic intervention.
The MMPs share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. The MMP family includes collagenases, stromelysins, gelatinases, and matrilysin, as discussed in greater detail below.
Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, II, III and X. Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon a skin. Interstitial collagenases are very specific matrix metalloproteases which cleave collagen to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenase results in the loss of structural integrity of the target tissue, essentially an irreversible process.
The gelatinases include two distinct, but highly related, enzymes: a 72-kD enzyme secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin.
The stromelysins (1 and 2) have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical domains.
Matrilysin (putative metalloprotease or PUMP) is a recently described member of the matrix metalloprotease family. Matrilysin has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin, and laminin. Its expression has been documented in mononuclear phagocytes, rat uterine explants and sporadically in tumors.
Inhibitors of MMPs provide useful treatments for diseases associated with the excessive degradation of extracellular matrix, such as arthritic diseases (rheumatoid arthritis and osteoarthritis), bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, periodontal disease, corneal ulceration, ulceration of the skin, tumor invasion and metastasis, and aberrant angiogenesis.
The design and uses of MMP inhibitors is described, for example, in
J. Enzyme Inhibition
(1987), Vol. 2, pp. 1-22
; Drug News
&
Prospectives
(1990), Vol. 3, No. 8, pp. 453-458
; Arthritis and Rheumatism
(1993), Vol. 36, No. 2, pp. 181-189
; Arthritis and Rheumatism
(1991), Vol. 34, No. 9, pp. 1073-1075
; Seminars in Arthritis and Rheumatism
(1990), Vol. 19, No. 4, Supplement 1 (February), pp. 16-20
; Drugs of the Future
(1990), Vol. 15, No. 5, pp. 495-508; and
J. Enzyme Inhibition
(1987), Vol. 2, pp. 1-22. MMP inhibitors are also the subject of various patents and patent applications, for example, U.S. Pat. No. 5,189,178 (Galardy) and U.S. Pat. No. 5,183,900 (Galardy), European Published Patent Applications 0 438 223 (Beecham) and 0 276 436 (F. Hoffmann-La Roche), and Patent Cooperation Treaty International Applications 92/21360 (Merck), 92/06966 (Beecham) and 92/09563 (Glycomed).
SUMMARY OF THE INVENTION
The invention provides new compounds which are useful as inhibitors of matrix metalloproteases and which are effective in treating disease-states characterized by excessive activity of matrix metalloproteases.
Accordingly, one aspect of the invention is directed to compounds of formula (I):
wherein:
R
1
is mercapto, acetylthio, carboxy, hydroxycarbamoyl, N-hydroxyformamide, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, benzyloxycarbamoyl or a group of the formula
 where R
6
is aryl or heteroaryl;
R
2
is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;
R
3
is alkyl, cycloalkyl, aralkyl, or heteroaralkyl;
R
7
is aryl, heteroaryl or heterocycloalkyl;
X is a group of the formula —(CH
2
)
m
—Y—(CH
2
)
n
—, where:
Y is O, S, or a single bond,
m is an integer from 0 to 4,
n is an integer from 0 to 4, and
m+n is an integer from 0 to 4;
p is an integer from 0 to 4, provided that R
2
—X is biphenylalkyl when
p is not 0;
and the pharmaceutically acceptable salts thereof.
Another aspect of the invention provides processes for synthesizing the compounds and salts of formula (I).
In another aspect, the invention is directed to a sub-genus of formula (I), i.e., the compounds of formula (II), as follows:
wherein:
R
1
is mercapto, acetylthio, carboxy, hydroxycarbamoyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, benzyloxyaminocarbonyl or a group of the formula
 where R
6
is aryl or heteroaryl;
R
2
is alkyl, aralkyl or cycloalkylalkyl;
R
3
is cycloalkyl, alkyl (optionally substituted by cycloalkyl, hydroxy, mercapto, alkylthio, aralkoxy, carboxy, amino, alkylamino, guanidino, carbamoyl, pyridinyl or indolyl), or aralkyl (optionally substituted by hydroxy, carboxy, alkyl or alkoxy);
R
4
is nitro, amino, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, alkylsulfonyl, haloalkyl, alkoxycarbonylalkyl, tetrazolyl, carbamoyl (optionally substituted by alkyl or dialkylaminoalkyl), or aminosulfonyl (optionally substituted by alkyl); and
R
5
is hydrogen, halo or hydroxy,
as a single stereoisomer or as a mixture thereof; and the pharmaceutically acceptable salts thereof.
Another aspect of the invention is directed to compounds of the formula
wherein:
R
2
is alkyl, aryl or heteroaryl; and
X is a group of the formula —(CH
2
)
m
—Y—(CH
2
)
n
, where:
Y is O, S, or a single bond,
m is an integer from 0 to 4,
n is an integer from 0 to 4, and
m+n is an integer from 0 to 4;
or R
2
and X together are lower alkenyl.
Another aspect of the invention is directed to processes for synthesizing a compound of the formula
wherein R
2
is aryl or heteroaryl, by
(a) hydrogenating a compound of the formula:
 in the presence of a palladium/carbon catalyst; or
(b) contacting a compound of the formula
 with sodium hexamethyldisilazide and t-butylbromoacetate.
Other aspects of the invention are directed to compounds of the formula
wherein R
2
is aryl or heteroaryl, and a process for synthesizing these compounds by
(a) contacting a compound of the formula:
 where R
2
is hydrogen, aryl or heteroaryl, with an excess of mesyl chloride in pyridine followed by refluxing under basic conditions, and
(b) where R
2
is hydrogen in step (a), reacting the product of step (a) with an aryl halide or a heteroaryl halide in the presence of a base and a palladium catalyst.
Another aspect of the inventio

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