Hydroxamic acid based collagenase inhibitors

Details Hydroxamic acid based collagenase inhibitors Hydroxamic acid based collagenase inhibitors

1991-07-08

1993-08-31

Russell, Mark

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

549 65, 548465, 548467, 5483151, 514397, 514414, 514575, 562622, 558254, A61K 3138, C07D33334

Patent

active

052409589

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

I. Field of the Invention
This invention relates to pharmaceutically and veterinarily active compounds, which are derivatives of hydroxamic acid.
II. Description of the Prior Art
The compounds of the present invention act as inhibitors of metalloproteases involved in tissue degradation, such as collagenase, which initiates collagen breakdown, stromelysin (protoglycanase), gelatinase and collagenase (IV). There is evidence implicating collagenase as one of the key enzymes in the breakdown of articular cartilage and bone in rheumatoid arthritis (Arthritis and Rheumatism, 20, 1231-1239, 1977). Potent inhibitors of collagenase and other metalloproteases involved in tissue degradation are useful in the treatment of rheumatoid arthritis and related diseases in which collagenolytic activity is important. Inhibitors of metalloproteases of this type can therefore be used in treating or preventing conditions which involve tissue breakdown; they are therefore useful in the treatment of arthropathy, dermatological conditions, bone resorption, inflammatory diseases and tumour invasion and in thepromotion of wound healing. Specifically, compounds of the present invention may be useful in the treatment of osteopenias such as osteoporosis, rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration and tumour invasion.
A number of small peptide like compounds which inhibit metalloproteases have been described. Perhaps the most notable of these are those relating to the angiotensin converting enzyme (ACE) where such agents act to block the conversion of the decapeptide angiotensin I to angiotensin II a potent pressor substance. Compounds of this type are described in EP-A-0012401.
Certain hydroxamic acids have been suggested as collagenase inhibitors as in U.S. Pat. No. 4,599,361 and EP-A-0236872. Other hydroxamic acids have been prepared as ACE inhibitors, for example in U.S. Pat. No. 4,105,789, while still others have been described as enkephalinase inhibitors as in U.S. Pat. No. 4,496,540.
EP-A-0012401 discloses antihypertensive compounds of the formula: ##STR3## wherein R and R.sup.6 are the same or different and are hydroxy, alkoxy, alkenoxy, dialkylamino alkoxy, acylamino alkoxy, acyloxy alkoxy, aryloxy, alkyloxy, substituted aryloxy or substituted aralkoxy wherein the substituent is methyl, halo, or methoxy, amino, alkylamino, dialkylamino, aralkylamino or hydroxyamino; branched, cyclic and unsaturated alkyl groups; amino, alkylamino, dialkylamino, acrylamino, arylamino, guanidino, imidazolyl, indolyl, mercapto, alkylthio, arylthio, carboxy, carboxamido, carbalkoxy, phenyl, substituted phenyl wherein the substituent is alkyl, alkoxy or halo; aralkyl or heteroaralkyl, aralkenyl or heteroaralkenyl, substituted aralkyl, substituted heteroaralkyl, substituted aralkenyl or substituted hetereoaralkenyl, wherein the substituent is halor or dihalo, alkyl, hydroxy, alkoxy, amino, aminomethyl, acrylamino, dialkylamino, alkylamino, carboxyl, haloalkyl, cyano or sulphonamido, aralkyl or hetereoaralkyl substituted on the alkyl portion by amino or acylamino; hydroxyphenylalkyl, hydroxyalkyl, acetylaminoalkyl, acylaminoalkyl, acylaminoalkyl aminoalkyl, dimethylaminoalkyl, haloalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, mercaptoalkyl and alkylthioalkyl; hydroxyalkyl, aminoalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, mercaptoalkyl or alkylthioalkyl; from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulphur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above, substituted with hydroxy, alkoxy or alkyl and the pharmaceutically acceptable salts thereof.
U.S. Pat. No. 4,599,361 discloses compounds of the formula: ##STR4## wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl; -C.sub.6 alkoxy)benzyl or benzyloxy(C.sub.1 -C.sub.6 alkyl); ##STR5## or a --(CR.sup.3 .dbd.CR.sup.4)-- group wherein b and c are chiral centres with optional R or S stereochemistry; -C.sub.6 alkyl) and R.sup.4 is hydrog

REFERENCES:
patent: 4105789 (1978-08-01), Ondetti et al.
patent: 4496540 (1985-01-01), Kim
patent: 4599361 (1986-07-01), Dickens et al.
patent: 4996358 (1991-02-01), Handa et al.
J. March, "Advanced Organic Chemistry" 3rd ed., pp. 370-371, John Wiley & Sons, New York (1985).
Wooley et al., Arthritis and Rheumatism, 20: (No. 6): 1231-1239 (1977).
Cawston and Barrett, Anal. Biochem. 99:340-345 (1979).
Cawston et al., Biochem. J. 195: 159-165 (1981).
Cawston and Murphy, Methods in Enzymology, 80:711-722 (1981).

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