Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-18
2000-08-29
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 544295, 544301, A01N 4358, A61K 31515, C07D40300, C07D23902
Patent
active
06110924&
DESCRIPTION:
BRIEF SUMMARY
In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteases which belong to at least three groups of matrix metalloproteases. These are the collagenases, geiatinases and stromelysins. Normally there are specific inhibitors for these catabolic enzymes such as .alpha..sub.2 macroglobuhnes and MMP (=tissue inhibitor of metalloproteases (MMP)) so that an excessive degradation of extraceilular matrix does not occur. A related group of proteases is the adamalysins. A prominent member of the adamalysins is TACE (TNF-.alpha.-converting enzyme).
At least 11 different and yet highly homologous MMP species have been characterized, including the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases, stromelysins (such as HSL-1) and HPUMP (for a recent review, see Birkedal-Hansen, H., Moore, W. G. I., Bodden, M. K., Windsor, L. J., Birkedal-Hansen, B., DeCarlo, A., Engler, J. A., Critical Rev. Oral Biol.Med. (1993) 4, 197-250. These proteinases share a number of structural and functional features but differ somewhat in their substrate specificity. Only HNC and HFC are capable of cleaving type I, II and III native triple-helical collagens at a single bond with the production of fragments 3/4 and 1/4 of the native chain length. This lowers the collagen melting point and makes them accessible to further attack by other matrix degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of rheumatoid arthritis, osteoarthritis, multiple sclerosis, in the formation of tumour metastases, corneal ulceration, inflamative diseases and invasion and in diseases of the bone and teeth.
It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloprotease inhibitors. A number of compounds in the meantime are known in the literature (see e.g. the review article of Nigel RA Beeley et al. Curr. Opin. ther. Patents 4 (1), 7 (1994)) or are described in the patent literature, these mainly being peptides with a hydroxamic acid residue, a thiol or phosphine group as a zinc binding group (see e.g. WO-A-9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche. WO-A-9005719 by British Biotechnology, EP-A-489 577 by Celitech. EP-A-320 118 by Beecham, U.S. Pat. No. 4,595,700 by Searle among others).
Some of these compounds have a high activity as inhibitors of matrix metalloproteases but only have a very low oral availability.
It has now been found that the claimed new barbituric acid derivatives are very efficacious as matrix metallo-protease inhibitors and have a good oral availability.
The present invention therefore concerns substances of the general formula I ##STR2## in which X, Y and Z are independently of one another oxygen sulphur or NH, alkyl or a C.sub.2 -C.sub.8 alkenyl group which is optionally once or several times substituted, or several heteroatoms, several carbon atoms are optionally substituted, alkyl or lower acyl represents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, arninocarbonyl, alkoxycarbonyl, oxy-carbonyl, alkylaminothiocarbonyl, aminothio-carbonyl which is optionally once or several times substituted, optionally once or several times interrupted by heteroatoms and the monocycle or bicycle is once or several times substituted, represent a ring which optionally can be interrupted by a further N atom, said ring can be condensed to a monocycle or bicycle, said ring can optionally be substituted once or several times independently by the residues hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitril or by E-G wherein E represents a dash, alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylarinocarbonyl, aminocarbonyl, alkoxycarbonyl, oxy-carbonyl, alkylaminothiocarbonyl, aminothiocarbonyl which is optionally substituted; G represents a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once
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Bosies Elmar
Esswein Angelika
Grams Frank
Krell Hans-Willi
Menta Ernesto
Roche Diagnostics GmbH
Schroeder Ben
Shah Mukund J.
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