Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1994-02-02
1996-06-25
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544160, 560 12, 560 13, 560 14, 560312, 560 79, C07D29522, C07D30706, A61K 31095, A61K 31535
Patent
active
055301282
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a novel class of peptidyl derivatives, to processes for their preparation and to their use in medicine.
BACKGROUND OF THE INVENTION
In normal tissues, cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium. Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cells, and is due, in part, to the activity of at least three groups of metalloproteinases. These are the collagenases, the gelatinases (or type-IV collagenases) and the stromelysins. Normally these catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as .alpha.2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with metalloproteinases.
The accelerated, uncontrolled breakdown of connective tissues by metalloproteinase catalysed resorption of the extracellular matrix is a feature of many pathological conditions, such as rheumatoid arthritis, corneal, epidermal or gastric ulceration; tumour metastasis or invasion; periodontal disease and bone disease. It can be expected that the pathogenesis of such diseases is likely to be modified in a beneficial manner by the administration of metalloproteinase inhibitors and numerous compounds have been suggested for this purpose [for a general review see Wahl, R. C. et al Ann. Rep. Med. Chem. 25, 175-184, Academic Press Inc., San Diego (1990)].
Certain hydroxamic acid peptidyl derivatives [see for example European Patent Specifications Nos. 214639, 231081, 236872 and 274453 and International Patent Specifications Nos. WO90/05716 and WO90/05719], have been described as collagenase and/or stromelysin inhibitors.
SUMMARY OF THE INVENTION
We have a now found a new class of peptidyl derivatives, members of which are metalloproteinase inhibitors and which, in particular, advantageously possess a potent and selective inhibitory action against gelatinase.
There is now much evidence that metalloproteinases are important in tumour invasion and metastasis. Tumour cell gelatinase, in particular, has been associated with the potential of tumour cells to invade and metastasise. Tumour invasion and metastasis is the major cause of treatment failure for cancer patients, and the use of a selective gelatinase inhibitor such as a compound of the present invention which is capable of inhibiting tumour cell invasion can be expected to improve the treatment of this disease.
Thus according to one aspect of the invention we provide a compound of formula (1) ##STR1## wherein R represents a --CONHOH, carboxyl (--CO.sub.2 H), esterified carboxyl or --P(O)(X.sup.1 R.sup.8)X.sup.2 R.sup.9 group, where X.sup.1 and X.sup.2, which may be the same or different is each an oxygen or a sulphur atom, and R.sup.8 and R.sup.9, which may be the same or different each represents a hydrogen atom or an optionally substituted alkyl, aryl, or aralkyl group.
R.sup.1 represents a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, heteroaralkyl or heteroarylthioalkyl group;
R.sup.2 represents an optionally substituted alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkoxy, or aralkylthio group, or an amino (--NH.sub.2), substituted amino, carboxyl (--CO.sub.2 H) or esterified carboxyl group;
R.sup.3 represents a hydrogen atom or an alkyl group;
R.sup.4 represents a hydrogen atom or an alkyl group;
R.sup.5 represents an optionally substituted alkyl or alkenyl group optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-- groups, [where R.sup.7 is a hydrogen atom or a C.sub.1-6 alkyl group] or a group --[Alk].sub.n R.sup.6 where Alk is an alkyl or alkenyl group optionally interrupted by one or more --O-- or --S-- atoms or --N(R.sup.7)-- groups, n is zero or an integer 1, and R.sup.6 is an o
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Beeley Nigel R. A.
Millican Thomas A.
Morphy John R.
Porter John R.
Celltech Therapeutics Limited
Higel Floyd D.
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