Succinamide derivatives, processes for their preparation and the

Details Succinamide derivatives, processes for their preparation and the Succinamide derivatives, processes for their preparation and the

1996-04-04

1998-10-27

Kumar, Shailendra

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

514616, 562621, 564139, 564153, A61K 3119, C07C25900

Patent

active

058278907

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/01697, filed Aug. 2, 1994.
This invention relates to N.sup.4 -hydroxy-N.sup.1 -(1-(S)-carbamoyl-2,2-dimethyl-propyl)-2-(R)-(4-chlorophenylpropyl)succina mide and analogues thereof, to processes for their preparation and to their use in medicine.
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..sub.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 Wahl, R. C. et al Ann. Rep. Med. Chem. 25, 175-184, Academic Press Inc., San Diego (1990)!.
Although numerous metalloproteinase inhibitors have been described, many have not been suitable for further development as medicines since they have lacked any useful activity when administered orally at pharmaceutically acceptable doses. What is therefore needed is a potent and selective orally active compound. In our International Patent Specification WO 92/09564 we describe a class of peptidyl derivatives which are potent and selective inhibitors of gelatinase. We have now found that certain previously undisclosed members of this class of compounds have advantageously good oral bioavailability, and after oral administration have an advantageously longer duration of action than structurally closely related compounds.
Thus according to one aspect of the invention we provide a compound of formula (1) ##STR2## wherein R.sup.1 represents ##STR3## where R.sup.3 is a hydrogen or halogen atom or a methyl, trifluoromethyl or methoxy group; R.sup.2 represents a hydrogen atom or a methyl group; and the salts, solvates, hydrates and prodrugs thereof.
In the formulae herein, the line and the """" line are used to represent an unique configuration at an asymmetric centre
When R.sup.3 in the compounds of formula (1) is a halogen atom, it may be for example a fluorine, chlorine, bromine or iodine atom.
Salts of compounds of formula (1) include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p-toluene sulphonates, phosphates, sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartarates and benzoates.
Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Prodrugs of compounds of formula (1) include those compounds, for example esters, alcohols or amines, which are convertible, in vivo, by metabolic means, e.g. by hydrolysis, reduction, oxidation or transesterification, to compounds of formula (1).
In general in compounds of formula (1) R.sup.2 is preferably a hydrogen atom.
Particularly usef

REFERENCES:
Stack et al., "Comparison of Vertebrate Collagenase and Gelatinase Using a New Flurogencic Substrate Peptide", Journal of Biological Chemistry, vol. 264, No. 8, (1989) pp. 4277-4281.
Moses et al., "Inhibitors of Angiogenesis", Bio/Technology, vol. 9 (1991) pp. 630-634.
Folkman et al., "Angiogenic Factors", Science, vol. 2, (1987) pp. 442-447.
Wahl et al., "Biocheistry and Inhibition of Collagenase and Stromelysin", Annual Reports in Medicinal Chemistry, No. 25, (1989) pp. 177-184.

Affiliated with

Also associated with

Rating

Succinamide derivatives, processes for their preparation and the does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Succinamide derivatives, processes for their preparation and the, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Succinamide derivatives, processes for their preparation and the will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1614257