Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastas

Details Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastas Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastas

1998-09-25

1999-11-30

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514212, 5142345, 514255, 514307, 514322, 514338, 514421, 540602, 544144, 544373, 546146, 546199, 5462767, 548453, A61K 3140, C07D48704

Patent

active

059943440

DESCRIPTION:

BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn.371 as a U.S. National Phase Application of International Application No. PCT/EP97/01530 filed Mar. 26, 1997, which claims priority from Great Britain application 9606508.1 filed Mar. 28, 1996 and Great Britain application 9623001.6 filed Nov. 5, 1996.
The present invention relates to therapeutically active bicyclic compounds, processes for the manufacture of said compounds, pharmaceutical formulations containing said compounds and the use of said compounds in chemotherapy. In particular, we have found a novel group of bicyclic compounds which are effective in treating inflammatory diseases.
Inflammation is a primary response to tissue injury or microbial invasion and is characterised by circulating leukocytes binding to and extravasation through vascular endothelium. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes.
The inflammatory process can be triggered in a number of ways, including by infection, tissue damage and autoimmune reactions. As part of the inflammatory process, neutrophils move from the bloodstream into the tissue at the site of tissue lesion. The neutrophils contain large numbers of different intracellular granules and when activated at the site of inflammation the contents of these granules are secreted into the tissue. The different granules contain a variety of enzymes and other proteins, many of which have antibacterial properties.
One of the enzymes found in the azurophilic granules is neutrophil elastase. Neutrophil elastase has a wide spectrum of activities in the body. For example, within the lung the enzyme increases mucus production and changes the cellular composition of the epithelium The enzyme also causes vascular permeability changes within the microcirculation of many tissues and it is a potent destructive agent against a number of connective tissue components.
Although there are within the body endogenous inhibitors of elastase, including the anti-trypsin and the leukocyte protease inhibitor, elastase activity has been implicated in the pathogenesis of a number of disease states including inflammatory diseases of the airways, the joints and the skin. The enzyme is also responsible for some or most of the symptoms of acute respiratory distress syndrome (ARDS) and other acute inflammatory states brought about by trauma and/or sepsis.
We have now found a novel group of compounds which inhibit neutrophil elastase. The compounds are therefore of potential therapeutic benefit in the treatment and amelioration of symptoms of diseases where elastase activity is implicated.
Thus, according to one aspect of this invention, we provide a compound of the general formula (I) ##STR1## wherein: R.sub.1 represents C.sub.1-6 alkyl; C.sub.2-6 alkenyl; aryl, aryl-C.sub.1-4 alkyl, aryl-C.sub.2-4 alkenyl, heteroaryl, heteroaryl-C.sub.1-4 alkyl, or heteroaryl-C.sub.2-4 alkenyl, or such a group in which the aryl or heteroaryl moiety is substituted by one or more C.sub.1-4 alkyl, halo, tetrazolyl, trifluoromethyl-sulphonamide, NR.sub.9 CO--C.sub.1-8 alkyl, --(CH.sub.2).sub.m --NR.sub.4 R.sub.5, --CN, --COOR.sub.9, --CONR.sub.9 R.sub.10, --NO.sub.2, --CF.sub.3 or C.sub.1-6 alkoxy groups; --(CH.sub.2).sub.n --NR.sub.4 R.sub.5 ; C.sub.2-8 alkenyl-NR.sub.4 R.sub.5 ; --(CH.sub.2).sub.n CONR.sub.4 R.sub.5 ; --(CH.sub.2).sub.n NR.sub.9 CO--C.sub.1-6 alkyl; C.sub.2-8 alkenyl-COOR.sub.9 ; (CH.sub.2).sub.n COOR.sub.9 ; and C.sub.2-8 alkenyl CONR.sub.4 R.sub.5 ; ##STR2## (where carbonyl is bound to the ring nitrogen); R.sub.2 represents C.sub.2-4 alkyl, C.sub.2-4 alkenyl, C.sub.1-3 alkoxy or C.sub.1-3 alkylthio; ; aryl or heteroaryl, which aryl or heteroaryl are mono-ring, or have two fused rings one of which may be saturated, and which aryl and heteroaryl groups may be substituted by one or more C.sub.1-4 alkyl, halo, --NR.sub.7 R.sub.8, --SO.sub.2 NR.sub.7 R.sub.8, --CONR.sub.7 R.sub.8, --C.sub.1-6 alkyl ester, --CN, --CH.sub

REFERENCES:
patent: 2932650 (1960-04-01), Cope et al.

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