Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-06-26
1999-01-05
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544183, C07D25310, A61K 3153
Patent
active
058563253
DESCRIPTION:
BRIEF SUMMARY
This is a National Stage Entry Application, filed under 35 U.S.C. 371, of PCT/EP93/03542, filed Dec. 15, 1993.
The subject of the present invention is the use of benzotriazines as PLA.sub.2 inhibitors, new benzotriazine derivatives, process for their preparation and medicaments which contain these compounds.
The invention concerns the use of benzotriazine derivatives of the general formula I ##STR2## for the preparation of medicaments with PLA.sub.2 -inhibiting action, whereby R.sub.1 signifies an amino, C.sub.1 -C.sub.6 -alkylamino, di-C.sub.1 -C.sub.6 -alkylamino or a hydroxyl group, R.sub.2 and R.sub.2, which are the same or different, each hydrogen, halogen, C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, cyano, carboxyl, halogen-C.sub.1 -C.sub.6 -alkyl, cyano-C.sub.1 -C.sub.6 -alkyl, carboxy-C.sub.1 -C.sub.6 -alkyl, hydroxyl, carboxy-C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkoxycarbonyl-C.sub.1 -C.sub.6 -alkoxy or aminocarbonyl-C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylaminocarbonyl-C.sub.1 -C.sub.6 -alkoxy or di-C.sub.1 -C.sub.6 -alkylamino-carbonyl-C.sub.1 -C.sub.6 -alkoxy and n the number. 0 or 1, their tautomers, as well as salts with non-toxic acids or bases.
Compounds of the formula I are in part known. Thus, e.g. in J. Amer. Chem. Soc. 76, 3551 (1954), compounds of the formula I with R.sub.2 =Cl or H and R.sub.1 =OH or NH.sub.2, R.sub.3 =H and n=O are described as anti-malarial agents. Further compounds with n=1 and R.sub.1 =NH.sub.2 are known from J. Chem. Soc. (B) 1970. 911. In these documents, they are described as dyestuffs, radiosensitisers, bactericides, insecticides, acaricides, cytotoxic agents and anti-malarial agents. An anti-inflammatory action is not stated.
The compounds of the formula I display valuable pharmacological properties, especially they can inhibit the activity of phospholipases. Therefore, they are suitable for the treatment of acute and chronic, allergic, non-allergic and traumatic inflammatory diseases, such as for example rheumatic arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respirarory diseases, septic shock, allergic shock, serum disease, auto-immune diseases, graft-versus-host reactions, host-versus-graft diseases, ischaemic or thrombotic diseases, for example coronary infarct or cerebral infarct.
The "alkyl parts" in the aliphatic groups mentioned in the case of R.sup.2 and R.sup.3 can be straight-chained or branched. Preferred radicals are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl and 3-pentyl radical. As C.sub.1 -C.sub.6 -alkoxy group, in this sense there come into question, for example, the methoxy, ethoxy, propoxy or butoxy group.
Halogen atoms are especially fluorine, chlorine and bromine.
Apart from the compounds mentioned in the Examples, the subject of the invention are especially all substances which display all possible combinations of the substituents mentioned in the Examples.
The subject of the invention are also new compounds of the formula Ia ##STR3## in which R.sub.2 signifies C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkoxy, cyano, halogen-C.sub.1 -C.sub.6 -alkyl, cyano-C.sub.1 -C.sub.6 -alkyl, carboxy-C.sub.1 -C.sub.6 -alkyl, hydroxyl, carboxy-C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkoxy-carbonyl-C.sub.1 -C.sub.6 -alkoxy, aminocarbonyl-C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylaminocarbonyl-C.sub.1 -C.sub.6 -alkoxy or di-C.sub.1 -C.sub.6 -alkylaminocanbonyl-C.sub.1 -C.sub.6 -alkoxy and R.sub.3 hydrogen or C.sub.1 -C.sub.6 -alkyl, their tautomers, as well as salts with non-toxic acids or bases.
The compounds of the formula I and Ia, respectively, are especially suitable for the preparation of medicaments for the treatment of acute or chronic diseases, especially those diseases with inflammatory, immunological, allergic, non-allergic or traumatic genesis. Since phospholipase A.sub.2 (PLA.sub.2) is a key enzyme in the causation of these: diseases, such diseases are effecively treated by inhibition of this enzyme.
REFERENCES:
patent: 2489351 (1949-11-01), Wolf et al.
patent: 2489352 (1949-11-01), Wolf et al.
patent: 2489353 (1949-11-01), Wolf et al.
patent: 2489357 (1949-11-01), Wolf et al.
patent: 2489359 (1949-11-01), Wolf et al.
patent: 3562270 (1971-02-01), Wagner-Jauregg et al.
patent: 3681334 (1972-08-01), Schmidt et al.
patent: 4067981 (1978-01-01), Sasse et al.
patent: 5175287 (1992-12-01), Lee et al.
Friebe Walter-Gunar
Scheuer Werner
Tibes Ulrich
Boehringer Mannheim GmbH
Ford John M.
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