Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-24
1998-12-29
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546123, A61K 31435, C07D47104
Patent
active
058542574
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP95/03808 filed Sep. 26, 1995.
The present invention relates to therapeutic agents and, in particular, to substituted alkyl 1-phenylalkyl-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylates, to processes for their preparation, to pharmaceutical compositions containing them and to their therapeutic activity as anti-rheumatic agents.
Rheumatoid arthritis is currently treated with anti-inflammatory agents, which alleviate the symptoms but do not affect the progression of the condition, or with disease-modifying antirheumatic drugs e.g. gold compounds, D-penicillamine, sulphasalazine, azathioprine and methotrexate. However, most disease-modifying antirheumatic drugs are associated with side-effects, often of a serious nature. This means that such drugs are often only used as a last resort in the most serious cases. Consequently a need exists for a less toxic, disease-modifying, antirheumatic drug which may be administered orally.
EP 452,873 discloses the use of substituted 1-aryl-1,8-naphthyridine-3-carboxamides of formula A ##STR2## in which X represents hydrogen, a C.sub.1-6 alkyl group, aralkyl, aryl, an aromatic heterocyclic group etc. and Y represents a single bond or alkylene, as antiinflammatory agents which are useful in the treatment of rheumatoid arthritis.
Japanese Patent Application 52-116495 (1977) discloses compounds of formula B ##STR3## in which R.sub.1 represents an alkyl group (optionally substituted), an alkenyl group or an aryl group; R.sub.2 represents, hydrogen, an alkyl group (optionally substituted) or an aryl group and R.sub.3 represents hydrogen or an acyl group, which allegedly possess analgesic, antiinflammatory, central nervous system depressant and diuretic effects. There is no suggestion in this document that the compounds have any anti-rheumatic activity.
U.S. Pat. No. 4,128,649 discloses compounds of formula C ##STR4## wherein R.sub.1 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl etc; R.sub.2 represents hydrogen, a C.sub.1-4 alkyl group, a C.sub.3-6 alkenyl group or a C.sub.3-6 alkynyl group; R.sub.3 and R.sub.4 independently represent hydrogen or a C.sub.1-4 alkyl group and/or salts thereof. Ethyl 1-benzyl-4-hydroxy-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxyl ate is specifically named. The use of these compounds as anti-allergic agents is also disclosed. There is no suggestion in this document that the compounds have any anti-rheumatic activity.
U.S. Pat. No. 4,215,123 discloses a method of treating peptic ulcers comprising the administration of a compound of formula D ##STR5## wherein R.sub.1 represents hydrogen, a C.sub.1-6 alkyl group, a C.sub.7-9 aralkyl group etc; R.sub.2 represents hydrogen, a C.sub.2-7 alkoxycarbonyl group, carboxy, carbamoyl, C.sub.2-7 N-alkylcarbamoyl etc; R.sub.4 is hydrogen or a C.sub.1-6 alkyl group and R.sub.5 and R.sub.6 are independently hydrogen or a C.sub.1-6 alkyl group or an alkali metal salt thereof. Ethyl 1-benzyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxyl ate is specifically exemplified. There is no suggestion in this document that the compounds have any anti-rheumatic activity.
The structure activity relationships of a series of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-ones, which are antiallergy agents, is reported in J. Med. Chem. 1988. 31. 2108-2121. 1-Benzyl-3-butyl-4-hydroxy-1,8-naphthyridin-2(1H)-one is disclosed as being inactive.
The present invention provides compounds of formula I ##STR6## including pharmaceutically acceptable salts thereof in which R.sub.1 represents a phenyl C.sub.1-6 alkyl group (in which the phenyl ring is optionally substituted by one or more of the following: halo, a C.sub.1-4 alkyl group, a C.sub.1-4 alkoxy group, hydroxy or trifluoromethyl) and the alkyl chain is optionally substituted by one or more C.sub.1-2 alkyl groups;
In a preferred group of compounds of formula I, R.sub.3 represents halo.
It will be understood that a group containing a chain of 3 or more carbon atoms may be straight or branched, for example, propyl inclu
REFERENCES:
patent: 4128649 (1978-12-01), Hardtmann
patent: 4215123 (1980-07-01), Scotese et al.
Pat. Abst. of Japan, vol. 16, No. 560, Dec. 2, 1992 (English abstract of JP 4217981, Aug. 7, 1992).
J. Med. Chem., vol. 31, 1988, pp. 2108-2121.
J. Med. Chem., vol. 30, 1987, pp. 2270-2277.
Armitage Bernard John
Leslie Bruce William
Dentz Bernard
Knoll Aktiengesellschaft
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