Naphthyridine derivatives

Details Naphthyridine derivatives Naphthyridine derivatives

1997-03-24

1998-01-27

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

057122865

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP 95/03769 filed Sep. 23, 1995 WO96/11198, Apr. 18, 1996.
The present invention relates to therapeutic agents and, in particular, to dialkyl 8-alkyl-5-hydroxy-7-oxo-1,8-naphthyridine-2,6-dicarboxylates, 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 ##STR1## 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 ##STR2## 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 ##STR3## 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 alkenyl group; R.sub.3 and R.sub.4 independently represent hydrogen or a C.sub.1-4 alkyl group and/or salts thereof. Ethyl 4-hydroxy-1,7-dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate is one of fourteen compounds specifically exemplified. 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 ##STR4## 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 4-hydroxy-1,7-dimethyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate and ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate are specifically exemplified. There is no suggestion in this document that the compounds have any anti-rheumatic activity.
In addition ethyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate is disclosed without any pharmacological activity in J. Med. Chem. 1987, 30, 2270, in which the structure activity relationships of these compounds are discussed.
The present invention provides compounds of formula I ##STR5## including pharmaceutically acceptable salts thereof in which R.sub.1 represents a C.sub.1-6 alkyl group; represents a C.sub.1-5 alkyl group; and represents a C.sub.1-5 alkyl group.
It will be understood that a group containing a chain of 3 or more carbon atoms may be straight or branched, for example, propyl includes n-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified for certain substituents

REFERENCES:
patent: 4128649 (1978-12-01), Hardtmann

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