Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-21
1998-07-14
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546122, 544350, 514303, A61K 31435, C07D47104
Patent
active
057804826
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application filed under 35 U.S.C. .sctn.371 of PCT/EP94/01923, filed Jun. 10, 1994.
The present invention relates to therapeutic agents, and in particular to substituted ring-fused 4-aminopyridines, 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 0,361,177 discloses compounds of formula A ##STR2## in which R represents alkyl, cyclopropyl, methylamino and p-fluorophenyl; R.sub.1 represents hydrogen or a C.sub.1-2 alkyl group; R.sub.2 represents halo and A represents --CH-- or --N--. It is disclosed that these compounds may be used to treat rheumatoid arthritis by intra-articular administration.
Japanese patent application number 38774/69, publication number J47-29519 (1972) discloses ethyl 4-anilino-7-methyl-1,8-naphthyridine-3-carboxylate amongst a number of compounds which are prepared as intermediates for use in the preparation of anti-bacterial agents. It is suggested that these intermediates possess anti-bacterial and antiprotozoal activity but no results are given.
2-Diethylaminomethyl-4-(7'-methyl-1',8'-naphthyridin-4'-ylamino)phenol and 2-diethylaminomethyl-4-(1',8'-naphthyridin-4-ylamino)phenol are disclosed in the Australian Journal of Chemistry, 1984, 37, 1065 as having minimal antimalarial activity.
WO 86/06718 discloses compounds of formula B ##STR3## in which X represents halo or haloalkyl; Y represents --CH-- or --N--; and R.sub.1, R.sub.2 represent hydrogen or various substituted aminoalkyl substituents in which R.sub.1 and R.sub.2 are not both hydrogen. The compounds are claimed to have antimalarial activity. Certain compounds of formula B in which R.sub.1 and R.sub.2 are both hydrogen are disclosed as intermediates.
Our co-pending application PCT/EP92/02901 (WO 93/13097) discloses compounds of formula C ##STR4## All compounds disclosed in that application are disclaimed from this present application.
The present invention relates to compounds of formula I ##STR5## and pharmaceutically acceptable salts thereof in which one of A or B represents N and the other represents N or C--R.sub.3 ; carboxy C.sub.2-4 alkenyl group, a C.sub.2-6 alkoxycarbonyl C.sub.2-4 alkenyl group, a hydroxy C.sub.1-6 alkyl group, a carboxy C.sub.1-4 alkyl group, a C.sub.2-6 alkoxycarbonyl C.sub.1-4 alkyl group, a C.sub.1-6 alkoxy group, a halogenated C.sub.1-6 alkyl group, a carboxy group, a C.sub.2-6 alkoxycarbonyl group, a C.sub.1-6 alkanoylamino group or a carbamoyl C.sub.2-4 alkenyl group; alkoxy group, hydroxy, a C.sub.1-6 alkanoyloxy group (which may be substituted by a C.sub.1-6 alkanoyloxy group), or a phenoxy group (optionally substituted by a C.sub.1-4 alkyl group, halo or a C.sub.1-4 alkoxy group); a benzyloxycarbonyl group (optionally substituted by a C.sub.1-4 alkyl group, halo or a C.sub.1-4 alkoxy group), a C.sub.1-6 alkanoyl group, a benzoyl group (optionally substituted by a C.sub.1-4 alkyl group, halo or by one or more hydroxy groups and or an amino group of formula --NR.sub.x R.sub.y (in which R.sub.x and R.sub.y independently represent hydrogen or a C.sub.1-4 alkyl group or R.sub.x and R.sub.y together with the nitrogen atom to which they are attached form a pyrrolidine ring, a morpholine ring or a piperidine ring)!, a carboxy group, a C.sub.1-6 alkylthio group or a R.sub.b independently represent hydrogen, a C.sub.1-6 alkyl group (optionally substituted by an amino group of formula
REFERENCES:
Barlin et al., Aust. J. Chem., vol. 37, 1984, pp. 1065-1073.
Arch. Pharm., vol. 324, No. 9, 600, 1991.
Sofia et al., Pharm. Res. Comm., vol. 11, No. 2, 1979.
Kuroda et al., J. Med. Chem., 1992, vol. 35, pp. 1130-1136.
Armitage Bernard John
Leslie Bruce William
Miller Thomas Kerr
Morley Christopher
Grumbling Matthew V.
Knoll Aktiengesellschaft
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