Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-04-27
2000-10-24
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546122, A61K 31435, C07D47104
Patent
active
061368210
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel 8-aryl-1,7-naphthyridines, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.
The present invention provides 8-aryl-1,7-naphthyridines, in free or pharmaceutically acceptable salt form. By "aryl" is meant a mono or bicyclic aromatic or heteroaromatic moiety having up to 10 aromatic non-hydrogen atoms and being linked to the 1,7-naphthyridine either directly (e.g., phenyl, pyridyl, tetrazolyl, benzofurazanyl, or benzothiadiazolyl) or via a methylene bridge (e.g., benzyl or pyridylmethyl); preferably a monocyclic aromatic moiety having up to six aromatic carbon atoms, up to two of which may be replaced with nitrogen, for example phenyl, benzyl, 4-pyridyl, or 4-pyridylmethyl, optionally bearing a carboxy, carboxy ester or hydroxy group. The 8-aryl moiety may optionally be further substituted, especially with an electron withdrawing substituent, e.g., nitro, nitrilo, imino, halogen or a halogen-containing substituent (e.g. trifluoromethyl), or cyano, preferably in the meta-position. For example, the 8-aryl moiety may be cyanophenyl, nitrophenyl, tetrazolylphenyl (e.g. tetrazol-1-ylphenyl), or chlorophenyl. Optionally, the double ring of the naphthyridine portion of the molecule may also be further substituted or disubstituted, especially 6-substituted, with hydroxy, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, amino, arylamino, diarylamino, alkamino, dialkamino, arylamido, or alkamido, wherein "alk" refers to an aliphatic moiety of up to eight carbon atoms, optionally bearing a carboxy, or carboxy ester or hydroxy group and/or optionally containing an ether linkage and/or ester linkage.
In particular, the invention provides novel 8-phenyl- and 8-benzyl-1,7-naphthyridines, wherein the 1,7-naphthyridine double ring is optionally 6-substituted, e.g., as exemplified below, and the phenyl ring is optionally substituted by an electron withdrawing substituent such as nitro; e.g., compounds of Formula I: ##STR1## wherein R.sub.1 is phenyl, benzyl, 3-nitrophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-(tetrazolyl)phenyl, benzofurazanyl, or benzothiadiazolyl; alkynyl, alkoxy, aryl, aralkyl, aryloxy, amino, arylamino, diarylamino, alkamino, dialkamino, alkaryl, arylamido, or alkamido,
In formula I and elsewhere in the present description "alk" and "aryl" have the meanings as given above in relation to the 8-aryl-1,7-naphthyridines of the invention.
Preferably, R.sub.2 is selected from hydroxy, amino, arylamino (e.g., phenylamino), aryl (e.g., phenyl), alkaryl (e.g. lower alkylphenyl), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), alkoxy containing an ether linkage and/or ester linkage (e.g., methoxycarbonylmethoxy), and alkamido (e.g., acetamido).
In particular it has been surprisingly discovered that a wholly new class of 6,8-aryl-1,7-naphthyridines are useful as pharmaceuticals, in particular as orally active PDE 4 inhibitors, e.g. for the treatment of asthma.
Thus in a preferred embodiment the invention provides 6-(carboxyphenyl or carboxymethylphenyl)-8-(phenyl, benzo[c]thiadiazolyl or benzo[c]furazanyl)-1,7-naphthyridines, and esters and amides thereof, in free or pharmaceutically acceptable salt form.
More preferably, the invention provides 6-(4-carboxyphenyl or 4-carboxymethylphenyl)-8-(phenyl, 4-benzo[c]thiadiazolyl or 4-benzo[c]furazanyl)-1,7-naphthyridines, and esters and amides thereof, in free or pharmaceutically acceptable salt form.
By benzo[c]thiadiazolyl and benzo[c]furazanyl are meant radicals of formula A and B respectively: ##STR2##
Thus in a particularly preferred embodiment the invention provides a compound of formula II ##STR3## wherein n is zero or one; preferably hydroxy or amino; and either (e.g. 1-tetrazolyl), and R.sub.5 and R.sub.6 together form an additional bond, or .dbd.N--S--N.dbd.;
Suitable pharmaceutically acceptable salt forms of the 8-aryl-1,7-naphthyridines, e.g., of Formula I or II, for pharmaceutical use are prepared by conventional means. For example, compounds having a free carboxylic
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Dentz Bernard
Loeschorn Carol A.
Novartis AG
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