Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-04-27
2001-07-10
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S532000, C514S557000, C514S570000, C560S019000, C560S051000, C560S053000, C560S055000
Reexamination Certificate
active
06258843
ABSTRACT:
The present invention relates to triaryl compounds, particularly biphenyl pyridines, biphenyl benzamides and biphenyl phenylcarboxy compounds, processes for their production, their use as pharmaceuticals and pharmaceutical compositions comprising them.
Specifically, the invention provides a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical, e.g. for use in the treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma.
In a further embodiment the invention provides a pharmaceutical composition comprising a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, e.g. in combination with a pharmaceutically acceptable diluent or carrier.
In a yet further embodiment the invention includes the use of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, for the preparation of a medicament for treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma.
In a still yet further embodiment the invention provides a method for treatment or prophylaxis of inflammation, particularly inflammatory or obstructive diseases of the airways, e.g. asthma, comprising administering an effective amount of a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, in free or pharmaceutically acceptable acid addition salt form, to a subject in need of such therapy.
The (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compounds of the invention and their pharmaceutically acceptable acid addition salt forms are hereinafter referred to as AGENTS OF THE INVENTION. In these compounds, the 4-oxy moiety is suitably (optionally fluoro-substituted)alkoxy, e.g., (fluoro
0-3
-)C
1-4
alkoxy, e.g. methyl, ethyl, difluoromethyl, or trifluoromethyl. The 3-aryl moiety is suitably a mono- or bicyclic moiety having at least one aromatic ring, e.g., azaryl, for example pyridyl, C
1-4
alkylpyridyl, or quinolinyl; aromatic 2,5-cyclohexadien-3,4-ylidine-1-yl, e.g., benzofurazanyl or benzofuranyl; or phenyl, preferably suitably substituted, e.g., meta- and/or para-substituted, with (i) one or two substitutents selected from nitro, carbamoyl, halo (e.g., chloro), trifluoromethyl, alkoxy (e.g. C
1-4
alkoxy), thioalkoxy (e.g. thio(C
1-4
)alkoxy), alkylsulphoxy (e.g. C
1-4
alkylsulphoxy), alkylsulphonyl (e.g. C
1-4
alkylsulphonyl), cyano, or phenoxy, or (ii) a bridging substituent of 3-5 atoms in length wherein the bridge atoms are selected from C, O, S, and N, e.g. indanyl, benzopyrolidonyl, indanonyl, or benzodioxolanyl. By “azaryl” is meant a nitrogen-containing aromatic group, for example, pyridine, e.g., 3-pyridine or 4-pyridine, quinoline, isoquinoline, imidazopyridine (e.g. imidazo[1,2-a]pyridine or benzamide, e.g., 3- or 4- benzomide. By “arylcarbonyloxy” is meant an aryl moiety, e.g. as defined above for the 3-aryl moiety, bearing at least one carbonyloxy substituent, e.g. in free acid, ester, amide or salt form, preferably a phenylcarboxy moiety, e.g. a phenyl-3- or phenyl-4-carboxy moiety, such as a phenyl carboxylic acid or phenyl carboxylate ester (e.g. lower alkyl phenyl carboxylate ester) or phenylcarboxamido moiety. Halo or halogen as used herein refers to F, Cl, Br or I unless otherwise indicated.
AGENTS OF THE INVENTION include compounds which are known per se but for which no pharmaceutical activity has been described or suggested. Thus Jin et al. (Macromol. Symp. (1995), 96 [International Conference on Liquid Crystal Polymers 1994], 125-134) describe methyl-4′-methoxy-3′-phenylbiphenyl-4-carboxylate and 4′-acetoxy-3′-phenylbiphenyl-4-carboxylic acid as intermediates in the preparation of copolyester liquid crystal materials. Buu-Hoi et al. (J. Org. Chem. 21, [1956], 136-138) describe the preparation of 2-(6-methoxy-biphenyl-3-yl)-quinoline and anolgues thereof further substituted in the quinoline ring by methyl or phenyl at position 3 and/or by carboxy at position 4, and (J. Org. Chem. 29, [1964], 762-763) also describe the preparation of 2-(6,2′-dimethoxy-biphenyl-3-yl)-quinoline and analogues thereof further substituted in the quinoline ring by methyl at position 3 and/or by carboxy at position 4. Buu-Hoi et al. do not identify any utility or activity for these quinoline compounds. Du Pont Belgian patent 652,320 describes the preparation of 5-(6-methoxy-biphenyl-3-yl)-2-methyl thiazole as an intermediate in the preparation 5,5′-diphenylthiazolecarbocyanine sensitisers of silver halide emulsions for photographic use.
Accordingly the present invention provides a (4-oxy-3-(aryl)phenyl)-azaryl or -arylcarbonyloxy compound, e.g. wherein the 4-oxy, 3-aryl, azaryl and arylcarbonyloxy moieties are as defined above, provided
that the 3-aryl moiety is not unsubstituted phenyl when the arylcarbonyloxy moiety is phenyl-4-carboxylic acid or phenyl-4-methylcarboxylate, or the azaryl moiety is 5-methylthiazol-2-yl, or
that the 3-aryl moiety is not unsubstituted phenyl or 2-methoxyphen-1-yl when the azaryl moiety is unsubstituted 2-quinoline or 2-quinoline substituted by methyl or phenyl at position 3 and/or by carboxy at position 4,
or a pharmaceutically acceptable acid addition salts thereof.
The novel compounds of this aspect of the invention are encompassed by the AGENTS OF THE INVENTION.
The AGENTS OF THE INVENTION may exist in free form or in the form of pharmaceutically acceptable acid addition salts. Pharmaceutically active acid addition salts for use in the precent invention include for example chlorhydrates, oxalates and fumarates.
In particular, the invention provides an AGENT OF THE INVENTION which is a 4-(oxy)-3-[phenyl or (2,5-cyclohexadien-3,4-ylidine-1-yl)]-phenyl-azaryl or -arylcarbonyloxy, in free or pharmaceutically acceptable acid addition salt form. Optionally, the 3-phenyl moiety is substituted e.g. 3- and/or4-substituted. The 2,5-cyclohexadien-3,4-ylidine-1-yl moiety is preferably a 2,5-cyclohexadien-3,4-N-ylidine-1-yl moiety, preferably aromatic. Preferably, the oxy moiety is alkoxy, e.g. C
1-4
alkoxy. The azaryl moiety is preferably pyridine, e.g., 4-pyridine, imidazopyridine, e.g. 6-imidazo[1,2-a]pyridine, or benzamide, e.g., 3- or 4-benzamide. Preferably the arylcarbonyloxy moiety is phenylcarboxy, e.g. phenyl-3- or-4-carboxy. For example, the AGENTS OF THE INVENTION include a [2-(C
1-4
alkoxy)-biphenyl-5-yl]pyridine, [2-(C
1-4
alkoxy)-biphenyl-5-yl]benzamide or [2-(C
1-4
alkoxy)-biphenyl-5-yl]phenylcarboxy wherein the biphenyl moiety is optionally 3′- and/or 4′-substituted or optionally 3′,4′-fused to a second aromatic ring, preferably a compound of formula Ia or formula Ib:
wherein
in formula Ia W is N or C—CO—R,
wherein R is OH, O—(C
1-6
)alkyl or NR
3
R
4
wherein R
3
and R
4
which may be the same or different are H or (C
1-6
)alkyl, or
in formula Ib Az is an azaryl group containing one or more nitrogen atoms, such as quinoline, isoquiniline, indole, imidazopyridine, e.g. imidazo[1,2-a]pyridine,
and in both formula Ia and Ib R
1
is (C
1-4
)alkyl, preferably methyl; and R
2
is a phenyl moiety, e.g., of formula II
wherein R
5
and R
6
are, independently, H, nitro, halo (e.g., chloro), trifluoromethyl, (C
1-4
)alkoxy, cyano, or phenoxy; or R
5
and R
6
together form a bridge of 3-5 atoms in length wherein the bridge atoms are selected from S, O, N, and C, e.g. —OCH
2
O—, or propylene;
or R
2
is a 2,5-cyclohexadien-3,4-ylidine-1-yl moiety, e.g., of formula III
wherein R
7
and R
8
together form an aromatic bridge of 3-5 atoms in length wherein the bride atoms are selected from S, O, N, and C, e.g. ═N—O—N═; in free or pharmaceutically acceptable acid addition salt form.
Most preferably, R
2
is selected from 3-nitrophenyl, 3-(trifluoromethyl)phenyl, 3-cyanop
Desai Rita
Loeschorn Carol A.
Novartis AG
Rotman Alan L.
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