Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-14
2004-12-21
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S251000, C548S306100, C514S399000
Reexamination Certificate
active
06833381
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a TNF-&agr; inhibitor which contains a heterocyclic compound having an angiotensin II antagonistic activity, its prodrug or a salt thereof and which is useful as preventives or remedies for an inflammatory disease and the like.
BACKGROUND ART
A TNF (tumor necrosis factor)-&agr; is believed to play an important role in various diseases. For example, chronic rheumatoid arthritis that is an inflammatory disease involves an increased TNF-&agr; production which may lead to the destruction of an articular tissue.
A TNF-&agr; inhibitor which has sufficiently excellent pharmaceutical characteristics such as an excellent prophylactic or therapeutic effect for an inflammatory disease and no side effects, is desired to be developed.
DISCLOSURE OF THE INVENTION
In view of these circumstances described above, the present inventors made an effort to develop an agent useful in inhibiting a TNF-&agr;, and found eventually that a heterocyclic compound having an angiotensin II antagonistic activity, especially a compound having an angiotensin II(AII) antagonistic activity which is represented by a certain structural formula, is extremely effective in inhibiting a TNF-&agr;, and a further investigations were made on the basis of this knowledge and the present invention was completed.
That is, the present invention relates to:
(1) A TNF-&agr; inhibitor comprising a heterocyclic compound having an angiotensin II antagonistic activity (a heterocyclic compound having an angiotensin II receptor-antagonistic action) which is represented by the formula:
wherein ring B is an optionally substituted nitrogen-containing heterocyclic ring, R
1
is a group capable of forming an anion or a group capable of being converted into such a group, X denotes that a phenylene group and a phenyl group are bound directly or through a spacer having 2 or less of atomic chains, and n is an integer of 1 or 2 (except for the compound represented by the formula:
[5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one]), its prodrug or a salt thereof;
(2) An agent according to the above-mentioned (1), wherein the heterocyclic compound is a compound having an oxygen atom in its molecule;
(3) An agent according to the above-mentioned (1), wherein the heterocyclic compound is a compound having an ether bond or a carbonyl group;
(4) An agent according to the above-mentioned (1), wherein ring B is an optionally substituted nitrogen-containing aromatic heterocyclic ring;
(5) An agent according to the above-mentioned (1), wherein ring B is an optionally substituted 5- to 6-membered nitrogen-containing heterocyclic ring;
(6) An agent according to the above-mentioned (1), wherein ring B is an optionally substituted imidazole ring;
(7) An agent according to the above-mentioned (1),wherein the heterocyclic compound is a compound represented by the formula (I):
wherein R
1
is a group capable of forming an anion or a group capable of being converted into such a group, X denotes that a phenylene group and a phenyl group are bound directly or through a spacer having 2 or less of atomic chains, n is an integer of 1 or 2, ring A is a further optionally substituted benzene ring, R
2
is a group capable of forming an anion or a group capable of being converted into such a group, R
3
is an optionally substituted hydrocarbon residue which may be bound through a heteroatom;
(8) An agent according to the above-mentioned (1), wherein the heterocyclic compound is losartan, eprosartan, candesartan cilexetil, candesartan, telmisartan, irbesartan, olmesartan or tasosartan;
(9) An agent according to the above-mentioned (1), wherein the heterocyclic compound is 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;
(10) An agent according to the above-mentioned (1), wherein the heterocyclic compound is 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate;
(11) An agent according to the above-mentioned (1), wherein the heterocyclic compound is 2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;
(12) An agent according to the above-mentioned (1), which is a prophylactic and therapeutic agent for a disease involving a TNF-&agr; (e.g., a disease which is developed or exacerbated as a result of the presence of a TNF-&agr;);
(13) An agent according to the above-mentioned (1), which is an anti-inflammatory agent;
(14) Use of a heterocyclic compound having an angiotensin II antagonistic activity, its prodrug or a salt thereof for inhibiting a TNF-&agr;;
(15) Use of a heterocyclic compound having an angiotensin II antagonistic activity, its prodrug or a salt thereof for the manufacture of a medicament for inhibiting a TNF-&agr;;
(16) A method for inhibiting a TNF-&agr; in mammals comprising administering to a mammal an effective dose of a heterocyclic compound having an angiotensin II antagonistic activity which is represented by the formula:
wherein ring B is an optionally substituted nitrogen-containing heterocyclic group, R
1
is a group capable of forming an anion or a group capable of being converted into such a group, X denotes that a phenylene group and a phenyl group are bound directly or through a spacer having 2 or less of atomic chains, and n is an integer of 1 or 2 (except for 5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one), its prodrug or a salt thereof;
(17) Use of a heterocyclic compound having an angiotensin II antagonistic activity which is represented by the formula:
wherein ring B is an optionally substituted nitrogen-containing heterocyclic group, R
1
is a group capable of forming an anion or a group capable of being converted into such a group, X denotes that a phenylene group and a phenyl group are bound directly or through a spacer having 2 or less of atomic chains, and n is an integer of 1 or 2 (except for 5,7-dimethyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-3,4-dihydro-1,6-naphthylidine-2(1H)-one), its prodrug or a salt thereof for the manufacture of a TNF-&agr; inhibitor; and the like.
A heterocyclic compound having an angiotensin II antagonistic activity according to the present invention, its prodrug or a salt thereof, can be employed advantageously for inhibiting a TNF-&agr; (e.g., inhibiting a TNF-&agr; by inhibiting the production of a TNF-&agr; or by inhibiting a TNF-&agr; receptor).
An angiotensin II-antagonistic activity according to the present invention means a competitive or non-competitive inhibitory effect on the binding of angiotensin II to an angiotensin II receptor on a cell membrane which lead to a reduction in a potent vasoconstrictive effect or vascular smooth muscle-proliferating effect induced by angiotensin.
A heterocyclic compound having an angiotensin II antagonistic activity used in this invention is preferably a non-peptide heterocyclic compound having an antagonistic activity exhibiting an advantageously prolonged duration of action. Such a heterocyclic compound having an angiotensin II antagonistic activity is preferably a compound having an oxygen atom in its molecule, above all, preferably a compound having an ether bond or a carbonyl group (said carbonyl group may be conjugated to form a hydroxyl group), more preferably a compound having ether bond or a ketone derivative, and most preferably an ether derivative.
In the formula above, an “optionally substituted nitrogen-containing heterocyclic ring” represented by ring B is preferably an optionally substituted nitrogen-containing aromatic heterocyclic ring. Such an “optionally substituted nitrogen-containing heterocyclic ring” represented by ring B is preferably an optionally substituted 5- to 6-membered nitrogen-containing heterocyclic ring,
Ikeya Kazuaki
Kitayoshi Takahito
McKane Joseph K.
Shameem Golam M M
Takeda Chemical Industries Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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