Pyridine derivatives having angiotensin II antagonism

Details Pyridine derivatives having angiotensin II antagonism Pyridine derivatives having angiotensin II antagonism

1991-09-10

1995-03-21

Fan, Jane T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514345, 514348, 514349, 514350, 514351, 546275, 546290, 546296, 546297, 546300, 546301, 546302, 546304, C07D40110, A61K 3144

Patent

active

053995660

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to pyridine derivatives having angiotensin II antagonism, processes for their preparation and a pharmaceutical composition containing at least one of them as an antihypertensive agent usable in the treatment of hypertension, as a therapeutic agent for the treatment of congestive heart failure, as an antianxiety agent, and as a cognitive enhancing agent.
2. Description of the Related Art
Angiotensin II is a hormone converted from angiotensin I by angiotensin converting enzyme, found in mammals including rat, dog and human as a strong pressor substance, and is one of the causes inducing hypertension. An inhibitor of angiotensin converting enzyme and an antagonist at angiotensin II receptor are now expected to be used in the treatment of hypertension and congestive heart failure. In addition, anxiolytic activity and cognitive enhancing activity based on the antagonism at angiotensin II receptor in brain have been reported in Neuro Report vol. 1, 15, (1990). They are, thus, expected to be used as an antianxiety agent and a cognitive enhancing agent. Captopril and Enalapril as inhibitors of angiotensin converting enzyme have been used clinically. While no antagonist at angiotensin II receptor is now used clinically, some peptide antagonists at angiotensin II receptor which are analogous to angiotensin II have been disclosed in Journal of Medicinal Chemistry, vol. 32, 466-, 898- and 1366-, 1989. As non-peptide antagonists at angiotensin II receptor, Japanese Patent Laid-Open Publication No. 240683/87 and EP-415886 specifications disclose imidazopyridine derivatives; Japanese Patent Publication No. 64428/88, Japanese Patent Laid-Open Publication No. 23868/88, WO/90-00281, WO/91-00277, EP-403158 and EP-403159 specifications disclose substituted imidazole derivatives; Japanese Patent Laid-Open Publication No. 287071/89, EP-411507, EP-412594 and EP-408332 specifications disclose substituted pyrrole, pyrazole and triazole derivatives; EP-411766 specification discloses quinazoline derivatives; Japanese Patent Laid-Open Publication No. 44377/91 and EP-419048 specification disclose pyrimidone derivatives; Japanese Patent Laid-Open Publication Nos. 5464/91, 27362/91 and 63264/91 and U.S. Patent No. 4,880,804 specifications disclose benzimidazole derivatives; EP-400974, EP-401030 and EP-407102 specifications disclose imidazole derivatives condensed with 5 to 7 membered ring. Pyridine derivatives as antagonists of angiotensin II receptor, however, have not been disclosed.


SUMMARY OF THE INVENTION

The inventors of the present invention have recently found that some pyridine derivatives have strong angiotensin II antagonism, and that they reveal, in the animal model, antihypertensive activity, anticardiac insufficiency activity, antianxiety activity and cognitive enhancing activity. The pyridine derivatives do not have agonist activity which is characteristic of peptide antagonists, and are excellent in oral absorption and duration of the activity. Furthermore, the angiotensin II antagonism of the pyridine derivatives is superior to that of conventional non-peptide angiotensin II antagonists.
Accordingly, an object of the present invention is to provide a novel pyridine derivative having angiotensin II antagonism.
Another object of the present invention is to provide a pharmaceutical composition comprising a novel pyridine derivative having angiotensin II antagonism, and particularly useful as an antihypertensive agent, an agent for congestive heart failure, an antianxiety agent, and a cognitive enhancing agent.
A further object of the present invention is to provide methods of treating hypertension, congestive heart failure and anxiety, and cognitive enhancing.
Pyridine derivatives according to the present invention are compounds represented by the following formula (I) ##STR3## and pharmaceutically acceptable salts thereof wherein A represents ##STR4## in which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 each independently represents hydrogen; halog

REFERENCES:
patent: 5250548 (1993-10-01), Winn et al.
Carini et al., "Nonpeptide Angiotensin II Receptor Antagonists: N-[(Benzyloxy)benzyl]imidazoles and Related Compounds as Potent Antihypertensives", J. Med. Chem. 1990, 33, 1330-1336.

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