Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-21
2003-08-26
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S221000, C514S307000, C514S423000, C514S396000, C514S561000, C514S824000, C514S091000, C514S108000, C514S543000
Reexamination Certificate
active
06610682
ABSTRACT:
The present invention relates to a pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents (particularly a pharmaceutical composition for prevention or treatment of arteriosclerosis), a kit including a first container comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and a second container comprising one or more insulin resistance improving agents for preparing a pharmaceutical composition (particularly a composition for prevention or treatment of arteriosclerosis), and a method which comprises administering in combination effective amounts of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents to warm-blooded animals for preventing or treating diseases (particularly arteriosclerosis).
BACKGROUND OF THE INVENTION
The occurrence of atherosclerosis is increasing with the adoption of Western-style diet and the growth of the aged population. This disease is the main cause of such disorders as myocardial infarction, cerebral infarction and cerebral apoplexy, and there is a need for its effective prevention and treatment. Examples of risk factors which cause atherosclerosis include hyperlipemia (particularly hypercholesterolemia), hypertension and saccharometabolism disorders based on insulin resistance. In addition, there are many cases in which these risk factors occur in the form of complications (Syndrome X), and are considered to be mutually interrelated Diabetes, 37, 1595-1607 (1988).
Efforts have been made for the purpose of preventing and treating atherosclerosis by suppression of various risk factors such as hyperlipemia, hypertension and insulin resistance. Although HMG-CoA reductase inhibitors like pravastatin improve hyperlipemia, their inhibitory activity on arteriosclerosis in a case of administration alone is not enough, Biochim. Biophys. Acta, 960, 294-302 (1988). In addition, even insulin resistance improving agents like troglitazone do not exhibit sufficient atherosclerosis inhibitory activity in a case of administration alone (Japanese Patent Application (Kokai) No. Hei 7-41423).
On the other hand, among drugs for the treatment of hypertension, it has been reported that atherosclerotic lesions are suppressed when angiotensin converting enzyme (ACE) inhibitors that inhibit the renin-angiotensin system Hypertension, 15, 327-331 (1990) or angiotensin II receptor antagonists Jpn. Circ. J., 60 (Suppl. I), 332 (1996) are administered to animals having normal blood pressure and hypercholesterolemia. Angiotensin II not only exhibits vasoconstrictive activity, but also activity that stimulates the production of growth factors such as PDGF Hypertension, 13, 706-711 (1989) and activity that stimulates migration of neutrophils and macrophages Eur. Heart J., 11, 100-107 (1990). Although the mechanism in which renin-angiotensin system inhibitors suppress atherosclerosis is not clear at the present time, there is a possibility that the mechanism for suppressing atherosclerosis may be a function at the site of the lesion which is different from their blood pressure lowering action. However, since inhibitors of renin-angiotensin system are unable to lower serum lipids J. Cardiovasc. Pharmacol., 15, S65-S72 (1990), their administration alone has limitations on the treatment of arteriosclerosis.
In addition, although troglitazone, glibenclamide and captopril are administered concomitantly to diabetes patients, there is no suggestion indicated whatsoever relating to the prevention and treatment of arteriosclerosis J. Clinical Therapeutic & Medicines, 9 (Supp. 3), 39-60 (1933).
SUMMARY OF THE INVENTION
As a result of earnestly conducting various research in consideration of the importance of the prevention and treatment of arteriosclerosis, the inventors of the present invention found a method to solve the above-mentioned problems involved in the prior art and to obtain a preventive and/or therapeutic effect on arteriosclerosis by using the combination of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and of one or more of insulin resistance improving agents.
The present invention provides a pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents (particularly a pharmaceutical composition for prevention or treatment of arteriosclerosis); a kit including a first container comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and a second container comprising one or more insulin resistance improving agents for prevention or treatment of arteriosclerosis; a method which comprises administering in combination effective amounts of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents to warm-blooded animals for prevention or treatment of diseases (particularly arteriosclerosis); or a pharmaceutical composition for administering at the same time or at a different time one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents (particularly a pharmaceutical composition for prevention of treatment of arteriosclerosis).
The active ingredients of the pharmaceutical composition of the present invention (particularly a pharmaceutical composition for the prevention or treatment of arteriosclerosis), or the active ingredients of a method for preventing or treating diseases (particularly arteriosclerosis) include one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents.
Representative examples of angiotensin II receptor antagonists as an active ingredient of the present invention include biphenyltetrazole compounds and biphenylcarboxylic acid compounds described in Japanese Patent Application (Kokai) No. Hei 5-78328, Japanese Patent Application (Kokai) No. Sho 63-23868, Japanese Patent Application (Kokai) No. Hei 4-364171, Japanese Patent Application (Kokai) No. Hei 4-159718 or Japanese PCT Application (Kokai) No. Hei 4-506222, preferably biphenyltetrazole compounds, more preferably CS-866, losartan, candesartan, valsartan or irbesartan, still more preferably CS-866, losartan or candesartan, and most preferably CS-866.
The following indicates the chemical planar structural formulae of some typical examples of angiotensin II receptor antagonists.
CS-866 is described in Japanese Patent Application No. (Kokai) No. Hei 5-78328 and the like, and its chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate. The CS-866 of the present application includes its carboxylic acid derivative, pharmacologically acceptable esters of its carboxylic acid derivative (such as CS-866) and their pharmacologically acceptable salts.
Losartan (DUP-753) is described in Japanese Patent Application (Kokai) No. Sho 63-23868, U.S. Pat. No. 5,138,069 and the like, and its chemical name is 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-methanol. The losartan of the present application includes its pharmacologically acceptable salts (such as losartan potassium salt).
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Fujiwara Toshihiko
Maeda Naoyuki
Sada Toshio
Tsujita Yoshio
Barts Samuel
Frishauf Holtz Goodman & Chick P.C.
Khare Devesh
Sankyo Company Limited
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