Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-18
2002-08-13
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000, C514S456000, C514S374000
Reexamination Certificate
active
06432996
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition comprising a compound having angiotensin II antagonistic activity or a salt thereof in combination with at least one species selected from the group consisting of a compound having the activity of increasing insulin-sensitivity, a compound having the activity of improving postprandial hyperglycemia in diabetes mellitus, an indane derivative having the activity of inhibiting angiotensin converting enzyme, a pyridine derivative having the activity of inhibiting HMG-Co A reductase or salts of them, and to the use of the composition.
BACKGROUND ART
Angiotensin II has a strong vasoconstrictive action, aldosterone-synthesizing action and cell-propagating action, which has been considered as one of the mediators of various circulatory diseases. An angiotensin II antagonistic drug suppressing the action of angiotensin, which antagonizes to this angiotensin II at angiotensin II receptor, is useful for the prophylaxis and therapy of circulatory diseases including hypertension, cardiac diseases (e.g. heart failure, myocardial infarction, etc.), cerebral apoplexy, nephritis, arteriosclerosis, etc. And, an angiotensin converting enzyme drug suppresses conversion of angiotensin I to angiotensin II, which is considered, like angiotensin II antagonistic drugs, as useful for the prophylaxis and therapy of circulatory diseases including hypertension, cardiac diseases (e.g. heart failure, myocardial infarction, etc.), cerebral apoplexy, nephritis, arteriosclerosis, etc. However, since angiotensin converting enzyme is the same enzyme as kininase II which destructs kinin, and it has no substrate specificity, it has such an undesirable side effect as depositing inflammatory peptide including kinin and the substance P to cause occurrence of cough.
On the other hand, in the therapy of diabetes mellitus, there has been given treatment with a medicine to improve postprandial hyperglycemia in diabetes mellitus or treatment with a medicine to increase insulin sensitivity for preventing lowering of insulin sensitivity to the intake of glucose in peripheral tissue.
Further, in the therapy of hyperlipemia, a medicine of inhibiting HMG-Co A reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) is employed to suppress the biosynthesis of cholesterol.
Above all, such diseases as hypertension, abnormal carbohydrate tolerance and abnormal lipid metabolism have been known to be complicated with one another. Especially, hypertension and insulin resistance, or hypertension and arteriosclerosis are considered to aggravate the respective counterpart diseases.
This invention is intended, by combination of a compound having angiotensin II antagonistic action or a salt thereof with a compound having action mechanism other than the above, to perform especially remarkable effects in angiotensin II-mediated diseases, especially hypertension, hyperlipemia, arteriosclerosis and so on, singly or complications of these diseases and to cover up various defects observed in administration of a medicine consisting of a single component.
Circumstances being such as above, the present inventors have actually combined, for the first time, a compound having angiotensin antagonistic activity or a salt thereof, which is the essential component, with at least one species selected from the group consisting of a compound having an insulin sensitivity increasing action, a compound having the activity of improving postprandial hyperglycoplasmia in diabetes mellitus, an indane derivative having the action of inhibiting angiotensin converting enzyme, a pyridine derivative having the action of HMG-Co A reductase or salts thereof, and, as a result, they have found that the co-use performs especially remarkable effects (e.g. in the treatment effect, safety, stability, dose, administration route, method of use, etc.) which were not observed in the administration of the respective compounds singly, and they have conducted further studies to accomplish the present invention.
SUMMARY OF THE INVENTION
More specifically, the present invention relates to
(1) a pharmaceutical composition comprising a compound having angiotensin II antagonistic activity or a salt thereof in combination with at least one species selected from the group consisting of a compound having the activity of increasing insulin-sensitivity, a compound having the activity of lowering postprandial hyperglycemia in diabetes mellitus, an indane derivative having the activity of inhibiting angiotensin converting enzyme, a pyridine derivative having the activity of inhibiting HMG-Co A reductase and their salts;
(2) the composition as described in the above (1), which is a prophylactic (preventing) or therapeutic (treating) agent of angiotensin II-mediated diseases;
(3) the composition as described in the above (2), which is directed to the prophylaxis or therapy of circulatory diseases;
(4) the composition as described in the above (2), which is directed to the prophylaxis (prevention) or therapy (treatment) of hypertension, cardiac insufficiency, cerebral apoplexy, ischemic peripheral circulation disturbances, myocardial ischemia, venous insufficiency, progressive cardiac insufficiency after myocardial infarction, diabetic nephropathy, nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, vascular hypertrophy or obstruction after percutaneous transluminal coronary angioplasty, vascular reobstruction after bypass surgery, hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, occular hypertension, hyperlipemia, myocardial infarction, angina pectoris, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, thrombosis, diseases of central nervous system, Alzheimer's disease, deficiency of memory, depression, amnesia, senile dementia, sensory disturbances, multiple system organ failure or scleroderma, or to the prevention or amelioration of anxiety neurosis, catatonia, indisposition or dyspeptic symptoms;
(5) the composition as described in the above (2), which is directed to the prophylaxis or therapy of complications of hypertension;
(6) the composition as described in the above (2), which is directed to the prophylaxis or therapy of arteriosclerosis;
(7) the composition as described in the above (5), which is directed to the prophylaxis or therapy of arteriosclerosis;
(8) the composition as described in the above (1), wherein the compound having angiotensin II antagonistic activity is a compound of the formula:
wherein R
1
stands for H or an optionally substituted hydrocarbon residue; R
2
stands for an optionally esterified carboxyl group; R
3
stands for a group capable of forming anion or a group convertible thereto; X shows that phenylene group and phenyl group are bonded directly or through a spacer having a chain length of 1 to 2 atoms; n denotes 1 or 2; the ring A is a benzene ring optionally having further substituents other than the group shown by R
2
; and Y stands for a bond, —O—, —S(O)m- (m denotes 0, 1 or 2) or —N(R
4
)— (R
4
stands for H or an optionally substituted alkyl group);
(9) the composition as described in the above (1), wherein the compound having angiotensin II antagonistic activity is (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate, 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid;
(10) the composition as described in the above (1), wherein the compound having the activity of increasing insulin-sensitivity is 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione or (R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-propyl]-2,4-oxazolidinedione;
(11) the composition as described in the above (1), wherein the compo
Ikeda Hitoshi
Sohda Takashi
Tamura Norikazu
Takeda Chemical Industries Ltd.
Travers Russell
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