JPH1081633A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition comprising a combination of medicine(s) such as an angiotensin II receptor antagonist and/or an angiotensin converting enzyme inhibitor with HMG-CoA reductase inhibitor and useful as a medicine for preventing or treating arteriosclerosis. SOLUTION: This medicinal composition is used by combining one or two or more kinds of agents selected from (A) angiotensin II receptor antagonists and (B) angiotensin converting enzyme inhibitors and one or two or more kinds of (C) HNG-CoA reductase inhibitors, preferably combining one kind of agent selected from agents A and B with one kind of the agent C. As the preferable manner suitable as the medicine, the agent A is phenyltetrazole compound, etc., and the agent B is tetrahydrothiazepin, etc., and the agent C is statine, etc. The daily dose of the agents A and B is about 0.01-200mg/adult and the daily dose of the agent C is about 0.5-100mg and administration rout of the medicine is generally oral rout and the medicine is administered in divided one to several portions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors and one of HMG-CoA reductase inhibitors. The present invention relates to a pharmaceutical composition (particularly a prophylactic or therapeutic agent for arteriosclerosis) comprising one or more drugs.

[0002]

[Prior Art] With the westernization of the diet and the aging of the population, etc.,
Atherosclerosis is on the rise.
This disease is mainly caused by myocardial infarction, cerebral infarction, cerebral extravasation, etc.
There is a need for effective prevention and treatment methods. Athero-
Risk factors that lead to atherosclerosis include hyperlipidemia (especially hypercholesterolemia), hypertension, and abnormal glucose metabolism due to insulin resistance. In addition, these risk factors often develop as complications (syndrome X), and it is considered that their etiologies are intertwined with each other [Diabitis, Vol. 37, No. 1595.
Pp. 1607 (1988): Diabetes, 37 , 1595-1607
(1988)]. For the purpose of preventing and treating atherosclerosis, attempts have been made to suppress various risk factors such as hyperlipidemia, hypertension and insulin resistance. HMG-CoA reductase inhibitors such as pravastatin ameliorate hyperlipidemia, but cannot be said to be effective in suppressing atherosclerosis with a single agent [BioChemica / Et / Biophysica / Acta] , Volume 960, Pages 294-
302 (1988): Biochim. Biophys. Acta, 960 , 294.
-302 (1988)]. Further, even with an insulin sensitizer such as troglitazone, the effect of suppressing atherosclerosis with a single agent cannot be said to be sufficient (JP-A-7-41423). In recent years, administration of renin-angiotensin system inhibitors such as angiotensin II receptor antagonists and angiotensin converting enzyme (ACE) inhibitors to normotensive hypercholesterolemic animals has resulted in atherosclerotic lesions. [Hypertension, Vol. 15, pp. 327 to 331 (1990): Hypert.
Jpn. Circ. J., 60 (Suppl. I), 332 (1996): Japanese Circulation Journal, Vol. 60 (Appendix I), pp. 332 (1996), 15 , 327-331 (1990). 199
6) etc.]. Angiotensin II has not only a vasoconstrictive effect but also a stimulating effect on the production of growth factors such as PDGF [Hypertension, Vol. 13, pp. 706 to 711 (1989)
Year): Hypertension, 13 , 706-711 (1989)] and neutrophils
The migration stimulating effect of macrophage [European Heart Journal, Vol. 11, pp. 100-107 (1990
Year): Eur. Heart J., 11 , 100-107 (1990)]. At this time, the mechanism of atherosclerosis suppression by renin-angiotensin system inhibitors is not clear, but it is possible that the mechanism is at a local site other than the blood pressure lowering effect. However, inhibitors of the renin-angiotensin system cannot reduce serum lipids [Journal of Cardiovascular Pharmacology, Volume 15, pages S65 to S72 (1990): J. Card.
iovasc. Pharmacol., 15 , S65-S72 (1990)], and there is a limit to treatment with a single agent.

[0003]

SUMMARY OF THE INVENTION The present inventors have conducted various studies on the importance of prevention and treatment of arteriosclerosis and, as a result, have found that the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. By using one or more drugs selected from the following drugs in combination with one or more drugs of the HMG-CoA reductase inhibitor, the above-mentioned problems in the prior art are solved. As a result, they have found a method for obtaining a preventive or / and therapeutic effect of arteriosclerosis. The present invention relates to angiotensin I
Pharmaceutical composition comprising one or more drugs selected from the group consisting of I receptor antagonists and angiotensin converting enzyme inhibitors and one or more drugs of HMG-CoA reductase inhibitors (In particular, a prophylactic or therapeutic drug for arteriosclerosis) or one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and HMG-CoA reductase inhibition Provided is a pharmaceutical composition (particularly, a pharmaceutical composition for preventing or treating arteriosclerosis) for administering one or more agents at the same time or at different times.

[0004]

The active ingredient of the pharmaceutical composition of the present invention (particularly, a pharmaceutical composition for preventing or treating arteriosclerosis) comprises an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor. It consists of one or more drugs selected from the group consisting of drugs and one or more drugs of HMG-CoA reductase inhibitors.

The angiotensin II receptor antagonist which is an active ingredient of the present invention is typically exemplified by, for example, JP-A-5-78328, JP-A-63-23868, and JP-A-4-364171. JP-A-4-15
No. 9718 or Japanese Unexamined Patent Publication No. 4-506222, etc., which may be a biphenyltetrazole compound or a biphenylcarboxylic acid compound, preferably a biphenyltetrazole compound, and more preferably a biphenyltetrazole compound. , CS-8
66, losartan, candesartan, valsartan or irbesartan, even more preferably CS-86
6, losartan or candesartan, particularly preferably CS-866. Below, angiotensin I
1 shows a planar structural formula of a typical I receptor antagonist.

[0006]

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[0007] CS-866 is described in JP-A-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 In addition, CS-866 of the present application includes a carboxylic acid derivative thereof, a pharmaceutically acceptable ester of the carboxylic acid derivative (such as CS-866), or a pharmaceutically acceptable salt thereof.

[0008] Losartan (DUP-753) is described in JP-A-63-23868, US Patent 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-
It is methanol, and the losartan of the present invention includes pharmacologically acceptable salts thereof (losartan potassium salt and the like).

Candesartan (TCV-116) is described in JP-A-4-364171, EP-459136, US Pat. No. 5,354,766 and the chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl. 2-ethoxy-1- [2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl]-
1H-benzimidazole-7-carboxylate, wherein candesartan of the present application is a carboxylic acid derivative thereof,
Pharmacologically acceptable esters of carboxylic acid derivatives (TCV
-116 etc.) or a pharmaceutically acceptable salt thereof.

[0010] Valsartan (CGP-48933) is
It is described in JP-A-4-159718, EP-433983, etc., and its chemical name is (S) -N-valeryl-N- [2 ′-(1H-tetrazol-5-yl) biphenyl- 4-ylmethyl) valine, and the valsartan of the present application includes a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Irbesartan (SR-47436)
Japanese Unexamined Patent Publication No. Hei 4-506222, WO 91-14679
And its chemical name is 2-N-butyl-
4-spirocyclopentane-1- [2 ′-(tetrazo-
Ru-5-yl) biphenyl-4-ylmethyl] -2-imidazolin-5-one, and the irbesartan of the present application includes pharmaceutically acceptable salts thereof.

When the above compound has an asymmetric carbon, the angiotensin II receptor antagonist of the present invention also includes optical isomers and a mixture of these isomers. Further, hydrates of the above compounds are also included.

The angiotensin converting enzyme inhibitors which are the active ingredient compounds of the present invention are typically exemplified by, for example, JP-A-61-267579 and JP-A-52-1.
No. 16457, U.S. Pat. No. 4,374,829, JP-A-58-126821, JP-A-58-20659.
No. 1, JP-A-57-77651 and JP-A-55-77651.
-9058, JP-A-58-203971 or JP-A-63-258449, for example, a tetrahydrothiazepine compound, a proline compound, a pyridazinodiazepine compound, a glycine compound, an imidazolidine compound or It can be an isoquinoline compound, preferably, temocapril, captopril, enalapril, lisinopril, cilazapril, delapril, alacepril,
It is imidapril or quinapril, more preferably temocapril, captopril or enalapril, and particularly preferably temocapril. The planar structural formulas of typical angiotensin converting enzyme inhibitors are shown below.

[0014]

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[0015]

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Temocapril is disclosed in JP-A-61-26757.
No. 9, US Pat. No. 4,699,905, etc.
Its chemical name is (+)-(2S, 6R)-[6- (1
S) -1-ethoxycarbonyl-3-phenylpropylamino] -5-oxo-2- (2-thienyl) perhydro-1,4-thiazepin-4-ylacetic acid, and temocapril of the present application is a dicarboxylic acid derivative thereof. Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable monoester or a pharmacologically acceptable salt thereof (such as temocapril hydrochloride).

Captopril is disclosed in JP-A-52-11645.
7, US Patent No. 4,046,889, etc.
Its chemical name is 1-[(2S) -3-mercapto-2-
Methylpropionyl] -L-proline, and the captopril of the present application includes a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Enalapril is described in US Pat. No. 4,374,829 and the like, and its chemical name is N-[(S) -1--
[Ethoxycarbonyl-3-phenylpropyl] -L-alanyl-L-proline, and enalapril of the present application is:
It includes its pharmacologically acceptable esters or its pharmacologically acceptable salts (such as enalapril maleate).

Lisinopril is disclosed in Japanese Patent Application Laid-Open No. 58-12686.
No. 1, US Pat. No. 4,555,502, etc.
Its chemical name is (S) -1- [N ^2- (1-carboxy-3-phenylpropyl) -L-lysyl] -L-proline, and lisinopril of the present application is a pharmaceutically acceptable ester or And its pharmacologically acceptable salts.

Cilazapril is disclosed in JP-A-58-20659.
No. 1, US Pat. No. 4,512,924, etc.
Its chemical name is (1S, 9S) -9-[(S) -1-ethoxycarbonyl-3-phenylpropylamino] octahydro-10-oxo-6H-pyridazino [1,2-
α] [1,2] diazepine-1-carboxylic acid, and the cilazapril of the present application includes a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof.

Delapril is described in JP-A-57-77651, US Pat. No. 4,385,051 and the like, and its chemical name is (S) -N- (2,3-dihydro-1H-indene-2-yl). Yl) -N- [N- (1-ethoxycarbonyl-3-phenylpropyl) -L-alanyl] glycine, and delapril of the present application includes a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof. I do.

Alacepril is described in JP-A-55-9058, U.S. Pat. No. 4,248,883, etc., and its chemical name is 1- (D-3-acetylthio-2-methylpropanoyl) -L-prolyl. -L-phenylalanine, and alacepril of the present application includes a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

Imidapril is disclosed in JP-A-58-20397.
No. 1, No. 4,508,727, etc.
Its chemical name is (4S) -3-[(2S) -2-[(1
S) -1-ethoxycarbonyl-3-phenylpropylamino] propionyl] -1-methyl-2-oxoimidazolidin-4-carboxylic acid, and imidapril of the present application is a pharmacologically acceptable ester or pharmacologically acceptable ester thereof. Includes acceptable salts.

Quinapril is disclosed in JP-A-63-258449.
No. 4,761,479, etc., and its chemical name is (S) -2-[(2S) -2- (1S)-
1-ethoxycarbonyl-3-phenylpropylamino) propionyl] -1,2,3,4-tetrahydro-
It is a 3-isoquinoline carboxylic acid, and the quinapril of the present application includes a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.

When the compound has an asymmetric carbon, the angiotensin converting enzyme inhibitor of the present invention also includes optical isomers and a mixture of these isomers. Further, hydrates of the above compounds are also included.

The other active ingredient of the present invention, HMG-C
oA reductase inhibitors are originally used as antihyperlipidemic agents, which include all of natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds. For example, Japanese Patent Application Laid-Open No. Sho 57-22
No. 40, JP-A-57-163374, JP-A-56-122375, JP-T-60-500015
Gazette, JP-A-1-216974 or JP-A-3-21674.
No. 58967, and the like, preferably pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastatin, more preferably pravastatin,
Lovastatin or simvastatin, particularly preferably pravastatin.

The planar structural formulas of typical HMG-CoA reductase inhibitors are shown below.

[0028]

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Pravastatin is disclosed in JP-A-57-2240.
No. 4,346,227 and its chemical name is (+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR)-.
6-hydroxy-2-methyl-8-[(S) -2-methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoic acid, and pravastatin of the present application is , A lactone ring closed form thereof or a pharmacologically acceptable salt thereof (eg, pravastatin sodium salt).

Lovastatin is disclosed in JP-A-57-16337.
4, No. 4,231,938, etc.
Its chemical name is (+)-(1S, 3R, 7S, 8S, 8
aR) -1,2,3,7,8,8a-Hexahydro-
3,7-dimethyl-8- [2-[(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (S) -2-methylbutyi Lovastatin of the present application includes the lactone ring-opened form or a pharmaceutically acceptable salt (such as a sodium salt) of the lactone ring-opened form.

Simvastatin is disclosed in JP-A-56-1223.
No. 75, U.S. Pat. No. 4,444,784, and the like, and its chemical name is (+)-(1S, 3R, 7S, 8).
S, 8aR) -1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8- [2-[(2R, 4R)-
Tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl 2,2-dimethylbutyrate, and the simvastatin of the present application is a lactone-opened product or a lactone-opened product thereof Pharmacologically acceptable salts (such as sodium salts).

Fluvastatin is disclosed in Tokushusho 60-5000
No. 15, No. 4,739,073, etc., and their chemical names are (±) (3R ^* , 5S ^* , 6E)-.
7- [3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -3,5-
It is dihydroxy-6-heptenoic acid, and the fluvastatin of the present application includes the lactone ring closed form or a pharmaceutically acceptable salt thereof (such as a sodium salt).

Rivastatin (BAY-W-6228)
Is, JP-A-1-216974, U.S. Pat.
No. 530, and its chemical name is (3R, 5
S, 6E) -7- [4- (4-Fluorophenyl)-
2,6-di- (1-methylethyl) -5-methoxymethylpyridin-3-yl] -3,5-dihydroxy-6
Heptenoic acid, rivastatin of the present application, includes its lactone ring closed form or its pharmaceutically acceptable salt (such as sodium salt).

Atorvastatin (CI-981) is described in JP-A-3-58967, US Pat. No. 5,273,995 and the like, and its chemical name is (3R, 5S) -7-
[2- (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid, The atorvastatin of the present application includes the lactone ring closed form or a pharmaceutically acceptable salt thereof (sodium salt, calcium salt and the like).

When the above compound has an asymmetric carbon, the HMG-CoA reductase inhibitor of the present invention also includes optical isomers and their isomers. Further, hydrates of the above compounds are also included.

In the present invention, one or two or more drugs of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor (preferably, drugs of the group consisting of an angiotensin II receptor antagonist) are used. One or more HMG-CoA reductase inhibitors are selected, and preferably one is selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. One of the HMG-CoA reductase inhibitors is selected and used in combination.

A preferred embodiment of the pharmaceutical composition of the present invention is
(1) The angiotensin II receptor antagonist as an active ingredient is a biphenyltetrazole compound or a biphenylcarboxylic acid compound, and the angiotensin converting enzyme inhibitor is a tetrahydrothiazepine compound, a proline compound, a pyridazinodiazepine compound, or a glycine compound. A pharmaceutical composition which is an imidazolidine compound or an isoquinoline compound,
(2) The group of drugs consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors as active ingredients is CS-866, losartan, candesartan, valsartan, irbesartan, temocapril, captopril, enalapril, lisinopril, cilazapril, delapril, alacepril. , A pharmaceutical composition of the group consisting of imidapril and quinapril, (3) a drug of the group consisting of the active ingredients angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor, wherein CS-866, losartan, candesartan, temocapril, A pharmaceutical composition which is a drug of the group consisting of captopril and enalapril; (4) a drug of the group consisting of the active ingredients angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor, CS-866; (5) a pharmaceutical composition, which is a drug of the group consisting of sultan and candesartan; (5) a pharmaceutical composition, wherein the drug of the group consisting of an active ingredient, an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, is CS-866; ) The active ingredient angiotensin II
A pharmaceutical composition, wherein the drug of the group consisting of a receptor antagonist and an angiotensin converting enzyme inhibitor is a drug of the group consisting of an angiotensin II receptor antagonist; (7) an angiotensin II receptor antagonist and an angiotensin converting enzyme as active ingredients A pharmaceutical composition, wherein the drug of the group consisting of inhibitors is CS-866, losartan, candesartan, valsantan and irbesartan; (8) a pharmaceutical composition comprising an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor as active ingredients; A pharmaceutical composition wherein the group of drugs is a group of drugs consisting of angiotensin converting enzyme inhibitors; and (9) a group of drugs comprising the active ingredients of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor, wherein temocapril and captopril are used. And enalapril A pharmaceutical composition, (10) a pharmaceutical composition in which the group of drugs consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor is temocapril, and (11) an HMG-CoA reductase inhibitor as an active ingredient. , A pharmaceutical composition which is a statin compound, (1
2) a pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin and altvastatin; (13) an active ingredient HMG-CoA reductase inhibitor
Pharmaceutical compositions wherein the CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin and simvastatin, and (14) a pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is pravastatin.

Further, a drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor as active ingredients is selected from the group consisting of (1) to (10), and an HMG-CoA reductase inhibitor as an active ingredient is selected. To (1
Pharmaceutical compositions obtained by selecting from the group consisting of 1) to (14) and arbitrarily combining them are also suitable, and examples thereof include the following.

(15) Angiotensin II as an active ingredient
The receptor antagonist is a biphenyltetrazole compound or a biphenylcarboxylic acid compound, and the angiotensin converting enzyme inhibitor is a tetrahydrothiazepine compound, a proline compound, a pyridazinodiazepine compound, a glycine compound, an imidazolidine compound or an isoquinoline compound. A pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is a statin compound; and (16) a drug of the group consisting of an active ingredient, an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, is CS-866. , Losartan, Candesartan, Valsantan, Irbesartan, Temocapril, Captopril, Enalapril, Lisinopril, Cilazapril, Delapril, Alacepril,
A group of drugs consisting of imidapril and quinapril,
A pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin and altvastatin; (17) an angiotensin II receptor antagonist as an active ingredient; A group of drugs consisting of angiotensin converting enzyme inhibitors is CS-866, losartan,
A drug of the group consisting of candesartan, temocapril, captopril and enalapril, wherein the active ingredient HMG-
A pharmaceutical composition wherein the CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin and altvastatin; (18) an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor as active ingredients A group of drugs consisting of CS-866, losartan, candesartan,
A pharmaceutical composition, which is a drug of the group consisting of temocapril, captopril and enalapril, wherein the active ingredient HMG-CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin and simvastatin, (19) angiotensin II receptor of the active ingredient A group of drugs consisting of body antagonists and angiotensin converting enzyme inhibitors is CS-8.
66, a group of drugs consisting of losartan, candesartan, temocapril, captopril and enalapril;
Pharmaceutical compositions wherein the active ingredient HMG-CoA reductase inhibitor is pravastatin, and (20) a group of drugs consisting of the active ingredients angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor, comprising CS-866 and temocapril The active ingredient HMG-C
a pharmaceutical composition wherein the oA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin and simvastatin; (21) a drug of the group consisting of an active ingredient, an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor, which is CS- 866 and temocapril, a pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is pravastatin, (22) an active ingredient comprising an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor The group of drugs is CS-86
6. A pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is pravastatin and (23) a group of drugs consisting of the active ingredients angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor, wherein temocapril is A pharmaceutical composition wherein the active ingredient HMG-CoA reductase inhibitor is pravastatin.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION A group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor which is an active ingredient of a pharmaceutical composition of the present invention (particularly a composition for preventing or treating arteriosclerosis). 1 selected from drugs
A drug comprising one or more drugs or two or more drugs of the HMG-CoA reductase inhibitor has an excellent progression-suppressing effect on arteriosclerosis in the aorta and develops in the limb joints It has an excellent onset-suppressing effect on xanthomas and has low toxicity, so it is used as a preventive or therapeutic agent for arteriosclerosis (especially a therapeutic agent) or a preventive or therapeutic agent for xanthomas (in particular, a therapeutic agent). Useful. According to the present invention, a group of drugs consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor and an HMG-CoA reductase inhibitor are compared with each single agent because they are combined and used. , Show excellent effect. In addition, such an effect can be obtained even when two drugs are not necessarily present in the body at the same time. That is, the effect is exhibited even when the two drugs do not have a certain level of blood concentration at the same time. It has been speculated that both drugs used in the present invention act to turn on the "switch" in the living body if they are taken up into the living body and reach the receptor. Even though it seems that it no longer has an effect at that blood concentration over time, it is actually a "switch"
Is already contained, and the effect of preventing or treating arteriosclerosis possessed by one type of substance is exhibited. In this state,
When a drug of the other system is administered, the effect of the previously administered drug is combined with the effect of the drug that has been previously administered, in addition to the effect of preventing or treating arteriosclerosis, resulting in an excellent effect. Of course, clinically, it is convenient for both lines of the drug to be administered simultaneously, and therefore the group of drugs consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors and H
The MG-CoA reductase inhibitor can be administered in the form of a combination preparation. When it is not preferable to mix both drugs physically simultaneously due to the formulation technique, each single drug can be administered simultaneously. Also, as described above, 2
Since the drugs of the series exert excellent effects even if they are not administered at the same time, it is also possible to administer each single drug successively at appropriate intervals. The maximum allowable interval between the administration of the two drugs to achieve the excellent effects provided by these two drugs can be confirmed by clinical or animal experiments.

The administration route of the agents of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor and an HMG-CoA reductase inhibitor used in the present invention is generally an oral route. . Therefore, 2
Each of the drugs in the system is in a separate unit dosage form,
Or they can be mixed and physically prepared in one unit dosage form. Such unit dosage forms include, for example, powders,
They can be granules, tablets, capsules and the like, and can be prepared by usual formulation techniques.

The dose and ratio of the drug of the group consisting of the angiotensin II receptor antagonist and the angiotensin converting enzyme inhibitor and the HMG-CoA reductase inhibitor used in the present invention depend on the activity of each drug, the patient's activity, Symptoms,
It can vary greatly depending on various conditions such as age and weight. For example, taking the group of drugs consisting of angiotensin converting enzyme inhibitors as an example, captopril and CS-866 have different in vivo activities using hypertensive rats. Can theoretically differ by an order of magnitude or more. In addition, the HMG-CoA reductase inhibitor is used at a lower dose in the case of preventing or treating arteriosclerosis in the present invention than the dose as an antihyperlipidemic agent which is the original use. And the superior effect of the combination of the agents of the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors may further reduce their dose. For example, CS-
When 866 and pravastatin or temocapril and pravastatin are used for the purpose of the present invention, their doses as antihypertensive and antihyperlipidemic drugs (m
g dose / day) of about 0.1-200 mg and about 5-1
Lower than 00mg, about 0.05-100m each
g and about 1-80 mg.

As mentioned above, the dosages of the HMG-CoA reductase inhibitor and the agents of the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors used in the present invention can vary widely, Rather, those doses (mg dose / day) can be about 0.01-200 mg and about 0.5-100 mg, respectively.

The dose ratios of these two agents can also vary widely, but generally speaking, the group of drugs consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors and HMG-CoA. The dose ratio of the reductase inhibitor is 1: 500 to 50 by weight.
It can be in the range of 0: 1.

In the present invention, the drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor and the HMG-CoA reductase inhibitor are prepared by dividing the above dose once or several times a day, respectively. Then, each is administered simultaneously or separately at different times.

Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the scope of the present invention is not limited thereto.

[0047]

【Example】

Example 1 Inhibition of Atherosclerosis Progression 2-3-month-old WHHL rabbit [Watanabe hereditary hyperlipidemic rabbit: previously described (Biochemical, et.
Actor: Biochimica et Biophysica Acta) 6-7
The animals were used as a group, and a certain amount of the drug was orally administered for 32 weeks. In addition, the amount of food consumed was limited to 120 g / day per animal. Immediately before starting drug administration and 4, 8, 1 after starting drug administration
Blood was collected at 2, 16, 20, 24, 28 and 32 weeks and total cholesterol (mg / dl) was determined. At 32 weeks, the test animals were dissected and the area ratio of aortic lesions (%) was examined. Table 1 shows the results.

[0048]

[Table 1] ────────────────────────────────── Experiment Test compound Dose Animal Plasma Cholester Arch lesion area Rate (%) Number (mg / kg) Number Roll (mg / dl) ───────────────────────────────── ─ 1 CS-866 1 ^**) + pravastatin ^*) 50 6 446 ± 31 58 ± 7 2 Temocapril 1 ^**) + pravastatin ^*) 50 7 406 ± 46 62 ± 9 −−−−−−−−−−−−− −−−−−−−−−−−−−−−−−−−−−−−−−− CS-866 1 ^**) 6 659 ± 38 68 ± 10 Temocapril 1 ^**) 6 667 ± 21 76 ± 4 Pravastatin ^*) 50 7 437 ± 27 80 ± 5 Control group-7 670 ± 28 83 ± 6 ────────────────────────────── ──── *) The sodium salt was used. **) 0.5 mg / kg was administered twice daily.

Formulation Example 1 Tablets CS-866 4.0 mg Pravastatin sodium salt 200.0 Lactose 244.0 Maize starch 50.0 Magnesium stearate 2.0 500 mg The powder having the above formulation was mixed, and the mixture was tableted with a tablet machine to give a tablet of 500 mg per tablet. I do.

The tablets can be sugar-coated if necessary.

[0051]

EFFECT OF THE INVENTION One or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors of the present invention and one or two of insulin HMG-CoA reductase inhibitors The composition consisting of the above drugs, against arteriosclerosis in the aorta,
It has an excellent progression-inhibiting effect, has an excellent onset-suppressing effect on xanthomas that develop in the limb joints, and has a low toxicity. Therefore, pharmaceuticals, particularly, an agent for preventing or treating arteriosclerosis (particularly, Therapeutic agent) or a prophylactic or therapeutic agent (particularly a therapeutic agent) for xanthomas.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication A61K 31/415 A61K 31/415 31/435 31/435 31/55 31/55 38/00 37 / 02 (72) Inventor Naoyuki Maeda Sankyo Co., Ltd. 2-58 Hiromachi, Shinagawa-ku, Tokyo

Claims (16)

[Claims] 1. One or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more HMG-CoA reductase inhibitors A pharmaceutical composition comprising a drug. 2. The angiotensin II receptor antagonist is a biphenyltetrazole compound or a biphenylcarboxylic acid compound, and the angiotensin converting enzyme inhibitor is a tetrahydrothiazepine compound, a proline compound, a pyridazinodiazepine compound, a glycine compound. The pharmaceutical composition according to claim 1, which is an imidazolidine compound or an isoquinoline compound. 3. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition of claim 1, which is a drug of the group consisting of S-866, losartan, candesartan, valsartan, irbesartan, temocapril, captopril, enalapril, lisinopril, cilazapril, delapril, alacepril, imidapril and quinapril. 4. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition of claim 1, which is a drug of the group consisting of S-866, losartan, candesartan, temocapril, captopril, and enalapril. 5. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition of claim 1, which is a drug of the group consisting of S-866, losartan and candesartan. 6. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition of claim 1, which is S-866. 7. The pharmaceutical composition according to claim 1, wherein the drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor is a drug of the group consisting of an angiotensin II receptor antagonist. 8. The drug of the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors,
2. A drug of the group consisting of S-866, Losartan, Candesartan, Valsantan and Irbesartan.
Pharmaceutical composition. 9. The pharmaceutical composition of claim 1, wherein the drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor is a drug of the group consisting of an angiotensin converting enzyme inhibitor. 10. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition of claim 1, which is in the group consisting of temocapril, captopril and enalapril. 11. A drug of the group consisting of an angiotensin II receptor antagonist and an angiotensin converting enzyme inhibitor,
The pharmaceutical composition according to claim 1, which is temocapril. 12. The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is a statin compound. 13. The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is a drug of the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin and altvastatin. 14. The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is a drug belonging to the group consisting of pravastatin, lovastatin and simvastatin. 15. The pharmaceutical composition according to claim 1, wherein the HMG-CoA reductase inhibitor is pravastatin. 16. An agent for preventing or treating arteriosclerosis, comprising the agent according to claim 1.