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WO2009088006A1 - Combined pharmaceutical agent - Google Patents

Combined pharmaceutical agent Download PDF

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Publication number
WO2009088006A1
WO2009088006A1 PCT/JP2009/050065 JP2009050065W WO2009088006A1 WO 2009088006 A1 WO2009088006 A1 WO 2009088006A1 JP 2009050065 W JP2009050065 W JP 2009050065W WO 2009088006 A1 WO2009088006 A1 WO 2009088006A1
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WO
WIPO (PCT)
Prior art keywords
angiotensin
insulin resistance
hypertension
receptor antagonist
therapeutic agent
Prior art date
Application number
PCT/JP2009/050065
Other languages
French (fr)
Japanese (ja)
Inventor
Takahiro Nagayama
Shoichi Kanda
Jun Ohsumi
Original Assignee
Daiichi Sankyo Company, Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2009088006A1 publication Critical patent/WO2009088006A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a medicine containing an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients.
  • Angiotensin II receptor antagonist is known as an effective drug for the prevention or treatment of diseases caused by hypertension such as hypertension, heart disease (angina, myocardial infarction, arrhythmia, heart failure, cardiac hypertrophy, etc.) and kidney disease. Many drugs are commercially available.
  • an insulin resistance improving agent is administered to a patient as a therapeutic agent for diabetes (especially a therapeutic agent for type 2 diabetes) in order to reduce the blood glucose level by improving insulin dysfunction.
  • insulin sensitizers are not only used for diabetes, but also for diseases caused by insulin resistance such as glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome, and atherosclerotic arteries. It is known to be effective for cardiovascular diseases such as sclerosis.
  • Examples of insulin resistance improving agents currently on the market include thiazolidinedione insulin resistance improving agents having PPAR ⁇ activation action such as pioglitazone and rosiglitazone.
  • Patent Document 1 The combined use of an angiotensin II receptor antagonist and an insulin resistance ameliorating agent is disclosed in Patent Document 1, but this document describes arteriosclerosis caused by a combination of an angiotensin II receptor antagonist and an insulin resistance improving agent.
  • the present invention relates to treatment, and there is no suggestion that the combination of the present invention exhibits a particularly excellent therapeutic effect on hypertension or a disease caused by hypertension.
  • the present inventors have conducted various studies in view of the importance of prevention and treatment of hypertension and the like, and as a result, by using a combination of an angiotensin II receptor antagonist and an insulin resistance improving agent, particularly excellent hypertension
  • a method capable of preventing or / and treating a disease caused by hypertension for example, heart disease such as angina pectoris, myocardial infarction, arrhythmia, heart failure or cardiac hypertrophy, kidney disease.
  • the present invention relates to a medicament (especially hypertension) comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs of insulin sensitizers. Or one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs for improving insulin resistance.
  • a pharmaceutical composition for administration at the same time or at different times is provided.
  • the active ingredient of the pharmaceutical composition of the present invention is composed of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs of insulin sensitizers. Become.
  • An angiotensin II receptor antagonist that is an active ingredient of the present invention is represented by the following structural formula.
  • Examples include olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, and biphenyltetrazole compounds such as platosartan, biphenylcarboxylic acid compounds such as telmisartan, eprosartan, azilsartan, and kamedoxomil.
  • biphenyltetrazo Olmesartan medoxomil, losartan, candesartan cilexetil, valsartan or irbesartan particularly preferably olmesartan medoxomil, losartan or candesartan cilexetil, most preferably olmesartan medoxomil.
  • Olmesartan medoxomil is described in JP-A-5-78328, U.S. Pat. No. 5,616,599, etc., 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, and olmesartan medoxomil of the present application is And pharmacologically acceptable salts thereof.
  • Losartan (DUP-753) is described in JP-A-63-23868, U.S. Pat.No. 5,138,069, etc., and its chemical name is 2-butyl-4-chloro-1- [2 ′-(1H- Tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-methanol, and losartan of the present application includes pharmacologically acceptable salts thereof (such as losartan / potassium salt).
  • Candesartan cilexetil is described in JP-A-4-364171, EP-459136, U.S. Pat. No. 5,354,766, and the chemical name thereof is 1- (cyclohexyloxycarbonyloxy) ethyl) -2-ethoxy-1- [ 2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-benzimidazole-7-carboxylate, and candesartan cilexetil of the present application includes pharmacologically acceptable salts thereof.
  • Valsartan (CGP-48933) is described in JP-A-4-159718, EP-433983, and the chemical name thereof is (S) -N-valeryl-N- [2 '-(1H-tetrazole- 5-yl) biphenyl-4-ylmethyl) valine, and valsartan of the present application includes pharmacologically acceptable esters or pharmacologically acceptable salts thereof.
  • Irbesartan (SR-47436) is described in JP-T-4-506222, WO91-14679 and the like, and its chemical name is 2-N-butyl-4-spirocyclopentane-1- [2'- (Tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazolin-5-one, and irbesartan of the present application includes pharmacologically acceptable salts thereof.
  • Eprosartan (SKB-108566) is described in US Pat. No. 5,185,351 and the chemical name thereof is 3- [1- (4-carboxyphenylmethyl) -2-n-butyl-imidazol-5-yl].
  • -2-thienyl-methyl-2-propenoic acid, and the eprosartan of the present application is a carboxylic acid derivative, a pharmacologically acceptable ester of the carboxylic acid derivative or a pharmacologically acceptable salt thereof (eprosartan mesylate) Etc.).
  • Pratosartan (DA-727) is described in U.S. Pat.No. 5,409,947 and the chemical name thereof is 2-propyl-3-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl] -5,6,7,8-tetrahydrocycloheptaimidazol-4 (3H) -one, and platosartan of the present application includes pharmacologically acceptable salts thereof.
  • Telmisartan (BIBR-277) is described in U.S. Pat.No. 5,591,762 and the chemical name thereof is 4′- [[4-methyl- 6- (1-methyl- 2- benzimidazolyl)-2-propyl- 1- benzimidazolyl] methyl]-2- biphenylcarboxylic acid, and telmisartan of the present application includes carboxylic acid derivatives, pharmacologically acceptable esters of carboxylic acid derivatives, or pharmacologically acceptable salts thereof.
  • Azilsartan kamedoxomil is described in Japanese Patent Publication No. 05-271228, US Pat. No. 5,243,054, and the chemical name thereof is potassium 3- [4 '-[(2-ethoxy-7-[[( 5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl] -1H-benzimidazol-1-yl) methyl] biphenyl-2-yl] -5-oxo-1,2, 4-Oxadiazole-4 (5H) -id.
  • the angiotensin II receptor antagonist of the present invention includes optical isomers and mixtures of these isomers. Furthermore, the hydrate of the said compound is also included.
  • the “insulin resistance improving agent”, which is the other active ingredient compound of the present invention, is a generic term for drugs that improve insulin resistance and enhance insulin sensitivity.
  • [4- [2- (4-Ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: pioglitazone, preferably pioglitazone hydrochloride), 5-[[4- [2- (methyl- 2-Pyridylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: rosiglitazone, preferably rosiglitazone maleate), 5-[[(3,4-dihydro-3-methyl- 4-oxo-2-quinazolinyl) methoxy] benzyl] -2,4-thiazolidinedione (generic name: baraglitazone), (2S) -2-methoxy-3- [4- [
  • TAK-379 can be mentioned.
  • pioglitazone, rosiglitazone, valaglitazone, 5- ⁇ 4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl ⁇ -1,3-thiazolidine-2,4 -Thiazolidinedione-based insulin resistance improvers such as dione and pharmacologically acceptable salts thereof.
  • Pioglitazone is a compound described in US Pat. No. 4,687,777, and pioglitazone of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like).
  • Rosiglitazone is a compound described in US Pat. No. 5,002,953, and rosiglitazone of the present invention includes pharmacologically acceptable salts thereof (maleic acid salt and the like).
  • Nabeglitazar is a compound described in International Publication No. 02/100813 pamphlet, and nabeglitazar of the present invention includes pharmacologically acceptable salts thereof (hydrochloride, etc.).
  • Baraglitazone is a compound described in International Publication No. 97/41097 pamphlet, and the balaglitazone of the present invention includes a pharmacologically acceptable salt (hydrochloride, etc.).
  • Metagridacene is a compound described in US Pat. No. 3,517,050, and metaglidacene of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like) thereof.
  • AMG-131 is a compound described in US Pat. No. 6,770,648, and AMG-131 of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like).
  • the insulin resistance improving agent of the present invention includes optical isomers and mixtures of these isomers. Furthermore, the hydrate of the said compound is also included.
  • angiotensin II receptor antagonists are selected, and one or more insulin resistance improving agents are also selected.
  • an angiotensin II receptor is used.
  • One type is selected from the antagonists, and one type is selected from the insulin sensitizers and used in combination.
  • a preferred embodiment of the medicament of the present invention is: (1) A prophylactic or therapeutic agent for hypertension or a disease caused by hypertension, comprising an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients, (2) The preventive or therapeutic agent according to (1) above, wherein the disease caused by hypertension is a heart disease or a kidney disease, (3) The preventive or therapeutic agent according to (2) above, wherein the heart disease caused by hypertension is heart failure, (4) The preventive or therapeutic agent according to (1) above, which reduces the mortality due to heart failure, (5) The preventive agent according to any one of (1) to (4) above, wherein the angiotensin II receptor antagonist is olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan, platosartan, or azilsartan kamedoxomil.
  • the insulin sensitizer is pioglitazone, rosiglitazone, valaglitazone, nabeglitazar, AMG-131, metaglidacene or 5- ⁇ 4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)
  • the prophylactic or therapeutic agent according to the above (1) to (6), wherein the insulin resistance improving agent is a PPAR ⁇ activator, (9)
  • the prophylactic or therapeutic agent according to the above (1) to (6), wherein the insulin resistance improving agent is a thiazolidinedione compound, (10) Insulin resistance improving agent is 5- ⁇ 4-
  • the active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan, platosartan, and azilsartan kamedoxomil;
  • the active ingredient insulin sensitizers are pioglitazone, rosiglitazone, valaglitazone, nabeglitazar, AMG-131, metaglidacene and 5- ⁇ 4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)
  • a prophylactic or therapeutic agent which is a drug of the group consisting of methoxy] benzyl ⁇ -1,3-thiazolidine-2,4-dione,
  • the active ingredient angiotensin II receptor antagonist is a drug of the group consisting of methoxy] benzyl ⁇
  • An agent comprising one or more drugs of an angiotensin II receptor antagonist and one or more drugs of an insulin resistance improving agent, which is an active ingredient of the medicament of the present invention, has a blood pressure lowering effect and a mortality reduction ( Since a prominent effect is seen with respect to the action of prolonging life, it is useful as a prophylactic or therapeutic agent for hypertension and diseases caused by hypertension (particularly, a prophylactic / therapeutic agent for hypertension or heart failure).
  • the angiotensin II receptor antagonist and the insulin resistance ameliorating agent show superior effects compared to the single agents because they are combined and used. Further, such an effect is brought about even if two systems of drugs are not present in the body at the same time.
  • both of the two drugs used in the present invention act to turn on the “switch” in the living body when they are taken into the living body and reach the receptor. Even though it seems that the blood concentration no longer works with time, the “switch” is actually turned on, and the effect of preventing or treating hypertension possessed by one substance of the family is exhibited. In this state, when the drug of the other system is administered, in addition to the effect of preventing or treating hypertension that the drug has, the effect of the previously administered drug is combined and an excellent effect is obtained. Of course, clinically, it is convenient to administer both drugs simultaneously.
  • the group consisting of the angiotensin II receptor antagonist and the insulin sensitizer should be administered in the form of a combination drug.
  • Can do When it is not preferable to mix both drugs physically at the same time due to formulation technology, each single drug can be administered simultaneously.
  • each single agent can be administered at an appropriate interval. The maximum interval between two drugs that are allowed to achieve the excellent effects provided by these two drugs can be confirmed clinically or by animal experiments.
  • the administration route of the angiotensin II receptor antagonist and the insulin resistance improving agent used in the present invention is generally an oral route.
  • the two systems of drugs can each be prepared separately in separate unit dosage forms, or mixed into a physically single unit dosage form.
  • Such unit dosage forms can be, for example, powders, granules, tablets, capsules and the like and can be prepared by conventional formulation techniques.
  • the doses and dose ratios of the angiotensin II receptor antagonist and insulin sensitizer used in the present invention can vary greatly depending on various conditions such as the activity of individual drugs, patient symptoms, age, weight, etc. .
  • an insulin resistance ameliorating agent as an example, pioglitazone and rosiglitazone have different in vivo activity in clinical and diabetic model animals, so the dosage of these two drugs is 1 Can be orders of magnitude or more different.
  • both of the group consisting of the angiotensin II receptor antagonist and the angiotensin converting enzyme inhibitor and the insulin resistance ameliorating agent are more than their original use as a hypotensive agent and a therapeutic agent for diabetes. In the case of the use for the prevention or treatment of hypertension in the present invention, these doses can be lowered, and those doses can be further lowered by the excellent effect of the combination of these two drugs.
  • the doses of angiotensin II receptor antagonist and insulin amelioration agent used in the present invention can vary widely, but generally speaking, their dose per adult (mg dose / day) Can be about 0.5-100 mg and about 0.05-1500 mg, respectively.
  • the dose ratio of angiotensin II receptor antagonist to insulin resistance ameliorating agent is 1: It can be in the range of 200 to 200: 1.
  • the angiotensin II receptor antagonist and the insulin resistance ameliorating agent are each divided into the above doses once a day or several times, respectively, at the same time or separately at different times. Be administered.
  • a composition comprising one or more drugs selected from the angiotensin II receptor antagonist of the present invention and one or more drugs of an insulin resistance ameliorating agent has an excellent progress inhibitory effect on hypertension. And has a life-prolonging effect, it is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for pharmaceuticals, particularly hypertension and diseases caused by hypertension (heart disease, renal disease, etc.).
  • olmesartan medoxomil is referred to as Compound A
  • 5- ⁇ 4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl ⁇ -1,3-thiazolidine-2, 4-dione hydrochloride is referred to as Compound B.
  • Compound A and Compound B combined use to lower blood pressure and reduce mortality (prolonging life)
  • Rats were assigned to 12 cases), the compound A administration group (10 cases), the compound B administration group (10 cases) and the combination group (10 cases).
  • the control group was 0.5% carboxymethylcellulose solution (0.5% CMC)
  • the compound A administration group was compound A 10 mg / kg body weight
  • the compound B administration group was compound B 1 mg / kg body weight
  • the combination group was Compound A (10 mg / kg body weight) and Compound B (1 mg / kg body weight) were orally administered by gavage once a day from 13 to 32 weeks of age.
  • Compound A and Compound B were each administered suspended in 0.5% CMC.
  • Table 1 shows the systolic blood pressure at the age of 20 weeks
  • Table 2 shows the hazard ratio.
  • the hazard ratio shown in the table indicates that the risk of mortality in the control group is 1, and if it is less than 1, it indicates a decrease in mortality, and if it is greater than 1, it indicates an increase in mortality.
  • Table 2 Survival hazard ratio (mortality) relative to the control group From Table 1, the combined administration of Compound A and Compound B showed a better blood pressure lowering effect than the single administration of Compound A or Compound B.

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Abstract

Disclosed is a pharmaceutical agent useful as a prophylactic or therapeutic agent for hypertension or a disease associated with hypertension. Specifically disclosed is a pharmaceutical agent comprising an angiotensin II receptor blocker and an insulin resistance-improving agent as active ingredients.

Description

併用医薬Concomitant medication
　本発明は、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する医薬に関する。 The present invention relates to a medicine containing an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients.
　アンジオテンシンＩＩ受容体拮抗剤は、高血圧症や心臓疾患（狭心症、心筋梗塞、不整脈、心不全、心肥大等）、腎疾患などの高血圧症に起因する疾病の予防又は治療に有効な薬剤として知られており、多くの薬剤が市販されている。 Angiotensin II receptor antagonist is known as an effective drug for the prevention or treatment of diseases caused by hypertension such as hypertension, heart disease (angina, myocardial infarction, arrhythmia, heart failure, cardiac hypertrophy, etc.) and kidney disease. Many drugs are commercially available.
　一方、インスリン抵抗性改善剤は、インスリンの作用不全を改善することにより血糖値を低下させるため、糖尿病治療薬（特に、2型糖尿病の治療薬）として患者に投与されている。さらに、インスリン抵抗性改善剤は、糖尿病ばかりでなく、耐糖能不全、高血圧症、高脂血症、糖尿病合併症、妊娠糖尿病、多嚢胞卵巣症候群などのインスリン抵抗性に起因する疾病やアテローム性動脈硬化症などの心血管系疾患にも有効であることが知られている。現在市販されているインスリン抵抗性改善剤としては、ピオグリタゾン、ロシグリタゾンなどのPPARγ活性化作用を有するチアゾリジンジオン系インスリン抵抗性改善剤が挙げられる。 On the other hand, an insulin resistance improving agent is administered to a patient as a therapeutic agent for diabetes (especially a therapeutic agent for type 2 diabetes) in order to reduce the blood glucose level by improving insulin dysfunction. Furthermore, insulin sensitizers are not only used for diabetes, but also for diseases caused by insulin resistance such as glucose intolerance, hypertension, hyperlipidemia, diabetic complications, gestational diabetes, polycystic ovary syndrome, and atherosclerotic arteries. It is known to be effective for cardiovascular diseases such as sclerosis. Examples of insulin resistance improving agents currently on the market include thiazolidinedione insulin resistance improving agents having PPARγ activation action such as pioglitazone and rosiglitazone.
　アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の併用については特許文献１中に開示されているが、該文献は、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の組み合わせによる動脈硬化症の治療に関するものであり、本発明の組み合わせが高血圧症又は高血圧症に起因する疾病に対し特に優れた治療効果を示すような示唆は全くされていない。 The combined use of an angiotensin II receptor antagonist and an insulin resistance ameliorating agent is disclosed in Patent Document 1, but this document describes arteriosclerosis caused by a combination of an angiotensin II receptor antagonist and an insulin resistance improving agent. The present invention relates to treatment, and there is no suggestion that the combination of the present invention exhibits a particularly excellent therapeutic effect on hypertension or a disease caused by hypertension.
国際公開第WO 98/02183号パンフレット（対応する米国特許：米国特許第6610682号公報）International Publication No. WO 98/02183 pamphlet (corresponding US patent: US Pat. No. 6610682)
　本発明者等は、高血圧症等の予防と治療の重要性にかんがみて種々研究を重ねた結果、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を組み合わせて使用することにより、特に優れた高血圧又は高血圧症に起因する疾病（例えば、狭心症、心筋梗塞、不整脈、心不全もしくは心肥大などの心臓疾患、腎疾患）の予防又は／及び治療効果の得られる方法を見い出すに至った。 The present inventors have conducted various studies in view of the importance of prevention and treatment of hypertension and the like, and as a result, by using a combination of an angiotensin II receptor antagonist and an insulin resistance improving agent, particularly excellent hypertension In addition, the inventors have found a method capable of preventing or / and treating a disease caused by hypertension (for example, heart disease such as angina pectoris, myocardial infarction, arrhythmia, heart failure or cardiac hypertrophy, kidney disease).
　本発明は、アンジオテンシンＩＩ受容体拮抗剤から成る群の薬剤から選択される１種又は２種以上の薬剤とインスリン抵抗性改善剤の１種又は２種以上の薬剤から成る医薬（特に、高血圧症又は心不全の予防剤若しくは治療剤）或はアンジオテンシンＩＩ受容体拮抗剤から成る群の薬剤から選択される１種又は２種以上の薬剤とインスリン抵抗性改善剤の１種又は２種以上の薬剤を同時又は時間を変えて投与するための医薬組成物（特に、高血圧症又は心不全の予防若しくは治療のための医薬組成物）を提供する。 The present invention relates to a medicament (especially hypertension) comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs of insulin sensitizers. Or one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs for improving insulin resistance. A pharmaceutical composition for administration at the same time or at different times (particularly, a pharmaceutical composition for the prevention or treatment of hypertension or heart failure) is provided.
　本発明の医薬組成物の有効成分は、アンジオテンシンＩＩ受容体拮抗剤から成る群の薬剤から選択される１種又は２種以上の薬剤とインスリン抵抗性改善剤の１種又は２種以上の薬剤から成る。 The active ingredient of the pharmaceutical composition of the present invention is composed of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and one or more drugs of insulin sensitizers. Become.
　本発明の有効成分であるアンジオテンシンＩＩ受容体拮抗剤は、以下の構造式で示される、 An angiotensin II receptor antagonist that is an active ingredient of the present invention is represented by the following structural formula.
Figure JPOXMLDOC01-appb-C000001
  　 
Figure JPOXMLDOC01-appb-C000001
  　 
Figure JPOXMLDOC01-appb-C000002
      
  　 
Figure JPOXMLDOC01-appb-C000002
      
  　 
オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン、イルベサルタン、プラトサルタン等のビフェニルテトラゾ－ル化合物、テルミサルタン等のビフェニルカルボン酸化合物、エプロサルタン、アジルサルタン　カメドキソミル等が挙げられ、好適には、ビフェニルテトラゾ－ル化合物であり、更に好適には、オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン又はイルベサルタンであり、特に好適には、オルメサルタン　メドキソミル、ロサルタン又はカンデサルタン　シレキセチルであり、最も好適には、オルメサルタン　メドキソミルである。
  Examples include olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, and biphenyltetrazole compounds such as platosartan, biphenylcarboxylic acid compounds such as telmisartan, eprosartan, azilsartan, and kamedoxomil.Preferably biphenyltetrazo Olmesartan medoxomil, losartan, candesartan cilexetil, valsartan or irbesartan, particularly preferably olmesartan medoxomil, losartan or candesartan cilexetil, most preferably olmesartan medoxomil.
　オルメサルタン　メドキソミルは、特開平5-78328号公報、米国特許第5,616,599号公報等に記載され、その化学名は、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メチル 4-(1-ヒドロキシ-1-メチルエチル)-2-プロピル-1-[2’-(1H-テトラゾール-5-イル)ビフェニル-4-イルメチル]イミダゾール-5-カルボキシレートであり、本願のオルメサルタン　メドキソミルは、その薬理上許容される塩を包含する。 Olmesartan medoxomil is described in JP-A-5-78328, U.S. Pat. No. 5,616,599, etc., 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, and olmesartan medoxomil of the present application is And pharmacologically acceptable salts thereof.
　ロサルタン(DUP-753)は、特開昭63-23868号公報、米国特許第5,138,069 号公報等に記載され、その化学名は、2-ブチル-4-クロロ-1-[2’-(1H-テトラゾール-5-イル)ビフェニル-4-イルメチル]-1H-イミダゾール-5-メタノールであり、本願のロサルタンは、その薬理上許容される塩（ロサルタン・カリウム塩等）を包含する。 Losartan (DUP-753) is described in JP-A-63-23868, U.S. Pat.No. 5,138,069, etc., and its chemical name is 2-butyl-4-chloro-1- [2 ′-(1H- Tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-imidazole-5-methanol, and losartan of the present application includes pharmacologically acceptable salts thereof (such as losartan / potassium salt).
　カンデサルタン　シレキセチルは、特開平4-364171号公報、EP-459136号公報、米国特許第5,354,766 号公報等に記載され、その化学名は、1-(シクロヘキシルオキシカルボニルオキシ)エチル 2-エトキシ-1-[2’-(1H-テトラゾール-5-イル)ビフェニル-4-イルメチル]-1H-ベンズイミダゾール-7-カルボキシレートであり、本願のカンデサルタン　シレキセチルは、その薬理上許容される塩を包含する。 Candesartan cilexetil is described in JP-A-4-364171, EP-459136, U.S. Pat. No. 5,354,766, and the chemical name thereof is 1- (cyclohexyloxycarbonyloxy) ethyl) -2-ethoxy-1- [ 2 '-(1H-tetrazol-5-yl) biphenyl-4-ylmethyl] -1H-benzimidazole-7-carboxylate, and candesartan cilexetil of the present application includes pharmacologically acceptable salts thereof.
　バルサルタン(CGP-48933)は、特開平4-159718号公報、EP-433983号公報等に記載され、その化学名は、(S)-N-バレリル-N-[2’-(1H-テトラゾール-5-イル）ビフェニル-4-イルメチル）バリンであり、本願のバルサルタンは、その薬理上許容されるエステル又はその薬理上許容される塩を包含する。 Valsartan (CGP-48933) is described in JP-A-4-159718, EP-433983, and the chemical name thereof is (S) -N-valeryl-N- [2 '-(1H-tetrazole- 5-yl) biphenyl-4-ylmethyl) valine, and valsartan of the present application includes pharmacologically acceptable esters or pharmacologically acceptable salts thereof.
　イルベサルタン(SR-47436)は、特表平4-506222号公報、WO91-14679号公報等に記載され、その化学名は、2-N-ブチル-4-スピロシクロペンタン-1-[2’-(テトラゾール-5-イル)ビフェニル-4-イルメチル]-2-イミダゾリン-5-オンであり、本願のイルベサルタンは、その薬理上許容される塩を包含する。 Irbesartan (SR-47436) is described in JP-T-4-506222, WO91-14679 and the like, and its chemical name is 2-N-butyl-4-spirocyclopentane-1- [2'- (Tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazolin-5-one, and irbesartan of the present application includes pharmacologically acceptable salts thereof.
　エプロサルタン(SKB-108566)は、米国特許第5,185,351号公報等に記載され、その化学名は、3-[1-(4-カルボキシフェニルメチル)-2-n-ブチル-イミダゾール-5-イル]-2-チエニル-メチル-2-プロペン酸であり、本願のエプロサルタンは、そのカルボン酸誘導体、カルボン酸誘導体の薬理上許容されるエステル又はその薬理上許容される塩（エプロサルタン・メシル酸塩等）を包含する。 Eprosartan (SKB-108566) is described in US Pat. No. 5,185,351 and the chemical name thereof is 3- [1- (4-carboxyphenylmethyl) -2-n-butyl-imidazol-5-yl]. -2-thienyl-methyl-2-propenoic acid, and the eprosartan of the present application is a carboxylic acid derivative, a pharmacologically acceptable ester of the carboxylic acid derivative or a pharmacologically acceptable salt thereof (eprosartan mesylate) Etc.).
　プラトサルタン(DA-727)は、米国特許第5,409,947号公報等に記載され、その化学名は、2-プロピル-3-[(2‘-(1H-テトラゾール-5-イル)ビフェニル-4-イル)メチル]-5,6,7,8-テトラヒドロシクロヘプタイミダゾール-4(3H)-オンであり、本願のプラトサルタンは、その薬理上許容される塩を包含する。 Pratosartan (DA-727) is described in U.S. Pat.No. 5,409,947 and the chemical name thereof is 2-propyl-3-[(2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl] -5,6,7,8-tetrahydrocycloheptaimidazol-4 (3H) -one, and platosartan of the present application includes pharmacologically acceptable salts thereof.
　テルミサルタン(BIBR-277)は、米国特許第5,591,762号公報等に記載され、その化学名は、4‘- [[4-メチル- 6- (1-メチル- 2- ベンズイミダゾリル)- 2-プロピル- 1- ベンズイミダゾリル]メチル]- 2- ビフェニルカルボン酸であり、本願のテルミサルタンは、そのカルボン酸誘導体、カルボン酸誘導体の薬理上許容されるエステル又はその薬理上許容される塩を包含する。 Telmisartan (BIBR-277) is described in U.S. Pat.No. 5,591,762 and the chemical name thereof is 4′- [[4-methyl- 6- (1-methyl- 2- benzimidazolyl)-2-propyl- 1- benzimidazolyl] methyl]-2- biphenylcarboxylic acid, and telmisartan of the present application includes carboxylic acid derivatives, pharmacologically acceptable esters of carboxylic acid derivatives, or pharmacologically acceptable salts thereof.
　アジルサルタン　カメドキソミルは、特許公開第平05-271228号公報、米国特許第5,243,054号公報等に記載され、その化学名は、ポタシウム　3-[4’-[(2-エトキシ-7-[[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル]-1H-ベンンズイミダゾール-1-イル)メチル]ビフェニル-2-イル]-5-オキソ-1,2,4-オキサジアゾール-4(5H)-イドである。 Azilsartan kamedoxomil is described in Japanese Patent Publication No. 05-271228, US Pat. No. 5,243,054, and the chemical name thereof is potassium 3- [4 '-[(2-ethoxy-7-[[( 5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl] -1H-benzimidazol-1-yl) methyl] biphenyl-2-yl] -5-oxo-1,2, 4-Oxadiazole-4 (5H) -id.
　又、上記化合物が不斉炭素を有する場合には、本発明のアンジオテンシンＩＩ受容体拮抗剤は、光学異性体及びそれらの異性体の混合物をも包含する。さらに、上記化合物の水和物も包含する。 In addition, when the above compound has an asymmetric carbon, the angiotensin II receptor antagonist of the present invention includes optical isomers and mixtures of these isomers. Furthermore, the hydrate of the said compound is also included.
　本発明の他方の有効成分化合物である「インスリン抵抗性改善剤」とは、インスリン抵抗性を改善し、インスリン感受性を増強する薬剤の総称であり、例えば以下の構造式で表される[4-[2-(4-エチル-2-ピリジル)エトキシ]ベンジル]-2,4-チアゾリジンジオン(一般名：ピオグリタゾン、好適には、ピオグリタゾン　塩酸塩）、5-[[4-[2-(メチル-2-ピリジルアミノ)エトキシ]フェニル]メチル]-2,4-チアゾリジンジオン(一般名：ロシグリタゾン、好適には、ロシグリタゾン　マレイン酸塩）、5-[[(3,4-ジヒドロ-3-メチル-4-オキソ-2-キナゾリニル)メトキシ]ベンジル]-2,4-チアゾリジンジオン （一般名：バラグリタゾン）、(2S)-2-メトキシ-3-[4-[3-(4-フェノキシフェノキシ)プロポキシ]フェニル]プロパン酸(LY-519818、一般名：ナベグリタザール)、AMG-131（好適には、AMG-131のパラトルエンスルホン酸塩）、MBX-102(一般名：メタグリダセン)、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオン及びその薬理上許容される塩(好適には、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝チアゾリジン-2,4-ジオン　塩酸塩）、 The “insulin resistance improving agent”, which is the other active ingredient compound of the present invention, is a generic term for drugs that improve insulin resistance and enhance insulin sensitivity. For example, [4- [2- (4-Ethyl-2-pyridyl) ethoxy] benzyl] -2,4-thiazolidinedione (generic name: pioglitazone, preferably pioglitazone hydrochloride), 5-[[4- [2- (methyl- 2-Pyridylamino) ethoxy] phenyl] methyl] -2,4-thiazolidinedione (generic name: rosiglitazone, preferably rosiglitazone maleate), 5-[[(3,4-dihydro-3-methyl- 4-oxo-2-quinazolinyl) methoxy] benzyl] -2,4-thiazolidinedione (generic name: baraglitazone), (2S) -2-methoxy-3- [4- [3- (4-phenoxyphenoxy) propoxy ] Phenyl] propanoic acid (LY-519818, generic name: nabeglitazar), AMG-131 (preferably AMG -131 paratoluenesulfonate), MBX-102 (generic name: metaglidacene), 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1 , 3-thiazolidine-2,4-dione and pharmacologically acceptable salts thereof (preferably 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl } Thiazolidine-2,4-dione hydrochloride),
Figure JPOXMLDOC01-appb-C000003
      
  　 
Figure JPOXMLDOC01-appb-C000003
      
  　 
BX-2044(メタグリダセンアナログ)、TAK-379を挙げることができる。好適には、ピオグリタゾン、ロシグリタゾン、バラグリタゾン、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオン及びその薬理上許容される塩のようなチアゾリジンジオン系インスリン抵抗性改善剤である。 BX-2044 (metagridacene analog), TAK-379 can be mentioned. Preferably, pioglitazone, rosiglitazone, valaglitazone, 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4 -Thiazolidinedione-based insulin resistance improvers such as dione and pharmacologically acceptable salts thereof.
　ピオグリタゾンは、米国特許第4,687,777号公報に記載された化合物であり、本発明のピオグリタゾンはその薬理上許容される塩（塩酸塩等）を包含する。 Pioglitazone is a compound described in US Pat. No. 4,687,777, and pioglitazone of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like).
　ロシグリタゾンは、米国特許第5,002,953号公報に記載された化合物であり、本発明のロシグリタゾンは、その薬理上許容される塩（マレイン酸塩等）を包含する。 Rosiglitazone is a compound described in US Pat. No. 5,002,953, and rosiglitazone of the present invention includes pharmacologically acceptable salts thereof (maleic acid salt and the like).
　ナベグリタザールは、国際公開第02/100813号パンフレットに記載された化合物であり、本発明のナベグリタザールはその薬理上許容される塩（塩酸塩等）を包含する。 Nabeglitazar is a compound described in International Publication No. 02/100813 pamphlet, and nabeglitazar of the present invention includes pharmacologically acceptable salts thereof (hydrochloride, etc.).
　バラグリタゾンは、国際公開第97/41097号パンフレットに記載された化合物であり、本発明のバラグリタゾンはその薬理上許容される塩（塩酸塩等）を包含する。 Baraglitazone is a compound described in International Publication No. 97/41097 pamphlet, and the balaglitazone of the present invention includes a pharmacologically acceptable salt (hydrochloride, etc.).
　メタグリダセンは、米国特許第3,517,050号公報に記載された化合物であり、本発明のメタグリダセンはその薬理上許容される塩（塩酸塩等）を包含する。 Metagridacene is a compound described in US Pat. No. 3,517,050, and metaglidacene of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like) thereof.
　AMG-131は、米国特許第6,770,648号公報に記載された化合物であり、本発明のAMG-131はその薬理上許容される塩（塩酸塩等）を包含する。 AMG-131 is a compound described in US Pat. No. 6,770,648, and AMG-131 of the present invention includes pharmacologically acceptable salts (hydrochlorides and the like).
　5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンは、以下の構造で表される化合物又はその薬理上許容される塩であり、 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione is a compound represented by the following structure Or a pharmacologically acceptable salt thereof,
Figure JPOXMLDOC01-appb-C000004
  　 
Figure JPOXMLDOC01-appb-C000004
  　 
特開平9-295970号、EP第0745600号、米国特許第5,886,014号及び国際公開第00/71540号パンフレットに記載されている化合物である。本発明の5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンは、その薬理上許容される塩（塩酸塩等）を包含する。 These compounds are described in JP-A-9-295970, EP 0745600, US Pat. No. 5,886,014 and WO 00/71540. 5- {4-[(6-Methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione of the present invention is pharmacologically acceptable. Salt (hydrochloride, etc.).
　又、上記化合物が不斉炭素を有する場合には、本発明のインスリン抵抗性改善剤は、光学異性体及びそれらの異性体の混合物をも包含する。さらに、上記化合物の水和物も包含する。 In addition, when the compound has an asymmetric carbon, the insulin resistance improving agent of the present invention includes optical isomers and mixtures of these isomers. Furthermore, the hydrate of the said compound is also included.
　本発明において、アンジオテンシンＩＩ受容体拮抗剤からは、１種又は２種以上が選択され、インスリン抵抗性改善剤も、１種又は２種以上が選択されるが、好適には、アンジオテンシンＩＩ受容体拮抗剤から１種が選択され、インスリン抵抗性改善剤から１種が選択され、組み合わせて使用される。 In the present invention, one or more kinds of angiotensin II receptor antagonists are selected, and one or more insulin resistance improving agents are also selected. Preferably, an angiotensin II receptor is used. One type is selected from the antagonists, and one type is selected from the insulin sensitizers and used in combination.
　本発明の医薬の好適な態様は、
（１）アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する高血圧症又は高血圧症に起因する疾病の予防剤若しくは治療剤、
（２）高血圧症に起因する疾病が、心臓疾患、腎疾患である上記（１）に記載の予防剤又は治療剤、
（３）高血圧症に起因する心臓疾患が、心不全である上記（２）に記載の予防剤又は治療剤、
（４）心不全に起因する死亡率を減少させることを特徴とする上記（１）に記載の予防剤又は治療剤、
（５）アンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン、イルベサルタン、テルミサルタン、エプロサルタン、プラトサルタン又はアジルサルタン　カメドキソミルである上記（１）～（４）に記載の予防剤又は治療剤、
（６）アンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミルである上記（１）～（４）に記載の予防剤又は治療剤、
（７）インスリン抵抗性改善剤が、ピオグリタゾン、ロシグリタゾン、バラグリタゾン、ナベグリタザール、AMG-131、メタグリダセン又は5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである上記（１）～（６）に記載の予防剤又は治療剤、
（８）インスリン抵抗性改善剤が、PPARγ活性化剤である上記（１）～（６）に記載の予防剤又は治療剤、
（９）インスリン抵抗性改善剤が、チアゾリジンジオン化合物である上記（１）～（６）に記載の予防剤又は治療剤、
（１０）インスリン抵抗性改善剤が、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである上記（１）～（６）に記載の予防剤又は治療剤、
（１１）アンジオテンシンＩＩ受容体拮抗剤がオルメサルタン　メドキソミルであり、インスリン抵抗性改善剤が5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオン塩酸塩である上記（１）～（４）に記載の予防剤又は治療剤、
（１２）高血圧症又は高血圧症に起因する疾病の予防用若しくは治療用の薬剤を製造するための、アンジオテンシンＩＩ受容体拮抗剤及びインスリン抵抗性改善剤の使用、
（１３）心不全に起因する死亡率を減少させる薬剤を製造するための、アンジオテンシンＩＩ受容体拮抗剤及びインスリン抵抗性改善剤の使用、
（１４）アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する薬剤を用いることを特徴とする、高血圧症又は高血圧症に起因する疾患の予防又は治療方法、
　又、有効成分のアンジオテンシンＩＩ受容体拮抗剤を（５）から成る群から選択し、有効成分のインスリン抵抗性改善剤を（７）－（１０）から成る群から選択し、これらを任意に組合せて得られる薬剤も好適であり、例えば、以下のものをあげることができる。
（１６）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン、イルベサルタン、テルミサルタン、エプロサルタン、プラトサルタン及びアジルサルタン　カメドキソミルから成る群の薬剤であり、
　有効成分のインスリン抵抗性改善剤が、ピオグリタゾン、ロシグリタゾン、バラグリタゾン、ナベグリタザール、AMG-131、メタグリダセン及び5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンから成る群の薬剤である予防剤又は治療剤、
（１７）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン、イルベサルタン、テルミサルタン、エプロサルタン及びプラトサルタンから成る群の薬剤であり、
　有効成分のインスリン抵抗性改善剤が、ピオグリタゾン、ロシグリタゾン及び5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンから成る群の薬剤である予防剤又は治療剤、
（１８）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン及びカンデサルタン　シレキセチルから成る群の薬剤であり、
　有効成分のインスリン抵抗性改善剤が、ピオグリタゾン、ロシグリタゾン及び5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンから成る群の薬剤である予防剤又は治療剤、
（１９）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン及びカンデサルタン　シレキセチルから成る群の薬剤であり、有効成分のインスリン抵抗性改善剤が、ピオグリタゾン及びロシグリタゾンから成る群の薬剤である予防剤又は治療剤、
（２０）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミルであり、有効成分のインスリン抵抗性改善剤が、ピオグリタゾンである医薬、
（２１）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン及びカンデサルタン　シレキセチルから成る群の薬剤であり、
　有効成分のインスリン抵抗性改善剤が、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである予防剤又は治療剤、
（２２）有効成分のアンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミルであり、有効成分のインスリン抵抗性改善剤が、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである予防剤又は治療剤。
  A preferred embodiment of the medicament of the present invention is:
(1) A prophylactic or therapeutic agent for hypertension or a disease caused by hypertension, comprising an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients,
(2) The preventive or therapeutic agent according to (1) above, wherein the disease caused by hypertension is a heart disease or a kidney disease,
(3) The preventive or therapeutic agent according to (2) above, wherein the heart disease caused by hypertension is heart failure,
(4) The preventive or therapeutic agent according to (1) above, which reduces the mortality due to heart failure,
(5) The preventive agent according to any one of (1) to (4) above, wherein the angiotensin II receptor antagonist is olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan, platosartan, or azilsartan kamedoxomil. Or therapeutic agent,
(6) The prophylactic or therapeutic agent according to the above (1) to (4), wherein the angiotensin II receptor antagonist is olmesartan medoxomil,
(7) The insulin sensitizer is pioglitazone, rosiglitazone, valaglitazone, nabeglitazar, AMG-131, metaglidacene or 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) A prophylactic or therapeutic agent according to the above (1) to (6), which is methoxy] benzyl} -1,3-thiazolidine-2,4-dione,
(8) The prophylactic or therapeutic agent according to the above (1) to (6), wherein the insulin resistance improving agent is a PPARγ activator,
(9) The prophylactic or therapeutic agent according to the above (1) to (6), wherein the insulin resistance improving agent is a thiazolidinedione compound,
(10) Insulin resistance improving agent is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione The preventive or therapeutic agent according to the above (1) to (6),
(11) The angiotensin II receptor antagonist is olmesartan medoxomil, and the insulin sensitizer is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl}- The prophylactic or therapeutic agent according to the above (1) to (4), which is 1,3-thiazolidine-2,4-dione hydrochloride,
(12) Use of an angiotensin II receptor antagonist and an insulin sensitizer for producing a drug for the prevention or treatment of hypertension or a disease caused by hypertension,
(13) Use of an angiotensin II receptor antagonist and an insulin sensitizer for producing a drug that reduces mortality caused by heart failure,
(14) A method for preventing or treating hypertension or a disease caused by hypertension, characterized by using a drug containing an angiotensin II receptor antagonist and an insulin sensitizer as active ingredients,
The active ingredient angiotensin II receptor antagonist is selected from the group consisting of (5), the active ingredient insulin resistance improving agent is selected from the group consisting of (7)-(10), and these are arbitrarily combined. Drugs obtained in this way are also suitable, and examples include the following.
(16) The active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan, platosartan, and azilsartan kamedoxomil;
The active ingredient insulin sensitizers are pioglitazone, rosiglitazone, valaglitazone, nabeglitazar, AMG-131, metaglidacene and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) A prophylactic or therapeutic agent which is a drug of the group consisting of methoxy] benzyl} -1,3-thiazolidine-2,4-dione,
(17) The active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan and pratosartan;
Insulin resistance improving agents as active ingredients are pioglitazone, rosiglitazone and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine- A prophylactic or therapeutic agent that is a drug of the group consisting of 2,4-diones,
(18) The active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan and candesartan cilexetil;
Insulin resistance improving agents as active ingredients are pioglitazone, rosiglitazone and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine- A prophylactic or therapeutic agent that is a drug of the group consisting of 2,4-diones,
(19) The active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan and candesartan cilexetil, and the active ingredient insulin resistance improving agent is a drug of the group consisting of pioglitazone and rosiglitazone Preventive or therapeutic agent,
(20) An active ingredient angiotensin II receptor antagonist is olmesartan medoxomil, and an active ingredient insulin resistance improving agent is pioglitazone,
(21) The active ingredient angiotensin II receptor antagonist is a drug of the group consisting of olmesartan medoxomil, losartan and candesartan cilexetil,
The active ingredient insulin sensitizer is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione A prophylactic or therapeutic agent,
(22) The active ingredient angiotensin II receptor antagonist is olmesartan medoxomil, and the active ingredient insulin resistance improving agent is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazole-2 A prophylactic or therapeutic agent that is -yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione.
　本発明の医薬の有効成分であるアンジオテンシンＩＩ受容体拮抗剤の１種又は２以上の薬剤とインスリン抵抗性改善剤の１種又は２以上の薬剤から成る薬剤は、血圧降下作用ならびに死亡率低下（延命）作用に関して顕著な効果が見られるため、高血圧及び高血圧症に起因する疾病の予防剤又は治療剤（特に、高血圧症又は心不全の予防剤／治療剤）として有用である。
  An agent comprising one or more drugs of an angiotensin II receptor antagonist and one or more drugs of an insulin resistance improving agent, which is an active ingredient of the medicament of the present invention, has a blood pressure lowering effect and a mortality reduction ( Since a prominent effect is seen with respect to the action of prolonging life, it is useful as a prophylactic or therapeutic agent for hypertension and diseases caused by hypertension (particularly, a prophylactic / therapeutic agent for hypertension or heart failure).
　本発明によれば、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤とは、それらが組み合わせられ、使用されることより各々の単剤と比べ、優れた効果を示す。又、このような効果は、必ずしも２系統の薬剤が同時に体内に存在していなくてももたらされる。 According to the present invention, the angiotensin II receptor antagonist and the insulin resistance ameliorating agent show superior effects compared to the single agents because they are combined and used. Further, such an effect is brought about even if two systems of drugs are not present in the body at the same time.
　即ち、２系統の薬剤が同時にある程度以上の血中濃度を有さなくても効果を示すのである。推測によれば、本発明に使用される２系統の薬剤は、共に、生体内に取り込まれて受容体に到達すれば、生体内の「スイッチ」を入れる作用を果たし、従って、投与後の経過時間につれてもはやその血中濃度では作用を示さないように見えても、実際は「スイッチ」はすでに入っており、一方の系統の物質が有する高血圧の予防または治療効果が奏される。この状態において、他方の系統の薬剤が投与されると、その薬剤が有する高血圧の予防または治療効果に加えて、先に投与された薬剤の効果が合さり、優れた効果が得られる。勿論、臨床上は両系統の薬剤が同時に投与されることが便宜であり、それゆえ、アンジオテンシンＩＩ受容体拮抗剤から成る群の薬剤とインスリン抵抗性改善剤は、配合剤の形態で投与することができる。製剤技術上、両薬剤を物理的に同時に混合することが好ましくない場合は、それぞれの単剤を同時に投与することもできる。また、前述のとおり、２系統の薬剤は同時に投与しなくても優れた効果を奏するので、それぞれの単剤を適当な間隔を置いて相前後して投与することもできる。かかる２系統の薬剤によりもたらされる優れた効果が達成されるのに許容される最大限の２系統薬剤の投与間隔は、臨床上または動物実験により確認することができる。 That is, even if the two drugs do not have a certain level of blood concentration at the same time, the effect is exhibited. According to the speculation, both of the two drugs used in the present invention act to turn on the “switch” in the living body when they are taken into the living body and reach the receptor. Even though it seems that the blood concentration no longer works with time, the “switch” is actually turned on, and the effect of preventing or treating hypertension possessed by one substance of the family is exhibited. In this state, when the drug of the other system is administered, in addition to the effect of preventing or treating hypertension that the drug has, the effect of the previously administered drug is combined and an excellent effect is obtained. Of course, clinically, it is convenient to administer both drugs simultaneously. Therefore, the group consisting of the angiotensin II receptor antagonist and the insulin sensitizer should be administered in the form of a combination drug. Can do. When it is not preferable to mix both drugs physically at the same time due to formulation technology, each single drug can be administered simultaneously. In addition, as described above, since the two drugs do not have to be administered at the same time, excellent effects can be obtained, so that each single agent can be administered at an appropriate interval. The maximum interval between two drugs that are allowed to achieve the excellent effects provided by these two drugs can be confirmed clinically or by animal experiments.
　本発明において使用されるアンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の投与ル－トは、一般的に経口ル－トである。従って、２系統の薬剤は、それぞれ単独で別々の単位投与形態に、又は混合して物理的に１個の単位投与形態に調製することができる。かかる単位投与形態は、たとえば、散剤、顆粒剤、錠剤、カプセル剤等であり得、通常の製剤技術により調製することができる。 The administration route of the angiotensin II receptor antagonist and the insulin resistance improving agent used in the present invention is generally an oral route. Thus, the two systems of drugs can each be prepared separately in separate unit dosage forms, or mixed into a physically single unit dosage form. Such unit dosage forms can be, for example, powders, granules, tablets, capsules and the like and can be prepared by conventional formulation techniques.
　本発明において使用されるアンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の投与量と投与比率は、個々の薬剤の活性、患者の症状、年齢、体重等の種々の条件により大幅に変化し得る。例えば、インスリン抵抗性改善剤を例に取ると、ピオグリタゾンとロシグリタゾンとでは、臨床や糖尿病性モデル動物を用いたイン・ビボ(in vivo) の活性は異なるので、これら２薬剤の投与量は１桁かそれ以上異なり得る。また、アンジオテンシンＩＩ受容体拮抗剤及びアンジオテンシン変換酵素阻害剤から成る群の薬剤とインスリン抵抗性改善剤の双方とも、それらの本来的な用途である血圧降下剤及び糖尿病治療剤としての用量よりも、本発明における高血圧症の予防又は治療の用途の場合はそれらの用量は低めになり得、又これら２系統の薬剤の併用による優れた効果によって、それらの用量はさらに低下し得る。 The doses and dose ratios of the angiotensin II receptor antagonist and insulin sensitizer used in the present invention can vary greatly depending on various conditions such as the activity of individual drugs, patient symptoms, age, weight, etc. . For example, taking an insulin resistance ameliorating agent as an example, pioglitazone and rosiglitazone have different in vivo activity in clinical and diabetic model animals, so the dosage of these two drugs is 1 Can be orders of magnitude or more different. In addition, both of the group consisting of the angiotensin II receptor antagonist and the angiotensin converting enzyme inhibitor and the insulin resistance ameliorating agent are more than their original use as a hypotensive agent and a therapeutic agent for diabetes. In the case of the use for the prevention or treatment of hypertension in the present invention, these doses can be lowered, and those doses can be further lowered by the excellent effect of the combination of these two drugs.
　上述のとおり、本発明において使用されるアンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の用量は大幅に変わり得るが、一般的に言って、それらの成人当りの用量（ｍｇ薬量／日）は、それぞれ約０．５－１００ｍｇ及び約０．０５－１５００ｍｇであり得る。 As mentioned above, the doses of angiotensin II receptor antagonist and insulin amelioration agent used in the present invention can vary widely, but generally speaking, their dose per adult (mg dose / day) Can be about 0.5-100 mg and about 0.05-1500 mg, respectively.
　これら２系統の薬剤の投与量の比率も、また、大幅に変わり得るが、一般的に言って、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤の投与量比率は、重量比で、１：２００ないし２００：１の範囲内であり得る。 Although the dose ratio of these two systems of drugs can also vary significantly, generally speaking, the dose ratio of angiotensin II receptor antagonist to insulin resistance ameliorating agent is 1: It can be in the range of 200 to 200: 1.
　本発明において、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤は、それぞれ上記の投与量を１日１回、または数回に分割して、それぞれを同時に、または時間を異にして別々に、投与される。
  In the present invention, the angiotensin II receptor antagonist and the insulin resistance ameliorating agent are each divided into the above doses once a day or several times, respectively, at the same time or separately at different times. Be administered.
　本発明のアンジオテンシンＩＩ受容体拮抗剤から選択される１種又は２以上の薬剤とインスリン抵抗性改善剤の１種又は２以上の薬剤から成る組成物は、高血圧に対して、優れた進展抑制効果を有し、延命効果も有しているため、医薬、特に高血圧症及び高血圧症に起因する疾病(心臓疾患、腎疾患等)の予防剤若しくは治療剤（特に、治療剤）として有用である。
  A composition comprising one or more drugs selected from the angiotensin II receptor antagonist of the present invention and one or more drugs of an insulin resistance ameliorating agent has an excellent progress inhibitory effect on hypertension. And has a life-prolonging effect, it is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for pharmaceuticals, particularly hypertension and diseases caused by hypertension (heart disease, renal disease, etc.).
　以下に、実施例及び製剤例をあげて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
  Hereinafter, the present invention will be described in more detail with reference to examples and formulation examples, but the scope of the present invention is not limited thereto.
　以下の記載においては、オルメサルタン　メドキソミルを化合物Ａとし、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオン塩酸塩を化合物Ｂとする。
＜実施例１＞
　化合物Ａと化合物Ｂの併用による血圧降下作用及び死亡率の減少（延命）作用
　雄性Dahlラット（Dahl-S/Iwai、日本エスエルシー株式会社）に、７週齢時から８％食塩を含む飼料（船橋農場株式会社）を給餌し、高血圧症を発症させた。12週齢時に非観血式血圧測定器（BP-98A、ソフトロン社製）を用いて血圧測定を行い、収縮期血圧、心拍数および体重が群間で均一になるように、対照群（12例）、化合物Ａ投与群（10例）、化合物Ｂ投与群（10例）および併用群（10例）にラットを割り付けた。対照群には0.5%カルボキシメチルセルロース溶液（0.5% CMC）を、化合物Ａ投与群には化合物Ａ 10 mg/kg体重 を、化合物Ｂ投与群には化合物Ｂ １ mg/kg体重 を、併用群には化合物Ａ 10 mg/kg体重 および化合物Ｂ １mg/kg体重 を、それぞれ13週齢より32週齢まで１日１回強制経口投与した。化合物Ａおよび化合物Ｂはそれぞれ0.5% CMCに懸濁して投与した。 In the following description, olmesartan medoxomil is referred to as Compound A, and 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2, 4-dione hydrochloride is referred to as Compound B.
<Example 1>
Compound A and Compound B combined use to lower blood pressure and reduce mortality (prolonging life) Male Dahl rats (Dahl-S / Iwai, SLC Japan) containing 8% salt from the age of 7 weeks ( Funabashi Farm Co., Ltd.) was fed to develop hypertension. At the age of 12 weeks, blood pressure was measured using a non-invasive blood pressure measuring instrument (BP-98A, Softron), and the control group (so that the systolic blood pressure, heart rate and weight were uniform among the groups) Rats were assigned to 12 cases), the compound A administration group (10 cases), the compound B administration group (10 cases) and the combination group (10 cases). The control group was 0.5% carboxymethylcellulose solution (0.5% CMC), the compound A administration group was compound A 10 mg / kg body weight, the compound B administration group was compound B 1 mg / kg body weight, and the combination group was Compound A (10 mg / kg body weight) and Compound B (1 mg / kg body weight) were orally administered by gavage once a day from 13 to 32 weeks of age. Compound A and Compound B were each administered suspended in 0.5% CMC.
　20週齢時において、薬剤投与24時間後の血圧値（トラフ値）を非観血的に測定した。また、32週齢時までの生存日数について、Coxの比例ハザードモデルを適用し、対照群に対するハザード比を算出した。 At 20 weeks of age, blood pressure values (trough values) 24 hours after drug administration were measured noninvasively. In addition, the Cox proportional hazard model was applied to the number of days remaining until the age of 32 weeks, and the hazard ratio relative to the control group was calculated.
　表１に20週齢時の収縮期血圧を、表２にハザード比をそれぞれ示す。表に示すハザード比は対照群の死亡リスクを１としており、１より小さければ死亡率の低下を、１より大きければ死亡率の増加を示す。
 
（表１）　収縮期血圧（２０週齢時、トラフ値）
Figure JPOXMLDOC01-appb-I000005
　＊対照群は、１匹死亡のため１１例となった。
 
（表２）　対照群に対する生存時間ハザード比（死亡率）
Figure JPOXMLDOC01-appb-I000006
　表１より、化合物Ａと化合物Ｂの併用投与は、化合物Ａ又は化合物Ｂの単独投与と比べ、より優れた血圧降下作用を示した。また、死亡率に関しては、表２より、対照群と比較して、化合物Ａ投与群では26.4％に低下し、化合物Ｂ投与群では73.2％に低下したが、併用群では8.2％まで顕著に低下した。この死亡率減少効果の理由の一つとしては、表１で示された優れた血圧降下作用があると考えられる。
  Table 1 shows the systolic blood pressure at the age of 20 weeks, and Table 2 shows the hazard ratio. The hazard ratio shown in the table indicates that the risk of mortality in the control group is 1, and if it is less than 1, it indicates a decrease in mortality, and if it is greater than 1, it indicates an increase in mortality.

(Table 1) Systolic blood pressure (20 weeks of age, trough value)
Figure JPOXMLDOC01-appb-I000005
* There were 11 cases in the control group due to the death of one animal.

(Table 2) Survival hazard ratio (mortality) relative to the control group
Figure JPOXMLDOC01-appb-I000006
From Table 1, the combined administration of Compound A and Compound B showed a better blood pressure lowering effect than the single administration of Compound A or Compound B. In addition, from Table 2, the mortality rate decreased to 26.4% in the compound A administration group and 73.2% in the compound B administration group compared to the control group, but significantly decreased to 8.2% in the combination group. did. One of the reasons for this mortality reduction effect is considered to be the excellent blood pressure lowering action shown in Table 1.
　食塩負荷Dahlラットとの主要な死因は、心不全と考えられている（Inoko M. et al., American Journal of Physiology, 267, H2471-2482 (1994年)）。従って、以上の結果より、アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する医薬は、高血圧症及び心不全等の高血圧症に起因する疾病の予防／治療に有効であることがわかる。
 
＜製剤例＞
＜製剤例１＞カプセル剤
Figure JPOXMLDOC01-appb-I000007
　上記で示される各成分の粉末を良く混合し、カプセルに詰めることによりカプセル剤を製造することができる。なお、有効成分の用量、各添加剤の含量・種類については、これに限定されるものではない。
 
＜製剤例２＞錠剤
Figure JPOXMLDOC01-appb-I000008
　上記で示される各成分の粉末を良く混合し、各170mg重量の錠剤に圧縮成型する。必要ならば、これらの錠剤は糖またはフィルムで被覆してもよい。なお、有効成分の用量、各添加剤の含量・種類については、これに限定されるものではない。
  The major cause of death with saline-loaded Dahl rats is thought to be heart failure (Inoko M. et al., American Journal of Physiology, 267, H2471-2482 (1994)). Therefore, based on the above results, a medicine containing an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients is effective for the prevention / treatment of diseases caused by hypertension such as hypertension and heart failure. Recognize.

<Formulation example>
<Formulation example 1> Capsule
Figure JPOXMLDOC01-appb-I000007
Capsules can be produced by thoroughly mixing the powders of the components shown above and filling the capsules. The dose of the active ingredient and the content / type of each additive are not limited thereto.

<Formulation example 2> Tablet
Figure JPOXMLDOC01-appb-I000008
The powder of each component shown above is mixed well and compressed into tablets of 170 mg weight. If necessary, these tablets may be coated with sugar or film. The dose of the active ingredient and the content / type of each additive are not limited thereto.

Claims (14)

  1. 　アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する高血圧症又は高血圧症に起因する疾病の予防剤若しくは治療剤。 An agent for preventing or treating hypertension or a disease caused by hypertension, which contains an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients.
  2. 　高血圧症に起因する疾病が、心臓疾患、腎疾患である請求項１に記載の予防剤又は治療剤。 The preventive agent or therapeutic agent according to claim 1, wherein the disease caused by hypertension is a heart disease or a renal disease.
  3. 　高血圧症に起因する心臓疾患が、心不全である請求項２に記載の予防剤又は治療剤。 The preventive or therapeutic agent according to claim 2, wherein the heart disease caused by hypertension is heart failure.
  4. 　心不全に起因する死亡率を減少させることを特徴とする請求項１に記載の予防剤又は治療剤。 The prophylactic or therapeutic agent according to claim 1, which reduces the mortality due to heart failure.
  5. 　アンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミル、ロサルタン、カンデサルタン　シレキセチル、バルサルタン、イルベサルタン、テルミサルタン、エプロサルタン、プラトサルタン又はアジルサルタン　カメドキソミルである請求項１乃至４のいずれか一つに記載の予防剤又は治療剤。 The preventive agent according to any one of claims 1 to 4, wherein the angiotensin II receptor antagonist is olmesartan medoxomil, losartan, candesartan cilexetil, valsartan, irbesartan, telmisartan, eprosartan, platosartan, or azilsartan kamedoxomil. Therapeutic agent.
  6. 　アンジオテンシンＩＩ受容体拮抗剤が、オルメサルタン　メドキソミルである請求項１乃至４のいずれか一つに記載の予防剤又は治療剤。 The preventive agent or therapeutic agent according to any one of claims 1 to 4, wherein the angiotensin II receptor antagonist is olmesartan medoxomil.
  7. 　インスリン抵抗性改善剤が、ピオグリタゾン、ロシグリタゾン、バラグリタゾン、ナベグリタザール、AMG-131、メタグリダセン又は5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである請求項１乃至６のいずれか一つに記載の予防剤又は治療剤。 Insulin resistance improving agent is pioglitazone, rosiglitazone, valaglitazone, nabeglitazar, AMG-131, metaglidacene or 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl } -1,3-thiazolidine-2,4-dione. The prophylactic or therapeutic agent according to any one of claims 1 to 6.
  8. 　インスリン抵抗性改善剤が、PPARγ活性化剤である請求項１乃至６のいずれか一つに記載の予防剤又は治療剤。 The prophylactic or therapeutic agent according to any one of claims 1 to 6, wherein the insulin resistance improving agent is a PPARγ activator.
  9. 　インスリン抵抗性改善剤が、チアゾリジンジオン化合物である請求項１乃至６のいずれか一つに記載の予防剤又は治療剤。 The prophylactic or therapeutic agent according to any one of claims 1 to 6, wherein the insulin resistance improving agent is a thiazolidinedione compound.
  10. 　インスリン抵抗性改善剤が、5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオンである請求項１乃至６のいずれか一つに記載の予防剤又は治療剤。 The insulin resistance improving agent is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3-thiazolidine-2,4-dione Item 7. A prophylactic or therapeutic agent according to any one of Items 1 to 6.
  11. 　アンジオテンシンＩＩ受容体拮抗剤がオルメサルタン　メドキソミルであり、インスリン抵抗性改善剤が5-｛4-[(6-メトキシ-1-メチル-1H-ベンズイミダゾール-2-イル)メトキシ]ベンジル｝-1,3-チアゾリジン-2,4-ジオン塩酸塩である請求項１乃至４のいずれか一つに記載の予防剤又は治療剤。 The angiotensin II receptor antagonist is olmesartan medoxomil, and the insulin resistance improving agent is 5- {4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy] benzyl} -1,3 The preventive or therapeutic agent according to any one of claims 1 to 4, which is -thiazolidine-2,4-dione hydrochloride.
  12. 　高血圧症又は高血圧症に起因する疾病の予防用若しくは治療用の薬剤を製造するための、アンジオテンシンＩＩ受容体拮抗剤及びインスリン抵抗性改善剤の使用。 Use of an angiotensin II receptor antagonist and an insulin resistance improving agent for the manufacture of a drug for the prevention or treatment of hypertension or a disease caused by hypertension.
  13. 　心不全に起因する死亡率を減少させる薬剤を製造するための、アンジオテンシンＩＩ受容体拮抗剤及びインスリン抵抗性改善剤の使用。 Use of an angiotensin II receptor antagonist and an insulin resistance ameliorating agent for producing a drug that reduces mortality due to heart failure.
  14. 　アンジオテンシンＩＩ受容体拮抗剤とインスリン抵抗性改善剤を有効成分として含有する薬剤を用いることを特徴とする、高血圧症又は高血圧症に起因する疾病の予防又は治療方法。
          A method for preventing or treating hypertension or a disease caused by hypertension, comprising using a drug containing an angiotensin II receptor antagonist and an insulin resistance improving agent as active ingredients.
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CN102351853A (en) * 2011-08-29 2012-02-15 石药集团欧意药业有限公司 Azilsartan medoxomil compound, preparation method and medicinal composition thereof
CN102351853B (en) * 2011-08-29 2014-03-12 石药集团欧意药业有限公司 Azilsartan medoxomil compound, preparation method and medicinal composition thereof
CN109498622A (en) * 2018-12-28 2019-03-22 成都恒瑞制药有限公司 A kind of Losartan Potassium and Rosiglitazone composition and preparation method thereof
CN113209123A (en) * 2021-04-20 2021-08-06 合肥康诺生物制药有限公司 Pharmaceutical composition for treating or preventing heart failure and application thereof

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