WO2009088006A1 - Agent pharmaceutique combiné - Google Patents

Agent pharmaceutique combiné 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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Prior art keywords
angiotensin
insulin resistance
hypertension
receptor antagonist
therapeutic agent
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PCT/JP2009/050065
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English (en)
Japanese (ja)
Inventor
Takahiro Nagayama
Shoichi Kanda
Jun Ohsumi
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Daiichi Sankyo Company, Limited
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Publication of WO2009088006A1 publication Critical patent/WO2009088006A1/fr

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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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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Organic Chemistry (AREA)
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  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
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Abstract

L'invention porte sur un agent pharmaceutique utile en tant qu'agent prophylactique ou thérapeutique pour l'hypertension ou une maladie associée à l'hypertension. De façon spécifique, l'invention porte sur un agent pharmaceutique comprenant un bloqueur du récepteur de l'angiotensine II et un agent améliorant la résistance à l'insuline en tant que principes actifs.
PCT/JP2009/050065 2008-01-10 2009-01-07 Agent pharmaceutique combiné WO2009088006A1 (fr)

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JP2008-003658 2008-01-10

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN102351853A (zh) * 2011-08-29 2012-02-15 石药集团欧意药业有限公司 一种阿齐沙坦酯化合物、制备方法及其药物组合物
CN109498622A (zh) * 2018-12-28 2019-03-22 成都恒瑞制药有限公司 一种氯沙坦钾与罗格列酮组合物及其制备方法
CN113209123A (zh) * 2021-04-20 2021-08-06 合肥康诺生物制药有限公司 治疗或预防心力衰竭的药物组合物及其用途

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JP2003113120A (ja) * 2001-08-03 2003-04-18 Takeda Chem Ind Ltd 徐放性医薬

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CN102351853B (zh) * 2011-08-29 2014-03-12 石药集团欧意药业有限公司 一种阿齐沙坦酯化合物、制备方法及其药物组合物
CN109498622A (zh) * 2018-12-28 2019-03-22 成都恒瑞制药有限公司 一种氯沙坦钾与罗格列酮组合物及其制备方法
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