WO2001013952A1 - Preventifs/remedes contre l'insuffisance cardiaque - Google Patents

Preventifs/remedes contre l'insuffisance cardiaque Download PDF

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Publication number
WO2001013952A1
WO2001013952A1 PCT/JP2000/005676 JP0005676W WO0113952A1 WO 2001013952 A1 WO2001013952 A1 WO 2001013952A1 JP 0005676 W JP0005676 W JP 0005676W WO 0113952 A1 WO0113952 A1 WO 0113952A1
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WO
WIPO (PCT)
Prior art keywords
heart failure
tranilast
heart
cardiac
effect
Prior art date
Application number
PCT/JP2000/005676
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English (en)
Japanese (ja)
Inventor
Akiro Matsumori
Original Assignee
Kissei Pharmaceutical Co., Ltd.
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
Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Publication of WO2001013952A1 publication Critical patent/WO2001013952A1/fr

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Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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

Definitions

  • the present invention relates to an agent for preventing and treating heart failure. More specifically, the present invention relates to a prophylactic / therapeutic agent for heart failure, comprising a compound having a cardiac mast cell activation inhibitory effect as an active ingredient.
  • 2_ (3,4-dimethoxycinnamoyl) aminobenzoic acid (generic name: tranilast, hereinafter referred to as tranilast) or a pharmacologically acceptable salt thereof, which has a cardiac mast cell activation inhibitory effect, or
  • the present invention relates to a prophylactic / therapeutic agent for heart failure, characterized by containing such a pharmacologically acceptable solvate as an active ingredient.
  • Heart failure is defined as end-diastolic pressure (PD) that causes the ventricle to fail to deliver the corresponding cardiac output during exercise, or to cause an increase in pulmonary artery wedge pressure ( Acute heart failure, in which the contraction force due to primary etiology (ischemia, mechanical stress, cardiomyopathy, etc.) is manifested as pump failure as it is, Chronic heart failure is manifested when it is no longer possible to compensate, depending on compensation mechanisms such as cardiac hypertrophy.
  • PD end-diastolic pressure
  • pulmonary artery wedge pressure Acute heart failure, in which the contraction force due to primary etiology (ischemia, mechanical stress, cardiomyopathy, etc.) is manifested as pump failure as it is, Chronic heart failure is manifested when it is no longer possible to compensate, depending on compensation mechanisms such as cardiac hypertrophy.
  • Various factors and diseases can be considered as causes of heart failure, for example, dietary changes, infections, poor use of drugs such as cardiac depressants, arrhythmias, myocardial ischemia, anemia, hyperthyroidism or hypothyroidism, metabolic abnormalities And renal function deterioration.
  • drugs such as cardiac depressants, arrhythmias, myocardial ischemia, anemia, hyperthyroidism or hypothyroidism, metabolic abnormalities And renal function deterioration.
  • cardiac hypertrophy which was considered to be a physiological adaptation to a chronic increase in workload, has limited adaptation.They fall from decompensated cardiac hypertrophy to decompensated cardiac hypertrophy. Stage, large-scale clinical study may be a risk factor for cardiovascular death Tests have revealed this.
  • treatment of heart failure mainly consisted of cardiotonic drugs such as digitalis and diuretics, and then the effectiveness of anti-loading therapy with vasodilators was proposed, and treatment with them was started. Furthermore, the importance of activating the nervous fluid system was elucidated along with elucidation of the pathophysiology of heart failure, and treatment with drugs aimed at protecting the myocardium has been widely performed.
  • Drugs that have been used to treat heart failure include digitalis and other cardiotonic agents, diuretics, vasodilators such as nitrates and calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and Neurohumoral antagonists such as blockers, and the like.
  • ACE angiotensin converting enzyme
  • TNF tumor necrosis factor
  • IL interleukin
  • IL 16 interleukin 16
  • mast cells which are known to produce a variety of inflammatory substances and cytokins such as histamine, serotonin, prostaglandin (PG), interleukin (IL), and interferon (IFN). It is also present in the heart, and it has been reported that mast cells increase in association with laboratory cardiac hypertrophy, and that mast cells increase in the heart of patients with heart failure. The relationship with has not yet been elucidated.
  • Tranilast and its pharmacologically acceptable salts include inhibitory effects on release of chemical mediators in allergic reactions, inhibitory effects on collagen overproduction, and inhibitory effects on postoperative restenosis in percutaneous coronary angioplasty (PTCA). It has been confirmed that it has allergic diseases such as allergic bronchitis, asthma, atopic dermatitis, allergic conjunctivitis, keloids, and hypertrophic properties. It is already widely used as an agent for treating scars. In addition, it is being developed as a restenosis inhibitor after PTCA.
  • tranilast has an effect of suppressing and regressing cardiac hypertrophy and an effect of suppressing heart stiffness in an animal experimental model using spontaneously hypertensive rats (SHR).
  • SHR spontaneously hypertensive rats
  • tranilast suppresses the release of cytokines such as malignant growth factors (TGF) -3) and IL-1 and prostaglandin (PG) E2 from human monocytic macrophages. . (Japan. J. Pharmacol. 60, 85-90, 1992)
  • TGF malignant growth factors
  • PG prostaglandin
  • tranilast exhibits a preventive or therapeutic effect on heart failure.
  • the present invention has simply found a novel compound having various actions, and the therapeutic effect of heart failure is a positive inotropic effect.
  • heart mast cells are involved in heart failure. It does not show or suggest that suppressing mast cell activation can suppress the onset of heart failure.
  • the present inventors have conducted intensive research to develop a safe and effective therapeutic agent for preventing heart failure, which has a different effect from conventional therapeutic agents, has no side effects, and as a result, heart mast cells are involved in heart failure. It is possible to suppress the onset of heart failure by suppressing mast cell activation, suppress mast cell activation, and release chemical mediators such as histamine and serotonin from mast cells.
  • the present inventors have found that tranilast, which has an inhibitory effect, significantly suppresses the onset of heart failure, and found that tranilast and other mast cell activation inhibitors such as tranilast are useful as preventive and therapeutic agents for heart failure. Reached.
  • the present inventor conducted research to elucidate the involvement of cardiac mast cells in heart failure.As a result, in the animal model of viral myocarditis inflammatory heart failure, necrosis and cell infiltration were lower in mast cell-deficient mice than in normal mice. As a result, they found that the survival rate was high, and that mast cells in the heart were involved in heart failure, and that the onset of heart failure could be suppressed by suppressing mast cell activation.
  • the present inventors used mast cell-deficient mice (WBB 6 F 1 -W / Wv) and normal mice (WB B 6 F 1 — + / +) syngeneic with them to produce encephalomyocarditis virus.
  • EMC V induced viral myocarditis heart failure, but in diabetic cell-deficient mice, the degree of necrosis and cell infiltration was significantly lower, the survival rate was significantly higher, and the onset of heart failure was suppressed. Confirmed that.
  • a compound having a mast cell activation inhibitory action such as tranilast or a pharmacologically acceptable salt thereof or a pharmacologically acceptable solvate thereof is contained as an active ingredient, whereby cardiac hypertrophy,
  • a pharmaceutical composition useful as an agent for preventing and treating cardiac dysfunction diseases such as heart failure caused by myocarditis and the like can be produced.
  • a pharmaceutical composition When a pharmaceutical composition is used for actual treatment, it is administered orally or parenterally in various dosage forms.
  • dosage forms include powders, granules, tablets, capsules, and dry syrups.
  • parenteral administration agents such as injections, vaginal suppositories, patches and the like.
  • compositions are prepared according to a conventional method by mixing appropriate excipients, disintegrants, binders, lubricants, and other pharmaceutical additives according to the dosage form according to ordinary pharmaceutical methods. It can be manufactured by doing.
  • powders are prepared by adding appropriate excipients, lubricants, and the like to the active ingredient, if necessary, and thoroughly mixing to obtain a powder.
  • Tablets are prepared by adding appropriate excipients, disintegrants, binders, lubricants and the like, if necessary, to the active ingredient and compressing the tablets according to the usual method. If necessary, the composition is coated as appropriate to obtain film-coated tablets, sugar-coated tablets, enteric-coated tablets and the like.
  • Capsules may be added to the active ingredient, if necessary, by adding appropriate excipients, lubricants, etc., and mixed well, or alternatively, formed into granules or fine granules by a conventional method, and filled in suitable capsules. Into capsules.
  • the dose of the active ingredient is It is determined as appropriate depending on the patient's age, body weight, degree of disease, etc., but when Tranilast or its pharmacologically acceptable salt or their pharmacologically acceptable solvate is used as the active ingredient In general, it is administered orally in an amount of 100 to 100 mg, preferably 300 to 600 mg, per day for an adult.
  • Tranilast or its pharmacologically acceptable salt or their pharmacologically acceptable solvate is used as the active ingredient
  • Tranilast or its pharmacologically acceptable salt or their pharmacologically acceptable solvate is used as the active ingredient
  • Tranilast or its pharmacologically acceptable salt or their pharmacologically acceptable solvate is used as the active ingredient
  • Tranilast or its pharmacologically acceptable salt or their pharmacologically acceptable solvate is used as the active ingredient
  • it is administered orally in an amount of 100 to 100 mg, preferably 300 to 600 mg, per day for an adult.
  • WBB 6 F 1— W / WV (hereinafter referred to as “deficient mouse”) and WBB 6 F 1— + Z + (hereinafter referred to as “normal mouse”) of normal mice of the same strain were used.
  • EMCV EMCV
  • Tranilast improves cardiac function
  • cardiac function was evaluated by echocardiography based on the difference in inner diameter between diastole and systole (internal shortening rate,% Fractional Shortening), and the effect of improving cardiac function was confirmed as compared to before administration.
  • the results were as follows.
  • Various preparations are made according to the prescription. The type and formulation of the dosage form are not limited to those listed as examples of preparation.
  • Tranilast and 900 g of lactose are mixed well to make 1000 g of a powder containing 10 Omg of Tranilast in 1 g .
  • Prescription example 2
  • tranilast 100 g of tranilast, 50 g of lactose, 40 g of 6% HPC lactose, 6 g of potato starch and 4 g of talc stearate are mixed well and tableted, and tablets containing 10 Omg of tranilast in 1 tablet, 1000 tablets Is manufactured.
  • Prescription example 4 100 g of tranilast, 50 g of lactose, 40 g of 6% HPC lactose, 6 g of potato starch and 4 g of talc stearate are mixed well and tableted, and tablets containing 10 Omg of tranilast in 1 tablet, 1000 tablets Is manufactured.
  • Tranilast 100 g of Tranilast, 90 g of lactose, 6 g of potato starch and 4 g of calcium stearate are mixed well and filled into hard capsules to produce 1000 capsules of capsenole containing 10 Omg of tranilast in one capsule.
  • the compound having a cardiac mast cell activation inhibitory effect is useful as a prophylactic / therapeutic agent for heart failure.
  • tranilast or a pharmacologically acceptable salt thereof which has an excellent cardiac mast cell activation inhibitory effect, is useful.
  • a pharmacologically acceptable solvate of the above as an active ingredient, an excellent agent for preventing and treating heart failure can be provided.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des préventifs/remèdes sûrs et efficaces contre l'insuffisance cardiaque lesquels ont un effet d'inhibition de l'activation des mastocytes du coeur et contiennent en tant que principe actif, par exemple, de l'acide 2-(3,4-diméthoxycinnamoyl)aminobenzoïque, un sel ou des solvates de celui-ci acceptables sur le plan pharmacologique.
PCT/JP2000/005676 1999-08-25 2000-08-24 Preventifs/remedes contre l'insuffisance cardiaque WO2001013952A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/237707 1999-08-25
JP23770799A JP2001064202A (ja) 1999-08-25 1999-08-25 心不全予防治療剤

Publications (1)

Publication Number Publication Date
WO2001013952A1 true WO2001013952A1 (fr) 2001-03-01

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PCT/JP2000/005676 WO2001013952A1 (fr) 1999-08-25 2000-08-24 Preventifs/remedes contre l'insuffisance cardiaque

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JP (1) JP2001064202A (fr)
WO (1) WO2001013952A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010147184A1 (fr) 2009-06-17 2010-12-23 国立大学法人熊本大学 Agent prophylactique et/ou thérapeutique pour dysménorrhée

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007503397A (ja) * 2003-08-22 2007-02-22 シエーリング アクチエンゲゼルシャフト ケモカインを阻害するピペラジン誘導体、及び、この誘導体の心筋炎治療のための使用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07277966A (ja) * 1994-04-08 1995-10-24 Kissei Pharmaceut Co Ltd 心肥大の予防および治療剤
WO1997020805A1 (fr) * 1995-12-06 1997-06-12 Venantius Limited Composes dimeres de l'indane a activite de relaxation des muscles lisses et/ou de stabilisation des mastocytes et/ou anti-inflammatoire
JPH09208482A (ja) * 1996-01-30 1997-08-12 Itouen:Kk 気道収縮抑制剤およびそれを含む食品
JPH1087493A (ja) * 1996-09-18 1998-04-07 Shionogi & Co Ltd セフェム系化合物を含有するキマーゼ阻害剤
JPH10101666A (ja) * 1996-10-02 1998-04-21 Shionogi & Co Ltd 新規ベンゾオキサシクロトリデシン化合物およびそれを含有する医薬組成物
WO1998043672A1 (fr) * 1997-03-31 1998-10-08 Kanebo, Limited Inhibiteur de melaninisation, preparation pour soins de la peau et produit pour bain
WO1999013874A1 (fr) * 1997-09-19 1999-03-25 Auburn University Traitement/prophylaxie de l'insuffisance cardiaque au moyen de l'inhibition de la degranulation des mastocytes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07277966A (ja) * 1994-04-08 1995-10-24 Kissei Pharmaceut Co Ltd 心肥大の予防および治療剤
WO1997020805A1 (fr) * 1995-12-06 1997-06-12 Venantius Limited Composes dimeres de l'indane a activite de relaxation des muscles lisses et/ou de stabilisation des mastocytes et/ou anti-inflammatoire
JPH09208482A (ja) * 1996-01-30 1997-08-12 Itouen:Kk 気道収縮抑制剤およびそれを含む食品
JPH1087493A (ja) * 1996-09-18 1998-04-07 Shionogi & Co Ltd セフェム系化合物を含有するキマーゼ阻害剤
JPH10101666A (ja) * 1996-10-02 1998-04-21 Shionogi & Co Ltd 新規ベンゾオキサシクロトリデシン化合物およびそれを含有する医薬組成物
WO1998043672A1 (fr) * 1997-03-31 1998-10-08 Kanebo, Limited Inhibiteur de melaninisation, preparation pour soins de la peau et produit pour bain
WO1999013874A1 (fr) * 1997-09-19 1999-03-25 Auburn University Traitement/prophylaxie de l'insuffisance cardiaque au moyen de l'inhibition de la degranulation des mastocytes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010147184A1 (fr) 2009-06-17 2010-12-23 国立大学法人熊本大学 Agent prophylactique et/ou thérapeutique pour dysménorrhée
US9592213B2 (en) 2009-06-17 2017-03-14 National University Corporation Kumamoto University Prophylactic and/or therapeutic agent for dysmenorrhea

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JP2001064202A (ja) 2001-03-13

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