WO2007123126A1 - Agent PERMETTANT D'AMÉLIORER la TOLÉRANCE DIMINUÉE À l'exercice dans l'insuffisance cardiaque chronique - Google Patents

Agent PERMETTANT D'AMÉLIORER la TOLÉRANCE DIMINUÉE À l'exercice dans l'insuffisance cardiaque chronique Download PDF

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Publication number
WO2007123126A1
WO2007123126A1 PCT/JP2007/058349 JP2007058349W WO2007123126A1 WO 2007123126 A1 WO2007123126 A1 WO 2007123126A1 JP 2007058349 W JP2007058349 W JP 2007058349W WO 2007123126 A1 WO2007123126 A1 WO 2007123126A1
Authority
WO
WIPO (PCT)
Prior art keywords
heart failure
hemoglobin
chronic heart
allosteric
hydrogen atom
Prior art date
Application number
PCT/JP2007/058349
Other languages
English (en)
Japanese (ja)
Inventor
Kinya Otsu
Tetsuya Watanabe
Original Assignee
Juridical Foundation Osaka Industrial Promotion Organization
Osaka University
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 Juridical Foundation Osaka Industrial Promotion Organization, Osaka University filed Critical Juridical Foundation Osaka Industrial Promotion Organization
Priority to JP2008512121A priority Critical patent/JPWO2007123126A1/ja
Publication of WO2007123126A1 publication Critical patent/WO2007123126A1/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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 improving exercise intolerance in chronic heart failure.
  • Heart failure is a "clinical syndrome" that occurs as a result of the inability to supply blood according to the demand for end organ tissue due to abnormal cardiac function or the imbalance of blood distribution among organs. It is a common pathological condition at the end stage of various organic heart diseases. Such heart failure is characterized by a rapid onset such as acute myocardial infarction over time (acute heart failure) and a gradually developing manifestation of myocardial damage over a long period of time (chronic heart failure). )
  • hemoglobin (Hb) is a tetrameric protein consisting of a globulin and j8 globulin, and its affinity for oxygen (O 2) is based on gas exchange in the lungs and acid in peripheral tissues.
  • Patent Document 1 Japanese Patent No. 3023422
  • Patent Document 2 Published in Japan 2003—529543
  • An object of the present invention is to provide a drug that improves QOL of patients with chronic heart failure, that is, a drug that improves exercise intolerance in chronic heart failure.
  • an object of the present invention is to provide a drug that improves exercise intolerance without affecting cardiac function in patients with chronic heart failure.
  • hemoglobin allosteric regulators markedly improved exercise tolerance decline in chronic heart failure without affecting cardiac function. We have found that this is possible, and have further studied to complete the present invention.
  • the present invention provides:
  • an agent for improving exercise intolerance in chronic heart failure characterized by comprising an allosteric regulator of hemoglobin as an active ingredient
  • CH and R to R are the same or different from each other, and may be a hydrogen atom or a halogen atom.
  • R and R are the same as each other or Differently, the force is a hydrogen atom or a C alkyl group, or R and R are terminal
  • R is a hydrogen atom or a substituted or unsubstituted group.
  • R ′ and R ′ are the same or different from each other, and a chlorine atom or a methyl group
  • An allosteric regulator of hemoglobin is 2- [4 — [(3,5-dimethyl-linocarbonyl) monomethyl] phenoxy] -2-methylpropionic acid or a pharmacologically acceptable salt thereof.
  • the improving agent [1] the improving agent, [6] A method for improving a decrease in exercise tolerance of a patient suffering from a decline in exercise tolerance by administering an allosteric regulator of hemoglobin to a patient with chronic heart failure, and
  • FIG. 1 shows the effect of RSR13 on the motility of chronic heart failure mice.
  • FIG. A shows the structural formula of the administered drug (compound RSR13).
  • Figure B shows the motility (travel distance) when a drug was administered to mice without chronic heart failure, and
  • Figures C and D show the motility (rest time and distance traveled) when the drug was administered to chronic heart failure mice. ).
  • the present invention is an agent for improving exercise tolerance in chronic heart failure, characterized by comprising a hemoglobin allosteric regulator as an active ingredient.
  • hemoglobin allosteric regulator used in the present invention known hemoglobin allosteric regulators can be used.
  • Such an allosteric regulator is represented by the general formula [I] described in Japanese Patent No. 3023422.
  • a compound represented by the above or a pharmacologically acceptable compound thereof is preferred.
  • X is NH and X is CH.
  • a compound represented by the above or a pharmacologically acceptable compound thereof is preferred. Further, in the above compound [la], R, R and R are hydrogen atoms, and R and R are
  • R ′ and R ′ are the same or different from each other, and a chlorine atom or a methyl group
  • a compound represented by the above or a pharmacologically acceptable compound thereof is preferred.
  • Specific examples of the above compound [lb] include, for example, 2- [4 [(3,5 dimethylarlinol group) -methyl] phenoxy] -2-methylpropionic acid (RSR13, generic name: Efapro) xiral), 2— [4— [(3,5 dichloroa-linocarbol) monomethyl] phenoxy] —2-methylpropionic acid (RSR4), 2— [4— [(3 -Methyl) phenoxy] -2-methylpropionic acid [103086], or a pharmacologically acceptable salt thereof (for example, sodium salt).
  • the hemoglobin allosteric regulator used in the present invention has an action of improving the tolerability of movement in chronic heart failure.
  • normal mice were used to examine the effects of drugs on the motility of the mice. That is, 30 minutes after the injection of the drug (for example, RSR13), the exercise test was started for 30 minutes at a speed of 15 mZ on a horizontal treadmill. Thereafter, the gradient was increased by 5 ° every 30 minutes. During the first 30 minutes, drug-free normal mice (control mice: C) traveled the same distance as RSR13-treated normal mice (treated mice: R). I was able to travel long distances (see Figure 1B).
  • the drug for example, RSR13
  • each group received the opposite treatment to that received in the previous session.
  • the test was repeated 4 times. Up to 60 minutes, both the RSR13-treated mice (treated mice: R) and the vehicle-treated mice (control mice: C) had almost the same total rest time and total distance traveled, but from 60 minutes to 90 minutes RSR13-treated mice (R) showed significantly shorter total rest time and significantly longer total mileage than vehicle-treated mice (C) (see FIGS. 1C and D). That is, the mileage for 30 minutes from 60 minutes to 90 minutes was 344.7 ⁇ 19.7 m in the RSR treatment group and 267.6 ⁇ 33.9 m in the control group.
  • an allosteric regulator of hemoglobin which is an active ingredient of the present invention, is used as an agent for reducing exercise tolerance in chronic heart failure
  • oral administration or parenteral administration is possible according to a method known per se.
  • a pharmaceutically acceptable carrier usually administered orally as solid preparations such as tablets, capsules, granules, powders, or injections, suppositories, or sublingual tablets intravenously, subcutaneously, intramuscularly, etc. As such, it is administered parenterally.
  • a sustained release preparation such as a sublingual tablet or microcapsule, it may be administered sublingually, subcutaneously or intramuscularly.
  • hemoglobin allosteric regulator for example, compound [I]
  • the dose of hemoglobin allosteric regulator varies depending on the subject, route of administration, degree of exercise intolerance in heart failure, etc., and is not limited, but is administered to adult heart failure patients.
  • the dose is usually about 0.01 to 1 OOmgZkg, and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms.
  • the content of the active ingredient in the improving agent of the present invention is about 0.01 to about LOO% by weight of the whole improving agent.
  • the pharmaceutically acceptable carrier various organic or inorganic carrier materials commonly used as pharmaceutical materials are used, and excipients, disintegrants, binders, lubricants, binders in solid preparations; It is formulated as a solvent, solubilizer, suspending agent, tonicity agent, buffer, and soothing agent in liquid preparations. If necessary, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used.
  • Examples of the excipient include lactose, starch, crystalline cellulose, sucrose, glucose, mannitol, calcium carbonate, calcium phosphate and the like.
  • Examples of the disintegrant include sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate and the like.
  • Examples of the binder include hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, polybutylpyrrolidone, ethylcellulose, glucose, sucrose and the like.
  • Examples of the lubricant include magnesium stearate, talc, macrogol, and hydrogenated vegetable oil.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, and macrogote. Sesame oil, sesame oil, corn oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-manntol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. It is done.
  • Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, salt benzethonium and glyceryl monostearate. It is done.
  • Examples of the isotonic agent include sodium chloride sodium, glycerin, D-mannol and the like.
  • the buffer include buffers such as phosphates, acetates, carbonates, citrates, and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite and ascorbic acid.
  • mice All experiments were performed on 8-9 week old male wild type mice.
  • the mouse was anesthetized with sodium pentobarbital (50 mgZkg, administered intraperitoneally), and the distal side of the left coronary artery (LCA) was ligated to the lmm distal side with silk thread (type 7-0) for myocardial infarction treatment.
  • LCA left coronary artery
  • silk thread type 7-0
  • mice that were anesthetized with 2.5% avertin (8 1 Zg) were subjected to ultrasonography (SONOS-5500, equipped with a 15 MHz linear transducer, Echocardiography was performed using Philips Medical Systems (see Proc Natl Acad Sci USA, Dish, 15883 (2003)).
  • the heart was imaged with a two-dimensional parasternal short-axis image and a mid-ventricle M-mode heart echo was recorded at the papillary muscle level.
  • This test determined physiological parameters of in vivo heart size and function in sham-operated mice (control mice) and myocardial infarction (Ml) mice. The results are shown in Table 1 below.
  • LVIDd Diastolic left ventricular diameter
  • LVIDs systolic left ventricular diameter
  • FS left ventricular diameter shortening rate
  • IVSd diastolic ventricular septal thickness
  • LVPWd diastolic left ventricular posterior wall thickness
  • bpm 1 Heart rate per minute.
  • the 1 ⁇ 13 scale administration group (1 ⁇ : black bar) has a significantly longer mileage than the control group (C: white bar) where no drug is administered ( * P ⁇ 0. 05). That is, the mileage for 30-60 minutes is 268.9 ⁇ 38.7 m, RSR1 (R) “C384.9 ⁇ 18 Om in the control group (C), and the mileage for 60-90 minutes is In the control group (C), it was 146.7 ⁇ 39.2 m; in the RSR group (R), it was 370.0 ⁇ 21.9 m.
  • the agent for reducing exercise tolerance in chronic heart failure according to the present invention can improve QOL of patients with chronic heart failure, and thus can be used in the pharmaceutical, medical and welfare industries.

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

Abstract

L'invention concerne un agent permettant d'améliorer la tolérance diminuée à l'exercice dans l'insuffisance cardiaque chronique, qui comprend un modificateur de l'hémoglobine allostérique (par exemple, l'efaproxiral) comme ingrédient actif. L'agent a moins d'influence sur la fonction cardiaque, peut améliorer la tolérance diminuée à l'exercice dans l'insuffisance cardiaque chronique et peut améliorer le QOL chez un patient souffrant d'une insuffisance cardiaque chronique.
PCT/JP2007/058349 2006-04-17 2007-04-17 Agent PERMETTANT D'AMÉLIORER la TOLÉRANCE DIMINUÉE À l'exercice dans l'insuffisance cardiaque chronique WO2007123126A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2008512121A JPWO2007123126A1 (ja) 2006-04-17 2007-04-17 慢性心不全における運動耐容能低下の改善剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006-113903 2006-04-17
JP2006113903 2006-04-17

Publications (1)

Publication Number Publication Date
WO2007123126A1 true WO2007123126A1 (fr) 2007-11-01

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016517892A (ja) * 2013-05-03 2016-06-20 ワシントン・ユニバーシティＷａｓｈｉｎｇｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ 血液代用組成物及びその使用方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04506812A (ja) * 1990-02-12 1992-11-26 ヴァージニア　コモンウェルス　ユニヴァーシティ ヘモグロビンのアロステリック修飾剤
JPH07508973A (ja) * 1991-05-20 1995-10-05 ヴァージニア　コモンウェルス　ユニヴァーシティ 血中酸素親和性の抑制のためのヘモグロビンのアロステリック修飾剤の使用
JP2003529543A (ja) * 1999-08-24 2003-10-07 ヴァージニア コモンウェルス ユニバーシティ 置換キラル・アロステリック・ヘモグロビン調節剤

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507430A (ja) * 1999-08-25 2003-02-25 ジーエムピー カンパニーズ，インコーポレーテッド 哺乳動物中で酸素運搬を向上する薬剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04506812A (ja) * 1990-02-12 1992-11-26 ヴァージニア　コモンウェルス　ユニヴァーシティ ヘモグロビンのアロステリック修飾剤
JPH07508973A (ja) * 1991-05-20 1995-10-05 ヴァージニア　コモンウェルス　ユニヴァーシティ 血中酸素親和性の抑制のためのヘモグロビンのアロステリック修飾剤の使用
JP2003529543A (ja) * 1999-08-24 2003-10-07 ヴァージニア コモンウェルス ユニバーシティ 置換キラル・アロステリック・ヘモグロビン調節剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AJISAKA R. ET AL.: "Undoji Sekkekkyu Nai Yuki Rinsan Dotai no Igi, Mansei Shinfuzen Rei ni okeru Kento", SHINZO SPECIAL EDITION, vol. 24, no. 2, 1992, pages 46 - 47, XP003018596 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016517892A (ja) * 2013-05-03 2016-06-20 ワシントン・ユニバーシティＷａｓｈｉｎｇｔｏｎ Ｕｎｉｖｅｒｓｉｔｙ 血液代用組成物及びその使用方法

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