WO2007123126A1

WO2007123126A1 - Agent for improving decreased exercise tolerance in chronic heart failure

Info

Publication number: WO2007123126A1
Application number: PCT/JP2007/058349
Authority: WO
Inventors: Kinya Otsu; Tetsuya Watanabe
Original assignee: Juridical Foundation Osaka Industrial Promotion Organization; Osaka University
Priority date: 2006-04-17
Filing date: 2007-04-17
Publication date: 2007-11-01
Also published as: JPWO2007123126A1

Abstract

Disclosed is an agent for improving the decreased exercise tolerance in chronic heart failure, which comprises an allosteric hemoglobin modifier (e.g., efaproxiral) as an active ingredient. The agent has less influence on the cardiac function, can improve the decreased exercise tolerance in chronic heart failure, and can improve the QOL in a patient suffering from chronic heart failure.

Description

Specification

Reducing agent for exercise tolerance in chronic heart failure

Technical field

[0001] The present invention relates to an agent for improving exercise intolerance in chronic heart failure.

Background art

[0002] 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). )

There are three goals for the treatment of chronic heart failure: (1) relief of symptoms, (2) prolongation of life, and (3) improvement of quality of life (QOL). The most common sign of chronic heart failure is a decline in exercise tolerance, which worsens quality of life. Traditionally, it has been centered on the quantitative approach of “how long to live”, but in recent years we have focused on the qualitative way of thinking “how to live well mentally and physically”, that is, the concept of QOL. The development of treatment has become important. In addition, it has become clear that cardiotonic agents that improve cardiac function have a poor prognosis, and the development of new drugs is desired.

[0003] On the other hand, 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.

2

It has an extremely important meaning for elementary transportation.

In addition, the allosteric structure of hemoglobin is involved in the affinity for oxygen, and various compounds that adjust this allosteric structure are known. For example, in Patent Documents 1 and 2, 2- [4-((3,5-dimethylaminolinocarbol) methyl] phenoxy] -2-methylpropionic acid (RSR13) is used as a compound useful for alosteric adjustment. Various phenoxypropionic acid derivatives are described, including. In these documents, such a phenoxypropionic acid derivative is used as an anti-ischemic agent or X-ray irradiation in cancer treatment. It is described as being useful as an anti-lipolytic agent in the production of blood substitutes and in blood storage as a shoot effect enhancer.

Patent Document 1: Japanese Patent No. 3023422

Patent Document 2: Published in Japan 2003—529543

Disclosure of the invention

Problems to be solved by the invention

[0004] 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. In particular, 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.

Means for solving the problem

[0005] As a result of various studies conducted by the present inventors to solve the above-mentioned problems, 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.

That is, the present invention provides:

[1] an agent for improving exercise intolerance in chronic heart failure, characterized by comprising an allosteric regulator of hemoglobin as an active ingredient,

[2] Allosteric regulator power of hemoglobin General formula

[Chemical 1]

(In the above formula, when each of X and Ο is CH, ΝΗ or Ο and X is CH Ζ

2 When 2 is ΝΗ or 、, when X is ΝΗ When 2 is CH or 、 When X is Ζ Ζ is ΝΗ

2

Or CH and R to R are the same or different from each other, and may be a hydrogen atom or a halogen atom.

2 1 5

Or a substituted or unsubstituted C alkyl group, and 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

1-2 6 7 are bonded to form a C alkylene group, and R is a hydrogen atom or a substituted or unsubstituted group.

4-6 8

This is a C alkyl group. )

1-3

Or the pharmacologically acceptable salt thereof, or the improver according to [1] above,

[0007] [3] Allosteric regulator power of hemoglobin General formula

[Chemical 2]

(In the above formula, the symbols have the same meaning as described above.)

[4] Hemoglobin allosteric regulator general formula

[Chemical 3]

(In the above formula, R ′ and R ′ are the same or different from each other, and a chlorine atom or a methyl group

twenty four

It is. )

[0009] [5] An allosteric regulator of hemoglobin is 2- [4 — [(3,5-dimethyl-linocarbonyl) monomethyl] phenoxy] -2-methylpropionic acid or a pharmacologically acceptable salt thereof. [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

[7] Use of hemoglobin allosteric regulator to produce an agent to improve exercise tolerance in chronic heart failure,

About.

Brief Description of Drawings

[0010] 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. ).

Explanation of symbols

[0011] C: Control group

R: Drug administration group

BEST MODE FOR CARRYING OUT THE INVENTION

[0012] 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.

[0013] (Active ingredient)

As the 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.

[Chemical 4]

(However, the symbols have the same meaning as above.)

A compound represented by the above or a pharmacologically acceptable compound thereof is preferred. [0014] Among the above compounds [I], X is NH and X is CH.

2

[Chemical 5]

(However, the symbols have the same meaning as above.)

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

1 3 5 6 7 General formula for methyl group [lb]:

[Chemical 6]

twenty four

It is. )

A compound represented by the above or a pharmacologically acceptable compound thereof is preferred.

[0016] 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).

Of these, 2- [4 [(3,5-dimethyl-linocarbol) -methyl] phenoxy] -2-methylpropionic acid (RSR13, generic name: Efaproxiral), or its pharmacologically acceptable (E.g. sodium salt). [0017] The above-mentioned compound [I] can be synthesized by the method described in Japanese Patent No. 3023422 and Japanese Patent Publication No. 2003-529543.

[0018] (Confirmation of improvement of exercise tolerance decline in chronic heart failure)

It was confirmed by the following method that the hemoglobin allosteric regulator used in the present invention has an action of improving the tolerability of movement in chronic heart failure. First, 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).

[0019] Next, the effect of a drug (eg, RSR13) on the motility of chronic heart failure model mice (myocardial infarction mice) was examined. Four weeks after ligation of the left coronary artery, myocardial infarction mice with chronic heart failure who showed ventricular dilation, cardiac dysfunction and pulmonary edema were injected with RSR1 3 or vehicle (n = 4Z group) . The RSR13 treatment group had no effect on heart rate, blood pressure, and echocardiographic parameters of heart size or function. Thereafter, an exercise test was performed in the same manner as that performed on RSR-treated mice except that the running speed was changed to 12.5 mZ. Three days later, the exercise test was performed again. However, 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.

From these results, it was clarified that the administration of hemoglobin allosteric regulator can improve and improve exercise tolerance in chronic heart failure.

[0020] (How to use) When 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, either oral administration or parenteral administration is possible according to a method known per se. Usually mixed with a pharmaceutically acceptable carrier and 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. In addition, as a sustained release preparation such as a sublingual tablet or microcapsule, it may be administered sublingually, subcutaneously or intramuscularly.

The dose of hemoglobin allosteric regulator, for example, compound [I], 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. In this case, 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.

[0021] As 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.

[0022] 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.

[0023] 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. Examples of 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.

Example

[0024] (1) Creation of chronic heart failure mice (myocardial infarction 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. (See Biochem Biophys Res Commun, 333, 562 (2005); Nature, 434, 652 (2005); Proc Natl Acad Sci USA, 100, 15883 (2003)). As a control, sham surgery was performed on wild-type mice.

[0025] (2) Cardiac examination by echo

After 4 weeks of sham surgery or myocardial infarction (Ml) treatment, 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.

[table 1]

The symbols in the table are as follows.

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.

[0027] From the above results, it can be seen that a state of chronic heart failure occurs 4 weeks after myocardial infarction surgery.

[0028] (3) Drug evaluation

(1) A 12-week-old male wild mouse was first trained 3 times daily for 3 minutes over 3 days. The treadmill speed was 15 mZ min. After this training, mice were exercised 5 times a week for 30 minutes at a speed of 15 mZ for 3 weeks. 2- [4— [(3,5-Dimethyldilinocarbol) -methyl] phenoxy] -2-methylsodium propionate (synthetic compound) synthesized by the method described in J Med Chem, 34, 752 (1991) Compound RSR13) was dissolved in dimethyl sulfoxide (DMSO) and Tris / Hepes buffer (pH 7.4) and injected intravenously at a dose of 150 mgZkg. An exercise test was conducted 30 minutes after the injection. This exercise test was performed at a speed of 15mZ, first on a horizontal surface for 30 minutes, The mice were run for 30 minutes on a 5 ° slope and finally for 30 minutes on a 10 ° slope.

Under these conditions, each running distance (m) from 0 to 30 minutes, 30 minutes force to 60 minutes, and 60 minutes to 90 minutes was calculated, and the average standard error (n = 4) was calculated. The result is shown in Fig. 1B.

[0029] From Fig. 1B, 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.

(2) Four weeks after the ligation of the left coronary artery, RSR13 or vehicle was injected into mice (n = 4 each), 30 minutes after injection, and 30 minutes after the injection at a rate of 12.5 mZ on the horizontal plane. We started a minute exercise test and then increased the gradient by 5 ° every 30 minutes. Three days later, the exercise test was performed again, but each group received the opposite treatment from that used in the previous session. The test was repeated 4 times. The total of the break time and distance traveled for each 30 minutes was calculated, and the average person average error was calculated. The results are as shown in Fig. 1 C and D.

[0030] From Fig. 1 C and D, the 1 ^ 1 ^ 13 administration group: black bar) is the control group (C:

Compared to white bars), there was no difference in break time and distance traveled up to 60 minutes, but there was also a significant difference in break time and distance traveled up to 90 minutes. I know (* P <0. 05). In other words, the 30-minute mileage from 60 to 90 minutes was 344.7 ± 19.7 m in the RSR-treated group and 267.6 ± 33.9 m in the control group.

[0031] (3) The above results indicate that RSR13 has an action to improve exercise tolerance decline in chronic heart failure.

Industrial applicability

[0032] 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.

Claims

A therapeutic agent for reducing exercise tolerance in chronic heart failure, characterized by comprising an allosteric regulator of hemoglobin as an active ingredient. Hemoglobin allosteric modifier general formula

[Chemical 1]

(In the above formula, when each of X and Ο is CH, ΝΗ or Ο and X is CH Ζ

2

2 1 5

Or a substituted or unsubstituted C alkyl group, and R and R are the same as each other or

1-3 6 7

Differently, the force is a hydrogen atom or a C alkyl group, or R and R are terminal

4-6 8

This is a C alkyl group. )

1-3

The improving agent according to claim 1, which is a compound represented by the formula (1) or a pharmacologically acceptable salt thereof.

Hemoglobin allosteric modifier general formula

[Chemical 2]

(Wherein R to R are the same or different from each other, a hydrogen atom, a halogen atom or

1 5

A substituted or unsubstituted C alkyl group, wherein R and R are the same or different from each other;

1-3 6 7

Either a hydrogen atom or a C alkyl group, or R and R bonded at the end To form an alkylene group of C and R is a hydrogen atom or substituted or unsubstituted

4-6 8

C is an alkyl group. )

13

Hemoglobin allosteric modifier general formula

[Chemical 3]

twenty four

It is. )

[5] Allosteric regulator power of hemoglobin 2— [4— [(3, 5-dimethyla-linocarbo

-L) Monomethyl] phenoxy] -2-methylpropionic acid or a pharmacologically acceptable salt thereof.

[6] A method of ameliorating exercise intolerance of a patient with chronic heart failure who has suffered a decline in exercise tolerance by administering an allosteric regulator of hemoglobin.

[7] Use of an allosteric regulator of hemoglobin for the manufacture of an agent to improve exercise tolerance in chronic heart failure.