WO2002072099A1

WO2002072099A1 - Therapeutic and/or preventive agent for diabetic ischemic heart disease

Info

Publication number: WO2002072099A1
Application number: PCT/JP2002/002286
Authority: WO
Inventors: Yoshimi Kitada
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2001-03-14
Filing date: 2002-03-12
Publication date: 2002-09-19

Abstract

A therapeutic and/or preventive agent for diabetic ischemic heart disease, characterized in that it comprises, as an active component, a phenylpyridazinone derivative represented by the following general formula (1) or (2): (1) (2) wherein R1 and R2 represent, for example, a hydrogen atom or the like, R3 represents, for example, a hydrogen atom or the like, and R4 represents, for example, a heterocycle, or a salt of the phenylpyridazinone derivative, or a hydrate or solvate thereof.

Description

Description Treatment of ischemic heart disease due to diabetes and Z or prophylactic agent Technical field

The present invention is based on the finding that the present invention relates to a specific phenylpyridazinone derivative or a salt thereof, or a hydrate or a solvate thereof. A therapeutic and / or prophylactic agent for ischemic heart disease due to diabetes, comprising as an active ingredient. Background art

In recent years, the number of diabetic patients has been increasing,

3 to 46% develop heart disease. Diabetes is considered to be a unique heart disease due to its ability to show cardiac muscular contraction and diastolic dysfunction without being caused by coronary artery disease, hypertension or known heart disease. It has been called ischemic heart disease (J. Am. Col. Cardiol. 1992; 19: 1165-1166, Heart View 1999, May). In ischemic heart disease due to diabetes, sarcoplasmic reticulum (hereinafter sometimes referred to as “SRJ”) may be referred to as calcium ion (hereinafter referred to as “Ca”). ) The uptake ability is remarkably reduced, and this is said to be the cause of diastolic dysfunction and contractile dysfunction (Am. J. Physiol. 1997; 272: H148-H 158 _s Diabetes Res. Clin. Practice 1996; 30 supp 1: S113-sl22). However, no drugs or treatments have been established to improve these disorders.

On the other hand, JP-A-62-16282 and JP-A-61-289032 each disclose a specific phenylene pyridazinone derivative. It is described that these compounds are useful as cardiotonic agents, but these compounds are As far as the inventor knows, it has an effect on improving the uptake of Ca into the sarcoplasmic reticulum in ischemic heart disease due to diabetes. Not yet reported. In addition, as far as the present inventors know, the use of these compounds in combination with the ampicillin dipin, which is known as a Ca antagonist, is not limited. No reports have been reported so far.

The present invention aims to provide a drug that is effective in treating ischemic heart disease due to diabetes, and more particularly, to a specific phenylpyrene known as a cardiotonic. It is intended to provide a therapeutic and / or preventive drug for ischemic heart disease due to diabetes, which comprises a lidazinone derivative as an active ingredient. Disclosure of the invention

The inventors of the present invention have focused on a decrease in the ability of SR to take up Ca, which is said to be a cause of ischemic heart disease due to diabetes, and will improve the SR function. We thought that the development of a therapeutic drug would improve the therapeutic results of these diseases, and we conducted intensive research to solve the above problems. as a result,

A specific phenylene pyridazinone derivative, which was previously only known as a cardiotonic agent, was used in the treatment of SR Ca in ischemic heart disease due to diabetes. It has been found that it has a function to improve the filling capacity. In addition, simultaneous administration of Ca antagonists, separately or over time, has been shown to reduce the cardioplegic effects often found in clinical use of Ca antagonists. Find out what can be reduced and thus provide new pharmacotherapy for the treatment and prevention or prevention of ischemic heart disease from diabetes This led to the completion of the present invention.

The gist of the present invention is as follows.

1. The following general formula (1) or (.2)

H

H

(In the above general formulas (1) and (2), R ₂ and R ₂ are each independently a hydrogen atom, a hydrogen atom, a hydrogen atom, an alkyl group, an amino group, R, carboxyl, nitro, cyano, trifluoromethyl, acylamino, or alkoxy, R ₃ represents a hydrogen atom, an acyl group or an alkynole group, and R ₄ is a 5- or 6-membered ring which may have a substituent on the ring. Represents a complex ring of.)

A derivative or a salt thereof, or a hydrate or a solvate thereof, represented by the formula: A therapeutic and / or prophylactic agent for ischemic heart disease due to diabetes, characterized by:

2. The effective component is represented by the following general formula (3) (

(In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, and on the ring, an alkynole group, a cyano group, or a hydroxyl group , Alkoxy group, amino group, alkynole amino group, genolex amino group, ash ole amino group, carboxy linole group, annel oxy group It may have at least one substituent selected from the group consisting of a carbohydrate group and a carbamoinole group.)

Or a salt or a hydrate or a solvate thereof of the phenylpyridazinone derivative represented by The therapeutic and / or prophylactic agent as described above, which is a feature.

3. In the general formula (1) or (2) described above, R t, R _2, and R ₃ are each independently a hydrogen atom methyl group. Is a ethynole group, and is a compound represented by 2—pyridyl group 4—pyridyl group, 2_pyrimidyl group or 4-quinolinole group. The therapeutic and / or Z or prophylactic agent according to any of the above, which is characterized in that:

4. The method according to any one of the above, wherein the effective component is a compound which is an A 4 -pyridinole group in the general formula (3) described above. Treatment and Z or prophylactic.

5. The therapeutic and / or Z- or prophylactic agent according to any of the above, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

6. Treatment and / or prevention of ischemic heart disease due to diabetes The therapeutic and / or prophylactic agent according to any of the above, which is based on an action of improving the ability of sarcoplasmic reticulum to take up calcium ion.

フ The pheninolepyridazinone derivative represented by the general formula (1) or (2) or a salt thereof or a hydrate thereof. And an agent for ameliorating cardiac function deterioration due to ischemic heart disease due to diabetes, comprising a solvate thereof as an active ingredient.

8. The ameliorating agent according to the above, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

9. The improving agent as described above, wherein the improvement of cardiac function is based on the effect of improving the uptake of sarcoplasmic reticulum by canoledium ion.

10. The phenylpyridazinone derivative represented by the general formula (1) or (2) or a salt thereof, or a hydrate thereof. An agent for improving sarcoplasmic reticulum uptake of calcium ion, characterized in that the solvate is an active ingredient.

1 1. The pheninolepyridazinone derivative represented by the general formula (1) or (2), a salt thereof, or a hydrate thereof is also included. A cardiostatic-reducing agent, characterized in that the solvate is an active ingredient.

12. The active ingredient may be a phenylpyridazinone derivative represented by the general formula (3), a salt thereof, or a hydrate thereof. Is a solvate thereof, wherein the agent for reducing cardiac depression is described above.

13. In the general formula (1) or (2), R ₂ and R ₃ each independently represent a hydrogen atom methyl group or a hydrogen atom methyl group. Is represented by an ethyl group, and represents a 2-pyridyl group 41-pyridyl group, a 2-pyrimidyl group or a 4-quinolinol group The cardioplegic inhibitor as described above, which is a compound represented by a group:

14. The method according to any one of the above, wherein the active ingredient is a compound which is an A 4 -pyridyl group in the general formula (3) described above. Cardiostatic effect reducing agent.

15 5. The method as described above, wherein the cardiac depressant effect is caused by a Ca antagonist having an effect of improving sarcoplasmic reticulum uptake of calcium ion. The cardioplegic reducing agent according to any one of the above.

16. The cardiac suppressive action-reducing agent according to the above, wherein the Ca antagonist is amlodipine.

17. The agent of any one of the above, which is characterized by being administered to a patient with ischemic heart disease due to diabetes.

18. The agent for reducing cardiosuppressive action as described above, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes. (A) As an active ingredient, a feninole pyridazinone derivative represented by the above general formula (1) or (2) or a salt or salt thereof. A medicament containing such a hydrate or a solvate thereof, and (b) as an active ingredient, uptake of calcium ion of sarcoplasmic reticulum A method for treating ischemic heart disease due to diabetes and a method for preventing or treating ischemic heart disease using a medicine containing a Ca antagonist having an activity-improving action, and Use of the medicament (b) at the same time, separately or over time, for the treatment and / or the prophylactic Z or ischemic heart disease of diabetes due to diabetes.

20. The therapeutic or Z or prophylactic agent as described above, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

21. The therapeutic and / or prophylactic agent as described above, wherein the Ca antagonist is amlodipine. 2 2. The treatment and / or prevention of ischemic heart disease due to diabetes is based on the ability of sarcoplasmic reticulum to improve the uptake of canoledium ion. The treatment and / or prophylactic agent according to any of the above.

23. (a) As an active ingredient, a phenylpyridazinone derivative represented by the above general formula (1) or (2) or a salt or a salt thereof. A medicament containing a hydrate or a solvate thereof, and (b) an effect of improving, as an active ingredient, the ability of sarcoplasmic reticulum to take up calcium ion. A drug for treating and preventing or preventing ischemic heart disease due to diabetes using a drug containing a Ca antagonist having the formula (a) and the drug (b) ) Is used simultaneously or separately or with time, to improve cardiac function for ischemic heart disease due to diabetes. 24. (a) As the active ingredient, a phenylpyridazinone derivative represented by the above general formula (1) or (2) or a salt or salt thereof A medicament containing these hydrates or solvates thereof, and (b) uptake of calcimion in the sarcoplasmic reticulum as an active ingredient. A therapeutic and / or prophylactic agent for ischemic heart disease due to diabetes using a drug containing a Ca antagonist having an effect of improving the performance of said drug (a) And improving the uptake ability of sarcoplasmic reticulum, characterized in that the medicament (b) is used simultaneously or separately or over time. Agent. Best form to carry out the invention

Hereinafter, the present invention will be described in further detail.

Examples of the active ingredient of the drug of the present invention include compounds represented by the above general formula (1) or (2). That is, in the above general formulas (1) and (2), Ri and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, and an amino group. , A carboxyl group, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group;

R ₃ represents a hydrogen atom, an acyl group or an alkyl group, and is a 5-membered or 6-membered ring which may have a substituent on the ring. Compounds that represent complex rings are mentioned. Among these, preferred compounds include the compound represented by the general formula (3), the general formula (1) or (2) In the formula, R ₂ and R ₃ are each independently represented by a hydrogen atom, a methylene group or an ethyl group, and R ₄ is 2 — pyriyl. Examples include a lig compound represented by a jyl group, a 41-pyridinole group, a 2-pyrimidinole group or a 4-quinolinole group. In the present invention, a particularly preferred compound is a compound represented by the general formula ('3), wherein the compound is an A 4 -pyridyl group. That is, 6_ [41- (4-pyridinoreamino) fuenoinore] _4,5—dinodidro_3 (2H) pyridazinon (below) Below, it may also be referred to as “MC 1—15 54.”) or its salts, or their hydrates or their solvates. Are listed.

Incidentally, these compounds are described in Japanese Patent Publication Nos. 58-81015, 58-81016, 58-14,076 and 60-12. No. 7, No. 7, 1157-1161 and published in the Journal of Medicinal Chemistry, 1987, vol. 30, No. 7, 1157-1161, and are described in these gazettes. It can be manufactured according to the method described above or according to the method.

At this point, these gazettes refer to the use as a cardiotonic agent for the fuirylpyridazinone derivative which is an effective component in the present invention. However, there is no description about the effect of improving the ability to take up Ca into SR of ischemic heart disease due to diabetes as shown in the examples described later. It has not been . In addition, as will be shown in the examples described later, the ability to incorporate Ca into this SR has been improved. Pimonbendan is a drug that enhances the sensitivity to 'Ca' as well as the virubilidazinone derivative, which is an effective component of the present invention. Because of its unrecognized potential, all compounds known to be cardiotonic are adaptable to ischemic heart disease due to diabetes. Can be said to be unlimited.

The salt of the drug of the present invention is not particularly limited as long as it is a salt acceptable as a drug. Salts with mineral acids such as hydrochloric acid, phosphoric acid, and lactic acid, vinegar And salts with organic acids such as acids.

In addition, in the present invention, the compound can be used as a hydrate or a solvate of the above-listed compounds, and can be used as a solvate. In some cases, there are no particular restrictions on solvents that are acceptable as drugs.

In the following, the present invention will be described using MCI-154 as an example. However, even when another compound is used as an active ingredient, the present invention will be described. With reference to the following, we can produce and use it appropriately.

In applying the active ingredient of the drug of the present invention to clinical practice, MCI-154 or a salt acceptable as the drug may be used without any modification. Is used as a pharmaceutical composition by blending a carrier acceptable as a drug. When used orally, it is preferable to administer 0.01 to 100 mg Zkg of the above compound one to three times a day, in the case of intravenous injection. It is preferable to administer 0.01 to 200 mg of the above compound 2 to 5 times a day or to continuously inject these doses by infusion. Also, in the case of rectal administration, it is preferable to administer 0.01 to 100 mg / kg of the above compound once to three times a day. The above doses may be used as appropriate, depending on age, condition, gender, symptom, etc.

In the case of Formulations, MCI-154 or as a drug Carriers for pharmaceutical preparations in which the acceptable salt thereof is usually used, that is, carriers that can be used as a composition containing excipients and other additives are solid. It can be liquid or liquid.

When a solid carrier is used, it can take the form of tablets, powders, granules, hard gelatin capsules, suppositories, lozenges, etc. . At this time, the amount of the solid carrier is arbitrary.

However, it is preferably about 1 mg to about 1 g.

Liquid carriers include syrups, emulsions, soft gelatin capsules, and sterile injectable solutions such as those containing a sample or aqueous or non-aqueous suspensions. Can be made into a liquid

The treatment and / or prophylactic agent of the present invention may be associated with SR C in diabetic ischemic heart disease, as shown in the Examples below. a To improve uptake ability and improve cardiac function in diabetic ischemic heart disease, it is recommended to improve ischemic heart disease due to diabetic, especially preferred for diabetic ischemic heart disease. It is used as a drug to treat and / or prevent cardiomyopathy. In the present invention, the improvement of sarcoplasmic reticulum ion uptake ability refers to the sarcoplasmic reticulum ion uptake ability. Is to normalize

According to the present invention, the above drug and a drug containing a Ca antagonist are simultaneously and separately administered for the treatment and / or prevention of ischemic heart disease due to diabetes. Or a drug which can be used over time, that is, a drug containing the compound represented by the above general formula (1) or (2) as an active ingredient; a.The physician who contains the antagonist should be treated with one drug based on the dosage determined by increasing or decreasing the patient's age, condition, sex, symptoms, etc., as appropriate. It can be administered as a pharmaceutical composition, or can be administered as separate pharmaceutical compositions. It is also possible. When administered as separate pharmaceutical compositions, they can be administered in the same or different dosage forms at the same time, or they can be administered simultaneously. Each with the same or different dosage forms, with different times on the same day or depending on the patient's age, illness, gender, symptoms, etc. Can be given at regular intervals for days, weeks or months

In the present invention, a compound of the above formula (1) or (2) is used as an active ingredient in the treatment or Z or prophylaxis of ischemic heart disease due to diabetes. The simultaneous use of a drug and a drug containing a Ca antagonist at the same time, separately or over time, can synergistically improve the SR function. In addition to the improvement in sR function, the problem of cardiac suppression often observed in the clinical use of Ca antagonists is also due to the above general formula (1) or ( It can be avoided by using a drug containing the compound described in 2) as an active ingredient. That is, the compound represented by the general formula (1) or (2) can be used as an agent for reducing the cardiac inhibitory effect of a Ca antagonist.

The antagonists used in the present invention are those that have the effect of improving the sarcoplasmic reticulum incorporation into the sarcoplasmic reticulum. There are no special restrictions. Specifically, there are those which have the function of improving the capability of retrieving the force as shown in the embodiment described later, and in particular, the one having the The use of pins is preferred. These Ca antagonists may be those that are commercially available as reagents, or if they are already marketed as pharmaceuticals, they may be used. You can use them. Example

Hereinafter, the present invention will be described specifically with reference to examples. The present invention is not limited to this. The MCI-154 used in the following examples was manufactured according to the method described in Example 1 described in Japanese Patent Application Publication No. 60-126282. I used what I did. Example 1

The diabetic cardiomyopathy model is an eight-week-old male male rat with striped zotocin (purchased from Sigma, hereinafter referred to as “STZ j”). This was caused by the administration of 40 mg Z kg in the tail vein (Am. J. Physiol. 1983; 244: E528-E535 J. Mo 1. Cell. 27: 169-179, Eur. Pharmacol. 1999; 374: 221-227). Rats seven months after the administration of STZ at which blood glucose levels are plotted. After anesthesia anesthesia, the heart was excised.The blood glucose level was 12.2 to 11.9 mg / d1 in a control rat, and 48 to 80 mg in a rat receiving STZ. 5 57.5 7 mg / d1.

As a method of cardiac function evaluation, a skid fiber sample that measures the ability of Ca to be taken into SR was used. The SR functions reflect both expansion and contraction functions. Methods are described in Endo and li no J. Mus C 1 e Res. Cell. Moti 1.1980; 1: 89-100) and Kitada et al. (J. Pharmacol. Ep. Ther., 1987; 243: 633-638). That is, a fiber having a left ventricular papillary muscle strength of 2.5 to 3.0 mm and a thickness of 0.25 mm is prepared under a microscope. Next, the fin fin was soaked in 50 μg m1 saponin for 30 minutes to prepare a ski fin.

Intake experiment for C a, C a — 丄 og [C a] mo 1) Incubate for 2 minutes using C a with a concentration of 6.7. As a result, Ca was imported into SR. MCI — 1 5 4 and AMLOJIPINE (purchased from Sigma) have been incubating for two minutes, and the following caffeine They coexisted until the end of the experiment in the satellite. Next, the Ca release from the SR force was completely suppressed by the 5 mM pro-fin, and all the Ca stored in the SR was released by the 5 OmM caffeine. The area of tension (AUC) that was drawn at the time of release was analyzed using NIH image ver. 1.61 (NIH). This area was taken as C a capture capability. All experiments were performed at room temperature.

In diabetic cardiomyopathy, the uptake of Ca by SR was markedly reduced. With STZ administration, it decreased to about 61% of the control (Table 1).

MCI one 1 5 4 normal action in reported in heart muscle shows of a Rere concentration ^{1 0 - 7 M (J. Pharmacol} Exp Ther 1987; 243:... 633-638) in diabetic . 2 C a Installing write only to have your sexual heart muscle disease to low under the SR 0 1% promotion, 1 0 - 8 0 in ^S M

It showed a remarkable promoting effect of 6% (Table 2). MCI one 1 5 4 and pin mode VENDOR emissions (purchase Ri by grayed Ma Co., Ltd.) of C a sensitive sensitizing strong agent the same rather than the 1 0 - ⁶ M及beauty 1 0 - ⁵ you have to act on the M (Table 3). Also, 1 0 one ⁴ M cAMP also such promote etc. does O coercive the Ca Installing write only of SR power, one was (Table 4). On the other hand, the Ca antagonist of SR, which has not been reported previously, has been reported on amlopine, a Ca antagonist used clinically as an antihypertensive. The presence of an embedding effect was a factor (Table 5). This effect was observed in a concentration-dependent manner from 10 to ¹⁸ M force to 10 to ⁵ M. C a拮1 for anti-work is certified Me et al are such have concentrations ^{0 - 7 M (Am J. Cardiol} 1994; 73:.. 2A-9A). In Te Contact Rere, 4 5 Ri preparative 2% C a Rush.

In addition, the concentration of 10 — ⁷ M, which is a concentration with a weak C uptake capacity, And CI one 1 5 4, Ho O to do etc. action is not name concentration (1 0 - ⁸ M) A-time Russia has to C a Installing of write minnow remarkable to by Ri SR in combination with di pin of An increase in calories was found (about twice as much as the control, Table 6). This has exceeded the level of SR function of the normal muscle

1 Comparison of the incorporation of a into the SR between normal rats and diabetic cardiomyopathy rats

Normal rat Diabetic cardiomyopathy rat

^{AUC (mm 2) 557. 2 344.} 0

AUC (%) 100 61. 7

2 M C I — Capability of capturing C a into SR of 154

Mouth opening MCI-■ 1 5 4

1 (Γ ⁷ Μ 10 " ⁶ Μ

AUC (ram ² ) 280.06 336.31 505.84

AUC (%) 100 120.1 180.6

3 Capability to capture C a into P

Concentration port

10— ⁶ Μ 10 ' ⁵

^{AUC (mm 2) 186. 11 171.} 97 171. 08

AUC (%) 100 92.4 91.9

4 c A M A Capability of C a incorporation into SR

Control 10 " ⁴ M cAMP

+ 50 μg / ral PKA

AUC (ram ² ) 262 264

AUC (%) 100 100.8 Table 5 Capability of Ammodipine to import Ca into SR

Table 6 Capability of incorporation of C a into the SR of the amodipine MCI154

From the above results, it is clear that MCI-154 improves cardiac function by improving SR function, which is reduced in cardiomyopathy due to diabetes mellitus. It is. This effect is recognized in conventional cardiotonic drugs that have an effect of increasing cAMP and in Pimobendan, which enhances Ca sensitivity as well as in MCI-154. These powers have been created. In other words, in the diabetic cardiomyopathy model, MCI-154 was incorporated into SR, which was not recognized as a conventional ca-sensitive potentiator. It can be seen that it has an activity-promoting effect and that it has its effect at a concentration lower than the previously effective pharmacological concentration.

In addition, a Ca antagonist, amlodipine, was also found to promote the incorporation of Ca into SR, indicating that MCI-154 was used in combination with am mouth dipine. Thus, the SR function improving effect, which is remarkable as a synergistic effect, is provided. This improvement is clearly evident in improving cardiac dysfunction in diabetic cardiomyopathy.

Therefore, the combination of MCI-154 with amlodipine may represent a new drug therapy. In addition, the cardioplegia problem that is often seen with the use of Ca antagonists in the clinical setting is also an issue with MCI-1. By using 54 in combination, the amount of Ca antagonist used can be reduced and the power S can be reduced, which also avoids side effects. Industrial applications

According to the present invention, it is possible to provide a new use of a specific phenylpyridazinone derivative which is known to have a cardiotonic effect. More specifically, it is possible to provide a new prophylactic and / or therapeutic agent for ischemic heart disease due to diabetes. This application was filed after claiming the priority of Japanese Patent Application No. 200-1 — 71302 and Japanese Patent Application No. 2001-17303. It is a thing.

Claims

The scope of the claims

Expression

1

\ /)

Ma

ί /,

Two

\)

R ₄ '' (2)

(Above in General Formula (1)及Beauty (2), R _t及beauty R ₂ are independent are each Re its a hydrogen atom, Nono b gain down atom, § Honoré key Honoré group, A Mino, carboxyl, nitro, cyano, trifluoromethyl, acyloamino, or alkoxy groups R ₃ represents a hydrogen atom, an acyl group or an alkyl group, and R ₄ is a 5-membered ring which may have a substituent on the ring and may have a substituent. Represents a 6-membered complex ring.)

Or a salt or a hydrate or a solvate thereof of the phenylpyridazinone derivative represented by A therapeutic and / or preventive drug for ischemic heart disease due to diabetes, which is characterized as being an ingredient.

2. The effective component is represented by the following general formula (3)

(

(In the above formula, A represents a 5-membered or 6-membered complex ring group containing 1 to 3 nitrogen atoms, and on the ring, an alkynole group, a Groups, hydroxyl groups, phenolic groups, amino groups, phenolic amino groups, phenolic amino groups, lacylamino groups, carboxyl groups It may have at least one substitution group selected from the group consisting of a sinole group, an alkoxycarbonyl group and a radical group.)

Or a salt or a hydrate or a solvate thereof of a phenylpyridazinone derivative represented by the formula: The treatment and / or prevention according to claim 1, characterized in that:

3. In the general formula (1) or (2) described in claim 1, R ₂ and R ₃ are independent of each other, and the effective component is hydrogen atom. R ₄ represents a 2-pyridyl group, a 4-pyridyl group, a 2-pyrimidinole group or a 4-quinoline, and is represented by a hydrogen atom, a methyl group or an ethyl group. 3. The therapeutic and Z or prophylactic agent according to claim 1 or 2, characterized in that it is a compound represented by a lilyl group.

4. A claim characterized in that the effective component is a lig compound which is an A-force S 4 —pyridyl group in the general formula (3) according to claim 2. The treatment and / or prophylactic agent according to any one of paragraphs 3 to 3.

5. Diabetes' The ischemic heart disease is diabetic cardiomyopathy. The therapeutic and / or Z or prophylactic agent according to any one of claims 1 to 4, which is characterized in that:

6. A claim characterized in that the treatment and / or prevention of ischemic heart disease due to diabetes is based on the improvement of sarcoplasmic reticulum uptake of calcium ion. Item 1. The therapeutic and Z or preventive drugs described in any of 1 to 5 above.

7. General formula (1) or (2) below

H

R ₄ '' (2)

H

(In the above general formulas (1) and (2), each of R ₂ and R ₂ independently represents a hydrogen atom, a hydrogen atom, a halogen atom, an alkyl group, an amino group, a · the sheet group, two collected by filtration group, and Table shea § cyano group, Application Benefits off Honoré O b methylation group, § Shi Le is a Mi amino group or a Le co key sheet group, R ₃ is a hydrogen atom And R ₄ represents an acyl group or an alkyl group, and R ₄ has a substituent on its ring and is a good 5-membered ring or Represents a 6-membered heterocyclic ring. )

The active ingredient is a phenylene pyridazinone derivative or a salt or hydrate or a solvate thereof represented by the following formula: An agent for improving cardiac function due to ischemic heart disease due to diabetes.

8. The ameliorating agent according to claim 7, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

9. The method according to claim 7 or 8, wherein the improvement in cardiac dysfunction is based on an action of improving sarcoplasmic reticulum uptake of calcium ion. Improver.

10. The following general formula (1) or (2)

H

(In the above general formulas (1) and (2), and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, an amino group, a carboxyl group , Nitro group, cyano group, trino group R ₃ represents a hydrogen atom, an acyl group or an alkyl group; R ₄ represents an ol-methyl group, an acylamino group or an alkoxy group; Represents a 5- or 6-membered heterocyclic ring which may have a substituent on the ring. )

The active ingredient is a phenylpyridazinone derivative or a salt or hydrate or a solvate thereof represented by the following formula: An agent for improving the ability of sarcoplasmic reticulum to take up calcium.

1 1. General formula (1) or (2) below

H

(In the above general formulas (1) and (2), R _t and R ₂ are each independently a hydrogen atom, a halogen atom, an anoalkyl group, an amino group, R ₃ represents a hydrogen atom, a carbon atom, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group; Represents a sil group or an alkyl group, R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring. )

The active ingredient is a phenylpyridazinone derivative represented by the formula or a salt or a hydrate or a solvate of the hydrate or a salt thereof. A cardiac depressant reducing agent characterized by the following.

1 2. The active ingredient is represented by the following general formula (3)

(

(In the above formula, A represents a 5- or 6-membered heterocyclic group containing 1 to 3 nitrogen atoms, and an alkyl group or a cyano group is provided on the ring. , Hydroxyl group, alkoxy group, amino group, alkylamino group, alkylamino group, acylamino group, carboxyl group, aluminum It may have at least one substituent selected from a carbonyl group and a non-functional group.

Or a salt or a hydrate or a solvate thereof of the phenylpyridazinone derivative represented by the formula: The cardioplegic effect-reducing agent according to claim 11, wherein the active ingredient is represented by the general formula (1) or (2) according to claim 11,, R ₂ and R ₃ is each independently represented by a hydrogen atom, a methyl group or an ethyl group, and R ₄ is a 2-pyridyl group, a 4-pyridyl group, and a 2-pyrimidyl group. Jill group or

4. The agent for reducing a cardiac inhibitory effect according to claim 11, wherein the agent is a compound represented by one quinolinol group. 14. The active ingredient is represented by the general formula (3) according to claim 12. 14. The agent according to any one of claims 11 to 13, wherein the agent is a compound which is an A 4 -pyridyl group.

15 5. The method according to claim 1, wherein the cardiac inhibitory effect is attributable to a Ca antagonist having an effect of improving the ability of sarcoplasmic reticulum to take up canoledium ion. 15. The agent for reducing cardiac depression according to any one of items 1 to 14.

16. The cardiac inhibitor according to claim 15, characterized in that it is a Ca antagonist, amylpine.

17. The agent of any one of claims 11 to 16, characterized in that the agent is administered to a patient with ischemic heart disease due to diabetes.

1, 8. The agent for reducing cardiac depression according to claim 17, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

1 9. (a) As the active ingredient, the following general formula (1) or (2)

(In the above general formulas (1) and (2), R _λ and R ₂ are each independently a hydrogen atom, a halogen atom, an anoalkyl group, an amino group, Represents a boxyl group, a nitro group, a cyano group, a triphenylphenol methyl group, an aminoreamino group or a vinyloxy group, and R ₃ is a hydrogen atom , An acyl group or an alkyl group, and R ₄ represents a 5- or 6-membered heterocyclic ring which may have a substituent on the ring. Do.)

A phenylpyridazinone derivative represented by the formula: or a salt thereof, or a hydrate or a solvate thereof, and a medicament containing the same. (B) using as an active ingredient a drug containing a Ca antagonist having an effect of improving the ability of sarcoplasmic reticulum to take up canoledium ion; A therapeutic and / or prophylactic agent for ischemic heart disease, comprising the medicament (a) and the medicament (b)

15 is characterized in that it is used simultaneously, separately or over time. A therapeutic and / or prophylactic agent for ischemic heart disease due to diabetes.

20. The therapeutic and / or Z- or prophylactic agent according to claim 19, wherein the ischemic heart disease due to diabetes is cardiomyopathy due to diabetes.

21. The therapeutic and / or prophylactic agent according to claim 19 or claim 20, wherein the Ca antagonist is amlodipine.

2 2. The treatment and Z or prophylaxis of ischemia from diabetes mellitus due to diabetic heart disease is based on the improvement of sarcoplasmic reticulum uptake of calcium ion. The treatment and / or prophylactic agent described in any one of claims 19 to 21.

23. (a) As the active ingredient, the following general formula (1) or (2)

R ₄ ,, (2)

H (In the above general formulas (1) and (2), and R ₂ are each independently a hydrogen atom, a halogen atom, an alkyl group, an amino group, a canoleboxyl group. group, two collected by filtration group, shea § cyano group, Application Benefits off Honoré O b main switch group, § Shi Le a Mi Roh Motoma other will display the a Le co key sheet group, R ₃ is a hydrogen atom, § Represents a silyl group or an alkyl group, and R ₄ represents a 5-membered or 6-membered heterocyclic ring which may have a substituent on the ring.)

A pharmaceutical comprising a phenylpyridazinone derivative or a salt or hydrate or solvate thereof represented by the formula: (B) using diabetes as an active ingredient and a drug containing a Ca antagonist having an effect of improving the ability of sarcoplasmic reticulum to take up the ability to take up muscle fluid; Treatment and treatment of ischemic heart disease

Z or a prophylactic drug, characterized in that said medicament (a) and said medicinal drug (b) are used simultaneously, separately or over time. An agent for improving cardiac function for ischemic heart disease.

24. (a) As the active ingredient, the following general formula (1) or (2)

R ₄ one (2)

H

(In the above general formulas (1) and (2), R i and R ₂ are each independently a hydrogen atom, a nitrogen atom, an alkynole group, an amino group, A boxinole group, a nitro group, a cyano group, a trifluoromethyl group, an acylamino group or an alkoxy group, and R ₃ is a hydrogen atom, an amino group Represents a sil group or an alkyl group, and R ₄ represents a 5- or 6-membered heterocyclic ring which may have a substituent on the ring.)

And a drug containing the phenylenediridazinone derivative or a salt or hydrate or solvate thereof represented by the formula: And (b) the use of a drug containing a Ca antagonist having an effect of improving sarcoplasmic reticulum uptake of sarcoplasmic reticulum as an active ingredient; The medicament (a) and the medicament (b), which are therapeutic and / or preventive drugs for blood heart disease. A sarcoplasmic reticulum uptake-improving agent characterized in that it is used simultaneously, separately or over time.