JP2743141B2 - Inhalant for treatment and prevention of heart failure - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an inhalant for treating and preventing heart failure.

[0002]

[Prior art and its problems] General formula

[0003]

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[Wherein R ¹ , R ² and R ³ each represent a lower alkyl group. A represents an unsaturated chain hydrocarbon residue having 2 to 6 carbon atoms. The dihydropyridine derivative represented by the formula (1) and a method for producing the same are described in JP-B-1-29187.
It is also known to be useful as a drug having a platelet aggregation inhibitory action and a phosphodiesterase inhibitory action.

[0005] On the other hand, as one of the treatments for heart failure, preload alleviation therapy for dilating venous blood vessels and suppressing blood inflow to the right heart system has been performed. Preload reduction therapy is a method of reducing the inflow of blood into the left ventricle, reducing left ventricular end-diastolic pressure and pulmonary capillary pressure, and improving pulmonary congestion and dyspnea in heart failure.

[0006] Calcium antagonists are drugs that strongly act on blood vessels in the arterial system and have an effect on cardiac function. Therefore, when administered, they reduce blood pressure and reduce cardiac contractility by reducing preload and postload. Reduced cardiac output can occur. Therefore, at present, calcium antagonists have not been used for the treatment and prevention of heart failure. Therefore, in the treatment and prevention of heart failure, it is desired to use a calcium antagonist without causing side effects such as deterioration of cardiac function.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted various studies, and when the dihydropyridine derivative represented by the general formula (1) or a salt thereof is inhaled into the body,
It has been found that it reduces left ventricular end-diastolic pressure and pulmonary capillary pressure without significantly reducing body blood pressure and cardiac function, and is effective in treating and preventing heart failure. The present invention has been completed based on such findings.

That is, the present invention relates to an inhalant for treating and / or preventing heart failure, comprising a dihydropyridine derivative represented by the above general formula (1) or a salt thereof as an active ingredient.

In the present specification, examples of heart failure include acute heart failure, chronic heart failure, congestive heart failure and the like. Acute heart failure includes acute left heart failure and acute right heart failure.Acute left heart failure is caused by, for example, heart failure due to acute myocardial ischemia such as myocardial infarction, infective endocarditis, cardiac tamponase, myocarditis, cardiomyopathy , Valvular heart disease, congenital heart disease, and the like, and diseases that cause acute right heart failure include, for example, right ventricular myocardial infarction, cerebral embolism, pulmonary infarction, acute tricuspid regurgitation, and the like. Examples of chronic heart failure include chronic left ventricular failure and chronic right ventricular failure, and those in which both are present.

In the present specification, examples of the lower alkyl group include methyl, ethyl, propyl, isopropyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, tert-butyl, pentyl, and hexyl groups.

Examples of the unsaturated chain hydrocarbon residue having 2 to 6 carbon atoms include vinylene, 1-propenylene,
-Methyl-1-propenylene, 2-methyl-1-propenylene, 2-propenylene, 2-butenylene, 1-butenylene, 3-butenylene, 2-pentenylene, 1-pentenylene, 3-pentenylene, 4-pentenylene, 1,
3-butadienylene, 1,3-pentadienylene, 2-
Pentene-4-inylene, 2-hexenylene, 1-hexenylene, 5-hexenylene, 3-hexenylene, 4-
Hexenylene, 3,3-dimethyl-1-propenylene,
2-ethyl-1-propenylene, ethinylene, 2-propynylene, 1-propynylene, 1,1-dimethyl-2-
Propynylene, 3,3-dimethyl-2-propynylene,
2-butynylene, 3-butynylene, 1-butynylene, 2
-Pentynylene, 1-pentynylene, 3-pentynylene, 4-pentynylene, 2-hexynylene, 1-hexynylene, 3-hexynylene, 4-hexynylene, 5-hexynylene, 1,3-hexadienylene, 1,4-hexadienylene, 1,3 Carbon number 2 having 1 to 3 double bonds and / or triple bonds such as 1,5-hexatrienylene group
And up to 6 straight-chain or branched unsaturated hydrocarbon residues.

Among the dihydropyridine derivatives represented by the general formula (1), compounds having a basic group can form salts with pharmacologically acceptable acids, and such salts are also used as the active ingredient of the drug of the present invention. Can be done. Specific examples of the acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, and benzoic acid. The dihydropyridine derivative of the present invention naturally includes an optical isomer.

The inhalant of the present invention is produced according to a conventional method. That is, an inhalant is produced by powdering or liquidifying the above-mentioned active ingredient compound, mixing it into a propellant for inhalation and / or a carrier, and filling an appropriate inhalation container. When the above-mentioned active ingredient compound is a powder, a usual mechanical powder inhaler can be used, and when the compound is a liquid, an inhaler such as a nebulizer can be used. Here, conventionally known propellants can be widely used, and Freon-11, Freon-12, Freon-21, Freon-22, Freon-113 and Freon-113 can be used.
114, Freon-123, Freon-142c, Freon-
134a, Freon-227, Freon-C318, 1,
Examples include fluorocarbons such as 1,1,2-tetrafluoroethane, hydrocarbons such as propane, isobutane and n-butane, ethers such as diethyl ether, and compressed gases such as nitrogen gas and carbon dioxide gas.

The inhalant of the present invention may further contain, if necessary, conventionally used surfactants, oils, seasonings, cyclodextrins or derivatives thereof. Here, as the surfactant, for example, oleic acid,
Lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate,
Glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridinium chloride, sorbitan trioleate (trade name: Span 8)
5), sorbitan monooleate (trade name: span 8)
0), sorbitan monola weight (trade name span 2)
0), polyoxyethylene hydrogenated castor oil (trade name: HCO
-60), polyoxyethylene (20) sorbitan monolaurate (trade name: Tween 20), polyoxyethylene (20) sorbitan monooleate (trade name: Tween 80), lecithin derived from natural resources (trade name: Epicron), oleyl Polyoxyethylene (2) ether (Bridge 92), stearyl polyoxyethylene (2) ether (Bridge 72), lauryl polyoxyethylene (4) ether (Bridge 30), oleyl polyoxyethylene (2 ) Ethers (trade name Genapol 0-020), block copolymers of oxyethylene and oxypropylene (trade name Synperonic), and the like. Examples of the oil include corn oil, olive oil, cottonseed oil, sunflower oil and the like.

In liquefying the active ingredient compound of the present invention, for example, the active ingredient compound may be dissolved in a liquid carrier. Examples of the liquid carrier include water, salt water, an organic solvent and the like, and among these, water is preferable. Upon dissolution, a surfactant such as polyethylene glycol having a molecular weight of 200 to 5000, polyoxyethylene (20) sorbitan monooleate, or the like, sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, or the like can be appropriately added. .

The amount of the active ingredient compound to be administered is not particularly limited and may be appropriately selected from a wide range. However, in order to achieve the desired effect, the amount of the active ingredient compound should be 0.1 mg / kg / day.
0001 to 1 mg, preferably 0.001 to 0.1 mg
It is good to do.

[0017]

The following are formulation examples and pharmacological test results.

Formulation Example 1 (Preparation of Liquid Formulation) A liquid formulation is prepared according to the following formulation.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 1 g Polyethylene glycol Molecular weight: 4000 (Japanese Pharmacopoeia) 0.9 g Sodium chloride (Japanese Pharmacopoeia) 0.9 g Polyoxyethylene sorbitan monooleate (Japanese Pharmacopoeia) 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben (Japanese Pharmacopoeia) 0.18 g Propyl-paraben (Japanese Pharmacopoeia) 0.02 g Appropriate amount of distilled water for injection Dissolve the above-mentioned parabens, sodium metabisulfite and sodium chloride in about half the above-mentioned distilled water at 80 ° C while stirring. The resulting solution was cooled to 40 ° C and methyl
3-phenyl-2-propenyl 1,4-dihydro-
2,6-Dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate and polyoxyethylene sorbitan monooleate are dissolved in the solution.
Next, distilled water for injection was added to the solution to give a final volume (10
0 ml) and sterilized by sterile filtration using a suitable filter paper.

Formulation Example 2 (Preparation of Liquid Formulation) A liquid formulation is prepared in the same manner as in Formulation Example 1, using the following various components.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.1 g Polyoxyethylene sorbitan monooleate ( 20 g concentrated glycerin 2.5 g methyl-paraben (Japanese Pharmacopoeia) 0.18 g propyl-paraben (Japanese Pharmacopoeia) 0.02 g Sterile purified water Appropriate amount Formulation Example 3 (Preparation of liquid formulation) Using the components, a liquid preparation is prepared in the same manner as in Preparation Example 1.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.001 g Polyoxyethylene sorbitan monooleate ( Japanese Pharmacopoeia product) 0.3 g Concentrated glycerin (Japanese Pharmacopoeia product) 2.5 g Methyl-paraben (Japanese Pharmacopoeia product) 0.18 g Propyl-paraben (Japanese Pharmacopoeia product) 0.02 g Sterilized purified water Appropriate amount Formulation Example 4 (Preparation of Liquid Preparation) A liquid preparation is prepared in the same manner as in Preparation Example 1 using the following various components.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.003 g Polyethylene glycol Molecular weight: 400 (Japan Pharmaceutical product) 10 g Benzalkonium chloride (Japanese Pharmacopoeia product) 0.001 g Sterile purified water Appropriate amount Formulation Example 5 (Preparation of liquid preparation) A liquid preparation is prepared in the same manner as Preparation Example 1 using the following various components.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.5 g Polyethylene glycol Molecular weight: 400 (Japan Pharmaceutical product) 30 g Benzalkonium chloride (Japanese Pharmacopoeia product) 0.001 g Sterile purified water Appropriate amount Formulation example 6 (Preparation of aerosol) Various components are blended according to the following formulation, and an aerosol is prepared according to a conventional method.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 1.5 g Freon-11 25 g Freon-12 100 g Freon-114 25 g Sorbitan trioleate 0.5 g Formulation Example 7 (Preparation of aerosol) Various components are blended according to the following formulation, and an aerosol is prepared according to a conventional method.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.15 g Freon-11 30 g Freon-12 70 g soy lecithin 0.02 g Formulation Example 8 (Preparation of Aerosol) Various components are blended according to the following formulation, and an aerosol is prepared according to a conventional method.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 0.15 g Freon-134a 60 g Freon-114 40 g Soybean lecithin 0.02 g Formulation Example 9 (Preparation of powder) Each component is made into a fine powder according to the following formulation, and stirred to form a uniform mixture to prepare a powder.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 10 g Lactose (Japanese Pharmacopoeia) 80 g Starch (Japanese Pharmacopoeia product) 30 g talc (Japanese Pharmacopoeia product) 5 g Magnesium stearate (Japanese Pharmacopoeia product) 1 g Formulation Example 10 (Preparation of powder) Each component is made into a fine powder by the following formulation to form a uniform mixture. To prepare a powder.

Methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylate 10 g Lactose (Japanese Pharmacopoeia) 100 g Pharmacology Test 1 Four mongrel dogs were anesthetized and thoracotomy opened, the left coronary artery was completely occluded, and a pump dysfunction dog was created after acute myocardial infarction. The left atrium was cannulated to monitor left atrial pressure, which was considered left ventricular end diastolic pressure. In addition, an arterial pressure monitor and blood sampling were performed from the femoral artery line. As a test compound, methyl 3-phenyl-2-propenyl 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl) pyridine-3,5-dicarboxylate was used. After dissolving 1 mg of this test compound in 3 ml of 60% dimethylformamide, the solution was dissolved in physiological saline 7
ml was added to prepare a 0.1 mg / ml inhalant. An ultrasonic nebulizer was used as a nebulizer. After the blood circulation condition of the heart failure dog was stabilized, the above-prepared inhalant was inhaled so that the injection amount of the test compound became 0.1 mg per minute.

After complete occlusion of the left circumcision, the left atrial pressure increased from 8.5 ± 0.7 mmHg before occlusion to 24.8 ± 2.
It increased to 5 mmHg. The left atrial pressure began to decrease 5 minutes after inhalation of the test compound, and 15.3 ± 0.9 mm after 15 minutes.
Hg and the effect lasted 60 minutes. During this time,
Body pressure did not change and arterial oxygen tension did not worsen.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kei Ohno 3-6-12-606 Kamishinda, Toyonaka City, Osaka (72) Inventor Satoshi Nakamura 63, Katsura Chiyoharacho, Nishikyo-ku, Kyoto, Kyoto

Claims (2)

(57) [Claims] 1. A compound of the general formula [Wherein R ¹ , R ² and R ³ each represent a lower alkyl group. A represents an unsaturated chain hydrocarbon residue having 2 to 6 carbon atoms. ] An inhalant for treating or preventing heart failure, comprising a dihydropyridine derivative represented by the formula (1) or a salt thereof as an active ingredient. 2. The method according to claim 1, wherein the dihydropyridine derivative is methyl 3-
Phenyl-2-propenyl 1,4-dihydro-2,6
-Dimethyl-4- (3-nitrophenyl) pyridine-
The inhalant according to claim 1, which is 3,5-dicarboxylate.