JPS63218622A - Remedy and prophylactic for ischemic heart diseases - Google Patents

Abstract

PURPOSE:To obtain a remedy or prophylactic for ischemic heart diseases which contains + or --4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2h)-phtha lazinone or its salt as an active ingredient. CONSTITUTION:The objective remedy or prophylactic is obtained by using the compound of the formula or its salt as an active ingredient and customary carriers for medicament preparation and making pharmaceutical preparations in a usual manner. The compound can be made into injection solution, suppository, external preparation, instillation solution and other parenteral preparations and powder, capsules, syrup and other oral preparations. The composition is preferably served in the form suitable for enteric absorption. The dose is 0.01-200mg/adult/day and given in portions. The compound of the formula inhibits leukocytes from infiltrating into the ischemic parts in cardiac muscles to suppress the necrosis of the ischemic cardiac muscles.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic and preventive agent for ischemic heart disease.

[Conventional technology]

With the Westernization of lifestyles, ischemic heart diseases such as angina pectoris and myocardial infarction have increased in Japan, and have become one of the leading causes of death. It is not uncommon for the disease to develop especially in people in their prime working age, around the age of 40.

Various compounds are used in countries around the world to treat and prevent these diseases, and are still under development.

[Problems to be solved by the invention]

Various compounds are already commercially available and in actual use as therapeutic and preventive agents for ischemic heart disease, but due to the nature of the disease, complete treatment is difficult, and there is a constant need for new therapeutic agents for ischemic heart disease. There is.

[Means for solving problems]

In view of these circumstances, the present inventors conducted various studies on new therapeutic agents for ischemic heart disease, and found that 4-(4-chlorobenzyl)-2-(hexahydro- 1-methyl-1H-azepin-4-yl”) −
It has been discovered that 1(2H)-phthalazinone or a pharmacologically acceptable salt thereof exhibits the effect of suppressing leukocyte infiltration into ischemic myocardial focus and thereby suppressing ischemic myocardial lysis. Therefore, the present compound ( The present invention was completed by confirming that I) is effective as a therapeutic/preventive agent for ischemic heart disease.

1 The compound represented by the above structural formula is called Azelastine, and its hydrochloride is already commercially available as an anti-allergy agent, especially as a treatment for asthma and nasal allergies, and is disclosed in Japanese Patent Publication No. 31154-1983. The compound is also specifically disclosed in the patent publication.

In the present invention, as a result of intensive studies on this azelastine, it was unexpectedly discovered that this compound (I) is also effective as a therapeutic agent for ischemic heart disease. Allergic diseases and ischemic heart diseases are not particularly related from the viewpoint of drug efficacy, and it is surprising that this compound is effective in treating ischemic heart diseases such as myocardial infarction.

In the present invention, pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, such as acetate,
Examples include organic acid salts such as maleate, tartrate, methanesulfonate, benzenesulfonate, and toluenesulfonate, or salts with amino acids such as arginine, aspartic acid, and glutamic acid.

Ischemic heart disease in the present invention typically includes myocardial infarction and angina pectoris as a precursor thereof, but also includes related diseases (Kawasaki disease, myocarditis, etc.). It shall be.

The hydrochloride of formula (I) (hereinafter referred to as azelastine hydrochloride), which is a representative compound in the present invention, can be used, for example, in Japanese Patent Publication No. 55-31
It can be produced by a method such as Example 10 in Publication No. 154.

Its physicochemical properties are as follows.

Molecular formula: Cz2Hz4CINJ・HCI Molecular weight: 4
18.37 I Physicochemical properties: White crystalline powder, odorless, bitter taste, slightly soluble in chloroform, dichloromethane or glacial acetic acid;
Slightly soluble in methanol, slightly soluble in water or absolute ethanol, almost insoluble in acetone, ether, ethyl acetate, or hahexane.

Melting point: about 225°C (decomposition) [Effect] Next, the effect of inhibiting melting of infarcted myocardium and toxicity of the compound of the present invention in animal experiments will be described.

As a result of investigating experimental myocardial infarction in dogs, the present inventor found that infiltrating neutrophils, which are observed after 9 hours of ischemia, are largely involved in the melting of structural proteins in the infarcted area, and that their preference is Infiltration of neutrophils is accompanied by depletion of ATP production due to collapse of glomerular function observed 1 hour after ischemia, vacuolization of the sarcoplasmic reticulum and increase in Ca''+, and subsequent arachidonic acid glue poxygenase metabolite (LxG). , ), especially 12-hydroxyeicosatetraenoic acid (l 2-hydroxyeicosatetraenoic acid)
I learned that an increase in aenoicacid...HE T E) is involved. This experimental example demonstrated that qualitative changes in the infarcted myocardium under permanent ischemia occur similarly when coronary blood flow is resumed after 3 hours of ischemia, and that the administration of the present compound under these conditions showed that this myocardial melting was strongly and significantly suppressed.

Method After an adult mongrel dog weighing 10 kg was given intravenous anesthesia by Labonard, the chest was opened under artificial respiration, and the left coronary artery was circumcised and ligated with two rubber cords under the auricular appendage under electrocardiogram (EKG) monitoring. After confirming infarct creation by ST elevation, thoracotomy is performed. After 3 hours, the rubber cord was released, and the heart was removed in layers after 21 hours (short-term) and 4 weeks (long-term).

Azelastine hydrochloride was dissolved in physiological saline to a concentration of 1 mg/kg body weight and intravenously injected 3 times immediately before thoracotomy, immediately after crown ligation, and 30 minutes later. Furthermore, the same amount was injected intraperitoneally just before the ligature was opened (3 hours later).

Physiological saline 1- was similarly administered to the control group.

The isolated heart was examined as follows.

For short-term cases, three consecutive myocardial pieces with a length of 5 cm were created on the left ventricular endometrial surface from the infarct center (posterior papilla apex: IM) to the non-infarcted area (NI), and each piece was treated with creatine phosphate. acid kinase (CPK), miniroba-oxidase (M
PO...neutrophil-specific enzyme) and 12-HETE using the Kidd method (Yatron Kidd) and Bradley (8r), respectively.
adley) method and reversed-phase high-pressure liquid chromatography method. Based on these, the degree of myocardial damage, the degree of neutrophil infiltration, and the amount of 12-HETE produced can be evaluated, respectively. Furthermore, myocardial pieces were examined histologically using hemotoxylin and eosin staining (H, B, staining).

On the other hand, for long-term cases, after formalin fixation, 5 equal short-axis horizontal sections were prepared between the base and apex of the ventricle, and the scar area was measured by Azan-Mallory staining, and the ratio of the total cross-sectional area to the total cross-sectional area was determined. was calculated to evaluate the degree of scratch formation.

Results The results are shown in Table 1.

Table 1 shows the myocardial NI and CP of each part of the IM in each group in the short-term case.
The average value or maximum value of K, MPo, and 12-HETE amount is shown.

Table 1 Case of zero major bleeding (1/9) is an exception 21) 0.70, 2)
In Table 60.4, the AZ group represents the group administered with azelastine hydrochloride, which is a compound of the present invention.

NI indicates non-infarcted area, IM indicates posterior papilla The tip of the muscle is shown.

n and d indicate that it is below the measurement limit.

As is clear from Table 1, the degree of injury in IM was clearly lower in the AZ group, and the range was narrower. Except for one case of major bleeding (reperfusion bleeding), the degree of neutrophil infiltration and 12-HETE were low, and histological findings were minor.

In addition, in long-term cases, the average scar area was 17.93 ± 2.11% in 7 patients in the control group, but 8% in 7 patients in the AZ group.
．． 3±2.8%, clearly there was a lot of remaining myocardium and the wall thickness was large, indicating that the infarcted myocardium had been repaired.

From the above experimental examples, it is clear that azelastine hydrochloride is effective as a therapeutic and preventive agent for myocardial infarction.

Next, the acute toxicity (LDso) of azelastine hydrochloride is as shown in Table 2.

Table 2 Acute toxicity LD. (mg/kg) When administering this compound as a therapeutic/preventive agent for ischemic heart disease, it may be administered parenterally as an injection, suppository, external preparation, or drip, or as a powder or granule. It may also be administered orally in the form of capsules, syrups, etc.

The dosage varies considerably depending on the severity of symptoms, age, oral or parenteral administration, etc., and is not particularly limited, but is usually about 0.01 to 200 mg per day for adults, divided into several doses per day.

When formulating the drug, it is produced by a conventional method using a conventional pharmaceutical carrier.

The compounds can be prepared for administration using any conventional method of formulation. Therefore, the present invention also includes a pharmaceutical composition containing at least one compound of the present invention suitable as a human medicine. Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients.

Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract.

When preparing injections, add pH adjusters, buffers, suspending agents, solubilizers, solubilizers, stabilizers, tonicity agents, preservatives, etc. to the main drug as necessary. subcutaneously by law;
As an intramuscular or intravenous injection.

Suspending agents include, for example, methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbicun monolaurate, etc., and solubilizing agents include propylene glycol, Polyoxyethylene hydrogenated castor oil, polysorbate 80,
Nicotinic acid amide, polyoxyethylene sorbicun monolaurate, tuna ko/pehimashi oil fatty acid ethylesteroneglucose, etc.; stabilizers include sodium sulfite, sodium metasulfite, ether, etc.; and preservatives include, Examples include methyl paraoxybenzoate, etinopesorbic acid paraoxybenzoate, phenol, cresol, and chlorocresol.

When preparing oral solid preparations, after adding excipients to the herbal medicine and further adding binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. as necessary, tablets or coated tablets are prepared using conventional methods. , granules, powders, capsules, etc.

Examples of excipients include lactose, cornstarch, white sugar,
Glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., binders include, for example, ethyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinyl pyrrolidone. Disintegrants include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, etc. Lubricants include magnesium stearate, talc, polyethylene, etc. Glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as colorants.
As the flavoring agent, cocoa powder, peppermint, aromatic acid, peppermint oil, dragonflies, cinnamon daikon, etc. are used. These tablets,
It goes without saying that the granules may be coated with sugar coating, gelatin coating, or other coatings as appropriate.

Claims (1)

[Claims] ±-4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)- represented by the following formula (I) A therapeutic/preventive agent for ischemic heart disease containing phthalazinone or a pharmacologically acceptable salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)