WO1996031238A1

WO1996031238A1 - Agent for circulatory organs

Info

Publication number: WO1996031238A1
Application number: PCT/JP1996/000775
Authority: WO
Inventors: Isamu Yamaguchi; Nobuya Matsuoka
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1995-04-03
Filing date: 1996-03-26
Publication date: 1996-10-10
Also published as: AU5015496A

Abstract

An agent for circulatory organs which contains as the active ingredient a psychotropic drug comprising a dopamine (D1) receptor antagonist or an NMDA receptor antagonist. The agent is useful as a remedy and preventive for stress-induced cardiomyopathy, myocarditis, cardiac failure, irregular pulse, ischemic cardiac diseases, valvular diseases, cardiac hypertrophy or sudden death caused thereby.

Description

明

Cardiovascular agent

Technical field

Currently, it is known that social and psychological stress is involved in various cardiovascular diseases, and sudden cardiac death is becoming a serious social problem.

Background art

One of the dopamine (D 1) receptor antagonists used in the present invention, SCH23390 (R — (+) — 7-chloro-8-hydroxy-3-methyl-1-phenyl-1,2,3,4, 5—Tetrahydro-1H—3-benzazepine is a selective antagonist of the dopamine (D 1) receptor and is known as a psychotropic drug [Journal of Pharmacology and Pharmaceuticals. 'Therapeutics (The Journal of Pnarraacology and Experimental Therapeutics), Vol. 266, No. 2, p. 726 (1993)].

The NMDA (N-ethyl-D-Aspartic Acid) receptor is one of excitatory amino acid receptors, and one of the selective antagonists of the NMDA receptor used in the present invention, MK-801 ( (+) — 5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5.10-imine.maleate) is known as a psychotropic drug [British. Journal 'Ob. Pharmacology, Br. J. Pharma, 91,403-409 (1987)].

An object of the present invention is to provide a therapeutic or preventive agent for various cardiovascular diseases in which social and psychological stress is one of the causes.

Disclosure of the invention

The inventors of the present invention have proposed that a psychotropic drug consisting of a dopamine (D 1) receptor antagonist or an NMDA receptor antagonist has an action of suppressing hypertrophy of various internal organs such as a kidney and a liver. The present invention was completed by finding that it is useful as an agent.

TECHNICAL FIELD The present invention relates to a cardiovascular agent comprising as an active ingredient a psychotropic drug consisting of a dopamine (D 1) receptor antagonist or an NMDA receptor antagonist.

Specifically, the present invention relates to a cardiomyopathy, myocarditis, heart failure, arrhythmia, ischemic heart disease comprising a psychotropic drug consisting of a dopamine (D 1) receptor antagonist or an NMDA receptor antagonist as an active ingredient. The present invention relates to the treatment and prevention of illness, valvular heart disease or cardiac hypertrophy or sudden death caused by them.

More specifically, the present invention relates to a cardiomyopathy, myocarditis, heart failure, arrhythmia, ischemic disease caused by stress load, comprising as an active ingredient a psychotropic drug consisting of a dopamine (D 1) receptor antagonist or an NMDA receptor antagonist. The present invention relates to a therapeutic and prophylactic agent for heart disease (eg, angina pectoris, myocardial infarction, etc.), valvular heart disease or cardiac hypertrophy or sudden death caused by them.

As the dopamine (D 1) receptor antagonist contained as an active ingredient in the cardiovascular agent of the present invention, in addition to SCH23390 described above, SCH-39166 ((—) 1 trans-1,6,7,7a.8, 9, 13b—Hexahi Draw 3-Chloro-1-hydroxy-1-N-methyl-5 H—Venzo [d] naphtho [2,1—b] azepine), A—69024 (1— (2 Mo, 4,5—dimethoxybenzyl) 1-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline), SKF—83566 (R — (+) — 7-bromo-8—hydroxy) 3-Methyl-1-phenyl 2,3,4,5—Tetrahi draw 1 H—3-Benzoazepine, NNC687 ((S) -15- (2,3-Dihidr 7-benzofuranyl) 1-2,3 , 4,5-Tetrahydro-3-methyl-8-nitro-1H-3-benzazepin-1 7-ol), YM435 ((S) 14-1 ( 3. 4-dihydroxyphenyl) 1,1,2,3,4-tetrahydro-7,8-isoquinoquinoldiol hydrochloride), NNC112 (5— (7-benzofuranyl) -18-chloro—2,3,4,5- Tetrahi Draw 3-Methyl-1H-3-benzazepine-7-ol), NNC756 ((S) -18-Chloro-5- (2,3-dihydro-7-Venzofuranyl) 1-2,3,4,5 —Tetrahydro-3-methyl-1-H—3-benzazepine-1- (7-ol), BW737C89 ((S) -1-6-chloro-1 -— [(2,5-dimethyl-4-propylphenyl) methyl] —1.2 , 3.4-tetrahydro-2-methyl- 7-isoquinolinol), ZD3638 (4— [2- (ethylesfinil) -13-pyridinyl] -1-1 [9,10-methanoanthracene-9 (10H ) -Irmethyl] 1-41-piridinol), JHSI136 (8-black mouth-5-phenyl-3) — [5- (dimethylamino) pentyl] -1-2.3.4,5-tetrahydro-1H—3-benzobenzopin-17-ol, JHSII198 (8-cyano 5—phenyl 3-—7 1- (dimethylamino) heptyl] 1,2,3,4,5-tetrahydro-1H-3: nzozepin-17-ol, JHSI I 271 (8-chloro-5-phenyl 3- [6-1-dimethylamino) hexyl General dopamine (D 1) receptor antagonists such as 1,2,3,4,5-tetrahydro-1H-3-benzozebine-17-ol) can be mentioned, with SCH23390 being preferred.

Further, as the NMDA receptor antagonist contained as an active ingredient in the cardiovascular agent of the present invention, in addition to the above-mentioned MK-801, AP-3 ((Sat) -12-amino-3-phosphonopropionic acid) ), AP-4 ((Sat) 1-2-amino-4-1-phosphonobutyric acid), AP-5 ((Sat) 1-2-amino-5-phosphonopentanoic acid), AP-7 ((Sat) 1-2-amino-7) —Phosphonoheptanoic acid), CGS—19755 (cis-141 (phosphonomethyl) piperidine-12-hydroxycarboxylic acid) and the like, among which MK801 is preferable.

Industrial applicability

Cardiomyopathic hamsters are transmissible animals with chronic heart failure as the predominant condition, a condition that is very similar to human idiopathic cardiomyopathy. If the cardiomyopathy hamster is subjected to cold restraint stress, most animals die within 12 weeks from immediately after the stress.

In addition, cardiomyopathy hamsters subjected to stress show a marked increase in weight of the adjunct, heart, kidney, liver, etc., and a marked decrease in spleen weight.

In order to demonstrate the pharmacological effects of the cardiovascular agent of the present invention, we conducted an experiment on the effect of a dopamine (D 1) receptor antagonist or NMDA receptor antagonist on the sudden death prevention of cardiomyopathy hamsters loaded with cold restraint stress. The results are shown below.

experimental method:

A male cardiomyopathy hamster (BI014.6, weight 90-110 g) was left in a refrigerator for 1 hour while being restrained with a stretchy adhesive tape on a PVC plate in a supine position. After the cold restraint stress was given for 5 days in a row, the animals were observed for one week.

Animals that died during the experimental period were immediately dissected and organ weights were measured. Surviving animals were dissected on the last day (day 12) and organ weights were measured.

The test compound is dissolved in physiological saline and injected intraperitoneally for 5 days immediately before stress application. Gave.

Test compound:

Compound A: SCH23390

Compound B: MK-801

Trial ·

_C showing the results in Tables 1 to 3

table 1

Table 2 Organs Relative site weight Test compound Dose Number of animals gZ body weight 1)

(mg / kg) Kidney Adrenal gland

SCH23390 10 7 15.67 ± 1.88 0.236 ± 0.021

(Content opening) 0 7 22.98 Sat 1.77 0.303 ± 0.018 Table 3

From the above results, the dopamine (D 1) receptor antagonist or the NMDA receptor antagonist, which is an active ingredient of the present invention, has an effect of suppressing the enlargement of organs such as kidney and adrenal gland, and has an effect of preventing sudden death. It is understood that it also has a usefulness as a cardiovascular agent.

The active ingredients of the cardiovascular agent used in the present invention include oral administration (including sublingual tablets), parenteral administration (eg, single or continuous injection intravenous injection, intraperitoneal, subcutaneous, intramuscular injection) Etc.) and topical (topical) administration (eg, rectal, transdermal, ophthalmic, nasal, etc.) and a mixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient. It is used for therapeutic purposes in the form of a conventional pharmaceutical preparation containing as an active ingredient.

Pharmaceutical preparations include tablets, granules, powders, lozenges, pills, suppositories, XuXu, capsules, microcapsules, enteric coatings, solutions, injections, suspensions, syrups, emulsions, limonade Conventional pharmaceutical preparations such as eye drops, nasal drops, sprays, inhalants and the like may be used.

The above pharmaceutical preparations include, for example, excipients such as sucrose, starch, mannite, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc., for example, cellulose, methyl cellulose, hydroxymethyl cellulose, polypropyl Binders such as pyrrolidone, gelatin, gum arabic, polyethylene dalicol, sucrose, starch, etc., for example, starch, carboxymethyl cellulose, hydroxypropyl starch, sodium hydrogen carbonate, calcium phosphate Disintegrators such as gum, calcium citrate, etc., glidants such as magnesium stearate, air syrup, talc, sodium lauryl sulfate, etc., flavoring agents, such as citrate, menthol, glycine, orange powder, etc. Preservatives such as sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben, etc., for example, stabilizers such as citric acid, sodium citrate, acetic acid, etc., such as methyl cellulose, polybutylpyrrolidone, aluminum stearate, etc. Opacifiers, for example, dispersants such as hydroxypropyl methylcellulose, for example, diluents, for example, water, etc. It can be manufactured by a standard method using a carrier. .

The dosage of the active ingredient contained in this cardiovascular agent varies depending on the age, condition, type of disease, type of active ingredient used, etc. of the patient, but is generally about 0.1 mg per day. A dose between lOOOmg or more may be administered to the patient. The active ingredient of this circulatory agent should be administered for treatment at an average dose of about 0.1 mg, lmg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, 100 mg, once to five times a day. I just need.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example

Example 1 (capsule)

SCH23390 5 mg

Lactose 80mg

The above components are mixed and filled into a normal hard gelatin capsule to form a capsule.

Example 2 (capsule)

SCH23390 5 mg

Lactose 65mg

A capsule is obtained in the same manner as in Example 1. Example 3 (capsule)

MK-801 5mg

Lactose 80mg

Example 4 (capsule)

MK-801 5mg

Zhato 65mg

A capsule is obtained in the same manner as in Example 3.

Example 5

SCH23390 10mg

10 ml of saline for injection

SCH23390 (10 mg) is dissolved in saline for injection (10 ml) to give an injection. Example 6

MK-801 10mg

10 ml of saline for injection

An injection is obtained in the same manner as in Example 5.

Claims

The scope of the claims

1. A cardiovascular agent containing as an active ingredient a psychotropic drug consisting of a dopamine (D1) receptor antagonist or an NMDA receptor antagonist.

2. Cardiomyopathy, myocarditis, heart failure, arrhythmia, ischemic heart disease, valvular heart disease, or heart containing a psychotropic drug consisting of dopamine (D1) receptor antagonist or NMDA receptor antagonist as an active ingredient An agent for treating and preventing hypertrophy or sudden death caused by them.

3. Dopamine (D1) receptor antagonist or NMDA receptor antagonist as an active ingredient, stress-induced cardiomyopathy, myocarditis, heart failure, arrhythmia, ischemic heart disease, valvular heart disease or heart disease An agent for treating and preventing hypertrophy or sudden death caused by them.

4. The circulatory agent according to claim 1, wherein the dopamine (D 1) receptor antagonist or the NMDA receptor antagonist is SCH23390 or MK-801.