JPS62283924A - Remedy for circulatory disease - Google Patents

Abstract

PURPOSE:To provide the titled remedy containing N-(hydroxystyryl)benzamide as an active component, having high safety and exhibiting remarkable dilating action to various vessels, diuretic action and hypotensive action. CONSTITUTION:The compound of formula is used as an active component of the objective remedy. The remedy is effective against hypertension, stenocardia, myocardial infarction, sequela of cerebral infarction, peripheral circulatory disorder, etc., and is administered at a rate of 0.5-500mg daily per 1kg of body weight. The compound of formula can be produced by reacting 4- hydroxyphenyl ethanolamine hydrochloride with benzoyl chloride and heating the resultant N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide in the presence or absence of catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a therapeutic agent for cardiovascular diseases containing N-(hydroxystyryl)benzamide as an active ingredient.

The compound N-(hydroxystyryl)benzamide according to the present invention has antihypertensive action, diuretic action, ischemic heart disease treatment action, cerebral vasodilatory action, peripheral vasodilator action, etc., and is extremely useful as a pharmaceutical.

[Prior Art] N-(hydroxystyryl)benzamide in the present invention is a known substance [Shigehiko Sugazawa; Pharmaceutical Journal, Vol. 55, 22
pp. 4-233 (1935), A. Gierrad (A.

Journal of the American Chemical Society (J, Amer, Chem, S
oc, ), vol. 72, pp. 4436-4439 (1950
)], the existence of cis and trans forms as structural isomers has been suggested.

The method for synthesizing this compound is described in the above-mentioned literature, but no literature has been published so far regarding its pharmacological action.

[Problems to be Solved by the Invention] In view of the above circumstances, the present inventors have conducted intensive research on the pharmacological action and safety of N-(hydroxystyryl)benzamide, and have determined that the compound is safe. We have discovered the novel fact that it has a high dilation effect, a diuretic effect, a blood pressure lowering effect, etc. on various blood vessels, and have completed the present invention based on this knowledge.

[Means and effects for solving the problems] That is, the gist of the present invention is a therapeutic agent for cardiovascular diseases characterized by containing N-(hydroxystyryl)benzamide represented by the following structural formula as an active ingredient. be.

The present invention will be explained in detail below.

The method for producing the compound N-(hydroxystyryl)benzamide according to the present invention is a known method (West German patent; 373
N-[2-hydroxy-2-(4
-hydroxyphenyl)ethyl]benzamide can be produced by heating without a catalyst or in the presence of a catalyst.

Examples of manufacturing the compounds according to the present invention are shown below. Note that the present invention is not limited to this.

The next day, add 10 ml of octopamine hydrochloride to a 300 ml Erlenmeyer flask.
After adding 100 ml of pyridine and dissolving it, 7.4 g of benzoyl chloride was added dropwise while stirring under cooling. After stirring was continued for 30 minutes after the completion of the dropwise addition, 100 ml of water was added to the reaction solution, and the mixture was extracted three times with 100 ml of chloroform using a separating funnel. After distilling off the solvent of the extract, 9.2 g of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide was obtained by recrystallization. N-[2-hydroxy-2 obtained here
-(4-hydroxyphenyl)ethyl]benzamide 9
．． Put 2g into a 3000ml three-necked flask, add 1500ml of toluene and 3.0g of aluminum oxide, and add 4.
The current flowed for 0 hours. The reaction product was filtered, the minor solvent was distilled off, and further separated by column chromatography using silica gel and purified by recrystallization to obtain cis-type (0.6 g) and trans-type (4.4 g) N-(4 -hydroxystyryl)benzamide was obtained.

Melting point: 182°C for cis form, 206°C for trans form N-(4-hydroxystyryl)benzamide synthesized according to the production example was subjected to acute toxicity tests and pharmacological property tests.

, J1 and J Shishi ICR female mice (6 weeks old, 5 mice per group) were used for intraperitoneal administration of 0.5% Karpoki dimethylcellulose sodium/2% (wt%) in physiological saline. For oral administration, suspend the suspension in olive oil to a concentration of 10% (wt%) using a 221/2 G injection needle. The maximum amount technically administrable (intraperitoneal administration: 60 ml/kg, oral administration: 30 ml/kg) was given.

As a result, during the 7-day observation period, no deaths, no decrease in body weight, and no noteworthy toxic symptoms were observed, and no similar abnormalities were observed in the autopsy performed on the 7th day.

As is clear from these results, the acute toxicity value (LD5o) of N-(4-hydroxystyryl)benzamide is 1200 mg/kg or more when administered intraperitoneally and 30 mg/kg or more when administered orally.
00 ff1g/kg, and it was found that the toxicity was low.

(1) Diuretic effect Using a Japanese native rabbit (male, weight 2.5-3.5 kg), a general method (edited by Keitsugu Takagi and Hikaru Kousei; Pharmacological Experiments, Nanzando 1978).

That is, a rabbit anesthetized with urethane was fixed in a dorsal position, the abdomen was incised, and a cannula was inserted into the ureter.

The test compound was suspended in 0.5% sodium carboxymethylcellulose and administered orally (200 mg/kg).
Changes in urine volume (ml) after administration were measured. The results are shown in Table-1.

(Space below) Table-1 ):;; Urine volume increase rate (%) = [Urine volume per 5 minutes after test compound administration (ml) - Urine ffi per 5 minutes before test compound administration (ml)] 100/Urine volume (ml) per 5 minutes before administration of test compound As is clear from Table 1, N-(4-hydroxystyryl)benzamide was found to have a diuretic effect.

(2) Blood pressure lowering effect Tests were conducted using Japanese native rabbits (male, body weight 2.5-3.5 kg) and SHR rats (male, body weight 350-400 g, systolic blood pressure 180 mmHg or higher).

(i) Test with rabbits Bendoparbital anesthesia (30B/kg i, v,)
The rabbit was fixed in a dorsal position, a pressure transducer was connected to a catheter inserted through the common carotid artery, and blood pressure was recorded on a recorder. The test compound was administered intraperitoneally at 100 mg/kg. For comparison, hydralazine hydrochloride was similarly administered at 1 mg/kg. The oral systolic blood pressure was measured before administration and 1.5 hours after administration, and the increase and decrease in blood pressure from before administration was calculated as a percentage change (%). The results are shown in Table-2.

(Leaving space below) Table 2 (ii) Test using SHR rats The test compound was suspended in 0.5% carboxymethylcellulose sodium to rats genetically prone to hypertension (SHR rats) at a dose of 50 mg/kg/day. like 3
It was administered continuously for several days. Blood pressure was measured using a ``Programmed Electro-Sfigmomanometer P'' manufactured by Nalco, USA.
E, 300” (Narao Co, Progra
medElectro-Sphygmomanomet
er-P, E, 300). After administration 1
．． Systolic blood pressure was determined at 4 and 8 hours, and the rate of change (%) from the same blood pressure before administration was calculated. The results are shown in Table-3.

The test compound numbers are as follows.

1: Control 2: N-C4-hydroxystyryl)benzamide (cis-type) IN-(4-hydroxystyryl)benzamide (trans-type) (blank below) Table 3 As is clear from Tables 2 and 3, N -(4-Hydroxystyryl)benzamide was found to have a hypotensive effect.

(3) Coronary blood vessel and cerebral vasodilatory effect (i) Preparation of coronary blood vessel specimen Urethane anesthetized rabbit (Japanese native species, male, weight 2.5
After exsanguination to death from the carotid artery (~3.5 kg), the hearts were quickly removed and immersed in Tyrode's solution aerated with 95% 02 + 5% CO2. Thereafter, the left coronary artery was extracted from the aorta in the same solution, and a spiral specimen with a convergence of about 1 mm and a length of about 10 cm was prepared under a stereoscopic microscope. This specimen was placed in a Magnus tube (10 ml, 37 mm) filled with Tyrode's solution aerated with 95% 0° + 5% CO2.
℃), and changes in tension caused by the drug were recorded isotropically using a transducer.

(ii) Preparation of cerebral blood vessel specimen This was carried out in accordance with the method described in Hikari's supervision, "Medicinal efficacy screening method for new drug development," Volume 1, Seishi Shoin (1984). i.e. bendoparbital anesthesia (3
0mg/kg i, v,) Shita mongrel adult dog (male, weight 1
After incising the common carotid artery of a patient weighing 5 to 20 kg and exsanguinating the animal to death, the basilar artery was quickly removed under a stereoscopic microscope.
02+5% C02 was immersed in aerated Tyrode's solution.

After removing the attached tissue, a spiral specimen with a width of about 1ffiffi and a length of about 1511II11 was prepared.

This specimen was suspended in a Magnus tube (10 mL, 37°C) filled with Tied solution through which 95% O + 5% CO2 was aerated, and the change in tension caused by the drug was recorded isotropically using a transducer.

After contracting the coronary blood vessel and cerebral blood vessel specimens prepared in (i) and (eye) with norepinephrine (2×10'14), the test compound was added to the Magnus tube. The concentration of test compound that causes 50% relaxation of constricted blood vessels was determined.

The results are shown in Table-4.

(The following is a blank space) Table 4 As is clear from Table 4, N-(4-hydroxystyryl)benzamide was found to have dilating effects on coronary blood vessels and cerebral blood vessels.

The above results revealed that the compound N=(4-hydroxystyryl)benzamide according to the present invention is highly safe and has an excellent therapeutic effect on cardiovascular diseases.

Next, the formulation of N-(4-hydroxystyryl)benzamide for use as a therapeutic agent for cardiovascular diseases will be described.

The therapeutic agent for cardiovascular diseases of the present invention can be used alone or as a mixture with pharmaceutically acceptable additives and other drugs.

The above-mentioned additives include lactose, starch, calcium carbonate, magnesium aluminate metasilicate, magnesium aluminum hydroxide, calcium hydrogen phosphate, sucrose, aluminum silicate, excipients such as microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, etc. , binders such as gum arabic, gelatin, and sodium alginate; lubricants such as talc, calcium stearate, and magnesium stearate; humectants such as glycerin, propylene glycol, and sorbitol; disintegrants such as agar and silicic anhydride; and interfaces. Examples include activators, buffers, preservatives, fragrances, pigments, and flavoring agents, and these may be used alone or in combination of two or more.

The therapeutic agent for cardiovascular diseases of the present invention can be administered either orally or parenterally.

For example, it can be administered orally in the form of tablets, capsules, powders, granules, syrups, etc., enterally in the form of suppositories, and administered as an injection 1.

Further, indications for the therapeutic agent for cardiovascular diseases of the present invention include hypertension, angina pectoris, myocardial infarction, sequelae of cerebral infarction, peripheral circulatory disorders, and the like.

The dosage of the therapeutic agent for cardiovascular diseases of the present invention depends on age, individual differences,
Although it varies depending on the symptoms, etc., in general, when targeting humans, the dose is 0.5 to 500 mg orally per day based on body weight IKg.
It can be administered once or in several doses.

Examples of the formulation of the therapeutic agent for cardiovascular diseases of the present invention will be described in more detail below with reference to Examples. Note that the present invention is not limited to this.

Formulation Example 1 Tablet N-(4-hydroxystyryl)benzamide 100m
Tablets containing 100 mg of microcrystalline cellulose and 100 mg of microcrystalline cellulose were prepared in a conventional manner and sugar-coated with syrup gelatin precipitated calcium carbonate.

This tablet is used in a single dose of 1 to 10 tablets.

Formulation Example 2 Granule N-(4-hydroxystyryl)benzamide 20g
and lactose 80g 1 water 10g and microcrystalline cellulose 90g
were uniformly mixed, crushed, granulated, dried, and sieved to obtain granules.

This granule is used in a single dose of 0.5 to 10 g.

Formulation Example 3 Capsule N-(4-hydroxystyryl)benzamide 100m
g, microcrystalline cellulose 100+eg and lactose 200m
g were mixed uniformly and filled into hard gelatin capsules.

The capsules are used in a single dose of 1 to 10 capsules.

(Margin below)

Claims (1)

[Claims] A therapeutic agent for cardiovascular diseases containing N-(hydroxystyryl)benzamide as an active ingredient represented by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼