JPS6368551A - N-(2-hydroxy-2-(4-hydroxyphenyl)ethyl)-benzamide and remedy for circulatory disease and skin external remedy containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula. USE:A remedy for circulatory disease and skin external remedy, having vasodilation action, vasodepressor action, etc., showing an effect for improving circulation and having action such as action for preventing and improving skin irritations, trichogenation, prevention agaist epilation, etc. Useful for remedy for hypertension, stenocardia, cardiac infarction aftereffect of cerebral infarction, peripheral circulation affection, etc., by circulatory disease. PREPARATION:4-Hydroxyphenyl ethanol amine hydrochloride reacted with benzoyl chloride in a solvent in the presence of a base such as pyridine, etc., to provide a compound expressed by the formula.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide and a therapeutic agent for cardiovascular diseases containing the compound as an active ingredient. It relates to external preparations for skin.

[Prior art] Compound N-[2-hydroxy-2-(4-
Hydroxyphenyl)ethyl]benzamide is a compound that has not been described in any literature, and of course, its usefulness centered on its pharmacological action is also unknown.

[Problems to be Solved by the Invention] In view of the above circumstances, the present inventors have conducted extensive research on the pharmacological usefulness of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide. As a result, we discovered that this compound has a wide range of effects, including vasodilatory effects, blood pressure lowering effects, and other circulation-improving effects, as well as skin roughness prevention and improvement effects, as well as hair growth promotion and hair loss prevention effects.
The present invention was completed based on these new findings.

[Means for Solving the Problems] That is, the present invention involves blending N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide represented by the following structural formula and the compound as an active ingredient. This article focuses on characteristic therapeutic agents for cardiovascular diseases and external preparations for skin.

The present invention will be explained in detail below.

Compound N-[2-hydroxy-2-(4-
The method for producing hydroxyphenyl)ethylcobenzamide is to prepare 4-hydroxyphenylethanolamine hydrochloride (4-hydroxyphenylethanolamine hydrochloride) obtained by a known method (West German patent; 373°286).
It can be produced in high yield by a method such as reacting octopamine hydrochloride with benzoyl chloride.

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

l1■ 10. Octopamine hydrochloride in a 300 ml Erlenmeyer flask.
After adding 100 ml of pyridine and dissolving it, 7.48 g of benzoyl chloride was added dropwise little by little 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, 9.28 N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl cobenzamide was obtained by recrystallization.

The compound synthesized according to the production example was identified as N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide from the following measurement data.

N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide mass spectrum; molecular weight = 257 Melting point: 165.7-167.1°C Infrared absorption spectrum (KBr tablet method, cm”): 33
00, 1605.1570.1545.1515.10
70° nuclear magnetic resonance spectrum (deuterated dimethyl sulfoxide) δ: ppm, 3.40 (2H, multiplet)
, 4.69 (IH9 triplet), 5.19 (l H, broad singlet), 6.72 (2H, doublet), 7.1
7 (2H1 doublet), 7.4-7.5 (3H, multiplet)
, 8.23 (I H.

Mie IIa), 9.09 (707-)'su-fEil
).

N-[2-hydroxy-2-(
Acute toxicity studies as well as studies of pharmacological properties were carried out on 4-hydroxyphenyl)ethyl]benzamide.

Breath two member Yu Ai! ICR female mice (6 weeks old, 5 mice per group) were used for intraperitoneal administration of 221, suspended in 0.5% carboxymethylcellulose sodium/physiological saline to a concentration of 2% (wt%). For oral administration, use a 10% (wt%) suspension in olive oil and use an oral needle to administer the maximum amount that can be technically administered ( Intraperitoneal administration = 60 ml/kg, oral administration: 30 ml/kg).

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

As is clear from this result, N-[2-hydroxy-
The acute toxicity value (LD) of 2-(4-hydroxyphenyl)ethyl]benzamide is 1200 after intraperitoneal administration.
mg/kg or more, and 3000 mg/kg when administered orally, and was found to have low toxicity.

Shisei Erisameyu (1) Blood pressure lowering effect 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) It was tested.

(1) Test on rabbits Bendoparbital anesthesia (30mg/kg i, v)
The rabbit was fixed in the anterior position, a pressure transducer was connected to a catheter inserted through the total 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 a dose of 1 mg/kg. Systolic blood pressure was measured before administration and 1.5 hours after administration, and the increase and decrease in blood pressure relative to before administration was calculated as a rate of change (%). The results are shown in Table-1.

Tsukeyoji 1 (if) Test using SHR rats The test compound was suspended in 0.5% carboxymethylcellulose sodium to rats genetically developing hypertension (SHR rats) at a dose of 50 mg/kg/day.
The drug was administered continuously for several days. Blood pressure was measured using a “Programmed Electro-Sfigmomanometer P, E” manufactured by Nalco, USA.
, 300'' (Marco Co, Program
dElectro-Sphygmomanometer
P, E, 300). 1.4 after administration
The systolic blood pressure was then measured at 8 hours, and the rate of change (%) from the same blood pressure before administration was calculated. The results are shown in Table-2.

The test compound numbers are as follows.

1: Control 2: N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide Table 2 As is clear from Tables 1 and 2, N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl] Hydroxyphenyl)ethyl]benzamide was found to have a hypotensive effect.

(2) Coronary blood vessel and cerebral vasodilator effect (1) Preparation of coronary blood vessel specimen Urethane anesthetized rabbit (Japanese native species, male, weight 2.5
After exsanguination from the carotid artery (~3.5 kg), the hearts were quickly removed and immersed in Tyrode's solution aerated with 95% 0° + 5% CO2. Thereafter, the left coronary trial artery was extracted from the aorta in the same solution, and a spiral specimen with a width of about 1 mm and a length of about 10 cm was prepared under a stereomicroscope. This specimen was placed in a Magnus tube (10 ml, 37°C) filled with Tyrode's solution aerated with 95% 02 + 5% CO2.
The drug was suspended in the tube, and the change in tension caused by the drug was recorded isointensely using a transducer.

(if) Preparation of non-volatile 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 (30
mg/kg i, v, ) Shita mongrel adult dog (male, weight 15~
After incising the artery of a total of 20 kg) and exsanguinating the animal to death,
Quickly remove the basilar artery under a stereomicroscope and achieve 95% 0□+
It was immersed in Tyrode's solution bubbled with 5% CO2. After removing the attached tissue, the width is about 1 man and the length is about 15 mm.
A spiral specimen was prepared.

This specimen was suspended in a Magnus tube (10 ml, 37°C) filled with Tyrode's solution through which 95% 02 + 5% CO2 was aerated, and the change in tension caused by the drug was recorded isostatically using a transducer.

After contracting the coronary blood vessel and cerebral blood vessel specimens prepared in (1) and (ii) above with norepinephrine (2×10 −8 M), 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-3.

1 N-[2-Hydroxy-2-
It has been found that (4-hydroxyphenyl)ethyl]benzamide has a dilating effect on coronary blood vessels and cerebral blood vessels.

The above results revealed that the compound N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide according to the present invention is highly safe and has an excellent therapeutic effect on cardiovascular diseases. .

Next, the formulation of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl cobenzamide as a therapeutic agent for cardiovascular diseases will be described.

The therapeutic agent for cardiovascular diseases of the present invention is N-[2-hydroxy-2
-(4-Hydroxyphenyl)ethyl]benzamide alone or as a mixture with pharmaceutically acceptable excipients and other agents.

The above additives include lactose, starch, calcium carbonate, magnesium aluminate metasilicate, magnesium aluminum hydroxide, calcium hydrogen phosphate, sucrose, aluminum silicate, excipients such as microcrystalline cellulose, carboxymethyl cellulose, Binders such as polyvinylpyrrolidone, 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 surfactants, buffers, preservatives, fragrances, pigments, flavoring agents, etc., and these may be used singly 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 halves, and administered as injections.

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.

Tablet N-[2-Hydroxy-2-(4-hydroxyphenyl)ethyl cobenzamide 100 mg and microcrystalline cellulose 100 mg were prepared according to a conventional method, and sugar-coated with syrup gelatin precipitated calcium carbonate. was applied.

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

Ml Town Example, Granule N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide 20g, lactose 808g, water 10g
and 90 g of microcrystalline cellulose were uniformly mixed, crushed, granulated, dried, and sieved to obtain granules.

The granules are used in a single dose of 0.5-108.

The following day, capsule preparation: 100 mg of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide, 100 mg of microcrystalline cellulose, and 200 mg of lactose were uniformly mixed and filled into hard gelatin capsules.

This capsule is used in one dose ff11-10 capsules.

Next, the skin external preparation of the present invention will be described.

The skin external preparation of the present invention is N-[2-hydroxy-2-(
4-Hydroxyphenyl)ethyl]benzamide is used in the form of a mixture with pharmaceutically acceptable excipients and other agents.

Examples of the additives include hinokitiol, hexachlorophene, phenol, benzalkonium chloride,
Antibacterial agents such as cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and bithionol, derivatives such as clycyrrhizic acid and its ammonium salts, anti-inflammatory or cooling agents such as allantoin and menthol, salicylic acid, zinc and its compounds, lactic acid and its alkyl Drugs such as esters, animal and vegetable oils such as olive oil, macadamia nut oil, and squalane, hydrocarbon oils such as liquid paraffin, ester oils such as isopropyl myristate, cetyl isooctanoate, and 2-ethylhexyl palmitate, and beeswax. Waxes such as, oils such as higher fatty acids and higher alcohols, water, derivatives such as lactic acid and its ethyl ester, polyethylene glycol, glycerin,
Examples include polyhydric alcohols such as sorbitol, lower alcohols such as ethanol, mucopolysaccharides, humectants such as pyrrolidone carboxylates, surfactants, fragrances, antioxidants, ultraviolet absorbers, pigments, etc. Use one type or a mixture of two or more types.

The external skin preparation of the present invention may be in any form as long as it can be applied externally, such as liquid preparations for external use such as lotions, liniments, and milky lotions, and semi-solid preparations for external use such as creams, ointments, pasta, jelly, and sprays. etc. can be mentioned.

The skin external preparation of the present invention contains 0.0001 to 10% by weight, preferably 0.0001 to 10% by weight of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide, which is an active ingredient.
．． It is contained in a range of 0.001 to 5% by weight.

The skin external preparation of the present invention is administered by transdermal administration, in which it is directly applied or sprayed onto the skin. It is best to apply topically 1 to 4 times a day.

The preferred dosage depends on age, individual differences, medical condition, etc.
Generally, the amount of N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide is between 0.0001 and 20 mg per kg of body weight and per day, more preferably between 0.001 and 2 B.

The method for formulating the external preparation for skin according to the present invention and the effect of applying it to the skin will be specifically explained below with reference to formulation examples.

It goes without saying that the technical scope of the present invention is not limited to these.

Next 5th grade - 1st grade A lotion having the following composition was prepared.

(% by weight) 95% ethanol 80. ON-[2-
Hydroxy-2- (4-hydroxyphenyl) 0.1 ethyl]benzamide Ethylene oxide 0.5 (40 mol) adduct of hydrogenated castor oil Purified water 19.0 Fragrance
Appropriate amount of pigment
Add N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide, hinokitiol, ethylene oxide (40 mol) adduct of hydrogenated castor oil, fragrance, and coloring matter to an appropriate amount of 95% ethanol, stir and dissolve, and then purify. Water was added to obtain a clear liquid lotion.

Layer 5゜ An emulsion was prepared from the physiognomy and B phase of the following composition.

(Phase A) (Weight%) Whale wax 0.5 cetanol
2.0 Vaseline
5.0 Squalane 10
．． 0 Polyoxyethylene (10 mol) 2.0 Monostearate N-[2-hydroxy-2- (4-hydroxyphenyl) 0.5 Ethyl]benzamide sorbitan monooleate 1.0 (Phase B) Glycerin 10.0 purified water
69.0 Fragrance, Color and Preservative Dissolve appropriate amounts of Phase A and Phase B by heating and keep at 80°C. Both phases were mixed and emulsified, and cooled to room temperature while stirring to obtain a milky lotion.

'RM' r pull-Miichi A cream was prepared from Phase A and Phase B having the following composition.

(Phase A) (% by weight) Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Vaseline
5.5 glycerin monostearate)
3.0 Polyoxyethylene (20 mol) 3.0 2-Octyldodecyl ether probylparaben 0.3 (B phase) N-[2-hydroxy-2- (4-hydroxyphenyl) 0.1 Ethyl]benzamide glycerin 7 .0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium hexametaphosphate
0.005 Purified water Dissolve appropriate amount of human face by heating and keep at 70°C. Separately, phase B is dissolved by heating and kept at 70°C. Phase B was added to phase A and stirred, and the resulting emulsion was cooled to obtain a cream.

Effect test example In order to investigate the hair-nourishing effect and beautifying effect of the skin external preparation of the present invention, a tricogram test, a final hair conversion rate test, and a questionnaire survey after actual use were conducted.

In the hair growth effect test, 20 male subjects were divided into two groups of 10 subjects each, and two different test liquids were given to each group of subjects for comparison. The two test solutions are shown in Table 4.

In addition, in the skin beautification effect test, a practical use test was conducted by 20 female panelists. That is, the lotion obtained in Formulation Example 4 and the essential component N-[2-hydroxy-
0.5 ml of each lotion (comparative example) obtained in the same manner as in Formulation Example 4 except for excluding 2-(4-hydroxyphenyl)ethyl]benzamide was applied twice a day to the inside of the left and right forearms. The product was applied continuously for a month, and a questionnaire survey was conducted on the effectiveness of the product.The panel members were asked to rate the skin's smoothness and moisturizing feeling in three stages: effective, somewhat effective, and ineffective. The results are shown in Table 4.

Table 4 Each test solution f! : 2 ml was applied to the subject's scalp in two divided doses per day.

(1) Trichogram test The removed hair roots are observed under a microscope before and after using both test solutions, and the number of telogen hair roots is calculated from the morphology of the hair roots. The hair growth effect was compared. A telogen hair root is a hair root that has stopped growing. People who complain of hair loss have more telogen hair roots than normal people, so the hair-nourishing effect was evaluated based on the decrease in telogen hair roots. The application of each test solution to the scalp was continued for 3 months, and 60 hair roots were removed for each test subject immediately before and immediately after the application. The results are shown in Table 5.

(ii) Terminal hair conversion rate test: Down hair region 3 of each of the 40 test subjects with androgenetic alopecia
The conversion rate from downy hair to terminal hair was compared before and after application of each test solution.

Terminal hair refers to hair other than downy hair, that is, hair with a length of 14 mm or more, and the conversion from downy hair to terminal hair means a hair-nourishing effect. Immediately after application of each test solution and immediately after completion of the 4-month application, close-up photographs of the above-mentioned down hair region of the head were taken to measure the conversion rate. The conversion rate to terminal hair is expressed as a percentage of the average of the three locations. The results are shown in Table 6.

As is clear from the above results, it was found that N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide exhibits an excellent hair-nourishing effect.

From the above results, it can be concluded that the skin condition in the area where Formulation Example 4 was applied is clearly improved. :confirmed.

There were no cases where the skin condition worsened.

Claims (3)

[Claims] (1) N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide shown by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼. (2) A therapeutic agent for cardiovascular diseases containing N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide represented by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼ as an active ingredient. (3) A skin external preparation characterized by containing N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]benzamide represented by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼.