KR950006062B1 - Hair growing agent - Google Patents

Abstract

The hair growth promoting agent [Y-NH(CH2)nNR1 R2 R3 (Q) (I, Q is anion selected from chloride, bromide, iodide, phosphate, sulfonate, acetate ; R1 R2 R3 = the same or not C < 4 lower alkyl or alkenyl ; Y = C < 16 aminoalkyl, benzoyl, H ; n = integer 2-4) was manufactured. The compound could be used as hairtonic, haircream, or hairlotion preparations. The concentration of above agent in the preparations was 0.1-1.0%.

Description

Hair growth promoter

1 is a graph showing the results of the cell growth promotion test of the hair growth promoter of the present invention.

The present invention relates to novel hair growth promoters. More specifically, the present invention relates to a hair growth promoter containing a compound represented by the following general formula (I) or a salt thereof.

[Y-NH (CH ₂ ) _n NR ₁ R ₂ R ₃ ] ⁺ (Q) ^- (I)

Wherein Q represents an anion such as chloride, bromide, iodide, phosphate, sulfonate, acetate, lactate, etc .; R ₁ , R ₂ , R ₃ represent lower alkyl or alkenyl having 4 or less carbon atoms which are the same or different from each other; Y represents aminoalkyl having 16 or less carbon atoms, alkanoyl having 2 to 4 carbon atoms, benzoyl or a hydrogen atom; n represents the integer of 2-4.

Human hair goes through periods of growth, degeneration and rest. The exact mechanism of the hair loss phenomenon is not yet known and there are various hypotheses about this. In other words, hormonal theory caused by hormonal imbalance, stress theory due to sudden mental pain, air pollution caused when hair is contaminated by particles such as toxic gas, and sebaceous glands mixed with dandruff and other secretions cover nutrition There is a hypothesis of blood circulation caused by overnutrition, such as animal fat, which occurs due to obstruction of blood flow due to obstruction of blood flow due to seborrheic or animal fat.

Hair is one of the skin appendages, ecologically derived from the epithelium, and forms from the second month of birth. The types of hair are classified into fine hairs (Vellus hair) and thick and hard hair (terminal hair) according to their thickness. Hair growth is periodic and does not hair temporarily. Each hair follicle goes through an intermittent phase of activity and cessation. During the growing phase, ie anagen, cells of the hair follicles actively differentiate to form growing hair. After this period, hair follicles enter the catagen, or transitional phase, where the stromal cell division ceases and goes to telogen, usually three years for growth, three weeks for degeneration, and three months for rest. This takes Normally, 85-95% of hair grows, but the number decreases with age, and faster in male baldness.

Male pattern baldness is also known as adult alopecia, and its causes are diverse and complex, and can be divided into two types. First, there is senescence, blood circulation disorders, scalp tension, mental stress, nutritional imbalance, hormonal imbalance, genetic literacy and excessive boredom. Second, the direct cause is that mucopolysaccharides in the scalp are reduced, causing blood vessels to be compressed and hair loss due to asphyxiation of the hair follicles. Looking at each cause

First, seborrhea and dandruff make the scalp seborable and unsaturated fatty acids in the seborrheic deposits promote hair loss.

Secondly, due to the nutritional imbalance (dietary factor), the amount of certain substances increases, leading to blood disorders of peripheral capillaries, which causes hair loss due to malnutrition of hair follicles.

Third, hair loss is caused by genetic predisposition.

Fourth, insufficient blood circulation; Hair loss rates increase in the summer, as the temperature of the scalp rises and compresses, resulting in improper distribution of blood flow.

Fifth, when the scalp is tense, hair follicles contract.

Sixth, hair loss is caused by mental stress.

Seventh, hair loss is caused by hormonal unbalance.

On the other hand, general hair tonics may contain various hormones and vitamins to help hair growth, and salicylic acid, hinokitiol, and actinolate, which inhibit the growth of microorganisms. do. In addition, menthol, a cooling substance, may be added to promote blood flow. Looking at the recent development trend of hair growth agents, first, tricosaccharide (tricosaccharide), which has been proved to have a tricotogenic action as a complex material of mucopolysaccharide (mucopolysaccharide) is used. Tricosaccharide is a complex of polycopolysaccharide and polydeoxyribonucleoprotein extracted from connective tissue of animal organs.It is used as a therapeutic agent for atherosclerosis due to its action of reducing blood viscosity and promoting blood circulation. come. Second, PDG (pentadecanoic acid glyceride), which promotes energy metabolism, is the main ingredient. PDG promotes hair growth by effectively supplying energy to hair follicles. The hair growth mechanism consists in that the glucose transported by the blood stream is broken down through the excess and releases ATP, an energy substance in the TCA cycle.

In addition, there is one using a substance that inhibits the action of 5-alpha-redactase. 5-alpha-redactase transforms testosterone into 5-alpha-dihydrotestosterone and infiltrates into cells, inhibiting the synthesis of lipids and synthesis of lipids due to the effects of the 5-alpha-dihydrotestosterone hormone in the cells. It is said that hair loss occurs by sending promotion order. Conventional 5-alpha-redactase derivatives such as beta-glychilechin, psychosaponin, oxendron are known, but their effects are insignificant. In addition to stimulating the hair roots to facilitate metabolism, such as menthol (menthol), acetyl choline (acetyl choline).

Various medicines have been used for the hair restorer which has been used conventionally. For example, vitamin E and its derivatives, blood stimulators such as nicotinic acid benzyl esters, sugar extracts, topical stimulants such as pepper tink, hair follicle activators such as hinokithiol, placenta extracts, photosensitizers, estradiol, estrone, 5-alpha It has been used in combination as an anti-male hormone such as reddactase inhibitors, keratinous agents such as salicylic acid and resorcin, fungicides such as benzalkonium chloride, other amino acids and herbal extracts. However, such wool formulations cannot be said to have excellent wool effects in terms of their efficacy.

The present inventors have carefully studied the materials exhibiting wool and hair growth effects that are excellent for hair loss in view of the above circumstances, and have confirmed that a specific compound or salt thereof exhibits excellent hair growth effects, and have completed the present invention. . That is, certain compounds of the present invention and salts thereof have a structure similar to acetylcholine, so it is expected to have an effect such as vasodilation due to cholinergic reaction on peripheral blood vessels and thus hair growth by promoting blood flow to hair follicles. . A substance having a similar action is to affect the hair growth by cholinergic action of carpronium chloride (GABA methyl ester), but the effect is not excellent. There have been reports of adverse reactions, etc. The present inventors have completed a material that is considered to be safe for the living body as well as excellent effect.

The present invention relates to a hair growth promoter containing a compound represented by the following general formula (I) or a salt thereof.

[Y-NH (CH ₂ ) _n NR ₁ R ₂ R ₃ ] ⁺ (Q) ^- (I)

Wherein Q represents an anion such as chloride, bromide, iodide, phosphate, sulfonate, acetate, lactate, etc .; R ₁ , R ₂ , R ₃ represent lower alkyl or alkenyl having 4 or less carbon atoms which are the same or different from each other; Y represents C16 or less aminoalkyl, C2-C4 alkanoyl, benzoyl, a hydrogen atom; n represents the integer of 2-4.

With respect to general formula (I), R ₁ , R ₂ , R ₃ represent lower alkyl or alkenyl having up to 4 carbon atoms which are the same or different from each other, for example methyl, ethyl, propyl, isopropyl, butyl.

Y represents aminoalkyl having 16 or less carbon atoms or alkanoyl, benzoyl, or hydrogen atom having 2 to 4 carbon atoms, and suitable amino acids in aminoalkyl include phenylalanine, alanine, tyrosine, histidine, and valine. Alkanoyl having 2 to 4 carbon atoms represents a group such as acetyl, propionyl, butyryl.

The following compound (2) whose Y is acetyl in general formula (I) can be obtained from compound (1).

NH ₂ (CH ₂ ) _n NR ₁ R ₂ (1)

[Z-NH (CH ₂ ) _n NR ₁ R ₂ R ₃ ] ⁺ (Q) ^- (2)

Alternatively, to obtain compound (2), the primary amine of compound (1) is protected with a suitable protecting group. Z of the compound (2) represents a protecting group and suitable protecting groups are benzoyl, acetyl and the like.

To prepare compound (2), the primary amine of compound (1) undergoes a nucleophilic substitution reaction with benzoyl chloride or acetic acid or acetic anhydride. Most suitably, it reacts with acetic anhydride. A small amount of acid or alkali is added to facilitate the nucleophilic substitution reaction. Suitable time for the reaction is from 1 hour to 3 hours. After protecting the primary amine of Compound (1) with Z, it again causes nucleophilic substitution with a lower alkyl compound having a leaving group rate such as halogen having 4 or less carbon atoms.

In the resulting compound (2), Q can be exchanged to the next anion using ion exchange chromatography or difference in solubility product. In the compound (2), a strong inorganic acid (HQ ₁ ) is added and reflux exchanged to obtain a compound (3) in the form of disalt by hydrolysis.

An alkylamino acid is coupled to the primary amine salt of compound (3) to bond aminoalkyl having 16 or less carbon atoms. At this time, primary amine salts are added with alkali such as diisopropylethylamine, triethylamine, sodium hydroxide, potassium hydroxide, and desalting in advance.

Various well-known compounds can be used for coupling, For example, dicyclohexyl carbodiimide, N-hydrosuccinimide, carbonylimidazole, N-ethyloxycarbonyl-2-ethyloxydihydroquinoline, N Isobutyloxycarbonyl-2-iso-butyloxy-1,2-dihydroquinoline can be used. Suitable solvents for the reaction include dichloromethane, dimethylformamide, tetrahydrofuran and dioxane, either alone or as a suitable ratio. The reaction temperature and reaction time depend on the structure and properties of the reactants. In general, the reaction temperature is -5 ℃ to 120 ℃. Suitably, it is 0 degreeC-100 degreeC. The reaction time is generally 10 minutes to 72 hours and suitably 1 hour to 48 hours.

During the synthesis process or at the final stage, the protecting group of the amino acid side chain can be selectively or completely removed by general methods such as catalytic reduction and acid decomposition.

Removal of impurities after the reaction can be removed by fractional crystallization and, if necessary, can be carried out by chromatography, i.e., silica gel chromatography or gel chromatography.

The hair growth promoter of the present invention can be used in combination with conventional wool and hair growth agents as long as the action thereof is not impaired. As the base, for example, purified water, monohydric alcohols (ethanol, propyl alcohol, etc.), polyhydric alcohols (glycerin, etc.), higher fatty acids (palmitylic acid, linolenic acid, etc.), fats and oils (fatty acid glycerides, olive oil, squalene, etc.). ), Liquid paraffin, surfactants, emulsifiers, solubilizers and the like can be used.

Hair growth promoter of the present invention can be prepared in the form of conventional hair tonic, hair cream, hair lotion and the like. In such a formulation, the compounding amount of the compound represented by the general formula (I) or a salt thereof as a hair growth promoter is possible in a wide range, but usually 0.1 to 10% by weight, preferably 0.1 to 5% by weight.

Hereinafter, the synthesis of the general formula (I) will be described in detail through the preparation examples.

[Production Example 1]

(1) Preparation of N, N-dimethyl-N'-acetylethylenediamine

90 ml of toluene was added to a 250 ml round flask equipped with an addition funnel, and 13.7 g of N, N-dimethylethylenediamine (manufactured by Aldrich) was added thereto. While stirring slowly as a magnetic sterler, 15.3 g of purified acetic anhydride was carefully added dropwise. At this time, the exothermic reaction occurred severely and the fever subsided after the dropping. The solution turned slightly yellow and the solution was stirred again under reflux for 90 minutes. After completion of the reaction, toluene was removed by distillation at 105 ~ 115 ° C. using a short column of 10 cm. The resulting reddish brown fraction was dissolved in 75 ml of purified water. The aqueous solution was saturated with K ₂ CO ₃ , transferred to a continuous extraction apparatus and extracted with 350 ml of chloroform for 48 hours. The chloroform extract was dehydrated as anhydrous magnesium sulfate, and chloroform was distilled off at 60 to 62 占 폚. The orange oil was distilled under vacuum (14torr) to obtain an orange oil having a fraction boiling point of 125 ~ 129 ℃. Yield: 1.59 g (72%)

The structure of the prepared material was confirmed from the results of absorption spectra of nuclear magnetic resonance and infrared spectroscopy.

NMR (CDCl ₃ ): 2.1 (s, 3H, CH ₃ CO-), 2.2 (s, 6H, -N (CH ₃ ) ₂ ), 2.5 (t, 2H, NCH _2- ), 3.4 (q, 2H, -CH ₂ NH), 6.4 (br, 1H, -CH ₂ NH)

IR (CHCl ₃ film): 3300cm ^-1 (NH, st), 1650cm ^-1 (C = 0, st), 1510cm ^-1 (NH, m)

(2) Preparation of 2-acetaminoethyltrimethylammonium iodide

5.9 g of N, N-dimethyl-N'-acetylethylene diamine was added to 45 mL of anhydrous ethanol, the solution was cooled (using an ice-salt bath), and 9.67 g of purified methyl iodide was slowly added dropwise using a dropping funnel. . After the addition was completed, the solution was stirred at reflux for 30 minutes. After completion of the reaction, about half of the alcohol was distilled off and ether was added until the solution became cloudy. After being left in the refrigerator overnight, 11.5 g of pale yellow material was obtained. Purity was confirmed by recrystallization with ethanol-hexane. Melting Point: 140 ~ 141 ℃ (lit. 139 ~ 140 ℃)

The structure of the prepared material was confirmed from the absorption band analysis and mass spectrometry of the infrared spectrometer as follows.

IR (KBr pellet): 3210cm ^-1 (NH, m), 1625 (C = 0, st), 1535 (NH, m)

m / e 127 (I) ⁺ : 63.5 (metastable peak), 58 (CH ₃ CONH) ⁺ , 43 (CH ₃ C = 0) ⁺

[Production Example 2]

Preparation of (2-aminoethyl) trimethylammonium chloride hydrochloride

11 g of 2-acetaminoethyltrimethyl ammonium iodide was dissolved in 30 ml of 5% hydrochloric acid solution. Silver chloride was prepared in the dark using silver nitrate and 4N hydrochloric acid, and then 7.5 g of silver chloride was added to the solution containing the reactants. A precipitate of silver iodide was produced, which was filtered off and washed with a small amount of distilled water (5 mL). 40 ml of concentrated hydrochloric acid was added to the filtrate, and the mixture was stirred under reflux for 1 hour. After the reaction was completed, the resultant was concentrated by vacuum rotary evaporator to obtain an oily substance. The oily material was dried under vacuum (5torr or less) to give a white solid. Recrystallized from methanol, and the product was obtained in the yield of 6.5g (97%). Melting Point: 263 ~ 265 ℃

The structure of the prepared material was confirmed from the following results of nuclear magnetic resonance, absorption band analysis and mass spectrometry of infrared spectroscopy.

IR (KBr pellet): 3200 ~ 2400㎝ ^-1 (NH, st), 1460 ~ 1390㎝ ^-1 (NH, m)

m / e 35: 37 = 3: 1 (isotope peak of Cl), 36 (HCl)

NMR (TFA): 3.1 (s, 9H, (CH ₃ ) ₃ N ⁺ -), 3.7 (m, 4H, -CH ₂ CH _2- ), 7.5 (Br, 3H, -NH ₃ )

[Manufacture example 3]

Preparation of (2-aminoethyl) trimethyl ammonium chloride

3.5 g of (2-aminoethyl) triethyl ammonium chloride hydrochloride was dissolved in 100 ml of methanol. KOH methanol solution was added to neutralize accurately and then stirred for 3 hours at room temperature. Precipitated KCl was removed by filtration, and the filtrate was concentrated by vacuum rotary evaporator. 3.24 g of a white solid product was obtained. Yield: 95%

[Production Example 4]

3.304 g of L-phenylalanine was added to 200 ml of distilled water, and the mixture was dispersed with stirring, and 0.68 g (20 mmol) of sodium bicarbonate was added thereto to dissolve the solution transparently. 3.253 g (20 mmol) of octanoyl chloride was added to 200 mL of tetrahydrofuran, and this was slowly added to the flask containing the reactant with stirring. The reaction was terminated after stirring at room temperature for 16 hours. The pH of the solution was adjusted to 2-3 as 1N-HCl. The organic layer (20 mL) was concentrated on a vacuum rotary evaporator. 100 ml of distilled water was added to the residue, and the precipitate was obtained by filtration. Recrystallized as methanol-water to give octanoylphenylalanine (60% yield).

27.5 g (90 mmol) of octanoylphenylalanine and 10.34 g (90 mmol) of N-hydroxysuccinimide were dissolved in 390 ml of dry ethyl acetate, and then 18.5 g of dicyclohexylcarbodiimide was immediately added. It was reacted for 22 hours at room temperature and left overnight. Filtration removed the precipitate.

15.6 g (90 mmol) of the compound of Preparation Example 3 were added to the filtrate, and a small amount of acetic acid was added thereto. The reaction was stirred with 48 hours and concentrated in vacuo.

Gel chromatography was carried out using methanol as the elution solvent to obtain 14.5 g of a pure compound.

Production Example 5

Preparation of 2-acetaminopropyltrimethyl ammonium iodide

N, N-dimethylpropylenediamine was reacted with acetic anhydride in the same manner as in Production Example 1 to obtain 2-acetaminopropyltrimethylamine.

6.5 g of 2-acetaminopropyltrimethylamine was added to 60 ml of anhydrous ethanol, and purified ethyl iodide was slowly added dropwise with stirring. Stir at reflux for 1 h. After completion of the reaction, about half of ethanol was distilled off, and ether was added to obtain a solid product. The filtrate was removed by filtration and the solid product was dried in a vacuum dryer to yield about 12.1 g of pale yellow material.

[Manufacture example 6]

Preparation of 2-aminopropyltrimethylammonium chloride hydrochloride

The 2-acetaminopropyltrimethyl ammonium iodide obtained in Preparation Example 5 was treated in the same manner as in Preparation Example 2 to obtain 7.1 g of 2-aminopropyltrimethylammonium chloride hydrochloride.

Hereinafter, the effect of the hair growth promoter of the present invention through the examples.

Example 1

Hair growth promotion effect test

The hair growth promoting effect test was performed using black mouse (C57BL / 6, male), 47-50 weeks old, to remove the hair on the back, and in the center of the head, such as 5 days per group, prepared in Preparation Example 2 Using (2-aminoethyl) trimethylammonium chloride hydrochloride as a test substance, 1 mg / mol (dissolved in 0.1 ml distilled water) of each test substance was injected by intradermal injection. In the case of the control group, 0.1 ml of distilled water was injected. Hair length and hair growth over time were compared with the control. The test results are shown in Table 1 below.

TABLE 1

Example 2

Cell growth promoting effect test

In order to investigate the effect on cell growth, fibroblasts, which are present in many skin tissues, were separated from the skin of two-day-old mice by trypsin treatment, and cells of 3 to 5 generations were used. The medium used for cell culture was Eagle's Minimum Essential Medium (EMEM) containing 5% fetal bovine serum and was cultured in 5% carbon dioxide-95% oxygen, 37 ° C., saturated incubator. Using (2-aminoethyl) trimethylammonium chloride hydrochloride prepared in Preparation Example 2 as a test substance, the test substance was adjusted to a final concentration of 0.5 to 0.5 x 10 ^-7 mM in the test solution, and then, a control group was prepared in a 96-well plate. Incubated with. The initial adjusted cell number was 5 × 10 ³ cells / well, and the test results were summarized by applying the cell proliferation assay for cell number changes after 3 days of treatment with the test material (MTT assay).

The result is shown in FIG.

As a result of the above test, it can be seen that the test substance is not only toxic to the cells but also shows an active effect on the cells at low concentration. Therefore, it is conceivable that the above test prescription substance is not only active against foreign cells but also has a clear active effect on hair follicle cells.

From the above results, it is considered that the hair growth promoter of the present invention exerts an excellent hair growth promoting effect.

Example 3

Hair tonic

Ethanol 65.0%

Castor Oil 5.0%

Glycerin 3.0%

(2-aminoethyl) trimethylammonium 0.1%

Chloride hydrochloride

Spices, pigments

Add purified water to make 100 whole quantity.

Example 4

Hair Cream

Liquid Paraffin 50.0%

Polyethylene Glycol 1.0%

Tween 20 0.1%

(2-aminoethyl) trimethylammonium 0.2%

Chloride hydrochloride

Add purified water to make 100 whole quantity.

Example 5

Hair lotion

Cetostearyl alcohol 2.0%

Stearyltrimethylammonium Chloride 2.0%

Hydroxyethyl cellulose 0.5%

(2-aminoethyl) trimethylammonium 0.5%

Chloride hydrochloride

Fragrances, pigments 1.0%

Add purified water to make 100 whole quantity.

Claims (3)

A hair growth promoter comprising a compound represented by the following general formula (I) or a salt thereof as an active ingredient. [Y-NH (CH ₂ ) _n NR ₁ R ₂ R ₃ ] ⁺ (Q) ^- (I) (In the general formula (I) (Q) ^- is chloride, bromide, iodide, phosphate, represents an anion selected from sulphonate, acetate, lactate, R _1, R _2, R ₃ are the same or different carbon atoms, Lower alkyl or alkenyl having 4 or less, Y represents an aminoalkyl group having 16 or less carbon atoms, a benzoyl group, a hydrogen atom, and n represents an integer of 2 to 4) The method of claim 1, wherein the hair growth promoter, characterized in that the formulation of hair tonic, hair cream, hair lotion. The hair growth promoter according to claim 2, which contains 0.1 to 1.0% of a compound of formula (I) or a salt thereof.