JPH0276804A - Hair tonic - Google Patents

Abstract

PURPOSE:To obtain a novel hair tonic showing excellent hair growing effects on alopecia free from side effects, comprising phytyl nicotinate, phytyl propionate, phytyl isobutyrate, etc., as an active ingredient. CONSTITUTION:A hair tonic comprising a compound (e.g., phytyl nicotinate, phytyl propionate, phytyl isobutyrate, etc., monophytyl succinate, phytyl 3,4- dioxymethylenebenzoate or phytyl acetylactate) shown by formula I (R<1> is 20C noncyclic branched chain higher aliphatic hydrocarbon group; R<2> is acyl) as an active ingredient. The compound shown by formula I, for example, is obtained by reacting a compound shown by formula II or a salt thereof with a compound shown by formula III or a reactive derivative at a carboxyl group thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel hair nourishing agent. More specifically, the general formula [I] R'-0-R2 [I] 1 In the formula, R1 is an acyclic branched higher aliphatic hydrocarbon group having 20 carbon atoms which may be substituted with an acyloxy group. of:
R2 represents an acyl group. This invention relates to a hair tonic containing a compound represented by the following as an active ingredient.

[Conventional technology] Conventionally, various active ingredients have been used in hair nourishing agents.
For example, amino acids such as serine and methionine; vasodilators such as niacetylcholine derivatives; anti-inflammatory agents such as salicylic acid Miyo and purple root extract; hormonal agents such as estradiol; vitamins such as vitamin E; dikeratolytic agents; humectants; fragrances. ; anti-dandruff agents; refreshing agents; crude drug extracts; and hair nourishing agents containing fatty acids and the like are known.

Further, JP-A No. 60-4113@ describes alcohols or derivatives thereof having an odd carbon chain length as an active ingredient of a hair tonic. Zarani, Japanese Patent Publication No. 61-207
No. 321 contains 22 to 22 carbon atoms as the active ingredients of the hair growth agent.
Thirty-four higher aliphatic alcohols have been described.

[Problems to be Solved by the Invention] However, the reality is that none of the hair growth agents that have been used so far has a sufficient hair growth effect.

[Means for Solving the Problems 1] In view of the above-mentioned circumstances, the present inventors conducted intensive research on substances that exhibit excellent hair growth effects against alopecia without any side effects, and found that the general formula [I ] It was discovered that a compound represented by the following formula exhibits an excellent hair growth effect, and the present invention was completed.

An object of the present invention is to provide a hair tonic containing as an active ingredient a compound that exhibits an excellent hair growth effect.

The present invention will be explained in detail below.

In the compound of general formula [I], the number of carbon atoms in R1 is 2
Examples of the acyclic branched higher aliphatic hydrocarbon group of 0 include phytyl group (3,7,11,15-tetramethyl-2-hexadecen-1-yl group), isophyl group (
3,7,11,15-tetramethyl-1-hexadecen-3-yl group), geranyllinalyl group (3,7,11,
15-tetramethylhexadecane-1.6.10.14
-tetraen-3-yl group) and 7-hydroxymethyl-3,11,15-trimethylhexadecane-2,6
, 10,14-tetraen-1-yl group and the like.

In addition, as the acyloxy group in the substituent of R1,
Examples include acyl-〇-groups composed of the same groups as the acyl group in R2 described later.

Further, as the acyl group in R2, for example, C2
~2o aliphatic acyl groups, such as acetyl, propionyl, butyryl, isobutyryl, isovaleryl, pivaloyl, lauroyl, balmitoyl and stearoyl, C alkenoyl groups such as acryloyl, propioloyl, etc. C-alkynoyl groups and C-cycloalkylcarbonyl groups such as cyclopropylcarbonyllohexylcarbonyl; aroyl groups such as benzoyl and naphthoyl; and nicotinoyl, isonicotinoyl,
Included are groups such as 5- or 6-membered heterocyclic carbonyl groups such as 1,4-dihydropyridylcarbonyl, prolyl, thenoyl and furoyl, which include C1-4 carbonyl groups such as methyl, ethyl, n-propyl and isopropyl.
Alkyl groups; C cycloalkyl groups such as cyclopropyl, cyclobutyl and cyclohexyl; C alkoxy groups such as methoxy, 3-7 ethoxy, n-propoxy and isopropoxy; C with isopropylthio alkylthio group niacetyloxy, 1-4 C with propionyloxy and butyryloxy
Acyloxy group; C alkylenedioxy group such as methylenedioxy and 2-4 and ethylenedioxy; hydroxyl group; aryl group such as phenyl, 3-nitrophenyl and naphthyl; carboxyl group; methoxycarbonyl and ethoxycarbonyl C alkoxycarboxyl groups such as 1-4 nyl groups; amino groups; C alkylamino groups such as methylamino and ethylamino; dimethyl 1-4 amino groups such as diethylamino, diethylamino and methylethylamino; and 1-4 trimethyl Ammonio and triethyl ammonium
Tri-C such as O, alkyl ammonio group 1 ~
4. May be substituted with one or more substituents selected from.

Among these, hydroxyl groups, carboxyl groups, amino groups, alkylamino groups, etc.
anic Synthesis) [Theodora W. Green]
, John Wiley & Sons, Inc.
nc. )] may be protected with a conventional protecting group such as those described in .

Next, a method for producing the compound of general formula [I] will be explained.

Production method (1) The compound of general formula [I] has the general formula [II] R1-OH'
[R1 [wherein, R1 has the same meaning as described above]. ] The compound or its salt represented by the general formula [m]R-
-0w1 [111] "In the formula, R- has the same meaning as defined above." It can be obtained by reacting a compound represented by the following or a reactive derivative thereof in the carboxyl group.

Examples of the salt of the compound of general formula [ff] include salts with alkali metals such as sodium and potassium.

Further, examples of reactive derivatives at the carboxyl group of the compound of general formula [111] include acid halides, active acid amides, active esters, acid anhydrides, and mixed acid anhydrides.

When using the compound of general formula [I[1], it is preferable to use a common dehydration condensation agent such as dicyclohexylcarbodiimide, and when using a reactive derivative in the carboxyl group of the compound of general formula [111], hydrogen Preference is given to using inorganic or organic bases such as sodium chloride, lysine and triethylamine.

This reaction may be carried out in a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction, but examples include aromatic hydrocarbons such as benzene and toluene; methylene chloride and Halogenated hydrocarbons such as chloroform; ethers such as tetrahydrofuran and dioxane; pyridine; amides such as hexamethylphosphoric triamide, N,N-dimethylformamide and N,N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. These solvents may be used alone or in combination of two or more.

In this reaction, the amount of the compound of general formula [II[] or its reactive derivative at the carboxyl group to be used is at least equimolar to the compound of general formula [nl] or its salt, and the amount of the dehydration condensing agent or When using bases,
The amount of the dehydration condensation agent or base to be used is at least equimolar to the compound of general formula [I[] or its salt.

This reaction may normally be carried out at 0 to 80°C for 10 minutes to 10 hours.

Production method (2) The compound of the general formula [II is the compound of the general formula [IV]R'-X
[IV] By reacting a salt of a compound represented by the general formula [m] with a compound represented by "In the formula, R1 has the same meaning as described above, and X represents a leaving group." Obtainable.

In the compound of general formula [IV], the leaving group for X includes, for example, a halogen atom such as fluorine, chlorine, bromine, and iodine; a C1-4 alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; or toluene Examples include arenesulfonyloxy groups such as sulfonyloxy and benzenesulfonyloxy.

Examples of the salts of the compound of general formula [I[] include salts with alkali metals such as sodium and potassium.

This reaction may be carried out in a solvent, and the solvent used is not particularly limited as long as it does not adversely affect the reaction, but specifically, the same solvents as mentioned in the above production method (1) can be used. can be mentioned.

In this reaction, the amount of the salt of the compound of general formula [I[1] to be used is equal to or more than the equivalent mole of the compound of general formula [IV].

This reaction is usually carried out at -70 to 150°C for 10 to 20 minutes.
All you have to do is time it.

The compound obtained by the above production method (1) or production method (2) is
After removing the protecting group by conventional methods, it can be purified by conventional means such as column separation and distillation.

In addition, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compound of general formula [II or a salt thereof, the present invention includes all such isomers, It also covers all crystal forms and solvates.

The content of the compound of general formula [I] in the hair nourishing agent (total weight) of the present invention is not particularly limited and can be selected within a wide range, but is usually 0.1 to 10%, preferably 0. It is sufficient if it is .5 to 5%.

The hair tonic of the present invention includes amino acids (serine, methionine, etc.), hormonal agents (progesterone, estradiol, etc.), anti-inflammatory agents (purple root extract, glycyrrhizinic acid, hydrocortisone acetate, etc.), vasodilators such as cotinic acid, minoxidil, etc.), herbal extracts (Japanese cabbage extract, carrot extract, etc.), anti-dandruff agents (hinokitiol, sulfur nato), cooling agents (1-menthol, camphor, etc.), Humectants (glycerin, mucopolysaccharides, pyrrolidone carboxylic acid, etc.), keratolytic agents (urea, resorcinol, etc.), fragrances (lavender oil, neroli, bergamot etc.), vitamin A, vitamin E or vitamin E derivatives, vitamin B6, Vitamin H, lecithin, fatty acids, etc. can be used singly or in combination of two or more.

Examples of base materials include purified water, -hydric alcohols (ethanol, isopropyl alcohol, etc.), polyhydric alcohols (glycerin, propylene glycol, etc.), higher fatty acids (palmitic acid, linoleic acid, etc.)
, fats and oils (fatty acid glycerides, olive oil, screens, beeswax, etc.), liquid paraffin, surfactants (polyoxyethylene hydrogenated castor oil, stearyltrimethylammonium chloride, distearyldimethylammonium chloride, sodium lauryl raate, etc.), emulsifiers (cetyl alcohol) and solubilizers, etc. can be used.

The hair tonic of the present invention can be prepared by a conventional method such as a hair tonic,
It can be prepared and used in various dosage forms such as hair cream, hair lotion, or hair spray.

Next, the effects of the hair tonic of the present invention will be explained.

(Hair growth promotion effect test) A group of 4 6-week-old BDFL male mice were pricked from the back to the buttocks with a safety razor, and from the next day, 2% (weighted) was used to suppress hair growth. An ethanol solution containing 0.2 m/mouse of testosterone was applied once a day for 1 week. From the 8th molar onwards, the same amount was applied twice/week for 3 weeks.

On the other hand, the test solution was applied once a day for 3 weeks (excluding Sundays) at a rate of 0.2 Idt/mouse from the 8th molar of the hair. In addition, for the control group, a solution (hereinafter abbreviated as mixed solution A) consisting of 85.5 parts by weight of ethanol, io, and 4 parts of glycerin, and 4.5 parts by weight of purified water (hereinafter abbreviated as mixed solution A) was applied to 0.2 m/mouse by pricking. It was applied once a day from the 8th mound for 3 weeks (excluding Sundays).

The hair growth promoting effect of the novel hair growth agent of the present invention was determined by observing the degree of hair growth with the naked eye every day and measuring the size of mice that had hair growth on the entire surface of the stinging site.

In addition, in Table 1, the hair growth promoting effect observed 2 weeks and 3 weeks after administration of the test solution is shown below. Indicated by

In addition, the test solution is the compound indicated by the reference side number in Table 1.
The mixture prepared by mixing with liquid mixture A at the temperature shown in 1 was used.

(The following is a blank space) Table 1 *1-Pentadecanoylglycerol book *Weight ratio to mixture A As is clear from these results, the hair growth agent of the present invention exhibits an excellent hair growth promoting effect.

[Effects of the Invention] The compound of the present invention represented by the general formula % "In the formula, R and R2 have the same meanings as described above" can be used as a hair nourishing agent.

Next, the method for producing the compound represented by the general formula [I] of the present invention will be specifically explained by giving reference examples.

All mixing ratios of mixed solvents are volume ratios, and the carrier in column chromatography is silica gel manufactured by Merck [Kiesel Gel 60,
Art, 7734 (in ieselgel 60.

Art. 7734)] was used.

Reference example 1 phytol 10.0g and triethylamine 9.03
Nicotinic acid chloride 7, 29 is added to a mixed solution of 50 ml of methylene chloride containing the following at 30 to 40°C, and the resulting mixture is stirred at the same temperature for 2 hours. After the reaction is completed, the reaction mixture is washed successively with dilute hydrochloric acid, a 3% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the iq residue was subjected to column chromatography (eluent: n-hexane: ethyl acetate = 9:
If purified by 1), oily phytyl nicotinate 12
．． 1 g (90% yield) is obtained.

IR) cm-1: 2920, 2850.
1725N) IR (CDCl2) δ value; 0, 86 (12H, d, J = 5.5Hz), 0.99 ~
1.65 (1911, m).

1, 76 (3H, s), 1. 70 ~2.
25 (2H, m).

4, 87 (2H, d, J = 7.0Hz), 5.48 (l
tl, t, J=6.4Hz).

7, 33, 7. 40 (IH, dd, J=7.
9Hz, J=4. 6Hz).

8, 22, 8. 35 (IH, dt, J=4.
6tlZ, J=1.9Hz).

8, 74, 8. 77 (11, dd, J=4.
6Hz, J=1. 9Hz).

9, 23 (1H, d, J=1.9Hz) In the same manner, the compounds shown in Table 2 are obtained.

Reference example 19 Phytol 10.09tj and triethylamine 4.5
10 d of a methylene chloride solution containing 10.0 g of chloroacetylmandelic acid chloride is added dropwise to a mixed solution of 30 d of methylene chloride containing 3 at 30 to 40° C., and the resulting mixture is stirred at the same temperature for 2 hours. After the reaction is completed, the reaction mixture is washed successively with dilute hydrochloric acid, 3% aqueous sodium bicarbonate solution, and water. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 50 ml of methanol. 3.8 ml of triethylamine and 2.97 ml of thiourea were added thereto at air temperature, and the resulting mixture was heated at the same temperature. Stir for 3 hours. After the reaction is completed, the reaction mixture is concentrated to dryness under reduced pressure, and the resulting residue is dissolved in ethyl acetate. This solution is washed successively with dilute hydrochloric acid, a 3% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: n-
If purified with hexane:ethyl acetate=9:1),
Oily phytyl mandelate13. (IJ (yield 90%)
get.

IR) cm-1; 3500.2920.28
50.173ONMR (CDCl2 > δ value: o, 8B (12H, d, J=5.5Hz), 0
．． 99-1.55 (191 L m).

1, 60 (3H, S), 1.70-2.20 (2H,
m).

3.64 (ltl, bs), 4.64 (21, d, J=
7.3Hz).

5, 14 (1H, s), 5.27 (IH, t, J
=7.0Hz).

7, 10-7.55 (5H, m) Reference example 20 Phytyl lactate is obtained in the same manner as in Reference Example 19.

IR) cm-1: 3450, 2920, 28
60.173ON) IR (CDCl2) δ value; 0.86 (1211, d, J=5.4Hz), 1.00
~1.60 (22H, m).

1.69 (311,s), 1.85-2.30 (211,s)
, m).

4, 10-4.50 (IH, m), 4.68 (2H,
d, J=6.8tlz).

5, 35 (111,t, J=6.8H2) Reference example 2
1 Add 10.0 bromophytyl to a mixture of 40 m of N,N-dimethylformamide containing 6.4 g of sodium nicotinate.
g is added and the resulting mixture is stirred at 60'C for 15 hours. After the reaction is complete, concentrate the reaction mixture under reduced pressure,
The resulting residue is dissolved in n-hexane. This solution is washed successively with dilute hydrochloric acid, a 3% aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: n-hexane: ethyl acetate = 9:
If purified by 1), 8.4 g of oily phytyl nicotinate
(yield 75%).

The physical properties (IR, NMR) of this compound matched those of the compound obtained in Reference Example 1.

Reference example 22 N-7 cetylglycine 4.749 and 4-(N.

A mixed solution of 70 d of methylene chloride containing 12.369 d of N-dimethylamine)pyridine is cooled to -50 DEG C., and 4.259 d of methanesulfonyl chloride is added dropwise thereto.

After the addition was completed, the resulting mixture was stirred at the same temperature for 1 hour,
Phytol io and oo g are added dropwise to this at the same temperature.

After the dropwise addition is completed, the temperature of the reaction mixture is raised to room temperature over a period of 6 hours. The reaction mixture is then washed successively with 2N hydrochloric acid, 3% aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (eluent: chloroform) to obtain 12.00 g of oily N-acetylglycylphityl (yield 90.2%). obtain.

IR) cm-1: 32B0.2920.28
60.1747° Open chain CDCl3>δ value; 0.86 (12H, d, J=5.5112), 1.0
0-1.60 (191, m).

1.69 (3H, S), 1.85-2.30 (5N, m
).

4, 01 (2H, d, J=4.9Hz), 4.
66 (2H, d, J=7.311z).

5.39 (IH, t, J=7.1Hz), 6.23
(IH, bs) Compounds shown in Table 3 are obtained in the same manner.

(Left below) Reference Example 27 N-trichloroethoxycarbonylglycine 5.0 (I
J and 4-(N,N-dimethylamino)pyridine 8
．． A mixture of 35 parts of methylene chloride containing 109 was heated to -50°C.
Cool to 2.10% of methanesulfonyl chloride!
Drip 7. After the dropwise addition is completed, the resulting mixture is stirred at the same temperature for 1 hour, and Phytol 4.939 is added dropwise thereto at the same temperature. After the dropwise addition is completed, the temperature of the reaction mixture is raised to room temperature over a period of 6 hours.

The reaction mixture is then washed successively with 2N hydrochloric acid, 3% aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in tetrahydrofuran 86d. To this solution are added 86d of 0.5N aqueous monobasic potassium phosphate solution and 13.409d of powdered zinc, and the resulting mixture is stirred at room temperature for 2 hours. Then, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and 30 ml of ethyl acetate was added to the resulting residue.
is added, washed with 2N hydrochloric acid, and then dried over anhydrous magnesium sulfate. After introducing hydrogen chloride gas into this solution, the solvent is distilled off from the resulting solution under reduced pressure.
Oily glycylphityl hydrochloride 5.809 (yield 90
%).

IR) cm-1; 3400.2920.28
60.1745N) IR (CDCl2>δ value; 0, 86 (12H, d, J=5.5Hz), 1.0
0-1.60 (19H, m).

1.68 (311,S), 1.95~2.12 (2N
, m).

3,99 (2tl,,s), 4.61 (2H,d,
J=6.6Hz).

5, 30 (IH, t, J=6.6112) Reference Example 28 In the same manner as in Reference Example 27, the hydrochloride of baryl phytyl is obtained.

IR) cm-1; 2910.2850.17
3ONHR (CDCl2) δ value; 0.50-1.05 (18H, m), 1.05-1.6
0 (19H, m).

1,71 (3H,m), 1.82~2.50 (3+
1. m).

4,00(IH,s), 4.70(2N, d, J
=7.0Hz).

5, 32 (IH, t, J = 7.0H7), 8.30 (2
N, S) Reference Example 29 N, N-dimethylglycylphityl 10. 4.53 ml of methyl iodide is added to a mixture of 30 ml of methylene chloride containing Og, and the resulting mixture is stirred at room temperature for 1 hour. After the reaction is completed, the solvent is distilled off under reduced pressure to obtain 12 g of oily α-trimethylammonioacetic acid phytyl ioside (yield: 88
%).

IR) cm-1: 2910.2850.17
35NMR (CDCl2>δ value: 0, 89 (12H, d, J=5.5NZ), 1.0
0-1.65 (19H, m).

1,71 (3H,s), 1.90-2.30 (2
H, m).

3°74 (9N, s), 4.70~5.10 (4H, m
).

5, 34 (1M, t, J = 6. IHz) Reference Example 30 6.63 ml of sodium cyanate was added little by little to a mixture of 950 rdl of vinegar containing phytol io, o9, and the resulting mixture was kept at room temperature for 6 hours. Stir. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (55%).
Dissolve to 0 tri. This solution is washed successively with a 3% aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. This solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography (eluent: benzene) to obtain oily phytyl carbamate 1.
0.09 (yield 87%) is obtained.

IR (knee I”) cm-1; 3320.2910
．． 2850.172ON) fR (CDCl2>δ value: 0.86 (12H, d, J=5.5Hz), 1.00
~1.60 (19H, m).

1,73 (3N, m), 1.80-2.30 (2H
, m).

4, 57 (2H, d, J=7.0Hz), 5.3
4 (IH, d, J=7.0tlz) [Example] Next, as an example of the present invention, various dosage forms of the hair tonic of the present invention are shown together with their compositions (% by weight). It is not limited to these.

Example 1 (hair lotion) (Ingredients) M content (wt%) L Purified water 11.4 Example 2 (
(Ingredients) Content (wt%) Example 3 (hair cream) (Ingredients) Content (wt%) Example 4 (hair rinse) (Ingredients) Content (wt%)

Claims (1)

[Claims] (1) General formula R^1-O-R^2 "In the formula, R^1 is an acyclic branched higher aliphatic hydrocarbon group having 20 carbon atoms which may be substituted with an acyloxy group;
R^2 represents an acyl group. A hair tonic containing a compound represented by the following as an active ingredient.