JP2001278873A - Hair tonic - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a hair tonic excellent in hair tonic effects such as prevention of alopecia and promotion of hair growth. SOLUTION: This hair tonic comprises a thiadiazole amide derivative represented by the following general formula (I) [R1 and R2 are each H, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a lower alkylaminoalkyl group, a cyclic aminoalkyl group, benzyloxy group or O-R (R is an unsaturated aliphatic hydrocarbon group); R3 is H, an aryl group, pyridyl group, a lower alkylamino group or a cyclic amino group; and A is a 1-5C bivalent saturated hydrocarbon group] or its salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hair restorer, particularly to a hair restorer containing a thiadiazole amide derivative as an active ingredient.

[0002]

2. Description of the Related Art Conventionally, baldness and hair loss have been caused by activation of male hormones in organs such as hair roots and sebaceous glands.
Abnormalities in the scalp due to decreased blood flow to the hair follicle, excessive secretion of sebum, and generation of peroxide are considered. For this reason,
Conventionally, a hair restorer (also referred to as a hair restorer or a hair growth enhancer) for the purpose of promoting hair growth and hair growth and preventing hair loss has the effect of removing or reducing the above-mentioned causes. Compounds or compositions having are generally formulated.

For example, vitamins such as vitamin B and vitamin E; amino acids such as serine and methionine; vasodilators such as assembly extract and acetylcholine derivatives; anti-inflammatory agents such as purple root extract and hinokitiol; and female hormones such as estradiol. And skin function enhancers such as cepharanthin.

[0004]

However, in spite of the fact that such a drug is incorporated, the conventional hair restorer does not always have sufficient hair-growth effects such as prevention of hair loss and promotion of hair growth. SUMMARY OF THE INVENTION The present invention has been made in view of the problems of the related art, and an object of the present invention is to provide a hair restorer having an excellent hair restore effect such as prevention of hair loss and promotion of hair growth.

[0005]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to achieve the above object, it has been found that specific thiadiazole amide derivatives and salts thereof have excellent hair growth promoting effects,
The present invention has been found to have a hair growth period extending effect, and has completed the present invention. That is, the hair restorer according to the present invention is characterized by comprising a thiadiazole amide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0006]

Embedded image (In the general formula (I), R ¹ and R ² are each a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a lower alkylaminoalkyl group, a cyclic aminoalkyl group, a benzyloxy group, Or -OR
Wherein R is an unsaturated aliphatic hydrocarbon group.
R ³ is a hydrogen atom, an aryl group, a pyridyl group, a lower alkylamino group, or a cyclic amino group. A has 1 to 1 carbon atoms
5 is a divalent saturated hydrocarbon group. )

In the hair restorer of the present invention, R ¹ is preferably a hydrogen atom. Further, it is preferable that R ² is a lower alkyl group. Further, it is preferable that R ² is a lower alkoxy group. Further, it is preferable that R ² is a lower alkylamino group. Further, it is preferable that R ² is a cyclic aminoalkyl group. Further, it is preferable that R ² is —O—R (R is an unsaturated aliphatic hydrocarbon group). Further, it is preferable that R ² is a hydrogen atom.

In the hair restorer of the present invention, R ¹ and R ² are preferably a lower alkyl group. Also,
In the hair restorer of the present invention, R ¹ is preferably a benzyloxy group, and R ² is preferably a lower alkyl group. In the hair restorer of the present invention, R ³ is preferably a lower alkylamino group or a cyclic amino group. Also,
It is preferred that R ³ is a hydrogen atom. Further, in the hair restorer of the present invention, A is preferably an ethylene group or a propylene group.

Further, the thiadiazolamide derivative according to the present invention is a compound represented by the following general formula (IA) or a salt thereof.

Embedded image (In the general formula (IA), R ¹ and R ² are each a hydrogen atom or an alkyl group having 7 to 10 carbon atoms, but at least one of R ¹ and R ² is not a hydrogen atom. R ³ is a hydrogen atom , an aryl group, a pyridyl group, a lower alkylamino group, or a cyclic amino group .A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms.) in the general formula (IA), -A-R ³ There - (CH _{2) 2} -
N (C ₂ H ₅ ) ₂ is preferred. In the general formula (IA), R ¹ is preferably a hydrogen atom, and R ² is preferably an n-octyl group.

The thiadiazole amide derivative according to the present invention is characterized in that it is 2- (4-n-pentylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. The thiadiazole amide derivative according to the present invention is characterized in that it is 2- (4-n-hexylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof.

The thiadiazole amide derivative according to the present invention is 2- (4-dimethylaminobenzoyl) amino-5
-Diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. Further, the thiadiazole amide derivative according to the present invention is 2- (3-dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4
-It is characterized by being thiadiazole or a salt thereof.

The thiadiazole amide derivative of the present invention is 2- (3-piperidinomethylbenzoyl) amino
-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole or a salt thereof. Moreover, the thiadiazole amide derivative according to the present invention is characterized in that it is 2-benzoylamino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The lower alkyl group for R ¹ and R ² is a linear or branched alkyl group having 1 to 10 carbon atoms. For example, methyl group, ethyl group, n-propyl group, n-butyl group, isopropyl group, isobutyl group,
1-methylpropyl group, tert-butyl group, n-pentyl group, 1-ethylpropyl group, isoamyl group, n-hexyl group, n-octyl group, n-nonyl group, n-decyl group and the like can be mentioned. Is preferably an n-octyl group. In the present invention, the definition of the lower alkyl group is the same unless otherwise specified.

The lower alkoxy group in R ¹ and R ² means a hydroxyl group having a hydrogen atom substituted by a lower alkyl group, preferably a branched lower alkoxy group, particularly preferably an isopropoxy group or tert-butoxy group. Group. In the present invention, unless otherwise specified.
The definition of lower alkoxy is the same.

Further, R ¹ and R ² may be substituted amino groups such as lower alkylamino group or cyclic amino group. A lower alkylamino group is an amino group whose hydrogen atom has been substituted by one or two identical or different lower alkyl groups. The cyclic amino group is a 4- to 8-membered saturated monocyclic amino group, and examples thereof include an azetidino group, a pyrrolidino group, and a piperidino group. Among the substituted amino groups in R ¹ and R ² , a lower alkylamino group is preferable, and a tert-butylamino group and a dimethylamino group are particularly preferable. In the present invention, lower alkylamino groups and cyclic amino groups have the same definitions unless otherwise specified.

Further, R ¹ and R ² may be an amino-substituted alkyl group such as a lower alkylaminoalkyl group or a cyclic aminoalkyl group. Of these, a cyclic aminoalkyl group is preferred, and a piperidinomethyl group is particularly preferred. The benzyloxy group in R ¹ and R ² is such that a substituent selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a nitro group and a cyano group is added to the benzene ring.
Or two. Among such substituents, preferred are halogen atoms, and particularly preferred is fluorine.

Further, R ¹ and R ² can be groups represented by —OR. R represents a linear or branched unsaturated aliphatic hydrocarbon group having at least one double bond and having 2 to 20 carbon atoms, and is preferably a branched chain.
As the branched unsaturated aliphatic hydrocarbon group, a prenyl group, a geranyl group, a neryl group, a farnesyl group and the like are preferable, and a geranyl group is particularly preferable. Among these, it is particularly preferred that R ¹ is a hydrogen atom and R ² is a hydrogen atom, a lower alkyl group or a cyclic aminoalkyl group.

R ³ can be a hydrogen atom, an aryl group such as a phenyl group or a naphthyl group, or a pyridyl group. The aryl group and the pyridyl group may have one or two substituents such as a lower alkyl group on the ring. For example, a tolyl group, a xylyl group and the like can be mentioned. In addition, R ³
May be a substituted amino group such as a lower alkylamino group or a cyclic amino group. The lower alkylamino group for R ³ is preferably a dimethylamino group, a diethylamino group, or a diisopropylamino group, and particularly preferably a diethylamino group. The cyclic amino group for R ³ is preferably a piperidino group.

Of these, R ³ is preferably a lower alkylamino group or a cyclic amino group, particularly preferably a lower alkylamino group. Carbon number 1 in A
Examples of the divalent saturated hydrocarbon group of Nos. To 5 include a methylene group, an ethylene group, a propylene group, a 2-methylpropylene group, a butylene group, a pentylene group, and the like, and preferably an ethylene group and a propylene group. The thiadiazole amide derivative and the salt thereof according to the present invention can be produced by a known method. For example, from the following carboxylic acid (II) and substituted thiadiazole (III), the compound of the present invention (A) by a known amide bond forming reaction such as a mixed acid anhydride method, an acid chloride method, a DCC method, a CDI method or an azide method. I) can be obtained.

[0020]

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The carboxylic acids (II) are commercially available or can be easily synthesized from benzoic acids having the corresponding functional groups. For example, when R ¹ or R ² is a lower alkoxy group, a lower alkylamino group, or —O—R
Carboxylic acid (II) is, after protecting the carboxyl group of a benzoic acid having a hydroxyl group or an amino group on the benzene ring, a lower alkyl group or a group R is introduced into the hydroxyl group or the amino group, and then a carboxyl group protecting group Can be obtained by deprotecting The introduction of the lower alkyl group or group R can be carried out by reaction with a corresponding alcohol or alkene under acidic conditions, or a corresponding alkyl halide or R—X (X is a halogen) under basic conditions.
Can be carried out by a reaction with

The carboxylic acid (II) wherein R ¹ or R ² is a lower alkylaminoalkyl group or a cyclic aminoalkyl group is obtained by protecting the carboxyl group of a benzoic acid having an alkyl group in a benzene ring, The compound can be obtained by introducing a halogen into a group, substituting the halogen with a lower alkylamino group or a cyclic amino group under basic conditions, and then deprotecting the carboxyl group-protecting group. The introduction of the halogen is carried out by N-bromosuccinimide
(NBS) or N-chlorosuccinimide (NCS).

The carboxylic acid (II) in which R ¹ is a lower alkyl group and R ² is a benzyloxy group is obtained by protecting the carboxyl group of a benzoic acid having a lower alkyl group and a hydroxyl group on a benzene ring. The hydroxyl group is converted to a benzyloxy group by reacting with a benzyl halide under basic conditions, and then the carboxyl protecting group is deprotected. In this case, the starting compound is commercially available or can be synthesized by a known method. For example, after protecting the carboxyl group of a benzoic acid having a hydroxyl group on the benzene ring, the alkenyl group is reacted with the corresponding alkenyl halide under basic conditions to convert the hydroxyl group to an alkenyloxy group. By sequentially performing a deprotection reaction of a carboxyl protecting group.

When R ¹ or R ² is a cyclic amino group, a known amide bond-forming reaction can be carried out from a benzoic acid having a halogen such as chlorine on the benzene ring as a substituent and a substituted thiadiazole (III). To form a thiadiazole amide, and then substituting the halogen with a cyclic amine to obtain the desired present compound (I). The substitution reaction of the cyclic amine with the halogen is usually performed at 70 to 140 ° C. in the absence of a solvent, and potassium carbonate and copper (II) chloride or copper (II) oxide may be added as necessary. On the other hand, substituted thiadiazole (III) is, for example, a 2-amino-5-mercapto-1,3,4-thiadiazole, by reacting the corresponding halide X-A-R ³ in basic conditions to give be able to.

For the above synthesizing method, the method described in JP-A-9-249656 can be referred to. The thiadiazole amide derivative which is an active ingredient of the hair restorer according to the present invention is exemplified below.

Compound 1: 2- (4-isopropylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 2: 2- (4-isopropylbenzoyl) amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole

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Compound 3 2- (4-isopropylbenzoyl) amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole hydrochloride

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Compound 4 2- (4-tert-butylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 5 2- (4-tert-butylbenzoyl) amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole

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Compound 6 2- (4-n-pentylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 7 2- (4-n-hexylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 8 2- (4-n-heptylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 9 2- (4-n-octylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 10 2- (3,5-di-tert-butylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 11 2- (4-isopropyloxybenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 12 2- (4-tert-butyloxybenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 13 2- (4-tert-butylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 14 2- (4-dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 15 2- (3-dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 16 2- (4-geranyloxybenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 17 2- (4-geranyloxybenzoyl) amino-5- [3- (diethylamino) propyl] thio-1,3,4-thiadiazole

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Compound 18 2- (4-geranyloxybenzoyl) amino-5-piperidinoethylthio-1,3,4-thiadiazole

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Compound 19 2- (4-geranyloxybenzoyl) amino-5- [3- (piperidino) propyl] thio-1,3,4-thiadiazole

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Compound 20 2- (4-geranyloxybenzoyl) amino-5- (2-pyridyl) methylthio-1,3,4-thiadiazole

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Compound 21 2- (4-geranyloxybenzoyl) amino-5-ethylthio-
1,3,4-thiadiazole

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Compound 22 2- (4-geranyloxybenzoyl) amino-5-propylthio-1,3,4-thiadiazole

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Compound 23 2- (4-geranyloxybenzoyl) amino-5-isobutylthio-1,3,4-thiadiazole

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Compound 24 2- (4-geranyloxybenzoyl) amino-5-benzylthio-1,3,4-thiadiazole

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Compound 25 2- (3-piperidinomethylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 26 2- (3-piperidinomethylbenzoyl) amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole

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Compound 27 2- [4- (4-fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-diethylaminoethylthio-1,3,4-thiadiazole

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Compound 28 2- [4- (4-fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-diethylaminoethylthio-1,3,4-thiadiazole hydrochloride

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Compound 29 2-benzoylamino-5-diethylaminoethylthio-1,3,
4-thiadiazole

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Although the mechanism of action of the thiadiazole amide derivative according to the present invention is not clear, it has an excellent hair growth promoting effect and an effect of extending the growth period of the hair cycle. Therefore, by applying it to the scalp, it is possible to treat, improve and prevent hair loss. Hair restoration agents containing the thiadiazole amide derivative as an active ingredient include so-called androgenetic alopecia and androgenetic alopecia, light hair and alopecia, as well as alopecia areata, pityriasis alopecia, seborrheic alopecia and the like. It can be applied to alopecia. The amount of the thiadiazole amide derivative used is to be appropriately determined according to sex, age, the degree of symptoms such as hair loss and light hair, etc.
0.01 to 50 mg / kg · day, preferably 0.1 to 2
0 mg / kg-day is applied or sprayed on the scalp once or several times a day.

When the hair restorer according to the present invention is used as a drug, a quasi-drug, or a cosmetic, its dosage form can be arbitrarily selected as long as it can exert the effects of the present invention.
For example, liquid, emulsion, ointment, cream, gel, aerosol, mousse and the like can be exemplified. Specific examples include tonics, lotions, conditioners, scalp treatments, shampoos, and rinses.

In these preparations, in addition to the thiadiazole amide derivative according to the present invention, a component which can be usually compounded in medicines and cosmetics can be compounded as long as the effects of the present invention are not impaired. For example, as a medicinal component, as a drug having a blood circulation promoting action, mention may be made of assembly extract, vitamin E and its derivatives, nicotinic acid esters such as nicotinic acid benzyl ester, and the like. Drugs that promote blood circulation by the action of local irritation include pepper tincture, tincture tincture, camphor, nonylate vanillylamide and the like. Examples of the drug having a hair follicle activating effect include hinokitiol, placenta extract, photosensitizer, pantothenic acid and derivatives thereof. Examples of the drug having an antiandrogen action include hormone drugs such as estradiol, ethinylestradiol, and estrone. Examples of drugs having antiseborrheic action include sulfur, thioxolone, and vitamin B ₆ and the like.

Other examples include salicylic acid and resorcinol, which have a keratolytic and bactericidal action to prevent dandruff, and glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, menthol to prevent scalp inflammation And amino acids such as serine, methionine, and arginine; vitamins such as biotin; and crude drug extracts for the purpose of supplementing the hair follicles and activating the enzyme activity.

Also, Althea, yokuinin, peppermint, iodine, capsicum, aloe, wolfberry, mugwort, rice, mankeishi, mannenrou, kosaiho, echidida, gentian, tanjin, loofah, kikyo, pine, kujin, touki, safflower, barberry, betel wax , Plant extracts such as eucalyptus, kagosou, mokutsu, gossip, psycho, tea, licorice, hops, chrysanthemum, senega, sesame, senkyu, kashuu, cuckoo, maikaika, saffron, rosemary, geese, mallow, etc. .

Vasodilators such as alkoxycarbonylpyridine N-oxide, carpronium chloride and acetylcholine derivatives; skin function enhancers such as cepharanthin; hexachlorophene, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanide, Antibacterial agents such as bitionol, phenol, and isopropylmethylphenol; zinc and its derivatives; lactic acid or its alkyl esters; citric acid; succinic acid; organic acids such as malic acid; and protease inhibitors such as tranexamic acid can also be added. . In addition, drugs such as cyclosporins, oxendrone, diazoxide, minoxidil and the like can also be added.

Alcohols such as ethanol and isopropyl alcohol; polyhydric alcohols such as glycerin, propylene glycol and polyethylene glycol; oils such as higher fatty acids, higher alcohols, hydrocarbon oils, natural oils and fats, ester oils and silicone oils; Surfactant; fragrance;
Chelating agents; humectants such as 1,3-butylene glycol, hyaluronic acid and derivatives thereof, maltitol, atelocollagen, sodium lactate; thickening agents such as quince, carboxyvinyl polymer, xanthan gum; polymer compounds; antioxidants UV absorbers; pigments; water; stabilizers and other components usually incorporated in pharmaceuticals and cosmetics. Hereinafter, the present invention will be described with reference to specific examples, but the present invention is not limited thereto.

Test Example 1 Hair Growth-Promoting Effect (1) Test Method The hair growth test was carried out using C3H / HeNCrj mice in the telogen phase of the hair cycle, using the method of Ogawa et al. (Normal and Abnormal Epidermal Differentiation Normal and Normal).
Abnormal Epidermal Differentiation, edited by M. Seiji and IA Bernstein, pp. 159-170, 1982, The University of Tokyo Press).

That is, each group consisted of 10 mice, and the back of each mouse was shaved by 3 × 4 cm with a hair clipper, and 0.1 ml of ethanol (negative control) or an ethanol solution of each test compound was applied once a day. The hair growth effect of each test compound was determined by measuring the area of the hair growth part on the back of the mouse 30 days after the start of application, and evaluating the area ratio of the hair growth part to the area of the shaved part as the hair regeneration area ratio (%). (2) Results Table 1 shows the average hair regeneration area ratio.

[0064]

[Table 1] Test compound Compound concentration (w / v%) Hair regeneration area ratio (%)  No addition (negative control) -0 Compound 3 0.523 Compound 4 0.519 Compound 5 0.516 Compound 7 2.030 Compound 8 2.035 Compound 9 0.599 Compound 14 2.0 13 Compound 16 0.529 Compound 25 2.0 82 Compound 26 5.0 70Compound 29 2.0 98

As apparent from Table 1, the thiadiazole amide derivative according to the present invention has a hair growth promoting effect. Test Example 2 Growth period extension effect on hair cycle A test was conducted according to the hair growth drug assay method described in JP-A-10-265341. This assay method determines whether the test compound has the effect of maintaining or prolonging the anagen phase in the hair cycle, depending on the degree of cell proliferation when the target substance is brought into contact with hair follicle epithelial cells in a serum-free medium. Is a method of determining Note that in this test example,
A hair follicle epithelial cultured cell of rat body hair obtained by the method described in Japanese Patent Publication No. 0-265341 was used.

(1) Culture medium supplemented with hair follicle epithelial cells Based on the number of viable cells calculated by a blood cell count plate, the final concentration of rat hair follicle epithelial cells was adjusted to 5.0 × 10 ⁴ cells / ml. It was adjusted with KGM medium (epidermal keratinocyte basal medium) to obtain a cultured cell suspension. The KGM medium is KB
M medium (modified MCDB medium: manufactured by Kronetics)
Bovine pituitary extract (final concentration: 0.4 vol%), insulin (final concentration: 0.5 μg / ml), hydrocortisone (final concentration: 0.5 μg / ml), h-EGF (Ep
a medium supplemented with idermal Growth Factor (final concentration: 0.1 ng / ml). 0.2 ml / well of the cultured cell suspension was placed in a 96-well plate (type I collagen-coated plate: manufactured by Falcon).
(1.0 × 10 ⁴ cells / well). After the cells were left at room temperature for about 20 minutes until they settled to the bottom of the well, the cells were cultured at 37 ° C. and 5% CO ₂ for one day to prepare a hair follicle epithelial cell culture medium.

(2) Test medium (a) Medium containing target substance: The target substance was dissolved in DMSO and added to KBM medium to a final concentration of 1.0 × 10 ⁻⁷ M (DMSO concentration 0.1%). ). (B) Negative control: DMSO in KBM medium
(DMSO concentration 0.1%) (c) Positive control: KGM medium was used. (D) KBM medium

(3) Medium exchange and assay KGM in the 96-well plate obtained in (1) above
The medium was removed with an aspirator, taking care not to damage cells adhering to the bottom of the well.
The medium was exchanged by adding at a well ratio. After culturing at 37 ° C. and 5% CO ₂ for 2 days, an alamar blue assay was performed, and the absorbance at 595 nm and 570 nm was measured using a microplate reader (manufactured by BIO RAD), and the cell growth of each medium relative to the negative control was measured. (%) Was calculated. Cell proliferation rate
From (I), a cell proliferation index was calculated according to the following formula.

[0069]

## EQU1 ## Cell growth promotion index = [(substance-containing medium I)-
(KBM medium I)] / [(Positive control I)-(KBM medium I)] At this time, the cell growth promotion index of the KBM medium is 0, and the cell growth promotion index of the positive control is 1. In addition, bovine pituitary extract in positive control,
h-EGF is a substance that is known to affect the growth of hair follicle epithelial cells in culture. Table 2 shows the results.

[0070]

[Table 2]Target substance Cell growth promotion index (mean ± SD)  Compound 1 1.7 ± 0.5 * Compound 3 1.4 ± 0.4 * Compound 4 2.2 ± 0.3 * Compound 5 1.8 ± 0.5 * Compound 6 1.7 ± 0.2 * Compound 7 2.5 ± 0.5 * Compound 8 1.9 ± 0.2 * Compound 9 1.8 ± 0.2 * Compound 10 1.8 ± 0.4 * Compound 11 2.0 ± 0.5 * Compound 12 1.8 ± 0.3 * Compound 13 1.7 ± 0.5 * Compound 15 1.5 ± 0.1 * Compound 16 1.7 ± 0.5 * Compound 18 1.6 ± 0.5 * Compound 21 1.5 ± 0.5 * Compound 25 2.8 ± 0.4 * Compound 26 2.1 ± 0.3 * Compound 28 2.0 ± 0.4 *DMSO (Negate Control) 0.2 ± 0.4  * Significant difference p <0.01

As shown in Table 2, proliferative activity of hair follicle epithelial cells was observed in the thiadiazole amide derivative according to the present invention. This suggests that these derivatives have an action of maintaining or prolonging the anagen phase of the hair cycle by maintaining the mitotic proliferation activity of hair follicle epithelial cells.

[0072]

EXAMPLES Production Example 1 2- (4-n-hexylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (compound 7) 2-amino-5-diethylaminoethylthio-1,3,3 0.99 ml of triethylamine was added to 15 ml of a chloroform solution of 1.50 g of 4-thiadiazole, and then 1.42 ml of 4-n-hexylbenzoyl chloride was added under ice-cooling, followed by stirring at room temperature for 19 hours. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline,
After drying over anhydrous sodium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol = 30: 1) to give 2.33 g of the title compound as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 8.07 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J =
8.4Hz), 3.38 (2H, t, J = 6.8Hz), 2.84 (2H, t, J = 6.8Hz), 2.69
(2H, t, J = 7.6Hz), 2.56 (4H, q, J = 7.2Hz), 1.65 (2H, quintet,
J = 7.6Hz), 1.40-1.24 (6H, m), 1.02 (6H, t, J = 7.2Hz), 0.89 (3
(H, t, J = 6.8Hz).

Production Example 2 2- (4-n-heptylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (compound 8) 2-amino-5-diethylaminoethylthio-1,3,4 0.93 ml of triethylamine was added to 14 ml of a chloroform solution of 1.40 g of thiadiazole, and then 1.44 ml of 4-n-heptylbenzoyl chloride was added under ice-cooling, followed by stirring at room temperature for 16 hours. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated saline,
After drying over anhydrous sodium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol = 50: 1 to 30: 1) to obtain 2.26 g of the title compound as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 8.09 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J =
(8.4Hz), 3.38 (2H, t, J = 7.2Hz), 2.84 (2H, t, J = 7.2Hz), 2.69
(2H, t, J = 7.6Hz), 2.56 (4H, q, J = 7.2Hz), 1.65 (2H, quintet,
J = 7.6Hz), 1.40-1.24 (8H, m), 1.01 (6H, t, J = 7.2Hz), 0.88 (3
(H, t, J = 6.8Hz).

Production Example 3 2- (4-Dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (Compound 14) To 1.20 g of 4-dimethylaminobenzoic acid was added 12 ml of chloroform.
1.01 ml of triethylamine was added, and then 0.64 ml of thionyl chloride was added under ice cooling, followed by stirring for 30 minutes. After concentration of the reaction solution, 16 ml of chloroform and 1.69 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole were added to the residue, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (silica gel 50 g, chloroform: methanol = 30: 1 to 10:
Purification in 1) gave the title compound as a pale yellow solid 2.2.
7 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 8.00 (2H, d, J = 8.8 Hz), 6.72 (2H, d, J =
8.8Hz), 3.37 (2H, t, J = 7.2Hz), 3.08 (6H, s), 2.84 (2H, t, J =
7.2Hz), 2.56 (4H, q, J = 7.2Hz), 1.01 (6H, t, J = 7.2Hz).

Production Example 4 2- (3-Dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (Compound 15) To 1.20 g of 3-dimethylaminobenzoic acid was added 12 ml of chloroform.
1.01 ml of triethylamine was added, and then 0.64 ml of thionyl chloride was added under ice cooling, followed by stirring for 30 minutes. After concentration of the reaction solution, 10 ml of chloroform and 1.69 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole were added to the residue, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (silica gel 50 g, chloroform: methanol = 30: 1 to 10:
Purification in 1) gave the title compound as a pale yellow solid 2.3
8 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.37 (2H, m), 7.33 (1H, m), 6.94 (1H,
m), 3.36 (2H, t, J = 7.3Hz), 3.01 (6H, s), 2.83 (2H, t, J = 7.3H
z), 2.56 (4H, q, J = 7.2Hz), 1.02 (6H, t, J = 7.2Hz).

Production Example 5 2- (3-piperidinomethylbenzoyl) amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole (compound 26) 2-amino-5-mercapto -1,3,4-thiadiazole 8.00
g, 3-dimethylaminopropyl chloride hydrochloride 9.50
g and potassium hydroxide (6.74 g) in 150 ml of methanol at room temperature for 16 hours, then at 40 ° C. for 4 hours, and further at 70 ° C. for 5 hours.
Stirred for hours. After the reaction solution was concentrated under reduced pressure, an aqueous solution of potassium hydroxide was added, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain 10.40 g of 2-amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole as a white solid.

To 1.60 g of 3-piperidinomethylbenzoic acid were added 16 ml of chloroform and 0.88 ml of triethylamine, and then 0.55 ml of thionyl chloride under ice-cooling, followed by stirring for 30 minutes. After concentrating the reaction solution, chloroform 8 ml, 2
-Amino-5- [3- (dimethylamino) propyl] thio-1,3,4-
1.37 g of thiadiazole was added, and the mixture was stirred at room temperature for 4.5 hours.
The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was recrystallized (n-hexane-ethanol) to give 1.74 g of the title compound as a pale yellow solid. ¹ H-NMR (CDCl ₃ ) δ: 8.02 (2H, m), 7.61 (1H, d, J = 8.0 Hz),
7.48 (1H, t, J = 8.0Hz), 3.55 (2H, s), 3.28 (2H, t, J = 7.2Hz),
2.40 (6H, t, J = 7.2Hz), 2.22 (6H, s), 1.92 (2H, quintet, J = 7.
2Hz), 1.57 (4H, m), 1.44 (2H, m).

Production Example 6 2-benzoylamino-5-diethylaminoethylthio-1,3,
4-Thiadiazole (compound 29) 1.32 ml of triethylamine was added to 20 ml of a chloroform solution of 2.00 g of 2-amino-5-diethylaminoethylthio-1,3,4-thiadiazole, and then 1.00 ml of benzoyl chloride was added under ice cooling. After stirring for 3 hours, the mixture was stirred at room temperature for 19.5 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (silica gel 75 g,
Purification with chloroform: methanol = 30: 1 to 10: 1) yielded 2.73 g of the title compound as a pale yellow solid. ¹ H
-NMR (CDCl ₃ ) δ: 8.19 (2H, d, J = 8.0 Hz), 7.63 (1H, t, J = 8.
0 Hz), 7.54 (2H, t, J = 8.0 Hz), 3.37 (2H, t, J = 7.2 Hz), 2.83 (2H, t, J = 7.2 Hz), 2.55 (4H,
q, J = 7.2Hz), 1.01 (6H, t, J = 7.2Hz).

Production Example 7 2- (4-n-pentylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (compound 6) 0.6 g of sodium hydride and 2-amino-5-diethylaminoethylthio 2.31 g of -1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. Separately,
1.92 g of 4-n-pentylbenzoic acid and 1.78 g of carbonyldiimidazole in 30 ml of tetrahydrofuran at room temperature for 30
Stirred for minutes. This was added to the previous reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). The obtained solid was recrystallized from n-hexane to give 2.97 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 8.15 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J =
(8.3Hz), 3.38 (2H, t, J = 6.8Hz), 2.83 (2H, t, J = 6.8Hz), 2.68
(2H, t, J = 7.3Hz), 2.55 (4H, q, J = 6.8Hz), 1.60-1.71 (2H, m),
1.00 (6H, t, J = 7.3Hz), 0.90 (3H, t, J = 6.8Hz).

Production Example 8 2- (4-n-octylbenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole (compound 9) 0.6 g of sodium hydride and 2-amino-5-diethylaminoethylthio 2.31 g of -1,3,4-thiadiazole was stirred in 30 ml of tetrahydrofuran under ice cooling for 30 minutes. Separately,
2.34 g of 4-n-octylbenzoic acid and 1.78 g of carbonyldiimidazole were added in 30 ml of tetrahydrofuran under ice-cooling to give 3
Stirred for 0 minutes. This was added to the previous reaction solution and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added, and extracted with chloroform. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1). By recrystallizing the obtained solid from n-hexane, 2.82 g of the title compound was obtained as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 8.14 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J =
8.3Hz), 3.40 (2H, t, J = 7.3Hz), 2.86 (2H, t, J = 7.3Hz), 2.68
(2H, t, J = 6.8Hz), 2.58 (4H, q, J = 6.8Hz), 1.72-1.58 (2H,
m), 1.38-1.19 (10H, m), 1.02 (6H, t, J = 6.8Hz), 0.88 (3
(H, t, J = 6.8Hz).

Production Example 9 2- [4- (4-Fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-diethylaminoethylthio-1,3,4-thiadiazole hydrochloride (Compound 28) 2.00 g of (4-fluorobenzyloxy) -3-isobutylbenzoyl] amino-5-diethylaminoethylthio-1,3,4-thiadiazole is dissolved in 50 ml of methanol, 10 ml of methanol containing 10% hydrochloric acid is added, and the mixture is stirred at room temperature for 10 minutes. Stirred.
This was concentrated under reduced pressure to obtain 2.10 g of the title compound as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 12.47 (1H, S), 8.06 (1H, d, J = 8.8 Hz),
7.91 (1H, S), 7.40 (2H, d, J = 8.8Hz), 7.09 (2H, t, J = 8.3Hz),
7.01 (1H, d, J = 8.3Hz), 3.90-3.86 (2H, m), 3.52-3.46 (2H,
m), 3.35-3.13 (4H, m), 2.59 (2H, d, J = 6.8Hz), 1.87-2.05 (1
H, m), 1.41 (6H, t, J = 7.3Hz), 0.91 (6H, d, J = 6.4Hz).

Formulation Example 1 lotion 95% ethanol 50.0% by weight monoammonium glycyrrhizinate 0.1 Compound 1 4.0 Sodium lauryl sulfate 0.1 POE (40) hydrogenated castor oil 0.5 Succinic acid qs perfume qs Dye Appropriate amount Purified water balance (Preparation method) Dissolve POE (40) hydrogenated castor oil and fragrance in 95% ethanol, then add purified water, add other components, stir and dissolve, and make clear liquid lotion I got

Formulation Example 2 Lotion 95% Ethanol 90.0% by Weight Vitamin E Acetate 0.05 Compound 25 5.0 Sodium Lauryl Sulfate 0.06 Propylene Glycol 0.1 POE (40) Hardened Castor Oil 0.5 Lactic Acid Sodium lactate qs Perfume qs Dye qs Purified water balance (Preparation method) Dissolve POE (40) hydrogenated castor oil and perfume in 95% ethanol, then add purified water, add other ingredients, stir and dissolve Thus, a transparent liquid lotion was obtained.

Formulation Example 3 Hair tonic compound 25 5.0% by weight Hinokitiol 1.0 Vitamin B6 0.2 Vitamin E acetate 0.02 Menthol 0.2 Assembly extract 1.0 Salicylic acid 0.1 Propylene glycol 2.0 POE ( 10) Monostearate 2.0 75% ethanol residue (Preparation method) Each component was sequentially added to 75% ethanol, and dissolved by stirring to obtain a hair tonic.

Formulation Example 4 Hair tonic compound 11 4.0% by weight Hinokitiol 1.0 Vitamin B6 0.2 Vitamin E 0.02 Menthol 0.2 Salicylic acid 0.1 Propylene glycol 2.0 Sodium hyaluronate 0.01 POE ( 10) Monostearate 2.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol and stirred to dissolve to obtain a hair tonic.

Formulation Example 5 O / W emulsion A phase: POE (60) hydrogenated castor oil 2.0% by weight glycerin 10.0 dipropylene glycol 10.0 1,3-butylene glycol 4.0 compound 3 3.0 polyethylene Glycol 1500 5.0 Phase B: Isocetyl octanoate 10.0 Squalane 5.0 Vaseline 2.0 Propylparaben 2.0 Phase C: 1% aqueous solution of carboxyvinyl polymer 30.0 Sodium hexametaphosphate 0.03 Ion-exchanged water 8.0 35 Phase D: Deionized water 4.5 Phase E: KOH 0.12 Deionized water Remainder

(Preparation method) The phases A and B were each dissolved by heating at 60 ° C., mixed, and treated with a homomixer to prepare a gel. Phase D was gradually added to the gel and dispersed with a homomixer. Next, C previously dissolved in this gel dispersion
The phase was added, and the previously dissolved phase E was added and emulsified with a homomixer to obtain an O / W emulsion.

Formulation Example 6 Cream A phase: dimethylhexyl POE (5) amine oxide 2.5% by weight liquid paraffin 5.0 cetostearyl alcohol 5.5 glyceryl monostearate 3.0 POE (20) 2-octyldodecyl ether 3.0 Propylparaben 0.3 Fragrance 0.1 Phase B: Compound 4 3.0 Glycerin 8.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium hexametaphosphate 0.005 Deionized water Residue (Preparation method) The phases A and B were each dissolved by heating, mixed, and emulsified by a homomixer to obtain a cream.

Formulation Example 7 Aerosol spray stock solution formulation: 95% ethanol 50.0% by weight glycyrrhetinic acid 0.1 Compound 5 3.0 Assembly extract 0.1 Sodium lauryl sulfate 0.1 POE (40) hydrogenated castor oil 0.5 Lactic acid appropriate amount Sodium lactate appropriate amount Fragrance appropriate amount Ion-exchanged water balance Filling formula: Stock solution 50.0 Liquefied petroleum gas 50.0 (Manufacturing method) After installing the valve, the gas was filled to obtain an aerosol spray.

Formulation Example 8 Shampoo (1) Sodium cocoyl methyl taurine 2.0% by weight (2) POE (8) Oleyl ether 2.0 (3) Lauric acid diethanolamide 4.0 (4) Ethylene glycol fatty acid ester 1. 0 (5) Glycerin 0.2 (6) Menthol 0.1 (7) Compound 10 2.0 (8) Disodium edetate 0.1 (9) Appropriate amount of perfume (10) Purified water balance (Preparation method) Purification The water was heated to 70 ° C., the components (1) to (9) were sequentially added, dissolved by stirring and mixing, and cooled to obtain a shampoo.

Formulation Example 9 Rinse (1) Stearyltrimethylammonium chloride 1.5% by weight (2) Dimethylpolysiloxane (20cs) 3.0 (3) POE (10) Oleyl ether 1.0 (4) Glycerin 5.0 (5) Compound 11 2.5 (6) Appropriate amount of 4-tert-butyl-4'-methoxybenzoylmethane (7) Appropriate amount of ultraviolet absorber (8) Purified water The remainder (Production method) (3) and (4) are added, and 70
Warming to ° C. gave an aqueous phase. Heat and melt the other ingredients to 70
Heated to ° C. to give an oil phase. The oil phase was added to the aqueous phase, mixed by stirring with an emulsifier, and cooled to obtain a rinse.

Formulation Example 10 Scalp treatment Stock solution formulation: (1) liquid paraffin 27.0 (2) stearic acid 5.0 (3) cetanol 5.0 (4) sorbitan monooleate 2.0 (5) POE sorbitan mono Oleate 3.0 (6) Compound 12 3.0 (7) 1,3-butylene glycol 5.0 (8) Preservatives Appropriate amount (9) Purified water Rest Filling formula: Stock solution 50.0 Liquefied petroleum gas 50 .0

(Preparation method) Components (5) and (6) were added to component (1).
After dissolving in (4) and heating to 80 ° C. to dissolve uniformly,
Components (7) to 30 ° C.
An undiluted solution was produced by mixing and stirring with (9). The stock solution was filled in a can with a propellant to obtain a scalp treatment.

Formulation Example 11 Scalp Treatment Stock Solution Formulation: (1) Hinokitiol 0.1% by weight (2) Assembly Extract 1.0 (3) Vitamin B6 0.1 (4) Vitamin E 0.01 (5) Menthol 0.1 1 (6) Salicylic acid 0.001 (7) Compound 13 2.5 (8) POE sorbitan monooleate 0.1 (9) Propylene glycol 2.0 (10) 75% ethanol Residue Filling formula: Stock solution 50.0 Dimethyl ether 50.0 (Production method) A scalp treatment was obtained in the same manner as in Preparation Example 10.

Formulation Example 12 Hair tonic compound 16 4.0% by weight Hinokitiol 0.05 Vitamin B6 0.2 Vitamin E 0.02 Menthol 1.0 Propylene glycol 2.0 Sodium hyaluronate 0.01 POE (10) Monostea Rate 2.0 70% ethanol Residue (Preparation method) Each component was sequentially added to 70% ethanol and dissolved by stirring to obtain a hair tonic.

Formulation Example 13 Hair tonic compound 18 3.0% by weight Vitamin B6 0.2 Vitamin E 0.02 Menthol 0.2 Salicylic acid 0.1 Propylene glycol 2.0 Sodium hyaluronate 0.01 POE (10) monostea Rate 2.0 70% ethanol Residue (Preparation method) Each component was sequentially added to 70% ethanol and dissolved by stirring to obtain a hair tonic.

Formulation Example 14 Hair tonic compound 21 2.0% by weight Hinokitiol 1.0 Vitamin E 0.02 Menthol 0.2 Salicylic acid 0.2 Propylene glycol 2.0 Sodium hyaluronate 0.05 POE (10) monostearate 2.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol, and stirred to dissolve to obtain a hair tonic.

Formulation Example 15 Hair tonic compound 7 2.5% by weight Hinokitiol 1.2 Vitamin E 0.02 Menthol 0.2 Salicylic acid 0.15 Propylene glycol 3.0 Sodium hyaluronate 0.02 POE (10) monostearate 2.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol, and stirred to dissolve to obtain a hair tonic.

Formulation Example 16 Hair tonic compound 8 3.5% by weight Hinokitiol 1.0 Vitamin B6 0.2 Vitamin E 0.02 Menthol 0.8 Salicylic acid 0.2 Propylene glycol 2.5 Sodium hyaluronate 0.01 POE ( 10) Monostearate 2.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol and stirred to dissolve to obtain a hair tonic.

Formulation Example 17 Hair tonic compound 15 4.0% by weight Hinokitiol 1.2 Vitamin B6 0.5 Vitamin E 0.03 Menthol 0.5 Salicylic acid 0.1 Propylene glycol 2.0 POE (10) monostearate 2 0.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol, and dissolved by stirring to obtain a hair tonic.

Formulation Example 18 Hair tonic compound 26 2.5% by weight Vitamin B6 0.2 Vitamin E 0.02 Menthol 0.2 Salicylic acid 0.1 Propylene glycol 4.0 Sodium hyaluronate 0.01 POE (10) monostea Rate 2.0 70% ethanol Residue (Preparation method) Each component was sequentially added to 70% ethanol and dissolved by stirring to obtain a hair tonic.

Formulation Example 19 Hair tonic compound 28 2.5% by weight Vitamin E 0.02 Menthol 0.5 Propylene glycol 3.0 Sodium hyaluronate 0.01 POE (10) monostearate 2.0 70% Ethanol Residue (Preparation method) Each component was sequentially added to 70% ethanol, and dissolved by stirring to obtain a hair tonic.

Formulation Example 20 Hair tonic compound 9 4.0% by weight Hinokitiol 0.05 Vitamin E 0.02 Menthol 0.5 Salicylic acid 0.1 Propylene glycol 2.5 Sodium hyaluronate 0.01 POE (10) monostearate 2.0 70% ethanol residue (Preparation method) Each component was sequentially added to 70% ethanol, and stirred to dissolve to obtain a hair tonic.

Formulation Example 21 Hair tonic compound 6 2.0% by weight Vitamin E 0.01 Menthol 0.5 Propylene glycol 2.0 POE (10) monostearate 2.0 70% ethanol Residue (Preparation method) 70% ethanol Was added sequentially to the mixture and dissolved by stirring to obtain a hair tonic.

[0105]

The hair restorer according to the present invention can exert a hair growth promoting effect and an effect of extending the anagen during the hair cycle by using a specific thiadiazole amide derivative or a salt thereof as an active ingredient. Very effective for treatment.

Continued on the front page (72) Inventor Koji Kobayashi 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside Shiseido Daiichi Research Center (72) Inventor Masahiro Tajima 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Co., Ltd. F-term in Shiseido Daiichi Research Center (reference) 4C036 AD08 AD20 AD22 AD27 AD30 4C083 AA082 AA112 AB032 AB052 AB282 AC012 AC022 AC072 AC102 AC122 AC182 AC242 AC292 AC302 AC352 AC392 AC402 AC432 AC442 AC472 AC532 AC562 AC642 AC692 AC7322 AD7921 AD7321 AD552 AD632 AD662 CC33 CC37 CC38 CC39 DD08 DD23 DD31 EE22 4C086 AA01 AA02 AA03 BC85 MA01 MA04 NA14 ZA92 ZB21

Claims (22)

[Claims] 1. A thiadiazole represented by the following general formula (I):
A hair restorer comprising a luamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Embedded image (In the general formula (I), R ¹ and R ² are each a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylamino group, a cyclic amino group, a lower alkylaminoalkyl group, a cyclic aminoalkyl group, a benzyloxy group, Or -OR
Wherein R is an unsaturated aliphatic hydrocarbon group.
R ³ is a hydrogen atom, an aryl group, a pyridyl group, a lower alkylamino group, or a cyclic amino group. A has 1 to 1 carbon atoms
5 is a divalent saturated hydrocarbon group. ) 2. The hair restorer according to claim 1, wherein R ¹ is a hydrogen atom. 3. The hair restorer according to claim 2, wherein R ² is a lower alkyl group. 4. The hair restorer according to claim 2, wherein R ² is a lower alkoxy group. 5. The hair restorer according to claim 2, wherein R ² is a lower alkylamino group. 6. The hair restorer according to claim 2, wherein R ² is a cyclic aminoalkyl group. 7. The hair restorer according to claim 2, wherein R ² is —OR (R is an unsaturated aliphatic hydrocarbon group). 8. The hair restorer according to claim 2, wherein R ² is a hydrogen atom. 9. The hair restorer according to claim 1, wherein R ¹ and R ² are lower alkyl groups. 10. The hair restorer according to claim 1, wherein R ¹
Is a benzyloxy group, and R ² is a lower alkyl group. 11. The hair restorer according to claim 1, wherein R ³ is a lower alkylamino group or a cyclic amino group. 12. The hair restorer according to claim 1, wherein R ³ is a hydrogen atom. 13. The hair restorer according to claim 1, wherein A is an ethylene group or a propylene group. 14. A thiadiazolamide derivative represented by the following general formula (IA) or a salt thereof. Embedded image (In the general formula (IA), R ¹ and R ² are each a hydrogen atom or an alkyl group having 7 to 10 carbon atoms, but at least one of R ¹ and R ² is not a hydrogen atom. R ³ is a hydrogen atom , An aryl group, a pyridyl group, a lower alkylamino group, or a cyclic amino group. A is a divalent saturated hydrocarbon group having 1 to 5 carbon atoms.) 15. The compound according to claim 14, wherein
AR³Is-(CH ₂)₂−N (C₂H₅)₂That is
Characteristic thiadiazole amide derivatives or salts thereof. 16. The thiadiazole amide derivative or a salt thereof according to claim 14, wherein R ¹ is a hydrogen atom and R ² is an n-octyl group. (17) 2- (4-n-pentylbenzoyl) amino-5
-Diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. (18) 2- (4-n-hexylbenzoyl) amino-5
-Diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. (19) A 2- (4-dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. 20. 2- (3-dimethylaminobenzoyl) amino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof. 21. 2- (3-Piperidinomethylbenzoyl) amino-5- [3- (dimethylamino) propyl] thio-1,3,4-thiadiazole or a salt thereof. 22. 2-benzoylamino-5-diethylaminoethylthio-1,3,4-thiadiazole or a salt thereof.