JP2791567B2 - Hair restoration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a hair restorer having an excellent hair growth-inhibiting effect such as hair loss prevention and hair growth effect. The invention finds particular use in the pharmaceutical, quasi-drug or cosmetics fields.

[Prior art] Conventionally, causes of baldness and hair loss include activation of androgens in organs such as hair roots and sebaceous glands, decreased blood flow to hair follicles, excessive secretion of sebum, and generation of peroxide. The scalp may be abnormal. For this reason, conventional hair restorations include
Compounds having an action to eliminate or reduce the above-mentioned causes are generally incorporated.

For example, vitamins such as vitamin B ₆ 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, female hormone agents such as estradiol, cepharanthin, etc. Are used in the prevention and treatment of alopecia.

[Problems to be Solved by the Invention] Problems of the Prior Art However, conventional hair nourishes are effective in preventing and improving dandruff, Kayumi, hair loss and the like, and promote hair growth and regrowth. The mechanism of hair growth is very complex,
Inhibition of androgen activation by conventional hair restorations and increase in blood flow of hair follicles alone have not been found to have sufficient hair loss prevention and hair growth effects.

Object of the invention The present inventor has searched for a substance that is effective against hair loss and hair loss in the above circumstances, and has an excellent hair growth preventing effect such as hair loss prevention and hair growth effect. I In the formula, R ₁ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms, and R ₂ represents hydrogen, 1 to 4 carbon atoms.
Alkyl group, an alkenyl group having 2 to 4 carbon atoms, R ₃
And R ₄ together with the nitrogen are a heterocyclic group selected from the group consisting of a piperidino group or a morpholino group, each of the heterocyclic groups having 0 to 0 carbon atoms as substituents.
It has three alkyl groups having 1 to 8 carbon atoms.

A triazine N-oxide derivative represented by the following formula: acylated product of the derivative, a tautomer thereof, and a pharmaceutically acceptable acid addition salt as described above. 2. The following general formula II In the formula, R ₁ is hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxyalkyl group having 2 to 10 carbon atoms, a phenyl group (here Wherein the phenyl moiety is optionally substituted with 1 to 3 carbon atoms of an alkyl group, bromine, chlorine, fluorine and iodine; a naphthyl group; a phenylalkyl group (where the alkyl moiety has 1 to 6 carbon atoms). Yes, the phenyl moiety has 1 oxygen
-4, alkyl, bromine, fluorine and iodine). R ₂ is hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,
8 cycloalkyl groups, phenyl, naphthyl, phenylalkyl groups (where the alkyl moiety has 1 to 6 carbon atoms) R ₃ and R ₄ are alkenyl groups having 2 to 8 carbon atoms, or
R ₃ and R ₄ together with nitrogen may be a piperidino group to a heterocyclic group, wherein the heterocyclic group is a substituent having a 0 to 3 alkyl group of 1 to 8 carbon atoms on a carbon atom. Have.

The invention was found that a triazine N-oxide derivative represented by the formula (1), an acylated product of the derivative, a tautomer thereof, and a pharmaceutically acceptable acid addition salt among those described above have a strong hair-growth effect. Was completed.

[Means for Solving the Problems] That is, the present invention provides: In the formula, R ₁ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkenyl group having 2 to 4 carbon atoms, and R ₂ represents hydrogen, 1 to 4 carbon atoms.
Alkyl group, an alkenyl group having 2 to 4 carbon atoms, R ₃
And R ₄ together with the nitrogen are a heterocyclic group selected from the group consisting of a piperidino group or a morpholino group, each of the heterocyclic groups having 0 to 0 carbon atoms as substituents.
It has three alkyl groups having 1 to 8 carbon atoms.

A triazine N-oxide derivative represented by the formula: and acylated product of the derivative, a tautomer thereof, a pharmaceutically acceptable acid addition salt as described above, and 2. In the formula, R ₁ is hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxyalkyl group having 2 to 10 carbon atoms, a phenyl group (here Wherein the phenyl moiety is optionally substituted with 1 to 3 alkyl groups having 1 to 4 carbon atoms, bromine, chlorine, fluorine, iodine, a naphthyl group, a phenylalkyl group (where the alkyl moiety has 1 to 4 carbon atoms). 6, and the phenyl moiety represents an alkyl group having 1 to 4 carbon atoms, and is optionally substituted with 1 to 3 of bromine, chlorine, fluorine and iodine). R ₂ is hydrogen, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 8 carbon atoms, phenyl, naphthyl, phenylalkyl group (where the alkyl portion has 1 to 6 carbon atoms) R ₃ and R ₄ are an alkenyl group having 2 to 8 carbon atoms, or R ₃ and R ₄ together with the nitrogen may be a piperidino group to a heterocyclic group, and the heterocyclic group has 0 to 3 alkyl group of 1 to 8 carbon atoms as a substituent on a carbon atom.

A triazine N-oxide derivative represented by the formula: or an acylated product of the derivative, a tautomer thereof, or a pharmaceutically acceptable acid addition salt as described above as an active ingredient. It is hair.

 Hereinafter, the configuration of the present invention will be described in detail.

The triazine N-oxide derivative used in the present invention has the following general formula I: In the formula, R ₁ represents hydrogen, an alkyl group having a prime number of 1 to 4, and an alkenyl group having 2 to 4 carbon atoms, and R ₂ represents hydrogen and having 1 to 4 carbon atoms.
4 represents an alkyl group, an alkenyl group having 2 to 4 carbon atoms,
R ₃ and R ₄ together with the nitrogen are a heterocyclic group selected from the group consisting of a piperidino group or a morpholino group, each of the heterocyclic groups having 0 as a substituent on a carbon atom.
It has up to 3 alkyl groups of 1 to 8 carbon atoms.

A triazine N-oxide derivative represented by the formula: and acylated product of the derivative, a tautomer thereof, a pharmaceutically acceptable acid addition salt as described above, and 2. In the formula, R ₁ is an alkyl group having 1 to 8 hydrogen carbon atoms, 2 carbon atoms.
An alkenyl group of 8 to 8, a cycloalkyl group having 3 to 8 carbon atoms,
An alkoxyalkyl group having 2 to 10 carbon atoms, a phenyl group (where the phenyl moiety is optionally substituted with 1 to 4 alkyl groups having 1 to 4 carbon atoms, bromine, chlorine, fluorine, iodine), a naphthyl group, A phenylalkyl group (where the alkyl moiety has 1 to 6 carbon atoms and the phenyl moiety has 1 carbon atom)
Alkyl groups, bromine, chlorine, nitrogen, iodine
Arbitrarily substituted up to). R ₂ is hydrogen, carbon number 1
-8 alkyl groups, alkenyl groups having 2-8 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, phenyl, naphthyl, phenylalkyl groups (where the alkyl moiety is
6 is a) R ₃ and R ₄ are alkenyl group having 2 to 8 carbon atoms,
Alternatively, R ₃ and R ₄ may be taken together with nitrogen to form a piperidino group to a heterocyclic group, wherein the heterocyclic group is an alkyl group of 0 to 3 carbon atoms having 1 to 3 carbon atoms as a substituent. Having.

A triazine N-oxide derivative represented by the following, and acylated products of the derivative, and tautomers thereof, furthermore, a pharmaceutically acceptable acid addition salt as described above,
In chemical terms, 2,4-diamino-6-piperidino-1,3,5
-Triazine-3-oxide, 2,4-diamino-6- (2,
6-dimethylmorpholino) -1,3,5-triazine-3-oxide, 2,4-diamino-6-morpholino-1,3,5-triazine-3-oxide, 2,4-bis (methylamino)-
6-piperidino-1,3,5-triazine-3-oxide,
2-amino-4-diallylamino-6-methyl-1,3,5
-Triazine-1-oxide, 2-amino-4-diallylamino-6-ethyl-1,3,5-triazine-1-oxide, 2-amino-4-methyl-6-morpholino-1,3,
5-triazine-3-oxide-2-amino-4-methyl-6-piperidino-1,3,5-triazine-3-oxide, 2-amino-4-benzyl-6-diallylamino-
1,3,5-triazine-3-oxide, 2-amino-4-
Cyclohexyl-6-diallylamino-1,3,5-triazine-3-oxide, 2-amino-4-diallylamino-6-phenyl-1,3,5-triazine-1-oxide,
2-amino-4-diallylamino-6- (2-methoxyethyl) -1,3,5-triazine-1-oxide, 2-amino-4-diallylamino-6-vinyl-1,3,5-triazine -1-oxide and the like. These are known compounds and are shown in U.S. Pat.
Useful for treating hypertension and shock. However, since it is not known to be used externally, and furthermore, there is no report on hair-growth action, there is no known application of these compounds to hair-growth.

The compounding amount of the triazine N-oxide derivative used in the present invention is 0.001 to 15% by weight, preferably 0.1 to 10% by weight in the hair restorer of the present invention. If the amount is less than 0.001% by weight, the effect of the anti-invention cannot be sufficiently obtained, and if the amount exceeds 15% by weight, it is not preferable from the viewpoint of formulation or skin irritation.

In addition to hair tonic fee according to the present invention is the triazine N- oxide derivatives, carpronium chloride, assembly extract, vasodilators such as acetylcholine derivatives, serine, amino acids such as methionine, vitamin B _6, vitamin E and derivatives thereof, biotin, etc. Vitamins, pantothenic acid shrimp and its derivatives, glycyrrhetinic acid and its derivatives, nicotinic acid esters such as benzyl nicotinate, skin function enhancers such as cepharanthin, female hormones such as estraol, and the like. Further, additives usually used for hair restoration, for example, hinokitiol, hexachlorophen, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, antibacterial agents such as trichlorocarbanilide and bitionol-au, refreshing agents such as menthol, salicylic acid, Drugs such as zinc and its derivatives, lactic acid and its alkyl esters, organic acids such as citric acid, amino acids such as arginine, olive oil, squalane, liquid paraffin, isopropyl myristate, higher fatty acids, oils such as higher alcohols, glycerin, propylene glycol Polyhydric alcohols, other surfactants, fragrances, antioxidants, ultraviolet absorbers, dyes, ethanol, water, humectants, thickeners and the like can be appropriately blended within a range that does not impair the effects of the present invention. .

The properties for use in the present invention may be any properties that can be applied to the outer skin such as liquids, emulsions and ointments.

The use of the present invention employs an administration method by transdermal administration which is applied or sprayed directly on the skin. In addition, the dosage of the hair nourishing composition of the present invention cannot be clearly determined because it varies depending on age, individual differences, medical conditions, and the like.However, the dosage for administration to humans is generally 1 kg body weight and 0.001 to 100 mg per day, preferably. Is 0.1
量 10 mg, and this amount can be administered once a day or divided into 2 to 4 times.

[Examples] Next, the production method and hair-growth action of the hair-growth material of the present invention will be described more specifically with reference to examples. The present invention is not limited by this. The compounding amount is% by weight.

(Production method) 2,4 diamine-6-piperidino-1, 95% ethanol
3,5-Triain-3-oxide and hydrogenated castor oil ethylene oxide (40 mol) adduct were added and dissolved by stirring, and then ion-exchanged water was added and mixed to obtain a liquid hair restorer of Example 1. Examples 2 to 11 and Comparative Example 1 were obtained in the same manner as in Example 1.

[Hair Growth Test] The hair growth tests of Examples 1 to 11 and Comparative Example 1 were performed using a C3H / HeNCrJ mouse in the telogen phase of the hair cycle, using the method from Ogawa (Normal and Abnormal Epidermala Differentiation [Normal end Abnormal]). Epidermal
Differentiation], edited by M. Seiji and IABernstein, pp. 159-170, 1982, The University of Tokyo Press).

That is, a group of 10 mice, no application, Example 1
-11 and 13 groups of Comparative Example 1, the back of the mouse was shaved with a clipper and a shaver, and 0.1 ml of each sample was applied once a day. The hair growth effect of each sample was measured by measuring the hair growth portion on the back of the mouse, and was compared based on the area ratio. Table 5 shows the number of days required for 50% hair growth rate by each sample
It was shown to.

As described above, the hair restoration according to the present invention has an excellent hair growth effect.

[Hair-growth test] Next, in order to examine the hair-growth effects such as the hair loss prevention and the hair-growth effect of the present invention, a tricogram test was performed on humans.
Examples 1 to 11 and Comparative Example 1 were used for the hair restoration.

(Trichogram test) Observation of the roots of the extracted hair before and after using the hair restoration under a microscope, counting the number of telogens from the root form, and comparing the hair growth effect of the hair restoration by increasing or decreasing the ratio did. The telogen follicles are the roots of hair that has stopped growing, and it has been recognized that those who complain of hair loss have a higher proportion of telogen follicles than normal people.

Each of the hair restorations of Examples 1 to 11 and Comparative Example 1 was applied to the scalp of 10 male subjects twice a day, 2 ml at a time, continuously for 6 months, immediately before the application and immediately after the completion of the application for 6 months. One hundred hairs were removed from each subject, and the hair roots were examined. The results are shown in Table 6.

As described above, the hair restoration according to the present invention has an excellent hair restoration action.

Example 12 (Phase A) 2,4-diamino-6-pipedino-1,3,5-triazine-
3-oxide 1.0 polyoxyethylene (60 mol) addition-hardened castor oil 2.0 glycerin 10.0 dipropylene glycol 10.0 1,3-butylene glycol 5.0 polyethylene glycol 1500 5.0 (phase B) cetylitooctate 10.0 squalane 5.0 petrolatum 2.0 propylparaben 2.0 ( C phase) 1% aqueous solution of carboxyvinyl polymer 30.0 Sodium hexametaphosphate 0.03 Ion-exchanged water 8.35 (D-phase) Ion-exchanged water 4.5 (E-phase) Kaseikari 0.12 Ion-exchanged water 5.0 (Production method) Heat, dissolve, mix and treat with a homomixer to form a gel. Phase D is gradually added thereto and dispersed with a homomixer.

Next, the dissolved C phase was added thereto, and finally, the dissolved E phase was added and emulsified with a homomixer to obtain an o / w emulsion type hair restorer.

An actual use test was performed on this hair-growing agent in the same manner as in Example 1, and it was confirmed that the hair-growing effect was excellent.

Example 13 (Phase A) 2-Amino-4-methyl-6-piperidino-1,3,5-triazine-3-oxide 2.0 Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostearate 3.0 EO (20 mol) -2 -Octyldodecyl ether 3.0 Propyl paraben 0.3 Fragrance 0.1 (Phase B) Glycerin 8.0 Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium hexametaphosphate 0.005 Deionized water 48.095 (Production method) A phase and B phase are each heated and dissolved, and mixed. The mixture was emulsified with a homomixer to obtain a creamy hair restorer. As a result of an actual use test of this hair restoring agent on a person in the same manner as in Example 1, it was confirmed that the hair restoring effect was excellent.

[Effects of the Invention] The present invention is a hair restorer having an excellent hair-growth effect such as an excellent hair loss prevention and hair growth effect.

──────────────────────────────────────────────────の Continued on the front page (72) Inventor Yoshiharu Tsuji 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside Shiseido Research Laboratories (72) Inventor Jotaro Nakanishi 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Shiseido Research Inc. (56) References JP-A-58-88306 (JP, A) JP-A-63-68515 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 7/06-7 / 155

Claims (5)

(57) [Claims] 1. A compound represented by the following general formula I In the formula, R ₁ is hydrogen, an alkyl group having 1 to 4 carbon atoms, 2 carbon atoms.
R ₂ represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, and R ₃ and R ₄ together form a nitrogen atom, a piperidino group or A heterocyclic group selected from the group consisting of a morpholino group, wherein each of the heterocyclic groups has 0
It has up to 3 alkyl groups of 1 to 8 carbon atoms. And an acylated product of the derivative, a tautomer thereof, and one or more pharmaceutically acceptable acid addition salts described above. And hair restoration. 2. The following general formula II In the formula, R ₁ is hydrogen, an alkyl group having 1 to 8 carbon atoms, and 2 carbon atoms.
Alkenyl group having 8 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, alkoxyalkyl group having 2 to 10 carbon atoms, phenyl group (where the phenyl moiety is an alkyl group having 1 to 4 carbon atoms, bromine, chlorine, fluorine, iodine , A naphthyl group, a phenylalkyl group (where the alkyl moiety has 1 to 6 carbon atoms and the phenyl moiety has 1 carbon atom)
1 to 4 alkyl groups, bromine, chlorine, fluorine and iodine
Arbitrarily substituted with 3). R ₂ is hydrogen, carbon number 1
To 8 alkyl groups, alkenyl groups having 2 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, phenyl, naphthyl, phenylalkyl groups (where the alkyl moiety is 1 to 6 carbon atoms)
R ₃ and R ₄ are alkenyl groups having 2 to 8 carbon atoms;
Alternatively, R ₃ and R ₄ may be taken together with nitrogen to form a heterocyclic group consisting of a piperidine group, wherein the heterocyclic group is a C 1-8 alkyl having 0-3 carbon atoms as a substituent on a carbon atom. Having a group. And an acylated product of the derivative, a tautomer thereof, and one or more pharmaceutically acceptable acid addition salts described above. Characteristic hair restoration. 3. In the general formula I, R ₁ is hydrogen, R ₂ is hydrogen, R ₃
The hair restorer according to claim 1, wherein R ₄ and R ₄ form a piperidino group together with nitrogen, and the compound is 2,4 diamino-6-piperidino 1,3,5-triazine-3-oxide. 4. A compound of formula II wherein R ₁ is a methyl group, R ₂ is hydrogen, R ₃ and R ₄ form a piperidino group together with nitrogen, and the compound is 2-amino-4-methyl-6-piperidino. 3. The hair restorer according to claim 2, which is -1,3,5-triazine-3-oxide. 5. In the general formula, R ₁ is a methyl group, R ₂ is hydrogen,
R ₃ and R ₄ are allyl groups, and the compound is 2-amino-4
-Diallylamino-6-methyl-1,3,5-triazine-
The hair restorer according to claim 2, which is 1-oxide.