JPH07324024A - Melanogenesis suppressing agent - Google Patents

Abstract

PURPOSE:To provide a melanogenesis suppressing agent useful as a skin- beautifying cosmetic, a skin-aging prevention agent, etc., by using a phenothiazine compound having remarkable melanogenesis-suppressing effect and high safety as an active component. CONSTITUTION:This melanogenesis suppressing agent contains a phenothiazine compound of formula I (R<1> and R<2> are each a 1-3C alkyl; R<3> is a 1-4C straight or branched alkylene; X is H, a halogen, a 1C halogenated alkyl or methoxy) as an active component. The compound of formula is, e.g. chlorpromazine hydrochloride, triflupromazine maleate or promethazine. For example, levomepromazine hydrochloride of formula II is produced by heating 3- methoxydiphenylamine of formula III in the presence of sulfur and iodine to effect the cyclization, refluxing the obtained 2-methoxyphenothiazine of formula IV in the presence of 3-dimethylamino-2-methylpropyl chloride and sodium amide in dry xylene and acidifying the ether extract of the product with hydrochloric acid.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor containing a phenothiazine compound as an active ingredient. The melanin production inhibitor is useful as a whitening cosmetic and a skin anti-aging agent.

[0002]

2. Description of the Related Art Pigmentation such as spots and freckles is one of the skin aging phenomena. Although the cause has not been completely clarified yet, it is considered that ultraviolet rays from sunlight or the like activate melanocytes that produce melanin, and excessively produced melanin is one of the causes of pigmentation. From such a viewpoint, as a therapeutic agent or an inhibitor for spots and freckles, in addition to an ultraviolet absorber, a reducing agent such as ascorbic acid or a hydroquinone derivative, kojic acid or linoleic acid (for example, JP-A-63- No. 284109,
JP-A-1-85907) and the like, a whitening agent containing catechol glycoside as a main component (for example, JP-A-4-1115), and a whitening agent containing flavonoid as a main component (for example, JP-A-55-92305), a whitening agent containing isoferulic acid as a main component (for example,
JP-A-62-10312), a whitening agent containing azelaic acid as a main component (for example, JP-A-61-85307), and the like have been developed.

On the other hand, it is known that phenothiazine compounds have an antihistamine action,
Compounds such as promethazine and alimemazine tartrate are effective against pruritus associated with skin diseases. In addition, compounds such as chlorpromazine hydrochloride, triflupromazine hydrochloride, and levomepromazine maleate are used as therapeutic agents for schizophrenia because they act on the central nervous system (Pharmaceutical Handbook, 5th edition, published by Yakuhin Jikkan Co. Ltd.). In addition, promethazine is an inhalation therapy agent for reducing bronchospasm (JP-A-53-5).
No. 9036), nausea suppressant (Tokusho Sho 62-500)
589), periodontal diseases, remedies for refractory infectious diseases such as athlete's foot (JP-A-4-89428), and agents for reducing the effects of excessive alcohol consumption (JP-A-5-971). It has been known. In addition, trifluoroperazine has been applied as a drug that acts on the central nervous system and suppresses seizures such as convulsions in mammals (Table 63-5005).
No. 98). However, it is not known that phenothiazine compounds have a melanin production inhibitory action.

[0004]

At present, none of the above-mentioned conventional whitening agents is sufficiently effective as a whitening agent, and as the market interest in preventing spots and freckles has increased significantly, Development of a whitening agent having a stronger melanin production suppressing action is desired. Therefore, an object of the present invention is to provide a melanin production inhibitor having a stronger melanin production inhibitory action.

[0005]

As a result of continuing the search for a melanin production inhibitor capable of solving the above-mentioned problems, the present inventors have found that phenothiazine compounds have a remarkable melanin production inhibitory action and are safe. It was found that the compound has high properties, and the present invention has been completed.

That is, according to the present invention, there is provided a melanin production inhibitor containing a phenothiazine compound represented by the following general formula (I) as an active ingredient.

[0007]

[Chemical 2]

(Wherein R ¹ and R ² represent a C _{1 to} C ₄ alkyl group, R ³ represents a C _{1 to} C ₄ linear or branched alkylene group, and X represents hydrogen, a halogen atom or C _{1 represents} a halogenated alkyl group or a methoxy group.)

The phenothiazine-based compound represented by the general formula (I)
Among the compounds, as a compound that can obtain a preferable effect,
For example, promethazine (R¹: CH₃, R²: CH₃, R
³: C at the branch₃, X: H), Alimemazine (R¹: CH
₃, R²: CH₃, R³: C at the branch_Four, X: H), birds
Flupromazine (R¹: CH₃, R²: CH₃, R³:
Straight chain C₃, X: 2-CF₃), Levomepromazine
(R¹: CH₃, R²: CH ₃, R³: C at the branch₃，
X: 2-OCH₃), Chlorpromazine (R¹: C
H₃, R²: CH₃, R³: Linear C₃, X: 2-C
l) and the like, as well as their physiologically acceptable salts
To be Examples of the salts here include hydrochloride and acetic acid.
Salt, sulfate, maleate, mesylate, tartrate, et
Examples thereof include salts such as nantoate and phendizoate.

Among the phenothiazine compounds, chlorpromazine hydrochloride, triflupromazine maleate,
Promethazine is available as a commercial product. Also,
Other phenothiazine-based compounds can be produced, for example, according to the method described in Pharmaceutical Synthetic Chemistry (1st), 17th edition (Nankodo). For example, in order to synthesize levomepromazine (II) hydrochloride by this method, 3-methoxydiphenylamine (III) is first heated in the presence of sulfur and iodine to cause ring closure to give 2-methoxyphenothiazine (IV) as follows. ) Get. This 2
-Methoxyphenothiazine (IV) is purified and then refluxed in the presence of 3-dimethylamino-2-methylpropyl chloride and sodium amide using, for example, dry xylene as a solvent, and the ether extract is acidified with hydrochloric acid to give levomepromazine hydrochloride. Can be obtained.

[0011]

[Chemical 3]

Next, in order to synthesize alimemazine tartrate (V) by this method, phenothiazine (VI) is refluxed in the presence of 3-dimethylamino-2-methylpropyl chloride using dry xylene as a solvent as follows. By making the ether extract acidic with tartaric acid, alimemazine tartrate can be obtained.

[0013]

[Chemical 4]

The melanin production inhibitor according to the present invention is an external preparation for skin such as cosmetics for the purpose of preventing the generation of spots, freckles, and dark skin due to sunburn, or a drug for treating pigmentation. It can be used as.
When the melanin production inhibitor of the present invention is used for the above-mentioned use, the amount of the phenothiazine compound to be added is not particularly limited, but is 0.1 to 20 per total weight of the external preparation for skin and the drug.
Weight% is preferable, and 0.5-5 weight% is more preferable.
If the amount used is less than 0.1% by weight, the purpose of preventing pigmentation may not be sufficiently exerted, and the amount is 20% by weight.
If it exceeds, when preparing a dosage form as described below,
It is not preferable because the preparation may be difficult in terms of solubility and dispersibility.

The melanin production inhibitor of the present invention can be prepared into a dosage form such as an ointment, cream, emulsion, pack and lotion by a known method. In addition, the types of constituent components that can be used when preparing these dosage forms and their compounding amounts are within a range that can be appropriately determined by those skilled in the art according to conventional examples. The types and blending amounts of these components are not limited to the examples below, and any component known to be capable of adjusting the intended dosage form and any blending ratio thereof can be used. In preparation of these skin external preparations and pharmaceuticals, conventionally used melanin production inhibitors, UV absorbers, UV scattering agents, anti-inflammatory agents and the like may be added together.

[0016]

EXAMPLES The present invention will be further described below with reference to examples, but it goes without saying that the scope of the present invention is not limited to these examples.

Examples 1 to 7 First, the results of an experiment for evaluating the effect of a phenothiazine compound which is an active ingredient of the melanin production inhibitor according to the present invention will be shown. HM3KO cell whitening effect The cells used for the cell whitening effect are human-skin derived melanoma cells HM3KO. Like the mouse-derived B16 melanoma cells that have been frequently used in this type of test, this cell has the property of producing a large amount of melanin intracellularly under normal conditions, and is suitable as a cell used in the above test. Is. In addition, since human-derived cells are used in this test, it is more suitable as a drug evaluation method considering application to the human body.

HM3KO cells were plated in a culture dish having a diameter of 10 cm at a density of 1 × 10 ⁵ cells / dish, and a Dulbecco's modified Eagle medium containing 10% fetal bovine serum was used.
The cells were cultured at 37 ° C for 24 hours. After that, the concentration in the medium was 6.
Various phenothiazine compounds were added so that the concentration was 25 to 50 μM, and the cells were cultured for 6 days. After culturing, cells were collected and centrifuged to form a cell pellet, and the color tone was visually observed to evaluate the degree of whitening by the following four-step evaluation method. The results are shown in Table 1.

++: Remarkable whitening ++: Sufficient whitening is recognized +: Slight whitening is recognized ±: No effect is recognized

On the other hand, as Comparative Examples 1 and 2, hydroquinone monobenzyl ether (see Japanese Patent Laid-Open No. 61-227516) and kojic acid (see Japanese Laid-Open Patent Publication No. 63-2770619), which are known to inhibit the formation of melanin, are respectively used. It compared with the said Examples 1-7 using it. The results are shown in Table 1.

[0021]

[Table 1]

As shown in Table 1, all of the seven phenothiazine compounds (Examples 1 to 7) according to the present invention have a stronger whitening effect than hydroquinone monobenzyl ether and kojic acid used for comparison. There is.

Next, compounding examples of the external preparation for suppressing melanin production of the present invention will be described.

Example 8 (Ointment 1) Ingredient Weight Part A Promethazine 1 White petrolatum 25 Stearyl alcohol 22 B Propyleneglycol 12 Sodium lauryl sulfate 1.5 Preservative / antioxidant Proper amount Perfume Proper amount Purified water Remaining amount ── ────────────────────────── Total 100 Ingredients that belong to A are melted in a hot water bath (oil phase), and ingredients that belong to B are heated separately. Dissolve (aqueous phase). Add the water phase to the oil phase,
The mixture was stirred, emulsified and cooled to obtain an ointment.

[0025] Example 9 (Ointment 2) Component Parts by weight A maleic Levomepromazine 5 white vaseline 40 Cetyl alcohol 15 Sorbitan sesquioleate 5 lauromacrogol 0.5 B preservative antioxidant qs Perfume qs Purified water Balance ──────────────────────────── Total 100 Ingredients that belong to A are dissolved in a hot water bath (oil phase), and ingredients that belong to B separately. Is dissolved by heating (aqueous phase). Add the water phase to the oil phase,
The mixture was stirred, emulsified and cooled to obtain an ointment.

[0026] Example 10 (neutral cream) Component Parts by weight A alimemazine tartrate 10 Stearyl alcohol 7 Stearic acid 2 Hydrogenated lanolin 2 Squalane 5 2-octyldodecyl alcohol 6 POE (25) cetyl alcohol ol 3 Glycerin monostearate 2 Propylene glycol 5 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Purified water Remaining amount ───────────────────────────── Total amount 100 For purified water Add propylene glycol and heat to 70 ℃
Keep (water phase). Other ingredients are mixed, heated and melted at 70 ℃
Keep (oil phase). The oil phase was added to the aqueous phase, preliminarily emulsified, and then uniformly emulsified with a homomixer to obtain a neutral cream.

[0027] Example 11 (emulsion) Component Parts by weight A chlorpromazine hydrochloride 0.5 Silicone KF56 2 isopropyl myristate 3 POE (20) POP (4) cetyl ether 1 B Glycerin 3 Hiviswako 105 0.2 Ethanol 5 Preservative・ Antioxidant Suitable amount Fragrance Suitable amount Purified water Remaining amount ──────────────────────────── Total amount 100 All of the above formulations A and B at 70 ° C Respectively, and A was added to B and emulsified uniformly to obtain an emulsion.

[0028] Example 12 (pack agent) Component Parts by weight hydrochloric triflupromazine 3 Ethyl alcohol 10 Glycerin 5 Dipropylene glycol 5 Polyethylene glycol 4000 1 Polyvinyl alcohol-ol 10 vinyl acetate resin emulsion 13 Titanium oxide 12 olive 3 Squalene 0.5 Preservative / antioxidant Proper amount Perfume Proper amount Purified water Residual amount ──────────────────────────── Total amount 100 Dissolve each component uniformly I got a pack.

[0029] Example 13 (Lotion) Component Parts by weight of maleic acid triflupromazine 0.5 Glycerin 4 1,3-butylene glycol 4 Ethanol 7 POE (20) oleyl alcohol 0.5 preservative antioxidant qs perfume Proper amount Purified water Residual amount ──────────────────────────── Total amount 100 Dissolve glycerin and 1,3-butylene glycol in purified water . Separately, isothipendyl hydrochloride and POE (20) oleyl alcohol were dissolved in ethanol, and this was added to the above aqueous solution and dissolved, and filtered to obtain a lotion.

[0030]

INDUSTRIAL APPLICABILITY As described above, the present invention provides a novel and remarkable melanin production inhibitory substance, and an external preparation or the like containing this compound as an active ingredient can exhibit an excellent whitening effect.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display area C07D 279/24

Claims (1)

[Claims] 1. A melanin production inhibitor comprising a phenothiazine compound represented by the following general formula (I) as an active ingredient. [Chemical 1] (In the formula, R ¹ and R ² each independently represent a C _{1 to} C ₃ alkyl group, R ³ represents a C _{1 to} C ₄ linear or branched alkylene group, and X represents hydrogen, a halogen atom or C ₁
Represents a halogenated alkyl group or a methoxy group. )