JP7043784B2 - Hair growth agent - Google Patents

Description

The present invention relates to a prophylactic or therapeutic agent for alopecia.

Alopecia includes male alopecia, seborrheic alopecia, senile alopecia, circular alopecia, drug-induced alopecia, scar alopecia, postpartum alopecia, postmenopausal female alopecia or diffuse alopecia, etc. There are various types. Most of them are not life-threatening, but they are often accompanied by mental distress due to their appearance problems, and an excellent preventive or therapeutic agent for alopecia is desired.

Hair is reborn through stages of growth, catagen, and telogen (hair cycle). This hair cycle usually takes a period of 2 to 7 years for one cycle, but if some abnormality occurs and this period is shortened, the growth of hair stops before it can grow sufficiently. As a result, a decrease in hair density and a decrease in hair thickness per hair are observed as the number of hair loss increases. Factors that disrupt the rhythm of the hair cycle include male hormones such as testosterone and dihydrotestosterone, radiation, drugs such as anticancer agents, aging, and stress.

Minoxidil, finasteride, dutasteride, carpronium chloride, adenosine, t-flabanone, 6-benzylaminopurine, pentadecanoic acid glyceride, etc. have been used for the prevention and treatment of androgenetic alopecia, and their effectiveness has been reported (non-patent). Document 1).

In recent years, 4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) -4-oxo-butanoic acid having an erythropoietin production enhancing effect has been found (Patent Documents 1, 2, Non). Patent Document 2). Although the use of the compound is mentioned in Patent Documents 1 and 2, there is no description of its use as a hair growth agent.

WO2014080640A1 JP 2015-189670

Edited by Masutaka Furue. New Strategy for Alopecia Treatment p113-132. Nakagawa Bookstore. Published in 2011 Ken-ichiro Hayashi et al. ACS Chem. Biol. , 2012, 7, 590-598

An object of the present invention is to provide a new therapeutic agent useful for the prevention or treatment of alopecia.

The present inventors have searched for a substance exhibiting a hair growth effect, and as a result of repeated diligent studies, 4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) represented by the following formula. It has been found that -4-oxo-butanoic acid or a pharmaceutically acceptable salt thereof solves the above-mentioned problems, and the present invention has been completed.
That is, the present invention
(1) The following formula,

で表される化合物又はその医薬上許容される塩を含有することを特徴とする、脱毛症の予防又は治療剤、
（２）脱毛症が男性型脱毛症、脂漏性脱毛症、老人性脱毛症、円形脱毛症、薬物性脱毛症、瘢痕性脱毛症、産後脱毛症、閉経後女性の脱毛症又はびまん型脱毛症である、（１）に記載の予防又は治療剤、又は
（３）外用剤である、（１）～（２）のいずれかに記載の予防又は治療剤である。

A prophylactic or therapeutic agent for alopecia, which comprises a compound represented by the above or a pharmaceutically acceptable salt thereof.
(2) Alopecia is male-type alopecia, seborrheic alopecia, senile alopecia, alopecia areata, drug-induced alopecia, scarring alopecia, postpartum alopecia, postmenopausal female alopecia or diffuse alopecia. The prophylactic or therapeutic agent according to any one of (1) and (2), which is a disease, the prophylactic or therapeutic agent according to (1), or (3) an external preparation.

4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) -4-oxo-butanoic acid showed an excellent hair growth promoting effect in a mouse hair cutting model.

The hair growth effect of 4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) -4-oxo-butanoic acid in a mouse hair cutting model is shown.

As used herein, the term "alopecia" means a state in which part or all of the hair has fallen off or disappeared, or has changed to thin, short hair. Alopecia is not particularly limited, but is male-type alopecia, seborrheic alopecia, senile alopecia, circular alopecia, drug-induced alopecia, scar alopecia, postpartum alopecia, postmenopausal alopecia. If you have alopecia or diffuse alopecia in women. Alopecia is often caused by disruption of the hair cycle, and is triggered by shortening of the growth period due to arrest of cell proliferation or the like.

The "hair cycle" refers to the hair growth cycle, (1) the growth phase (the period in which hair follicle cells repeat division and the hair grows actively, and lasts for 2 to 6 years for hair). (2) Regression period (a period in which hair growth weakens and hair follicles atrophy, lasting 1 to 2 weeks for hair), and (3) Rest period (hair follicles completely regress and rest) It is a period consisting of three periods (lasting 3 to 4 months for hair). Normally, 80-90% of hair is in anagen, less than 1% is in catagen, and the rest are in telogen. Alopecia causes abnormalities in the hair cycle, but especially in androgenetic alopecia, the period of the growth phase is shortened, and the hair transitions to the degeneration / rest phase before it grows into thick and hard hair. There is an increase in hair ratio and a change from hard hair to fine vellus hair.

Further, the "preventive or therapeutic agent for alopecia" of the present invention includes (1) induction from telogen to anagen (hair growth induction), (2) promotion of hair growth, and (3) extension of anagen. 4) Those having any one of inhibition, delay, or reduction of hair loss, and those having a plurality of actions are desired.

The active ingredient of the prophylactic or therapeutic agent for alopecia of the present invention is 4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) -4-oxo-butanoic acid or pharmaceutically acceptable thereof. It is a salt (hereinafter referred to as a compound of the present invention) and is represented by the following formula.

The compound of the present invention can be produced by using a general synthetic method, and can be produced, for example, by the method described in International Publication WO2014 / 080640.

Pharmaceutically acceptable salts in the compound of the present invention include metal salts with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like, N, N'-dibenzylethylenediamine, chloroprocine, choline, diethanolamine and the like. Organic salts and the like can be mentioned.

The compound of the present invention may also exist as various solvates. In addition, it may be a hydrate from the viewpoint of applicability as a medicine.

The compound of the present invention contains optical isomers and includes all enantiomers, any proportion of enantiomer mixtures, racemates and the like.

The prophylactic or therapeutic agent for alopecia of the present invention can be prepared by appropriately using the above-mentioned compound of the present invention, a known carrier, a diluent and the like, and formulating it into an appropriate pharmaceutical composition form. Specifically, oral preparations can be used as tablets, powders, powders, granules and liquids, capsules, dry syrups, jelly and the like, and external preparations can be used as liquids, lotions, ointments, packs and creams.

The prophylactic or therapeutic agent for alopecia of the present invention can be administered orally or parenterally (for example, intravenous, topical, rectal administration, etc.), but the preferred dosage form is that it can be directly administered to the affected area. External agents can be mentioned because they are easy to administer and the possibility of systemic side effects is reduced.

When the prophylactic or therapeutic agent for alopecia of the present invention is in the form of an oral preparation, other known additives such as vitamins and amino acids are used as necessary within a qualitative and quantitative range that does not impair the effects of the present invention. , Crude drugs, natural products, excipients, pH adjusters, refreshing agents, suspending agents, thickening agents, solubilizing agents, disintegrating agents, binders, lubricants, antioxidants, coating agents, coloring agents , Excipients, surfactants, plasticizers, fragrances and the like can be mixed.

On the other hand, when the prophylactic or therapeutic agent for alopecia of the present invention is used as an external preparation, other known additives such as 1,3- Solvents such as butylene glycol, propylene glycol, glycerin, dipropylene glycol, ethanol, methanol and purified water, preservatives such as parabens, bactericides such as hinokithiol, oils such as white petrolatum, squalane and paraffin, cetyl isooctanoate, cetyl caprate And esters such as glycerin monooleate, silicone derivatives such as silicone resin and silicone oil, surfactants such as polyoxyethylene hydrogenated castor oil, carboxyvinyl polymers, gelling agents such as polyvinyl alcohol, pH adjusters, antioxidants, etc. Colorants and the like can be mixed.

The dose of the prophylactic or therapeutic agent for alopecia of the present invention can be appropriately increased or decreased depending on the body weight, age, sex, etc. of the patient. Specifically, when used as an external preparation, the compound of the present invention is contained at a concentration of 0.0001 to 20 w / v%, preferably 0.1 to 10 w / v%, particularly preferably 1 to 10 w / v%. A method of applying 0.1 to 10 mL, preferably 0.2 to 5 mL, particularly preferably 0.5 to 2 mL per dose to the affected area using an external preparation, once to several times a day, preferably 1 to 1 to It can be administered twice, particularly preferably once.

When used as an oral preparation, the compound of the present invention may be administered at 1 to 1000 mg / kg per day for an adult, and may be administered 1 to several times a day.

Furthermore, the prophylactic or therapeutic agent for alopecia of the present invention can also be used in combination with the active ingredient of other alopecia preventive or therapeutic agents. Examples of the drug that can be used in combination include, but are not limited to, minoxidil, finasteride, dutasteride, carpronium chloride, adenosine, pentadecanoic acid glyceride, t-flavanone, and 6-benzylaminopurine. In addition, with other agents such as hair growth agents / hair growth agents, vasodilators, antiandrogens, cyclosporin derivatives, antibacterial agents, anti-inflammatory agents, thyroid hormone derivatives, prostaglandin agonists or antagonists, retinoids, triterpenes and the like. It can be used together. The prophylactic or therapeutic agent for alopecia of the present invention and the active ingredient of another prophylactic or therapeutic agent for alopecia may be used as separate preparations or as one combination drug.

The present invention will be described in more detail below with reference to synthetic examples and test examples. The present invention is not limited to these examples.

1. 1. Synthesis Example 4- (2,4-difluorophenyl) -2- (1H-indole-3-yl) -4-oxo-butanoic acid (Compound 1) synthetic compound 1 is described in International Publication WO2014 / 080640. It was synthesized by a method similar to the above method.

１,３－ジフルオロベンゼン（23 g）と無水マレイン酸（19.4 g）を丸底フラスコに入れ氷冷下撹拌した。反応液に塩化アルミニウム（53.8 g）を少量ずつ加えた後、生じた気泡をスパーテルで潰しながら1時間撹拌した。反応液を一晩放置すると固体に変化した。生じた固体を砕いた後、少量ずつ冷水（200 mL）に加えた。これに酢酸エチル、濃塩酸（22 ｍL）を加え、固体を溶解させた。有機層を分離した後、水層を酢酸エチルで２回抽出した。合わせた有機層を水、飽和食塩水で洗浄した後、硫酸ナトリウムによる乾燥、ろ過、濃縮を行い黄色い残渣を得た。得られた残渣に酢酸エチルを加えた後、水浴で加熱を行い、固体を溶解させた。得られた溶液にヘキサンをゆっくり加えた後、氷冷下２時間撹拌した。生じた固体をろ取した後、ヘキサンによる洗浄、通気乾燥を行い（トランス）－4－（２,４－ジフルオロフェニル）－４－オキソ－２－ブテン酸（27.0 g、黄色固体）を得た。
1H NMR (Acetone) δ: 7.93-8.04 (m, 1H), 7.71 (dd, J=15.6, 3.5 Hz, 1H), 7.17-7.32 (m, 2H), 6.75 (dd, J=15.5, 1.2 Hz, 1H), 6.41 (s, 1H).

1,3-Difluorobenzene (23 g) and maleic anhydride (19.4 g) were placed in a round-bottom flask and stirred under ice-cooling. After adding aluminum chloride (53.8 g) little by little to the reaction solution, the generated bubbles were crushed with a spatula and stirred for 1 hour. When the reaction solution was left overnight, it changed to a solid. After crushing the resulting solid, it was added little by little to cold water (200 mL). Ethyl acetate and concentrated hydrochloric acid (22 mL) were added thereto to dissolve the solid. After separating the organic layer, the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain a yellow residue. After adding ethyl acetate to the obtained residue, the solid was dissolved by heating in a water bath. Hexane was slowly added to the obtained solution, and the mixture was stirred under ice-cooling for 2 hours. After the resulting solid was collected by filtration, it was washed with hexane and air-dried to obtain (trans) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (27.0 g, yellow solid). ..
1H NMR (Acetone) δ: 7.93-8.04 (m, 1H), 7.71 (dd, J = 15.6, 3.5 Hz, 1H), 7.17-7.32 (m, 2H), 6.75 (dd, J = 15.5, 1.2 Hz, 1H), 6.41 (s, 1H).

(Trans) -4- (2,4-difluorophenyl) -4-oxo-2-butenoic acid (20 g), indole (22.1 g), toluene (440 mL) are placed in a 1 L flask and heated in an oil bath. did. After the temperature of the oil bath reached 80 ° C., the temperature was raised to 120 ° C. and the mixture was stirred for 4 hours. The mixture was stirred overnight while gradually allowing to cool to room temperature. The oil bath was heated to 120 ° C. again, stirred for 5 hours, and then slowly allowed to cool to room temperature. After filtering the reaction solution, the solid was washed twice with toluene and twice with hexane to obtain a light brown solid. The obtained solid was washed with acetonitrile three times, then washed with hexane and air-dried to obtain Compound 1 (21.9 g, pale yellow solid).
MS (ESI neg.) M / z: 328 ([MH] ^- ).
1H NMR (DMSO-d ₆ ) δ: 12.23 (br s, 1H), 11.00 (br s, 1H), 7.98 (td, J = 8.7, 6.8 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H) ), 7.31-7.49 (m, 2H), 7.18-7.30 (m, 2H), 7.04-7.15 (m, 1H), 6.94-7.03 (m, 1H), 4.33 (dd, J = 10.5, 3.9 Hz, 1H ), 3.89 (ddd, J = 18.4, 10.6, 2.8 Hz, 1H), 3.22-3.29 (m, 1H).

2. 2. Test example <Hair growth effect in mouse hair cutting model>
Method The back body hair of C57BL mice (7 weeks old, female) was cut, and 0.1 mL of a solvent or a 5 w / v% compound 1 solution was applied once a day from 3 days after the hair cut. Twenty mice were used in a group. The hair growth status of the cut hair was scored using the following hair growth score criteria on the first day of administration (1st day), 8th day, and every 2 or 3 days thereafter.
Hair growth score criterion 1 = Hair growth in less than 5% of the hair cut 2 = Hair growth in 5% or more of the hair cut, hair growth in less than 30% 3 = Hair growth in 30% or more of the hair cut, hair growth in less than 60% 4 = Hair growth on 60% or more and less than 90% of the hair cut 5 = Hair growth on 90% or more of the hair cut

Results As shown in FIG. 1, the group to which the 5% compound 1 solution was administered increased the hair growth score from an early stage as compared with the group to which the solvent was administered. The hair growth score of the compound 1 administration group was higher than that of the solvent administration group in the test period after the 27th day of administration. It was clarified that this compound shows an excellent hair growth promoting effect.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a new therapeutic agent useful for the prevention or treatment of alopecia. The prophylactic or therapeutic agent for alopecia of the present invention can be used as a drug, a quasi drug, or a hair cosmetic.

Claims (3)

The following formula,

A prophylactic or therapeutic agent for alopecia, which comprises a compound represented by the above or a pharmaceutically acceptable salt thereof. Alopecia is male alopecia, seborrheic alopecia, senile alopecia, alopecia areata, drug-induced alopecia, scar alopecia, postpartum alopecia, postmenopausal female alopecia or diffuse alopecia. , The prophylactic or therapeutic agent according to claim 1. The prophylactic or therapeutic agent according to any one of claims 1 and 2, which is an external preparation.

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