WO2002072049A1

WO2002072049A1 - Medicinal compositions for stimulating hair growth

Info

Publication number: WO2002072049A1
Application number: PCT/JP2002/001740
Authority: WO
Inventors: Wataru Uchida; Katsumi Sudoh; Yuzo Matsumoto
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 2001-02-27
Filing date: 2002-02-26
Publication date: 2002-09-19
Also published as: JPWO2002072049A1

Abstract

Medicinal compositions for stimulating hair growth which contain as the active ingredient aromatic fused ring oxazine derivatives or pharmaceutically acceptable salts thereof.

Description

Technical Description Pharmaceutical composition for hair growth Technical field

The present invention relates to a pharmaceutical composition for hair growth comprising an aromatic ring fused oxazine derivative or a salt thereof as an active ingredient. Background art

Alopecia can be broadly classified into mild alopecia caused by abnormalities in the hair growth cycle and rapid alopecia due to physical or mental stress. Normally, human scalp hair has 3 to 7 years of anagen, 2 to 3 weeks of regression, and 4 to 6 months of telogen.Repeats three cycles: the ability to maintain hair, especially caused by abnormalities in this hair growth cycle In mature alopecia (also known as male pattern baldness or androgenic alopecia), the growth period is shortened and the telogen is prolonged gradually, and the hair, which is the anagen, is relatively reduced. The hair shaft elongates due to cell division in the growth phase of hair matrix cells separated from Pavila cells, and is maintained buried in the outer root sheath during the telogen phase, and no elongation is observed. Consequently, shortening anagen and prolonging the telogen shorten terminal hair length.

In addition, the size of the follicle fluctuates with the hair cycle, and the follicle enlargement is observed especially during the transition from telogen to anagen. The size of the anagen hair follicle at this time is the thickness and height of the hair shaft that differentiates from the hair mother cell! Because of the correlation, the hair follicles at the bald area in age-related alopecia are not sufficiently enlarged compared to normal hair follicles, and the hair follicles (hair ). In other words, age-related alopecia can be said to be a miniature dwarf due to shortening of the anagen phase in the hair cycle and shrinking of the hair follicle, and thinning of the hair. Since age-related alopecia is due to the effects of male hormones, its frequency increases with puberty, adolescence and aging. Symptoms are so-called “balding”, and most of them have bald areas localized to the frontal and parietal regions. The bald spots may occur alone or simultaneously. As mentioned above, the terminal hairs shrink and regrown as they regrow, resulting in the receding of the hairline on the frontal region and the bald area on the parietal region, which gradually expand and fuse. Eventually, all of the hair is removed except for the back and temporal regions. Age-related alopecia is predominantly male, but also affects women and children. In that case, the hair on the frontal region, temporal region or parietal region becomes thinner as in men. It is extremely rare to have complete hair loss like a man.

By the way, because of its vasorelaxant relaxing action based on K channel opening action, minoxidil, which was initially developed as an oral antihypertensive drug, has attracted attention as a post-marketing side effect of minoxidil. Has been reported. Among the compounds known as K-channel openers, those known for their hair-growth effects include pinacidil, nicorandil, cromakalim, and diazoxide (all disclosed in Japanese Patent Application Publication No. 10-203935), 4- [[(Cyanoimino) [(1,2,2-trimethylpropyl) amino] methyl] amino] benzonitrile (see Japanese Patent Application No. 2001-515034), spirocyclic benzopyran The imidazolines (see JP-A-6-510060) are fisted.

Initially, compounds having K channel opening activity were thought to express hair growth activity by a vasodilating action around the hair follicle based on the action. However, at present, there are compounds that have K-channel opening activity but no hair-growth activity, and that minoxidil can show hair-growth activity even under conditions that do not involve blood supply such as hair follicle culture. There is no recognition that peripheral vasodilatory action based on exocytosis directly leads to activities useful for alopecia and hair loss dysfunction. In particular, there are other unknown direct effects other than K channel opening activity, which are thought to express hair growth activity (Japanese Pharmacological Journal, Vol. 114, No. 1, p. 79, 1999). Therefore, it is a technical recognition of those skilled in the art at present that even compounds that have been conventionally known to have K-channel opening activity cannot be said to have the hair-growth activity. On the other hand, the above-mentioned minoxidil is still known as the most effective hair restorer and is widely used. However, there were reports that no improvement was seen in about three-quarters of cases (Kochi Medical Association Medical Journal, Vol. 6, No. 1, p. 88, 2001), atypical angina, cluster headache There is also a report (Japanese Circulation Journal, 64 (suppl.III), 894, 2000, Clinical Neurology, 40 (8), 864, 2000) that circulatory system side effects are seen. In addition to minoxidil, natural product extracts or synthetic drugs having various actions are used, but all of them cannot achieve a sufficient effect with a small amount of addition, and are not suitable for a large amount of addition. In some cases, it gave an unpleasant irritant feeling and dermatitis occurred when used continuously. In addition, age-related alopecia is now remarkably young and is increasing, and women are becoming a major source of trouble as the number of places of activity in society increases. Therefore, there is a strong demand for the development of an excellent hair restorer capable of suppressing the onset and / or progress of age-related alopecia or improving the symptoms and having an activity equal to or higher than that of minoxidil. Disclosure of the invention

The present inventors have conducted intensive studies on the hair-growth activity of a compound having a κ channel opening action. As a result, an aromatic-ring-fused oxazine derivative or a salt thereof having a completely different structure from minoxidil, which is currently commercially available and widely used as a therapeutic agent for alopecia, In addition, it was confirmed that Minoxidil had a hair-growth effect equivalent to or better than Minoxidil, and the present invention was completed.

That is, according to the present invention, there is provided a pharmaceutical composition for hair growth comprising an aromatic condensed oxazine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[The symbols in the formula have the following meanings.

R ¹ , R ² and R ³ : the same or different and a hydrogen atom or lower alkyl.

R ⁴ : a hydrogen atom, lower alkyl or a group represented by the formula (II).

^ OY ( ^{1 1} )

Υ: hydrogen atom, lower alkyl, lower alkylene monoaryl, -CO-lower alkyl, carpamoyl which may be substituted by one or two lower alkyls, or two-port.

X: carbon atom or nitrogen atom

(1) when X is a carbon atom;

(1-a)

R ⁵ , R ⁶ , R ⁷ and R ⁸ : the same or different and may be substituted with a hydrogen atom, halogen, lower alkyl optionally substituted with one or more halogen, -0-lower alkyl, cyano, nitro, one or two lower alkyl optionally substituted with Amino, -NHCO- lower § alkyl, -N (lower alkyl) CO- lower alkyl, -NHS0 ₂ - lower alkyl, -S0 ₂ - lower alkyl, or - S0 ₂ -Ariel. Or,

(1-b)

R ⁵ and R ^8: a hydrogen atom.

R ⁶ and R ^7: together with the adjacent two carbon atoms, at least two nitrogen source 5- or 6-membered heterocyclic ring which has a substituent and may further have an oxygen atom, a sulfur atom or a nitrogen atom.

(2) when X is a nitrogen atom;

R ⁵ , R ⁶ and R ⁸ : identical or different, substituted by hydrogen atom, halogen, lower alkyl optionally substituted with halogen, -0-lower alkyl, cyano, nitro, one or two lower alkyls is optionally Amino, -NHCO- lower alkyl, -N (lower alkyl) CO- lower alkyl, -NHS0 ₂ - lower alkyl, -S0 ₂ - lower alkyl, or - S0 ₂ - Ariru.

R ⁷ : absent or N-oxide together with X.

R ⁹ : a group selected from the group consisting of a hydrogen atom and lower alkyl. In addition, 1 to 4 groups may be present on the ring.

m: 0 or 1.

n: 0 or 1. ]

Among the pharmaceutical compositions for hair growth comprising the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, preferably, 2- (3,4-dihydro-2,2-dimethyl -6-nitole -2H-1, 4-benzoxazine-4-ynole) pyridine 1-oxide (hereinafter referred to as "compound 1"), 2- (7,8-dihydro-6,6-dimethyl-6H) -[1,4] oxazino [2,3-/] [2,1,3] benzoxaziazol-8-yl) pyridine 1-oxide (hereinafter, referred to as “compound 2 J”) or 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-inole) pyridin 1-oxide (hereinafter, referred to as "compound 3"), or a pharmaceutical preparation thereof A hair-growing pharmaceutical composition containing a chemically acceptable salt as an active ingredient, and more preferably a hair-growing hair containing Compound 3 or a pharmaceutically acceptable salt thereof as an active ingredient. It is a pharmaceutical composition.

Further, according to the present invention, an aromatic ring fused oxazine derivative represented by the above general formula (I), preferably compound 1, compound 2 or compound 3, more preferably compound 3 or a pharmaceutical composition for hair restoration characterized by being a pharmaceutical composition for the treatment of chronic alopecia comprising a pharmaceutically acceptable salt thereof as an active ingredient.

Further, the present invention relates to a compound represented by the above general formula (I), preferably compound 1, compound 2 or compound 3 for the production of a hair restorer and a hair restorer which is a therapeutic agent for Z or age-related alopecia. More preferably, it relates to the use of compound 3, or a pharmaceutically acceptable salt thereof. '

Further, according to the present invention, the therapeutic efficacy of the compound represented by the above general formula (I), preferably compound 1, compound 2 or compound 3, more preferably compound 3, or a pharmaceutically acceptable salt thereof is provided. There is provided a hair growth method comprising administering an amount to a patient, and a hair growth method which is a method for treating Z or age-related alopecia.

The present invention relates to a novel use of a benzoxazine derivative represented by the following general formula, which is disclosed in European Patent Applications EP432893 and EP500319.

(Refer to the official gazette for symbols in the formula)

Some of the aromatic ring-fused oxazine derivatives which are the active ingredients of the pharmaceutical composition of the present invention are known compounds described in Examples of the above-mentioned EP432893 and EP500319, and the compounds described in these publications are referred to as K It is disclosed as a channel opener. Further, the detailed description of the invention in the publication describes that peripheral vasodilation based on K channel opening activity is useful for alopecia or dysplasia. However, there is no description that the compound is useful for those symptoms or has a hair-growth effect.

The compound of the present invention is further described as follows. In the present specification, “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.

Accordingly, "lower alkyl" refers to C Les ₆ alkyl; e.g. methylation, Echiru, propyl, isopropyl Honoré, butyl, tert- butyl, pentyl, neopentyl, hexyl and the like to, Preferably, it is methyl, ethyl, propyl, or isopropyl of C _1-3 alkyl.

“Lower alkylene” means C _1-6 alkylene, and specific examples include methylene, ethylene, propylene, dimethylmethylene, and 2,2-dimethylpropylene.

“Aryl” means a C _6-14 monocyclic to tricyclic aromatic ring which may have a substituent, and preferably phenyl, naphthyl and the like. Acceptable substituents include lower alkyl, -0-lower alkyl, rho, logen, nitro, cyano and the like.

"Halogen" includes, for example, fluorine, chlorine, bromine and iodine atoms. Accordingly, “lower alkyl optionally substituted with halogen” means the above “lower alkyl” which may be substituted or unsubstituted with the above “halogen”. Specific examples thereof include, in addition to the above “lower alkyl”, fluoromethyl, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trichloromethyl and the like.

Further, the term “5- or 6-membered heterocyclic ring having at least two nitrogen atoms and optionally having an oxygen atom, a sulfur atom, or a nitrogen atom” is specifically, for example, oxaziazole or thiadiazole , Triazole, pyrazine, oxaziazine and the like. The compound of the present invention represented by the general formula (I) may contain an asymmetric carbon atom depending on the type of the substituent, and an optical isomer based on this may exist. The present invention includes all mixtures and isolated forms of these optical isomers.

In addition, the compound of the present invention may form an acid addition salt. As long as the salt is acceptable, it is included in the present invention. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, conodic acid, Acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, P-toluenesulfonic acid, aspartic acid or glutamic acid, and the like. Furthermore, the present invention includes various hydrates, solvates, and substances having crystalline polymorphs of the compound of the present invention and pharmaceutically acceptable salts thereof. The compounds of the present invention include all compounds that are metabolized in vivo and converted into the compound having the general formula (I) or a salt thereof, so-called prodrugs. Examples of the group that forms the prodrug of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), and “Developing Pharmaceuticals”, 1990, Hirokawa Shoten, Vol. 7, Molecular Design 163-198. And the groups described in the above.

Also, among the compounds of the present invention represented by the general formula (I), particularly preferred are the 2- (3,4-dihydro- compounds described in JP-A-4-178375 and JP-A-5-70464. 2,2-Dimethyl-6-dito-2H-1,4-benzoxazine-4-inole) pyridine 1-oxide, 2- (7,8-dihydroto-6,6-dimethyl-6H- [ 1,4] oxazino [2,3-] [2,1,3] benzoxaziazol-8-inole) pyridine 1-oxide or 2- (6-cyano-3,4-dihydro-2, 2-dimethyl-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide or a pharmaceutically acceptable salt thereof.

The compound of the present invention represented by the general formula (I) can be easily obtained by the production method described in the above-mentioned JP-A-4-178375 or JP-A-5-70464, or according to it.

In the hair restorer of the present invention, it is preferable that one or more active substances of the compound of the present invention represented by the general formula (I) are contained in an amount of 0.001 to 99.999% by weight based on the total amount of the hair restorer. It is more preferably 0.001 to 10% by weight, particularly preferably 0.003 to 3% by weight. The drug of the present invention is generally used by using at least one compound of the present invention represented by the general formula (I) and a simple substance, excipient, and other additives usually used for formulation. Can be prepared by the following method. Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids; injections, such as intravenous and intramuscular injections; or parenteral, such as suppositories, nasally, transmucosally, and transdermally. May be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances comprise one or more inert diluents such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. Mixed with magnesium metasilicate aluminate and the like. According to a conventional method, the composition may contain additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose dalycholate, a stabilizer such as ratatose, glutamic acid or It may contain an auxiliary agent for melting angle such as aspartic acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylsenorellose, hydroxypropynolemethinole cellulose phthalate or the like, or with a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as purified water , Containing ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include, for example, propylene glycol, polyethylene glycol and olive oil, vegetable oils, alcohols such as ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents, for example, stabilizing agents such as lactose, solubilizing agents such as glutamic acid-aspartic acid, and the like. . this Are sterilized by, for example, filtration through a pateria retaining filter, blending of a bactericide or irradiation. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile injection solvent before use.

Transdermal preparations for parenteral administration include ointments, lotions, cataplasms, gels, creams, solutions, sprays, baths, patches and the like. In these preparations, one or more active ingredients may contain one or more inert additives, for example, hydrocarbons such as petrolatum, squalane, liquid paraffin, higher alcohols such as stearyl alcohol, cetanol, and the like. Lower alkyl esters of higher fatty acids such as isopropyl myristate and isopropyl palmitate; animal fats and oils such as lanolin; polyhydric alcohols such as glycerin and propylene glycol; polyethylene glycols such as McGolle 400 and McGoal 4000 Glycerin fatty acid esters such as glyceryl monostearate, sodium lauryl sulfate, polyethylene glycol monostearate, surfactants such as polyxethylene alkyl ether phosphoric acid, sorbitan sesquiate, etc., lactic acid, sodium taenoate, Sodium carbonate Beam, various salts such as anhydrous sulfuric Natoriumu, ethanol, 蠟, resin, water and optionally by Paraokishi benzoate, para Okishi acid Echiru, Paraokishi propyl benzoate, is mixed with a preservative such as Paraokishi butyl benzoate.

Specifically, for example, a transdermal agent can be prepared by mixing 30.3 g of the compound, 30 mL of ethanol, and 50 mL of propylene glycol, and adding distilled water to a total volume of 100 mL.

The pharmaceutical composition for hair restoration according to the present invention may be a lotion, an emulsion, a cream, an ointment, a pack or the like, or a hair coating, a hair lotion, a hair term, a hair conditioner, a shampoo, It can be in the form of a hair restorer such as rinse, hair elixir, hair mist, and foam. Also, surfactants, humectants, pH adjusters, thickeners, bactericides, preservatives, keratolytic agents, antioxidants, fragrances, dyes, UV absorbers Excipients, pigments, female hormonal agents, antiandrogenic agents, and the like can be appropriately compounded within a range that does not impair the purpose of the present invention.

Usually, in the case of oral administration, the daily dose is about 0.0001 to 50 mg / kg of active ingredient per body weight, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg. It is administered once or in 2 to 4 divided doses. When administered intravenously, the daily dosage should be about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg, of the active ingredient per body weight. Administration. In the case of transdermal administration, the daily dosage is about 0.01 to 200 mg, preferably about 0.01 to 100 mg, and more preferably about 0.01 to 10 mg of the active ingredient per person. It is administered once or more than once a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like. Industrial applicability

ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition for hair growth excellent or the pharmaceutical composition for the treatment of adolescent alopecia can be provided. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail based on test examples, but the present invention is not limited to these examples. Table 1 shows the structures of Compound 1, Compound 2 and Compound 3 used in the following test examples. (table 1 )

Test Example 1 Test of hair growth effect of compound 1, compound 2 and minoxidil in mice Animals used: C3H / HeNCrj male mice (7 weeks old), 10 cases per group.

Administration method: A shaved surface of about 2 cm × 2 cm was formed on the back of the mouse using an electric clipper and an electric shaver, and 0.1 mL of the test substance solution was applied once a day for 7 days. Dosage: Compounds 1 and 2 are 1% solutions (solvent: 70% aqueous ethanol, 1 mg / site / day), and minoxidil are 5% solutions (solvent: 70% aqueous ethanol, 5 mg / site / day). For the control, a 70% aqueous ethanol solution was used.

Evaluation method: From 4 days after the start of the application to 16 days after the start of the application (10 days after the end of the application), the hair growth state was determined by visual observation once a day in accordance with Table 2.

(Table 2)

Statistical analysis: The results are shown as the average value of the 10 subjects subjected to the test (Table 3). For the significance test of the hair growth effect, after one-way analysis of variance, the control group was subjected to a corresponding V and multiple comparison (Dunnett test), and a risk factor of less than 5% was considered significant. (Table 3)

Average score

Days after start of administration

4 5 6 7 8 9 10 Compound 1 0 0 0 0 0.1 1.1 * Compound 2 0 0 0 0 0.1 0.7 ** 1.2 * Minoxidil 0 0 0 0 Q 7e * 1.5 **

3 outlet 0 0 0 0 0 0 0.3

1 1 12 13 14 15 16

Compound 1 1.5 ** 2.2 ** 2.6 ** 3.0 ** 3 **

Compound 2 2.2 ** 2.5 ** 2 9 ** 3.8 ** 4 1 **

1 Q ** 2.4 ** 2 ** 3.5 ** 3 9 ** 4.6 **

; 13 nt 13 0.9 0.4 0.9 1.0 1.3 1.9 2.4

*: Ρ <0.05, **: P <0.01 vs control group Result: As shown in Table 3, both Compound 1 and Compound 2 were administered at a lower dose of 1 mg / site / day than minoxidil. It promoted hair growth to the same extent as 5 mg / site / day. ο

* *

Test Example 2 Test of hair growth effect of compound 3 and minoxidil in mice Animals used: C3H / HeNCrj male mice (5 weeks old), 10 cases per group.

Administration method: The back of the mouse is about 2cmX using an electric palycan and an electric sealer.

A 2 cm shaved surface was prepared, and 0.1 mL of the test substance solution was applied once a day for 28 days. Dosage: Compound 3 is a 0.3% solution (solvent: 70% aqueous ethanol, 0.3 mg / site / day), and minoxidil is a 5% solution (solvent: 70% aqueous ethanol, 5 mg / site / day). The solution used was a 70% aqueous ethanol solution.

Evaluation method: From the first day of application to the 28th day after the start of application, the hair growth state was determined by visual observation once a day according to Table * of Test Example 1 described above (* Table 2).

Statistical analysis: The results were shown as the average value of 10 subjects subjected to the test (Table 4). The significance test for the hair growth effect was performed by one-way analysis of variance with multiple comparisons (Dunnett's test) that were not associated with the control group, and a risk factor of less than 5% was considered significant.

(Table 4)

Average score

Day after start of administration

4 5 6 7 8 9 10 1 1 Compound 3 0.0 0.0 0.0 0.3 0.4 0.9 * 0.9 1.3

0.0 0.0 0.0 0.3 0.4 0.8 0.9 1.5

; Π Π ル

12 13 14 15 16 17 18 19 Compound 3 1.4 1.7 2 7 ** 3.8 ** 4 0 ** 4.5 * 4.5 4.5

1.5 1.9 2.7 * 3.5 3.9 4.1 4.1

: =! 1.3 1.3 1.7 2.3 2.7 3.3 3.4 3.4

*: P <0.05, **: P <0.0] vs control group Result: As shown in Table 4, the dose of compound 3 was 3 mg / site / day, which was significantly lower than that of minoxidil, at a dose of 0.3 mg / site / day. Hair growth was promoted at least as high as / day. Hereinafter, chemical names of other active ingredients of the pharmaceutical composition of the present invention are shown. These compounds or pharmaceutically acceptable salts thereof can also exhibit a hair growth promoting effect equivalent to that of compound 1, compound 2 or compound 3 described above.

The number given before the chemical name indicates the compound number.

A1; 2-[(6-bromo-3,4-dihydrido-2,2-dimethyl-2H-1,4-benzoxazine-4-ynole) methyl] pyridine 1-oxide, A2; 2- (3, 4-dihydro-2,2-dimethyl-6-phenenolesnorefolinore-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A3; 2- (3,4-dihydro-2, 2-dimethyl-6--2-to-2H-1,4-benzoxazin-4-yl) -6-methylpyridine 1-oxide, A4; 2- (3,4-dihydroto-6-nitro-2H) -1, 4-benzoxazin-4-yl) pyridine 1-oxide, A5; 2- (6-co mouth-3,4-dihydro-2,2-dimethyl-7-nitole -2H-1, 4-benzoxazine-4-yl) pyridine 1-oxide, A6; 2- (6-amino-3,4-dihydro-2,2-dimethinole-2H-1,4-benzoxazin-4-yl) pyridine 1 -Oxide, A7; 2- (6-acetoamide-3,4-dihydrido-2,2-dimethyl-2H-1, 4-benzoxazine-4-inole) pyridi 1-oxide, A8; 2- (3,4-dihydro-2,2-dimethyl-6-methylsulfonyl-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A9; 2- (3,4-dihydro-2,2-dimethyl-6-methanesulfonamide-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A10; 2- (3,4-dihydro -2,2-dimethyl-6-trifluoromethyl-2H-1, 4-benzoxazine-4-inole) pyridine 1-oxoside hydrochloride, A11; 2- (3,4-dihydro-2,2- Dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide hydrochloride, A12; 2- (7-acetoamide-3,4-dihydro-2,2-dimethyl-6 -2H-1,4-benzoxazin-4-yl) pyridine 1-oxide 0.5ethanol solvate, A13; 2- (7-amino-3,4-dihydro-2,2-dimethinole-6 -Nitto-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A14; 2- (6-acetate Mid-3,4-dihydro-2,2-dimethinole-7-dito-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A15; 2- (6-amino-3 , 4-dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine-4-inole) pyridine 1-oxide, A16; 7,8-dihydro-6,6-dimethyl-8 -(1-Oxide-2-pyridi -6H- [1,2,5] -oxaziazo mouth [3,4-g] [1,4] benzoxazine 3-oxide, A17; 2- (1,6,7,8-tetrahydro- [1 , 2,3] Triazolo [4,5-g] [l, 4] benzoxazine-8-inole) pyridine 1-oxide, A18; 2- (8,9-dihydro-7,7-dimethyl-7H- [1,4] oxazino [2,3-g] quinoxaline-9-yl) pyridine 1-oxide, A19; 2- (7,8-dihydro-6,6-dimethyl-6H- [1,2 , 5] Thiadiazolo [3,4-g] [l, 4] benzoxazine-8-inole) pyridine 1-oxide, A20; 2- (1,6,7,8-tetrahydro-2,6,6-trimethylimidazo [4,5-g] [l, 4] benzoxazin-8-yl) pyridine 1-oxide, A21; 2- (6,6-dimethyl-1,2,3,6,7,8-hexahydro -2-oxoimidazo [4,5-g] [l, 4] benzoxazine-8-inole) pyridine 1-oxide, A22; 2- (3,4-dihydro-2,2-dimethyl-6-ethyl-2H -1,4-benzoxazine-4-inole) pyridine

1-oxide hydrochloride, A23; 2- (3,4-dihydro-2,2-dimethyl-6-methoxy-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A24; 2- (3,4-dihydro-2,2-dimethyl-2H-pyrido [4,3-b] -l, 4-oxazin-4-yl) pyridine 1-oxide, A25; 3,4-dihydro -2,2-dimethyl-4- (1-oxide-2-pyridyl) -2H-pyrido [4,3-mi] -1,4-oxazine 6-oxide, A26; 2- (3,4-dihid) Dro-2-hydroxymethyl-2-methyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A27; 2- (3,4-dihydro-2-methoxymethyl- 2-methyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide hydrochloride, A28;

2- (3,4-dihydro-2-methyl-2- (N-methinolecarbamoyloxymethyl) -6-butout-2H-1,4-benzoxazine-4-ynole) pyridine 1-oxide, A29; 2- (2-butoxymethyl-3,4-dihydroxy-2-methyl-6-but-2-h-1,4-benzoxazine-4-inole) pyridine 1-oxide hydrochloride, A30; 2 -(2-benzyloxymethyl-3,4-dihydro-2-methyl-6-etro-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A31; 2- (2-acetyl Oxymethyl-3,4-dihydro-2-methynole-6-nitro-2H-1,4-benzoxazine-4-ynole) pyridine 1-oxoside, A32; 2- (3,4-dihydro- 2-methyl-6-ditro-2--2-nitrooxymethyl-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, A33; 3,4-dihydro-2,2-dimethyl-6- 2-Toro-4-pyridine-3-inole-2H-1,4-benzoxazine, A34; 4-Γ3.4-dihi Russia - 2,2-dimethyl Tyl-6-2-to-2 mouth-2H-1,4-benzoxazine-4-inole) pyridine 1-oxide, A35; 3-[(6-cyano-3,4-dihydro-2,2-dimethinole-2H- 1,4-benzoxazine-4-ynole) methinole] pyridin 1-oxide.

Claims

5 Scope of request

1. A pharmaceutical composition for hair growth comprising an aromatic condensed oxazine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[The symbols in the formula have the following meanings.

_ _0Y (II)

Y: hydrogen atom, lower alkyl, mono-lower alkylene aryl, -CO-lower alkyl, carpamoyl which may be substituted by one or two lower alkyls, or two-port.

X: carbon atom or nitrogen atom

(1) when X is a carbon atom;

(11-a)

R ⁵ , R ⁶ , R ⁷ and R ⁸ : the same or different and may be substituted with a hydrogen atom, halogen, lower alkyl optionally substituted with one or more halogen, -0-lower alkyl, cyano, nitro, one or two lower alkyl optionally substituted with Amino, -NHCO- lower § alkyl, -N (lower alkyl) CO- lower alkyl, -NHS0 ₂ - lower alkyl, -S0 ₂ - low Grade alkyl, or - so ₂ - Ariru. Or,

(1-1 b)

R ⁵及Pi R ^8: a hydrogen atom.

R ⁶ and R ⁷ : having at least two nitrogen atoms in combination with two adjacent carbon atoms, and optionally having an oxygen atom, a sulfur atom, or a nitrogen atom 5 or 6-membered heterocycle. -(2) when X is a nitrogen atom;

R ⁵ , R ⁶ and R ⁸ : identical or different, substituted by hydrogen atom, halogen, lower alkyl optionally substituted by halogen, -0-lower alkyl, cyano, nitro, one or two lower alkyls which may be Amino, -NHCO- lower alkyl, -N (lower alkyl) CO- lower alkyl, -NHS0 ₂ - lower alkyl, -S0 ₂ - lower alkyl, or - S0 ₂ - Ariru.

R ⁷ : absent or N-oxide together with X.

m: 0 or 1.

n: 0 or 1. ]

2. The active ingredient is 2- (3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide, 2- (7, 8-dihydrid -6,6-dimethyl-6H- [1,4] oxazino [2,3-] [2,1,3] benzoxoxadiazonol-8-inole) pyridine 1-oxide Or 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-ynole) pyridin 1-oxide, or a pharmaceutically acceptable salt thereof The pharmaceutical composition for hair restoration according to claim 1, which is a salt.

3. The active ingredient is 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide or a pharmaceutically acceptable product thereof. Claims that are salts 2. The pharmaceutical composition for hair restoration according to item 1.

4. The pharmaceutical composition for hair restoration according to claim 1, claim 2 or claim 3, which is a pharmaceutical composition for treating alopecia areata.

Use of an aromatic ring-fused oxazine derivative represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the production of a hair restorer.

2- (3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine-4-ynole) pyridine 1-oxide, 2- (7, 8-dihydro-6,6-dimethyl-6H- [1,4] oxazino [2,3-] [2,1,3] benzoxaziazol-8-inole) pyridine 1-oxide or 2 - (6-Shiano-3,4-dihydro - 2,2-dimethyl-2H-1,4 Benzooki spoon - ₄ _ I le) pyridine 1 Okishido, or the use of their pharmaceutically acceptable salts .

2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl) pyridine 1-oxide or a pharmaceutically acceptable salt thereof for producing a hair restorer Use of acceptable salts.

Use of the compound according to claim 5, claim 6, or claim 7 for the manufacture of a hair restorer which is a therapeutic agent for alopecia age.

A hair growth method comprising administering to a patient a therapeutically effective amount of an aromatic ring-fused oxazine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

. 2- (3,4-dihydro-2,2-dimethyl-6-dimethoxy-2H-1,4-benzoxazine-4-inole) pyridine 1-oxide, 2- (7,8-dihydro- 6,6-Dimethinole-6H- [1,4] oxazino [2,3-] [2,1,3] benzoxazazole-8-yl) pyridine 1-oxide or 2- (6- A therapeutically effective amount of cyano-3,4-dihydro-2,2-dimethinole-2H-1,4-benzoxazine-4-ynole) pyridine 1-oxide or a pharmaceutically acceptable salt thereof is administered to a patient. A hair growth method comprising administering.

. 2- (6-cyano-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine-4-inole) pi A hair growth method comprising administering to a patient a therapeutically effective amount of lysine 1-oxide or a pharmaceutically acceptable salt thereof.

A hair-growth method which is a method for treating alopecia baldens, comprising administering to a patient a therapeutically effective amount of the compound according to claim 9, claim 10, or claim 11.