JP2001354567A - Remedy for dermatitis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a remedy for dermatitis, not giving such a side effect as caused by a steroid medicament, highly safe, and therefore especially used as a remedy for atopic dermatitis. SOLUTION: This remedy for dermatitis contains a compound expressed by the formula (I) (R is H or a halogen), its pharmaceutical acceptable salt, or its pharmaceutical acceptable hydrate as an active ingredient. The remedy is preferably used as a remedy for the atopic dermatitis. The remedy inhibits significantly and dose-relatedly an antigen-induced mouse auricle edematization reaction which is a model for the atopic dermatitis, and further inhibits significantly a mouse antigen-induced flare reaction accompanied therewith. The remedy does not give any side effect on the skin, and therefore has extremely high usefulness as a highly safe medicament against the atopic dermatitis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 7-amino-3-benzyl-
The present invention relates to a pharmaceutical use of a 1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative as a therapeutic agent for dermatitis, particularly a therapeutic agent for atopic dermatitis.

[0002]

2. Description of the Related Art Dermatitis is an inflammatory reaction of the skin to various extrinsic and intrinsic factors, and is the most frequent disease among skin diseases. Usually, eczema is synonymous. A typical acute-phase clinical picture first develops edematous erythema, followed by papules and serous papules on the erythema, vesicles, pustules, erosions, crusts,
Form scales and go for healing. Chronicity causes skin thickening, lichenification, pigmentation, and in most cases, pruritus. Histologically, it is characterized by interepidermal edema (sponge) in the acute phase. Contact dermatitis, atopic dermatitis, seborrheic dermatitis, monetary eczema, Vidal lichen, stasis dermatitis, dysphoric eczema, sebum-deficient eczema, self-sensitizing eczema, etc. are the categories of dermatitis include.

Atopic dermatitis is thought to be caused by atopy, ie, an allergic reaction involving immunoglobulin E (IgE), but the cause of the onset has not yet been clarified. Atopic dermatitis is often accompanied by high blood IgE and eosinophilia.
Atopy itself belongs to type I, but atopic dermatitis is pathologically similar to eczema and contact dermatitis.
The involvement of type V allergy (delayed type) has been suggested. It has been suggested that late onset reactions involving infiltration of eosinophils and lymphocytes play an important role in the onset and chronicity of atopic dermatitis (Iwamoto et al .: J. Leukoc. Bi
ol., 52, pp. 572-578 (1992), a paper by Frigas et al .: J. All.
ergy. Clin. Immunol., 77, pp. 527-537 (1986) and the like). Symptoms of atopic dermatitis begin with moist eczema on the face from about 2 to 6 months after birth, and gradually spread to the extremities and trunk. It is also characterized by strong itching. Symptoms change with age, infancy (up to 2 years), infancy (2-12 years).
Aged) and adulthood. During infancy, it is mainly confined to the face, but gradually the trunk skin dries and develops papular papules (atopic skin). In childhood and childhood, the lesions dry out, causing a thickened aspect in the cubital and popliteal fossa (lichenification). Healing often occurs by about 12 years of age, but those who have transitioned to adulthood are more severe, often relapse or hatred even once they are remissioned, and there are cases where it takes a long time to complete or cases that do not lead to complete cure is there. Treatment is most effective when topical steroids (such as ointments) are applied, and no alternative treatment has been established.

[0004] Meanwhile, steroids commonly used in the treatment of dermatitis such as atopic dermatitis are agents that exhibit sharp side effects of clinical effects and various side effects. Although various side effects of steroids have been reported, external harmful effects such as thinning, atrophy and flushing of the skin in external preparations such as ointments are socially significant as serious side effects. It has become. As described above, existing steroids which are widely used as therapeutic agents for dermatitis and atopic dermatitis have a serious side effect problem, and have fewer side effects and are highly safe, and can be used safely. Are eagerly sought in patients and medical settings.

[0005] The compounds used in the therapeutic agent for dermatitis of the present invention include novel compounds having a bronchodilator effect.
A patent application (JP-A-2000-119272) has already been filed. Further, a compound having a pyrido [2,3-d] pyrimidine skeleton having a similar structure has an antiallergic effect (JP-A-63-45279), and 7-aminopyrido [2,3-d] pyrimidine That the compound having a skeleton has a bronchodilator effect (JP-A-8-3046, JP-A-8-304)
3164 and JP-A-8-3165).

[0006]

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems of the prior art, and is a highly safe dermatitis with little side effects, which is desired by patients and medical sites. It is an object of the present invention to provide a therapeutic agent, particularly a therapeutic agent for atopic dermatitis.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies on 7-aminopyrido [2,3-d] pyrimidine derivatives and found that 7-amino-3-benzyl-1-phenylpyrido [2,3-
d] The pyrimidine-2,4-dione derivative was found to be useful as a therapeutic agent for dermatitis, particularly a therapeutic agent for atopic dermatitis, and found to have few side effects on the skin, thus completing the present invention.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a therapeutic agent for dermatitis, particularly atopic dermatitis, comprising a compound represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. Related to therapeutic agents.

Embedded image [In the formula, R represents hydrogen or halogen. ]

In the substituents of formula (I), R represents hydrogen or halogen, preferably halogen such as fluorine, chlorine, bromine and iodine.

Hereinafter, preferred embodiments of the present invention will be described. (1) A therapeutic agent for dermatitis comprising, as an active ingredient, the compound represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof. (2) The therapeutic agent for dermatitis according to the above (1), which is a therapeutic agent for atopic dermatitis. (3) The therapeutic agent for dermatitis according to any one of the above (1) or (2), which is an external preparation. (4) Any one of the above (1) to (3), which contains, as an active ingredient, the compound represented by the above general formula (I) wherein R is hydrogen, or a pharmaceutically acceptable salt or hydrate thereof. The therapeutic agent for dermatitis according to Item. (5) The above (1) to (3), wherein the compound represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof wherein R is substituted at the ortho position is contained as an active ingredient. The therapeutic agent for dermatitis according to any one of the above. (6) The therapeutic agent for dermatitis according to (5), which comprises a compound represented by the general formula (I) wherein R is chlorine or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

Among the compounds represented by the general formula (I) used in the therapeutic agent for dermatitis of the present invention, particularly preferred compounds are as follows. 7-amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 1] 7-amino-3- (2-chlorobenzyl ) -1,2,3,4-tetrahydro
1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [Compound 2] Among the above compounds, the most preferred compound is 7-amino-3-benzyl-1,2,3,4-tetrahydro-1 -Phenylpyrido [2,3-
d] pyrimidine-2,4-dione [compound 1].

The compound represented by the general formula (I) used in the therapeutic agent for dermatitis of the present invention is disclosed in JP-A-63-45279.
JP-A-8-3046, JP-A-8-3164 or JP-A-8-3165 and JP-A-2000-119
The compound can be produced according to or according to the method described in the application specification of No. 272, and the production method is described in detail in Examples below.

The compound represented by the above general formula (I) includes various salts of pharmaceutically acceptable salts, if any, such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and the like.
Phosphoric acid, perchloric acid, thiocyanic acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid, glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid,
Fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, p-
An addition salt with an acid such as toluenesulfonic acid, naphthalenesulfonic acid, and sulfanilic acid can be given. These salts can be produced from the respective free compounds or can be mutually converted by known methods. In addition, cis-trans isomers, optical isomers, stereoisomers such as conformers, or when present in the form of hydrates or metal complex compounds,
The present invention includes all stereoisomers, hydrates and complex compounds.

The compound represented by the general formula (I) can be combined with a suitable pharmaceutical carrier or diluent to prepare a medicament, which can be used as the therapeutic agent for dermatitis of the present invention. As a method of formulation, any ordinary method may be used. As a therapeutic agent for dermatitis, it is most suitable to formulate an external preparation such as a liquid, suspension / emulsion, plaster, ointment, cataplasm, liniment, lotion and the like. In the formulation, the compound represented by the general formula (I) may be used in the form of a pharmaceutically acceptable salt or hydrate, or may be used as a combination with other pharmaceutically active ingredients. The preparation method of the external preparation is described in detail in, for example, the General Rules for Preparations in the Japanese Pharmacopoeia Manual, 13th Revision (published by Hirokawa Shoten, 1996).

Ointments are prepared according to the type of base used.
It can be broadly classified into oily ointments, emulsion ointments, water-soluble ointments, and suspension ointments. The production of these ointments, for example,
Fatty, fatty oils, lanolin, petrolatum, paraffin, wax, resins, plastics, glycols, higher alcohols, glycerin, water, emulsifiers, suspending agents, or other suitable additives As a base,
It can be carried out by adding the compound of the present invention and mixing to make the whole quality uniform.

To formulate a poultice, the powder of the compound represented by the general formula (I) and an essential oil component may be mixed to produce a slurry. Depending on the type and condition of the disease, it can be formulated into a dosage form other than the above that is optimal for the treatment.

The desired dose of the compound of the present invention may be appropriately set depending on the administration subject, dosage form, administration method, administration period and the like. For example, in general, in order to obtain a desired effect on an adult, an ointment containing the compound of the present invention in an amount of 0.1% to 15% may be appropriately applied to an affected area once to several times a day.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

[0019]

EXAMPLES Starting materials may be purchased from Aldrich Chemical Company, Inc., Fluka Chemical, Inc., Lancaster Synthesis, Inc., Maybridge Chemical Company Limited, Tokyo Chemical Industry, or the like. Or J. Org. Chem., 16, p. 1879 (1951), J. Org.
The starting compound can be produced according to a known method described in the literature such as Am. Chem. Soc., 75, p.114 (1953).

Embodiment 1 Preparation of ointment (1) Production of 6-amino-1-phenyluracil Potassium t-butoxide (67.3) was added to methanol (400 mL).
g, 0.6 mol), add phenylurea (68.1
g, 0.5 mol) and ethyl cyanoacetate (53 mL, 0.5 mol). The mixture was refluxed for 5.5 hours, the solvent was evaporated under reduced pressure until a residue was formed, and the residue was dissolved in hot water (2 L). Glacial acetic acid was added to the solution until the solution became acidic and the uracil derivative was obtained as a bulky yellowish precipitate. The precipitate is collected by filtration, washed several times with water, 50
Dried at 6 ° C. and 6-amino-1-phenyluracil (67.4
g) was obtained in a yield of 66%. Mp> 280 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 4.67 (s, 1H), 6.08 (s, 2H), 7.31
(d, 2H, J = 7Hz), 7.47-7.54 (m, 3H), 10.43 (s, 1H) IR (KBr): 3478, 3334, 2981, 1712, 1634, 1476, 138
7, 1299, 704 cm ^-1 MS (EI) m / z: 203 [M ⁺ ], 160, 132, 77

(2) 7-amino-1,2,3,4-tetrahydro-1-
Preparation of phenylpyrido [2,3-d] pyrimidine-2,4-dione t-butanol (300 mL) was added to potassium t-butoxide (18.7
g, 225 mmol), 6-amino-1-phenyluracil (30.5 g, 150 mmol) and 3-methoxycyanated propene (25 mL, 225 mmol) were added. The mixture was heated at 110 ° C. for 12 hours with stirring. Butanol was evaporated, water (200 mL) was added to the residue, and the mixture was acidified with acetic acid.
The precipitate was collected by filtration, washed with hot ethanol, and 7-amino-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione (20 g) was added. Obtained in 53% yield. Mp> 300 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 6.27 (d, 1H, J = 9 Hz), 6.89 (s, 2H),
7.20-7.87 (m, 5H), 7.88 (d, 1H, J = 9Hz), 11.26 (s, 1H) IR (KBr): 3038, 1709, 1605, 1417, 789 cm ^-1 MS (EI) m / z : 254 [M ⁺ ], 211, 77

(3) Preparation of 7-amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 1] 7-amino-1,2,3,4 in silazane (100 mL)
-Tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,
4-dione (3 g, 12 mmol) and ammonium sulfate (500 m
The suspension to which g) was added was refluxed at room temperature and atmospheric pressure for 24 hours. The solvent was evaporated and the residue was dissolved in 100 mL of L (-)-5,6,7,8-tetrahydrofolic acid (THF). To this solution, add THF
Benzyl bromide (2 mL, 18 mmol) in (14 mL, 14 mmol)
And a solution to which 1M Bu ₄ NF was added was added dropwise while refluxing.
The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (benzene: acetone = 5: 1) and recrystallized from methanol to give 7-amino-3-benzyl-1,2,3,4-tetrahydro-1-phenylpyrido [2 , 3-d] pyrimidine-2,4-dione [compound 1] (1
g) was obtained in 27% yield. Mp 261-262 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 5.08 (s, 2H), 6.32 (d, 1H, J = 8 Hz),
6.98 (s, 2H), 7.22-7.49 (m, 10H), 7.94 (d, 1H, J = 8 Hz) IR (KBr): 3498, 3392, 1695, 1655, 1618, 787, 700
cm ^-1 Anal.Calcd for C ₂₀ H ₁₆ N ₄ O ₂ : C, 69.76; H, 4.68; N,
16.27, Found: C, 69.81; H, 4.77; N, 16.13 MS (EI) m / z: 344 [M ⁺ ], 211, 91 Also, applying the above methods (1) to (3), -Amino-3- (2-chlorobenzyl) -1,2,3,4-tetrahydro-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione [compound 2] was obtained.

(4) Compound 1 or 2 obtained as described above is sufficiently suspended in white petrolatum in a mortar, and the final content is
It was formulated in ointments to be 0.3%, 1%, 3% and 10%. An ointment containing only a base was prepared as a control, and an ointment containing 0.12% betamethasone valerate (steroid drug) was prepared as a positive control.

Embodiment 2 FIG. Preparation of Atopic Dermatitis Model Animals Seven-week-old BALB / c female (SPF) mice were purchased and used for experiments. Tanaka et al.'S method (Allergy, 46, pp.42-48 (199
According to 7)), ovalbumin (final concentration 2 μg / mL) and aluminum hydroxide gel (final concentration 10 mg / mL) were suspended in physiological saline, and 0.5 mL of the suspension was intraperitoneally sensitized on the first day of the test.
On the day, they re-improved under the same conditions. In addition, 20 μg / m on day 28
L ovalbumin (physiological saline) (25 μL) was intradermally administered to the right auricle of the mouse to induce an edema reaction.

The edema response peaked at 4 hours after the antigen induction, but a significantly higher edema response was observed even after 24 to 48 hours with respect to the induction-only control (no sensitization).
In this model, the response 1 to 4 hours after induction is considered to be an immediate edema response triggered by various mediators from mast cells, and there is little involvement of inflammatory cells such as eosinophils and lymphocytes. Seem. On the other hand, from induction 24
Edema at 48 hours is considered to be a so-called delayed edema reaction with infiltration of eosinophils, neutrophils and lymphocytes. In addition, the appearance of a redness reaction peaked at 24 hours after the induction was observed in the pinna of the antigen-induced site. Redness is one of the important symptoms of inflammation along with edema. Although the mechanism of this redness reaction is unknown, it can be said that it is a delayed type redness reaction from the time course of the onset. Thus, it can be said that this model animal in which both immediate and delayed inflammations are induced is suitable as an atopic dermatitis model animal. In the following experiments, the effects of the therapeutic agent for dermatitis of the present invention were tested using this animal model for pathological conditions.

The following Examples 3 to 8 show the results of studies on the action and safety of the therapeutic agent for dermatitis of the present invention.
As a statistical process in the following examples, the results are expressed as mean ± standard error, and the test between groups was performed using a statistical library (Yukms). Between, unpaired t-te on both sides of Student
St and between the control group and the test drug administration group were analyzed by Dunnett's two-sided multiple comparison test or Mann-Whitney-test.

Embodiment 3 FIG. Inhibitory effect of antigen-induced mouse auricular edema response Mouse base (control), test drug (therapeutic agent for dermatitis of the present invention, positive control) was added to the antigen-induced site (right auricle) of mice that induced an edema response according to Example 2. Was applied 2 hours before and 4 hours after induction, respectively. DIAL for evoked pinna thickness over time after induction
Measured by THICKNESS GAUGE (Ozaki Seisakusho). The response intensity was expressed as an increase in pinna thickness by subtracting the thickness of the right pinna (pre-value) measured before the induction from the thickness of the induced pinna. The ear edema suppression rate of the test drug was calculated by the following equation. Inhibition rate (%) = 100 × (increase in auricle thickness of base only control−increase in auricle thickness of test group) / (increase of auricle thickness of vehicle only control−increase of auricle thickness in induction only group) Result Are shown in Tables 1 and 2. The therapeutic agent for dermatitis of the present invention significantly and antigen-dependently suppressed the antigen-induced ear edema reaction in mice.

[0028]

[Table 1]

[0029]

[Table 2]

Embodiment 4 FIG. Inhibitory effect of mouse antigen-induced redness response A base (control) and a test agent (the therapeutic agent for dermatitis of the present invention, a positive control) were induced at the antigen-induced site (right auricle) of the mouse that induced the edema response according to Example 2. The coating was performed 2 hours before and 4 hours after, respectively. The right pinna was visually observed, and the degree of redness was scored according to the following evaluation criteria. 0: no redness 1: redness can be confirmed, the color is clear red or pale red, small in size 2: intermediate between score 3 and score 1: 3: redness is clear red, large in size Table 3 shows an example of the result. The therapeutic agent for dermatitis of the present invention significantly suppressed mouse antigen-induced redness reaction.

[0031]

[Table 3]

Embodiment 5 FIG. Inhibitory effect of eosinophil infiltration on mouse antigen-induced auricle Eosinophil infiltration into mouse auricle was measured using eosinophil peroxidase activity in skin tissue homogenate as an index. A vehicle (control) and a test agent (the therapeutic agent for dermatitis of the present invention, a positive control) were applied to the antigen-induced site (right auricle) of the mouse that induced the edema reaction according to Example 2 2 hours before and 4 hours after the induction. Applied. Twenty-four hours after induction, the right auricle is severed,
The pinna tissues in the group were pooled together, and a homogenate of pinna tissues was prepared according to the method of Holliday et al. (Toxicology, 106, pp. 237-242 (1996)). This homogenate
Centrifuge at 20,000 rpm for 20 minutes (Kubota, KR-20000T) and determine the peroxidase activity of the supernatant with o-phenyleneiamine.
The measurement was performed using dihydrochloride (Sigma) as a substrate. The absorbance at 492 nm was measured over time, and the response curve was evaluated in a linear relationship range.
It was expressed as 0% and compared. The therapeutic agent for dermatitis of the present invention suppressed eosinophil infiltration into the pinna induced by mouse antigen in a dose-dependent manner.
In addition, the eosinophil infiltration inhibitory effect of 3% ointment of Compound 1 was comparable to the inhibitory effect of the positive control steroid agent.

Embodiment 6 FIG. Effect of Repeated Application on Ear Thickness of Normal Mice The therapeutic agent of the present invention or a positive control (steroid agent) was applied to the right ear of normal mice twice a day for a total of 9 times, and 2 hours after the end of the final application The pinna thickness was measured. Table 4 shows an example of the results.
Shown in As shown in the above test results, the therapeutic agent for dermatitis of the present invention showed excellent auricular edema inhibitory action, redness inhibitory action, and eosinophil infiltration inhibitory action with 3% ointment. Repeated application of 10% ointment had no effect on the skin, but repeated application of positive control (steroid) significantly reduced pinna thickness.

[0034]

[Table 4]

Embodiment 7 FIG. Inhibition of guinea pig peritoneal eosinophil migration
LTB for production_FourOf the invention on peritoneal eosinophil migration in guinea pigs
The effect of the compound was examined using the Boyden Chamber method. Immediately
Using Hartley male guinea pigs, prepare
The guinea pig peritoneal eosinophils were tested with a test agent (the skin of the present invention).
In the presence or absence of an anti-inflammatory agent)^-7 M LTB_FourAgainst
It was allowed to migrate at 37 ° C. for 2 hours. Fixes migrating cells and Giemsa staining
After coloration, the number of migrated cells is viewed with a 400 × microscope for 10 times.
Field measurement. This experiment was performed several times, and the following equation was used.
Regression by least squares method based on the suppression rate in each experiment
Obtain the 50% inhibition concentration (IC₅₀) Was calculated. Inhibition rate (%) = 100 × (Eosinophil migration number in control group−Test drug)
Number of eosinophils migrated) / (number of eosinophils migrated in control group−spontaneous eosinophils)
Experiments were performed five times using compound 1 as a test drug. So
As a result, IC of compound 1 ₅₀Is 1.9 ± 0.4 μmol / L, which is very
It showed a strong inhibitory effect on eosinophil migration.

Embodiment 8 FIG. Phosphodiesterase inhibitory activity The inhibitory activity of the compounds of the present invention on phosphodiesterase (PDE) isozymes was examined according to a conventional method. Type II phosphodiesterase from human platelets (PDE II), type III phosphodiesterase from human platelets (PDE III),
Type IV phosphodiesterase from human U937 cells (PDE I
V) and human platelet-derived phosphodiesterase V (PD
EV) The inhibitory effect of the compounds of the present invention on each was examined. Compound 1 at 100 μM contained PDEs II, III, IV and
V inhibited 6, 22, 82 and 15%, respectively, indicating a selective inhibitory effect of PDE IV. The PDE IV inhibitory effect of Compound 1 was dose-dependent.

[0037]

As shown in the above animal experiments, 7-amino-3
-Benzyl-1-phenylpyrido [2,3-d] pyrimidine-2,4-dione derivative significantly and dose-dependently inhibits the antigen-induced ear edema in mice, a model of atopic dermatitis Mouse antigen-induced redness response was also significantly suppressed. Furthermore, it had an inhibitory effect on eosinophil infiltration into the ear pinna induced by mouse antigen, an inhibitory effect on guinea pig peritoneal eosinophil migration, and a selective inhibitory effect on PDE IV. Therefore,
The 7-amino-3-benzyl-1-phenylpyrido [2,3-
The d] pyrimidine-2,4-dione derivative is useful as a therapeutic agent for dermatitis such as atopic dermatitis, eczema, and contact dermatitis. In addition, direct harmful effects (side effects) on the skin, such as thinning of the skin, which occur with steroids, were not observed at all with the therapeutic agent for dermatitis of the present invention, and were extremely safe. . As described above, the therapeutic agent for dermatitis of the present invention is useful as a therapeutic agent for atopic dermatitis and further dermatitis,
It is a drug that solves the problems of the prior art with few side effects and high safety, and is highly useful as a drug that has been eagerly desired by patients and medical sites.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C065 AA04 BB11 CC01 DD03 EE02 HH01 JJ07 KK01 LL04 PP03 4C086 AA01 AA02 CB09 MA01 MA04 MA63 NA14 ZA89

Claims (3)

[Claims] 1. A therapeutic agent for dermatitis comprising a compound represented by the following general formula (I) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. Embedded image [In the formula, R represents hydrogen or halogen. ] 2. The composition according to claim 1, which is a therapeutic agent for atopic dermatitis.
The dermatitis therapeutic agent according to the above. 3. The therapeutic agent for dermatitis according to claim 1, which is an external preparation.