JPH11222432A - Preparation for external use containing amide derivative inducing interferon - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for external use having both suppressing actions on eosinophil infiltration due to the strong interferon induction activity and excellent percutaneous absorptivity by including a specific amide derivative (an acid addition salt), a dissolution and absorption promoter and a base therein. SOLUTION: This preparation for external use is obtained by including (A) 0.001-10% of an amide derivative (an acid addition salt) represented by the formula R1 and R2 are each a 1-6C (branched)alkyl or the like; X and Y are each O, S(O)p [(p) is 0-2] or the like; Z is an aromatic ring, a heterocyclic ring or the like; R3 is H, a (substituted)phenyl or the like; (g), (i) and (k) are each 0-6; (h), (j) and (l) are each 0 or 1; (m) is 0-5; (n) is 2-12}, (B) a dissolution and absorption promoter and (C) a base. Alcohols (ethanol, 1,3-butanol, glycerol, etc.), higher fatty acids (isostearic acid, oleic acid, etc.), etc. are cited as the ingredient B. An ointment, a cream, a lotion, a gel, a plaster, a spray etc. are cited as the dosage form of the preparation for external use.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation containing a novel amide derivative useful as a therapeutic agent for atopic dermatitis and the like, which strongly induces interferon and suppresses the eosinophil infiltration reaction of the skin.

[0002]

2. Description of the Related Art For the treatment of atopic dermatitis, topical use of steroids and oral use of antihistamines or antiallergic agents have been basically performed, and also desensitization therapy, allergens (ticks and foods). Ablation therapy, PUVA
(Psoralen-long wavelength ultraviolet irradiation) therapy, bacterial vaccine therapy and the like have been attempted. However, none of these are decisive factors.In particular, topical steroids have good sharpness, but atrophy, capillary dilation, flushing,
Side effects such as purpura and susceptibility have become a problem.

Recently, the direction of treatment for atopic dermatitis has been moving from steroids to cytokine therapies, whose mechanism of action is novel (Hidemi Nakagawa, Clinical Immunity, 27 [supple 16] 59)
7-602, 1995, Shoko Kobayashi et al., Clinical Immunity, 27, [supple 16] 603
-609,1995). In patients with atopic dermatitis, Th1
There is an imbalance in the balance between helper cells and Th2 helper cells, that is, in a state where Th2 cells predominate, and as a result of increased production of cytokines such as interleukin-4 and interleukin-5 from Th2 cells, IgE production and eosinophils The theory that inflammation is induced by enhancing the differentiation, proliferation and invasion of inflammatory cells has been prevailing. In general, administration of an antigen to sensitized human skin produces a skin reaction that is maximal immediately after administration and 4-8 hours later and lasts for 24-48 hours. The former is called an immediate reaction (involving IgE-mast cells), and the latter is called a late allergic reaction. In particular, it has been pointed out that late-onset reactions are closely related to the pathology of allergic diseases including asthma. The mechanism of late-onset response has long been unknown, but today
The late phase reaction of the type I allergic reaction involving IgE-mast cells
It is type I allergy, and eosinophil infiltration due to Th2 helper cell dominance has been considered to be deeply involved (Motohiro Kurosawa, Clinical Immunity, 27 (5), 564-574, 1995). Th
The balance between 1 helper cells and Th2 helper cells is regulated by interferon, and interferon (α, γ) promotes differentiation of Th0 cells into Th1 cells. Therefore, interferons (α, γ) which correct the Th2 cell dominance have been tried for the treatment of atopic dermatitis.

The mainstream of interferon therapy is recombinant interferon α (Paukkonen K. et. Al .: Act
a. Derm. Venereol. 73, 141-142, 1993) and interferon gamma (Hanifin JM: J. Am. Dermatol. 28, 189-197, 199)
3, Nishioka K.et.al .: J. Dermatol. 22 (3), 181-185,199
It is a subcutaneous injection of 5), and it is reported that skin symptoms are improved and blood eosinophil count is decreased. Since interferon has an immunopotentiating effect, no side effects such as susceptibility to infection that are often observed with steroids are observed. However, it is not yet a satisfactory drug in terms of high cost and other side effects (fever, cold-like symptoms, headache).

[0005] Although interferon itself still has some problems, if an interferon-inducing agent of a low molecular weight compound is developed, there is a problem with topical steroid preparations and interferon injections due to its local application (external use) ( It is highly possible to solve the cost and side effects).
Several compounds that induce interferon have been known so far. For example, 1-substituted-1H-imidazo [4,5-c] quinolin-4-amines include 1-isobutyl-1H-imidazo [4, an antiviral agent.
5-c] quinolin-4-amine (imiquimod) and several others (EP 145340,
U.S. Pat. No. 4,689,338, U.S. Pat.
8, U.S. Pat. No. 4,929,624, European Patent 385
630, U.S. Pat. No. 5,346,905).

[0006] Their interferon-inducing activity in humans is low, and no effect on eosinophil infiltration is described. Therefore, an external preparation containing a compound having high interferon-inducing activity and suppressing eosinophil infiltration in the local skin is desired.

[0007]

Accordingly, the present invention provides a novel compound which has an eosinophil infiltration-inhibiting effect due to a strong interferon-inducing activity and excellent transdermal absorption, and is therefore effective for atopic dermatitis and the like. An object of the present invention is to provide an external preparation to be contained.

[0008]

The present invention for solving the above-mentioned problems is as follows.

The compound contained in the external preparation of the present invention is an amide derivative represented by the following formula I and a pharmaceutically acceptable acid addition salt thereof, which are dissolved in a sufficient amount to exhibit at least an effect. An external preparation containing an absorption enhancer is provided.

[0010]

Embedded image

(In the formula (I), R ₁ and R _{2 each} have 1 to 6 carbon atoms.
Represents an optionally branched alkyl group of R ₁ and R ₂
May be united to form a ring. Further, either R ₁ or R ₂ may be combined with X, Y or any atom in the methylene chain to form a ring.

X and Y each independently represent an oxygen atom, S (О)
p (p represents an integer of 0 to 2), NR ₄ , CR ₅ = C
R ₆ , CR ₇ R ₈ or a phenylene group which may be substituted. Here, R ₄ , R ₅ , R ₆ , R ₇ and R ₈ independently represent a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkyl-substituted amino group, a carboxyl group, It represents a lower alkoxycarbonyl group, an optionally substituted aromatic ring group, or an optionally substituted heterocyclic group.

Z represents an aromatic ring or a heterocyclic ring, and may have a substituent such as a lower alkyl group, a hydroxyl group, a lower alkoxy group or a halogen.

R ₃ represents a hydrogen atom, a phenyl group which may be substituted, a lower alkyl group (a phenyl group, a phenoxy group, a benzyloxy group, a lower alkoxy group, an amino group,
It may be substituted with a mono- or di-lower alkyl-substituted amino group, carboxyl group or lower alkoxycarbonyl group. ).

G, i and k each independently represent an integer of 0 to 6, h, j and 1 each independently represent 0 or 1;
m represents an integer of 0 to 5, and n represents an integer of 2 to 12. ) The pharmaceutically acceptable acid addition salts to the amide derivatives of the formula I include hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, acetic, lactic, maleic, fumaric, citric, malic acid And salts such as tartaric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid, which are prepared by a conventional method.

Many of the amide derivatives represented by the formula I have an asymmetric carbon in the molecule and are racemic mixtures. However, if necessary, each optically active compound can be isolated by a method such as optical resolution or asymmetric synthesis. , It is possible to use.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The amide derivative represented by the formula I of the present invention and a pharmaceutically acceptable acid addition salt thereof (hereinafter abbreviated as acid addition salt) can be administered as a therapeutic agent for atopic dermatitis. it can.

Examples of the dosage form of the external preparation include ointments, creams, lotions, gels, patches, sprays and the like. In any of the dosage forms, appropriate pharmaceutically or pharmaceutically acceptable additives can be used during preparation. Additives include excipients, binders, lubricants, disintegrants, diluents, flavoring agents, coloring agents, dissolving agents, suspending agents, emulsifiers, preservatives, buffers, isotonic agents, ointment bases Agents, oils, dissolution aids, absorption promoters, adhesives, sprays and the like.

Since the amide derivative represented by the formula I and the acid addition salt thereof have an inhibitory effect on eosinophil infiltration, other diseases on which the effect is effective, such as allergic rhinitis, urticaria, pemphigoid It is suggested to be useful for eosinophilic pustular folliculitis, asthma, etc. In addition, since it strongly induces interferon α and γ, it is also useful for various cancer diseases such as multiple myeloma, renal cancer, skin malignant tumor, bladder cancer, hairy cell leukemia, chronic myelogenous leukemia, and rheumatoid arthritis. is there. Furthermore, the present invention is applicable to various viral diseases such as chronic active hepatitis B and C, herpes simplex keratitis, genital warts, condyloma acuminatum, shingles, and AIDS.

The most preferred compounds belonging to formula I are represented by the following formula:

N- [4- (4-Amino-1H-imidazo [4,5-c] quinoli
n-1-yl) butyl] -4-{[2- (dimethylamino) ethoxy] phenylme
thyl} benzamide

[0022]

Embedded image

Hereinafter, it is abbreviated as compound (II).

This compound is synthesized, for example, by the following method.

Α- (2-dimethylaminoethoxy) -α
-Phenyl-P-toluic acid 0.44 g (1.47 mmol)
Was suspended in 10 ml of chloroform, and 0.21 m of thionyl chloride was suspended.
l (2.94 mmol) is added and the mixture is refluxed for 2.5 hours. The reaction solution was concentrated under reduced pressure to synthesize a crude acid chloride product, and then 0.38 g of 1- (4-aminobutyl) -1H-imidazo [4,5-c] quinolin-4-amine (1.3. 4
7 mmol) was dissolved in a mixed solvent of 22 ml of ethanol and 15 ml of water, and 1.47 ml of a 1N aqueous solution of sodium hydroxide was added. Then, a 5 ml suspension of the acid chloride obtained in chloroform was added under ice-cooling. Let stir for 20 minutes. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, extracted with chloroform and a mixed solution of chloroform and methanol (10: 1 (v / v)), the organic layer was dried, the solvent was distilled off, and the residue was subjected to alumina column chromatography (chloroform : Methanol = 200: 1 to 30: 1 (v / v)). Finally, it is triturated with ether and collected by filtration to give compound (II)
0.44 g (0.820 mmol) of a slightly orange-white powder (mp: 1)
10-114 ° C).

The amide derivative represented by the formula I and the acid addition salt thereof are used in an amount of 0.001 to 10%, preferably 0.01%, in the base of an external preparation (ointment, cream, lotion, gel).
It is used to be 4-1%.

In the present invention, when the amide derivative represented by the formula I and the acid addition salt thereof are used as an external preparation, they are dissolved in advance in a dissolution / absorption promoter. Dissolution of the present invention
Absorption enhancers preferably refer to compounds as at least 0.0
It means a substance that can be dissolved at a concentration of 1% or more and that can absorb the amide derivative represented by the formula I and its acid addition salt from the skin when formulated as an external preparation. In other words, it can provide the amide derivative represented by the formula I and its acid addition salt with solubility and absorption.

It should be noted that those having only one of the dissolving ability and the absorbing ability are also included in the scope of the dissolution / absorption accelerator of the present invention.

As a result of various studies on bases satisfying the above two requirements, the following can be mentioned as dissolution / absorption accelerators.

1. 1. alcohols (ethanol, 1,3-butanediol, glycerin, etc.) 2. Higher fatty acids (isostearic acid, oleic acid, etc.) Organic value is 30 to 1000 on the organic conceptual diagram,
Dissolution / absorption accelerators having an inorganic value of 50 to 1000 and a ratio of the inorganic value to the organic value of 0.5 to 2.0, for example, lower alkylene carbonates (propylene carbonate,
Surfactants (sorbitan monolaurate (SP-20), sorbitan monostearate (S
P-60), DMSO, etc.); monoglycerides (glyceryl monostearate (MGS), glyceryl monooleate (MGO)); crotamiton.

4. Mixtures of these compounds In this specification, an organic conceptual diagram means that the source of all organic compounds is methane (CH ₄ ), and all other compounds are regarded as derivatives of methane, and their carbon numbers, substituents, transformation parts, ring Set a certain numerical value for each, etc., add the scores to obtain the organic value and the inorganic value, and plot this value on a diagram with the organic value on the χ axis and the inorganic value on the y axis. It is something that goes.

This organic conceptual diagram is based on the design of Mr. Atsushi Fujita, and details thereof are described in KUMAMOTO PHARMA.
CEUTICAL BULLETIN, No. 1, No. 1
Item 16 (1954), Chemistry, Volume 11, Volume 10
No. 719-725 (1957), Fragrance Journal, No. 34, 97-111 (1979)
Year), Fragrance Journal, No. 50, Nos. 79-8
2 (1981).

Therefore, an organic conceptual diagram of each compound can be easily obtained according to the method described in these documents.

Table 1 shows the dissolution / absorption accelerators suitably used for the compound (II) and their organic and inorganic values.

[0035]

[Table 1]

On the other hand, when the compound (II) is not in the range of the above-mentioned organic and inorganic values, the dissolving bases generally used, for example, cetyl lactate, diethyl sebacate, olive oil, coconut oil (Miglyol 812) ) Is extremely poor in solubility and is not suitable as a dissolution / absorption promoter.

Table 2 shows these organic values and inorganic values.

[0038]

[Table 2]

In the present invention, a solution containing the amide derivative represented by the formula I and an acid addition salt thereof (in a dissolution / absorption promoter) is prepared by using a base of an external preparation by a means known in the art. Formulated. Examples of the base include oleaginous bases (white petrolatum, liquid paraffin, beeswax, castor oil, etc.). These are preferably used in appropriate combinations.

The external preparation of the present invention comprises, in addition to the above base,
Other additives that can be used in external preparations, such as fragrances, coloring agents, preservatives, and absorption enhancers such as higher alkenoic acids, and other agents effective for skin diseases may be included.

According to one aspect of the present invention, the amide derivative represented by the formula I and the acid addition salt thereof are dissolved in a dissolution / absorption promoter, the resulting solution and the base are mixed, and the resulting mixture is mixed. A method for producing an ointment comprising stirring or heating and then cooling to obtain an external preparation is provided.

In this way, one or more additives and, optionally, additional amounts of the same or different solubilizing and absorption enhancing agents used in the solution of the amide derivative of the formula I and its acid addition salts, You may add simultaneously with a base.

In the external preparation of the present invention, the compound of formula I
In some cases, the amide derivative represented by and the acid addition salt thereof may partially exist as crystals, and such a case is also included in the scope of the present invention.

The external preparation of the present invention is applied to the affected area of the skin 1 to 3 times a day.
It can be used by applying it six times.

[0045]

Example 1 A 5% compound (II) ointment according to the present invention was prepared by the following components and method.

5 g of the compound (II) was dissolved in 25 g of sorbitan monolaurate (SP-20) by heating at 80 ° C. (Solution A). Solution A was added to a solution prepared by heating and dissolving 70 g of white petrolatum at 80 ° C., followed by stirring for 10 minutes, and then mixing while cooling to room temperature.

Example 2 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) is dissolved in 10 g of sorbitan monolaurate (SP-20) by heating at 80 ° C. (Solution A). Solution A was added to a solution prepared by heating and dissolving 89 g of white petrolatum at 80 ° C., followed by stirring for 10 minutes, and then mixing while cooling to room temperature.

Example 3 A 0.2% compound (II) ointment according to the present invention was prepared using the following components:
Adjusted by the method.

0.2 g of the compound (II) is dissolved under heat at 80 ° C. in 10 g of sorbitan monolaurate (SP-20) (Solution A). Solution A was added to a solution obtained by heating and dissolving 89.8 g of white petrolatum at 80 ° C., followed by stirring for 10 minutes, and then mixing while cooling to room temperature.

Example 4 A 0.04% compound (II) ointment according to the present invention was prepared by the following components and method.

0.04 g of the compound (II) is dissolved under heat at 80 ° C. in 10 g of sorbitan monolaurate (SP-20) (Solution A). Solution A was added to a solution obtained by heating and dissolving 89.96 g of white petrolatum at 80 ° C., followed by stirring for 10 minutes, and then mixing while cooling to room temperature.

Example 5 A 0.008% compound (II) ointment according to the present invention was prepared by the following components and method.

0.008 g of the compound (II) is dissolved in 10 g of sorbitan monolaurate (SP-20) by heating at 80 ° C. (Solution A). 89.992 g of white petrolatum at 80 ° C.
Solution A was added to the solution heated and dissolved in, and the mixture was stirred for 10 minutes, and then mixed while cooling to room temperature.

Example 6 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) is dissolved under heat at 80 ° C. in 10 g of sorbitan monostearate (SP-60) (Solution A). 5 g of polyoxyethylene (10) hardened castor oil (hereinafter abbreviated as HCO-10), white petrolatum 84
g was heated and dissolved at 80 ° C., the solution A was added, the mixture was stirred for 10 minutes, and then mixed while cooling to room temperature.

Example 8 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) is dissolved in 10 g of glyceryl monostearate (MGS) by heating at 80 ° C. (A
liquid). 5 g of HCO-10 and 84 g of white petrolatum in 80
The solution A was added to the solution which was heated and dissolved at ° C, and the mixture was stirred for 10 minutes, and then mixed while cooling to room temperature.

Example 9 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) is dissolved in 10 g of glyceryl monooleate (MGO) by heating at 80 ° C. (A
liquid). 5 g of HCO-10 and 84 g of white petrolatum in 80
The solution A was added to the solution which was heated and dissolved at ° C, and the mixture was stirred for 10 minutes, and then mixed while cooling to room temperature.

Example 10 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) was dissolved in 5 g of 1,3-butanediol by heating at 70 ° C. (Solution A). On the other hand, 3 g of stearic acid, 0.5 g of stearyl alcohol, 0.5 g of beeswax, 3 g of glyceryl monostearate, HCO
-10 0.5 g, diethyl sebacate 0.25 g, and white petrolatum 86.25 g were dissolved under heating at 70 ° C. and uniformly mixed (solution B). Next, the solution A was added while stirring the solution B under heating at 60 ° C., and the mixture was stirred for 10 minutes and mixed while cooling to room temperature.

Example 11 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) was dissolved in a mixed solution of 5 g of sorbitan monolaurate (SP-20) and 2 g of crotamiton heated at 80 ° C. (Solution A). HCO-10
5 g and 87 g of white petrolatum heated and dissolved at 80 ° C. were added with the solution A, stirred for 10 minutes, and then mixed while cooling to room temperature.

Example 12 A 1% compound (II) cream according to the present invention was prepared using the following ingredients:
Adjusted by the method.

After dissolving 1 g of the compound (II) in 10 g of isostearic acid heated at 80 ° C., at 80 ° C., 2 g of benzyl alcohol, 2.2 g of cetyl alcohol, 3.1 g of stearyl alcohol, 2.55 g of Polysorbate 60,
0.45 g of sorbitan monostearate was added and dissolved by stirring (solution A). On the other hand, glycerin 2 g, methyl paraben 0.2 g, propyl paraben 0.02 g, purified water 7
6.48 g was dissolved under heating at 80 ° C. and mixed uniformly (solution B). The solution A and the solution B were heated to almost the same temperature (75 ° C.), the solution B was added to the solution A, and mixed with an Ace Homogenizer (AM-3) (Nippon Seiki Seisakusho) for 10 minutes (12000 rpm).
Then, the mixture was mixed at a low rotation for 15 minutes while cooling with water.

Example 13 A 1% compound (II) lotion according to the present invention was prepared by the following components and method.

1 g of the compound (II) was dissolved in 69 g of 1,3-butanediol heated at 70 ° C., and 30 g of purified water was dissolved.
Was added and stirred.

Example 14 A 1% compound (II) lotion according to the present invention was prepared by the following components and method.

1 g of the compound (II) was dissolved in 49 g of 1,3-butanediol heated at 70 ° C., and 50 g of purified water was dissolved.
Was added and stirred.

Example 15 A 1% compound (II) lotion according to the present invention was prepared by the following components and method.

1 g of the compound (II) was dissolved in 10 g of sorbitan monolaurate (SP-20) heated at 70 ° C., 89 g of liquid paraffin was added and the mixture was stirred.

Comparative Example 1 A 1% compound (II) ointment according to the present invention was prepared by the following components and method.

1 g of the compound (II) was added to Miglyol 812
The mixture was heated and suspended in 10 g at 80 ° C. (Solution A). Solution A was added to a solution prepared by heating and melting 89 g of white petrolatum at 80 ° C.
Stir for 0 minutes and then mix while cooling to room temperature.

Next, the percutaneous absorption test and the pharmacological test of the ointment of the present invention will be described.

The interferon-inducing active compound (II) was quantified by ELISA using human interferon-α measuring kit (Otsuka Pharmaceutical) and human interferon-γ measuring kit (BioSource International), and as a result, high interferon-induced It was confirmed to have activity.

Transdermal absorbability (1) Test method Animals were purchased from a 4-week-old hairless mouse (male) from CLEA Japan, Inc., and subjected to an experiment after a one-week acclimatization period.

The transdermal absorption experiment was carried out according to the method of Tomohiro Hikima (Pharmaceutics, Vol. 55 (2), 122-126, 1995).

The back skin of the mouse was cut off in an intact skin state and attached to a vertical two-cell membrane permeation test apparatus (VIDREZX). The ointment (300 mg) prepared by the method of Example 2, Example 8, or Comparative Example 1 was added onto the skin of a toner cell, and penicillin (50) was added to the receptor cell.
U / ml) and PBS containing streptomycin (50μg / ml)
Was satisfied. The permeation experiment was performed while the receptor solution was kept at a constant temperature (37 ° C.). 100 from the sample mouth over time
μl was sampled and the drug was quantified by HPLC.

From these results, the drug skin permeation rate was determined.

(2) Results As shown in Table 3, it was confirmed that the preparations of Examples 2 and 8 exhibited excellent transdermal absorbability.

[0082]

[Table 3]

Skin eosinophil infiltration inhibitory effect The eosinophil infiltration inhibitory effect of this preparation is examined using a mouse skin eosinophil infiltration model.

(1) Test method Animal breeding method The animal was a 4-week-old Balb / c mouse (male) prepared by CLEA Japan, Inc.
After the acclimatization period of 1 week or more under the conditions of room temperature 23 ± 2 ° C. and humidity 50 ± 10% (lighting time (8: 00-20: 00), all the experiments were performed under non-fasting conditions. Water and feed were freely ingested during the experiment period after administration of the test substance (body weight at the time of experiment: 18 to 32 g).

Sensitization and Induction 3.8 ml of RO water and 1.2 ml of physiological saline were added to tick extract-Dp (Cosmo Bio) equivalent to 10 mg of protein to prepare a solution (stock solution) having a protein amount of 2 mg / ml. A sensitizing solution was prepared by adding a 1/40 volume of a pertussis solution to a solution prepared by adjusting the stock solution to a protein amount of 500 μg / ml with physiological saline. The sensitization was performed by using a Myjector (manufactured by Terumo Corporation) and administering 200 μl of this solution subcutaneously to the neck of the mouse. With this sensitization method, sensitization was performed three times every seven days including the first sensitization.

The challenge was carried out 21 days after the first sensitization, using a mijector (manufactured by Terumo Corporation) using a mijector (manufactured by Terumo Co.) with a mite antigen solution prepared to a protein concentration of 200 μg / ml with physiological saline.
This was performed by administering 0 μl.

Skin collection and observation of pathological specimens 48 hours after the inoculation, the mice were sacrificed by cervical dislocation, the skin on the back was peeled off, and the skin was cut 1 cm square around the marked part. The collected skin was placed in a 10% neutral formalin buffer solution (using a 15 ml centrifuge tube of Corning) and allowed to stand at room temperature for at least one day to be fixed. The fixed skin was subjected to Luna staining after preparing a paraffin section according to a conventional method (cutting was performed at two places in the direction perpendicular to the body axis, at the center of the skin sample and 2 mm above the head side). The number of eosinophils per 1 cm of one section was counted with an optical microscope (400 times) for observation of the specimen.

The inhibition by the drug (test compound) was calculated from the following equation.

[0089]

(Equation 1)

Preparation of Each Test Drug The ointments of Examples 3 to 5 were used. As an external preparation of betamethasone valerate, 0.12% Rinderon V ointment (Shionogi Pharmaceutical) was used as it was.

Drug administration method Transdermal administration (occlusive dressing technique)
(ODT)) The mice were anesthetized with ether, and the center of the back was shaved with an electric clipper so as not to damage the skin. The area of the center of the back corresponding to the evoked point was previously marked with oily magic. The drug (test compound) was applied 3 cm square in the pre-administration centering on the marked part of the back, and 2 cm square centering on the evoked part after the induction. Furthermore, a polyethylene impermeable sheet is placed so as to cover the coating section, and a stretchable tape (Johnso
n & Johnson MEDICAL INC: Elascotin). In the control group, only the substrate was applied.

The dose was 50 mg / day per animal, and the administration schedule was as shown below, and the rats were continuously injected for 4 days from the day before the induction.

[0093] Two days before the trigger → date of the trigger (immediately after the trigger) →
The day after induction (total 3 times) (2) Results Table 4 shows the inhibitory effects of the test drugs of Examples 3 to 5 and 0.12% betamethasone valerate on the eosinophil infiltration reaction of tick-induced mouse skin. The ointments of Examples 3 and 4 suppressed eosinophil infiltration as well as betamethasone valerate ointment (steroid) (Table 4).

[0094]

[Table 4]

[0095]

As described above, a novel external preparation can be obtained according to the present invention. The amide derivative contained in the present preparation has a strong interferon (α, γ) inducing effect, and is particularly useful for treating atopic dermatitis due to its effect of suppressing skin eosinophil infiltration.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor: Mieko Ueda 1500 Inoguchi, Nakai-machi, Ashigara-kami, Kanagawa Prefecture Terumo Corporation

Claims (4)

[Claims] An external preparation comprising an amide derivative represented by the following formula I and a pharmaceutically acceptable acid addition salt thereof, a dissolution / absorption promoter, and a base. Embedded image (In the formula I, R ₁ and R ₂ represent an alkyl group having 1 to 6 carbon atoms which may be branched, and R ₁ and R ₂ may be combined to form a ring. Either R ₁ or R ₂ may be combined with X, Y or any atom in the methylene chain to form a ring, wherein X and Y are independently an oxygen atom, S (О ) p (p represents an integer of 0 to 2), NR ₄ , CR ₅ ＣＲCR ₆ , CR ₇ R ₈ or an optionally substituted phenylene group, wherein R ₄ ,
R ₅ , R ₆ , R ₇ and R ₈ are independently a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkyl-substituted amino group, a carboxyl group, a lower alkoxycarbonyl group, Represents an optionally substituted aromatic ring group or an optionally substituted heterocyclic group. Z represents an aromatic ring or a heterocyclic ring, and may have a substituent such as a lower alkyl group, a hydroxyl group, a lower alkoxy group or a halogen. R ₃ is a hydrogen atom, a phenyl group which may be substituted, a lower alkyl group (phenyl group, phenoxy group, benzyloxy group, lower alkoxy group, amino group, mono- or di-lower alkyl-substituted amino group, carboxyl group, or lower Which may be substituted with an alkoxycarbonyl group). g, i and k each independently represent an integer from 0 to 6, h, j and l independently represent 0 or 1; m represents an integer from 0 to 5;
Represents an integer of 2 to 12. ) 2. The method according to claim 1, wherein the content of the amide derivative according to claim 1 and a pharmaceutically acceptable acid addition salt thereof in an external preparation is 0.001 to 10% (w / w). External preparation. 3. A dissolution / absorption accelerator capable of dissolving the amide derivative according to claim 1 and a pharmaceutically acceptable acid addition salt thereof, which is an alcohol (ethanol, ethylene glycol,
Propylene glycol, 1,3 butanediol, glycerin, etc.) and / or higher fatty acids (isostearic acid, oleic acid, etc.) and / or an organic value of 30 to 1000, an inorganic value on an organic conceptual diagram defined in the text. And at least one selected from dissolution / absorption accelerators in the range of 50 to 1000 and an inorganic value to an organic value of 0.5 to 2.0. External preparation according to the description. 4. The external preparation according to claim 1, wherein the content of the dissolution / absorption promoter in the external preparation is 0.1 to 70% (w / w).