WO2006022450A1

WO2006022450A1 - Remedy for skin disease

Info

Publication number: WO2006022450A1
Application number: PCT/JP2005/016059
Authority: WO
Inventors: Naoki Shinoda; Kazuhiro Hosoi; Toshimi Ikuse; Shin-Ichiro Hirai; Kenji Imoto
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2004-08-26
Filing date: 2005-08-26
Publication date: 2006-03-02

Abstract

It is intended to search for a novel medicinal use of 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-dione or its salt. Because of exhibiting excellent therapeutic and preventive effects in a skin irritation test and an atopic dermatitis test, 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidin-2,4-dione or its salt is useful as a remedy or a preventive for skin diseases such as contact dermatitis, dry skin and atopic dermatitis.

Description

Memo book Skin disease treatment

Technical field

The present invention comprises 5- [4- (6-methoxy-1-monomethyl-1- 1H-benzoimidazole-2-benzyloxy) benzyl] thiazolidin-1,4-dione or a salt thereof as an active ingredient. The present invention relates to a therapeutic or preventive agent for skin diseases such as contact dermatitis, xeroderma, and atopic dermatitis. Background art

The skin covers the surface of the human body and forms the boundary with the outside world. Examples of skin diseases include contact dermatitis, xeroderma, and atopic dermatitis. Contact dermatitis is an inflammation of the skin caused by mechanical or chemical irritation of external substances that come into contact with the skin. Xeroderma is a decrease in the secretion of sebum and sweat. It is a symptom that becomes dry and rough and loses gloss. In addition, atopic dermatitis is an eczema-like change that occurs in individuals who are predisposed to atopy due to food alleles, house dust, ticks, etc. . When suffering from such skin diseases, waiting for recovery through natural healing takes a long time, and itching and pain continue, so therapeutic agents can be administered to the affected area. It is desirable to actively promote the healing of skin diseases.

On the other hand, Patent Document 1 states that 5 — [4 1 (6 — methoxy 1 1 — methyl 1 H- benzimidazole 2 — ilmethoxy) benzyl] thiazolidin 1 2, 4 — dione has an excellent hypoglycemic effect. It is effective as a treatment for diseases caused by insulin resistance such as diabetes, hyperglycemia, diabetic complications, hyperlipidemia, and inflammatory diseases such as osteoarthritis and rheumatoid arthritis. In addition, Patent Document 2 and Patent Document 3 show that the solubility of the hydrochloride salt of the above compound is significantly improved compared to that of the unitary compound (compound that does not form a salt). As a result, excellent It is disclosed that the mouth absorbability is exhibited.

However, there are no reports on the pharmacological effects of the above compounds on skin diseases such as contact dermatitis, xeroderma, and atopic dermatitis.

Patent Document 1 Japanese Patent No. 2 9 7 6 8 8 5

Patent Document 2 Japanese Patent Laid-Open No. 2 0 0 1 — 3 9 9 7 6

Patent Document 3 Japanese Patent Laid-Open No. 2 0 0 2-2 2 0 3 3 6 Disclosure of Invention

5 — [4-1 (6 -Methoxy 1 1 Methyl 1 1 H-Benzimidazole 2 1 -Ilmethoxy) Benzyl] Thiazolidin 1 2,4-Dione and its salts are very important to explore new pharmaceutical uses This is an interesting topic.

The inventors of the present invention have conducted intensive studies to search for new pharmaceutical uses of the above compounds, and found that the above compounds are excellent against skin diseases in skin irritation tests and atopic dermatitis tests. The present invention has been found to exhibit improved improving effects and preventive effects.

That is, the present invention relates to 5- [4-((6-Methoxy-1- 1-methyl-1 H-benzomidazole-2-ylmethoxy) benzyl] thiazolidin-1,2,4-dione or a salt thereof as an active ingredient. It is a therapeutic or preventive agent for skin diseases such as contact dermatitis, xeroderma, and atopic dermatitis.

5- [4 1 (6-Methoxy 1 monomethyl 1 1 H-Benzimidazole 1 2-ylmethoxy) benzyl] thiazolidin 1 2,4-dione of the present invention

“This compound” is a condensed heterocyclic compound represented by the following chemical structural formula [1]. The salt of this compound is not particularly limited as long as it is a pharmaceutically acceptable salt, salt with inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, etc. And salts with organic acids. A more preferred salt is hydrochloride. Further, quaternary ammonium salts of the present compounds are also included in the salts in the present invention. In addition, if the compound has a geometric isomer or optical isomer, The isomers are also included within the scope of the present invention. The compound may take the form of hydrate or solvate.

Examples of the skin disease in the present invention include contact dermatitis, xeroderma, and atopic dermatitis.

The therapeutic or prophylactic agent for skin diseases of the present invention can be formulated using a widely used technique. The preparation forms include ointments, jellies, patches, patches, lotions, creams, sprays, aerosols, plasters, suspensions, emulsions, tablets, pills, etc. It can also be used as a liquid agent by selecting an appropriate solvent. In addition, in order to prepare a therapeutic or preventive agent for skin diseases, fillers, excipients, bases, disintegrants, bulking agents, binders, film agents, lubricants, coloring agents depending on the dosage form. , PH adjuster, solubilizer, suspending agent, buffer, stabilizer, preservative, preservative, surfactant, antioxidant, dispersant, emulsifier, solubilizer, solubilizer, etc. it can.

Examples of the carrier for the above preparation include white petrolatum, liquid paraffin, gelled hydrocarbon, cetyl alcohol, polyethylene glycol, gelatin, cone starch, sodium alginate, methylcellulose, and hydroxychestite. Noresenorelose, canoleboxymethylenoses / relose, plastic base nodrophilic, gelatin, dextrin, cetyl alcohol, stearyl alcohol, polyethylene glycol, polyvinyl alcohol, methoxyethylene — maleic anhydride Polymers consisting of acid copolymer, polyvinyl ether, bulurpyrrolidone 'copolymer, oils such as sodium stearate, magnesium stearate, benzalkonium chloride, olive oil, camellia oil, soybean oil Examples include fats, lactose, and water.

The therapeutic or prophylactic agent for skin diseases of the present invention can be administered in various forms depending on the disease site and the degree of the disease. For example, when it is used as an external preparation, it is desirable to directly apply, spray, or apply the agent to the required site (affected area) such as the skin. 1-methyl 1 1-H-benzomidazole 1-ylmethoxy) benzyl] Thiazolidin-1,4-dione or a salt thereof is also related to a method for treating or preventing skin diseases, wherein an effective amount of thiazolidin-1,4-dione or its salt is administered to a patient.

The dosage of the therapeutic or prophylactic agent for skin diseases of the present invention can be appropriately selected in consideration of symptoms, age, and dosage form, and the compound and its pharmaceutically acceptable salts are usually any one per day. Also, 0.0 1 to 500 mg, preferably 0.0 1 to 100 mg, is administered in one or several divided doses.

As can be seen from the results of the skin irritation preventive effect test described below, 5— [4 1 (6-methoxy 1 1 methyl 1 1 H-benzoid imidazole 2 —ilmethoxy) benzyl] thiazolidin 2. , 4-dione (this compound) has an excellent inhibitory effect on the onset of skin reactions caused by irritating substances, and its effect is a comparative compound. 5 — [p — [(1-methylcyclohexane Xylyl) benzil] better than 1,2,4-thiazolidinedione (ciglitazone). In addition, according to the results of the skin irritation improvement effect test, the application of this compound to the skin can effectively improve the appearance of skin peeling. Thus, the present compound was found to have a therapeutic and preventive effect on skin diseases, and the effect was superior to that of ciglitazone, which is a control drug. Brief Description of Drawings

Fig. 1 is a photograph showing the results of a skin irritation preventive effect test using erythema as an index. Application of 10% sodium lauryl sulfate ointment 2 6 hours after guinea pig skin application 1% This shows the difference in the degree of erythema between the application site of this compound ointment (left side) and the application site of white petrolatum (right side). BEST MODE FOR CARRYING OUT THE INVENTION

Formulation examples and pharmacological test results are shown below, but these examples are for better understanding of the present invention and are not intended to limit the scope of the present invention.

[Pharmacological test]

(1) Skin irritation prevention test using erythema as an index

The flank of the guinea pig (Hartley) is shaved to form two application sites per animal, with white petrolatum on one side and 5- [4— (6-methoxy-1 1 methyl on the other]. 1 H-Benzoimidazole-2-ylmethoxy) Benzyl] Thiazolidine 1, 2, 4-dione (this compound) 1% ointment (1% of this compound + 9 9% of white usaline) twice a day Open application. The next day, 10% sodium lauryl sulfate ointment, an irritant substance, was applied openly to each application site, and the effect of preventing skin irritation was examined using the induced skin reaction (erythema) as an index. . For comparison, instead of this compound, a known compound having a thiazolidinedione skeleton, 5-[p- [(1 -methylcyclohexyl) meth] benzyl] 1,2,4-thiazolidinedione (hereinafter “ 1% ointment of “Comparative compound” was applied twice a day, and the other operations were the same as above. ·

Using erythema as an index, the skin reaction was observed over time after application of 10% sodium lauryl sulfate ointment (26 hours, 48 hours, 72 hours), and the Draize method. (J. Pharmacol. Exp. Ther., 83: 377-390 (1944))) The skin reaction of each group was evaluated. The specific criteria are as follows. .

Judgment criteria

0: No erythema. 1: Extremely mild erythema that can be confirmed visually. 2: Clear erythema

3: Moderate to strong erythema

4: Formation of light crusts in deep crimson erythema Table 1 shows the results of a skin irritation preventive effect test using erythema as an index. Figure 1 is a photograph showing the difference in the degree of erythema between the application site of 1% compound ointment and the application site of white agate cerium 26 hours after application of 10% sodium lauryl sulfate ointment. The From this photograph, it can be seen that the erythema is more marked on the white petrolatum application site (right side) than on the application site (left side) of the 1% compound ointment.

The average value in the table is the average value of 4 cases in each group. The lower the erythema score, the greater the preventive effect on skin irritation.

table 1

[Result]

When the skin was pretreated with this compound, the skin irritation effect of sodium lauryl sulfate was markedly suppressed, and the effect was superior to the comparative compound.

(2) Skin irritation prevention test using epidermis peeling as an index

After performing the same experimental procedure as the skin irritation preventive effect test using erythema as an index, after applying 10% sodium lauryl sulfate ointment, 48 hours later, 72 hours later The epidermis was observed and the frequency of epidermal detachment in each group was evaluated. Table 2 shows the results of the skin irritation preventive effect test using epidermis peeling as an index. The frequency of occurrence in the table is the result of 4 cases per group.

Table 2

[Result]

When the skin was pretreated with this compound, epidermal peeling after applying sodium lauryl sulfate was remarkably suppressed, and its action was superior to the comparative compound.

(3) Skin irritation improvement test using epidermis peeling as an index

The flank of the guinea pig (Hartley) is shaved to form two application sites per animal, and an irritating substance, 10% sodium lauryl sulfate sulfate ointment, is applied to each application site. Open application. The next day, white petrolatum was applied to one side and 1% of the compound ointment (1% of the compound + 99% white petrolatum) was applied to the other side twice a day. The epidermis was observed over time (after 48 hours and 72 hours) after application of 10% sodium lauryl sulfate ointment, and the frequency of occurrence of epidermal peeling in each group was evaluated.

Table 3 shows the results of the skin irritation improvement test using epidermis peeling as an index. The frequency of occurrence in the table is the result of 4 cases per group. Table 3

[Result]

Post-treatment of the skin with this compound suppressed epidermal peeling after application of sodium lauryl sulfate.

(4) Atopic dermatitis test

The improvement effect on atopic dermatitis was evaluated by a modified method of Nagai et al. (J. Pharmacol. Exp. Ther., 283: 321-327 (1997)) shown below. '

Dermatitis was induced once a week (Tuesday) and 5 times over 4 weeks by applying 25 μL of 0.15% DNFB solution to both sides of the mouse auricle. 1% This compound ointment (1% this compound + 9% white petrolatum), white selenium 5 times a week (Monday to Friday) from the day before the first DNF Β coating to the day before the 5th application 2 Administered once by applying 25 L per side of mouse pinna to both sides of both pinna. Immediately after the 5th application of DNF sputum solution, mice were injected with 0.2% E vans B 1 ue solution from the tail vein, 2 hours after dye tail vein injection (2 hours after application), and the mice that were the site of dye leakage The pinna was removed and the pigment was extracted with a pigment extract. Subsequently, the absorbance of the extracted dye was measured, and the amount of the leaked dye was calculated from the obtained absorbance to evaluate the action of the present compound against dermatitis. Table 4 shows the average value and color of the leaked pigment 2 hours after the 5th DN 'FB application. (1 [Amount of leaked pigment in this compound ointment group] [White amber serine group 0 0 Table 4

[Result]

The amount of leaked pigment after DNFB application in the group treated with this compound is significantly reduced compared to the white petrolatum group, so this compound is useful as a therapeutic and preventive agent for atopic dermatitis. It is.

[Formulation example]

The typical formulation example of this invention is shown below.

Formulation Example 1 (Ointment A— 1)

In 1 g

This compound 10 mg

Flowing paraffin 2 0 0 mg

White petrolatum appropriate amount

By changing the amount of this compound added, the concentration was adjusted to 0.0 1% (w / w) (ointment A-2), 0.1% (w / w) (ointment A-3), 3% (w (Ointment A — 4), 10% (w / w) (Ointment A—5) ointment can be prepared. · Formulation example 2 (Ointment B— 1)

In 1 g

This compound 10 mg. Ascorbic acid 2 mg

Flowing paraffin 2 0 0 mg

White silk

Plasticity Hydrophyll Proper amount By changing the amount of this compound added, the concentration will be 0.0 1% (w / w) (ointment B— 2), 0.1% (w / w) (ointment Ointments of B-3), 3% (w / w) (ointment B-4) and 10% (w / w) (ointment B-5) can be prepared. Industrial applicability

The present invention provides a therapeutic agent and a preventive agent exhibiting an excellent improvement effect and a preventive effect on skin diseases.

Claims

The scope of the claims

1.5 One [4— (6 —Methoxy 1 —Methyl 1 1 H—Benzoyl Midazol 1—2-Methyloxy) Benzyl] Thiazolidin 1, 2, 4-dione or its salts are effective A therapeutic or prophylactic agent for skin diseases contained as an ingredient.

2. The therapeutic or prophylactic agent for a skin disease according to claim 1, wherein the skin disease is contact dermatitis, xeroderma or atopic dermatitis.

3.5- [4- (6-Methoxy-1- 1-methyl-1-H 1-benzimidazole-2-2-inolemethoxy) benzyl] Thiazolidin 1,4-dione or its salt in an effective dose To treat or prevent skin diseases.

4. The method for treating or preventing a skin disease according to claim 3, wherein the skin disease is contact dermatitis, xeroderma or atopic dermatitis.

5. 5- [4— (6-Methoxy-1 H-benzoidimidazole-2-ylmethoxy) benzyl] thiazolidine 1, 4— for the manufacture of therapeutic or preventive agents for skin diseases Use of dione or its salts.

6. The use according to claim 5, wherein the skin disease is contact dermatitis, xeroderma or atopic dermatitis.