JP2008127359A - Preventive and / or therapeutic agent for atopic dermatitis - Google Patents

Abstract

To provide a novel preventive and / or therapeutic agent for atopic dermatitis which acts by a novel mechanism.
A prophylactic and / or therapeutic agent for atopic dermatitis comprising a substance having histamine H4 receptor antagonistic activity as an active ingredient. The substance having histamine H4 receptor antagonistic action is 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof. The administration means is oral administration, transdermal administration, inhalation administration, eye drop administration, nasal administration, or ear administration.
[Selection figure] None

Description

  The present invention relates to a preventive and / or therapeutic agent for atopic dermatitis comprising a substance having histamine H4 receptor antagonistic activity as an active ingredient.

  Atopic dermatitis is an eczema-like change that occurs in individuals who are predisposed to atopy due to food allergies, house dust, ticks, etc., and is a refractory disease that becomes susceptible to infections when severe. . If you suffer from atopic dermatitis, it will take a long time to recover by natural healing, and itching and pain will continue and exacerbation will occur due to scratching. It is desirable to promote healing.

  On the other hand, histamine is a biogenic amine mediator that induces various biological reactions, and the presence of each of the receptors H1, H2, H3, and H4 is known as its receptor. H1 receptors are distributed in a wide range of tissues, and their functions in peripheral nerves, vascular endothelium, bronchi, ileum, etc. have been clarified. Various allergic symptoms that occur through H1 receptors are improved by the receptor antagonists. The H2 receptors play an important role in the control of the digestive system via the peripheral nervous system and gastric secretory cells, and H2 receptor antagonists have a protective action on the digestive tract. H3 receptor is mainly expressed in the central nervous system and has been reported to be associated with nerve function. In addition, H4 receptor is expressed in peripheral leukocytes, pancreas, thymus and colon, etc., suggesting a relationship with immune function, and reported to be involved in the migration and accumulation of inflammatory cells and the production of inflammatory mediators. (Non-Patent Document 1).

で示される縮合複素環化合物である。この化合物は、主要なヒスタミンＨ４受容体拮抗剤として生物学的評価が確立されている、現在知られている唯一の化合物である。 As a histamine H4 receptor antagonist, 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine (the compound of Example 1 in Patent Document 1: (5-chloro-1H) -Indol-2-yl)-(4-methylpiperazin-1-yl) -methanone: hereinafter sometimes referred to as compound (1)) is known.
Compound (1) has the following formula (1):

It is a condensed heterocyclic compound shown by these. This compound is the only compound currently known that has established biological evaluation as a major histamine H4 receptor antagonist.

  Patent Document 1 discloses that compound (1) suppresses selective binding of histamine to the H4 receptor, zymosan-induced peritonitis, and acute inflammatory dermatitis caused by croton oil administration, inflammatory disorders, asthma, Disclosed to be effective as a therapeutic agent for psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune diseases, lymphatic disorders and immunodeficiency disorders Yes.

However, there is no report which investigated the pharmacological action with respect to atopic dermatitis of compound (1). Furthermore, the histamine H3 / H4 receptor antagonist Thioperamide showed an effective pharmacological effect on the basis of its H4 receptor antagonism in the zymosan-induced peritonitis model of Patent Document 1, whereas in Non-Patent Document 2, Thioperamide It has been shown to be ineffective in the scratching behavior of NC / Nga mice that spontaneously developed atopic dermatitis, and a substance having histamine H4 receptor antagonistic activity is useful as a preventive and / or therapeutic agent for atopic dermatitis It was not known whether or not.
Special table 2004-520434 gazette Iwan J.I. P. et al. Trends. Pharmacol. Sci. 2005, 26, 462-9. Hashimoto Y. et al. et. al. Allergol. Int. 2004, 53, 349-358

Atopic dermatitis requires a long period of time for prevention and / or treatment, and the effects of already used preventive and / or therapeutic agents tend to decrease as the administration period becomes longer. Therefore, there has been a demand for a novel preventive and / or therapeutic agent for atopic dermatitis that acts by a novel mechanism so that it can be used even when such long-term administration is required.
Moreover, it is a very interesting subject to search for a new pharmaceutical use of a substance having a histamine H4 receptor antagonistic action.

  In view of the above circumstances, the present inventors have conducted extensive research on the prevention and / or treatment of novel atopic dermatitis, and have histamine H4 receptor antagonism in atopic dermatitis tests. The present inventors have found that the compound exhibits an excellent improvement effect and a preventive effect, and have completed the present invention.

  That is, the present invention provides a preventive and / or therapeutic agent for atopic dermatitis containing a substance having histamine H4 receptor antagonistic activity as an active ingredient.

  The present invention also relates to atopic dermatitis comprising 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof as an active ingredient. It provides a preventive and / or therapeutic agent.

  The present invention also provides a preventive and / or therapeutic agent for atopic dermatitis containing a substance having histamine H4 receptor antagonistic activity as an active ingredient, the administration means of which is oral administration.

  Furthermore, the present invention provides 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof as an active ingredient, wherein the administration means is oral administration. The present invention provides a preventive and / or therapeutic agent for atopic dermatitis.

  In addition, the present invention provides an atopy containing a substance having an histamine H4 receptor antagonistic action as an active ingredient, wherein the administration means is a topical administration such as transdermal administration, inhalation administration, eye drop administration, nasal administration or ear drop administration. The present invention provides a preventive and / or therapeutic agent for atopic dermatitis. As an administration means for external administration, transdermal administration is particularly preferred.

  Furthermore, the present invention provides 1-[(5-chloro-1H-indol-2-yl)-, wherein the administration means is transdermal administration, inhalation administration, eye drop administration, nasal administration, ear drop administration or the like. Carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof as an active ingredient provides a preventive and / or therapeutic agent for atopic dermatitis. As an administration means for external administration, transdermal administration is particularly preferred.

  The present invention also relates to a preventive and / or therapeutic agent for atopic dermatitis comprising a substance having an histamine H4 receptor antagonistic action as an active ingredient and a pharmaceutically acceptable carrier.

  Furthermore, the present invention provides 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof as an active ingredient, and pharmaceutically acceptable. The present invention relates to a preventive and / or therapeutic agent for atopic dermatitis, comprising a carrier.

  Furthermore, the present invention is also in the use of a substance having histamine H4 receptor antagonistic activity for producing a preventive and / or therapeutic agent for atopic dermatitis.

  Furthermore, the present invention relates to 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof for producing a preventive and / or therapeutic agent for atopic dermatitis. Or the use of their solvates.

  Furthermore, the present invention also lies in a method for preventing and / or treating atopic dermatitis by administering an effective amount of a substance having histamine H4 receptor antagonistic activity.

  Furthermore, the present invention provides atopic properties by administering an effective amount of 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof. There is also a method for the prevention and / or treatment of dermatitis.

  Furthermore, the present invention relates to a method for orally administering an effective amount of 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof. There is also a method for the prevention and / or treatment of atopic dermatitis.

  Furthermore, the present invention provides an effective amount of 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof, transdermally or by inhalation. In addition, there is a method for preventing and / or treating atopic dermatitis by external administration such as ophthalmic administration, nasal administration or ear-dose administration. As an administration means for external administration, transdermal administration is particularly preferred.

  Since the preventive and / or therapeutic agent for atopic dermatitis of the present invention exhibits an excellent therapeutic effect and preventive effect in the atopic dermatitis test, it is effective as a prophylactic and / or therapeutic agent for atopic dermatitis. . Furthermore, since it is thought that the effect is exerted by a mechanism different from the conventionally known mechanism, it is effective even for patients with atopic dermatitis, which is in a state in which the effect is difficult to appear with conventional drugs. Prophylactic agents and / or therapeutic means are provided.

で表される化合物（１）：（１−［（５−クロロ−１Ｈ−インドール−２−イル）−カルボニル］−４−メチルピペラジン）を挙げることができる。 Examples of the substance having histamine H4 receptor antagonistic activity of the present invention include the following formula (1):

And (1): (1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine).

  Compound (1) can be synthesized according to the method described in JP-T-2004-520434. Compound (1) can also be obtained as a commercial product (trade name: JNJ7777120, Sigma).

  Compound (1) may be used in the form of a salt, and the salt is not particularly limited as long as it is a pharmaceutically used salt. For example, inorganic acid addition salts (for example, hydrochloride, bromide, etc.) Hydrogenates, sulfates, phosphates, etc.); organic carboxylic or sulfonic acid addition salts (eg formate, acetate, trifluoroacetate, maleate, tartrate, citrate, fumarate, Methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); salts with acidic amino acids (eg, aspartic acid, glutamic acid, etc.).

  In addition, compound (1) or a salt thereof may exist in the form of a solvate represented by a hydrate, and such a solvate is also encompassed in the present invention.

  The prophylactic and / or therapeutic agent for atopic dermatitis of the present invention can be formulated using a widely used technique. Examples of the dosage form 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. Moreover, in order to prepare the preventive and / or therapeutic agent for atopic dermatitis of the present invention, a known filler, excipient, base, disintegrant, extender, binder, Film agent, lubricant, colorant, pH adjuster, solubilizer, suspending agent, buffer, stabilizer, preservative, preservative, surfactant, antioxidant, dispersant, emulsifier, dissolution An agent, a solubilizing agent, etc. can be added.

  Examples of the carrier for the preparation include white petrolatum, liquid paraffin, gelled hydrocarbon, cetyl alcohol, polyethylene glycol, gelatin, corn starch, sodium alginate, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, plastic base hydrophilic, gelatin, Dextrin, cetyl alcohol, stearyl alcohol, polyethylene glycol, polyvinyl alcohol, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, polymer / copolymer comprising vinylpyrrolidone, sodium stearate, magnesium stearate, chloride Benzalkonium, olive oil, camellia oil, soybean oil and other fats, lactose, water and the like.

  The preventive and / or therapeutic agent for atopic dermatitis of the present invention can be administered in various forms depending on the disease site and the degree of the disease. The dosage form may be any of external preparations such as oral preparations, injection preparations, suppositories, etc., as well as transdermal preparations, inhalants, eye drops, nasal drops, ear drops, etc. In this case, it is desirable to apply, spray, or apply this agent directly to the required site (affected area) of the skin.

  The effective dose of the preventive and / or therapeutic agent for atopic dermatitis of the present invention can be appropriately selected in consideration of symptoms, age, dosage form, etc., and the present compound and pharmaceutically acceptable salts thereof are In terms of 50 kg adults, the daily dose is usually in the range of 0.001 to 5000 mg, preferably 0.01 to 1000 mg, particularly preferably 0.1 to 500 mg, and these are administered once or divided into several times. can do.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

Effect of oral administration of a substance having histamine H4 receptor antagonistic activity on mouse atopic dermatitis model (1) Induction of sensitization and dermatitis Start test using male BALB / C mice (purchased from CLEA Japan) 7 The day before (day-7), 0.01% of 0.5% picryl chloride (PC) dissolved in acetone was applied to the front and back of the left auricle for sensitization. On the test start date (day 0), day 2, day 5, day 7 and day 9, apply 0.01 mL of 0.5% picryl chloride (PC) solution dissolved in acetone on the front or back of the left auricle to cause dermatitis. did.
(2) Measurement of dermatitis Auricular thickness was measured before dermatitis was induced (day 0, day 2, day 5, day 7, day 9) and day 12.
(3) Preparation and administration of test substance Compound (1) was suspended in 0.5% MC (methylcellulose) and used as a test substance having histamine H4 receptor antagonistic activity. The test substance was orally administered at 30 mg / kg daily on day 0-11. When dermatitis was induced, it was orally administered 30 minutes before dermatitis was induced. In addition, the compound (1) used what was synthesize | combined according to the method of Japanese translations of PCT publication No. 2004-520434 gazette (same also in Example 2).
(4) Data processing The results of the experiment are shown in FIG. The compound (1) as a test substance dispersed in 0.5% MC and orally administered at 30 mg / kg is shown as “30 mg / kg compound (1)”, and only 0.5% MC was administered as a control. The results are shown as “MC”. The results are shown as mean ± standard error. The Student's t-test was used for the significant difference test, and a risk rate of less than 5% was considered significant (*: p <0.05, 30 mg / kg compound (1): N = 8, MC: N = 5). As shown in FIG. 1, compound (1) exhibited an atopic dermatitis inhibitory effect by oral administration.

Effect of local administration of substance having histamine H4 receptor antagonistic action on mouse atopic dermatitis model (1) Sensitization and induction of dermatitis were carried out in the same manner as in Example 1.
(2) Dermatitis was measured in the same manner as in Example 1.
(3) Preparation and administration of test substance As a test substance having a histamine H4 receptor antagonistic activity, compound (1) was dissolved in acetone and used. The test substance was applied daily on day 0-11 on the front and back of the left auricle with 0.015 mL of a 0.2% or 2% solution, for a total of 0.03 mL. When dermatitis was induced, it was applied 5 minutes after dermatitis was induced.
(4) Data processing The results of the experiment are shown in FIG. The results of transdermal administration of compound (1) dissolved in acetone as a test substance are shown as “0.2% compound (1)” and “2% compound (1)”, and the result of administration of acetone alone as this control Was designated as “acetone”. The results are shown as mean ± standard error. The Student's t-test was used for the significant difference test, and a significance level of less than 5% was considered significant (*: p <0.05, N = 5). As shown in FIG. 2, the compound (1) exhibited an atopic dermatitis inhibitory effect by external administration.

It is a figure which shows the atopic dermatitis therapeutic effect by oral administration of a compound (1). It is a figure which shows the atopic dermatitis therapeutic effect by local administration of a compound (1).

Claims (5)

  A prophylactic and / or therapeutic agent for atopic dermatitis comprising a substance having histamine H4 receptor antagonistic activity as an active ingredient.   The substance having histamine H4 receptor antagonistic activity is 1-[(5-chloro-1H-indol-2-yl) -carbonyl] -4-methylpiperazine or a salt thereof or a solvate thereof. The preventive and / or therapeutic agent according to 1.   The preventive and / or therapeutic agent according to any one of claims 1 and 2, wherein the administration means is oral administration.   The preventive and / or therapeutic agent according to any one of claims 1 and 2, wherein the administration means is external administration.   The preventive and / or therapeutic agent according to claim 4, wherein the external administration is transdermal administration, inhalation administration, eye drop administration, nasal administration or ear drop administration.

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