JPH08208518A - Antipruritic agent - Google Patents

Abstract

PURPOSE: To obtain an antipruritic agent which contains a hydroxytryptamine antagonist as an active ingredient and is effective for treating itching, particularly efficacious for improving atopic dermatitis resistant to conventional anti- inflammatory analgesic agents. CONSTITUTION: This agent contains a 5-hydroxytryptamine antagonist, typically 1-methylindol-3-yl-carbonyl-4,5,6,7-tetrahydrobenzimidazole. The daily doses of the 5-hydroxytryptamine antagonist are 1-1,000mg orally., 0.1-500mg in injection and 0.1-500mg percutaneously per an adult. This agent is preferably used in the form of an external preparation for skin since it can be applied near a lesion with side-effect reduced, and the external preparation contains this agent in a concentration of 0.1-5wt.%.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an antipruritic agent, more specifically to 5-
The present invention relates to an antipruritic agent containing a hydroxytryptamine antagonist as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Pruritus, typified by atopic dermatitis, has a complicated expression mechanism and many parts thereof have not yet been elucidated. In addition, the number of pruritus patients has increased remarkably in recent years compared to the past due to the effect of marked changes in lifestyle patterns. However, regarding the treatment method,
Since the mechanism of its onset is often unknown, it has not been established, and antihistamines and steroids that are highly effective against inflammation have little effect on atopic dermatitis and the like. Therefore, development of an anti-pruritic agent effective against pruritus represented by atopic dermatitis has been awaited.

On the other hand, 5-hydroxytryptamine antagonists are known to have anti-emetic action, anti-gastric ulcer action, anti-depressant action and anti-migraine action, but have anti-pruritic action. Was not known.

[0004]

Therefore, an object of the present invention is to provide an antipruritic agent effective for treating pruritus typified by atopic dermatitis.

[0005]

Under these circumstances, the present inventors have made diligent efforts to find a compound effective for pruritus, and as a result, the 5-hydroxytryptamine antagonist was excellent in the treatment of pruritus. The present invention has been completed upon finding out that the effect is exhibited.

That is, the present invention provides an antipruritic agent containing a 5-hydroxytryptamine antagonist as an active ingredient.

The 5-hydroxytryptamine antagonist is
Depending on the type of receptor involved in this, 5HT1, 5
It is classified into four types of HT2, 5HT3 and 5HT4, and any of these can be used as the antipruritic agent of the present invention. Examples of these 5-hydroxytryptamine antagonists include 1,2,3,4,10,14b-
Hexahydro-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine (Compound 1), 1-methylindol-3-yl-carbonyl-4,5,6,7-tetrahydrobenzimidazole (Compound 2 ), 1-methyl-N- (endo-9-methyl-9-azabicyclo [3,3,1] non-3-yl) -H-indole-3.
-Carboxamide (compound 3), 2,3-dihydro-9
-Methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one (Compound 4), 3- [2- [4- (4-Fluorobenzoyl)-
1-piperazinyl] ethyl] -2,4- [1H, 3H]
Examples thereof include quinazolinedione (Compound 5).

[0008]

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These compounds can also be used as their physiologically acceptable salts. The salt is not particularly limited, and for example, mineral acid salts such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, etc., organic acid salts such as citric acid, oxalic acid, etc. are used. From the viewpoint of safety, a mineral acid salt, particularly a hydrochloride salt is preferable.

The above compounds 1 to 5 are all known compounds, and compound 1, compound 3, compound 4 and compound 5 are already on the market as antidepressants and antiemetics. Further, a method for synthesizing compound 2 is also known, for example, N, N-diethyl-4,5,6,7-tetrahydrobenzimidazole-
5-carboxamide hydrochloride, the equivalent of 1-methylindole and 1.5 times equivalent of phosphorus oxychloride at 80 ° C
The reaction solution can be easily obtained by basifying the reaction solution with heating and stirring, extracting with a solvent, and purifying with a normal column such as silica gel column chromatography and ODS. The optical isomer of this compound can be resolved by a chiral column, but it may be used without resolution in the present invention.

The compound 1 of the present invention is 5HT1, and the compound 2 is
4 belongs to 5HT3 and compound 5 belongs to 5HT2, and since these are all effective for pruritus, 5-hydroxytryptamine antagonists are used as antipruritic agents of the present invention regardless of the type of receptor. be able to. The antipruritic agent of the present invention is effective in treating pruritus such as atopic dermatitis, which is difficult for antihistamines and steroids to work effectively.

The preferred dose of the 5-hydroxytryptamine antagonist of the present invention varies depending on the patient's age, physique, symptoms, sex, type of disease, etc., but is 1 to 1000 mg by oral administration per adult per day by injection. It is preferable to administer 0.1 to 500 mg and percutaneous administration to 0.1 to 500 mg in several divided doses. All of the compounds of the present invention are clinically used as antiemetic agents, and there is no particular problem regarding safety.

The antipruritic agent of the present invention may contain any of the commonly used ingredients for formulation or stabilization. In addition, analgesics, anti-inflammatory agents, antihistamines, steroids, etc., which are said to have some effect on pruritus, can also be added as necessary. As an optional component for formulation or stabilization, an emulsifying dispersant, a solubilizer, animal and vegetable oils and fats, petroleum oils and fats, polyhydric alcohols, water-soluble polymers, ultraviolet absorbers, antioxidants, preservatives, and binding agents. Examples thereof include agents, extenders, disintegrants, coating agents, lubricants, flavoring agents, coloring agents, pH adjusting agents, isotonic agents and the like.

The dosage form of the antipruritic agent of the present invention depends on the type of administration route, but is not particularly limited as long as it is a dosage form generally used as a pharmaceutical product, for example, an oral dosage form and injection. Agents, transdermal agents (skin external preparations) and the like,
The dosage form may be selected as needed. Among these, in that it can be administered near the affected area and the occurrence of side effects can be reduced,
The skin external preparation is most preferable. The content of the 5-hydroxytryptamine antagonist of the present invention in the external preparation for skin is preferably 0.01 to 10% by weight, more preferably 0.1.
~ 5% by weight.

In the present invention, the injections include, for example, intravenous injection, arterial injection, intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection and the like, but intradermal injection that can be administered in the vicinity of the affected area is the most preferable. preferable.

In the present invention, the orally-administered agent is not particularly limited as long as it is usually used as a medicine, but from the viewpoint of bioavailability, an enteric coating agent, a gastric-soluble coating agent, Alternatively, it is preferably used as a sustained release agent after being coated with a water-soluble coating agent, a water-insoluble coating agent or the like.

[0017]

EXAMPLES The present invention will be described in more detail below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Example 1 Antipruritic activity The antipruritic activity was examined using male ddy mice. That is, 30 μg / 50 μl / site of 5-hydroxytryptamine was intradermally injected into the back of the mouse to induce pruritus. In the drug administration group, a 0.1% physiological saline solution of the drug was administered by 50 μl intradermal injection when 5-hydroxytryptamine was administered. In the control group, only physiological saline was administered by intradermal injection in an amount of 50 μl instead of the physiological saline solution of the drug. The number of scratching behaviors of the animals was counted for 40 minutes after the administration. The results are shown in Table 1. From this, it can be seen that the antipruritic agent of the present invention suppresses the number of scratching behaviors and exhibits a suppressive action against pruritus. Further, upon intradermal administration, the antipruritic agent of the present invention did not show any reaction unfavorable to safety such as inflammation and edema.

[0019]

[Table 1]

Example 2 Anti-pruritic effect Compound 3 was examined for anti-pruritic effect by transdermal administration in the same manner as in Example 1. Induction of pruritus was carried out in the same manner as in Example 1. The drug is administered in this 0.1% saline solution 0.0
5 ml was immersed in a lint cloth of a patch test plaster, and this was applied to the 5-hydroxytryptamine administration site. As a control, only physiological saline was used. As a result, the number of scratching behaviors for 40 minutes was 101 times in the drug administration group and 224 times in the control group, and the antipruritic agent of the present invention has an excellent pruritus suppressing action even in transdermal administration. I understand. Furthermore, this result is shown in Example 1.
It can be seen that the transdermal administration is superior in suppressing scratching behavior when compared with. Therefore, it is understood that transdermal administration is preferable to intradermal administration as the administration route of the antipruritic agent of the present invention.

Examples 3 to 7 Ointment The components shown in Table 2 were kneaded and mixed in a kneader to prepare an ointment.

[0022]

[Table 2]

Example 8 Use test The ointment of the present invention prepared in Examples 3 to 7 and the ointment of the present invention
For Comparative Example 1 in which the hydroxytryptamine antagonist was replaced with bufexamac and for the control of the base alone, a panel of 10 panelists suffering from atopic dermatitis conducted a 2-week use test to improve atopic dermatitis. The effect was investigated. The improvement effect was evaluated from the result of the questionnaire to the subjects. The results are shown in Table 3. From this, it can be seen that the antipruritic agent of the present invention is effective for atopic dermatitis for which conventional analgesic and anti-inflammatory agents were not effective.

[0024]

[Table 3]

[0025]

INDUSTRIAL APPLICABILITY The antipruritic agent of the present invention has an excellent feature that it is effective for treating pruritus, and in particular, it is also effective for improving atopic dermatitis, which is not effective with conventional anti-inflammatory analgesics.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 ADA C07D 401/06 239 403/06 233 235 451/00 // C07D 487/04 150 9271-4C (C07D 401/06 211: 32 239: 96) (C07D 403/06 209: 12 235: 06) (C07D 403/06 209: 86 233: 58) (72) Toshiaki Iso Iso Yokohama City, Kanagawa Prefecture 560 Kashio-cho, Totsuka-ku Pola Chemical Industry Co., Ltd.In the Totsuka Laboratory (72) Inventor Masayuki Endo 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Prefecture In the Totsuka Laboratory (72) Inventor Naoki Hiyama Totsuka-ku, Yokohama 560 Kashio-cho Pola Kasei Kogyo Co., Ltd. Totsuka Laboratory (72) Inventor Minako Umeda 560 Kashio-cho Totsuka-ku, Yokohama-shi, Kanagawa Pola Kasei Kogyo Co., Ltd. Inside the laboratory

Claims (4)

[Claims] 1. An antipruritic agent containing a 5-hydroxytryptamine antagonist as an active ingredient. 2. A 5-hydroxytryptamine antagonist is 1,2,3,4,10,14b-hexahydro-2.
-Methyldibenzo [c, f] pyrazino [1,2-a] azepine, 1-methylindol-3-yl-carbonyl-4,5,6,7-tetrahydrobenzimidazole,
1-Methyl-N- (endo-9-methyl-9-azabicyclo [3,3,1] non-3-yl) -H-indole-3-carboxamide, 2,3-dihydro-9-methyl-3- [(2-Methylimidazol-1-yl) methyl] -4H-carbazol-4-one, 3- [2- [4
The antipruritic agent according to claim 1, which is-(4-fluorobenzoyl) -1-piperazinyl] ethyl] -2,4- [1H, 3H] quinazolinedione or a physiologically acceptable salt thereof. 3. The antipruritic agent according to claim 1, which is used for treating atopic dermatitis. 4. The method according to claim 1, which is in the form of a skin external preparation.
The described antipruritic agent.