JPH08217677A - Antipruritic skin preparation for external use - Google Patents

Abstract

PURPOSE: To obtain a preparation for external use, containing a specific antagonistic agent and a diester and effective in treating pruritus such as atopic dermatitis. CONSTITUTION: This preparation for external use contains (A) a 5- hydroxytryptamine antagonistic agent and (B) one or more diesters of a dibasic acid of formula I (N is 0-8; R1 is a 1-4C alkyl), preferably 0.01-1wt.% content of the ingredient (A) and 1-20wt.% content of the ingredient (B). 1,2,3,4,10,14b- Hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepine of formula II, 1- methylindol-3-yl-carbonyl-4,5,6,7-tetgrahydrobenzimidazole of formula III, 1- methyl-N-(endo-9-methyl-9-azabicyclo[3.3.1]non-3-yl)-H-indole-3-carbox amide of formula IV, etc., are preferably used as the ingredient (A) and diethyl malonate, diethyl adipate, etc., are preferably used as the ingredient (B).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antipruritic skin external preparation, and more specifically, it contains a 5-hydroxytryptamine antagonist and one or more diesters of dibasic acid represented by the general formula (I). The present invention relates to a skin external preparation for treating pruritus, which is characterized by the above.

[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, possibly due to the significant change in lifestyle patterns. However, the therapeutic mechanism is not established because there are many unclear mechanisms, and antihistamines and steroids, which are highly effective against inflammation, have little effect on atopic dermatitis. That is, the development of a skin external preparation effective for pruritus typified 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. Further, it has not been known that it has an excellent therapeutic effect on pruritus when compounded with a diester of a dibasic acid represented by the general formula (I) described below in an external preparation for skin.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and is a drug effective for treating pruritus, in which conventional drugs represented by atopic dermatitis were not effective, and which were effective. The task is to provide.

[0005]

[Means for Solving the Problems]

(1) 5-Hydroxytryptamine Antagonist Used in the Present Invention The 5-hydroxytryptamine antagonist used in the present invention or a physiologically acceptable salt thereof. The 5-hydroxytryptamine antagonists are classified into 4 types of 5HT1, 5HT2, 5HT3, and 5HT4 depending on the types of receptors involved, and any of these are used as the 5-hydroxytryptamine antagonists used in the present invention. Things are possible. Among these 5-hydroxytryptamine antagonists, preferred are 1,2,3,4,10,14b-hexahydro-2-methyldibenzo [c, f] pyrazino [1,
2-a] azepine (5HT antagonist 1, structural formula 1), 1-
Methylindol-3-yl-carbonyl-4,5,5
6,7-Tetrahydrobenzimidazole (5HT antagonist 2, structural formula 2), 1-methyl-N- (endo-9-methyl-9-azabicyclo [3,3,1] non-3-yl)
-H-indole-3-carboxamide (5HT antagonist 3, structural formula 3), 2,3-dihydro-9-methyl-3-
[(2-Methylimidazol-1-yl) methyl] -4
H-carbazol-4-one (5HT antagonist 4, structural formula 4), 3- [2- [4- (4-fluorobenzoyl)-
1-piperazinyl] ethyl] -2,4 [1H, 3H] quinazolinedione (5HT antagonist 5, structural formula 5).
All of these compounds are known substances,
3,4,10,14b-Hexahydro-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine, 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- (4
-Fluorobenzoyl) -1-piperazinyl] ethyl]
Four compounds of -2,4 [1H, 3H] quinazolinedione are already on the market as antidepressants and antiemetics. Furthermore, their synthetic methods have already been clarified, and their availability is easy. Further, a method for synthesizing 1-methylindol-3-yl-carbonyl-4,5,6,7-tetrahydrobenzimidazole is already known. That is, N, N-diethyl-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide / hydrochloride, the equivalent of 1-methylindole, and 1.5 times equivalent of phosphorus oxychloride were added at 80 ° C.
It can be easily obtained by heating and stirring with to make it basic, then extracting with a solvent, and purifying with an ordinary column such as silica gel column chromatography and ODS. Further, it can be optically resolved by purification by chiral column chromatography. The salt can be easily obtained by mixing with a solution of the corresponding acid in a polar solvent or a non-polar solvent and recrystallization. Here, 5HT antagonist 1 is an antagonist of 5HT1 and
Antagonists 2, 3, and 4 are 5HT3 antagonists, and 5HT antagonist 5 is a 5HT2 antagonist. As shown below, since these compounds are all effective for pruritus, 5H
It can be seen that any type of receptor can be used as long as it is a T antagonist. Therefore, it is possible to use the 5HT antagonist in the external preparation for skin of the present invention regardless of the type of receptor.

[0006]

[Chemical 7]

[0007]

Embedded image

[0008]

[Chemical 9]

[0009]

[Chemical 10]

[0010]

[Chemical 11]

The salts of these compounds are not particularly limited as long as they are physiologically acceptable. For example, mineral acid salts such as hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, and organic acids such as citric acid and oxalic acid. Examples thereof include salts, but from the viewpoint of solubility and safety, mineral acid salts are most preferable, and hydrochloride salts are most preferable.

(2) Dibasic acid diester used in the external skin preparation of the present invention The dibasic acid diester used in the external skin preparation of the present invention is represented by the following general formula (I). These esters have a function of promoting percutaneous absorption of 5-hydroxytryptamine, which is an active ingredient of the external preparation for skin. These esters may be used alone or in combination of two or more. Preferred among these esters are diethyl malonate, diethyl adipate, diisopropyl adipate, diethyl sebacate. All of these are generally used as external preparations for skin. Also, it is easy to obtain these because they are on the market.

[0013]

[Chemical 12] (However, N represents an integer of 0 to 8 and R1 represents an alkyl group having 1 to 4 carbon atoms which may be branched.)

(3) External preparation for skin treatment for pruritus of the present invention The external preparation for skin treatment for pruritus of the present invention is characterized by containing the above-mentioned 5-hydroxytryptamine antagonist and diester of dibasic acid. To do. In addition to these, the skin external preparation of the present invention can also contain, as an optional component, components generally used in skin external preparations. Such optional components include, for example, hydrocarbons such as petrolatum and microcrystalline wax, esters such as saposi tribase and jojoba oil, triglycerides such as olive oil and beef tallow,
Alcohols such as cetanol and cholesterol, fatty acid monoglyceride, fatty acid polyoxyethylene ester, nonionic surfactants such as higher alcohol polyoxyethylene ether, anionic surfactants such as SLS and sulfosuccinate, preservatives, UV absorbers, Examples include antioxidants, pH adjusters, colorants, fragrances, water-soluble polymers, polyhydric alcohols, thickeners, and the like. Further, in the external preparation for skin of the present invention, it is possible to add an antihistamine, an anti-inflammatory agent, an analgesic or the like, which has an inhibitory effect on pruritus to some extent.

The preferred content of the 5-hydroxytryptamine antagonist in the external preparation for skin of the present invention is one or more selected from the above-mentioned 5-hydroxytryptamine antagonist or a salt thereof in total. Then, it is 0.01 to 1% by weight. Even more preferable is an anti-pruritic effect of 0.
It is from 05 to 0.5% by weight.

The preferable content of the diester of dibasic acid in the external preparation for skin of the present invention is 1 to 20% by weight where the solvent effect appears. More preferably, it is 5 to 10% by weight. This is because the transdermal absorption promoting action is remarkable.

[0017]

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

Examples 1 to 3 Formulation Examples External preparations for skin were prepared according to the formulations shown in Table 1 below. That is, the prescription ingredients were heated to 80 ° C. with stirring to be solubilized and cooled to obtain a skin external preparation.

[0019]

[Table 1]

Example 4 Test Example The antipruritic effect was examined using male ddy mice. That is, 5-hydroxytryptamine (5H
Pruritus was induced by intradermal injection of T) at 30 μg / 50 μl / site. When the drug administration group was administered 5HT,
0.05 ml of the lint cloth part of the patch adhesive plaster for patch test was impregnated with the external skin preparation of 3 in a closed test for 24 hours. Comparative group 1 is 0.1% of 5HT antagonist 3
0.05 ml of physiological saline solution is closed patch,
In Comparative Example 2, when 5HT was administered, 0.1 of 5HT antagonist 3 was used.
% Saline solution was administered by intradermal injection in 50 μl.
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. Table 2 shows the results. From this, it can be seen that the external preparation for skin of the present invention is excellent in suppressing the number of scratching behaviors as compared with intradermal administration and simple closed patch administration of physiological saline solution, and is an effective preparation against pruritus. . Further, upon transdermal administration of the external preparation for skin of the present invention by a closed patch, no reaction unfavorable for safety such as occurrence of inflammation or edema was exhibited. Therefore, it is understood that the external preparation for skin of the present invention is excellent in safety. Further, comparing the external preparations for skin of the present invention, it can be seen that the inhibitory effect increases as the amount of diisopropyl adipate, which is a diester of dibasic acid, increases.

[0021]

[Table 2]

Examples 5 to 8 Formulation Examples As shown in Table 3, the skin external preparations were similarly prepared for the 5HT antagonists 1, 2, 4, and 5 according to the formulation of Example 3.

[0023]

[Table 3]

Example 9 Test Example The external preparations for skin of Examples 3, 5, 6, 7, and 8 were examined for their action on pruritus in the same manner as in Example 4. The results are shown in Table 4. From this, it is clear that any 5HT antagonist can be used in the external preparation for skin of the present invention.

[0025]

[Table 4]

Examples 10 to 12 Formulation Examples The skin external preparations shown in Table 5 were prepared in the same manner as in the above examples.

[0027]

[Table 5]

Example 13 Test Example Similar to the above test example, the action against pruritus was tested in Example 1
0-12 external preparations for skin were investigated. The results are shown in Table 6. From this, even if the diester of dibasic acid is changed to diethyl malonate, diethyl adipate, and diethyl sebacate, the same effect can be obtained. Therefore, the compound represented by the general formula (I) can give the same effect. It became clear that can be expected.

[0029]

[Table 6]

Example 14 Usage test The external preparation for skin of Example 3 was subjected to a usage test using a panelist suffering from atopic dermatitis, and the degree of improvement of atopic dermatitis was determined by a questionnaire. As a comparative example,
A 0.1% aqueous solution of 5HT antagonist 3 was used, and as a control, a product obtained by replacing 5HT antagonist 3 in the formulation of Example 3 with diisopropyl adipate was used. The results are shown in Table 7. From this, it is clear that the result of the use test reflected the result of the animal experiment.

[0031]

[Table 7]

[0032]

The external preparation for skin of the present invention can effectively treat pruritus such as atopic dermatitis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 45/06 AED A61K 45/06 AED 47/14 47/14 E C07D 401/06 239 C07D 401 / 06 239 403/06 209 403/06 209 451/04 451/04 // C07D 487/04 150 9271-4C 487/04 150 (72) Inventor Toshiaki Iso 560 POLA CHEMICAL INDUSTRIES CO., LTD. Company Totsuka Institute (72) Inventor Nobuo Funayama 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pola Chemical Industry Co., Ltd. (72) Inventor Naoki Hiyama 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa Pola Chemical Industry Co., Ltd. (72) Inventor Minako Umeda 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Totsuka Research Laboratory

Claims (5)

[Claims] 1. A skin external preparation for treating pruritus, which comprises a 5-hydroxytryptamine antagonist and at least one diester of a dibasic acid represented by the general formula (I). Embedded image (However, N represents an integer of 0 to 8 and R1 represents an alkyl group having 1 to 4 carbon atoms which may be branched.) 2. A 5-hydroxytryptamine antagonist is 1,2,3,4,10,14b-hexahydro-2-methyldibenzo [c, f] pyrazino [1,2-a] azepine (5HT antagonist 1, Structural formula 1), 1-methylindol-3-yl-carbonyl-4,5,6,7-tetrahydrobenzimidazole (5HT antagonist 2, structural formula 2), 1-methyl-N- (endo-9-methyl -9-azabicyclo [3,3,1] non-3-yl) -H-indole-3-carboxamide (5HT antagonist 3, structural formula 3), 2,3-dihydro-9-methyl-3-[( 2-Methylimidazol-1-yl) methyl] -4H-carbazol-4-one (5HT antagonist 4, structural formula 4), 3-
[2- [4- (4-Fluorobenzoyl) -1-piperazinyl] ethyl] -2,4 [1H, 3H] quinazolinedione (5HT antagonist 5, structural formula 5) or physiologically acceptable salts thereof 1. One or more selected from
The skin external preparation described. Embedded image Embedded image [Chemical 4] Embedded image [Chemical 6] 3. The external preparation for skin according to claim 1, wherein the content of the diester of the dibasic acid represented by the general formula (I) is 1 to 20% by weight. 4. The diester of dibasic acid is any one of diethyl malonate, diethyl adipate, diisopropyl adipate, and diethyl sebacate.
The external preparation for skin according to any one of 1. 5. The content of the 5-hydroxytryptamine antagonist or its salt is 0.01 to 1% by weight.
5. The external preparation for skin according to any one of 4 to 4.