JPH0448B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antiallergic agent, and more particularly to an antiallergic agent containing an epoxysuccinic acid derivative as an active ingredient. Conventional treatments for allergic diseases include symptomatic treatment, such as suppressing the destruction of tissue cells and chemical mediators caused by allergic reactions, or alleviating allergic symptoms caused by free chemical mediators. I was just getting used to it. That is, conventional antiallergic agents are symptomatic treatment agents, and none are capable of specifically suppressing the production of immunoglobulin (ie, IgE) that causes allergic diseases. As a result of intensive research to resolve the drawbacks of conventional anti-allergic agents, the present inventors have found that they specifically suppress only the production of IgE, which causes allergic diseases.
The present invention was completed by discovering an epoxysuccinic acid derivative that does not suppress the production of immunoglobulins (ie, IgG, IgM, etc.) that govern normal immune reactions. The present invention is based on the general formula (In the formula, R ¹ represents a hydrogen atom or an ethyl group,
^R2 represents a butyl group substituted with one group selected from "the group consisting of guanidyl group, amino group, methyl group, benzyloxycarbonylamino group, and acetylamino group" (hereinafter referred to as compound) ) is an anti-allergic agent containing as an active ingredient. The various active ingredients included in the compound are disclosed in Japanese Patent Publication No. 54-8759, Japanese Patent Application Laid-open No. 145678/1983, and
JP-A-55-115878, JP-A-55-153778, JP-A-52-23021, Agricultural
Biological Chemistry Vol. 42 No. 3 No. 523-541
Page (1978) and Journal of
Biochemistry Vol. 90, pp. 255-257 (1981)
It can be manufactured by the method described in . Table 1 shows the structural formulas and physical properties of the main ones.

[Table] The compound's effect on IgE and IgG production in mice and acute toxicity tests revealed that it has an excellent allergy suppressing effect and is highly safe. Conventional pharmaceutically acceptable carriers for the compound (binders, excipients, lubricants, diluents, ointment bases, etc.)
Orally administered by mixing, dissolving or dispersing in a suspension, solution, syrup, powder, granule, tablet, pill, capsule, inhaler, etc.
injections, injections, suppositories, creams, ointments, plasters,
It can be administered parenterally in the form of a liniment, patch, etc. As the carrier, sugars (glucose, sucrose,
Lactose, starch syrup, honey, etc.), celluloses (methyl cellulose, crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, etc.), starches (corn starch, potato starch, etc.), vegetable natural rubber resins (gum arabic powder, tragacanth powder, etc.), crude drugs (licorice,
gentian powder or extract), yeast powder or extract, gelatin, agar, alcohols (ethyl alcohol, isopropyl alcohol, benzyl alcohol, oleyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, propylene glycol, glycerin, polyethylene glycol , sorbitol, etc.), oils and fats (sesame oil, soybean oil, cacao butter, etc.),
Waxes (beeswax, lanolin, etc.), paraffinic hydrocarbons (liquid paraffin, light liquid paraffin, paraffin, white ointment paraffin, white vaseline, ceresin, etc.), synthetic resins (polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, etc.), high grade Fatty acid metal salts (calcium stearate, magnesium stearate, etc.), higher fatty acid esters (isopropyl myristate, octyldodecyl myristate, etc.), minerals (calcium phosphate, talc, silicic anhydride, etc.), surfactants (sorbitan fatty acid ester, polyoxy Sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin, etc.), preservatives (paraoxybenzoic acid ester, benzalkonium chloride, sorbate, etc.), purified water, etc. can be used. Coloring agents, fragrances, flavoring agents, etc. can also be added as necessary. The antiallergic agent of the present invention is administered to adults at a dose of 10 to 500 mg two to three times a day. The dosage can be adjusted as appropriate depending on the age, weight, symptoms, etc. of the patient. The anti-allergy agent of the present invention, which contains a compound as an active ingredient, specifically suppresses the production of IgE that causes allergic diseases and controls normal immune responses.
It does not suppress the production of IgG, IgM, etc., and has little toxicity, so it is useful as a medicine. The present invention will be specifically explained below with reference to Test Examples and Examples. Test Example 1 Effect on IgE production in mice BALB/c female mice (body weight 18 to 22 g) were used as samples in groups of 10 mice. Compounds A, B, C, D, E, F, G, and H were used as test drugs, and a control containing no active ingredient was used at various concentrations (31.25, 31.25,
62.5, 125, 250, 500 mg/Kg) were administered intraperitoneally or subcutaneously to separate groups of mice. Two hours after administration of the test drug, 4 mg of aluminum hydroxide adsorbed with 1 μg of ovalbumin was intraperitoneally administered for sensitization. Blood was collected on the 10th or 14th day after sensitization.
International Archives of Allergy and
Applied Immunology Volume 48, Page 16 (1975)
) (Ovary, Z; Caiazza, SS; Kojima,
S: PCA reactions with mouse antibodies in
The amount of antibody produced was determined by the passive cutaneous anaphylaxis (PCA) reaction described in Mice and Rats. That is, the collected serum was diluted to various concentrations and added to different rats (Wistar strain, male, weight 200-250 g).
was injected intradermally. Ovalbumin 4 hours later
mg was dissolved in 1 ml of 0.5% Evans Blue physiological saline and administered intravenously to determine the serum boundary concentration of dye exudation. The results are shown in Table 2. From this result, it is clear that the compound suppresses the production of IgE.

【table】

[Table] Test Example 2 Effect on IgG production in mice BALB/c female mice (body weight 18-22 g) were used as samples in groups of 10 mice. Compounds A, B, C, D, E, F, G, and H were used as test drugs, and a drug containing no active ingredient was used as a control, and 500 mg/Kg of each was intraperitoneally administered to separate groups of mice. Two hours after administration of the test drug, 1 mg of ovalbumin was dissolved in 0.2 ml of physiological saline and added to Freund's Complete Adjuvant.
Sensitization was carried out by subcutaneously administering an emulsion prepared by mixing 0.2 ml of the emulsion. Blood was collected on the 10th day after sensitization, diluted to various concentrations, and administered intradermally to another mouse.
The amount of antibody produced was determined according to . The results are shown in Table 3. From this result, it is clear that the compound does not suppress IgG production.

【table】

[Table] Test Example 3 Acute Toxicity Test Ddy male mice (body weight 20-25 g) were used as samples in groups of 10 mice. The above compounds A, B, C, D, E, F, G, H
The test drug was dissolved or suspended in 0.5% gum arabic-physiological saline solution, and the control drug contained no active ingredient. Each was orally administered to separate groups of mice, and within 3 weeks after administration. Calculate the 50% lethal dose by dead mice,
Acute toxicity was investigated. The results are shown in Table 4.

[Table] Example 1 100 g of the above compound A, 350 g of lactose, 50 g of cornstarch, and 1 g of polyvinylpyrrolidone were thoroughly mixed, granulated with ethyl alcohol in a conventional manner, and sized after drying. This includes magnesium stearate.
Add 0.5% by weight, mix, and make one tablet 250mg using the usual method.
Tablets were obtained by compressing the mixture into tablets. Tablets were obtained for Compound G in the same manner. Example 2 20 g of the compound B and 80 g of lactose were thoroughly mixed, sieved through a 48% sieve, and then packaged into 500 mg portions to obtain a powder. A powder was obtained for Compound H in the same manner. Example 3 150 g of the above compound C, 150 g of lactose, 40 g of starch
g, talc 4g, magnesium stearate 1g
Mix well and pour this into a hard gelatin capsule.
Capsules were obtained by filling mg each. Example 4 1 g of the above compound D was ball milled with 30 g of liquid paraffin, and 95% of the total particles had a particle size of 5μ.
The following paste was obtained. This paste was diluted with 30 g of liquid paraffin and taken out, and the ball mill was washed off with 40 g of liquid paraffin, and both were combined. This was maintained at 50° C., and while stirring, white ointment paraffin at the same temperature was gradually added to bring the total amount to 1000 g. Stirring was continued until the temperature returned to room temperature to obtain a homogeneous ointment. Example 5 1 g of the compound E was ball milled with 20 g of liquid paraffin, and 95% of the total particles had a particle size of 5μ.
The following paste was obtained. Separately, 150 g of white beeswax, 70 g of cetostearyl alcohol, and 30 g of "ceto macrogel 1000" were mixed, melted, and kept at 65°C. Mix and melt the previously obtained paste and a ball mill rinsed with 30 g of liquid paraffin, and add the resulting oil phase component.
It was kept at 60℃. Dissolve 1 g of chlorocresol in 700 g of distilled water at 100°C, cool it to 65°C, add the oil phase component at 60°C, and adjust the gelling point (40 to 40°C) with rapid stirring.
The mixture was rapidly cooled to below 45°C, and then stirred at low speed until solidified to obtain a cream. Example 6 Compound F0.1g and sorbitan fatty acid ester
After uniformly mixing and pulverizing 0.5 g and filling this mixture into a pressure-resistant aluminum container, a valve was attached and 49.7 g of trichloromonofluoromethane and 49.7 g of dichlorodifluoromethane were pressure filled to obtain an inhalant. Ta. Example 7 Distilled water for injection was added to 1.5 g of the above compound B to dissolve it, making the total volume 100 ml. 2 ml of the solution was filled into a light-shielding ampoule, and the space of the ampoule was replaced with nitrogen gas and then sealed to obtain an injection.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or an ethyl group,
R ² represents a butyl group substituted with one group selected from "the group consisting of a guanidyl group, an amino group, a methyl group, a benzyloxycarbonylamino group, and an acetylamino group." ) An anti-allergic agent whose active ingredient is a compound represented by