JPH0624978A - Antiallergic agent - Google Patents

Abstract

PURPOSE:To obtain an antiallergic agent having low toxicity and no side effects, not showing immunosuppressive action, selectively controlling production of IgE, comprising a specific compound as an active ingredient. CONSTITUTION:This antiallergic agent comprises a compound of th formula (R1 to R3 are H, halogen, OH, amino, cyano, carbamoyl, carboxyl, carboxyalkenyl, carboxyalkyl or alkyl) such as 5-(carboxymethyl)imidazole as an active ingredient. A dose of the compound as the active ingredient is usually 50mg-5g per adult daily and preferably administered once or dividedly.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antiallergic agent containing imidazole or a derivative thereof as an active ingredient.

[0002]

2. Description of the Related Art When an organism is stimulated by an antigen, the organism produces an antibody that specifically reacts with that antigen, and when the same antigen again invades the organism, a protective reaction is aimed at destroying or eliminating the antigen. Occur. However, sometimes hypersensitivity reaction such as local inflammation or sudden shock symptom may occur due to antigen stimulation, and this hypersensitivity reaction is called allergic reaction. The allergic reaction is classified into a type I allergic reaction, a type II allergic reaction, a type III allergic reaction and a type IV allergic reaction depending on the mechanism of its onset, the difference in symptoms, and the like.

A typical allergic reaction is a type I allergic reaction, which is also called an immediate allergic reaction. In the type I allergic reaction, immunoglobulin E (IgE) is generated by an antigen that enters the body, and this binds to mast cells in tissues or basophilic cells in blood (first
Step), IgE bound to those cells binds to the above-mentioned antigen to release histamine, serotonin, and other various chemical mediators contained in the cells (second phase), and the chemical mediators By acting on various organs, allergic symptoms occur (step 3). Since other immunoglobulins (eg, immunoglobulin A and immunoglobulin G) are unable to bind to these cells or bind with extremely low affinity, it is not possible to cause immediate allergy by the same mechanism as IgE. Absent. Therefore, it is not an exaggeration to say that almost all human allergic diseases are caused by IgE (edited by Yuichi Yamamura, “Immunology 4”).
Cellular immunity and allergy "(May 20, 1982, published by Nakayama Shoten), pp. 113-115).

At present, a large number of chemical mediator release inhibitors from mast cells and basophilic cells and chemical mediator antagonists (eg antihistamines) have been developed as drugs for suppressing type I allergic reaction. However, there are few chemical mediators known to have the above-mentioned agents that specifically suppress release or production or specific antagonists, and since there are various chemical mediators, it is necessary to suppress type I allergic reactions. At present, it is necessary to analyze the interactions of various chemical mediators (Yuichi Yamamura).
Supervised "Immunology 4 Cellular immunity / allergy" (May 1982
Published by Nakayama Shoten on May 20, 2004, pp. 131-132). In addition, the above drugs are the root cause of allergic reactions
It does not mean that IgE production is suppressed, and in that sense, it cannot be a fundamental therapeutic agent.

Attempts have also been made to suppress IgE production by immunosuppressive agents such as cyclosporin A to treat allergic diseases, but to overcome the problem of side effects due to nonspecific immunosuppression. It is difficult.

[0006]

An object of the present invention is to provide an anti-allergic agent which does not exhibit general immunosuppressive action and can selectively suppress IgE production.

[0007]

According to the present invention, the above-mentioned object is achieved by the following general formula (I):

[0008]

[Chemical 2]

(In the formula, R ↓ 1, R ↓ 2 and R ↓ 3 are each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group, a carboxyl group, a carboxyalkenyl group, a carboxyalkyl group or an alkyl group. It is achieved by providing an anti-allergic agent containing a compound represented by the formula (hereinafter referred to as the active ingredient compound (I)) as an active ingredient.

R ↓ 1, R ↓ 2 in the above general formula (I)
Examples of the alkyl group portion of the alkyl group and the carboxyalkyl group represented by R and R ↓ 3 include, for example, methyl group, ethyl group, propyl group, hexyl group, octyl group,
Examples include dodecyl group.

The active ingredient compound (I) is a known substance,
Typical examples of the compound include imidazole (hereinafter, referred to as compound (1)), 5- (carboxymethyl) imidazole (hereinafter, referred to as compound (2)), 2-ethylimidazole (hereinafter, referred to as compound). (Referred to as (3)), 5-amino-4-carbamoylimidazole (hereinafter referred to as compound (4)), 4,5-
Dicyanoimidazole (hereinafter, referred to as compound (5)), 2-dodecylimidazole (hereinafter, referred to as compound (6)), 5- (carboxyvinyl) imidazole (hereinafter, referred to as compound (7)), 4 , 5-dichloroimidazole (hereinafter referred to as compound (8)), 4,5-dihydroxyimidazole (hereinafter referred to as compound (9)), 4,5-dicarboxyimidazole (hereinafter referred to as compound (8)) 10))).

The active ingredient compound (I) in the present invention is
As is clear from the test examples described later, it has a specific action of specifically suppressing the production of IgE, but not affecting the production of other classes of immunoglobulins. Furthermore, it has been confirmed that the active ingredient compound (I) has low toxicity and has no side effect.

From the above results, the active ingredient compound (I)
Can be used as an anti-allergic agent.

The dose of the active ingredient compound (I) varies depending on the disease, the severity of the patient, the drug tolerance, etc.
Usually 10 mg to 10 g, preferably 50 mg per day for an adult
It is an amount of ˜5 g, which may be administered in single or divided doses. The administration can take any form suitable for the administration route.

The active ingredient compound (I) can be prepared for administration using any conventional formulation method. Therefore, the present invention also includes a pharmaceutical composition containing the active ingredient compound (I). Such a composition is prepared by a conventional means using any necessary pharmaceutical carriers, excipients and other pharmaceutically acceptable additives.

When this composition is an oral preparation,
Desirably, the formulation is provided in a form suitable for absorption from the gastrointestinal tract. Oral tablets and capsules are unit dosage forms and include binders such as syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone; excipients such as lactose, corn starch, calcium phosphate, sorbit, glycine; Containing lubricants such as magnesium stearate, talc, polyethylene glycol, silica and the like; disintegrating agents such as potato starch and the like; or acceptable wetting agents such as conventional excipients such as sodium lauryl sulfate. Good. The tablets may be coated by methods well known in the art. Liquid oral preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc. or may be dry products which are redissolved in water or other suitable vehicle before use. . Such liquid formulations include commonly used formulation additives such as suspending agents such as sorbit syrup, methyl cellulose,
Glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible fats and the like; emulsifiers such as lecithin, sorbitan monooleate, gum arabic and the like; non-aqueous solvents such as almond oil, fractionated coconut oil, Oily esters, propylene glycol, ethyl alcohol and the like; preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and sorbic acid may be contained.

When preparing an injection, a pH adjusting agent, a buffering agent, a stabilizer, a preservative, a solubilizing agent and the like are added to the active ingredient compound (I), if necessary, and subcutaneously,
Intramuscular or intravenous injection.

[0018]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these examples.

Test Example 1 Effect on in vitro IgE antibody production in mouse spleen cells 10 μg trinitrophenylated keyhole phosphorus adsorbed on 3 mg aluminum hydroxide gel intraperitoneally in BALB / c mice of 8-10 weeks old. Pet hemocyanin (trinit
rophenyl keyhole limpet hemocyanin, TNP-KL
H) was administered, and at the same time, 1 μg of pertussis toxin was subcutaneously administered. Three weeks later, a second immunization was performed with 2 μg of TNP-KLH and 2 mg of aluminum hydroxide gel, and after 4 weeks, the spleen was excised and ground to prepare an antigen-sensitized spleen cell suspension. 6 × 10 6 of the spleen cells were placed in 1 ml of RPMI-1640 medium containing 10% fetal calf serum.
After culturing with 0 ng / ml of TNP-KLH for 2 days, the cells were washed and further cultured for 4 days in a fresh medium containing no antigen, and the supernatant was recovered. Anti-TNP-IgE in supernatant
The antibody was quantified by the enzyme immunoassay using a 96-well microplate on which a rat anti-mouse IgE monoclonal antibody was adsorbed and TNP-conjugated β-galactosidase. The amount of anti-TNP-IgG1 antibody was determined by rabbit anti-mouse IgG.
1 The same procedure was performed using a 96-well microplate on which a polyclonal antibody was adsorbed. The sample (active ingredient compound (I)) was added to the medium over the entire culture period. The results are shown in Table 1.

[0020]

[Table 1]

Test Example 2 Effect on in vivo IgE antibody production in mice A group of 5 BDF1 mice was intraperitoneally injected with 2 μg of TNP-KLH and 0.8 mg of aluminum hydroxide gel,
The drug was orally administered 40 mg / kg (daily dose 80 mg / kg) twice a day for 4 days from the day of injection. At the third week after immunization, the same amount of the antigen was intraperitoneally administered again, and the drug was twice daily for the same 4 days.
40 mg / kg was orally administered. Serum was collected 5 days after the second immunization, and the amount of anti-TNP-IgE in the serum was quantified by the enzyme immunoassay described above. The results are shown in Table 2.

[0022]

[Table 2]

Example 1 Tablets Imidazole 25 mg, corn starch 20 mg, hydroxypropyl cellulose 3 mg, magnesium stearate 2 mg and lactose 100 mg were mixed and the resulting mixture 15
0 mg is prepared into tablets using a tablet press.

Example 2 Granules Take 25 mg of imidazole, 20 mg of corn starch, 3 mg of hydroxypropyl cellulose and 102 mg of lactose,
Granules are prepared according to a conventional method.

Example 3 Injection 5% glucose solution in which imidazole was dissolved at a ratio of 10 mg / 1 ml was sterilized by filtration through a filter having a pore size of 0.22 m and then aseptically dispensed in 5 ml aliquots into heat-sterilized vials. To make an injection.

[0026]

INDUSTRIAL APPLICABILITY The antiallergic agent provided by the present invention does not exhibit general immunosuppressive action and can selectively suppress IgE production.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 233/88 233/90 BA

Claims (1)

[Claims] 1. The following general formula: (In the formula, R ↓ 1, R ↓ 2 and R ↓ 3 each represent a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a carbamoyl group, a carboxyl group, a carboxyalkenyl group, a carboxyalkyl group or an alkyl group. )
An anti-allergic agent containing the compound represented by as an active ingredient.