WO2001068121A1

WO2001068121A1 - Remedies for allergic diseases

Info

Publication number: WO2001068121A1
Application number: PCT/JP2001/002076
Authority: WO
Inventors: Takayuki Kajiura; Hideki Suzuki; Seiichi Sato; Sonoko Ishizaki; Junko Shinozaki; Makoto Shiozaki
Original assignee: Ajinomoto Co., Inc.
Priority date: 2000-03-17
Filing date: 2001-03-16
Publication date: 2001-09-20
Also published as: AU2001241162A1

Abstract

Cyclic lypopeptide derivatives such as rakicidin A and rakicidin B exert an excellent effect of selectively suppressing immune reactions causing allergic diseases without inhibiting any immune reactions which are important in biological protection. By using these derivatives as the active ingredient, drugs, in particular remedies for allergic diseases (namely, drugs appropriate for the prevention, amelioration, treatment, etc.) can be provided. Thus, efficacious remedies for allergic diseases having elevated safety or methods for treating these diseases, etc. are provided.

Description

Specification

Agent for treating allergic diseases

Technical field

The present invention relates to a novel therapeutic agent for allergic diseases such as bronchial asthma, conjunctivitis, rhinitis and dermatitis using a cyclic lipopeptide derivative having a specific structure described later as an active ingredient, that is, its prevention, improvement and Z or A drug suitable for treatment, etc .; a method for preventing, ameliorating and treating Z or gallium which administers the active ingredient in a living body, particularly to an animal (human, etc.), or a medicament of the active ingredient, especially for the allergic disorder. Prevention, improvement and / or use for the manufacture of therapeutics.

Background art

Allergic diseases such as bronchial asthma, conjunctivitis, rhinitis, dermatitis, etc. are caused by certain allergens and their immune response. That is, the allergen and the IgE antibody against it bind on the cell surface of mast cells or basophils, and these cells release various chemical mediators such as histamine, oralkotriene, and thromboxane. This causes, for example, in bronchial asthma, dyspnea due to contraction of airway smooth muscle and edema of bronchial mucosa due to increased vascular permeability. In addition, tissue damage caused by eosinophils infiltrating from the bloodstream exacerbates and inflames lesions.

Recent studies have revealed that lymphocytes called type 2 helper T cells (hereinafter referred to as "Th2 cells") are involved in the control of reactions in these allergic diseases. . That is, IgE production from B lymphocytes is induced by inulin-1 (hereinafter referred to as "IL-4") produced from Th2 cells [Pene, et al. See National Academy of Sciences (Proceedings in National Academy of Science, USA), Vol. 85, p. 680 (1989). Interleukin-5 (hereinafter referred to as “IL-15”), also produced from Th2 cells, works to maintain and activate eosinophils [Kinashi, T et al., Nature, Vol. 3 2 4 volumes, 70 pages ( See 1 9 8 6). ]. IL-4 also acts on the production and proliferation of Th2 cells themselves. These facts indicate that Th2 cells cause exacerbation and chronicity of allergic diseases through production of IL-4, IL-5, and the like.

As a treatment for allergic diseases, symptomatic treatment is generally used. For example, a bronchodilator is used for asthma. In addition, antiallergic agents such as azelastine, which inhibits the dissociation of chemical media overnight, and tranilast, which is an inhibitor of chemical mediators, are also used, but these act on the immune response that causes allergic diseases. is not. Steroids are also used to control allergic inflammation. However, for example, in atopic dermatitis, side effects such as skin atrophy become a problem due to continuous use of topical steroids. It is considered that a drug that overcomes the problems of these therapeutic drugs and a drug that suppresses immune response will be useful as a causative therapeutic drug for allergic diseases. In fact, FK506, a drug that suppresses T lymphocytes, has been used as an external preparation for the treatment of atopic dermatitis and has been effective. However, such drugs have a problem because they have no selectivity for Th2 cells and thus suppress not only immune reactions related to allergy but also immune reactions related to infection protection.

Under such circumstances, there is a strong demand for the development and commercialization of more effective and safer therapeutic agents for allergic diseases.

Problems of the Invention

The problem to be solved by the present invention is to use, as an active ingredient, a compound that selectively suppresses an immune response that causes an allergic disease without inhibiting an immune response that is important for host defense. Another object of the present invention is to provide a remedy for allergic diseases with high safety. As a result, it is possible to use the active ingredient in the manufacture of pharmaceuticals, and it is also possible to provide a method for treating the above-mentioned diseases as an object.

Disclosure of the invention

The present inventors have investigated the production of compounds that have little effect on immune responses important for host defense, particularly the production of IgE and the production of IL-14 that induces the proliferation of Th2 cells themselves. Compound becomes a drug that suppresses allergic reactions and can solve the above problems Therefore, we searched for a drug that selectively inhibits the production of IL-4 from various naturally occurring substances. As a result, among the substances produced by actinomycetes, cyclic lipopeptide derivatives having the structure represented by the following general formula (I), in particular, two compounds of laxidine A and laxidine B exhibit selective IL-4 production inhibitory activity. And found that the present invention was completed.

That is, the present invention provides a method for preventing an allergic disease comprising, as an active ingredient, at least one selected from a cyclic lipopeptide derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof. A drug suitable for improvement and / or treatment (referred to as “therapeutic agent of the present invention”).

(Wherein, R is a hydrogen atom, a straight-chain or branched-chain acyl group having 1 to 8 carbon atoms, and a straight-chain or branched alkyl group having 1 to 8 carbon atoms; n is an integer of 6 to 18) And Me represents a methyl group, respectively.

The term "straight-chain or branched-chain acyl group" means that the acyl group contains a straight-chain or branched alkyl group. Further, as described above, the therapeutic agent of the present invention broadly means an agent aimed at preventing, ameliorating, treating, and the like of allergic diseases.

In the above general formula (I), R is a hydrogen atom, and n is 11; raxidine A; R is a hydrogen atom, and laxidine B is 12 (raki cid in B) ) Is particularly useful as a therapeutic agent of the present invention, that is, a therapeutic agent for allergic diseases.

The above-mentioned luxidine A and luxidine B have already been isolated as compounds having cytocidal activity against cultured cancer cells [McBrien, K et al. See The Journal of Antibiotics, vol. 48, p. 1446 (1995). Therefore, it is helpful when preparing those compounds. However, the selective action on T lymphocytes, the therapeutic effect on allergic diseases, the anti-inflammatory action, and the like of these compounds have not been known at all, and no reports have been found.

Furthermore, the present invention provides, as another form, administering at least one selected from the cyclic lipopeptide derivative represented by the general formula (I) and a pharmaceutically acceptable salt thereof to a living body. A method for treating, ameliorating and preventing or preventing an allergic disease having a characteristic, and as still another form, selected from the cyclic ribopeptide rust conductor represented by the general formula (I) and a pharmaceutically acceptable salt thereof. An embodiment directed to at least one medicament, particularly for use in the treatment, amelioration and manufacture of Z or prophylactic drugs for said allergic diseases

Hereinafter, embodiments of the present invention will be described.

The subject to which the therapeutic agent of the present invention is administered is not particularly limited as long as it seeks prevention, amelioration, treatment, etc. of an allergic disease or a disease caused by allergy. Patient).

The cyclic lipobeptide derivative used as a therapeutic agent for an allergic disease of the present invention, for example, in the above general formula (I), R is a hydrogen atom, luxidine A in which n is 11 or R is a hydrogen atom, and n is 12 Laxidine B can be isolated from a culture solution of a microorganism using a known method (see the above-mentioned literature). Microorganisms used for the production of the cyclic lipopeptide derivative used in the present invention as an effective component thereof can be any microorganisms that produce Rakicidins, for example, Yamanakako, Yamanashi Prefecture Microorganisms having the following mycological properties, ie, strain AJ9562, collected from the soil of the above can also be used. Incidentally, the bacteriological properties of this strain are as follows.

1. Morphological features

ISP [International Streptomyces Project] After culturing at 28 ° C for 14 days on a defined agar medium, Under microscopic observation, the basal hyphae elongate and branch well and are brown to black. No zigzag elongation like Nocardia strains is observed. No formation of aerial hyphae is observed. Upon maturation, a large number of monospores grow on the basal hypha and turn black. The spores are spherical to ovoid, usually 0.4-1.0X1.0-1.5 ^ m in size. Spores do not show migratory properties.

2. Growth and culture characteristics on various agar media (28 :, 14 days culture)

3. Growth temperature (Auto:-agar medium, cultured for 14 days)

10 ° C: No growth 30 ° C: Good growth

15 :: Slightly growing 35 ° C: Good growth

20 ° C: Normal growth 40 ° C: Normal growth

25 ° C: good growth 45 ° C: no growth 4. Physiological properties (cultured for 28 days for 14 days)

5. Utilization of carbon sources

Prideham Gottlieb agar was used as a basal medium, and the following various sugars were added thereto and cultured at 28 ° C for 14 days.

D—Glucose + Laurafiinoinosu +

D—xylose + D—mannitol

L-arabinose + inositol

L-Ramnose-1 Shish Yu-Keuro Loose +

D—Fulk! ^ Iss + DD ---- Gagararak 1 I ^^ Isss +

6. Cell components

Meso-diaminopimelic acid, 3-ΔH-diaminopimelic acid and glycine were detected from the cell wall, and the cell wall type is considered to be type II. In addition, the whole cell sugar components, which are characteristics of the classification, were arabinose and xylose, and the sugar pattern was D-type. The acyl type of the cell wall peptide darican was a glycolyl type.

From the above, it is clear that this strain belongs to the genus Micromonosbora among actinomycetes. Therefore, the AJ9562 strain was transformed into Micromonospora sp. 562 (Micromon os poras p. AJ 9562).

This strain is available from the Ministry of Economy, Trade and Industry of the Ministry of International Trade and Industry of Japan (currently the Ministry of Economy, Trade and Industry, National Institute of Advanced Industrial Science and Technology). No. 3) to FERM P— 1754 on September 3, 1999

Deposit No. 8 and transferred to the International Deposit under the Budapest Treaty on March 14, 2001, and given the accession number FERM BP-7501.

As in the case of other actinomycetes, lactic acid-producing bacteria belonging to the genus Micromonospora can be irradiated with, for example, X-rays or ultraviolet rays, for example, nitrogen, nitrogen, azaserine, nitrite, or 2-amino acid. A commonly used bacterial species conversion method such as treatment with a mutagenic agent such as Blin or N-methyl-N'-nitro-N-nitrosoguanidine (NTG), phage contact, transformation, transduction or conjugation Even such mutants or naturally obtained mutants are not substantially different from the taxonomic properties described above, and furthermore produce the compound. All those having the properties described above can be used for producing the compounds used as the active ingredients in the present invention.

(Culture method)

When culturing a microorganism when producing a compound used as an active ingredient of the therapeutic agent of the present invention, the culturing is performed using a medium containing a nutrient source used by the microorganism. As the medium, any of a synthetic, semi-synthetic or natural, solid or liquid medium may be used, but usually a liquid medium containing a natural nutrient is suitable. The nutrient source added to the culture medium may be any carbon compound as long as it is an assimilable carbon compound.For example, arabinose, sucrose, starch, glucose, glucose, dextrin, coconut oil, soybean oil, etc., alone or in combination Used. Further, alcohols, organic acids, and the like may be used. As inorganic and nitrogen sources, ammonium chloride, ammonium nitrate, urea, etc., as organic nitrogen sources, peptone, yeast extract, dried yeast, meat exercise, gluten meal, corn steep liquor, soy flour, fish meal, peanut Powder, cottonseed kashiwa, casamino acid and various amino acids are used alone or in combination.

If necessary, add sodium, potassium, magnesium, and calcium to the medium. Sulfates, nitrates, chlorides, phosphates, and the like of metals such as zinc, iron, and cobalt can be added. The cultivation is preferably carried out under aerobic conditions, and any of stationary, shaking, and aeration and stirring cultures is possible. Shaking or aeration and stirring culture is advantageous. The cultivation temperature is preferably in the range of about 25 to 35, and especially about 28 is advantageous. Further, it is preferable that the pH value of the medium is maintained at about neutral pH of about 5.5 to 8.5. The cultivation period varies depending on the culture conditions such as the composition of the medium and the temperature, but it is usually about 3 to 10 days, and the cultivation should be performed at an appropriate time based on the timing at which the akicidins reach the maximum titer. finish.

In order to isolate and purify the lactidine (Rakidin) accumulated in the culture cultured in this manner, a commonly used isolation and purification means may be applied. When the Micromonospora sp. AJ9562 strain is cultured under the cultivation conditions described in Examples described later, at least two types of luxidine-related substances are accumulated in the culture solution.

In this manner, laxidine A or laxidine B can be produced. Further, other compounds have the structure represented by the above general formula by using these as raw materials and utilizing ordinary organic synthesis techniques. In the compound (I), a cyclic lipopeptide derivative wherein n is other than 11 or 12 can be produced. Next, in order to produce a derivative in which R represents a straight-chain or branched-chain acyl group having 1 to 8 carbon atoms, the desired acyl group can be obtained by employing a method known as an acylation method for acylating a hydroxyl group. An acylated derivative into which is introduced can be easily produced. As the acetyl group in this case, an acetyl group, a benzoyl group or the like can be employed as a particularly preferable one.

On the other hand, in order to produce a conductor in which R represents a linear or branched alkyl group having 1 to 8 carbon atoms, a method known as an etherification method in which a hydrogen atom of a hydroxyl group is substituted with an alkyl group is employed. Thus, an alkylated derivative having an intended alkyl group introduced therein can be easily produced. As the alkyl group in this case, a methyl group, an ethyl group, a benzyl group and the like can be mentioned as preferred alkyl groups.

The active ingredient used in the therapeutic agent of the present invention may be in a free form or in the form of a pharmaceutically acceptable salt. The salt form in that case In order to produce the desired salt, the desired salt can be easily produced by subjecting it to a usual salt-forming step, for example, using a free form or another salt. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloride, sulfate, and nitrate.

In the present invention, when the cyclic lipopeptide derivative (or a salt thereof) is used as an active ingredient as a therapeutic agent for allergic diseases, the form of the preparation is not particularly limited. Formulations suitable for various administrations such as inhalation administration, oral administration, intravenous administration, transdermal administration, ophthalmic administration, and the like can be produced. The dosage in that case depends on the patient's condition, age, and administration method, but when using laxidine A or B, expressed as its net weight, preferably 1 to 300 mg by oral administration It is about ZkgZ days, more preferably about 5-100 mg / kg. Also, for example, in the case of intravenous administration, the amount of the active ingredient used is about ten to one-twentieth, which is sufficient, compared to the case of oral administration, and other techniques known as intravenous administration such as injections are used. Thus, a pharmaceutical preparation can be manufactured. Derivatives other than laxidine A and B (including salt forms) can be manufactured by determining the amount of the target preparation to be used based on these contents and other known preparation techniques.

The active ingredient (compound) used in the therapeutic agent of the present invention can be formulated by a conventional method. The form of the preparation is not particularly limited. Examples of the form of the preparation include inhalants, injections, tablets, granules, fine granules, powders, capsules, creams, ointments, suppositories, etc.Examples of the carrier for the preparation include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose sodium salt, magnesium stearate, talc, acetyl Cellulose, sucrose, titanium oxide, benzoic acid, paraoxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, simple syrup, citric acid, distilled water, Lyserine, propylene glycol, macrogol, sodium monohydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dextrose, sodium chloride, phenol, thimerosal, sodium bisulfite Depending on the form of the desired preparation, it is used by mixing with the compound of the active ingredient used in the therapeutic agent of the present invention.

Furthermore, the content of the active ingredient of the present invention in the preparation for the therapeutic agent of the present invention greatly varies depending on the form of the preparation, and is not particularly limited. Preferably it is about 0.01 to 100% by weight, more preferably about 1 to 100% by weight.

Preferred embodiment

Hereinafter, the present invention will be described in more detail with reference to Production Examples and Examples.

(Production example) Production of luxidine A and B

Prepare a medium (pH 7.2) containing 1.0% starch, 0.5% glucose, 0.5% polypeptone, 0.5% yeast extract, 0.5% tryptone and 0.1% calcium carbonate. Was dispensed into a 50 Om 1 Erlenmeyer flask at a rate of 10 Om each, and sterilized at 120 for 20 minutes, scraped and inoculated with the hypha of Micromonosbora sp.AJ 9562 strain grown on Bennett agar medium. Then, shaking culture was performed at 28 for 72 hours to prepare a seed culture solution.

Next, a medium (pH 7.0) containing 1.0% dextrose, 1.0% malt extract, 10% tomato juice, 0.1% yeast extract and 0.2% calcium carbonate was prepared, and this was 50 Om Each 10 Om was poured into each Erlenmeyer flask (1) and sterilized at 120 for 20 minutes, and the seed culture was inoculated at a rate of 2.0%. The culture was carried out at a temperature of 28 for 96 hours at 180 rotations.

The culture solution (7 L) thus obtained was separated into a supernatant and cells by centrifugation. The supernatant was extracted with toluene (2.5 L), and the solvent was concentrated under reduced pressure to obtain about 300 ml of a water suspension. After methanol (200 ml) was added to the suspension, the mixture was extracted with black-mouthed form (350 ml × 2). The black mouth form layer was concentrated to dryness under reduced pressure. The obtained residue (1.2 g) was subjected to reverse phase column chromatography (COSMOSIL 140C | ₈ -OPN), and the fraction eluted with 70-80% aqueous nitrile solution was analyzed by high-speed ODS column. Purification by liquid chromatography (HPLC) yielded luxidine A (3 mg) and luxidine B (2.5 mg).

(Example 1) Inhibition of IL-14 production in mouse spleen T cells The spleen was excised from a mouse (Balb / c strain, female), and spleen cells were prepared by a conventional method.播 Seed in RPMI-1640 medium containing 10% fetal serum, add anti-CD3 antibody to stimulate IL-4 production from helper T cells in spleen cells, and simultaneously add raki cidin A or rakicidin B. The cells were cultured for 20 hours at 37 ° C. in the presence of 5% C ₂ . After completion of the culture, the culture supernatant was recovered, and the amount of IL-14 produced and secreted by the helper T cells in the culture supernatant was quantified by enzyme immunoassay. The amount of interferon (IFNr) produced and secreted by helper T cells in the same culture supernatant was also quantified by enzyme immunoassay. The results are shown in Table 1.

As shown in Table 1, rakicidin A and rakicidin B suppressed IL_4 production. On the other hand, since no suppression of IFNr produced by helper T cells was observed in the same culture supernatant, rakicidin A and rakicidin B inhibited IL-4 production without suppressing IFNa production. It was shown to selectively suppress.

In addition, the presence or absence of a cell killing effect on the cultured cancer cells was measured by MTT assay. P388 cells (derived from mouse) or Jurkat cells (human), © shea RPM 1 containing 10% calf serum - 1640 seeded in culture medium (P388 cells 2 x 10 m 1 and Jurkat cells 5 say yes 10 ^4: 111), was added Rakicidin a or B, 72 h, were cultured in the presence of 5% C_〇 ₂ at 37. After 72 hours, add ^ 07 (3- (4,5-dimethylthiazol-2-y 1) -2,5-diphenyltetrazolium bromide) to 0.2 mg / m 1 and then add 3 hours, 37 hours The cells were cultured in the presence of 5% C ^ ₂ . An equal amount of 0.04 N hydrochloric acid containing 10% SDS (sodium dodecyl sulfate) was added to the culture system to lyse the cells, and the generated formazan was quantified by absorbance at 570 nm. The results are shown in Table 1.

As is clear from Table 1, it was shown that rakicidin A and B had no cell killing activity at the concentration at which IL-4 production was suppressed. [Table 1] Inhibition of IL-14 production

* The Rakicidin A or concentration of IL one 4 and I FN _T of culture supernatant cultured without the addition of B, expressed the IL one 4 and I FN concentration of § drug added culture as 100%, respectively. one-

** The number of viable cells in the drug-added culture was expressed assuming that MTT color development in each culture of P388 and Jurkat performed without adding rakicidin A or B was 100%.

(Example 2) Inhibition of allergic airway inflammation in a mouse asthma model For a mouse asthma model, see Corry et al. [Corry, D et al., Journal of Experimental Medicine, Journal of Experimental Medicine, Vol. 183, p. 109 (1996). . ] Was partially modified.

Mice (Balb / c, female) were immunized with ovalbumin saline solution containing aluminum hydroxide, gel and adjuvant. The same immunization was performed again on the sixth day after the immunization, and a physiological saline solution containing ovalbumin was inhaled once a day from the 11th to the 14th day. rakicidin A was administered by inhalation of a 200 ng / ml saline solution once daily through the nasal cavity from day 11 to day 14. Therefore, the total dose of rakicidin A is 40 ng per individual. Control animals that received the same immunization were treated with physiological saline solution without rakicidin A in the same manner. On the 15th day, the lungs were removed and fixed in formalin, and tissue sections were prepared. The allergic inflammation was scored using the degree of eosinophil infiltration as an index. The results are shown in Table 2. As is clear from Table 2, it was shown that the allergic inflammatory pattern of the lung tissue caused by the ovalbumin treatment was suppressed by rakicidin A administration.

[Table 2] Suppression of allergic inflammation of lung in asthma model

Test group Inflammation score

Control group individual No. 1 II

2 III

3 IV

Rakicidin A administration group individual No.1 II

2 II

3 I

The definition of the inflammation score is as follows.

I: no infiltration of eosinophils;

II: eosinophils slightly infiltrate around blood vessels;

III: Eosinophils infiltrate around blood vessels (mild) not infiltrate into alveoli;

IV: eosinophil infiltration around blood vessels and alveoli (moderate); and

V: Eosinophils infiltrate around blood vessels and alveoli (severe) Loss of alveolar structure.

(Example 3) Improvement of airway resistance in a rat asthma model

For a mouse asthma model, see Eidelman et al. [Eidelman, D et al., American Review of Respiratory Disease, Vol. 137, p. 1033 (1988). ] Was partially modified. Rats (Brown Norway strain, male) were immunized with an ovalbumin saline solution containing aluminum hydroxide / gel / adjuvant. After immunization, a physiological saline solution containing ovalbumin was inhaled, and the increase in airway resistance due to the induced asthmatic response was measured. rakicidin A is a saline solution of 1 or 10 igZm 1 in 0.1 ml each, 10 minutes before and 10 minutes after asthma induction by ovalbumin inhalation. Administered by inhalation. Therefore, the dose of rakicidin A is 0.2 uL g MS 2 ti g per individual. A control group of animals to which the same immunization was performed was administered a physiological saline solution containing no rakicid in A in the same manner. Table 3 shows the results. As is clear from Table 3, it was shown that administration of rakicidin A suppressed an increase in airway resistance due to asthma.

[Table 3] Inhibition of airway resistance increase by rakicidin A administration

The invention's effect

In the present invention, an excellent therapeutic agent for allergic diseases that hardly inhibits immune reactions important for biological defense, that is, prevention of allergic diseases, Drugs suitable for improvement and / or treatment can be provided. As a result, a method for preventing, ameliorating, and / or treating such a disease can also be provided.

Claims

The scope of the claims

1. A therapeutic agent for an allergic disease comprising as an active ingredient at least one selected from a cyclic lipopeptide derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof:

However, in the above formula, R represents any one of a hydrogen atom, a straight-chain or branched-chain acyl group having 1 to 8 carbon atoms, and a straight-chain or branched alkyl group having 1 to 8 carbon atoms, and n represents 6 to Represents the integers of 18 respectively.

2. The therapeutic agent according to claim 1, wherein the cyclic lipopeptide derivative comprises luxidine A and luxidine B.

3. The therapeutic agent according to claim 1 or 2, wherein the allergic disease is any of bronchial asthma, conjunctivitis, rhinitis and dermatitis.

4. Treatment and improvement of an allergic disease characterized by administering at least one selected from the group consisting of a cyclic lipopeptide derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof to a living body. And / or preventive measures.

5. Use for the manufacture of at least one drug selected from the cyclic lipopeptide derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof.

6. Use according to claim 5, wherein the medicament is a therapeutic, ameliorating and / or prophylactic agent for allergic diseases.