JPH01254625A - Anti-allergic agent - Google Patents

Abstract

PURPOSE:To obtain an anti-allergic agent effective in remedying allergic diseases such as bronchial asthma or collagen diseases, by using benzoylmesaconine as an active component. CONSTITUTION:The objective agent contains the compound of formula I (Bz is group of formula II) which is a component of the extract of SHUJIBUSHI (a chinese herb drug). The anti-allergic agent is administered as an oral drug at a rate of 5-500mg of said compound per day in several divided doses or as a parenteral drug at a rage of 0.5-100mg per day by intravenous injection, intravenous drip, subcutaneous injection or intramuscular injection. The compound of formula I can be produced by extracting SHUJIBUSHI with a solvent (e.g., methanol or n-hexane), distilling out the solvent, fractionating the obtained extract with ammonia water and chloroform, extracting the chloroform-soluble fraction with the above solvent, subjecting the solvent-insoluble fraction to chromatography, developing by using methanol, ethyl acetate, benzene, chloroform, etc., as elution solvents, collecting the fraction containing the objective compound and recrystallizing the compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an antiallergic agent effective in treating allergic diseases such as bronchial asthma and collagen diseases (rheumatism, lupus erythematosus, etc.).

[Prior Art and Problems] Allergic diseases represented by bronchial asthma and collagen diseases have various causes, and many of them are caused by bacteria, viruses, drugs, chemicals, and the like. Currently, hormonal agents and immunosuppressants are effective drugs for treating these allergic diseases, but the therapeutic effects of both cannot be said to be definitive.

Therefore, an object of the present invention is to provide an antiallergic agent that is effective in treating allergic diseases and has few side effects.

[Means for solving the problem] In order to achieve the above objective, we conducted extensive research to provide an anti-allergic agent that is effective in treating allergic diseases.As a result, we found that benzoylmesaconine, an extracted component of Shujitsushi, has anti-allergenic properties. They discovered that it has an allergic effect and completed the present invention.

That is, the present invention is an antiallergic agent containing benzoylmesaconine as an active ingredient.

The structural formula of benzoylmethaconine is as shown below.

However, benzoylmesaconine can be obtained, for example, as follows.

Shujifuji is extracted with at least one solvent selected from methanol, ethanol, n-hexane, ethyl acetate, acetone, benzene, etc., and the extract obtained by distilling off the solvent is distributed between aqueous ammonia and chloroform. The chloroform soluble part was mixed with methanol, ethanol, n-hexane,
It is extracted with a single solvent or a mixed solvent selected from ethyl acetate, acetone, benzene, etc., and the solvent-insoluble part is subjected to chromatography, and extracted with methanol, ethyl acetate, benzene,
Develop using chloroform or the like as an elution solvent, separate both fractions containing the target substance, and further recrystallize to obtain benzoylmesaconine.

A specific example of the production of benzoylmethaconine is shown below.

Specific Example Shuji Fushi powder 10c19 was subjected to chaotic extraction with methanol 40012, and this process was repeated 5 times. 9 was partitioned into 11.0 g of the obtained methanol extract and extracted with aqueous ammonia and chloroform, and 882 g of the chloroform-transferred portion was extracted with 2.0 g of hexane.
5a each was dissolved repeatedly 15 times, and the hexane-insoluble portion was 297.
g was subjected to column chromatography using silica gel, eluted with a mixed solvent of benzene-ethyl acetate-methanol, the solvent was distilled off, and recrystallization was performed to obtain white amorphous powder 309. The physicochemical properties of this powder were as follows, and were consistent with those of benzoylmesaconine.

Specific optical rotation=[α]o+16.9° (c=1.13, CHCf23) mass spectrum EI-MS m/z: 589 (M”).

558 (100%), 540° infrared absorption spectrum ゛νg':': ” C711-
': 3300-3600.1720 Ultraviolet absorption spectrum λ two lips 'n17! (logε)
230(4,14) Proton nuclear magnetic resonance spectrum (δppm in CDCl: 2.31 (3H, s), 3.26, 3.2 B.

3.30, 3.69 (each 3H, s).

4. 0 8 (l H,brd,J
= 7 Hz).

4.51 (l H,d, J = 6 Hz) 4.9
9 (I H,d, J = 5 Hz).

7.38 to 8.03 (5H, m) Next, the usefulness of benzoylmesaconine as an antiallergic agent will be explained using experimental examples.

Experimental Example I Female Fischer rats (7 weeks old) were sensitized intraperitoneally with anti-ovalbumin rat serum (ovalbumin) together with aluminum hydroxide gel and Bordetella pertussis vaccine.The PCA titer was 256 times higher. serum) 20
It was diluted twice and 0.057 of the diluted solution was intradermally administered for passive sensitization. After sensitization, 0.57 mg of physiological saline containing 1 mg of antigen and 1% Evans blue was administered through the tail vein to induce an allergic reaction. Benzoylmethaconine was administered intraperitoneally 1 hour before antigen administration. 30 minutes after antigen administration, the rats were killed by exsanguination, the back skin was peeled off, the amount of dye leaked from the reaction site was measured, and compared with the control group.
The PCA inhibition rate was calculated.

The results are shown in Table 1.

Table 1 Experimental Example 2 BALB/c female mice (6 weeks old) were
For 5 days, 5×10' sheep red blood cells (hereinafter referred to as 5flBC) were administered into the tail vein for sensitization. 20 more
A reaction was induced by subcutaneously administering 2XlO' 5RBC daily into the left ankle. After 3 hours, the thickness of the left calf was measured using a dial thickness gauge (manufactured by Ozaki Co., Ltd.), and the edema rate was determined by comparing it with the value of reaction moe. Benzoylmesaconine was dissolved in physiological saline and administered intraperitoneally 1 hour before the induction of the reaction.

The results are shown in Table 2.

Table 2 Experimental Example 3 BALB/c female mice (6 weeks old) were given 2'
O' pieces of 5RPC were administered through the tail vein for sensitization. Four days later, 108 g of 5RBC was subcutaneously administered to the left foot to induce a reaction, and edema was measured 24 hours later using a dial sickness gauge (manufactured by Amagasaki Seisakusho). The edema rate was determined by comparing with the value before the reaction induction. Benzoylmesaconine was dissolved in physiological saline and administered intraperitoneally 1 hour before reaction induction and 3 hours before measurement.

The results are shown in Table 3.

Table 3 From these results, the antiallergic effect of benzoylmesaconine was confirmed.

Therefore, the antiallergic agent of the present invention is useful for allergic diseases such as bronchial asthma and collagen disease.

Next, an acute toxicity test of benzoylmethaconine was conducted using ddY male mice and Wistar male rats, and the LD5° of benzoylmethaconine obtained in the specific example was 810/9/9 after oral administration. 9,
240 j for intraperitoneal administration! It was 9 on y/.

Next, the dosage and formulation of benzoylmethaconine will be explained.

Benzoylmethaconine can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to achieve the desired effect as an oral agent, it is usually necessary for an adult to administer 5 to 500 tsti of benzoylmethaconine in divided doses several times a day, although this will vary depending on the person's age, weight, and severity of disease. It seems appropriate to take .

Oral preparations such as benzoyl mesaconine tablets, capsules, and granules contain, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the excipients listed above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, etc. may be used in this type of preparation. reactor. Specific examples of each are shown below.

[Binder co-starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant co-starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant Sodium colauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

Mata, benzoylmethaconine can also be administered as a suspension, emulsion, syrup, or elixir, and these various formulations may contain flavorings and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary to administer 0.5 to 100 mg of benzoyl mesaconine per day for adults, although it varies depending on the age, weight, and severity of the disease of the patient.
Intravenous injection up to R9, intravenous drip infusion, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and diluents generally include distilled water for injection, physiological saline, glucose aqueous solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. can be used. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

Example 1 ■Corn starch 449 ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 5g ■Light anhydrous silicic acid 0.5g ■Magnesium stearate 0.59■Benzoyl mesaconine 109 Total 1009 Mix ■~■ uniformly according to the above recipe, Compression molding was performed using a tablet machine to obtain some 200 R9 tablets.

These tablets contain 20 parts of benzoylmethaconine, and adults should take 5 to 25 tablets a day in several doses.

Example 2 ■ Crystalline cellulose 84.59 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 59 ■ Benzoyl mesaconine 10 g Total 1009 After uniformly mixing ■, ■, and part of ■ according to the above recipe and compression molding. The mixture was crushed, the remaining amounts of ■ and ■ were added and mixed, and the mixture was compressed and molded using a tablet machine to obtain a portion of 200719 tablets.

This tablet contains 20xg of benzoylmethaconine, and adults should take 5 to 25 tablets a day in several doses.

Example 3 ■ Crystalline cellulose 34.59 ■ 10% hydroxypropyl cellulose ethanol solution 509 ■ Carboxymethyl cellulose calcium 59 ■ Magnesium stearate 0.5 g ■ Benzoylmesaconine IOg Total 1009 ■, ■, and ■ were uniformly mixed according to the above recipe. After that, it was strung up using a conventional method, granulated using an extrusion granulator, dried and crushed, and then mixed with ■ and ■ and compressed using a tablet machine to obtain a portion of 200 tablets. Ta.

This tablet contains 20 to 20 benzoylmethaconine, and adults should take 5 to 25 tablets a day in several doses.

Example 4 ■Corn starch 849 ■Magnesium stearate 0.59■Calcium carboxymethyl cellulose 5g ■Light silicic anhydride 0.57■Benzoyl mesaconine 109 Total 100g Mix ■~■ uniformly according to the above recipe, and place in a compression molding machine. After compression molding, the mixture was crushed using a crusher and sieved to obtain granules.

This granule tg contains 100 to 100 mg of benzoyl mesaconine, and adults should take 0.5 to 59 mg per day in several doses.

Example 5 ■ Crystalline cellulose 409 ■ 10% hydroxypropyl cellulose ethanol solution 50 g ■ Benzoyl mesaconine 10 Total 1009 According to the above recipe, ■ to ■ were mixed uniformly and made into a paste. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

1 g of this granule contains benzoylmethaconine 10019
It contains 0.5 to 5 g per day for adults, divided into several doses.

Example 6 ■Corn starch 89.59■Light silicic anhydride 0.5g■Benzoylmesaconine
10g total 100g Mix ■～■ uniformly according to the above recipe, and mix 200 m
g was filled into a No. 2 capsule.

This capsule contains benzoylmethaconine 2019, and adults should take 5 to 25 capsules a day in several doses.

Example 7 ■ Soybean oil 59 ■ Distilled water for injection 89.59 ■ Soybean phospholipid
2.59 ■ Glycerin 2 g According to the above recipe, ■ was dissolved in ■ and ■, and the solutions of ■ and ■ were added to emulsify to obtain an injection.

Patent applicant Tsumura Juntendo Co., Ltd.

Claims (1)

[Claims] Benzoylmesaconine
An anti-allergic agent containing pine) as an active ingredient.