JPS61243019A - Antiallergic agent - Google Patents

Abstract

PURPOSE:An antiallergic agent, containing a specific flavone derivative as an active constituent, having improved liberation inhibitory activity of chemical mediators, e.g. histamine or SRS-A, by the oral administration with low toxicity. CONSTITUTION:An antiallergic agent containing a compound expressed by the formula (R is H or acetyl) or a pharmaceutically acceptable salt thereof as an active constituent. The compound expressed by the formula is capable of inhibiting the second stage of allergic reaction liberating chemical mediators, e.g. histamine or SRS-A, etc. to the outside of cell. Specific examples thereof include 7-hydroxy-8-nitroflavone, etc. The agent is administered preferably by the oral route in 0.1-500mg dose range. The agent is useful for prevention and treatment of various allergic diseases caused by the chemical mediators.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a compound represented by the general formula (I): (wherein R is hydrogen or an acetyl group) or a pharmaceutically acceptable salt thereof. The present invention relates to an antiallergic agent that is effective when administered orally.

(Prior Art) Research and development of preventive and therapeutic agents for various allergic symptoms has been carried out, and various drugs are already on the market. Among these allergic symptoms, bronchial asthma, hives, and allergic rhinitis are immediate allergies classified as type I.

This type IO allergy is generally classified into three stages based on the mechanism of allergic reaction and the point of action of antiallergic agents. That is, macrophages respond to foreign antigens that have invaded the body.

IgE antibodies are produced by the interaction of T cells and B cells, and sensitization is established when these IgE antibodies adhere to IgE receptors on mast cells and basophils in the tissue. It's called a stage. Next, when a foreign antigen enters the body again, the foreign antigen binds to the IgE fixed to the cell's IgE receptor, triggering an antigen-antibody reaction that activates cell membrane enzymes and releases calcium into the cell. An influx of ions occurs, which causes biochemical changes such as enzyme reactions and histological changes such as degranulation. As a result, histamine and SR5-A (sl
ow reacting 5 ubstance of
chemical mediators such as anaphylaxis) are released outside the cell.

This process is called the second stage. The chemical mediators liberated outside the cells in the second step cause smooth muscle spasms, capillary permeability light channels, and secretion-promoting effects.
Causes various allergic symptoms. This process is called the third stage.

Among conventionally known antiallergic agents, antibody production inhibitors are drugs that act in the first step, and antihistamines are drugs that act in the third step.

In addition, DSC is an antiallergic agent that acts in the second stage.
G, Toranilast, etc. are known.

(Objective of the Invention) As a result of repeated research in order to obtain a drug that exhibits excellent antiallergic effects on the process of the above-mentioned second-stage allergic reaction, the present inventors found that specific flavone derivatives such as histamine and 5R5- It was discovered that the present invention has excellent activity in inhibiting the release of chemical mediators such as A, and the present invention was completed. In other words, 1. The present invention is directed to chemical mediators.
The present invention provides an allergy agent that is useful for the prevention and treatment of various allergic diseases caused by oral administration.

(Structure of the Invention) The present invention is an antiallergic agent comprising a compound represented by general formula (I): (R is hydrogen or an acetyl group) or a pharmaceutically acceptable salt thereof.

Sodium salt is a pharmaceutically acceptable salt.

Examples include potassium salt, A/S/um salt, magnesium salt, ammonium salt, and the like.

Among these compounds, the following compounds can be mentioned as compounds that exhibit particularly excellent pharmacological effects.

Compound l 7-Hydroxy-8-nitroflavone [melting point 228-230°C (literature value 228°C)] Compound 25-hydroxy-8-nitroflavone [melting point 189°C decomposition (literature value 215°C)] Compound 37-bitroxy-6 -Nitroflavone [melting point 225℃ decomposition (literature value 232-3℃)]
Compound 45-hydroxy-6-nitroflavone [melting point 2
31-4℃ (Literature value 232℃) Compound 5-acetoxy-8-nitroflavone [Melting point 156-8℃ (Literature value 1
55-6℃)] Compound 67-acedoquiV-8-nitroflavone [Melting point 1.72-4℃ (Literature value 168-170℃)
)] Among the compounds represented by the general formula (I), compounds in which R represents hydrogen are produced according to the following method.

0 (■) [In the formula, R1 represents hydrogen or a methyμ group. ] That is, it can be produced in good yield by heating the compound represented by the general formula (I[) together with benzoic anhydride and sodium benzoate under a nitrogen stream, and then hydrolyzing it with an alcoholic potassium hydroxide solution. .

Also, among hydroxynitroflavones, the nitro group is 8
The compound in position can also be produced by the following method.

(V) (■) In other words, hydroxy-8-nitrofufuvone (Vl) can be obtained by reacting hydroxyflavone (V) with concentrated nitric acid in acetic acid or a mixed solvent of acetic acid and nitrobenzene.

Among the compounds represented by the general formula (I), the compound in which R represents an acetyl group can be obtained by reacting the corresponding hydroxy-trophlavone 01> with acetic anhydride in the presence of pyridine to obtain the target compound (■) in high yield. can be manufactured.

(■) (■) The compounds obtained in this manner have been reported in the following literature, but there are no reports on antiallergic effects.

Reference 1: A, M. Mehta et al., Proc In
dian Acad, Sci.

29A, 314 (I949).

Reference 2: R, M, N cod, etc., 37A, 77
4 (I953).

Reference 3: R, M, Na1k, etc., 38A, 31 (
I953).

Reference 4: D, V, Joshi Hiroshi* J, Org
, Chem, = 21.1104 (I956).

Reference 5: S. 5eshadri et al., 23.1.
735 (I958).

Reference 6: P, E, McCusker et al. J, Ch
em, Soc, 2374 (I963).

Reference 7: F, A-Atchabba et al. J, In
dian Chem, Soc.

32.206 (I955).

Reference 8: K, G, Gore et al.* J, Univ, P
oona+Sci.

Technol, 18.73 (I960).

7-hydroxy + 8-nitroflavone (compound I)
See references 1.4 and 5.

For 5-hydroxy-8-nitrofubone (compound 2), see references 3 to 6.

For 7-bitroxy-6-nitroflavone (compound 3), see references 2, 7 and 8.

For 5-hydroxyv-6-nitroflavone (compound 4), see references 2, 5 and 6.

For 5-acetoxy-8-nitroflavone (compound 5), see references 1 and 5.0 For 7-acetoxy-8-nitroflavone (compound 6), see references 3 and 5.

(Example) Next, pharmacological tests, toxicity and administration methods regarding the flavone derivative represented by general formula (I) will be explained.

Chemical mediator release inhibition activity Hartley guinea pigs (male, body weight approximately 40 oz) were passively sensitized by intravenously administering anti-Agmin guinea pig serum, and 48 hours later, the clamps were removed and cut into small pieces. A lung suspension was prepared. A test compound and egg white apmin were added thereto and incubated at 37°C. After one reaction, the lung sections were filtered off and the amounts of histamine and 5R8-A in the filtrate were measured. The amount of histamine was determined by the method of May et al. (J, All
erg, Vol. 40, p. 12 (I970)].

The amount of 5R3-A was measured by a bioassay using guinea pig ileum. That is, an antihistamine agent, an antiacetylcholine agent, and a test solution were added to the guinea pig ileum suspended in a Magnus tank, and 5R3-
The amount of A was calculated. Table 1 shows the inhibition rate of the release of histamine and 5R5-A at a concentration of 100 μM of the compound of the present invention.

Table 1: Passive cutaneous anaphylaxis (PCA) [Response ovalbumin rat serum was added to Wist@r system (1 male weighing approximately 200 cm, 0.1 wl each on each side of the dorsal midline, 2 points for a total of 4 I passively sensitized the point by injecting it with iron.4
After 8 hours, ovalbumin and Epansp - mixture 1
d was administered through the tail vein to induce a PCA (passive cutaneous anaphylaxis) yc response. After 30 minutes, cut out the blue-stained area and measure the amount of leaked dye using the method of Kitsiyama et al. (Mi
Crobiol Immunol, Volume 22, Page 89 (I978)]. To induce the PCA reaction, one song of 200 wq/kf was orally administered. Table 2 shows the PCA reaction inhibition rate of the compounds of the present invention.

Table 2 Acute toxicity test Compounds of the present invention (I-6) were suspended in a 0.51 CMC solution and orally administered at 500 v/kr to Wistar type Tuts, but no deaths were observed in any of them.

Administration Method The compounds of the present invention are generally administered systemically, for example, orally. Administered rectally or parenterally. Dosage depends on age, symptoms, therapeutic effects, and administration method.

Although it varies depending on the treatment time etc., it is usually preferable to administer O6 orally.
It is administered in the range of 1 - 500v, and when an emergency treatment is required, it is continuously infused intravenously in the range of 1μt-1y/hour.

Compounds of the invention can be applied to pharmaceutical compositions in the manner described below. Such pharmaceutical compositions can be used in a conventional manner with any desired pharmaceutical carrier or excipient. The composition is preferably provided in a form suitable for absorption from the gastrointestinal tract, but is not limited thereto and may be administered parenterally. Tablets, powders, fine granules, pills, granules, and tablets (hard capsules, soft capsules) are examples of unit dosage forms, and binders such as syrup, gum arabic, gelatin, sorbitol, etc. .

tragacanth or polyvinylpyrrolidone, polyvinylalco-p. Hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose sodium, etc., excipients 1 such as lactose, sucrose, corn and wheat starch, psium phosphate, sodium chloride, etc. 〃Pi) The lubricant 1 is such as crystalline cellulose, lubricant 1 is such as magnesium stearate, silica, polyethylene glycol, or silica, and the disintegrant is 1 such as potato starch, low-substituted hydroxypropylcellulose, microcrystalline cellulose, etc. ．． Alternatively, it may contain conventional excipients such as acceptable wetting agents, such as Thuri/I/sodium sulfate. In addition, soft capsules may contain a commonly used vehicle such as vegetable oil, polyethylene glycol-μ, or glycerin, or may contain an oily suspension or solution as described in the next section.

It may also contain a wetting agent such as a surfactant.

Liquid formulations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or dry products, including lyophilizates, that are redissolved in water or other suitable vehicle before use. There may be. Such liquid preparations may contain commonly used additives, such as suspending agents, such as methylcellulose, hydroxymethylcellulose, sodium cellulose, hydroxypropylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, gum acacia. , tragacanth gum,
Gelatin, sodium alginate, etc., emulsifier 1, such as Vtin, sorbitan, fatty acid esters. or gum arabic, gum tragacanth, etc.

Wetting agent 2 For example, polyoxyethylene sorbitan fatty acid ester P, polyoxyethylene derivative of hydrogenated castor V oil, non-aqueous vehicle/I/. For example, sesame oil, vegetable oil in soybean oil, propylene glycol, polyethylene glycol-μ
or ethyl alcohol-/I/.

Preservative 1 For example methyl p-hydroxybenzoate.

May contain p-hydroxybenzoic acid propylate or sopic acid, monosyrup, V-sucrose, sophic acid, and mannitol as sweetening agents.As a base for rectal administration, cocoa butter, triglycephyte ( Witepzo/L/(L registered trademark)
) or a water-soluble base such as polyethylene glyco-N are used.

Also used are so-called Lecta μ capsules suspended in vegetable oil and made into gelatin capsules.

These preparations can be made into sustained-release preparations using commonly used methods and forms, and can also be made into microcapsules. The active ingredient(s) of the present invention will generally be present in the formulation in an amount of about 0.1 to 99% of the total composition, usually 0.5 to 90%.

Next, examples of formulations containing the compound of the present invention as a main ingredient will be described.

Formulation example 1゜7-hydroxy-f3-diroflavone (compound 1)
302. Lactose 70? , potato starch 20f.

After uniformly mixing carboxymethylcellulose 15f and methylcellulose 10F, a 50% ethanol solution is added to granulate the mixture using a transfer granulator, and the mixture is dried using a fluidized fluidized dryer. After drying, the grains are sized using 32-mesh knots. Next, 3 f of μg and 2 f of magnesium stearate were added to this and compression molded using a rotary tablet machine to give 1 weight of 150 capes (I
Compound 1 in the tablet contains 301q).

Formulation Example 2゜7-HydroxyV-8-nitro7rabone (Compound 1) 30
Using R, mixed granules for capsules were prepared in the same manner as in Formulation Example 1, and this was filled into No. 2 hard capsules with a capsule filling machine at 150 q per capsule (3 ml of the compound in 1 capsule).
011P).

(Effects of the Invention) From the above results, it was found that the compound of the present invention (CI) has an excellent antiallergic effect when administered orally and has extremely low toxicity. Therefore, it is effective in preventing and treating allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, and allergic dermatitis.

Claims (1)

[Claims] General formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) (wherein R is hydrogen or an acetyl group) A compound represented by the formula (I) (wherein R is hydrogen or an acetyl group) or a pharmaceutically acceptable thereof Anti-allergic agent consisting of salt.