JPH0588229B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel compound having a chroman skeleton and an antiallergic agent containing the compound as an active ingredient. [Prior Art] A living body generates an immune reaction as a defense reaction against infection by bacteria or viruses, or invasion by foreign proteins or drugs, and the living body is maintained by this immune reaction. However, immune reactions are not only beneficial to the body, but can also lead to allergic reactions that may cause damage. Allergic reactions can be of different types depending on the mechanism that causes tissue damage.
It is classified into four types: type and type. Among these, the type is called the immediate type or anaphylactic type, and typical diseases include bronchial asthma, allergic rhinitis, and acute urticaria.Therapeutic drugs for these include sodium cromoglycate, tranilast, and ketotifen. It is used clinically. However, for allergic diseases classified into types, types, and mechanisms, no effective therapeutic agents have been known so far, other than steroids such as hydrocortisone, betamethasone, methylprednisolone, and dexamethasone. [Problems to be solved by the invention] The above-mentioned sodium cromoglycate does not exhibit antiallergic effects when administered orally, which is the most convenient administration method, and tranilast exhibits cystitis-like side effects such as hematuria, pyuria, and dysuria. In addition, ketotifen has undesirable properties as a drug, such as its slow-acting antiallergic effect, which does not appear until about 4 to 6 weeks after administration, and side effects such as drowsiness. It is known that there are In addition, steroids have a remarkable anti-inflammatory effect as well as an immunosuppressive effect, making them highly effective drugs for allergic diseases, but on the other hand, they also have significant side effects, so extreme caution should be taken when using them. is required. Under these circumstances, there is currently a desire to develop antiallergic agents that have less toxicity and side effects and can be administered orally. Therefore, one of the objects of the present invention is to provide a novel compound that has excellent antiallergic effects and is highly safe. Another object of the present invention is to provide the use of the new compound as an antiallergic agent. Still another object of the present invention is to provide an antiallergic agent that can be administered orally. [Means for Solving the Problems] According to the present invention, the above object is achieved by solving the general formula

[Chemical Formula] (In the formula, R ¹ and R ⁴ each represent a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom or a lower alkoxyl group, R ³ represents a hydrogen atom, a lower alkyl group, or a lower alkoxyl group, (n represents an integer of 0, 1 or 2) 3,4-dihydro-2H-benzopyran derivatives or pharmacologically acceptable esters or salts thereof (hereinafter these compounds will be referred to as 3,4-dihydro- (collectively called 2H-benzopyran derivatives)
This is achieved by providing 3 and 4
This is achieved by providing an antiallergic agent containing -dihydro-2H-benzopyran derivatives as an active ingredient. In the above general formula (), examples of lower alkyl groups represented by R ¹ , R ³ and R ⁴ include methyl group, ethyl group, propyl group, butyl group, and lower alkyl groups represented by R ³ and R ⁴ . Examples of the group include methoxy group, ethoxy group, propoxy group, and butoxy group. 3,4-dihydro- represented by general formula ()
The following compounds can be mentioned as representative examples of 2H-benzopyran derivatives. N-[4-(3,4-dihydro-6-methoxy-
2,5,7,8-tetramethyl-2H-benzopyran-2-yl)-2-butenoyl]anthranilic acid [compound (1)]

[Chemical formula] N-[5-(3,4-dihydro-6-methoxy-
2,5,7,8-tetramethyl-2H-benzopyran-2-yl)-2-pentenoyl]anthranilic acid [compound (2)]

[Chemical formula] N-[4-(3,4-dihydro-6-methoxy-
2-Methyl-2H-benzopyran-2-yl)-
2-Butenoyl]anthranilic acid [Compound (3)]

[Chemical] N-[4-(3,4-dihydro-7-methoxy-
2-Methyl-2H-benzopyran-2-yl)-
2-Butenoyl]anthranilic acid [Compound (4)]

[Chemical formula] N-[3-(3,4-dihydro-6-methoxy-
2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acryloyl]anthranilic acid [compound (5)]

[Formula] 3,4-dihydro- represented by the general formula ()
Examples of pharmacologically acceptable esters of 2H-benzopyran derivatives include alkyl esters such as methyl ester, ethyl ester, propyl ester, butyl ester, octyl ester, tetradecyl ester, and stearyl ester. In addition, pharmacologically acceptable salts of the 3,4-dihydro-2H-benzopyran derivative represented by the general formula () include salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline metals such as calcium and magnesium; Salts of similar metals;
Examples include aluminum salts; ammonium salts; salts of organic amines such as diethylamine and piperidine. 3,4-dihydro- represented by general formula ()
The 2H-benzopyran derivative can be produced, for example, by the following method.

[Chemical formula] (In the above formula, R ¹ , R ² , R ³ , R ⁴ and n are as defined above.) That is, the aldehyde represented by the general formula () has about 1.0 to Horner's reagent prepared from 1.2 mol of triethylphosphonoacetate and sodium hydride was heated at about 0 to 40°C in a solvent such as an ether solvent such as tetrahydrofuran or diethyl ether, or an aromatic hydrocarbon such as benzene or toluene. By reacting within the temperature range of , a substituted acrylic ester represented by the general formula () is obtained. This substituted acrylic acid ester is hydrolyzed by a conventional method to obtain the corresponding substituted acrylic acid, and then about 1.2 to 10 times the molar amount of thionyl chloride is added to the substituted acrylic acid in an inert solvent such as dichloromethane or benzene. The corresponding substituted acrylic acid chloride is obtained by reacting in the presence or absence at a temperature range of about 0 to 80°C for about 1 to 8 hours. Next, this substituted acrylic acid chloride and about 1.0 to 1.2 times the molar amount of anthranilic acid are mixed in an inert solvent such as methylene chloride, benzene, or dichloroethane in the presence of a tertiary amine such as pyridine or triethylamine. A 3,4-dihydro-2H-benzopyran derivative represented by the general formula () can be produced by reacting the compound at a temperature of about 0 to 50°C. 3,4-dihydro- represented by general formula ()
Pharmacologically acceptable esters and salts of 2H-benzopyran derivatives can be obtained by subjecting the 3,4-dihydro-2H-benzopyran derivatives represented by the general formula () to conventionally known general esterification reactions or salt-forming reactions. Manufactured by subjecting to. Below, tests on the effects of compounds (1) to (5) of the present invention and hydrocortisone used as a control drug on type (delayed type) allergies and the results thereof are shown. Test method: Wistar female rats (weighing approximately 200g) were used.
A 40% (w/
v) Elmagillon was injected in a 1:1 volume ratio of homonate and Freund's complete adjuvant, and immediately 0.05 ml of pertussis vaccine was injected intramuscularly into the dorsum of the foot. Next, a predetermined amount of the test compound was suspended in 5% gum arabic powder and administered orally, and then administered once a day for 10 consecutive days. The number of rats that died due to encephalomyelitis from day 10 to day 15 after the start of administration was determined, and the antiallergic effect of the test compound was investigated. In addition, to the control group, gum arabic powder was suspended in distilled water and orally administered. Test results: Calculate the mortality rate from the dose of the test compound, the number of rats subjected to the test, and the number of rats that died.
The results are shown in Table 1.

【table】

〔Example〕

EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples. Example 1

[C] Tetrahydrofuran dried under nitrogen atmosphere
triethylphosphonoacetate in a suspension consisting of 130 ml and 1.21 g (50 mmol) of sodium hydride.
10.8 g (48 mmol) was added dropwise under ice-cooling, and after the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour. Next, (3,4-dihydro-6-methoxy-2,5,
7,8-tetramethyl-2H-benzopyran-2
11.4 g (46 mmol) of carbaldehyde
was added dropwise, and the mixture was stirred at room temperature for 2 hours. The resulting reaction solution was poured into water and extracted with diethyl ether. The ether layer was washed with a 5% aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate, and then low-boiling substances were distilled off under reduced pressure. By purifying the residue using silica gel column chromatography, 3-(3,4-
7.5 g of ethyl dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acrylate was obtained. Yield 59%. ¹ H-NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.20 (s, 3H), 1.25 (t, J=8Hz, 3H), 1.70-2.60 (m, 2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.40-2.70 (m, 2H), 3.60 (s, 3H), 4.14 (q, J = 8Hz, 2H), 5.85 (d, J = 16Hz,
1H), 6.99 (d, J=16Hz, 1H)

[Chemical formula] 3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H- obtained in (a) above)
benzopyran-2-yl)ethyl acrylate
Add 6.2 g of 50% potassium hydroxide aqueous solution to a solution consisting of 7.5 g (24.5 mmol) and 100 ml of ethanol,
Stirred at room temperature for 30 minutes. Ethanol was distilled off from the reaction solution under reduced pressure, and 100 ml of water was added to the residue, which was washed with diethyl ether. Add hydrochloric acid to the aqueous layer,
The aqueous layer was made acidic and then extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and low-boiling substances were distilled off under reduced pressure. By purifying the residue by silica gel column chromatography, 3-(3,4-dihydro-6-methoxy-
4.8 g of 2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acrylic acid was obtained. Yield 70.4%. ¹ H-NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.20 (s, 3H), 1.70-2.00 (m, 2H), 2.07 (s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.40 ~2.70 (m, 2H), 3.60 (s, 3H), 5.85 (d, J=16Hz, 1H), 7.00 (d, J=16Hz, 1H), 11.4 (s, 1H)

[Chemical formula] 3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H- obtained in (b) above)
Benzopyran-2-yl)acrylic acid 3.3g
(12 mmol), 2 drops of dimethylformamide, 2 ml of thionyl chloride and 100 ml of benzene.
The mixture was heated to reflux for an hour. Low boilers were distilled off from the reaction mixture under reduced pressure to give 3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-
Benzopyran-2-yl)acrylic acid chloride was obtained. Next, 1.64 g of anthranilic acid, 1.9 g of pyridine
and 100 ml of benzene.
(3,4-dihydro-6-methoxy-2,5,7,
8-Tetramethyl-2H-benzopyran-2-yl)acrylic acid chloride was added dropwise at room temperature, and after the addition was completed, the mixture was further stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and low-boiling substances were distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain N-[3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran) having the following physical properties. 2.8 g of -2-yl)acryloyl]anthranilic acid [compound (5)] was obtained. Yield 57.0%. FD mass spectrum: [M] ⁺ 409 NMR spectrum (90MHz) δ ^HMS _CDCl3 : 1.40 (s, 3H), 1.75-2.00 (m, 2H), 2.0-2.15 (m, 9H), 2.35-2.65 (m, 2H) ), 3.55 (s, 3H), 5.85~6.05
(d, J=15Hz, 2H), 6.80-7.80 (m, 4H), 11.0 (s, 1H) Examples 2-5

[Chemical formula] In Example 1-(a), (3,4-dihydro-6
-methoxy-2,5,7,8-tetramethyl-
(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetaldehyde instead of 11.4 g (46 mmol) of 2H-benzopyran-2-yl)carbaldehyde. , β-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)propionaldehyde,
(3,4-dihydro-6-methoxy-2H-benzopyran-2-yl)acetaldehyde or (3,4-dihydro-6-methoxy-2H-benzopyran-2-yl)acetaldehyde or
each of 4-dihydro-7-methoxy-2H-benzopyran-2-yl)acetaldehyde
Corresponding substituted ethyl acrylates (') were obtained by carrying out the reaction and separation operations in the same manner except that 46 mmol was used. The yield and physical properties of the product are shown in Table 1.

【table】

【table】

[Chemical formula] In Example 1-(b), 7.5 g (24.5 24.5 mmol of each substituted ethyl acrylate (') obtained in (a) above instead of
The reaction and separation operations were carried out in the same manner except that . The corresponding substituted acrylic acid thus obtained was prepared in Example 1-(c) using 3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2- The desired 3,4-dihydro-2H-benzopyran derivative () was obtained by carrying out the reaction and separation procedure in the same manner except that acrylic acid was used instead of acrylic acid.
The yield and physical properties of the product are shown in Table 2. In addition,
Yield refers to the total yield from substituted ethyl acrylate (').

〔Effect of the invention〕

3,4-dihydro- provided by the present invention
2H-benzopyran derivatives have excellent antiallergic effects, as is clear from the results of the above pharmacological tests, and 3,4-dihydro-2H
-An antiallergic agent containing benzopyran derivatives as an active ingredient effectively exhibits the excellent antiallergic action of the 3,4-dihydro-2H-benzopyran derivatives.

Claims (1)

[Scope of Claims ^{] 1 General formula} a 3,4-dihydro-2H-benzopyran derivative or a pharmacologically acceptable ester or salt thereof; ^{2. General formula _} (wherein n represents an integer of 0, 1 or 2) An anti-allergic agent containing as an active ingredient a 3,4-dihydro-2H-benzopyran derivative or a pharmacologically acceptable ester or salt thereof.