JPH0588237B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention has the effect of suppressing the release of histamine, etc., and has an antiallergic effect useful for the prevention and treatment of asthma, etc. 2-Amino-5-oxo-5H-
[1] Benzopyrano[2,3-b]pyridine-3
-Regarding a carboxylic acid derivative or a salt thereof, and a method for producing the same. BACKGROUND ART Bronchial asthma attacks are caused by the release of chemical mediators such as histamine from mast cells, basophils, and others due to antigen-antibody reactions, which constrict bronchial smooth muscles and increase mucus secretion. It is believed that. 2-Amino-5-oxo-5H-, which has the effect of suppressing the release of chemical mediators from mast cells, etc.
[1] Benzopyrano[2,3-b]pyridine-3
- Documents related to carboxylic acid derivatives include JP-A-53-111096. Problems to be Solved by the Invention However, with respect to the compound described in JP-A-53-111096, it has been desired to further enhance the action, reduce toxicity, or increase water solubility. Means for Solving the Problems The present inventors completed the present invention as a result of research to find a compound that meets the above objectives. The present invention is based on the general formula ()

[Formula] 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acid derivative represented by [wherein R and R ¹ represent hydrogen or lower alkyl] or a salt thereof, and the general formula ()

[Formula] [In the formula, R and R ¹ represent hydrogen or lower alkyl, and R ² represents lower alkyl.] A general formula characterized by subjecting a compound represented by the formula to a hydrolysis reaction.

[Formula] [In the formula, R and R ¹ have the same meanings as above]
2-Amino-5-oxo-5H-
[1] Benzopyrano[2,3-b]pyridine-3
- A method for producing a carboxylic acid derivative or a salt thereof. In the above formula, substituent

The substitution position in [Formula] may be any of the 6, 7, 8, and 9 positions, and the lower alkyl represented by R and R ¹ is an alkyl having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, etc. Among them, for R, an alkyl group having 1 to 2 carbon atoms is practically preferable. Lower alkyl represented by ^R2 includes methyl, ethyl, n-propyl, n-butyl, n-
Examples include alkyl groups having 1 to 6 carbon atoms such as pentyl and n-hexyl, and among them, alkyl groups having 1 to 3 carbon atoms are practically preferred. The compound of general formula () of the present invention can be produced by hydrolyzing the compound of general formula (). Hydrolysis is carried out under alkaline or acidic conditions, and the alkalis used include, for example, sodium hydroxide, potassium hydroxide, etc., and the acids used include sulfuric acid, hydrochloric acid, phosphoric acid, etc. The reaction under alkaline conditions is methanol,
The reaction under acidic conditions is carried out with alcohols such as ethanol and propanol, and with organic acids such as formic acid and acetic acid, usually by heating at around 50-150°C. The amount of these alkali hydroxides or acids used is 1 to 1 mole of compound ().
100 mol is used as appropriate, and the reaction time is usually about 1 hour to several days. The compound () is, for example, ethanolamine,
dl-methylefedrin, 1-(3,5-dihydroxyphenyel)-L-isopropylaminoethanol, isoproterenol, dextromethorphan, hetrazan (diethylcarbamazine),
Organic amines such as diethylamine and triethylamine, or alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or ammonia, and the compound () are mixed in an appropriate solvent and heated, for example, by a method known per se. Metal salts or ammonium salts can be obtained by reacting according to the method. Note that compound (), which is a raw material for producing compound (), can be produced, for example, by the steps shown below.

[Chemical formula] (In each formula, R, R ¹ and R ² have the same meanings as above.) That is, by reacting the compound of the general formula () with 1 to 8 equivalents of N-bromosuccinimide, the compound of the general formula The compound () can be produced. Solvents used in this reaction include chloroform,
Examples include carbon tetrachloride, dichloromethane, and tetrachloroethane. The reaction temperature is generally from 50°C to around the boiling point of the solvent. At this time, in order to accelerate the reaction, it is preferable to irradiate with light or add a radical reaction initiator such as benzoyl peroxide. Next, a compound of general formula () can be produced by reacting the obtained compound () with a base such as sodium acetate, potassium acetate, sodium hydroxide, or potassium hydroxide. The solvent is not particularly limited, but dimethylformamide, water, a mixture thereof, etc. are suitable. Appropriate conditions are used for the reaction temperature, ranging from room temperature to around 100°C. Alternatively, compound () can be obtained by reacting compound () in an acidic aqueous solution, such as an acetic acid-water solution, or a compound of general formula () can be produced by reacting compound () with an alkali. , then add this to hydrochloric acid, sulfuric acid,
Compound () can also be prepared by reacting with an acid such as para-toluenesulfonic acid. A compound of general formula () can be produced by reacting the thus produced compound () with cyanacetic ester in the presence of a base. Examples of the cyanacetic acid ester that is a raw material for producing compound () include methyl, ethyl, propyl, butyl, ester, and the like. The amount of these cyanacetic esters to be used is usually about 1 to 10 times the mole of the compound () in practice. Organic amines are used as bases for the above reaction.
For example, primary amines such as n-butylamine, benzylamine, aniline, secondary amines such as diethylamine, dipropylamine, dibutylamine, piperidine, pyrrolidine, morpholine, etc.
Examples include tertiary amines such as 8-diazabicyclo[5,4,0]-7-undecene and triethylamine, and heterocyclic bases such as imidazole and 2-methylimidazole. The amount of these organic bases to be used is usually about a catalytic amount to about 5 times the mole of the compound (). It is generally preferable to carry out the reaction in an organic solvent, and examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons such as benzene and toluene, and dimethylformamide.
Other reaction conditions such as reaction temperature and reaction time are not particularly limited, but the reaction is generally carried out at room temperature to around the boiling point of the solvent used for about 1 hour to 24 hours. By reacting the thus obtained compound () with a peracid such as m-chlorobenzoic acid or peracetic acid, a compound of general formula () can be produced. Examples of the solvent used in the reaction include chloroform, dichloromethane, carbon tetrachloride, tetrachloroethane, etc., and the reaction temperature is room temperature -
A temperature close to the boiling point of the solvent is suitably used. Next, the desired raw material compound () can be produced by subjecting the compound () to catalytic reduction.
Various catalysts can be used for catalytic reduction, including commonly used palladium-based catalysts and platinum-based catalysts, and although there are no particular restrictions, it is common to use palladium catalysts such as palladium-carbon. It is true. Ethanol, tetrahydrofuran, etc. are commonly used as solvents for the reaction. When compound () or its salts are used as a prophylactic or therapeutic agent for allergic diseases such as allergic asthma, allergic dermatitis, and hay fever, the adult dosage is usually about 1 to 500 mg/day in tablets or capsules. In addition to oral administration in the form of tablets, powders, solutions, etc., it can also be administered in appropriate dosage forms such as injections, inhalers, and ointments. EXAMPLES The present invention will be explained in more detail by referring to Reference Examples and Examples below. Reference example 1 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (10.65 g) was suspended in carbon tetrachloride (300 ml), N-bromosuccinimide (8.90 g) was added, and an infrared lamp was added. (Toshiba,
After heating under reflux for 2 hours under irradiation (100 V, 375 WR), the mixture was cooled to room temperature and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), washed with water three times, dried and concentrated, the precipitated crystals were collected by filtration, and 6-(1-bromo-1-methyl)ethyl-4 -oxo-4H-1-benzopyran-3
- Colorless prism crystals (7.0 g) of carbonitrile were obtained. Melting point: 115°-117°C Reference example 2 6-(1-bromo-1-methyl)ethyl-4-
Oxo-4H-1-benzopyran-3-carbonitrile (9.6g) was added to 1N sodium hydroxide (250ml).
Dissolved in, stirred at room temperature for 2 hours, then cooled.
Acidified with concentrated hydrochloric acid. Ethyl acetate (200ml x 3)
After extracting with
The mixture was subjected to column chromatography and eluted with chloroform-acetone-formic acid (90:10:1). After distilling off the solvent, ethanol was added to the residue, and after standing overnight, the precipitate was collected by filtration, and 6-(1-hydroxy-1-methyl)ethyl-4-oxo-4H
Crystals (4.36 g) of -1-benzopyran-3-carbonitrile were obtained. When this product was recrystallized from ethanol, it became colorless plate-like crystals. Melting point: 166°-167°C Reference example 3 6-(1-bromo-1-methyl)ethyl-4-
A mixture of oxo-4H-1-benzopyran-3-carbonitrile (2.0 g), acetic acid (20 ml) and water (5 ml) was heated at 100°C for 1 hour and then concentrated. The residue was applied to a column of silica gel (100 g) and eluted with chloroform-acetone-formic acid (20:1:0.1).
The first eluate was recrystallized from ethanol to give colorless crystals of 6-isopropenyl-4-oxo-4H-1-benzopyran-3-carbonitrile (600 mg).
I got it. Melting point: 142°-144°C Reference example 4 6-(1-bromo-1-methyl)ethyl-4-
A mixture of oxo-4H-1-benzopyran-3-carbonitrile (2.0 g), sodium acetate (575 mg), and dimethylformamide (20 ml) was heated at 60°C for 1 hour, then concentrated, and the residue was dissolved in chloroform. After washing with water and drying (sodium sulfate), chloroform was distilled off, and the residue was applied to a column of silica gel (100 g) and eluted with chloroform-acetone-formic acid (20:1:0.1). The first eluate was recrystallized from ethanol and 6-isopropenyl-4-oxo-4H-1-benzopyran-3
-Colorless crystals (1.07 g) of carbonitrile were obtained.
Melting point: 142°-144°C Reference example 5 6-isopropenyl-4-oxo-4H-1-
A mixture of benzopyran-3-carbonitrile (800 mg), ethanol (40 ml), piperidine (0.6 ml), and cyanoacetic acid ethyl ester (0.7 ml) was heated under reflux for 3 hours and then left at room temperature overnight. The precipitated crystals were collected by filtration and recrystallized from ethanol to give colorless crystals of ethyl 2-amino-7-isopropenyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate. (1.09g)
was gotten. Melting point: 227°-230°C (decomposition) Reference example 6 Ethyl 7-isopropenyl-5-oxo-
A mixture of 5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (400 mg), m-chloroperbenzoic acid (340 mg), and chloroform (20 ml) was heated under reflux for 1 hour, then water and 10 % aqueous sodium hydrosulfite solution and then water, and the chloroform layer was dried (sodium sulfate). Chloroform was distilled off, and the residue was mixed with silica gel (50 g) and chloroform-acetone-formic acid (20:
1:0.1). The eluate was first recrystallized from chloroform, resulting in ethyl 2-amino-7-
(1,2-epoxy-1-methyl)ethyl-5-
Oxo-5H-[1]benzopyrano[2,3-b]
Colorless crystals (230 mg) of pyridine-3-carboxylate were obtained. This product does not have a clear melting point. NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7Hz),
1.79 (3H, s), 2.83 (1H, d, J=5Hz), 3.03
(1H, d, J = 5Hz), 4.40 (2H, q, J = 7
Hz), 5.95 (1H, br), 7.45 (1H, d, J=9Hz),
7.70 (1H, dd, J=2and9Hz), 8.27 (1H, d, J
= 2Hz), 8.35 (1H, br), 9.14 (1H, s). Reference example 7 Ethyl 2-amino-7-(1,2-epoxy-1-methyl)ethyl-5-oxo-5H-[1]
A mixture of benzopyrano[2,3-b]pyridine-3-carboxylate (800 mg), 5% palladium on carbon (700 mg), ethanol (50 ml), and tetrahydrofuran (150 ml) was subjected to catalytic reduction at room temperature and normal pressure for 2 hours. After the reaction was completed, the catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was purified with silica gel (80 g) and chloroform-acetone-formic acid (9:1:0.1). After evaporating the solvent, the residue was recrystallized from chloroform to give ethyl 2-amino-7-(2-hydroxy-1-methyl)ethyl-5-oxo-5H.
-[1]benzopyrano[2,3-b]pyridine-
Colorless prismatic crystals of 3-carboxylate (499mg)
I got it. Melting point: 255°-256°C Example 1 Ethyl 2-amino-7-(2-hydroxy-
1-Methyl)ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylate (480 mg), ethanol (40 ml), water (5 ml), 1N sodium hydroxide (5 ml) The mixture was heated at 50° C. for 80 minutes, concentrated, and the residue was dissolved in water and acidified with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water, and recrystallized from dimethylformamide-ethanol-water to give 2-amino-7-(2-hydroxy-1-methyl)ethyl-5-oxo-5H-[1]
Colorless crystals of benzopyrano[2,3-b]pyridine-3-carboxylic acid (386 mg) were obtained. Melting point: >300°C Effects of the invention The compounds of the present invention () or their salts have anti-allergic effects, and in particular, salts with specific organic amines as mentioned above exhibit particularly excellent anti-allergic effects. In particular, it is useful as a prophylactic or therapeutic agent for allergic diseases such as allergic asthma, allergic dermatitis, and hay fever. Furthermore, these alkali metal salts and organic amine salts have good solubility in water, and their aqueous solutions are stable and convenient for formulation into injections, water solutions, and the like.

Claims (1)

[Scope of Claims] 1 General formula [Formula] 2-amino-5-oxo-5H-[1]benzopyrano[ ^2,3- b] Pyridine-3-carboxylic acid derivative or its salt, 2 Hydrolysis of a compound represented by the general formula [Formula] [wherein R and R ¹ represent hydrogen or lower alkyl, and R ² represents lower alkyl] A general formula characterized by being subjected to a reaction. [Formula] [In the formula, R and R ¹ have the same meanings as above]
2-Amino-5-oxo-5H-
[1] Benzopyrano[2,3-b]pyridine-3
- A method for producing a carboxylic acid derivative or a salt thereof.