JPS61172880A - 2-amino-5-oxo-5h-(1)benzopyrano(2,3-b)pyridine-3-carboxylic acid derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R is H or lower alkyl; A is group of formula II (R<1> is H or lower alkyl) or -CO-]. EXAMPLE:2-Amino-7-( 1-hydroxy-1-methyl )-ethyl-5-oxo-5H-[ 1 ]benzopyrano[ 2,3-b]pyridine-3-carboxylic acid. USE:Anti-allergic agent. Useful as a preventive and remedy for allergic diseases such as allergic asthma, allergic dermatitis, hay fever, etc. PREPARATION:The compound of formula I can be prepared by hydrolyzing the compound of formula II (R<2> is lower alkyl). The alkali metal salt and organic amine salt of the compound of formula I have high solubility in water, and the solution has high stability. Accordingly the compound is convenient to be prepared in the form of drug such as injection, solution, etc.

Description

Detailed Description of the Invention Industrial Application Field The present invention has an 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-carboxylic acid derivative or its manufacturing method.

Conventional technology Bronchial asthma attacks occur when mast cells,
It is thought that chemical mediators such as histamine are released from the base method and others, and this is caused by contraction of bronchial smooth muscle and increased mucus secretion.

Until now, 2-amino-5-oxo-5H-[2-amino-5-oxo-5H-[
1]-Benzopyrano[2,3-b]pyridine-3-carboxylic acid derivatives include JP-A-53-11
Publication No. 1096 is mentioned.

Problems to be Solved by the Invention However, with respect to the compounds 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-mentioned objectives.

The present invention relates to a compound having the general formula (I) υ [wherein R represents hydrogen or lower alkyl, and A represents H-C- (R' represents hydrogen or lower alkyl) or -co-, respectively. 2-amino-5-oxo-5H-[1]benzopyrano-[2,3-
b] Hydrolysis of a pyridine-3-carboxylic acid derivative or a salt thereof, and a compound represented by the general formula (n) υ [wherein R and A have the same meanings as above, and R'' represents lower alkyl] This is a method for producing a compound represented by general formula (I) or a salt thereof, which is characterized by subjecting it to a reaction.

In the above formula, the substitution position of the substituent R-X- is 6,7°8.9
The lower alkyl represented by R, R' and R'', which may be in any position, is methyl, ethyl.

Carbon number of n-propyl, n-butyl, n-pentyl, n-hexyl, etc.! to 6 alkyl groups, in particular, R is an alkyl group having 1 to 5 carbon atoms, R1 is an alkyl group having 1 to 2 carbon atoms, and R2 is an alkyl group having 1 to 3 carbon atoms, respectively. Practically preferred.

The compound (I) of the general formula of the present invention has the general formula (III) [wherein R and A represent the same meanings as described above]. It can be produced by hydrolyzing a compound of the general formula (n) obtained by reacting the compound represented by the above with cyanacetic ester.

Examples of the cyanacetic acid ester that is a raw material for producing compound (II) include methyl, ethyl, propyl, butyl esters, and the like. The amount of these cyanacetic esters to be used is usually 1 to 10 in practical terms per 1 mol of compound (III).
It is about double the mole.

In the above reaction, the presence of a base is generally desirable, and the base used includes organic amines, such as primary amines such as n-butylamine, benzylamine, and aniline, diethylamine, and dipropylamine.

Secondary amines such as dibutylamine, piperidine, pyrrolidine, morpholine, 1,8-diazabicyclo[5,4
,0]-7-Undecene and tertiary amines such as triethylamine, and heterocyclic bases such as imidazole and 2-methylimidazole. The amount of these organic bases used is usually about catalytic amount to about 5 times mole per mole of compound (■).

It is generally preferable to carry out the reaction in an organic solvent, examples of which include alcohols such as methanol, ethanol, propatool, and butanol, aromatic hydrocarbons such as benzene and toluene, and trimethylformamide. It will be done. 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 hydrolyzing the compound (If) obtained as described above, a compound represented by the general formula (I) is obtained. 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 is usually carried out by heating at around 50-150° C. with alcohols such as methanol, ethanol, propatool, etc. or organic acids such as formic acid and acetic acid. The amount of these alkali hydroxides or acids used is 1 to 100 mol per 1 mol of compound (II), and the reaction time is usually 1 to 100 mol.
It takes about hours to several days.

Compound (I) is, for example, ethanolamine, d9°-
Methylephedrine, 1-(3,5-dihydroxyphenyl)-L-isopropylaminoethanol, isoproterenol, dextromethorphan.

Organic amines such as hetrazan (diethylcarbamacine), diethylamine, and triethylamine, or alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or ammonia, and compound (1) are mixed together in an appropriate solvent. An organic amine salt, alkali metal salt, or ammonium salt corresponding to compound (1) can be obtained by reacting with a method known per se, such as mixing and heating.

The compound represented by the general formula (III), which is one of the raw materials of the present invention, is known from Japanese Patent Application Publication No. 103578/1983, or is a general compound that can be produced according to the method described in the publication. Formula (IV) [wherein R and R1 represent the same meanings as above]. ] It can be produced by reacting the compound shown with N-bromosuccinimide and then reacting it with an aqueous alkali solution. Also, R-A- is R-
The compound can be produced according to the method described in Japanese Patent Publication No. 58-54150.

On the other hand, when RA- is -CHo, J.

It can be produced according to the method described in Med, Chem, 22.290 (1979). That is, general formula (V)
υ [wherein R' represents a lower acyloxy group such as acetoxy or propionyloxy] By reacting a compound represented by cyanoacetate with the general formula (
VI) It can be produced by obtaining a compound represented by the formula [wherein R3 has the same meaning as defined above] and subjecting it to a mild hydrolysis reaction using dilute hydrochloric acid or the like.

Action Compound (I) or its salts produced in this manner have anti-allergic effects, and among them, salts with specific organic amines such as those mentioned above have particularly excellent anti-allergic effects. sexual asthma,
It is useful as a prophylactic and therapeutic agent for allergic diseases such as allergic asthma and hay fever. Additionally, these alkali metal salts.

Organic amine salts have good solubility in water, and their aqueous solutions are stable, making them convenient for formulation into injections, solutions, and the like.

When compound (I) or its salts are used, for example, as a prophylactic or therapeutic agent for the aforementioned allergic diseases, the usual adult dosage is about 1 to 500 mg/day for oral administration in the form of tablets, capsules, powders, solutions, etc. In addition, it can be administered in appropriate dosage forms such as injections, atomized inhalants, and ointments.

EXAMPLES The present invention will be explained in more detail by referring to Reference Examples and Examples below.

Reference example! 6-itubrobyl-4-oxo-4H-1-benzopyran-3-carbonitrile (to, 65 g) was suspended in carbon tetrachloride (300 ml), and N-bromosuccinimide (
8.90g) and an infrared lamp (Toshiba, l OOV
After heating under reflux for 2 hours under irradiation with Te, 375WR), the mixture was cooled to room temperature, and insoluble materials were filtered off.

The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (150 ml).
The crystals were dissolved in water, washed three times with water, dried and concentrated, and the precipitated crystals were collected by filtration to give 6-(1-bromo-I-methyl)ethyl-4
Colorless prism crystals (7°0 g) of -oxo-48-1-benzopyran-3-carbonitrile were obtained.

Melting point: 115°-117°C Reference example 2 6-(l-bromo-1-methyl)ethyl-4-oxo-
4H-1-benzopyran-3-carbonitrile (9,6
g) in IN sodium hydroxide (250 ml),
After stirring at room temperature for 2 hours, the mixture was cooled and acidified with concentrated hydrochloric acid. After extraction with ethyl acetate (200 ml x 3), washing with water and drying (sodium sulfate), ethyl acetate was distilled off, and the residue was subjected to column chromatography on silica gel (200 g) to obtain chloroform/acetone/formic acid (90:10:
1) was eluted.

After distilling off the solvent, ethanol was added to the residue, and after standing overnight, the precipitate was collected by filtration to give 6-(I-hydroxy-1-methyl)ethyl-4-oxo-4[(-1-penzopyran- Crystals of 3-carbonitrile (4.36 g) were obtained. Recrystallization of the ice crystals from ethanol gave colorless plate-like crystals.

Melting point = 166°-167°C Reference example 3 6-(1-hydroxy-1-methyl)ethyl-4-oxo-4H-1-benzopyran-3-carbonitrile (4
, 7g), cyanacetic acid ethyl ester (2.5g), and ethanol (100n+1) were added with piperidine (1°9g), heated under reflux for 3 hours, cooled, and the precipitated crystals were collected by filtration. Dissolve this in chloroform and silica gel (
120 g) and eluted with chloroform/acetone/formic acid (90:10:1). After distilling off the solvent, the residue and ethanol were added, and the poorly soluble material was collected by filtration and recrystallized from chloroform to give ethyl 2-amino-7-(1-hydroxy-1-methyl)ethyl-5-
Colorless needle crystals of oxo-5H-[1]benzopyrano[2,3-b copyridine-3-carboxylade (4,86 g
) was obtained.

Melting point = 236°-264°C Reference example 4 6-acetyl-4-oxo-4H-1-benzopyran-
3-carbonitrile (32g) was dissolved in ethanol (800n
+1), ethyl cyanacetate (23°9ml),
After adding piperidine (23.7ml) and heating under reflux for 1 hour, the crystals were returned to room temperature, collected by filtration, washed with ethanol and acetone, and dried to obtain ethyl 7-acetyl-2-amino-5-oxo. Yellow crystals (46°3 g) of -5H-[1]benzopyrano[2,3-b]copyridine 3-carboxylade were obtained.

Melting point: >aOO°C Example 1 Ethyl 2-amino-7-(l-hydroxy-1-methyl)ethyl-5-oxo-5H-[+]benzopyrano[
2,3-b]copyridine 3-carboquinlade (37,
A suspension of 3g), ethanol (2,3), and 0.5N sodium hydroxide (620ml) was stirred at 50°C for 2 hours, and then the ethanol was distilled off.

The concentrate was acidified with hydrochloric acid (pH 1-4), the precipitate was collected by filtration,
After washing with water, 2-amino-7
-(l-Hydroxy-1-methyl)ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]copyridine 3-carboxylic acid (32.5 g) was obtained.

NMR (DMS Ods) δ: 1.53
(6H, s), 5.12 (IH, m), 7.50 (
IH, d, J = 9Hz), 7.92 (IH, dd, J
=2 and 9Hz), 8.20(IH, d, J=2
Hz), 8.20 (2H, m).

8.85 (IH, s), 13.38 (LH, m) 16
10, 1535.1230.1220.1160.11
20.830° Example 2 Ethyl 7-acetyl-2-amino-5-oxo-5H
-[+]benzopyrano[2,3-bcopyridine-3-carboxylade (46 g) was suspended in ethanol (3 g), water (460 ml), IN sodium hydroxide (4
62+nl) and incubated at room temperature for 1.5 hours then 50-
After stirring at 55°C for 2 hours, precipitated crystals were collected by filtration and washed with ethanol. The obtained crystals are soaked in warm water (approximately 2
9), added concentrated hydrochloric acid (20 ml), stirred for 20 minutes, filtered off the hardly soluble materials, washed with water, and dissolved in dimethylformamide.
Recrystallization from water gave colorless crystals (39.3 g) of 7-acetyl-2-amino-5-oxo-5H-[1cobenzopyrano[2,3-b]copyridine 3-carboxylic acid.

Melting point: >300°C Effects of the Invention The compound (1) of the present invention has an antiallergic effect and can be used for the prevention and treatment of asthma and the like.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R is hydrogen or lower alkyl, A is ▲ Numerical formula,
There are chemical formulas, tables, etc. 2-amino-5-oxo-5H-[1]benzopyrano[2,3-b] represented by ▼ (R^1 represents hydrogen or lower alkyl) or -CO-, respectively] ] Pyridine-3-carboxylic acid derivative or salt thereof. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is hydrogen or lower alkyl, A is ▲ Mathematical formula,
There are chemical formulas, tables, etc. ▼ (R^1 represents hydrogen or lower alkyl) or -CO-, R^2 represents lower alkyl] A general method characterized by subjecting a compound represented by the following formula to a hydrolysis reaction. 2-Amino-5-oxo-5H-[1]benzopyrano[2,3-b] represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R and A have the same meanings as above) A method for producing a pyridine-3-carboxylic acid derivative or a salt thereof.