JPS633864B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ₁ represents alkoxy or monoalkylamino, R ₂ represents alkyl, and m represents 0, 1 or 2] and a method for producing the same. More specifically, the compound represented by the general formula () is the compound represented by the general formula () [In the formula, R ₁ , R ₂ and m have the same meanings as above,
R ₃ represents a cyano or alkoxycarbonyl group, respectively]. The 1-azaxanthone-3-carboxylic acid derivative represented by the general formula () of the present invention has an antiallergic effect and is useful as a medicine such as an antiallergic agent. In each of the above formulas, the substituent R ₁ represents an alkoxy or monoalkylamino group, and the alkyl moiety thereof includes methyl, ethyl, n-propyl,
Examples include alkyl groups having 1 to 6 carbon atoms such as n-butyl and n-hexyl. As the alkyl group represented by the substituent R ₂ ,
Examples include straight chain, branched, and cyclic alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, hexyl, and cyclohexyl groups; 1 to 3 lower alkyl groups are practically preferred. The alkyl moiety of the alkoxycarbonyl group represented by the substituent R ₃ includes methyl, ethyl, n
Examples include alkyl groups having 1 to 6 carbon atoms such as -propyl, n-butyl, and n-hexyl. The compound represented by the general formula () of the present invention is produced by hydrolyzing the compound represented by the general formula (). As conditions for hydrolysis, ordinary acidic hydrolysis is used. For example, sulfuric acid,
Hydrochloric acid, phosphoric acid, etc. are used in excess, and the acid alone or together with an organic solvent, such as an organic acid such as formic acid or acetic acid, or an alcohol such as methanol, ethanol, or propanol, is usually heated at 50 to 150°C.
This is done by heating nearby. The reaction time varies depending on the compound, but is usually about 1 hour to several days. For example, the following compounds can also be produced by the method of the present invention. 7-Methyl-2-methylamino-1-azaxanthone-3-carboxylic acid 7-ethyl-2-methylamino-1-azaxanthone-3-carboxylic acid 7-isopropyl-2-methylamino-1-azaxanthone- 7-n-Butyl-3-carboxylic acid 7-n-butyl-2-methylamino-1-azaxanthone-3-carboxylic acid 7,9-dimethyl-2-methylamino-1-azaxanthone-3-carboxylic acid 7-methoxy-2- Methylamino-1-azaxanthone-3-carboxylic acid 9-methoxy-2-methylamino-1-azaxanthone-3-carboxylic acid 7-chloro-2-methylamino-1-azaxanthone-3-carboxylic acid 7- Nitro-2-methylamino-1-azaxanthone-3-carboxylic acid 2-methylamino-benzo[h]-1-azaxanthone-3-carboxylic acid 7-methyl-2-methoxy-1-azaxanthone-3- 7-ethyl-2-methoxy-1-azaxanthone-3-carboxylate 7-n-butyl-2-methoxy-1-azaxanthone-3-carboxylate 2,7-dimethoxy-1-azaxanthone-3
-carboxylic acid 2,9-dimethoxy-1-azaxanthone-3
-Carboxylic acid 7-chloro-2-methoxy-1-azaxanthone-3-carboxylic acid 2-methoxy-benzo[h]-1-azaxanthone-3-carboxylic acid The compound of general formula () thus produced is It has allergic effects and is useful as a prophylactic and therapeutic agent for allergic diseases such as allergic asthma, allergic dermatitis, and hay fever. When the compound of general formula () is used, for example, as a prophylactic or therapeutic agent for the aforementioned allergic diseases, the adult dosage is usually about 1 to 500 mg/day in tablets,
In addition to oral administration in the form of capsules, powders, solutions, etc., it can also be administered in appropriate dosage forms such as injections, atomized inhalants, and ointments. In addition, the general formula () which is the raw material compound of the present invention
The compound can be produced by the method described below. In other words, the general formula () manufactured by the method disclosed in Japanese Patent Publication No. 51-18955 or a method similar thereto [In the formula, R ₂ and m represent the same meanings as above]
By reacting water in the presence of a base with a compound of the general formula () [In the formula, R ₂ and m represent the same meanings as above]
A compound represented by is produced. The base used in the reaction includes organic amines such as ethylamine, n-propylamine, n-butylamine,
Primary amines such as benzylamine and aniline, dimethylamine, diethylamine, dipropylamine, dibutylamine, morpholine, piperidine,
Secondary amines such as pyrrolidine, tertiary amines such as triethylamine, heterocyclic bases such as imidazole, 2-methylimidazole, and pyridine,
Examples include inorganic bases such as aqueous ammonia, ammonium acetate, ammonium carbonate, sodium carbonate, and sodium hydrogen carbonate. These bases can be used in a catalytic amount to a large excess, and are not particularly limited. The reaction is generally preferably carried out in a solvent that is miscible with water, such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or organic acids such as formic acid, acetic acid, and propionic acid.
Examples include ethers such as tetrahydrofuran and dioxane. 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 about 100°C for several minutes to about 3 hours. To the compound of general formula () thus produced,
By reacting an active methylene compound, the general formula () [In the formula, R ₂ , R ₃ and m have the same meanings as above,
In addition, a compound represented by R ₁ 'represents a hydroxyl group or an amino group] is produced. Examples of the active methylene compound used in the reaction include diethyl malonate, dimethyl malonate, ethyl cyanacetate, methyl cyanacetate, malonitrile, and the like. The amount of these active methylene compounds to be used is generally about 1 to 10 times in mole per mole of the raw material compound of general formula (). In the above reaction, the presence of a base is generally desirable, and the bases used include organic amines, for example,
Tertiary amines such as 1,8-diazabicyclo[5,4,0]-7-undecene and triethylamine, secondary amines such as piperidine, pyrrolidine, morpholine, diethylamine, dipropylamine, dibutylamine, n-butylamine, benzyl Examples include primary amines such as amine and aniline, 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 raw material compound of general formula (). 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. The thus obtained compound in the general formula () in which R ₁ ' is an amino group is converted into a compound in which R ₁ ' is a hydroxyl group by reaction with nitrous acid. Nitrous acid used in the reaction is preferably used as an alkali salt, examples include sodium nitrite, potassium nitrite, etc.
The amount used is generally about 1 to 20 times the mole of the compound of general formula () in practice. The reaction is generally preferably carried out in a water-containing organic acid, and examples of the organic acid include formic acid, acetic acid, and propionic acid, which are usually used in large excess with respect to the compound (). Although there are no particular restrictions on the reaction temperature and reaction time, it is common to carry out the reaction at 60-100°C for one to several hours. In the thus obtained general formula (), R ₁ ' is a hydroxyl group, and diazomethane or an alkyl halide such as methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, isobutyl iodide, etc. By reacting in the presence of a base such as potassium carbonate, a raw material compound of the general formula () in which R ₁ is an alkoxy group is produced. The reaction is preferably carried out in an organic solvent, for example ether, chloroform, dichloromethane,
Examples include organic solvents such as acetone and methyl ethyl ketone. The reaction is generally carried out at a temperature from 0° C. to around the boiling point of the solvent used, and is carried out for several minutes to several hours. Further, a raw material compound in the general formula () in which R ₁ is an alkylamino group is produced by the following operation. That is, by reacting a mixture of phosphorus oxychloride and phosphorus pentachloride at 100-120°C for several hours to several days with a compound in which R ₁ ' is a hydroxyl group in the general formula (), a compound in which R ₁ ' has changed to chlorine is obtained. . By dissolving this in an organic solvent such as chloroform or dichloromethane and reacting it with a solution of a monoalkylamine such as methylamine, ethylamine, or propylamine, a raw material compound in the general formula () in which R is an alkylamino group can be produced. Ru. Examples of the solvent for monoalkylamine include methanol, ethanol, propanol, and chloroform. Although there are no particular restrictions on the reaction temperature, time, and other conditions, the reaction is generally carried out at a temperature of 0° C. to room temperature for about 3 hours. Reference example 1 2 ml of morpholine, 3 ml of dimethylformamide,
4-Oxo-4H-1-benzopyran- was prepared by heating a mixture of 10 ml of water to 60°C and powdering it while stirring.
1.71 g of 3-carbonitrile was added over 5 minutes. After heating for 1 hour, the precipitate was collected by filtration, washed with water, recrystallized from acetic acid, and washed with chloroform to give 2-amino-4-oxo-4H-
1.32 g of crystals of 1-benzopyran-3-carboxaldehyde were obtained. Melting point 252-255℃ (decomposition) Nuclear magnetic resonance spectrum (DMSO- _d6 ) δ: 10.19 (1H, S), 9.67 (Ca1.5H, br, s), 8.11
(1H, dd, J=2.8Hz), 7.97−7.30 (3H, m) Elemental analysis As C ₁₀ H ₇ NO ₃ Calculated value: C63.49; H3.73; N7.41 Actual value: C63.59; H3 .44; N7.45 The following compound was obtained in the same manner.

【table】

[Table] Reference example 2 2-amino-6-ethyl-4-oxo-4H-
1-benzopyran-3-carboxaldehyde
A mixture of 2.17 g, 4.0 ml of ethyl cyanacetate, 50 ml of ethanol, and 5.0 ml of piperidine was heated under reflux for 30 minutes, and after cooling, the precipitated crystals were collected by filtration and washed with chloroform to give ethyl 2-amino-7-ethyl-1- 2.07 g of colorless needles of azaxanthone-3-carboxylate were obtained. Melting point 279-280℃ Elemental analysis as C ₁₇ H ₁₆ N ₂ O ₄ Calculated value: C65.37; H5.16; N8.97 Actual value: C65.24; H5.08; N8.86 A compound was prepared.

【table】

[Table] Reference example 3 2-amino-6-ethyl-4-oxo-4H-
1-benzopyran-3-carboxaldehyde
3.17g, diethyl malonate 8g, pyridine 15ml, 1,
A mixture of 1 ml of 8-diazabicyclo[5,4,0]-7-undecene and 50 ml of ethanol was heated under reflux with stirring for 15 hours. Concentrate the reaction solution under reduced pressure,
Dilute hydrochloric acid was added to the residue to make it acidic. The precipitate was collected by filtration, washed with water, and then recrystallized from ethanol to obtain ethyl 7-ethyl-2-hydroxy-1-azaxanthone-3.
-1.23 g of pale yellow needles of carboxylate were obtained.
Melting point 200-204℃ Infrared absorption spectrum (KBr) cm ^-1 : 1675, 1610 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.35 (3H, t, J = 7Hz), 1.53 (3H, t, J =
7Hz), 2.87 (2H, q, J = 7Hz), 8.23 (1H,
q, J=2Hz), 9.30 (1H, s), 4.58 (2H, q,
J=7Hz), 7.4-7.8 (2H) Reference example 4 2-Amino-6,8-dimethyl-4-oxo-
4H-1-benzopyran-3-carboxaldehyde 326 mg, ethanol 7.5 ml, pyridine 2.0 ml,
Malonic acid diethyl ester 2.0ml, 1,8-diazabicyclo[5,4,0]-7-undecene 0.1ml
The mixture was heated under reflux for 4 hours. Distill the solvent,
Add 1N hydrochloric acid to the residue, filter out the hardly soluble material, dissolve it in chloroform, apply silica gel chromatography, and add chloroform-acetone-formic acid (9:1:
0.1), recrystallized from ethanol,
Ethyl 2-hydroxy-7,9-dimethyl-1
20 mg of pale yellow crystals of -azaxanthone-3-carboxylate were obtained. Melting point 251-253℃ Infrared absorption spectrum (Nujol) cm ^-1 : 1700, 1675, 1650 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 12.30 (1H, br), 9.22 (1H, s), 7.93 (1H,
s), 7.45 (1H, s), 4.55 (2H, q, J=7
Hz), 2.57 (3H, s), 2.43 (3H, s), 1.50 (3H,
t). The following compounds were produced in the same manner.

[Table] Reference example 5 2-amino-6-ethyl-4-oxo-4H-
1-benzopyran-3-carboxaldehyde
217mg, Maronitrile 300mg, Ethanol 55ml,
While stirring the mixture of 0.5 ml of piperidine, 15
The mixture was heated under reflux for a minute, and after cooling, hardly soluble materials were collected by filtration. Recrystallization from dimethylformamide gives 2-amino-
160 mg of colorless needles of 7-ethyl-1-azaxanthone-3-carbonitrile were obtained. Melting point>300
°C Infrared absorption spectrum (Nujol) cm ^-1 : 3325, 3125, 2225, 1660 Nuclear magnetic resonance spectrum (CF ₃ COOD) δ: 9.07 (1H, s), 8.16 (1H, d, J = 2Hz),
7.88 (1H, dd), 7.63 (1H, d, J=9Hz),
2.92 (2H, q, J = 7Hz), 1.39 (3H, t, J =
7Hz) Elemental analysis As C ₁₅ H ₁₁ N ₃ O ₂ Calculated value: C67.91; H4.18; N15.84 Actual value: C67.75; H4.01; N16.00 In the same manner, the following compounds are manufactured.

【table】

[Table] Reference example 6 Ethyl 2.5g of 2-amino-7-ethyl-1-azaxanthone-3-carboxylate was dissolved in 90% acetic acid.
The suspension was suspended in 250 ml, and while heating to 75°C, 4.0 g of sodium nitrite was added over 30 minutes, followed by further stirring for 2 hours. After distilling off the solvent, add 150ml of water and incubate at 80℃ for 30 minutes.
After stirring for a minute, the precipitated crystals were cooled on ice, collected by filtration, washed with water, recrystallized from ethanol, and ethyl
2.41 g of colorless needles of 7-ethyl-2-hydroxy-1-azaxanthone-3-carboxylate were obtained. Melting point: 200-204℃ Reference example 7 Ethyl 7-ethyl-2-hydroxy-1-azaxanthone-3-carboxylate (1.0 g) was dissolved in chloroform (20 ml), and while stirring at room temperature, excess diazomethane ether solution was added dropwise over 15 minutes. . After stirring at room temperature for 45 minutes, a small amount of acetic acid was added to decompose the diazomethane. After distilling off the solvent, the residue was applied to a 100 g column of silica gel and eluted with chloroform, acetone, and formic acid (20:1:0.1).
The first fraction was recrystallized from acetone to give 615 colorless needles of ethyl 7-ethyl-2-methoxy-1-azaxanthone-3-carboxylate.
I got mg. Melting point 145-146℃ Elemental analysis C ₁₈ H ₁₇ NO ₅ Calculated value: C66.05; H5.42; N4.28 Actual value: C66.12; H5.23; N4.21 Infrared absorption spectrum (Nujol) cm ^{- 1} : 1730, 1670, 1605, 1590, 1310, 1240, 1220,
815, 790 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 9.17 (1H, s), 8.13 (1H, bs), 7.55 (2H, m),
4.43 (2H, q, J = 7Hz), 4.20 (3H, s),
2.82 (2H, q, j = 7Hz), 1.43 (3H, t, J =
7 Hz), 1.32 (3H, t, J = 7 Hz) Reference example 8 Add 974 mg of ethyl 7-ethyl-2-hydroxy-1-azaxanthone-3-carboxylate to a mixture of 25 ml of phosphorus oxychloride and 3 g of phosphorus pentachloride, After heating and stirring at 120°C for 12 hours, phosphorus oxychloride was distilled off under reduced pressure. Ethanol was added little by little to the residue under ice-cooling to dissolve it, and then the solvent was distilled off.
The residue was chromatographed on silica gel, eluted with benzene, and recrystallized from isopropyl ether.
658 mg colorless crystals of ethyl 2-chloro-7-ethyl-1-azaxanthone-3-carboxylate
get. Melting point 160-161℃ Elemental analysis value C ₁₇ H ₁₄ NO ₄ As Cl Calculated value: C61.54; H4.25; N4.22 Actual value: C61.46; H3.98; N4.27 Infrared absorption spectrum (Nujol) cm ^-1 : 1720, 1658, 1585, 1265, 1210, 1130 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 9.06 (1H, s), 8.03 (1H, d, J = 2Hz),
7.63 (1H, dd, J=2 and 8Hz), 7.43 (1H,
d, J = 8Hz), 4.46 (2H, q, J = 7Hz),
2.73 (2H, q, J = 7Hz), 1.43 (3H, t, J =
7 Hz), 1.30 (3H, t, J = 7 Hz) Reference example 9 Dissolve 884 mg of ethyl 2-chloro-7-ethyl-1-azaxanthone-3-carboxylate in 20 ml of chloroform, and add 3 ml of 30% methylamine methanol solution. After stirring at room temperature for 2 hours, the solvent was distilled off. Water was added to the residue, the precipitate was collected by filtration, and recrystallized from dimethylformamide to give 730 mg of colorless crystals of ethyl 7-ethyl-2-methylamino-1-azaxanthone-3-carboxylate.
get. Melting point 205-207℃ Elemental analysis value as C ₁₈ H ₁₈ N ₂ O ₄ Calculated value: C66.24; H5.56; N8.58 Actual value: C66.22; H5.47; N8.74 Infrared absorption spectrum (Nujol ) cm ^-1 : 3250, 1660, 1610, 1582, 1280, 1240 Nuclear magnetic resonance spectrum (CF ₃ CO ₂ D) δ: 9.43 (1H, s), 8.20 (1H, d, J = 2Hz),
7.90 (1H, dd, J=2 and 8Hz), 7.60 (1H,
d, J = 8Hz), 4.60 (2H, q, J = 7Hz),
3.50 (3H, s), 2.90 (2H, q, J=7Hz),
1.53 (3H, t, J = 7Hz), 1.36 (3H, t, J =
7 Hz) Example 1 To 500 mg of ethyl 7-ethyl-2-methoxy-1-azaxanthone-3-carboxylate, add 10 ml of acetic acid and 5 ml of 55% sulfuric acid, stir at 80°C for 2 hours, add 20 ml of water, and continue for another 10 minutes. Stirred.
After cooling, the precipitate was collected by filtration, washed with water, dried, dissolved in 3 ml of dimethylformamide, and 3 g of silica gel was added.
After stirring well, dimethylformamide was distilled off. This was layered on a 50g column of silica gel,
Chloroform/acetone/formic acid (9:1:0.1)
7-ethyl-2-methoxy-1-
Colorless needle crystals of azaxanthone-3-carboxylic acid
Obtained 358 mg. Melting point 226-228℃ Elemental analysis value C ₁₆ H ₁₃ NO ₅ Calculated value: C64.21; H4.38; N4.68 Actual value: C64.10; H4.24; N4.71 Infrared absorption spectrum (Nujol) cm ^-1 : 1690, 1660, 1600, 1590, 1290, 825, 790 Nuclear magnetic resonance spectrum ( _d6 -DMSO) δ: 8.70 (1H, s), 7.80 (1H, m), 7.40-7.63
(2H, m), 4.05 (3H, s), 2.73 (2H, q, J
= 7.5Hz), 1.23 (3H, t, J = 7.5Hz) Example 2 Ethyl 7-ethyl-2-methylamino-1-
Azaxanthone-3-carboxylate 681mg
Dissolved in 3.5ml of 50% sulfuric acid-acetic acid (1:1) and heated at 100℃.
After heating for 6 hours, heat with 10% sodium hydroxide aqueous solution.
Adjust the pH to 5, collect the precipitate by filtration, and wash with water. Recrystallized from methylformamide-ethanol to give 7-ethyl-2-
488 mg of crystals of methylamino-1-azaxanthone-3-carboxylic acid were obtained. Melting point > 300℃ Elemental analysis value as C ₁₆ H ₁₄ N ₂ O ₄ Calculated value: C64.42; H4.73; N9.39 Actual value: C64.24; H4.50; N9.19 Infrared absorption spectrum (Nujol) cm ^-1 : 3270, 1690, 1605, 1570, 1300, 1127 Nuclear magnetic resonance absorption spectrum (d ₆ -DMSO) δ: 8.70 (1H, s) 7.80 (1H, d, J = 2Hz), 7.2
−7.8 (2H, m), 3.03 (3H, d, J=4Hz),
2.73 (2H, q, J = 7.5Hz), 1.25 (3H, t, J
=7.5Hz)

Claims (1)

[Claims] 1. General formula A _1- azaxanthone-3-carboxylic acid derivative represented by [wherein R 1 represents alkoxy or monoalkylamino, R ₂ represents alkyl, and m represents 0, 1 or 2]. 2 General formula [In the formula, R ₁ represents alkoxy or monoalkylamino, R ₂ represents alkyl, R ₃ represents cyano or alkoxycarbonyl, and m represents 0, 1 or 2] is subjected to a hydrolysis reaction. A general formula characterized by A method for producing a 1-azaxanthone-3-carboxylic acid derivative represented by the formula [wherein R ₁ , R ₂ and m have the same meanings as above].