JPS6019737B2 - Novel anthranilic acid derivative - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula (1) (wherein, X is a halogen atom, RI is a hydrogen atom or a lower alkyl group, and R2 is a methoxy group at any position of
The present invention relates to a novel anthranilic acid derivative represented by a penzoyl group or a cinnamoyl group substituted with

In recent years, it has been confirmed that N-(3,4-dimethoxycinnamoyl)anthranilic acid has an excellent antiallergic effect.

(J. pannacol. 58, 483-488, 1
976). This compound, unlike conventional anti-allergic agents, is an anti-allergic agent that suppresses the release of chemical mediators caused by antigen-antibody reactions. The present inventors synthesized a series of new anthranilic acid derivatives with the aim of developing even better antiallergic agents, and after conducting various studies on their pharmacological effects, found that a halogen atom was added to the 5-position of anthranilic acid, and a halogen atom was added to the 2-position of the anthranilic acid. The present invention was completed based on the discovery that the introduction of 3,4,5-trimethoxybenzoyl group etc. into the compound enhances the pharmacological activity and causes fewer side effects. 5 The antiallergic effect of the present invention will be shown below through pharmacological experiments.

Experimental method Homologous passive skin reaction in rats
a, OK; J. lmmunol,106,1002,1
Homologous passive skin reaction (H
omolog. PCM) was tested in male Wistar rats aged 170-190 days.

That is, dinitrophenol (DNP) was reacted with extracted protein of Ascarlssuum to form DNP-As (DiniVo, phenyl complex).
Carissum extract) was obtained and used as an antigen. Anti-DNP-As rat serum was prepared using this antigen and used as an antibody. This antibody with sufficient titer was injected into the hairless dorsal skin of the rat at 0.1 m/s at 3 locations on one side, and physiological saline was injected at 0.1 m/s at 3 locations on the pond side.
ite was injected intradermally to check for experimental errors. After 4 hours, 1.0 ml of antigen (2.0 O as protein content) solution containing 0.25% Evans Blue was injected intravenously.

After 30 minutes, the rats were sacrificed by exsanguination and the skin was peeled to determine the area of pigment leakage.Harada, M. et al(Harad
a,M. , Takeuchi, M., F. &
Katag elbow, K. ;J. pharm. phannaC
.

1. The amount of leaked dye was measured by the method of , 23, 218, 1971).

The drug was administered intraperitoneally at a dose of 100 females/kg 30 minutes before challenge administration. In addition, disodium chromoglycate (DSCG) and N-(3,4-dimethoxycinnamoyl)anthranilic acid (N-5') were selected as control drugs. The results of the above pharmacological experiments revealed that the compound of the present invention has an excellent antiallergic effect and is effective when administered orally. Next, the method for producing the compound of the present invention will be explained, but these are only examples, and the compound can also be produced by other chemically similar methods.

Production method A: A method in which a compound represented by general formula (b) is reacted with a reactive derivative of benzoic acid represented by general formula (m).

(In the formula, X, RI and R2 have the same meanings as above)
Production method B* A method of hydrolyzing a penzoxazine derivative represented by general formula (W).

(In the formula, X has the same meaning as above, and R3 means a phenyl group or a styryl group substituted with 1 to 3 methoxy groups at any position).

More specifically, production method A involves adding a reactive derivative of benzoic acid (e.g., an acid halide, an acid anhydride) to an anthranilic acid derivative m) represented by the general formula (0). may be reacted in an organic solvent such as tetrahydrofuran, acetone, chloroform, pyridine, benzene, or toluene.

Further, when using an acid halide, the reaction proceeds quickly by using a deoxidizing agent (for example, trimethylamine, triethylamine, pyridine, sodium carbonate, potassium carbonate, etc.). Further, among the anthranilic acid derivatives obtained by this method, the ester form can be further hydrolyzed if desired. Hydrolysis is carried out in water, acetic acid, methanol, ethanol, propyl alcohol, and mixed solvents such as water and alcohols, water and acetic acid, etc., with acids (e.g., hydrochloric acid, sulfuric acid, etc.) or alkalis (e.g., potassium hydroxide, sodium hydroxide, etc.). ) at room temperature or under heating. The reaction conditions are appropriately selected depending on the solvent used, the amount of acid or alkali, and the temperature. In production method B, a penzoxazine derivative represented by the general formula (W) is mixed with sodium hydroxide,
Hydrolysis is carried out using an alkali such as potassium hydroxide or a mineral acid such as hydrochloric acid or sulfuric acid.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 A tetrahydrofuran solution containing 2.6 parts of 3,4,5-trimethoxybenzoic acid chloride was added dropwise to a solution of 1.7 parts of 5-chloroanthranilic acid dissolved in 40 parts of pyridine under cooling.

After that, it was lit for 2 hours at room temperature and 30 minutes at 8,000 ℃.
After the reaction, the solvent was removed under reduced pressure, water was added to the residue, and the precipitated crystals were recrystallized from acetone to give colorless needle-like crystals N-(
1.4 ml of 3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 273-27500 Elemental analysis value C, 7 days, 6C〆N06 Theoretical value C: 55.82H: 4.41N: 3.83
Actual measurement value C: 55.79H: 4. Total N: 3.75 Example 3.49 of 25-chloroanthranilic acid was dissolved in a mixture of 30' of chloroform and 3' of triethylamine.

A solution of 4.5 ml of 3,4-dimethoxycinnamic acid chloride in chloroform was added dropwise to this under cooling. Thereafter, the mixture was allowed to react under reflux for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the remaining light was made weakly acidic by adding water and diluted hydrochloric acid, and the precipitated crystals were collected in a furnace and recrystallized from ethyl alcohol to give pale yellow needle-like crystals of N-(3,4- 3.1 ml of dimethoxycinnamoyl-5-chloroanthranilic acid was obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 210-213qo Elemental analysis value C, 8 days, 6C〆NQ Theoretical value C: 59.76H: 4.46N: 3.88
Actual measurement value C: 59.52H: 4. Spot N: 3.86 Example 36-chloro-2-(3,4,5-trimethoxystyryl) 14 days 3,1-benzoxazin-4-one 2.5 days 5% aqueous sodium hydroxide solution The mixture was added to a boiling solution for 50 minutes, left overnight at room temperature under a candle, and then made acidic by adding dilute hydrochloric acid to precipitate crystals.

The precipitate was collected in a furnace and recrystallized from ethyl alcohol to obtain 1.9 kg of N-(3,4,5-trimethoxycinnamoyl)-15-chloroanthranilic acid as pale yellow crystals. The melting point and elemental analysis values of this substance were as follows.

Melting point 223-22400 Elemental analysis value C, Niji, 8CkuN06 Theoretical value C: Satoshi. 24H: 4.63N: 3.57 Actual value C: 58.27H: 4.56N: 3.44 Example 4N-(3,4,5-trimethoxybenzoyl)
-5-Chloranthranilic acid methyl ester (1.9 g), 10% aqueous sodium hydroxide solution (40 g) and ethanol (20 g.) were added and stirred at room temperature for 1 hour.

The reaction solution was poured into 100% water and diluted hydrochloric acid was added under cooling to make it acidic.
Recrystallization from N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid 1.
I got 45 evenings. The melting point of this substance was as follows.

Melting point: 273-27,500 Example 5 1.3 parts of 5-chloroanthranilic acid methyl ester and 1.8 parts of 3,4,5-trimethoxybenzoyl chloride were dissolved in 30 parts of tetrahydrofuran, and 1 part of triethylamine was dissolved under cooling. I dropped 5 drops.

After the dropwise addition, the mixture was incubated at room temperature for 2 hours, and then reacted under reflux for 1 hour. After the reaction, the solvent was removed under reduced pressure, water was added to the residue, and the precipitated crystals were collected in a furnace and recrystallized from a mixed solvent of chloroform and ether to form colorless prism crystals of N-(3,4,
1.4 hours of 5-trimethoxybenzoyl)-5-chloroasotranilic acid methyl ester were obtained. The melting point and elemental analysis values of this substance were as follows.

Melting point 179-18030 Elemental analysis value C, 8 days, 8C〆NQ Theoretical value C: 59.42H: 4.99N: 3.85
Actual measurement value C: 59. Pine H: 5.17 N: 3.72 The following compounds were synthesized according to the method of Example 5.

N-(3,4,5-trimethoxybenzoyl)-5-chloroanthranilic acid ethyl ester Melting point 158~
160°C N-(3,4,5-trimethoxycinnamoyl)-5-chloroanthranilic acid methyl ester melting point 174-176°C N-(3,4-dimethoxycinnamoyl)-5-chloroanthranilic acid methyl ester melting point
Point 197-198℃

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, 1 in position
A novel anthranilic acid derivative represented by ˜3-substituted benzoyl group or cinnamoyl group.