JPH01287066A - Novel anthranilic acid derivative - Google Patents

Abstract

NEW MATERIAL:An anthranilic acid derivative expressed by formula I (R is OH or lower alkoxy; X is halogen; m is 1, 2 or 3; n is 0, 1 or 2; ring A is bicyclic aromatic ring in which at least one is benzene ring) and pharmacologically acceptable salt thereof. EXAMPLE:N-(6-Methoxyquinolin-2-carbonyl)anthranilic acid. USE:An antiallergic agent, stable to light and having excellent cell permeating action and antiallergic activity with mostly 5-lipoxygenase inhibitory activity and further action of inhibiting biosynthesis of allergic critical factors. PREPARATION:A reactive derivative of a carboxylic acid expressed by formula II is reacted with an anthranilic acid derivative expressed by formula III to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION 1) Industrial Field of Application The present invention relates to a novel anthranilic acid derivative useful as a medicine, particularly as an antiallergic agent, and a pharmacologically acceptable salt thereof.

2) Prior Art Conventionally, histamine receptor antagonistic drugs have been used as anti-allergic drugs, but currently drugs that inhibit histamine release are the mainstream. A representative drug is sodium cromoglycate (DSCG), which is a therapeutic agent for allergic diseases that suppresses the release of chemical mediators caused by antigen-antibody reactions [J, Msd, Che.
m,, 15,583 (1972); Adv, Dru
g Res, 5, 115 (1970), but
This compound had no effect when administered orally, and its use was limited.

On the other hand, in order to solve these drawbacks, N-(3,4-dimethoxycinnamoyl)anthranilic acid (tranilast), which has an antiallergic effect when administered orally, has recently been developed and put into clinical use [Br, J. Pharmacol. ,
58, 483 (1976)].

However, this compound is unstable to light;
There were stability problems such as isomerization of the cinnamoyl moiety.

In addition, leukotriene C4, which is a factor in the development of allergies,
Leukotrienes such as (LTC,) and leukotriene D4 (LTD,) are derived from arachidonic acid in vivo.
Since it is biosynthesized by the action of lipoxygenase, it has been pointed out that inhibition of this enzyme suppresses the biosynthesis of the above-mentioned allergy-causing factor. However, conventional antiallergic agents have no 5-lipoxygenase inhibitory activity ().

3) Problems to be solved by the invention As described above, conventional antiallergic agents are unsatisfactory because they cannot be administered orally or have problems with stability, and they also lack essential antiallergic effects. ing.

Therefore, the present invention solves these problems.

4) Means for solving the problems The above problems can be solved by the present invention when the general formula (I) (wherein R
means a hydroxy group or a lower alkoxy group, X means a halogen atom, m and n each mean 1 to 3° and 0 to 2, ring A is a bicyclic aromatic ring in which at least one is a benzene ring. means. ) and its pharmacologically acceptable salts.

Here, the A ring includes naphthalene, quinoline, indole, benzofuran, benzothiophene, benzothiazole and the like. Examples of the lower alkoxy group for R include methoxy, ethoxy, impropoxy, n-propoxy, and butoxy groups. Also, X is fluorine,
A halogen atom such as chlorine or bromine, especially a fluorine atom, is preferred. Pharmacologically acceptable salts include inorganic alkali metal salts of carboxylic acids, such as sodium, potassium,
Specific examples include calcium and ammonium salts.

5) Effect: We have long known that the hydrophilic anthranilic acid moiety of tranilast is the active site, and the fat-soluble cinnamoyl moiety is the drug's cell-permeating site. We have synthesized and researched many anthranilic acid derivatives that retain this partial structure and do not cause isomerization.6 In the anthranilic acid derivative of the present invention, one ring is fixed with a benzene ring. Since it is a cyclic aromatic ring, it has an excellent cell permeation effect. Unlike tranilast, it is stable against light and has excellent anti-allergic activity. In addition, many of the compounds of the present invention also have 5-lipoxygenase inhibitory activity, and have the effect of suppressing the biosynthesis of the above-mentioned allergy-inducing factors.

The compound represented by the above general formula D) can be produced by various methods, and one preferred example thereof is, for example, by the following known method.

A reactive derivative of carboxylic acid represented by general formula (II) (wherein A, R and m are the same as above) and an anthranilic acid derivative represented by the following formula, (wherein X and n is the same as above), and the product is isolated by a conventional method.

Specific examples of reactive derivatives of the compound represented by formula (II) include acid chlorides, acid anhydrides, mixed acid anhydrides, and the like. Acid chlorides are prepared by combining a compound of formula (n) with an acid halogenating agent, such as thionyl chloride, in an inert solvent for 30 minutes to 2 hours.
Obtained by heating for hours. Acid anhydride is the formula (■)
It can be obtained by reacting the compound with acetic anhydride or p-toluenesulfonic acid chloride.

In this reaction, compound (II) and the above anthranilic acid derivative are deoxidized in an inert solvent such as chloroform, methylene chloride, acetone, pyridine, benzene, toluene, tetrahydrofuran, or dioxane at 0 to 100°C, preferably at room temperature. In the presence of a drug, for 30 minutes to 12 hours, usually 1 to
This can be carried out by mixing and stirring for 5 hours. Incidentally, a base such as triethylamine or pyridine is generally used as a deoxidizing agent.

The target compound (I) and its salts thus obtained have extremely low toxicity and are useful as therapeutic agents for allergic diseases.

6) Examples Next, the compounds of the present invention will be explained in more detail with reference to Examples.

Example 1゜6-Medoxyquinoline-2-carboxylic acid 1.0g (4
, 93 mmol) and refluxed, excess thionyl chloride was distilled off under reduced pressure to quantitatively obtain acid chloride. Separately, 1.01 g of anthranilic acid (7,3
7 mmol) and triethylamine 0.84 g (8,3
2 mmol) was dissolved in purified chloroform.

To this was added dropwise the above solution of the acid chloride in chloroform (10 Ill) at room temperature. After stirring at room temperature for 3 hours, IN-hydrochloric acid was added and the precipitated crystals were collected by filtration, washed with water, dried, and diluted with ethanol.
Obtained by recrystallization from a mixed solvent of water (yield: 0.48 g)
.

Melting point: 242-3℃ Mass spectrometry: 322 (M”), 278,158 Elemental analysis: C□, H□4N204・1/2H,0 Theoretical value H4
, 56%, C65, 25%, N 8.45% Actual value H4, 21%, C65, 09%, N 8.37%
Example 2゜N-(6,7-simethoxyquinoline-2-carbonyl)
Anthranilic acid.

Example 1. Similarly, 6,7-simethoxyquinoline-2
- Acid chloride quantitatively obtained from 0.13 g (0.56 mmol) of carboxylic acid and thionyl chloride 3111 is added with 0.11 g (0°80% 1 mol) of anthranilic acid and 0.09 g (0.89 m+*ol) of triethylamine. It is synthesized by reacting and recrystallized from a mixed solvent of ethanol and water (yield: 0.17 g).

Melting point: 255-7℃ Mass spectrometry: 352 (M”), 308,188 Elemental analysis: C1, H Engineering GNNOS 1/2H, ○Theoretical value H4
, 73%, C63, 15%, N 7.75% Actual value H4, 24%, C62, 95%, N 8.24%
Example 3゜Example 1. Similarly, 6,7-simethoxyquinoline-3
-Synthesized by reacting an acid chloride quantitatively obtained from 1.89 g (8.11 mmol) of carboxylic acid and thionyl chloride with 1.66 g (12.1 mmol) of anthranilic acid and 1.7 ml (12.29 mmol) of triethylamine. and recrystallized from a mixed solvent of DMF and water (yield: 1
．． 374g).

Melting point: 275-5.5°C (decomposition) Mass spectrometry: 352 (M”), 216 elemental analysis: C,
,H,,N,O,(MW=352.346) Theoretical value H
4,58%, C64,77%, N 7.95% Actual value H4,56bu, C64,65%, N 8.07
% Example 4°N-(2-naphthoyl)anthranilic acid.

Example 1. Similarly, 2.736 g of 2-naphthoic acid (
15,9+u.

1) and the acid chloride quantitatively obtained from thionyl chloride, 4.378 g (31,956 + 1 mol) of anthranilic acid was added.
and triethylamine 1.94g (19.2m+wol
) and recrystallized from a mixed solvent of ethanol and water (yield: 3.067 g).

Melting point: 216-7℃ (decomposed) Mass spectrometry: 291 (M"), 273,155 Elemental analysis: C□.H, No, (MW = 29'1.306) Theoretical value H4, 50%, C74,22 %, N 4.81
% actual value H4, 37%, C74, 35%, N 4
．． 81% Example 5゜Example 1. Similarly, 5,6.7-drimethoxy 2-
Naphthoic acid 2. Anthranilic acid 2.1 was added to the acid chloride quantitatively obtained from Ig (8, Ommol) and thionyl chloride.
9g (16, Ommol) and triethylamine 1.3
ml (9.4 mmol) and recrystallized from a mixed solvent of ethanol and water (yield: 1.28 mmol).
g).

Melting point: 183-4℃ Mass spectrometry: 381 (M'), 363,245 Elemental analysis: C, 1H1sNOs (MW=381.384) Theoretical value H5.02%, C66.14%, N 3.6
7% actual measurement H5,00%, C66,11%, N
3.57% Example 6゜N-(6-medoxy-2-naphthoyl)anthranil a
6 Example 1. Similarly, 2.0 g of anthranilic acid (
14.6 mmol) and triethylamine 1.05 ml
(7,6++v+.1) is synthesized by reacting and recrystallized from a mixed solvent of ethanol and water (yield: 1.31g).
).

Melting point: 132-3℃ Mass spectrometry: 321 (M+), 303,185 Elemental analysis: C1, H□, No4 (MW = 321.332) Theoretical value H4,71%, C71,02 stone, N 4.36
% actual value H4, 62%, C71,03%, N 4
．． 35% Example 7゜Example 1. Similarly, 1.37 g of anthranilic acid was added to the acid chloride quantitatively obtained from 2.32 g (10.0 mmol) of 6,7-simethoxy-2-naphthoic acid and thionyl chloride.
g (10,0 dragon o1) and triethylamine 3. kl
(21.7 mmol), purified by silica gel column chromatography (chloroform), and recrystallized from ethanol (yield: 1.055 g).

Melting point: 245-6℃ Mass spectrometry: 351 (M”), 333,215 Elemental analysis 202゜H, NO5 (MW = 351.358) Theoretical value H4, 88%, C68, 37%, N 3.99
% Actual value H4, 89%, C68, 45%, N 3
．． 85% Example 8゜Example 1. Similarly, anthranyl li 20.9
45g (6.9mmol) and triethylamine 0.4
Synthesize by reacting 35ml (4.3mmol).

Obtained by recrystallizing twice from a mixed solvent of ethanol and water (yield: 0.135 g).

Melting point = 186-8°C Mass spectrometry: 351 (M'), 333,215 Elemental analysis: CzaHxtNOs (MW = 351.358) Theoretical value H4, 88%, 068.37%, N 3.9
9% actual value H4, 89%, C68, 34%, N
3.93% Example 9゜Example 1. Similarly, 0.9 g of anthranilic acid was added to the acid chloride quantitatively obtained from 0.41 g (2.0 mmol) of 6,7-cyhydroxy-2-naphthoic acid and thionyl chloride.
(6,57m+mol) and triethylamine 0.9m
It is synthesized by reacting 1 (6,5 nuool) and recrystallized twice from a mixed solvent of ethanol and water (yield: 0.
15g).

Melting point: 263-4℃ Mass spectrometry: 323 (M+), 305,187 Elemental analysis: C1゜H, No, (Mw=a23.304) Theoretical value H4.05%, C66.87%, N 4.33%
Actual value H4, (11 stones, C66, 39 stones, N 4
．． 26 stones Example 10゜1) 4,6-difluoroanthranilic acid.

3.5-difluoroaniline 10g (7BIIImo
l), chloral hydrate 13.96g (84.4mmo
l), anhydrous sodium sulfate 8.82g (62mmol)
, 6.6a+1 (73 mmol) of concentrated hydrochloric acid and 17.06 g (245 mmol) of hydroxylamine hydrochloride were dissolved in 640 ml of water and allowed to flow at a rate of 40 min. After cooling, the precipitated crystals were collected by filtration and dried to give 7.03 g of 3.5-difluoro-
(α-isonitroso)acetanilide is obtained. 32 ml of concentrated sulfuric acid was added to this anilide 7, Og (35 n+mol), heated at 90°C for 30 minutes, poured into ice water, extracted with ethyl acetate, and the organic phase was dried with Glauber's salt and concentrated to 6.0 g.
4,6-difluoroisatin is obtained. This was dissolved without isolation in 49.1+++1 IN-sodium hydroxide.

35% hydrogen peroxide solution 4.4 resistant was added dropwise at room temperature and heated to 1 at 60°C.
After stirring for an hour, the mixture was acidified with dilute sulfuric acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 5.19 g of 4,6-difluoroanthranilic acid.

Example 1. Similarly, 0.55 g of 4,6-difluoroanthranilic acid obtained in 1) was added to the acid chloride quantitatively obtained from 0.373 g (1,61 mmol) of 6,7-simethoxy-2-naphthoic acid and thionyl chloride. (3,18 mmo
l) and triethylamine 0.27 ml (1,95 mmo
It is synthesized by reacting 1) and recrystallized from ethanol (yield: 0.23 g).

Melting point = 256-7℃ Mass spectrometry: 387 (M+), 215 elemental analysis 2C2
゜Hl, F, No, ・1/2H,0 theoretical value H4,07
%, C60, 61%, N 3.53% actual value H4
, 02%, C60, 73%, N 3,55% Example 11゜1) 3.5-difluoroanthranilic acid.

2.4-difluoroaniline Log (77,5◜o1
), 35% hydrochloric acid 9.7 resistant was dissolved in 100 nl of water, cooled to 0°C, and 4.19 ml of bromine (81 nmol
) was added dropwise with vigorous stirring.

After stirring for 30 minutes, the precipitated crystals were collected by filtration, dissolved in ether, treated with activated carbon, dried over sodium sulfate, and concentrated. Purified by silica gel column chromatography (hexane), 8.1 g of 2-
Bromo-4,6-difluoroaniline is obtained. This aniline 5-0g (24m+mol) and cupric cyanide 2
．． Add 5 g (28 mmol) to 36 ml of DMF and add 6
After flowing for an hour, 4.7 g of sodium cyanide (96
An aqueous solution of lSm1 (m+5 ol) was added at 80°C and stirred vigorously. After cooling, the mixture was extracted with ether, treated with activated carbon, dried over Glauber's salt, and concentrated to obtain 2.91 g of 2-amino-3,5-difluorobenzonitrile. This nitrile 0.74
Add 10 75% sulfuric acid to g (4゜8 mmol) and add 10
After heating at 0°C for 2.5 hours, 50ml of water was added, extracted with ether, dried with Glauber's salt, concentrated, and 0.71g of 3,
5-difluoroanthranilic acid is obtained.

Example 1. Similarly, 0.43 g of 3,5-difluoroanthranilic acid obtained in 1) was added to the acid chloride quantitatively obtained from 0.290 g (1,25 mmol) of 6,7-simethoxy-2-naphthoic acid and thionyl chloride. (2.5 mmol
) and triethylamine 0.21ml (1゜5mmol
), purified by silica gel column chromatography (chloroform), and recrystallized from ethanol (yield: 0.17 g).

Melting point: 218.5-219°C Mass spectrometry: 387 (M”), 215 elemental analysis: C2
゜H□, F2No, ・1/2H,0 theoretical value H4,07
%, C60, 61%, N 3.53% actual value H3
, 80%, C60, 99%, N 3.49% Example 12°N-(5-methoxy-2-indoyl)anthranilic acid.

Similarly to Example 18, 7.0 g of anthranilic acid was added to the acid chloride quantitatively obtained from 5.0 g (26.32 mmol) of 5-methoxyindole-2-carboxylic acid and thionyl chloride.
15g (52,19mmol) and triethylamine 4
．． 3sl (31.12 mmol) was reacted and subjected to 3 silica gel column chromatography (1st time: ester, 2nd time: chloroform/methanol 20:1, 3rd time: hexane/ethyl acetate 2:1). Purified and recrystallized from a mixed solvent of ethanol and water (yield: 0.47g)
).

Melting point: 169-171°C Mass spectrometry: 310 (M'), 292,277.17
Three element analysis 200, H14N, 04 (MW=310.
309) Theoretical value H4, 55%, C65, 80%,
N 9.03% Actual value H4, 46%, C65, 44
%, N 8.91%Example 13゜Example 1. Similarly, 6-medoxybenzothiazole-2-carboxylic acid 1. The acid chloride quantitatively obtained from 1Og (5,26o1) and thionyl chloride was synthesized by reacting 1.10g (8,03+amol) of anthranilic acid with 0.9sl (6,5io+ol) of triethylamine. Obtained by recrystallization from (yield 0.63g)
.

Melting point = 249-251°C Elemental analysis: C,, Hl, N, 0.5 ・1/2H, 0
Theoretical value H3, 88%, C56, 97%, N 8.
30% actual value 83.80%, C57.01%, N
8.32% Example 14゜Example 1. Similarly, 5,6-simethoxybenzofuran=2-carboxylic acid 2. To the acid chloride quantitatively obtained from Og (9 mmol) and thionyl chloride, 1.
85 g (13,5 mmol) and 1.
It is synthesized by reacting 87 ml (13.53 mmol) and recrystallized from a mixed solvent of ethanol, DMF, and water (yield: 2.23 g).

Melting point: 276-7°C Mass spectrometry: 341 (M'), 323,205 Elemental analysis: C1, H,, No, (MW=341.319) Theoretical value H4, 43%, C63, 34%, N 4. 10
% actual value H4, 44%, C63, 19%, N 4
．． 09% Example 15゜Example 1. Similarly, 1.73 g (12.6 mmol) of anthranilic acid was added to the acid chloride quantitatively obtained from 1.8 g (7.6 mmol) of 5,6-simethoxybenzothiophene-2-carboxylic acid and thionyl chloride. and triethylamine (1.4 sl (10.1 mmol)), and recrystallized from a mixed solvent of DMF and water (yield: 2
．． 39g).

Melting point: 255-6°C Mass spectrometry: 357 (M+), 339,221 Elemental analysis: C1, H1, No, S (MW=357.384)
Theoretical value H4, 23%, C60, 49%, N 3.
92% actual value H4, 20%, C60, 37%, N
3.99%7) Effect of the invention The usefulness of the compound of the present invention as an antiallergic agent is 1n
Its effectiveness was proven by the following biological tests in vitro and in vivo.

The homologous passive cutaneous anaphylactic, laxie (PC:A) reaction was performed using the method of Tayo et al. [J, Immunol, 106.
1002 (1971)]. Specifically, an extracted protein (DNP-As) of 2,4-dinitrophenylated swine roundworms was used as an antigen for male Wistar rats, anti-DNP-As rat serum was prepared from this antigen, used as an antibody, and this was used to eliminate rats. Ironically 4 places on the back of the hair, O, 1
ul was injected. After 48 hours, 0.5 ul of antigen solution containing 0.5% Evans Blue was intravenously injected, and 30 minutes later, the rats were killed by exsanguination and the skin at the site of dye leakage was peeled off using the method of Katayama et al. [Microbiol, Immun.
, 22.89 (1978)], the amount of leaked dye was measured. The drug was administered at a dose of 50-200 mg/30 minutes before antigen administration.
kg was administered orally. Incidentally, tranilast was used as a control drug.

In addition, the 5-lipoxygenase inhibitory activity was determined by J, C, 5ir.
The method of car et al. [Bioche+m, Phar@ac,
, 32, 170 (1983)]. That is, 0.5% containing 5.25% propylene glycol.
A 1% aqueous solution of the drug in sodium bicarbonate was added to 1M)-Lis-HCl buffer (pH 9) to adjust the concentration to 0 to 200 μM, and this 1.6+al was added to the same concentration of 5-lipoxygenase. Add 0.2 ul of 100 υ Co., Ltd.) and 25°C.
The mixture was heated for 10 minutes. To this, 0.2 ul of the same sodium lylphate buffer (2 mM) was added, time scan was performed while heating at 25° C., and the absorbance at 234 nm was measured to determine ΔOD. Note that tranilast and caffeic acid were used as control drugs.

Table 1. As can be seen from Table 6 showing the results of both tests,
Most of the compounds of the present invention have a PCA reaction inhibitory effect equal to or better than that of tranilast and a 5-lipoxygenase inhibitory effect that tranilast does not have, and among them, the compounds of Examples 8 and 9 have very excellent effects. I understand something.

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R means a hydroxy group or lower alkoxy group, X means a halogen atom, m, n is each 1 to 3,
0 to 2, and ring A means a bicyclic aromatic ring in which at least one is a benzene ring. ) An anthranilic acid derivative represented by: and a pharmacologically acceptable salt thereof.