DE2526092C2 - Aminobenzoic acid derivatives, processes for their preparation and pharmaceuticals containing these compounds - Google Patents

Description

in which R ₁ and R ₂ each represent a hydrogen or halogen atom or an alkyl radical having 1 to 6 carbon atoms and their alkali metal salts.

2. N-11'-carboxyphenyO- ^ chloranthranilic acid.

3. N-Ü'-Carboxy ^ '- methylphenyl ^ chloranthra-

nilic acid.

4. N- (2'-carboxy-6'-methylphenyl) -4-chloranthra-

nilic acid.

5. N-ß'-Carboxy-S'-chlorophenyl ^ chloranthranil-

acid.

6. N- (2'-carboxy-3 ', 6 ^r -dimethylphenyI) -4-chloro-

thranilic acid.

7. Process for the preparation of the aminobenzoic acid derivatives according to Claim 1, characterized in that that a 2-halobenzoic acid of the general formula (II)

30th

(H)

35

in which X represents a halogen atom, with an aminobenzoic acid of the general formula (III)

40

(III)

COOH

in which R ₁ and R _{2 have} the meaning given above, are reacted in a manner known per se and, if appropriate, the compound obtained is converted into its alkali salt using a base. 8. Medicaments consisting of a compound according to claim 1 and customary carriers and / or auxiliaries and / or diluents.

55

The invention relates to aminobenzoic acid derivatives, a process for their preparation and these Medicinal preparations containing compound according to the preceding claims.

Specific examples of aminobenzoic acid derivatives of the invention are:

N- (2'-Carboxy-4'-chlorophenyl) -4-chloranthranilic acid, N- (2'-Carboxyphenyl) -4-chloranthranilic acid N- (2'-Carboxy-4'-methylphenyl) -4-chloranthranilic acid N - ^ '- Carboxy ^' - ethylphenylM-chloranthranilic acid N- (2'-Carboxy-4'-propylphenyl) -4-chloranthranilic acid, N- (2'-Carboxy-4'-butylphenyl) -4-chloranthranilic acid

N- (2'-Carboxy-6'-methylphenyl) -4-chloroanthranilic acid

N- (2'-carboxy-5'-methylphenyl) -4-chloranthranilic acid

N-i ^ '- Carboxy-S'-methylphenylj ^ chloranthranilic acid

N-i ^ '- Carboxy-S' ^ '- dimethylphenyl ^ chloranthranil-

N-2'-carboxy-5'-chlorophenyl-4-chloranthranilic acid.

Specific examples of 2-halobenzoic acids (II) used according to the invention are 2-chlorobenzoic acid, 2,4-dichlorobenzoic acid and 2,4-dibromobenzoic acid.

Examples of aminobenzoic acids (III) used as starting compounds according to the invention are anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic acid, 4-chloroanthranilic acid, 5-chloroanthranilic acid, 4-chloro-3-methylanthranilic acid, 3-methylanthranilic acid, 5-methylanthranilic acid and 3,6-dimethylanthranilic acid.

Solvents which can be used according to the invention are used Isoamyl alcohol, dimethyl sulfoxide, dimethylformamide, ethanol, butanol, η-amyl alcohol, diethylene glycol dimethyl ether, Nitrobenzene and water in question.

To ensure a smooth implementation process and to increase the yield, may be one molar equivalent or more based on the total molar amount of the compounds (II) and (III), a basic reacting compound such as potassium carbonate, sodium carbonate or copper carbonate, and a small amount of a metal or metal containing compound such as Copper powder, copper (I) chloride, copper (I) bromide and Copper acetate, can be used as a catalyst. With the additional use of a catalytic amount of iodine or an iodine-containing compound, such as sodium iodide or copper (I) iodide, the yield can still be significant increase.

The aminobenzoic acid derivatives (I) can be converted into the corresponding alkali metal salts, such as in a manner known per se the sodium and potassium salts.

The compounds according to the invention and their salts are valuable medicaments since they contain the triglycerides in the Break down liver and promote bile secretion and thus improve liver function. Besides, they are valuable immunopotentiators due to their adjuvant effect on the body's own immune system, which improve antibody production and cell immunity. The compounds according to the invention can to customary dosage forms are packaged and administered orally or parenterally.

On application technology progress:

Attempt 1

Breakdown of triglycerides in the liver

(cf. N.R. Di Luziou. Mitarb., Lab. Invest., Vol. 16 (1967),

P. 616).

Groups of four female rats of the Sprague-Da.wley strain with a body weight of 170 to 200 g, which has not been given food for 15 hours orally a dose of 100 mg / kg of one of the claimed compounds and 30 minutes thereafter ethanol in one Dose of 6 g / kg administered. Liver is removed from each rat 24 hours after the administration of ethanol and measured in the usual way the neutral lipid level in the liver to inhibit the increase found on triglyceride in the liver. In the same way as the experimental groups, a control group is given the same amount of ethanol and a another control group an aqueous glucose solution, the caloric value of which is that of an equal amount of ethanol corresponds to administered. The positive control group receives the im

Commercially available 2-mercaptopropionylglycine administered. The results are summarized in Table I:

Table I. Table II

Test connection

GNP remainder (%)

Test connection

claimed connections

Inhibition of the increase (%) *)

N- (2'-carboxyphenyl) -4-chloranthranilic acid 67.1

Sodium salt of N- (2'-carboxyphenyl) -4-chloranthranilic acid 63.6

N- (2'-carboxy-4'-methylphenyl) -4-chloranthranilic acid 53.2

N- (2'-carboxyphenyl) -5-methylanthranilic acid 20.1

N- (2'-carboxy-6'-methylphenyl) -4-chloranthranilic acid 25.2 ■

N - ^ '- Carboxy-S'-chlorophenyO- ^ chloranthranilic acid 57.2

N- (2'-carboxy-3 ', 6'-dimethylphenyl) -4-chloranthranilic acid 45.8

N- (2'-carboxyphenyl) -4-chloro-3-methylanthranilic acid 40.5

Compounds not claimed: N- (4'-carboxyphenyl) -4-chloranthranilic acid 19.2

N- (3'-carboxyphenyl) -4-chloranthranilic acid 19.6

N- (2'-carboxyphenyl) -5-chloranthranilic acid 30.0

Comparison: 2-mercaptopropionylglycine 9.3

*) The inhibition of the increase (%) is calculated with the following equation:

Inhibition of increase (%) =

control

(physiological saline solution)

N- (2'-carboxyphenyl) -4-chloro-

anthranilic acid

51.9 + 6.7

10 ** 17.3 ± 8.4 **)
(P <0.01)
') Significant: t-test based on the mean

15th

20th

25th

30th

35

b) Indocyanine Green (ICG) test

Groups of four female Sprague-Dawley rats with a body weight of 180 to 210 g, those who have not been given feed for 15 hours are given an oral dose of 100 mg / kg of one of the test compounds administered. 60 minutes after the administration each rat was injected with ICG 2 mg / head through the tail vein. 15 minutes after the injection, each rat will Blood drawn from the heart and the ICG concentration in the blood is determined colorimetrically in a conventional manner. A control group is held in place administered a physiological saline solution to the test compound. The results are summarized in Table III :

Table III

Test connection

Amount of triglyceride
in the liver
that group
the ethanol
was administered

¹ amount of triglyceride in the liver of the group containing ethanol and a test compound

; was administered

-xiOO

Amount of triglyceride
in the liver
that group
the ethanol
was administered j

Triglyceride amount 1 in the liver of the group the glucose was administered ι

45

50

Attempt 2

Effect on bile secretion (cf. Carrol M. Leevy et al., Ann. N. Y. Academy of Siences, Vol. Ill (1963), p. 161)

a) Bromosulfophthalein (BSP) test

Groups of four female Sprague-Dawley rats with a body weight of 150 to 190 g, not fed for 15 hours, a dose of 100 mg / kg of one of the test compounds is given orally administered. Sixty minutes thereafter, 28 mg per head of BSP are injected into each rat through the tail vein. 30 minutes after the injection, blood is drawn from the heart of each rat and the BSP concentration is determined is determined colorimetrically in a conventional manner. A control group is used in place of the test compound orally administered a physiological saline solution. The results are summarized in Table II:

ICG remainder (%)

7.8 + 1.5

5.1 ± 0.2 **)
(P <0.02)

control

(physiological saline solution)

N- (2'-carboxyphenyl) -4-chloro-

anthranilic acid

**) as defined in Table II.

c) Effect on bilirubin excretion

Groups of six female Sprague-Dawley rats with a body weight of 160 to 200 g, not fed for 15 hours, a dose of 100 mg / kg of one of the test compounds is given orally administered. Sixty minutes after the administration, each rat receives 150 g per head of bilirubin through the tail vein injected. Blood is drawn from the heart of each rat 20 minutes after the injection, and the bilirubin concentration is determined in the blood is determined in a conventional manner. A control group is used in place of the test compound administered a physiological saline solution. The results are summarized in Table IV!

Table IV

Test connection

Bilirubin residue (%)

85.4 ± 9.8

39.7 ± 13.3 **)
(P <0.01)

control

(physiological saline solution)

N- (2'-carboxyphenyl) -4-chloro-

anthranilic acid

**) as defined in Table II.

Attempt 3

Effect as an immunopotentiator

(see A. J. Cunningham and A. Szenberg, Immunology.

Vol. 14 (1968), p. 599)

Six groups of five or six male Sprague-Dawley rats each weighing

200 to 220 g is given on the day before sensitization with an antigen (sheep erythrocytes, hereinafter referred to as ES), on the day of the sensitization itself and on the four following days orally one dose of each 100 mg / kg of N- (2'-carboxyphenyl) -4-chloranthranilic acid administered all at once. The ES are given intravenously to the rats Control groups are injected as a 2 percent suspension in an amount of 1 ml through the tail vein administer an equal amount of physiological saline solution in the same way on the day of sensitization. Five days after sensitization, the rats are sacrificed, the spleen is removed and a blood sample is taken taken. The number of cells that form plaques and the number of antibodies in the blood are determined using the "plaque technique" determined by Jerne and a hemolysis method. The results are in Tables V and VI summarized:

Table V

Increase in the number of plaque-binding cells

Administration day related
on raising awareness

Number of plaque forming cells / 10 ⁶ cells

+ 1
+ 2
+ 3
+ 4
control

Table VI
Antibody titre in the blood

93.2 ± 28.6

193.4 + 26.6 **) (P <0.01) 316.8 ± 38.2 **) (P <0.01)

76.5 ± 16.3 101.0 + 11.2

95.5 ± 35.3

49.7 ± 16.0

25th

30th

Administration day related. Hemolysis at final dilution on sensitization

+ 1
+ 2
+ 3
+ 4
control

*) significant
* ♦) strongly significant

₂ 9.5

2 ^{10 8} *) (P <0.05) 2'3 **) (P <0.01)

40

45

From Table V it can be seen that when the test compound was administered on the day of sensitization itself as well as one day after the number of plaque-forming cells increases sharply. The increase reaches about six times the value of the control group.

Table VIII

From Table VI it can be seen that when the test compound was administered on the day of sensitization with SE even as well as the day after the antibody titer of the blood rises sharply.

Attempt 4

Breakdown of triglycerides in the liver

Experiment 1 is repeated using the compounds given in Table VII. The last two Compounds in the table correspond to compounds XXVII and XXVIII of the publication YAKAGAKU ZASSHI (Japan), 89, 1392-1400 (1969). The test results are also summarized in Table VII. The inhibition of the increase is calculated in the same way as in Experiment 1.

Table VII

. ²⁰ test connection

Inhibition of increase (%)

N-2'-carboxyphenyl-4-chloranthranilic acid 65

NW-Carboxy ^ '- methylphenyM-chloranthranilic acid 57

N-2'-carboxy-5'-chlorophenyl-4-chloroanthranilic acid 56

N- (2'-chloro-3'-methyl-6'-carbo) cyphenyl) anthranilic acid (Comparison) 24 N- (3'-trifluoromethyl-6'-carboxyphenyl) anthranilic acid (comparison) 9

Trial effect in the treatment of adjuvant arthritis

Experiment 3 is carried out using the respective disodium salt of the compounds from Table VIII, with the change that N- (2'-carboxyphenyl) -4-chloranthranilic acid administered at a dose of 25 mg / kg once a day for a week. The administration starts on the 7th day after sensitization. The swelling of the hind paws of each rat will be on Measured 17th, 19th, 21st and 25th day after sensitization.

The test results are summarized in Table VIII, which also gives the results of the statistical tests for each value. . From Table VIII it can be seen that 19, 21 and 25 days after administration of the compounds to be tested, respectively the values for the compound of the invention are lower than for known comparative compounds ;.

ι ag after awareness

17 19

21

25th

control

N- (3'-trifluoromethyl-6'-

carboxyphenyl) anthranilic acid

(Comparison)

N- (2'-chloro-3'-methyl-6'-

carboxyphenyl! anthranilic acid

(Comparison)

N-2'-carboxyphenyl-4-

chloranthranilic acid

(according to the invention)

3.21 ± 0.10 ^<m "

3.19 ± 0.09

3.19 + 0.11

3.18 ± 0.110

3.60 ± 0.09 ^{| m} "3.92 ± 0.12 ^(m " 3.68 ^{± 0.09 (ml)}

3.43 ± 0.10

3.39 ± 0.11

3.78 ± 0.13

3.62 + 0.11

3.65 + 0.18

3.43 ± 0.18

3.01 + 0.11 ** 3.20 ± 0.09 ** 3.3O ± 0.09 **

*) T test (P <0.01) based on the average value

example 1

a) In a 500ml three-necked flask equipped with a stirrer and a reflux condenser, 250ml isoamyl alcohol, 12g 2,4-dichlorobenzoic acid, 17.5 g anthranilic acid, 18 g potassium carbonate, 500 mg copper powder and a small amount of iodine are added and five Heated and stirred under reflux for hours. The reaction mixture is then allowed to cool to room temperature, then 500 ml of water are added and the mixture is filtered. During the addition of water to remove the isoamyl alcohol, the filtrate is condensed under reduced pressure, cooled in an ice-water bath and acidified with 6N hydrochloric acid. The resulting crystals are suspended in ethanol. The suspension is refluxed for 3 to 4 hours and cooled. The resulting crystals are filtered and dissolved in tetrahydrofuran. The solution is treated with activated charcoal, then heated under reflux for 4 to 5 hours and, after removal of the activated charcoal, evaporated under reduced pressure in order to remove the tetrahydrofuran. The residue is suspended in methanol, refluxed for 3 to 4 hours and then allowed to cool to room temperature. The crystals obtained are filtered. 14 g of N- (2'-carboxyphenyl) -4-chloranthranilic acid with a melting point of 340 ^° C. are obtained.

b) 50 ml of isoamyl alcohol, Z4g of 2,4-dichlorobenzoic acid, 3.5 g of anthranilic acid, 3.6 g of anhydrous potassium carbonate and 0.4 g of copper powder are placed in a 200 ml flask and heated under reflux and stirred for 5 hours. When the reaction has ended, the reaction mixture is cooled to room temperature, water is added and the mixture is filtered off with suction. While water is added to remove the isoamyl alcohol, the filtrate is evaporated under reduced pressure and then acidified with 6N hydrochloric acid. The crystals obtained are dissolved in tetrahydrofuran, treated with activated charcoal and, after removing the activated charcoal, evaporated to remove the tetrahydrofuran. The residue is mixed with methanol, heated under reflux and then cooled to room temperature. 1.1 g of the N- (2'-carboxyphenyl) -4-chloranthraniI-acid also obtained in Example 1 are obtained as a yellow amorphous substance (mp about 340 ^° C.).

c) 110 g of N-2'-carboxyphenyl-4-chloranthranilic acid are dissolved in a solution of 30 g of sodium hydroxide in 2 liters of water. Ethanol is then added to the solution. 88 g of the sodium salt of N- (2'-carboxyphenyl) -4-chloranthranilic acid with a melting point of 345 ^° C. are obtained.

Example 2

Example 1 is repeated, but 2,4-dichlorobenzoic acid and 5-methylanthranilic acid are used. It becomes N- (2'-carboxy-4'-methylphenyl) -4-chloranthranilic acid with a melting point of 316 to 318 ° C (decomp.) in 71.5 percent strength Yield obtained.

Example 3

Example 1 is repeated, but 2,4-dichlorobenzoic acid and 3-methylanthranilic acid are used. There is obtained N- (2'-Carboxy-6'-methylphenyl) -4-chloranthranil · acid, melting at 302 to 304 ⁰ C (dec.) In 66prozentiger yield.

Example 4

Example 1 is repeated, except that 2,4-dichlorobenzoic acid and 4-chloroanthranilic acid are used. There is obtained N- (2'-carboxy-5'-chlorophenyl) -4-chloroanthranilic 340 ⁰ C in 59prozentiger yield, mp.

Example 5

Example 1 is repeated, but 2,4-dichlorobenzoic acid and 3,6-dimethylanthranilic acid are used. It is N- (2'-carboxy-3 ', 6'-dimethylphenyl) -4-chloroanthranilic acid, melting at 283 ⁰ C in 45prozentiger yield.

Claims (1)

Claims: 1. Aminobenzoic acid derivatives of the general formula (I) COOH (I) 10 COOH