DE1768818C3 - Anthranilic acid amides and processes for their preparation - Google Patents

Description

2. Process for the preparation of the compounds according to claim 1, characterized in that a) a substituted benzamide of the general formula

CO · O · CO · OR ₈

NH

20th

wherein R2 to R4 have the meaning given above and R7 represents a halogen group or a reactive ester group, with a substituted aminobenzene of the general formula

in which R ₅ and R ₆ are as defined above, or b) a mixed anhydride composed of an anthranilic acid substituted as indicated above and a carbonic acid monoalkyl ester of the general formula

wherein R _{8 is} alkyl with a diamine of the general formula

(NR ₁ NH ₁

the general formula

with a diamine of the general formula RR ₄ NR ₁ NH ₂ in a known manner for implementation.

The present invention relates to N-substituted anthranilic acids which are basicly substituted in the amide group and which are effective as analgesics and very suitable for pharmaceuticals because they have low toxicity. They are distinguished by the fact that they have little or no antipyretic effect and do not show any bucking effect in mice. The compounds according to the invention are not destroyed in the stomach and, in many cases, they can be _{denoted as} J; _can be administered orally with no effect. They form amine salts, for example hydrochlorides or citrates, which in many cases crystallize well and are suitable for the production of fixed dosage units, such as pills or tablets for oral administration.

The compounds according to the invention have the general formula!

CONH-R ² -N

NH

R ⁴

or c) an N-substituted isatoic anhydride ** "in which R ^{2 is} an ethylene or propylene group, R ³ and R ^{4 are} methyl or ethyl and R ⁵ and R <> are hydrogen, methyl, halogen or CF ₃ with the proviso that only one of the substituents R ⁵

and R ⁶ can be hydrogen.

To illustrate the biological effect of the previously unknown compounds according to the invention Table I summarizes the results obtained with mice using the hot plate method

_{have become so} . For each individual substance the dose is

"(in mg / kg body weight) given at the 30 minutes after subcutaneous injection of this dose a Doubling the reaction time observed without injection is obtained, the reaction time being the Is the length of time that elapses before the mice become restless and raise their paws. As a reference substance Codeine is used, and it appears that the novel compounds according to the invention have an effect of at least of the same size as that of codeine. On the other hand, they do not show the disadvantages of codeine, especially no narcotic effect in humans.

Table I! gives the results obtained when measuring the analgesic effect with the aid of the Acetic acid side have been obtained in mice. After receiving intraperitoneally injected doses of 0.2 ml of 0.5% acetic acid show a typical mice Syndrome that consists of a periodic curvature of the

The number of bends can be counted using a counting device. the Comparison with an untreated comparison group robs the quantitative determination of the analgesic Effect.

Table I.

/ r.aletic effect measured by the Hcißplallen method in mice

Doses in mg / kg s. C. the 30 minutes after the injection cause a doubling of the response time

N- (2-Me! Hy] phenyl) anthranilic acid

(2-dimethylaminoethyl) amide

js [. (3-methylphenyl) anthranilic acid

(3-dimethylaminopropyl) amide

^. ^ - XylylJ-anthranilic acid-

(2-di'methylaminopropyl) amide

N- (2-methyl-3-chlorophenyl) -anthranil-

acid- (2-dimethylaminoethyl) -amide N- (3-trifluoromethylphenyl) -anthranil-

acid (2-dimethylaminoethyl) amide

Codeine
Table II

20 26

39

16

33 or other salts of the amine are for oral and parenteral administration well suited in human therapy.

The invention also relates to processes for the preparation of the compounds of general formula I, which then exist that in a known manner a benzamide which is basically substituted in the amide group with the general formula II

R,

NR ₂ -N

(in

wherein R2 to R4 have the meaning given above and R7 represents a halogen atom or a reactive ester group with a substituted one Aminobenzene with the general formula III

H, N

(III)

Analgesic effect as measured by the acetic acid test in mice

DE ₅₀ mg / kg sc

17.0 7.8

41.0 15.7

13.0

N- (2-chlorophenyl) anthranilic acid (3-dimethylaminopropyI) amide
N- (3-chlorophenyl) anthranilic acid (3-dimethylaminopropyl) amide
N- (2-methyl-3-chlorophenyl) -anthranil- 13,0 acid- (2-diethylaminop: ropyl) -amide N- (3-trifluoromethy! Phenyl) -anthranil- 12,5 acid- (3-dimethylaminopropyl) -amid amidopyrine

N- (2-methylphenyl) anthranilic acid

(3-diethylaminopropyl) amide

N- (3-chlorophenyl) anthranilic acid

(3-diethylaminopropyl) amide

The animals are injected with the test substance subcutaneously 30 minutes before the acetic acid is injected. the The number of writhes is counted for 20 minutes after the acetic acid injection. The percentage The reduction in curvature syndrome is relative to the number of curvatures in animals Control group calculated. The table shows the dose at which the number of bends around 50% is reduced. Amidopyrine has been used as the reference substance.

The tests clearly show a considerable improvement in the effect compared with known ones Analetics.

The same effect can be obtained with oral administration, although the experiments have been carried out by parenteral administration of the amine in the form of its salts, namely the hydrochlorides and the citrates. Both the amine and the reacts, where R ₅ and R _{6 have} the meaning given above, or that in a manner known per se, a mixed anhydride of the _{anthranilic acid substituted by R 5} and R & with the above meaning and a carbonic acid mono'kyl ester with the general formula

COOCO- OR _K

NH

wherein R _{8 is} alkyl, with the diamine of the general formula

NR ₂ -NH ₂

converts, or that one in a conventional manner an N-substituted isatoic anhydride of the general formula

CO

with a diamine of the general formula R3R4NR2NH2. If the first mentioned If the procedure is used, the reaction should be carried out in an organic solvent such as dimethylformamide or amyl alcohol, and with the addition of an acid binder, for example potassium carbonate, and optionally take place of copper as a catalyst. After isolating the amine, for example by

Distilling off the solvent and, if necessary, carrying out a redistillation and recrystallization, the amide can if desired after itself known processes can be converted into one of the above-mentioned amine salts.

The invention is further illustrated below with the aid of the examples.

example 1

30 g of N-p-dimethylamine propyO-o-chlorobenzamide (0.125 mol), 75 ml dimethylformamide, 45 g m-aminobenzene methyl trifluoride (0.28 mole), 19 g of anhydrous granulated potassium carbonate and 1 g of copper bronze are mixed at room temperature, after which the mixture is refluxed for 8 hours will. After cooling, the mass is filtered clear, and the dimethylformamide is distilled at about 12 mm Hg away.

A dark oil remains, which is redistilled, the ^{fraction which condenses at 0.2 mm Hg between 195 and 20O 0} C is obtained. This fraction consists of the free amide, the yield is

¹⁵ S-The amide is dissolved in 200 ml of ether, and in the

Solution, dry hydrogen chloride is introduced, an oil separating out. This oil is dissolved in 100 ml of acetone. When gasoline is added to this solution, an oil separates out, which is then dissolved in 100 ml of chloroform. Upon addition of 800 ml ethers to this solution to a sticky mass separates which becomes crystalline on standing and can be dried at 70 ⁰ C. In this way, 9.5 g of the hydrochloride of N- (3-trifluoromethylphenyl) anthranilic acid (3-dimethylaminopropyl) amide with a melting point = 1.32 to 135 ° C. are obtained.

Example 2

28.4 g of N- (2-dimethyiaminoethyl) -o-chlorobenzamide (0.125 mol), 75 ml of amyl alcohol, 29.96 g of o-toluidine (0.28 Mol), 19 g of anhydrous granulated potassium carbonate (1.4 mol) and 1 g of copper bronze are at room temperature mixed. The mixture is refluxed for 8 hours, cooled and filtered clear. The amyl alcohol is removed by distillation at about 12 mm Hg.

What remains is a dark oil that is distilled with those at 0.1 to 0.2 mm Hg between 184 and 195 ° C condensing fraction is collected.

This fraction consists of the Artid, which is obtained in the amount of 6 g, and of ether underneath Formation of a white powder can be recrystallized, the yield of which is 3.5 g and the one F. = 111 to 113 ° C.

The free amide is dissolved in 400 ml of ether and dry hydrogen chloride is introduced, whereby a pale yellow oily mass separates. When standing, this mass crystallizes to form a product, that's hard as glass. The product is crushed and dried at 80 ° C.

The crystalline product consists of the hydrochloride of N- (2-methylphenyl) anthranilic acid (2-dimethylaminoethyl) amide, found for that a m.p. = 144 to 146 ° C will. The yield is 3.4 g.

Example 3

56.8 g of N- (2-dimethylaminoethyl) -o-chlorobenzamide (0.125 mol), 150 ml of dimethylformamide, 70 g of 3-chloro-2-methylaniline (0.28 mol), 35 g of anhydrous granulated potassium carbonate (1.4 mol), 1 g of copper bronze and 1 g Copper chloride are mixed at room temperature.

The mixture is heated under reflux conditions for 8 hours, cooled, filtered clear and filtered through Freed from dimethylformamide by distillation at about 12 mm Hg. The residue consists of a dark one oil that is distilled, one at 0.1-0.2 mm Hg between 200 and 210 ° C condensing fraction is collected. This fraction consists of the amide and is presented in a yield. 8 g received.

The amide is dissolved in 200 ml of ether and dry hydrogen chloride is introduced, an oily mass separating out. This mass is recovered and dissolved in about 50 ml of acetone. About 2 liters of ether are added to this solution until an oil separates out, which is recovered and dissolved in 50 ml of acetone. By adding about 2 liters of ether a milky mixture is obtained, from which a yellowish substance is deposited after standing for a day and night. This substance is a hydrochloride of N - ^ - methyl-S-chlorophenyO-anthranilic acid ^ -dimethylaminoethyl amide.

The hydrochloride is isolated and dried at 6O ⁰ C and then weighs 5 g. It has an F. =! 44 to 147 ° C.

Example 4

It becomes a mixed anhydride of N- (2-methyl-3-chlorophenyl) anthranilic acid and the carbonic acid monoethyl ester. For this purpose, a mixture of 26 g of N- (2-methyl-3-chlorophenyl) anthranilic acid (0.1 mol) and ethyl chloroformate prepared, including 10.6 g of triethylamine (0.105 mol) dropwise 25 ° C in the course of 30 minutes. The formed product is kept at 25 ° C for 24 hours left to stand, after which it is heated on a steam bath for 8 hours, then cooled, and it 300 ml of benzene are added. The mixture is stirred thoroughly and filtered, leaving a clear Solution of the mixed anhydride in benzene is obtained. This solution becomes complete in a vacuum Removal of the benzene evaporated, leaving the mixed anhydride in the form of a viscous, yellow oil is obtained with an ester-like odor. The yield is 34 g, which is about 100% of the theoretical Yield corresponds.

12.8 g of dimethylaminopropylamine (0.125 moles) are added mixed with 52 ml of water, after which the mixture is heated under reflux conditions and 33.4 g (0.1 mol) of the mixed anhydride prepared above was added in small amounts over the course of 20 minutes will. After the mixed anhydride is added, the mixture is refluxed for an additional 15 minutes heated, after which it was cooled to room temperature and diluted hydrochloric acid was added to adjust the pH to 1. Some insoluble by-products precipitate. You will go through The filtration is removed and sodium hydroxide solution is added to the aqueous layer to bring the pH up 10 to be asked. This causes an oil to separate out Shaking is converted into ether and dried with sodium sulfate, after which the ether is removed and the oily residue is distilled. The yield of the desired amine with a boiling point of 210 to 220 ° C at 0.1 mm Hg is 20 g, which corresponds to 58% of theory.

The amide base obtained in this way is dissolved in 150 ml of ether

dissolved, after which dilute hydrochloric acid is added to adjust the pH to 1 and 100 ml Water can be added. The aqueous layer is removed, filtered clear with decalite and applied in vacuo evaporated to dryness in the steam bath. The residue; nd is recrystallized from 100 ml of acetone. the Yield is 17 g of the hydrochloride of N- (2-Met-

iyl-3-chlorophenyl) anthranilic acid (3-dimethylaminopropyl) amides, which corresponds to 77% of the theoretically possible yield, based on the amide base. The Product has a F. = 194 to 196 ° C.

Example 5

To the

one

from

after cooling to υ ^ -π *, ₆ "

given, the addition happening in the course of. During the encore the ' however, cooling is provided to the

to keep at no higher than 25 ° C, The.

The mixture is then left to stand at 25 ° C for 24 hours,

Filtering is removed ■ _{h | behan} deli

The filtered benzene solution "rf" _c ^ K ^

and to 200 ml. "" 8 ^da ™ I £, "X is won. This crystallizes the anhydrfuniw ^ g .__ ^

LS '™ n ^en 3U ¹ a ° what 54, * of the theory "Snntird a M ^ chujg

Minutes have been added and

insoluble by-product ^a . ^u , "" T _7U "of _the aqueous solution, after which a sodium hydroxide solution is added to the ^^ layer to give ^ e. pH-W «at ^ ^ ^ The amine base separates as υ ^ ^

poured out from ether becomes won »h ^

Solution with sodium- '& ^ ° ™ £ * _bteinöl back, removed by evaporation wd fcsDie _{N. (2} 3-Xy-

that is distilled The distillation continues. ^

l _v l) -anthranilic acid-i; 3-d, methyhmno _P opy. ^

at a pressure of 0.1 mm Hg at _the

boils. The yield is 17 g. «As theoretically possible yield.

The Am.dbase obtained is dissolved, after which diluted chlorine washes

_{which corresponds to} qq.40 / 0, based on the melting point is 188 to 191 C.

Example 6

To a mixture of 79 g of phosgene (0.8 mol) in 425 g of toluene and 51 g of N- (3-methylphenyl) anthranilic acid (0.244 mol) are added dropwise, after cooling to ⁰ ° C., 44.8 g of triethylamine (0.448 mol) with the dropwise addition being carried out over a period of about 60 minutes.

During the dropwise addition, the temperature rises, but it is achieved by cooling at a Temperature not exceeding 25 ° C. The mixture is at this temperature for 24 hours left to stand, after which it is heated to 95 ° C for 4 hours. Then it goes to dryness in a vacuum evaporated. The residue obtained in this way is refluxed with 1200 ml of benzene for 30 minutes boiling causing it to dissolve leaving a small amount of insoluble by-product, the is removed from the solution by filtration. The solution in benzene is treated with charcoal in the heat and then evaporated to 800 ml, cooled and mixed with 1100 ml of benzene with vigorous stirring the anhydride precipitates in a yield of 34 g, which corresponds to 60% of the theoretical yield, and shows a melting point between 183 and 185 ° C.

11 g of 2-dimethylaminoethylamine (0.125 Mol) mixed with 52 ml of water, after which the mixture is heated to boiling under reflux conditions and 25.3 g of N- (3-methylphenyl) isatoic anhydride (0.1 mol), obtained as described above, are added will. The reaction mixture is refluxed for an additional 15 minutes and then cooled to room temperature. The pH is adjusted to 1 with dilute hydrochloric acid posed, creating an insoluble by-product; separates, which is removed by filtration. To the Sodium hydroxide solution is then added to the aqueous layer to adjust the pH to 10. This separates the amide base turns out as an oil, which is shaken out with ether, after which the ether phase with ο Sodium sulfate is dried and the ether is removed. The residue forms an oil that is distilled, taking a yield of 20 g, corresponding to 67% of the theoretically possible yield, product with a Boiling point of 197 to 200 "C at 0.2 mm Hg is obtained. For the production of the hydrochloride of the so N- (3-methylphenyV) anthranilic acid (2-dimethylaminoethyl) amides obtained this is dissolved in 150 ml of ether, after which dilute hydrochloric acid to pH 1 is added, after which 100 ml of water are added. The aqueous layer is clear and unc is isolated and evaporated to dryness in vacuo on the steam bath. The residue is in chloro form dissolved, placed in a Petri dish and evaporated in a vacuum desiccator and dried. There Product is hygroscopic. The yield is 19 g, corresponding to 84.5%, based on the amide base.

Examples of connections according to the invention are those according to the method of operation described above can be produced are:

N- (2,3-XyIyI) -anthranilicäur'i- (3-dimethylamino-

propyl) amide,

Kp. -2Kibis 212 "C at 0.1 mm Hg.

The hydrochloride has a F. = 188 to 191 "C.

- N - (3-Trinuormethylphenyl) -anthranil-

acid (3-dimethylaminopropyl) amide, Bp - 195 to 200 ° C at about 0.2 mm. Hydrochloride F. - 132 to 135 "C.

N- (3-methylphenyl) anthranilic acid (3-dimethylaminopropyl) amyl,

Bp = 204-210 ° C at 0.1 mm Hg.

Hydrochloride R = 123 to 126 ° C.

N- (3-trifluoromethylphenyl) -anthraniI-acid- (2-dimethylaminoethyl) amide, Kp. = 190-198 ° C at 0.2 mm Hg. The hydrochloride is hygroscopic, R = at 5O ⁰ C.

10

N- (2-methyl-3-chlorophenyl) -anthranilsäure- (2-dimethylaminoethyl) amide, Kp. = 200 ° to 210 ⁰ C at 0.1 mm Hg to 0.2. Hydrochloride R-144 to 147 ° C.

N- (23-xylyl) anthranilic acid- (2-dimethyl- ' ⁵

aminoethyl amide,

Bp = 187 to 200 ° C at 0.1 mm Hg.

Hydrochloride R = 138 to 140 ⁰ C.

N- (3-methylphenyl) anthranilic acid (2-dimethylaminoethyl) amide,

Bp = 194 to 200 ° C at 0.2 mm Hg.

Citrate F. = 50 to 53 ° C.

N- (2-methylphenyl) anthranilic acid (2-dimethylaminoethyl) amide, b.p. = 184 to 195 ° C at 0.1 to 0.2 mm Hg. Hydrochloride R = 144 to 146 ° C.

N- (2-methyl-3-chlorophenyl) anthranilic acid (3-diethylaminopropyl) amide, Bp = 200 to 210 ° C at 0.2 mm Hg.Citrate R = 55 to 60 ° C.

N- (3-trifluoromethylphenyl) anthranilic acid (3-diethylaminopropyl) amide,

Bp = 185 to 200 ° C at 0 ,! up to 0.4 mm Hg.

The citrate is somewhat hygroscopic and has a F. = up to 44 ° C.

N- (23-xylyl) anthranilic acid (3-diethylaminopropyl) amide,

Bp = 205 to 213 ° C at 0.2 to 0.4 mm Hg.

Citrate R = 80 to 85 ° C.

N- (3-methylphenyl) anthranilic acid (3-diethylaminopropyl) amide,

Bp = 210 to 224 ° C at 0.2 to 0.5 mm Hg.

Citrate F. = 78 to 85 ° C.

N- (2-methylphenyl) anthranilic acid (2-dimethylaminoethyl) amide,

Bp = 184 to l95 ° C at 0.1 to 0.2 mm Hg.

Ether F. = III to III ° C, hydrochloride R = 144 to 146 ⁰ C.

N- (2-methylphenyl) -anthranilic acid- (3-diethyl-

aminophenyl) amide,

Bp = 212-218 ° C at 0.2mmHg.

Citrate R = 145 ° C (dec.).

N- (2-methylphenyl) -anthranilic acid- (2-dimethyl-

aminopropyl) amide,

Bp = 193 to 198 ° C at 0.5 mm Hg.

Hydrochloride F. = 164 to 166 ⁰ C.

N- (2-methylphenyl) -anthranilic acid- (3-dimethyl-

aminopropyl) amide,

Bp = 200-207 ° C at 0.2mmHg.

Hydrochloride m.p. = 136-139 ° C.

N- (3-methylphenyl) anthranilic acid (2-dimethylaminopropyl) amide,

Bp = 204 to 210 ° C at 0.1 mm Hg.

Hydrochloride R = 123 to 126 ° C.

N- (2-chlorophenyl) anthranilic acid (2-dimethylaminoethyl) amide,

Bp = 210 to 215 ° C at 0.2 mm Hg.

Hydrochloride R = 149 to 151 ° C.

N- (2-chlorophenyl) anthranilic acid (2-dimethylaminoethyl) amide,

Bp = 212-217 ° C at 0.2mmHg.

Hydrochloride R = 147 to 150 ⁰ C.

N- (2-chlorophenyl) anthranilic acid (3-diethylaminopropyl) amide,

Bp = 225 to 233 ° C at 0.2 to 0.4 mm Hg.

Citrate R = 117 to 120 ^° C

N- (3-chlorophenyl) anthraniI acid (2-dimethylaminoethyl) amide,

Bp = 206 to 210 ^° C at 0.1 mm Hg.

Hydrochloride is hygroscopic.

N- (3-chlorophenyl) anthranilic acid (3-dimethylaminopropyl) amide,

Bp = 220 to 228 ° C at 0.4 to 0.6 mm Hg.

Hydrochloride R = 155 to 157 ° C.

N- (3-chlorophenyl) anthranilic acid (3-diethylaminopropyl) amide,

Bp = 223 to 232 ° C at 0.2 to 0.5 mm Hg.

Citrate R = 140 ⁰ C (dec.).

N- (3-chlorophenyl) -anthranilic acid- (2-dimethyl-

aminopropyl) amide,

Bp = 215-220 ° C at 0.2mmHg.

Hydrochloride R = 132 to 135 ° C.

N- (2,3-xylyl) anthranilic acid (2-dimethylaminopropyl) amide,
Bp = 202 to 206 ° C at 0.2 mm Hg. Hydrochloride R = 182 to 185 ° C.

N- (2-methyl-3-chlorophenyl) -anthranilsäure- (3-dimethyIaminopropyl) amide, Kp. = 220 ⁰ C at 210bis 0,2bis0,4 mm Hg. Hydrochloride R = 146-150 ⁰ C.

N- (2-chloro-3-methylphenyl) anthranilic acid (2-dimethylaminopropyl) amide, b.p. 204-208 ° C.
Hydrochloride F. = 173 to 176 ° C.

For comparison, certain compounds, di not within the objects of the present Erfindunj, by the same methods hergestell

been, for example N- (4-chlorophenyl) anthranilic acid re (2-dimethy! aminopropy]) - amide with a bp = 201 to 209 ⁰ C at 0.2 mm Hg, hydrochloride M = 75 to 82 ⁰ C (hygroscopic).

It has been found that these and similar ii

(> o p-position in the phenyl group substituted or ii this group unsubstituted compounds germ or only have a very low analgesic effect. This applies inter alia to the compounds in which R ₃ and R ₄ ethyl groups and R ₂ C ₂ H ₄ or CjH

(> s mean.

Claims (1)

Patent claims: 1. Basically substituted amides of N-substituted antranilic acids of the general formula R ⁵ IO in which R ^{2 is} an ethylene or propylene group, R ³ and R ^{4 are} methyl or ethyl and R ⁵ and R ^{6 are} hydrogen, methyl, halogen or CF ₃ with the proviso that only one of the substituents R ⁵ and R ^{6 is} hydrogen can be as well as their salts.