NO131930B - - Google Patents

Description

The present invention relates to analog methods

for the production of new benzylideneamino-oxyalkylcarboxylic acids and carboxylic acid derivatives with anti-inflammatory and analgesic effects.

It is well known that rheumatic disorders belong to the more serious diseases. There are known preparations and drugs for combating the aforementioned disorders, but these usually have unwanted side effects. It can e.g. it is mentioned that the highly effective (N-p.chlorophenyl-5-methoxyindolyl-3)-acetic acid has such a high toxicity that its therapeutic application is therefore relatively limited.

The invention thus relates to analogous methods for the production of new benzylideneamino-oxycarboxylic acids and carboxylic acid derivatives with anti-inflammatory and analgesic effects and with the general formula

in which R-^ means halogen, R2 means halogen or hydrogen, R^ means an optionally branched alkylene group with up to 3 carbon atoms, Rg means OH, alkoxy with up to 8 carbon atoms, benzyloxy, NH2, monoalkyl-

amino, with the alkyl group containing up to 3 carbon atoms or the radical ORj, with R^ meaning a metal atom, an ammonium group, a hydroxyethyldimethylammonium group or a hydroxyethyldiethylammonium group.

Very strong activity has e.g. compounds with the general formula:

CH,

where R-^' is bromine or chlorine and Rg' is NH2 > OH, an alkoxy group with up to three carbon atoms or the radical OR^, where R^ has the same meaning as stated above. This applies in particular to l~(a-methyl-4-chloro-benzylideneamino)oxy/acetic acid and its salts as well as /"(a-methyl-^-chloro-benzylideneamino)oxy_7acetic acid methyl ester and more particularly /_—(a-methyl-4 -chlorobenzylideneamino)oxy_7acetamide.

Due to their properties, said compounds according to the present invention can be used to combat rheumatic arthritis, Bechterew's disease, psoriatic arthritis, collagen disorder, severe osteoarthritis, acute gout, periarthritis humeroscapularis, acute, sterile non-infected bursitis, tromophlebitis and acute poly - rheumatoid arthritis etc.

The quantities and the frequency with which said compounds must be added to combat these disorders depend on their nature. However, it will usually not be difficult for a doctor to find the correct treatment. Usually, patients will be able to be given from 50 to 1000 mg daily, if desired, divided into several portions. Usually from 100 to 500 mg daily will be sufficient.

The anti-inflammatory activity of the compounds was determined in the carrageenan test performed according to a modification of the method of Winter, Risley and Nuss, Proe. Soc. Exp. Biol. 111 - 5^4 - (1962).

In this test, the reduction of a swelling produced by carrageenin serves as a measure of the anti-inflammatory effect.

The test was carried out with male rats weighing approx. 220 grams. The animals were fasted for 16 hours before the test. The substance or substances to be tested were suspended in a l# tragacanth solution and administered orally. Immediately after the administration of the substance, each animal was administered approx. 5 ml of water. 1 hour later, 0.05 ml of a 1.5 µg carrageenan solution was injected into the sole of the foot, after which the thickness of the foot was measured using a special micrometer. 3 hours after the carrageenan was added, the thickness of the edema was determined. The swelling of the foot was expressed as a percentage in relation to the thickness of the foot before the test. Percent inhibition was assessed using the equation:

Percentage for control group times percentage for sample group

Percentage for control group - 100

From the results for a series of dosages, an ED^q value was calculated. This is a dose that gives a reduction of 50% compared to the control group.

The analgesic activity of the present compounds was determined by a modification of the method of Randall and Sellito (Arch. Int. Pharmacodyn. 109 409 (1957)).

As a criterion for the analgesic activity, the reduction of a pain produced by increasing pressure on a rat's foot which was yeast-inflamed was used.

The test was carried out with male rats weighing from 100 to

150 grams. One hour before the test preparation was administered, the animals were given an injection in the sole of the foot with 0.1 ml of a 20% xg yeast suspension. The compounds to be tested were suspended in a 1% tragacanth solution and administered orally. One hour, two hours and four hours after the administration of the test substance, the pain threshold was measured with increasing pressure on the inflamed foot.

As a control, the pain response was measured for a group of animals that had not been treated at all.

The results were expressed as a percentage of the mean control value.

From the results of a series of doses, an EDcjQ value was calculated, i.e. the dose which produces a 100% increase in the pain threshold.

As compounds with interesting activity against Rhino virus can be mentioned: r~(α-methyl-4-chlorobenzylidene nano)oxy/acetamide,

£~ (α-methyl-3,4-dichlorobenzylideneamino)oxy/acetamide, N-n. but yl-/_—(a-me ty 1-4-kl orb en zy lidenamino) oxy7acetamide, l_ (a-me ty 1-2 , 4 -dichlorobenzyl lidenamino) oxy7acetic acid, 4-/~(a-methyl1-4 -chlorobenzylideneamino)oxy7butyric acid.

The invention thus relates to analog methods of the type mentioned at the outset, the method being characterized by either

a) a compound with the general formula

in which R- and R2 have the same meaning as above and M means a metal atom, is reacted with a compound of the general formula

in which R^ has the above meaning, Hal means a halogen atom and Rg" means OH, NH2, monoalkylamino, the alkyl group containing up to 3 carbon atoms, benzyloxy or an alkoxy group with up to 8 carbon atoms, the acids formed, if necessary, with the help of bases being converted in salts, or

b) a compound of formula

in which R 1 and R 2 have the above-mentioned meaning, is reacted with a compound of formula

in which R^ and Rg have the above meaning, or

c) a compound of formula

in which R-j^ and R 2 have the same meaning as above and M means a metal atom, is reacted with a compound of formula

in which R^' means a propylene or an ethylene group, or

d) a compound of formula

in which M means a metal atom and FL and R 2 have the above meaning, is reacted with a compound of formula

wherein R,-" means an ethenyl, propenyl-1,-2 or -3 group, or

e) a compound of formula

in which R-p, R2 and R^ have the above-mentioned meanings, are reacted with lye or

f) 'a compound of formula

in which R^, R2 and R^ have the above meaning, is reacted with an alcohol ROH in the presence of an acid and by cleavage of the reaction product with water, where R means an alkyl group with up to 8 C atoms or a benzyl group, or g) reaction of the formed acids of formula I with alcohols of formula ROH, where R means an alkyl group with up to 8 carbon atoms or a benzyl group, or h) by converting the formed esters of formula I with ammonia, or mono-alkylamines, in which the alkyl group contains

up to 3 carbon atoms in corresponding amides, or i) by conversion of formed amides and esters by saponification in the corresponding acids and their salts.

Compounds according to the present invention can be prepared into pharmaceutical preparations, e.g. tablets, pills, powders, injection fluids, ointments, suppositories and the like are known

procedures,

Suitable carrier materials are the substances that are usually used for this purpose in the pharmaceutical industry.

The following examples illustrate the invention.

1) //"(α-methyl 1-3, 4-dichlorobenzylideneamino)oxy7acetic acid .

4.73 grams of 3,4-dichloroacetophenone and 2.74 grams of aminooxyacetic acid hemihydrochloride were dissolved in 50 ml of 90% ethanol. The solution was mixed with 6.15 grams of sodium acetate and then refluxed for 20 minutes. The reaction mixture was then concentrated by evaporation in vacuo. After an excess of 2N sodium hydroxide was added, the residue was extracted twice with ether, after which the remaining aqueous solution was acidified with 2N hydrochloric acid and again extracted twice with ether. The final ether solution was washed twice with water, then dried over anhydrous sodium sulfate and then concentrated by evaporation. The residue was crystallized from a mixture of ether and petroleum ether, then from highly dilute ethanol and finally twice from a mixture of benzene and petroleum ether. The compound produced melted at 128 to 129°C.

2) r~ (α-methyl-4-chlorobenzylideneamino)oxy/acetic acid.

15.7 grams of 4'-chloroacetophenoxime was added to a solution of 2.13 grams of sodium in 80 ml of absolute ethanol. The solvent was distilled off as far as possible in vacuum. The residue was mixed with 33 grams of α-chloroacetic acid ethyl ester and then refluxed for half an hour. Then the excess of the α-chloroacetic acid ester was removed at 80°C in vacuum. The residue contained the ethyl ester of (α-methyl-4-chlorobenzylideneamino)oxy7acetic acid.

This ester was saponified by boiling it with 55 ml

2N sodium hydroxide for 1 hour. The reaction mixture was cooled and then extracted 5 times with ether. The extracted alkaline solution was acidified with 100 ml of 2N hydrochloric acid and then extracted twice with ether. The last ether extracts were washed 4 times with water, after which the ether was distilled off. The solid residue was crystallized once from a mixture of benzene and petroleum ether and then purified by washing a solution of the residue in a caustic soda solution with ether and then again acidifying it. After recrystallization from a mixture of benzene and petroleum ether, the pure substance was obtained. Melting point 115.5 to 116.5°C.

3(2-/_(α-methyl-4-chlorobenzylideneamino)oxy7-propionic acid.

To a solution of 1.85 grams of sodium in 150 ml of absolute ethanol was added 6.8 grams of 4-chloroacetophenoxime and then 8.6 grams of ct-bromopropionic acid. After the mixture was stirred for 1 hour, the ethanol was removed in vacuo. The residue was mixed with water and the mixture was washed twice with ether. The aqueous solution was then acidified and extracted twice with ether. The ether extract was washed 6 times with water, dried over anhydrous sodium sulfate and concentrated by evaporation. After the residue was crystallized from petroleum ether, the above-mentioned substance was obtained. After it had been washed once with water and crystallized from a mixture of benzene and petroleum ether, the melting point was 88-89°C.

4) 1-(α-methyl-4-chlorobenzylideneamino)oxy7acetamide.

A solution of 2.9 grams of sodium in 75 ml of absolute ethanol was mixed with 21.4 grams of 4'-chloroacetophenoxime and then concentrated by evaporation in vacuo to constant weight. The residue was mixed with 75 ml of dimethylformamide and 11.8 grams of α-chloroacetamide. The temperature was kept below 40°C by means of cooling. The mixture was stirred overnight at room temperature, after which the solvent was removed in vacuo. The residue was dissolved in ether and water. The ether solution was washed twice with sodium hydroxide and three times with water. The solution was then mixed with a small amount of chloroform, treated once with activated carbon and then with the aid of a filtration aid (hyflo), after which a certain concentration by evaporation and an addition of petroleum ether resulted in a crystallization of it. above mentioned substance. It was recrystallized from a mixture of chloroform, ether and petroleum ether. Melting point 103 to 104°C.

5 ) _/_(α-methyl-4-chlorobenzylideneamino)exyacetic acid methyl ester.

A solution of 17.0 grams of the 1-(α-methyl-4-chloro-benzylideneamino)oxy7acetic acid prepared by a method described in one of the aforementioned examples in 60 ml of ethanol was added with 1 ml of concentrated sulfuric acid and then refluxed. for 8 hours. The majority of the methanol was then distilled off in vacuum, after which the residue was washed with ether.

This ether solution was washed once with water and four times with 20 ml portions of 2N sodium hydroxide. The solution was dried over anhydrous sodium sulfate after which the solvent was distilled off. After distillation in vacuum, the above was obtained

said substance. Boiling point 130 to 132°C at a pressure of 0.1 mm Hg.

6) 1<_> (α-meth<y>1-4-chlorobenz<y>lideneamino)oxy7-N-methyl-acetamide.

A mixture of 5.0 grams of the (α-methyl-4-chlorobenzylideneamino)oxy-7-acetic acid methyl ester prepared by the method indicated in Example 3 and 40 ml of a 35% aqueous methylamino solution was stirred for 2 hours. The precipitated solid was dissolved by extracting the mixture three times with ether and chloroform. The extract was washed three times with water, dried over anhydrous sodium sulfate and then concentrated by evaporation. A crystallization of the residue from a benzene-petroleum ether mixture gave the above substance. Melting point 115 - 116°C.

7) 1-(α-methyl-3,4-dichlorobenzylideneamino)oxy7acetamide.

A solution of 5.0 grams of 3',4'-dichloroacetophenone in 50 ml of 90% ethanol was mixed with 2.4 grams of aminooxyacetamide and then boiled. The solvent was removed in vacuo and the residue was extracted with chloroform. The chloroform solution was washed three times with water, dried over anhydrous sodium sulfate and then concentrated by evaporation in vacuo. After adding ether and petroleum ether, the above-mentioned substance was crystallized. Melting point 111 - 111.5°C.

8) r~ (α-methyl-4-chlorobenzylideneamino)oxyacetic acid methyl ester.

Of the (α-methyl-4-chlorobenzylideneamino)oxyacetonitrile (melting point 57 - 58.5°C) obtained by reacting the sodium salt of 4'-chloroacetophenoxime with chloroacetonitrile in dimethylformamide, an amount of 11.3 grams was dissolved in diisopropyl ether in which 1.94 grams of hydrogen chloride and 1.73 grams of methanol had previously been dissolved. The solution was diluted with 25 ml of diisopropyl ether and then stirred overnight. The precipitate was filtered off, washed with absolute ether and dried in vacuo. The resulting hydrochloride of methyl (α-methyl-4-chlorobenzylideneamino)oxy-acetimidate melted at 95°C with decomposition. After the substance was dissolved in water, the above-mentioned ester was separated from the solution. It was extracted with ether and distilled in vacuo. Boiling point at a pressure of 0.1 mm Hg: 130 - 132°C.

9 ) _/""(a-me ty 1-4-chlorobenzy lidenamino) oxy7acetic acid .

Of the α-methyl-4-chlorobenzylideneamino)oxy-7acetonitrile described in Example 10, 1.0 gram was dissolved in 20 ml of 0.5 N alcoholic potassium hydroxide. The solution was left at room temperature for 3 days, after which the crystallized substance was filtered off. It was dissolved in 20 ml of water, the solution was then acidified with 2N hydrochloric acid and then extracted with ether. The above-mentioned substance was prepared from the aforementioned ether solution after distilling off the solvent. Melting point 115.5 - 116.5°C.

10) 3~/_ (α-methyl-4-chlorobenzylideneamino)oxv_7propionic acid.

1/'" GRAM of 4'-chloroacetophenone oxime was added to a solution of 1.38 grams of sodium in 75 ml of ethanol. After the oxime had dissolved, the solvent was removed in vacuo and the residue suspended in 150 ml of benzene. This suspension was added a solution of 4.32 grams of 3-propionlactone in 20 ml of benzene with stirring and cooling to 5° C. under a nitrogen atmosphere. The reaction mixture was then stirred for 1.5 hours at 5° C. and then for 2 hours at room temperature. the solvent distilled off in vacuo at 30° C. and the residue mixed with 750 ml of water. The undissolved substances were removed by filtration, after which the solution was acidified with acetic acid and extracted three times with 150 ml of ether.

The ether extract was washed three times with 25 ml of water and then extracted with 2N sodium hydroxide. The alkaline extract was washed twice with ether, then acidified with 2N hydrochloric acid and then extracted three times with 150 ml of ether. The last ether extracts were washed three times with a small amount of water and then dried over sodium sulfate. After the ether was distilled off, a substance with the above formula was obtained, and after crystallization from petroleum ether, the melting point was 80 to 83°C.

11) 3-C(α-methyl-4-chlorobenzylideneamino)oxy/propionic acid.

During 10 minutes, 75 grams of acrylic acid ethyl ester was added dropwise to a solution of 41.4 grams of 4'-chloroacetophenoxime in 75 ml of sodium ethylate solution (prepared from 0.50 grams of sodium and ethanol). After the addition, the mixture was cooled to room temperature and then stirred for 16 hours. Then 3.0 ml of acetic acid was added and the resulting mixture was concentrated by evaporation at 70°C and a pressure of 0.01 mm Hg until nothing could be overdistilled. The residue was mixed with 300 ml of petroleum ether, after which it was all filtered. The filtrate was washed three times with dilute sodium hydroxide, dried over anhydrous sodium sulfate and finally concentrated by evaporation at 50°C and a pressure of 12 mm Hg. The residue persisted

of the ethyl ester of 3-_/~"(α-ethyl-4-chlorobenzylideneamino)oxy/propionic acid (boiling point 130 - 132°C at a pressure of 0.7 mm Hg). By leaving a 5# solution of this ester in 0.5 N alcoholic potassium hydroxide to stand for 24 hours at room temperature, the potassium salt of the above acid was prepared. By extracting an aqueous solution of this salt after acidification with an equivalent amount of 2N acid with ether,

drying the ether extract and concentrating this by evaporation, the above-mentioned acid was produced. Melting point from 80 - 85°C.

12) 3-[(α-methyl-4-chlorobenzylideneamino)oxyTpropionamide.

15j6 grams of the ethyl ester of J>-/_ (α-methyl-4-chloroben;zylideneamino)oxy/propionic acid which was mentioned in example 13 was dissolved in 100 ml of methanol saturated with ammonia at 25°C. Said solution was then kept at 70°C in an autoclave for 7 hours. It was then concentrated by evaporation in a vacuum at 40°C, and the semi-solid residue was dissolved by means of 200 ml of diethyl ester, 100 ml of benzene, 200 ml of chloroform and 200 ml of methylene chloride. The resulting solution was extracted three times with dilute sodium hydroxide, then dried over anhydrous sodium sulfate and finally concentrated by evaporation in vacuo. The residue obtained was crystallized from a mixture of 50 ml of benzene, 50 ml of chloroform and 25 ml of petroleum ether. Melting point 149 - 150°C.

13) 3-[(α-methyl-4-chlorobenzylideneamino)oxy/propionic acid.

A solution of 2.4 grams of sodium hydroxide in 55 ml of 85% ethanol was mixed with 6.78 grams of 4'-chloroacetophenoxime and 2.88 grams of acrylic acid. The mixture was then refluxed for 2.5 hours, diluted with 10 ml of water and concentrated by evaporation in vacuo after .2 hours. The residue was dissolved in 50 ml of ether and 50 ml of water, and the layers formed were separated. The aqueous layer was extracted with 50 ml of ether and then acidified with 40 ml of 2N hydrochloric acid. The acid solution was extracted with 100 ml of ether, and the ether solution was then dried over sodium sulfate. The solvent was distilled off and the last traces removed, together with higher boiling substances at a pressure of 0.01 mm of mercury and a temperature of 50°C. The residue was crystallized from petroleum ether. Melting point 80 - 83°C

14) 4-[(α-methyl-4-chlorobenzylideneamino)oxyTsbutyric acid.

A solution of 11.9 grams of 4'-chloroacetophenoxime in 28 ml of N-methyl-2-pyrrolidone was mixed with 1.72 grams of crushed sodium and stirred at 60°C until all the sodium had dissolved. The reaction mixture was then cooled to room temperature and mixed with 6.0 grams of iodobuturolactone. The reaction mixture was then heated to boiling and refluxed for 4 hours. After part of the solvent had been distilled off in vacuum, the residue was poured over, into 1 liter of water. The aqueous solution was filtered and then acidified with acetic acid. As a result, a compound with the above formula was isolated.

This was filtered off, washed with water and recrystallized from 30% acetic acid. Melting point 106.5 - 108.5°C.

The following compounds were prepared by methods corresponding to those mentioned above in the Examples.

Claims (1)

Analogous methods for the production of new benzylideneamino-oxycarboxylic acids and carboxylic acid derivatives with anti-inflammatory and analgesic effects and with the general formula in which R-^ means halogen, R2 means halogen or hydrogen, R,- means an optionally branched alkylene group with up to 3 carbon atoms, Rg means OH, alkoxy with up to 8 carbon atoms, benzyloxy, NH2, monoalkylamino, the alkyl group containing up to 3 carbon atoms or the radical ORj, where R^ means a metal atom, an ammonium group, a hydroxyethyldimethylammonium group or a hydroxyethyldiethylammonium group, characterized in that either a) a compound with the general formula in which R-j_ and Rg have the same meaning as above and M means a metal atom,' is reacted with a compound of the general formula in which R^ has the above meaning, Hal means a halogen atom and Rg" means OH, NHg, monoalkylamino, the alkyl group containing up to 3 carbon atoms, benzyloxy or an alkoxy group with up to 8 carbon atoms, the acids formed if necessary, with the help of bases is converted into salts, or b) a compound of formula in which R-^ and Rg have the above-mentioned meaning, is reacted with a compound of formula in which R^ and Rg have the above meaning, or c) a compound of formula in which R-^ and Rg have the same meaning as above and M means a metal atom, is reacted with a compound of formula in which R^' means a propylene or an ethylene group, or d) a compound of formula "in which M means a metal atom and R-^ and Rg have the above meaning, is reacted with a compound of formula in which R^" means an ethenyl-, propenyl-1,-2 or -3 group, or e) a compound of formula in which R-^, Rg °g Rj- has the above-mentioned meaning, is reacted with lye or f) a compound of formula in which R-j^j Rg and R ^ has the above-mentioned meaning, is reacted with an alcohol ROH in the presence of an acid and by cleavage of the reaction product with water, R' meaning an alkyl group with up to 8 C atoms or a benzyl group, or g) reaction of the formed acids with formula I with alcohols of formula ROH, wherein R means an alkyl group with up to 8 carbon atoms or a benzyl group, or h) ' by converting the formed esters of formula I with ammonia, or mono-alkylamines, in which the alkyl group contains up to 3 carbon atoms in corresponding amides, or i) by conversion of formed amides and esters by saponification ing in the corresponding acids and their salts.