DE2016057C3 - Square brackets on (thenylidene (2) -amino) -oxy] -alkylcarboxylic acids, their salts and alkyl esters, processes for their production and pharmaceutical preparations containing them - Google Patents

Description

R "- COOR ³

in which R ⁴ 'is an ethenyl or propenyl-1-, -2-

or -3-Gruppc and R ^{3 has} the same meaning

as in claim 1, reacts, or

d) a compound of the general formula

R ² CHj

in which R ¹ and R ^{2 are} hydrogen, chlorine or bromine, η is an integer from 1 to 3 and R ^{3 is} hydrogen or a QQ-alkyl group or a salt of the acid (R ³ = H).

2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se

a) a compound of the general formula; o

R ² CH ₃

Y ^{c == N} °

in which R ¹ , R ² and η have the same meaning as in claim I, saponified with alkali and if desired converts the salt obtained into other salts, into the free acid or into an ester, or e) a compound of the general formula

R ²

in which R ¹ and R ^{2 have} the same meaning as in claim 1 and M represents a metal atom, with a compound of the general formula

Hal— (CH ₂ ), - COOR ³ '

in which Hai represents a halogen atom and R ³ 'represents hydrogen, a Q-Cj-alkyl group or an alkali metal, the acids obtained being converted into salts, if desired, or

b) a compound of the general formula

R ² CH ₃

C = O

40 CH ₃

C = NO- (CH ₂₎ ,, - CN

in which R ¹ , R ² and / 1 have the same meaning as in claim 1, in the presence of an acid with an alcohol of the formula

RAW

in which R ³ "represents a C -C -alkyl group, reacted and then decomposed the reaction product with water.

3. Pharmaceutical preparations, characterized by a '.' N content of a compound according to Claim 1 as an active ingredient.

in which R ¹ and R ^{2 have} the same meaning as in claim 1, with a compound of the general formula

H, N - O - (CH ₂ J _n -COOR ³

in which / 1 and R ^{3 have} the same meaning as in claim 1, converts or

c) a compound of the general formula

in which R ¹ and R ^{2 have} the same meaning as in claim 1 and M represents a metal atom,

n) with a compound of the general formula Rheumatic diseases belong to the most serious illnesses. Means are known with which these diseases are combated be able; however, these usually have unfavorable side effects. So has the very powerful [N- (p-chlorobenzoyl) -5-methoxy-indolyl-3] acetic acid high toxicity, which ultimately makes the therapeutic index low.

The invention relates to new active ingredients that have a strong anti-inflammatory effect and

5s have a strong analgesic effect and the also have very low toxicity.

The new active ingredients are [(Thenyliden (2) -amino) -oxy] -alkylcai bonsäuren and their salts and alkyl esters of the general formula

(.0 R ² CH ₃

R ¹ ->

> - C = - N - C) - (C 11 ₂ ) "- COOR ³

OR ⁴ -CO

in which R ^{4 represents} an optionally branched ethylene or propylene group, reacts and <, _s in which R ¹ and R ^{2 are} hydrogen, chlorine or bromine, π is an integer from 1 to 3 and R ^{3 is} hydrogen or a (VC ₅ - Is an alkyl group or a salt of the acid (R ³ = H).

In particular |> -Methyl-5- ^ 101-2-lhenylidene (2) -amino) -oxy] -acetic acid and their salts are very potent.

Due to their properties, the compounds according to the invention can be used to combat rheumatoid arthritis, Beehter's disease, psoriatic arthritis, collagen disease, serious osteoarthritis, acute gout, humeroscapular periarthritis, acute sterile uninfected bursitis, thrombophlebitis, acute polyarthritis rheumatica 11. The like. Used will.

The dosage and the frequency of administration of the compounds to combat them Illnesses depend on the degree of illness. In general, patients will be a crowd of 50 up to 1000 mg administered daily, if necessary divided into several servings. Usually is a lot from 100 to 500 mg is sufficient.

The anti-inflammatory effect of the compounds was determined in the carrageenin test, which after a modification of that of Winter, R i s 1 e y and Nuss in Proc. Soc. Exp. Biol. 111, 544 (1962) described method was carried out.

The reduction of the swelling caused by carrageenin serves in this experiment as a measure of its anti-inflammatory effects.

The experiment is carried out on male rats weighing approximately 220 g. The animals are fasted 16 hours before the experiment is carried out. The substances to be tested are suspended in a 1% tragacanth solution and administered orally. Immediately after administration of the substance there is a water load of up to 5 ml per animal. One hour after administration of test substance or, where appropriate after exposure to water is administered intraplantar0,05 ml of a l ^l / 2% carrageenin and the thickness of the paw is (dorsal plantar distance) is determined by means of a special designed for this purpose micrometer.

The thickness of the developed edema is determined three hours after administration of the Carragcenin. the Paw swelling is expressed as a percentage of the zero hour value. The inhibition percentage becomes calculated according to the relationship

% Control animals -% test group c
% Control animals - 100 canth solution suspended and administered orally. I, 2 and 4 hours after the administration of the test substance, the pain threshold is measured with increasing pressure on the infected paw.

In comparison, the susceptibility of a group of animals not treated with drug is used definitely.

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

_{An ED 50} -WCn was calculated from the results of a series of doses, ie the dose at which an increase of 100% of the pain threshold is obtained.

The superiority of the substances according to the invention over the known and comparable in terms of effectiveness Active ingredient acetylsalicylic acid emerges from the following test results:

The ED ₅₀ values (mg / kg) were determined using the carrageenin test described above. These values and the LD ₅₀ -WCrIe (mg / kp) were determined for compounds according to the invention in the following examples and the comparison substance:

U) ₅₁₁

237 320

> 320

> 320

not determined • 320

750

The compounds according to the invention can be prepared by methods known per se.

Accordingly, the invention also relates to a process for the preparation of the [(thenylidene (2) -amino) -oxy] -alkylcarboxylic acids of the general formula given above and their salts and alkyl esters, which is characterized in that one in a known manner

a) a compound of the general formula

Example no. KD ₅₁ , 1 27% *) -> 34 2 B 90 2 c 24% *) 4th 90 50 Aectylsalicylic 111 acid *) Hs became 50 mg / kg administered.

_{An ED 51)} value was calculated from the results of a series of dosages, ie that dosage at which a reduction of 50% with respect to the control group is obtained.

The analgesic effectiveness of the compounds was determined by a modification of the R a η d a 1 1 and Sei Ii to (Arch. Int. Pharmacodyn. 109, 409 [1957J) described method.

The lowering of the pain threshold caused by increasing pressure on a person infected with yeast Ratlcnpfotc is brought about serves as a criterion for the analgesic effect.

The experiment is carried out on male rats weighing KK) up to 150 g. One hour before the administration of the test preparation, 0.1 ml of an intraplantar injection is given to the animals 20% yeast suspension injected. The connections to be checked are carried out in a 1%

C = N-O-M

in which R ¹ and R ^{2 have} the same meaning as in the general formula given above and M represents a metal atom, with a compound of the general formula

Hal (CH,

COOR ' ¹

in which I IaI represents a halogen atom and R ¹ 'represents hydrogen, a C ₁ C ₅ alkyl group or an alkali metal, the acids obtained

wünschtcnl'alls converted into salts grazing, or b) a compound of general I ⁷ OmIeI

in which R ¹ and R ^{2 have} the same meaning as in the general formula given above, with a compound of the general formula

H ₂ N - O - (CH ₂ ) ,, - COOR ³

in which / i and R- ^{1 have} the same meaning as in the general formula given above, converts, or
c) a compound of the general formula

R ²

CH ₁

- Ο- N --O - M

in which R 'and R ^{2 have} the same meaning as in the general F- ¹ OrmcI given above and M represents a metal atom,

α) with a compound of the general formula

O-R ⁴ -C-O

in which R ^{4 represents} an optionally branched propylene or ethylene group, can react, and the salts obtained, optionally in acids. Converts esters or other salts, or
/ O with a compound of the general formula

R ⁴ '-COOR-'

in which R ⁴ 'is an ethenyl or a propynyl-I, -2 or -3 group and R' has the same meaning as in the general formula given above. reacts or
d) a compound of the general F-Ormel

- (CH ₂ ) ,, -CN

in which R ¹ , R ² and η have the same meaning as in the general formula given above, saponified with alkali and, if desired, the salt obtained is converted into other salts, into the free acid or into an ester, or
e) a compound of the general formula

R ²

CH ₁

C N O (CU,) ,, CN

in the R ¹ . R- and ii have the same meaning as in the general formula given above, in counter wan an acid with an alcohol of the formula R "'-OH

in which R- "'represents a CVCy-alkyl group and then decompose the reaction product with water. The compounds according to the invention can by processes known per se to pharmaceutical preparations, such as /. B. tablets, pills. Powders. ίο Injection wedges, ointments, suppositories. Coated tablets and the like., processed. The invention therefore also relates to pharmaceutical preparations.

The substances listed in is de pharmacy common.

The invention is explained in more detail with reference to the following examples.

Example I.

f H-methyl-4-brc) m-2- (heriylidena miuol-o.x} ''] - acetic acid

A solution of 4.2 g of 4-bromo-2-acetylthiophene in 42 ml of ethanol was mixed with 2.2 g of Hcmihydrochloride 2-Amino-oxy-acetic acid and then with a warm solution of 4.90 g of anhydrous sodium acetal in 8ml water mixed. The reaction mixture was then refluxed for 3 hours. After a small amount of solvent had been distilled off in vacuo, the sodium salt crystallized of the reaction product. This crystallizate was filtered off. after which the filtrate was further concentrated in vacuo. 13 filter off solid was together with the residue obtained in K) OmI water, 20 ml of 2η sodium hydroxide solution and 30 ml Ether dissolved. The ether layer was deposited, and the alkaline layer was used twice more 40 ml of ether extracted. Then the alkaline water layer was acidified with 10 ml of concentrated hydrochloric acid and extracted again three times with ether. The latter was ether extrakl with anhydrous Dried sodium sulfate, after which the solvent was removed. The [(u-methyl-4-bromo-2-thenvlidenamino) -oxv] acetic acid thus obtained was crystallized from some benzene (2 "u from 10 ml), after which it was at

Melted 140 to 141 C. "

Example 2

['(II-methyl-5-chloro-2-thenylidcnamino) -oxy / ^so acetic acid

A solution of 6.4 g of 5-chloro-2-acetylthiophene in 100 ml of 80% ethanol was mixed with 4.4 g of hydrochloride the aminooxyacetic acid and 9.8 g

ss anhydrous sodium acetal mixed, after which the Mixture was refluxed for one hour. The reaction mixture was then concentrated in vacuo, after which the residue was mixed with 75 ml of 2N sodium hydroxide solution. This mixture was used twice

(,,, washed with ether. The alkaline water layer Then wind acidified with 125 ml of 2η hydrochloric acid and then extracted three times with ether essential extract was washed three times with a little water and then over anhydrous sodium sulfate

ι, s dried. The dried solution became that Solvent removed by evaporation, after which the residue with a mixture of benzene and Peirole ether was crystallized. This crystallized

the [(<! - methyl - 5 - chloro - 2 - thenylideneamino) - oxy] acetic acid with a melting point of 116 to 132 ° C. To that described in Examples 1 and 2 Ways were obtained:

2a) [(«-Methyl-2-thenylideneamino) -oxy] -acetic acid with melting point 91 to 118" C.

2 b) [(«-Methyl - ^ - i-dibromo-1-thenylideneamino) -oxy] acetic acid with a melting point of 166 to 168 ° C.

2c) [(a-Methyl ^ S-dichloro ^ -thenylideneamino) -oxy] -acetic acid with melting point 97 to 98 "C.

Example 3
[(α, 5-Dimethyl-2-thenylideneamino) -oxy] -acetic acid

A solution of 1.85 g of sodium in 150 ml of ethanol were successively with stirring 6.2 g of 5-methyl-2-acetylthiophenoxime and 7.8 g of bromoacetic acid were added. The mixture was then stirred for one hour and then the ethanol was separated off in vacuo. The obtained residue was mixed with water, and this mixture was extracted three times with ether. The aqueous alkaline solution was then acidified with 2η hydrochloric acid and again three times with Ether extracted. The latter ether extract was washed four times with water and then over anhydrous Dried sodium sulfate. After the solvent was distilled off, the residue became crystallized from a mixture of benzene and petroleum ether. The [(<i, 5-Dimethyl-2-thcnylidenamino) -oxy] -acetic acid thus obtained melted at 126-127 ° C.

Example 4

4 - [(<i-Methyl-5-chloro-2-thynylidycnamino) -oxy] -butyric acid

2.0 g of S-chloro-2-acctylthiophenoxime were added to a solution of 0.26 g of sodium in 15 ml of absolute ethanol. After the oxime had been dissolved, the solvent was removed in vacuo and the residue obtained was dissolved in 10 ml of N-methylpyrrolidone-2 with heating. To this solution was added 0.87 ml of butyrolactone. The mixture was refluxed for 4 hours. The warm reaction mixture was then poured into water and the aqueous solution was filtered. The Filtiul was acidified with acetic acid and the precipitated solid was filtered off with suction. This solid was dissolved in acetone, then the acetone solution was concentrated again with Noril and after filtration. The residue was then crystallized from 30% acetic acid, whereby 4 - [(«- methyl - 5 - chloro - 2 - thenylideneamino) - oxy] - butyric acid with a melting point of 92 to 96 ° C. was obtained. 5

Example 5

2 - [(d-Methyl-5-chloro-2-thenylideneamino) -oxy] -acetic acid methyl ester

A solution of 1.0 g of 2 - [(«- methyl-5-chloro-2-thenylideneamino) -oxy) acetic acid in 10 ml of methanol was mixed with three drops of concentrated sulfuric acid and then refluxed for 18 hours. The methanol was then distilled off in a vacuum and the residue obtained was dissolved in 25 ml of ether. The ethereal solution was washed successively with water (three times with 10 ml), with 10 ml of 2η sodium hydroxide solution and again three times with 10 ml of water. Then it was dried over anhydrous sodium sulfate and, after filtration, concentrated in vacuo. The residue, which consisted of 2 - [(u-methyl - 5 - chloro - 2 - thenylideneamino) - oxy] - acetic acid methyl ester, was crystallized ^{from 47 ml of petroleum ether with a boiling point of 40 to 60 11 C.} ZS melting point 99 to 101 ⁰ C.

Preparation 1

200 g of [(a-methyl-5-chloro-2-thenylideneamino) -oxy] acetic acid was mixed with 190 g of secondary calcium phosphate, 90 g of microcrystalline cellulose and 120 g of a mixture of 200 parts of corn starch and 32 parts of talc and 4 parts Magncsiumlearate mixed until a homogeneous mixture was obtained. Then were out this mixture tablets with a diameter

is shaped by 13 mm and a weight of 600 mg.

Preparation 2

100 mg of f ((i-methyl-5-chloro-2-thenylidcnamino) -oxy] -acetic acid c was made into a suppository with 1.5 g of suppository mass 4 <>.

Preparation 3

KX) mg l ((i-methyl-5-chloro-2-thenylideneamino) oxy] acetic acid was used in an equimolar amount

.is I n-Natronluugc dissolved and the solution then mi 15 g of benzyl alcohol mixed. The solution then became a volume with distilled water of KX) ml diluted. Then it was filtered through a bottle of paper and became ampoules of

or 2 ml aseptically filled with this solution,

Claims (1)

Patent claims: 1. [(thenylidene (2) - amino) - oxy] - alky carboxylic acids and their salts and Alkylcster the general ^s common formula R ² CH ₃ -0- (CH ₂ ) ,, - COOR ³ IO optionally converting the salts obtained into acids, fibers or other salts, or
/ O with a compound of the general formula