DE2430077C3 - 2 "- square bracket on 3 '- (2-Benzofuroyl) phenyl square bracket to propionic acid, its optically active isomers, its pharmacologically acceptable lower alkyl esters, processes for their production and pharmaceuticals containing them - Google Patents

Description

CH ₃ Siegmund test

,. Ui-, -i. (Proc. Soc. Exp. Biol. Med. 1957, 95, 729-31)

and their optically active isomers and pharma- ' ^v

ecologically harmless lower alkyl esters. '5 By intraperitoneal injection of 0.25 ml of a

2. A process for the preparation of the compounds solution of 2-phenyl-l, 4-benzoquinone in aqueous according to claim 1, characterized in that alcohol in a concentration of 0.02% is a special salicylaldehyde of the mouse in a manner known per se Syndrome is produced, which is characterized by stretching of the hind legs and curvature of the trunk of the general formula ^2O with an (a-haloacetyl) -arylacetic acid derivative. Same groups from 20 to

30 mice with an average weight of 20 g

/ r \ are used. The animals receive the test sub-

! l punch at time zero. 1 hour later that will

Phenylbenzoquinone injected intraperitoneally. The X ^- CH ₂ --CO CH - COOR 25 animals are individually for a period of 5 minutes

between the 5th and 10th minute after the injection

CH _{3 of} the phenylbenzoquinone observed. That is noted

Number of stretches each animal has during the

in which R is a lower alkyl radical and X has an observation time. Means of comparison of the halogen atom, is reacted and, where _Z ah jo \ of writhings of the treated animals if the ester thus formed saponified. \ _m compared to the animals of comparison, the pro / on-

3. Drugs containing the _tua connects i _e efficacy of the test substance determined,
fertilize according to claim 1 in addition to the usual pharmaceutically acceptable carriers and auxiliaries. _c) Anti-inflammatory effect

1. Acute carraghenin edema

(C. A. W i η s t e'r. E. A. R i s 1 e y, G. W. N u s s.

Proc. Soc. Biol. Med. 1962, 3, 544 7)

The invention relates to 2 "- [3- (2-Benzofuroyl) - 40 By injection of 0.05 ml of an aqueous 1%

phenyl] propionic acid, the optically active isomer of which is Carragheningels in the sole of the rat paw

and pharmacologically acceptable lower alkyl localized edema produced, which with an electrical

esters and a process for their production and mercury plethysmograph can be measured. The measuring

medicaments containing these compounds. sung the volume of the paw before and 3 hours after

The compounds according to the invention have anal- 45 the injection of the carraghenin enables the calculation table and anti-inflammatory properties, ting the percentage of inflammation. The test die Never is particularly beneficial for a therapeutic compound 1 hour before the carraghenin is taken orally Make treatment. administered. Even animals are used as test animals

In US-PS 36 82 976 phenyl-benzo groups of 10 male rats with a gene

furan-acetic acid compounds with an anti-inflammatory weight of 180 ± 10 g. This is generated for each animal

described effect. In contrast, edema have been calculated as follows:
the compounds of the invention mainly

analgesic effect. ^Vl ~ ^Vo

Furthermore, from DT-OS 22 35 941 6-y-dialkyl Vo
aminoalkoxy-jj-dimethoxy-benzofuran _{derivatives increase the volume of the pfole after} 3 _hours
knows, which is also analgesic and inflammatory _{Vo; Volume of pf} , _{to z} , ₀
The compounds according to the invention have inhibitory properties, but the compounds according to the invention have these properties. The proeinc known for the comparison group has a much stronger effect and a lower centual edema is toxicity for the treated groups, as can be seen from the following comparison results under the influence of the test substance . Protection determined.

a) Acute toxicity 2. With the tetrahydrofurfuryl ester of

The acute toxicity is determined as follows: The nicotinic acid (turfyl nicotinate) produces erythema

Compounds to be tested will be mice and fts The experiment is based on the slightly modified

Oral deprived rats performed the oral method of H a i η i η g as follows

administered. The acid prepared according to Example 1 (Br. Jl Pharmacol. 1963, 21, 104-12): As a test

is in 3% homogeneous gum arabic solution animals serve even groups of 6 to 12

male albino guinea pigs from 300 to 400 g, whose fur on the back was carefully checked the evening before has been depilated. On the day of the experiment, a Antibiogram disc applied, soaked with a 5% alcoholic solution of Turfylnicotin is. The observation is made after 5 minutes. The results are considered positive or negative expressed as a function of whether erythema occurs at the site of application of the disc or not. The test compound is administered orally in an equal amount of 1 hour before the test 1 ml / kg body weight administered. The joints are made even with 3% gum arabic suspended. The comparison animals receive an equal volume of the vehicle. This is compared with the treated animals occurring erythema as a percentage, based on the simultaneously treated comparison group.

20th

3. Chronic arthritis induced with adjuvant

Pearson's method (J. Chronic. Dis. 1963, 16, 863-874); R.D.Jones and J.R. Ward (Recent progress in hormone research. Volume XlX, 1963. Ac. Press), T. R. W a r d, R. S. J ο η e s (Arthritis and Rheumatism, 1962, 5, 557-564)

Male rats weighing 151 ± 20 g are used as test animals and on day 0 0.05 ml of a suspension of Mycobacterium _ _1C butyricum in paraffin oil is injected into the skin of the tail root (12 mg killed microorganisms per ml). The animals are selected on day 14 and divided into equal groups of 15 rats. The test compounds are administered orally daily from the 14th day to the 28th day. ,. Chronic arthritis is assessed according to two criteria:

a) Arthritis index through separate assessment of the lesions (erythema, edema, deformations) each of the four limbs (evaluation numbers from 0 '' to 3, sum of the evaluation numbers maximum 12) for each animal on the 14th, 18th ... 21st, 24th and 28th day (evaluation is made arbitrarily by two various examiners).

b) Sedimentation velocity according to Kowarski (Pipette inclined at an angle of 45. Reading time 30 minutes).

The blood is taken retroorbicularly. The determination is made on the 14th, 21st and 28th day.

The statistical analysis is carried out after the test t for the sedimentation velocities and after the Test U (Mann and Whitney) for the arthritis indices performed.

d) Action as an antagonist of bradykinin

The antagonistic effect of the acid produced in Example 1 on one produced with bradykinin Bronchostriction (20 µg / kg i.v. in guinea pigs) was examined. The attempt was made carried out according to the classical method described by K ο η ζ e 11 and R ο s s 1 e r (Artch. Exp. Path. Pharmakol, 195, 71-74) and by Haric h a u χ was resumed (C. R. Soc. Rinl 158. 12. 2437 2441). The one evoked with bradykinin Bronchospasm is caused by this compound when administered intravenously in one go Dose of 100 y / kg inhibited.

The results of the experiments described above are in the following Tables I, II and compiled.

Table I.

Connection Siegmund test from example

Carraghenine edema

Turfyl

nikolinai-

erythema

1 (acid) 0.72 mg / kg

2 <6 mg / kg

3 <6 mg / kg

Table II

9 mg / kg 3.6 mg / kg

8 mg / kg Z3 mg / kg

-11.5 mg / kg 8 mg / kg

Tested connection

Example I (acid) ethyl ester of Example 1 phenylbutazone (known)

Table III

Tested connection

DL _5n test according to Carra- Turfyl-

Mouse oral victory- gccnin- nicotinal-

m u η d edema erythema

EN ₅₀ EN ₅₀

Imgkgl (mg kg) <mg kg)

2500 0.72 9 3.6

1300 1

600 90 65

DL ₅₁ , Amilgct effect Inflammatory mouse inhibiting orul effect

Carrageenin

(mg kg) (mg kgl

(mg kg)

45

2500 dose: 0.72 dose:

Protection: 50% Protection: 50%

13 (X) dose: 1 dose:

Protection: 50% Protection: 50%

575 dose: 50 dose:

Protection: 60% Protection: 70%

475 dose: 50 dose:

Protection: 70% Slit: 50%

Example 1 (acid) ethyl ester of Example 1 Benzofuran derivative No. 71 256 der DT-OS 22 35 341 Benzofuran derivative No. 72 157 of DT-OS 22 35Ml

, In addition, the well-known connection 72 156 diuretic. At a dose of 20 mg / kg, it causes an increase of 100% in diuresis. This means that this compound cannot be used in therapy as an analgesic.

. The compounds according to the invention are used in pharmaceutical preparations, in particular orally, e.g. B. administered in the form of tablets or capsules or rectally as suppositories, the active ingredient each

because together with the usual inert carrier or Auxiliary materials is combined. Advantageously used in the case of oral or rectal administration for example a dose of 0.050 to 1 g of active ingredient per 24 hours.

The compounds according to the invention are prepared by one known per se Way salicylaldehyde with a ία-haloaceiyl) -arylacetic acid derivative the general formula

X-CH, -CO

CH COOR

CH ₃

in which R denotes a lower alkyl radical and X denotes a halogen atom, and optionally converts the here formed ester verieft to the corresponding acid. jo

The condensation of salicylaldehyde with the (-haloacetyl-arylacetic acid derivative is advantageously carried out in such a way that an equimolar mixture of the components in an organic solvent, generally an alcohol or in acetone, in the presence of an alkaline agent, e.g. sodium carbonate or potassium carbonate or Sodium or potassium bicarbonate, is heated at the reflux condenser.

Due to the methyl substituent in the position of the carboxyl group, there is an asymmetrical carbon atom in (i-position of the carboxyl group. The two optical isomers can be selected from processes known from the literature are isolated by adding a salt of this racemic acid with an optically active 1- or d-amine e.g. B. the «-Methylbenzylamin produces and from the formed Salt sets the isomer in question free.

The («-HalogenacetyD-arylacetic acid derivative to be used as the starting material can be prepared by halogenation of the corresponding acetyl derivative. The acclyl derivative in turn can through produced a Friedel-Crafts reaction between the corresponding arylacetic acid derivative and acetyl chloride will. This reaction is carried out in the presence of aluminum chloride, using as a solvent generally carbon disulfide, methylene chloride, 1,2-dichloroethane is used. The The resulting mixture of p- and m-acetyl acetic acid derivatives is separated according to traditional methods, for example by means of a spinning band column. It is also possible to mix the two in question To convert esters into a mixture of the resulting acids by alkaline or acidic saponification and to separate the pure p- and m-acids from this by fractional crystallization.

example 1

2 "- [. V- (2-Beii7ofuroyl) phenyl] propionic acid

and their ethyl ester λο

Ethyl 2 "- [3 '- (2-Benzofuroyl) phenyl] propionate

A mixture of 0.1 mol of m - («- bromoacetyl) -2-phenylethyl propionate, 0.2 mol of dry potassium carbonate, 0.1 mol of salicylaldehyde and 200 ml of ethanol is refluxed for 5 hours with thorough stirring. The yellow starting mixture turns maroon on heating. It is then allowed to cool, the precipitate is filtered off with suction, the alcohol is evaporated under reduced pressure, the remaining residue is taken up in ethyl acetate, the organic phase is washed with water until the wash water is neutral, dried and evaporated and the residue is distilled. A thick oil of b.p. _{o 05} 210 to 220 "C. is obtained.

A second distillation of this oil gives pure 2 "- [3 '- (2 - Benzofuroyl) phenyl] propionic acid ethyl ester, that of a mixture of equal parts sulfuric acid ether / petroleum ether 40-60 C in fine white crystals crystallized. Melting point 55-56X. The yield is 25%.

Preparation of 2 "- [3 '- {2-Benzofuroyl) phenyl] propionic acid

0.05 mol of the ester obtained above is dissolved in methyl alcohol and treated with 0.15 mol sodium hydroxide, that is dissolved in the minimum amount of water, left to stand at room temperature for 24 hours, whereby the ester is saponified. The alcohol is then evaporated off, and water and ether are added to the residue added, acidified with 2N HCl and extracted with ether The ether extract is washed with water and then evaporated. The residue obtained in this way is made from a small amount of methanol recrystallized. The 2 "- [3 '- (2-Benzofuroyl) phenyl] propionic acid is obtained as a white powder with a temperature of 140 ° C. The yield is 80%.

The m - («- Bromoacetyl) -2-phenylethylpropionate used as the starting material above is as follows manufactured:

a) Preparation of a mixture of
p- and m-acetyl-2-phenylethyl propionate

To a well-stirred suspension of 1.2 mol of aluminum chloride which is kept at -IOC by cooling in 0.5 ml of methylene chloride, a solution of 0.3 mol of 2-phenylethyl propionate in methylene chloride and then slowly one after the other a solution of 1.2 mol of acetyl chloride in methylene chloride was added. The temperature of the mixture must not exceed 10 C during the addition of the reactants. The mixture will then stirred at room temperature for a further 24 hours. The mixture is then poured into a mixture of ice and hydrochloric acid (about 50 ml), decanted and then extracted the aqueous phase again with methylene chloride. The organic phases are combined, washed neutral with water, over sodium sulfate dried, and then the solvent is distilled off. The oily residue is distilled. At the Bp., Between 140 and 145 "C, a mixture of p- and m-acetyl-2-phenylethylpropionate passes over Yield is 52%.

b) Separation of the mixture from a)

The mixture obtained under a) is separated by fractional distillation with a spinning band column performed. The m-isomer passes over first. The purity of each fraction is determined by Gas chromatography determined. The boiling points of the m- and p-ethyl esters are almost identical: bp, 165— 170 C. The two isomers can be fractionated by distillation with a spinning band column. The p- and m-derivatives are clear oils of bp. 141-142 C and of bp. 144-145 C / l mm.

c) Preparation of m- (u-bromoacetyl) -2-phenylethyl propionate

To a well stirred and cooled mixture, which is a solution of 0.1 mol of the obtained according to b) 2- (m-Acetylphenyl) ethyl propionate in 100 ml dry Containing ether and some aluminum chloride, 0.1 mol of bromine are added dropwise. The reaction mixture is then stirred for 1 hour at room temperature and then poured into a mixture of Poured ice and water. Extract with ether, wash the ether extract neutral with water and dry the organic solution and evaporates the ether. The crude m- (u-bromoacetyl) -2-phenylethylpropionate remains as a residue in the form of a light yellow oil.

Example 2

d-2 "- [3 '- (2-BenzofuroyI) phenyl] propionic acid

20th

In 60 ml of ethyl acetate, 0.01 mol of racemic 2- [3- (2-benzofuroyl) phenyl] prepared according to Example 1 propionic acid and 0.01 mole of 1-a-methylbenzylamine solved. The slowly settling white crystals are sucked off. These crystals become recrystallized three times from ethyl acetate. The salt in question melts at 145 to 146 C.

The acid is released by mixing the aqueous solution of the organic salt with dilute hydrochloric acid acidified. The acid is extracted with ethyl ether or ethyl acetate. The organic phase will washed with water until the wash waters are neutral. It is made over anhydrous sodium sulfate dried, then the solvent evaporated under reduced pressure. The residue becomes solid and can be recrystallized from methanol. The d-isomer of 2 "- [3 '- (2-Benzofurovl) -phenyl] propionic acid is obtained. This acid melts at 135 to 126 ° C.

["]" = +26 (methanol).

Example 3
1-2 "- [3 '- (2-Benzofuroyl) phenyl] propionic acid

According to Example 2, using d-u-methylbenzylamine instead of the 1-isomer the salt in question from F. 145 to 146 C.

This becomes the l-2 "- [3 '- (2-Benzofuroyl) -phenyl] propionic acid received from F. 126 C.

[ _(l ] »= -27 (methanol).

Claims (1)

homogsn suspended. The animals are observed according to the claims: treatment for 14 days. 1.2 "- [3 '- (2-Benzofuroyl) phenyl] propionic acid _{DL rat λ 300 mg / kg} the formula. DL ₅₀ MaUS 2,500 mg / kg J \. For the compounds according to Examples 2 and 3 Γ Ji J | _ _co _h / ~ \ the following DL ₅₀ results: X ^ ⁰ "^^ \ DL ₅₀ mouse> 2,000 mg / kg CH-COOH ¹⁰ _b) Analgesic effect