CS196901B1 - Antiinflammatory active substituted 3-phenyl-2-methylpropionic acid - Google Patents

Description

The present invention relates to the anti-inflammatory activity of the 3-phenyl-2-methylpropionic acid of the formula I

CH.CHCOOH

CH <

(i) wherein R ¹ is hydrogen or chlorine and R ² is straight or branched (C 1 -C 6) alkyl and pharmaceutically acceptable salts thereof with inorganic or organic bases.

The compounds of the formula I which are novel are very toxic and have no ulcerogenic effects. They may be used to prepare therapeutic compositions which may contain one or more active ingredients in admixture with pharmaceutically acceptable excipients, liquid or solid, which are customary in the manufacture of dosage forms. Significant anti-inflammatory effects have been found especially in the cyclohexylammonium salt of 3- (3‘-chloro-4‘-isobutoxyphenyl) -2-methylpropionic acid and 3- (4‘-isopropoxyphenyl) -2-methylpropionic acid.

Compounds of formula I may be prepared, for example, from substituted benzyl halides of formula II

K ^and O - / y - cH _and x ^J (II),

198901 in which R ¹ and R ² is the same as in formula I and X is a chlorine or bromine atom which, by reaction with an octyl malonate, provides a substituted benzyl malonate in the presence of an alkali metal alcoholate such as sodium ethylate of ethyl (III)

R * 0

(III), wherein R ¹ and R ² is the same as in Formula I, and that by treatment with methyl iodide in the presence of an alkali metal alcoholate such as sodium methylate or ethylate in an inert organic solvent such as ethanol or methanol affords 2- ethyl methyl 2-menzylmalonate of formula IV

R ^and 0

CHaCÍCOOCjtHg)

CH ₉ (IV), wherein R ¹ and R ^{2 are the} same as in Formula I, whose alkaline hydrolysis, e.g. , preferably at 190 to 200 ° C, provides a substituted 3-phenyl-2-methylpropionic acid of formula I. The acids obtained can be converted, if desired, either to salts with inorganic bases, for example sodium or organic bases, preferably cyclohexylamine , to the corresponding cyclohexylammonium salt.

The results of anti-inflammatory testing and acute toxicity determination of several of the most active substances according to the invention are given in the table (dose 100 mg / kg):

X —Μ- (η)

X ¹ X ² LD50 (mg / kg) % Inhibition Kaolin edema ^a Freund's adjuvant ^b ISSO-C3H7O H > 1000 43 30 IS0-C4H9O Cl > 1000 39 44 CH3O H > 1000 48 36 Mervan ^c 1000 27 Mar: 41 Brufen ^d > 1000 53 37

^and Assay performed according to: Hillebrecht J .: Arzneim. — Forsch. 9,625 (1959);

^and Determination according to: Hillebrecht J .: Arzjnová J .: Cesk. Fysiol. 17,137 (1968);

^c 3-chloro-4-allyloxyphenylacetic acid ^d 2- (4'-isobutylphenyl) propionic acid

The following examples illustrate the invention sufficiently, but do not limit it in any way.

Examples

Example 1

3- (3‘-Chloro-4‘-methoxyphenyl) -2-methylpropionic acid

a) To a solution of sodium ethylate prepared from 17.3 g of sodium and 450 ml of ethanol, 133.3 g of ethyl malonate is added over 30 minutes, followed by a solution of 144.5 g of 3-chloro-4-methoxybenzyl chloride in 250 ml of ethanol. so that the temperature does not exceed 30 ° C. The reaction mixture is then heated at reflux for 8 hours, the solvent is evaporated off under vacuum and the residue is poured into 350 ml of water and 350 ml of ether. After shaking, the ether solution is separated and the aqueous layer is extracted with 200 ml of ether. The combined ether extracts were washed with water (2.times.200 ml), dried (MgSO4) and the ether evaporated in vacuo. Vacuum distillation yielded 130 g (57.4% of theory) of ethyl 3-chloro-4-methoxybenzylmalonate having a boiling point of 137-140 [deg.] C./2 mm Hg.

hj To a solution of sodium ethylate prepared from 10.3 g of sodium and 300 ml of ethanol was added 130 g of ethyl 3-chloro-4-methoxybenzyl malonate at a temperature of 10-15 ° C. Then, 75.5 g of methyl iodide dissolved in 40 ml of ethanol are added at 0 to 2 ° C and the reaction mixture is maintained at 2 to 5 ° C for 1 hour. After boiling for 8 hours, ethanol is distilled off and the residue is poured into 350 ml of water and 350 ml of ether. After shaking and separating the ether extract, the aqueous layer is washed with an additional 200 ml of ether. The combined ether extracts were washed with water (2.times.200 ml), dried (MgSO4) and the ether distilled off in vacuo. Vacuum distillation of the residue gave 117 g (85.7% of theory) of ethyl 2- (3‘-chloro-4‘-methoxybenzyl) -2-methylmalonate, b.p. 131-133 ° C / 13.3 Pa.

c) 15.8 g of the obtained malonate are heated to boiling with 120 ml of a 10% aqueous methanolic potassium hydroxide solution for 6 hours. The reaction mixture was then evaporated to dryness and the residue was heated to boiling with 30 g of 50% aqueous potassium hydroxide for a further 2 hours. After cooling, the suspension is dissolved by the addition of 30 ml of water and the solution is filtered with charcoal. 2- (3'-Chloro-4'-methoxybenzyl) -2-methylmalonic acid, m.p. 168 DEG-171 DEG C., which, after drying, without further purification, is decarboxylated by heating to 190 DEG C. 195 ° C for 20 minutes. After cooling, the residue is dissolved by addition of 50 ml of water and basified with 5% sodium hydroxide solution to pH 10-11. After drying and evaporation of the ether solution, a residue is obtained which is crystallized from aqueous methanol (3: 2) to give 3- (3'-chloro-4'-methoxyphenyl) -2-methylpropionic acid (9.8 g, 85%). M.p. 73.5-74.5 ° C.

In the same manner and in a similar yield, the following acids were prepared from the corresponding benzyl chlorides:

3- (4‘-isopropoxyphenyl) -2'-methylpropionic acid, boiling point 133-135 ° C / 60 Pa,

3- (4‘-Methoxyphenyl) -2-methylpropionic acid, boiling range 108 to 110 ° C / 100 Pa,

3- (3‘-Chloro-4‘-isobutoxyphenyl) -2-methylpropionic acid, m.p. 81-82 ° C; and

3- (3‘-Chloro-4‘-n-hexyloxyphenyl) -2-methylpropionic acid, m.p. 76-77 ° C.

Example 2

Cyclohexylammonium salt of 3- (4'-isopropoxyphenyl) -2-methylpropionic acid To a solution of 5.5 g of 3- (4'-isopropoxyphenyl) -2-methylpropionic acid in 35 ml of ether is added a solution of 3.0 g of cyclohexylamine in 10 ml of stirring. ml of ether. The precipitate formed is filtered and washed with ether after standing for 2 hours at 5 ° C. 7.3 g (91.0% of theory) of the cyclohexylammonium salt of 3- (4‘-isopropoxyphenyl) -2-methylpropionic acid, m.p. 127 DEG-128 DEG C., are obtained.

The following salts were prepared in the same manner as in Example 2: cyclohexylammonium salt of 3- (4'-methoxyphenyl) -2-methylpropionic acid, m.p. 130-131 ° C, cyclohexylammonium salt of 3- (3'-chloro-4); 129-130 ° C, 3- (3'-chloro-4'-isopropoxyphenyl) -2-methylpropionic acid cyclohexylammonium salt, m.p. 96-97.5 ° C, and cyclohexylammonium. 3- (3'-chloro-4'-isobutoxyphenyl) -2-methylpropionic acid salt, m.p. 118-119 ° C.

Example 3

3- (3‘-Chloro-4‘-methoxyphenyl) -2-methylpropionic acid, sodium salt

To a solution of 4.6 g of 3- (3‘-chloro-4‘-methoxyphenyl) -2-methylpropionic acid in 50 ml of benzene is added, with stirring, 20 ml of a 1 N solution of sodium ethylate in ethanol. After 30 minutes, the reaction mixture is diluted with 250 ml of ether and the precipitate formed is filtered off with suction and washed with ether. 5.0 g of 3- (3‘-chloro-4‘-methoxyphenyl) -2-methylpropionic acid sodium salt, m.p. 185 DEG-187 DEG C., are obtained.

Similarly, 3- (3 3--chloro-4‘-isobutoxyphenyl) -2-methylpropionic acid sodium salt, m.p. 204-206 ° C, was prepared.

Object of the invention

Claims (3)

Object of the invention An anti-inflammatory active substituted 3-phenyl-2-methylpropionic acid of the general formula I R < --CHjCHCOOH CH _and (i) wherein R ¹ is hydrogen chloro and R ² is straight or branched (C 1 -C 6) alkyl and pharmaceutically acceptable salts thereof with inorganic or organic bases. 2. Cyclohexylammonium salt of 3- (4‘-isopropoxyphenyl) -2-methylpropionic acid. 3. Cyclohexylammonium salt of 3- (3‘-chloro-4‘-iso butoxyphenyl) -2-methylpropionic acid. Vychodoceske tiskarny n. P., Provoz 19 Litomysl Price: 2.40 Kčs