CS247572B1 - 2-aryl-8-chloro-6-flavonylaliphatic acids - Google Patents

Abstract

The solution relates to 2-aryl-8-chloro-6- -flavonylaliphatic acids of general formula I which can be prepared from suitably substituted 3-benzylideneacetyl-4- -hydroxy-5-chlorophenylaliphatic acids by addition of bromine and subsequent dehydrobromination cyclization in alkaline medium. The acids of formula I are characterized by an antiulcer effect comparable to cimetidine while being less toxic.

Description

The invention relates to 2-aryl-8-chloro-6-flavonylaliphatic acids of the general formula I.CHCOOH

X*

Cl in which R is a hydrogen atom or methyl and X ¹ is a hydrogen atom or an alkyl with one to four carbon atoms. These acids are characterized by an antiulcer effect, which is probably associated with inhibition of gastric Slavs secretion. At the same time, these substances are characterized by low toxicity.

They can be used to prepare therapeutic compositions, which may contain the active substance in admixture with pharmaceutically acceptable additives, liquid or solid, which are customary in the manufacture of dosage forms. Significant antiulcer and antisecretory effects were found in particular with 2-(4'-isopropylphenyl)-6-flavonyl-8-chloroacetic acid.

Compounds of general formula I can be prepared, for example, by reacting a suitably substituted chalcone of general formula II

in which X ¹ and R have the same meaning as in formula I, is reacted with bromine in a suitable inert solvent, preferably acetic acid, at a temperature of 15 to 40°C, preferably at 20 to 25°C.

The resulting dibromo derivative of general formula III

(III) in which x ¹ and R are the same as in formula I, is cyclized without further purification by the action of potassium hydroxide in a mixture of water and a lower alcohol, preferably ethanol, at a temperature of 10 to 30 °C, preferably at 20 to 25 °C.

The desired chalcones of general formula II can be advantageously prepared by reacting a substituted benzaldehyde of general formula IV ^(IV) χ'-θ-CHO in which X ¹ is the same as in formula I, with a 3-acetyl-4-hydroxy-5-chlorophenylaliphatic acid of general formula V

Cl

HIM

CHCOOH (V)

CH ₃ CO' in which R means the same as in formula X, in a mixture of water and an alcohol, for example ethanol, in an alkaline medium, for example in the presence of potassium hydroxide at a temperature of 10 to 15 °C.

The results of testing the antiulcer and antisecretory effects and determining the acute toxicity of 2-(4'-isopropylphenyl)-8-chloro-6-flavonylacetic acid are summarized in the table. The results of evaluating the antiulcer effect of cimetidine are presented for comparison.

Table Antiulcer and antisecretory efficacy of 2-(4'-isopropylphenyl)-8-chloro-6-flavonylacetic acid

Dose (mg/kg) Bleeding erosion Number; of ulcers defects % of rats Ulcerogenic % ulcer area (mm5 with ulcers index Immobilization ulcers ^and 100 0.3 0.3 1.0 1.3 40 24 0.53 Indomethacin ulcers* ³ 100 0.3 0.7 1.9 2.6 40 32 0.28 Q Cimetidine 200 0.5/0.1 0 .7/0.8 1.7/1.8 23/2.6 40/40 55/32 0.22/0.12 Check ^d - 2.1/2.4 2 ,4/2,7 5.4/22.3 7.8/24, 0 100/100 300/250 3.36/10.45 Dose (mg/kg) Volume (ml/100g) gastric contents Free HCl output (m. eq/100 g/2 h) Total acidity (g/2 h) Toxicity ^f (g/kg) Antisecretory Efficacy® 100 0.76 0, .003 0.019 1.0 Checks 1.30 0, .032 0.068

^a ' ^Immobilization and indomethacin ulcers were evaluated on a ten-member group of Wistar rats by the method according to: Němec J., Cesk. Farm. 27,317 (1978); ^c the first number indicates the effectiveness for immobilization ulcers, the second number for indomethacin ulcers; ^antisecretory efficacy was tested on rats with pyloric ligation by the method according to: Shay H. et al., Gastroenterology 26,906 (1954); ^í is understood in mice and rats.

The following examples of embodiments sufficiently illustrate the invention, but are not intended to limit it in any way.

Example 1

2-(4'-isopropylphenyl)-8-chloro-6-flavonylacetic acid

AND

3-chloro-4-hydroxy-5-(4'-isopropylbenzylideneacetyl)phenylacetic acid 24.3 g (70.5 mmol) is placed in a reaction flask and 940 ml of acetic acid is poured over. 13.6 g (84.5 mmol) of bromine is added dropwise to the solution so that the temperature of the reaction mixture does not exceed 20 °C and then stirred at this temperature for another 5 hours. 1,125 ml of 1% sodium thiosulfite solution is added; the reaction mixture is decolorized and at the same time the partially crystalline dibromo derivative III (X ¹ = Í-C3H7, R = Η) is precipitated, which crystallizes after 12 hours of standing. The precipitate is then filtered, washed with water and dissolved in 450 ml of ethanol. A solution of 22.8 g of potassium hydroxide in 235 ml of water is added dropwise to the solution. After 6 hours of stirring at 20 °C, ethanol is evaporated from the reaction mixture and approximately 500 ml of water is added to the residue, so that the separated oil goes into solution.

After filtration with activated carbon, the filtrate is acidified with 50% sulfuric acid under cooling.

The yellow precipitate is filtered off with suction, washed with water and, after drying, crystallized from 350 ml of 60% ethanol. 12.5 g (52.1%) of lemon yellow 2-(4'-isopropylphenyl)-8-chloro-6-flavonylacetic acid in the form of a monohydrate (CjqH^CIO^.HjO) with a melting point of 181-183 °C are obtained.

In the same way as in Example 1, the following were prepared:

2-phenyl-8-chloro-6-flavonylacetic acid in a yield of 51.5% with a melting point of 258 to 261 °C after crystallization from ethanol:

2-(4'-isobutylphenyl)-8-chloro-6-flavonylacetic acid in 45.2% yield with m.p. above 270 °C after crystallization from 75% methanol. For Cj^^ClO* (370, 82) calculated: 68.01% C, 5.16% Ή,

9.56% Cl; found: 67.69% C, 5.35% H, 9.52% Cl.

Example 2

2-(2'-Phenyl-8'-chloro-6'-flavone-1)propanoic acid

It was prepared from 2-(3'-chloro-4'-hydroxy-5'-benzylideneacetylphenyl)propanoic acid by bromination and subsequent cyclization in the same manner as in Example 1 in a yield of 37.6% with a m.p. above 270 °C after crystallization from ethanol. For CjgH^jClO^ (328.74) calculated: 65.75% C, 3.99%

H, 10.79% Cl; found: 65.75% C, 4.01% H, 10.53% Cl.

Example 3

3-Chloro-4-hydroxy-5-(4'-isopropylbenzylideneacetyl)phenylacetic acid

24.2 g (0.16 mol) of 4-isopropylbenzaldehyde, 34.6 g (0.15 mol) of 3-chloro-4-hydroxy-5-acetylphenylacetic acid and 420 ml of ethanol are placed in a flask. The slightly cloudy solution is cooled to 10 °C and 140 ml of 40% potassium hydroxide are added dropwise. The reaction mixture is clarified and the solution is stirred for 48 hours at 20 °C (the course of the reaction can be monitored by thin-layer chromatography on silica gel with a 3:1 mixture of benzene and ether as the mobile phase, a sample of the reaction mixture is acidified with 50% sulfuric acid and extracted into ether). After the reaction is complete, the mixture is evaporated to half its volume and the residue is poured into 900 ml of 20% hydrochloric acid with vigorous stirring. The orange precipitate that separated was dried to constant weight and crystallized from 330 ml of 75% acetic acid. After filtration under boiling with activated carbon, the filtrate was cooled and the separated product was filtered off with suction and washed with cooled 50% acetic acid. 38.8 g, i.e. 72.0%, of 3-chloro-4-hydroxy-5(4'-isopropylbenzylideneacetyl)phenylacetic acid with a melting point of

137-139 °C after crystallization from 75% acetic acid.

The following were prepared in the same way:

3-chloro-4-hydroxy-5-benzylideneacetylphenylacetic acid (from benzaldehyde and 3-chloro-4-hydroxy-5-acetylphenylacetic acid) in a yield of 73.8% with a m.p. of 203 to 204 °C after crystallization from ethanol;

3-chloro-4-hydroxy-5-(4'-isobutylbenzylideneacetyl)phenylacetic acid (from 4-isobutylbenzaldehyde and 3-chloro-4-hydroxy-5-acetylphenylacetic acid) in a yield of 52.6% with a m.p. of 154-155 °C after crystallization from 67% acetic acid;

2'7<3-chloro-4-hydroxy-5-benzylideneacetylphenyl)propanoic acid (from benzaldehyde and 2-(3'-chloro-4'-hydroxy-5'-acetylphenyl)propanoic acid) in a yield of 72.0% with a m.p. of 182 to 184 °C after crystallization from ethanol.

Claims (2)

OF THE INVENTION 2-Aryl-8-chloro-6-flavonylaliphatic acids of formula I (I) wherein R is hydrogen or methyl and X is hydrogen or C 1 -C 4 alkyl.