CS212520B1 - 4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid derivatives - Google Patents

Abstract

The invention relates to new esters of 7-ethyl-4-(4-ethylphenyl)-2,3-dibromonaphthyl-1-oxyacetic acid and the ethyl ester, respectively, of 4-phenyl-2,3-dibromonaphthyl-1-oxyacetic acid, which exhibit antineoplastic activity in animals with experimental tumors, manifested by a decrease in tumor size. According to the invention, the above-mentioned substances are prepared by reacting the acid chloride, prepared from 7-ethyl-4-(4-ethylphenyl)-2,3-dibromonaphthyl-1-oxyacetic acid by reaction with thionyl chloride, with the corresponding alcohol at elevated temperature. The ethyl ester of 4-phenyl-2,3-dibromonaphthyl-1-oxyacetic acid is prepared by reacting 4-phenyl-2,3-dibromo-alpha-naphthol with ethyl bromoacetate, in the presence of sodium ethoxide. Hydrolysis of the ethyl ester thus formed with an aqueous-alcoholic solution of sodium hydroxide yields the corresponding 4-phenyl-2,3-dibromonaphthyl-1-oxyacetic acid.

Description

The present invention relates to 4-phenyl-2,3-dibromo-1-naphthyloxyacetic acid derivatives of the general formula I

Wherein R is hydrogen or ethyl and R is hydrogen or a carbon chain, straight or branched, having from 1 to 4 carbon atoms or cyclopentyl.

These derivatives showed an biological evaluation in animals with transplanted tumors antineoplastic effect, in accordance with the previously ascertained the effect of ethyl 7-ethyl-4- (4-ethylphenyl ^of) -2,3-dibromo-1-nařtyloxyoetové (MS. Author's Certificate No. 203,291) and are therefore potential chemotherapeutics of human reservoir diseases. Compounds of formula 1 at a dose of 50 mg / kg / day, administered to mouse strain H for 12 days, significantly reduced the tumor size of treated animals with S 37 by 10-20%, without affecting the survival of the animals. At a dose of 50 mg / kg / day administered sc for 8 days, a similar effect was found, reducing the tumor size by 20 to 30%. The n-butyl 7-ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid n-butyl ester showed the most pronounced effect of the investigated group.

i 2

Compounds of formula 1 in which R is ethyl and R is carbon chain, straight or branched, having from 1 to 4 carbon atoms or cyclopentyl, are prepared, for example, from a compound of formula IX

och ₂ cor ³ in which r 'is the same as in formula I and R' is hydroxy which is converted by reaction with 1 to 2 mol equivalents of thionyl chloride in an inert solvent of the chlorinated aliphatic hydrocarbon or aromatic hydrocarbon type, e.g. wherein r 'denotes the same as in formula I and a chlorine atom which is condensed with an excess of the corresponding straight or branched carbon chain alcohol, 3 to 4 carbon atoms, or cyclopentanol; the alcohol used also serves as the reaction medium. The reaction temperature may range from 50 to 100 ° C, and the reaction time may range from 2 to 8 hours.

Other methods, conventional and special, for example acid-catalyzed esterifications, optionally reactions in the presence of carbonyldiimidazole or cyclohexylcarbodiimide, can be used to esterify a compound of formula II in which R @ ¹ is the same as in formula I and R @ ³ . however, these methods are less economically advantageous.

The starting material of formula (II), in which r 'denotes the same as in formula (I) and R (1) is hydroxy, is known and readily obtainable by the above-mentioned cit. copyright certificate.

2

A compound of formula I in which R is hydrogen and R is ethyl is preferably prepared from a compound of formula III

OH by reacting with 1 to 2 mol equivalents of ethyl bromoacetate, in ethanol, in the presence of 1 to 2 mol equivalents of sodium ethylate, at a temperature of from 20 ° C to the boiling point of the reaction mixture for 1 to 8 hours.

The reaction mixture obtained is worked up in the customary manner, for example, after filtration of sodium bromide, it is concentrated, the residue is dissolved in chloroform, freed from the unreacted starting material by shaking with water and concentrated to crystallize.

i 2

A compound of formula (I) wherein R and R are hydrogen is prepared from a compound of formula (I) wherein R is hydrogen and R is ethyl by hydrolysis using a 5-10% alkali metal hydroxide solution, preferably hydroxide sodium, in an environment of 40 to 50% aqueous ethanol, at a temperature of from 20 ° C to the boiling point of the reaction mixture, for 1 to 8 hours.

The reaction mixture obtained is worked up in the customary manner, for example, after filtration of sodium bromide, it is concentrated, the residue is dissolved in chloroform, freed from the unreacted starting material by shaking with water and concentrated to crystallize.

2

A compound of formula I wherein R and R are hydrogen is prepared from a compound of formula I wherein R ¹ is hydrogen and R ² is ethyl, by hydrolysis using a 5 to 0% alkali metal hydroxide solution, and the advantage of sodium hydroxide, in an environment of 40 to 50% aqueous ethanol, at a temperature of from 20 ° C to the boiling point of the reaction mixture, for 1 to 8 hours.

After hydrolysis, the reaction mixture is worked up in the usual manner for this type of reaction, for example after acidification with hydrochloric acid (10 94), the precipitated substance is taken up in a water-immiscible organic solvent and purified by crystallization.

The compound of formula III is readily recoverable, e.g. certificate number 204 211.

More detailed information on the preparation of the compounds of formula I is given in the following examples. The melting points given in the examples are determined on the Kofler block and are not corrected.

Example 1

7-Ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid methyl ester

To a suspension of 9.84 g (20 mmol) of 7-ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid in 50 ml of benzene was added 2.62 g (22 mmol) of thionyl chloride. and 0.1 ml of dimethylformamide and the reaction mixture was refluxed for 4 hours. After distilling off the volatiles in a water-jet vacuum, the oily residue is poured over 100 ml of ethanol and the solution is refluxed for 4 hours and then left to stand overnight in the refrigerator. The precipitate was filtered off with suction, washed with methanol and recrystallized in methanol. Melting point 87-88 ° C.

Similarly, the following compounds are prepared using the corresponding alcohols:

7-Ethyl-4- (4'-ethylphenyl) -2,3-dibroa-1-naphthyloxyacetic acid isopropyl ester, m.p.

up to 89 ° C (methanol);

Butyl 7-ethyl-4- ^{(4-ethylphenyl)} -2,3-dibromo-1-naphthyloxyacetic, mp 85-87 ° C (methanol);

7-ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid cyclopentyl ester, mp 76-78 ° C (methanol).

Example 2

4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid ethyl ester

To a solution of 151.1 g (0.4 mol) of 4-phenyl-2,3-dibromo-alpha-naphthol in an ethanolic solution of sodium ethylate, prepared by dissolving 10.1 g (0.44 mol) of sodium in 1400 ml of ethanol, 73.5 g (0.44 mol) of ethyl bromoacetate are added and the reaction mixture is refluxed for 2 hours.

After filtering off the sodium bromide and distilling off the volatiles, the residue is dissolved in chloroform, shaken with an equal volume of water and the chloroform fraction is concentrated to crystallize. The crude product was recrystallized from benzene-hexane (1: 3), mp 79-81 ° C.

Example 3

4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid

A suspension of 139 g (0.3 mol) of 4-phenyl-2,3-dibromo-1-naphthyloxyacetic acid ethyl ester in 1600 ml of a 1: 1 aqueous ethanolic solution of sodium hydroxide (7.5 96) was stirred at room temperature for 1 hour. 20-25 ° C and then refluxed for 2 hours. After hydrolysis, the reaction mixture is acidified with 10% hydrochloric acid and the separated organic layer is taken up in chloroform, shaken with water and concentrated to crystallize. Recrystallization of the crude product from chloroform gave the pure product, mp 202-203 ° C.

Claims (7)

CLAIMS 1. 4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid derivatives of the formula I Wherein R represents a hydrogen atom or an ethyl group and R represents a hydrogen atom or a carbon chain, straight or branched, having from 1 to 4 carbon atoms, or a cyclopentyl group. 2. 4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid ethyl ester. 3 4-Phenyl-2,3-dibromo-1-naphthyloxyacetic acid. 4. 7-Ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthylacetic acid ethyl ester. 5. Isopropyl 7-ethyl-4- (4 ^- ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid. 6. 7-Ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid butyl ester. 7. 7-Ethyl-4- (4'-ethylphenyl) -2,3-dibromo-1-naphthyloxyacetic acid cyclopentyl ester