CS221324B1 - 5,5-disubstituted acids of the 2-aminobarbiturate - Google Patents

Abstract

5,5-disubstituted 2-aminobarbituric acid formula I, O nh-4 R Η2ΝΛ X N-COOH (AND) O wherein R is chlorine, bromine, propyl, allyl, propargyl, phenyl or a 4-carboxybutyl group having antineoplastic effect in animals s experimental transplant dory.

Description

The present invention relates to 5,5-disubstituted 2-aminobarbituric acids of formula (I)

O

R

CO OH (I) wherein R represents a chlorine, bromine, propyl, allyl, propargyl, phenyl or 4-carboxybutyl group.

The compounds of formula (I), as defined above for R, are derivatives of 4 - [(2-amino-4-oxo-6-hydroxy-3,4-dihydro-5-pyrimidinyl) methyl] benzoic acid or its tautomeric forms which have shown a significant antinenplastic effect in animals with experimental tumors (see, for example, US Patent No. 211196). Compounds of formula I, as defined above, have demonstrated an antineoplastic effect, in a dose range of 50-100 mg / kg, administered subcutaneously in screening trials in animals with experimental transplantable tumors, resulting in reduced experimental tumor size or prolonged survival of experimental animals. The compounds of the formula I, with the meaning of R mentioned above, always influenced one of the monitored parameters in the range of 10 to 20%. The most pronounced activity was found for the compound of formula I in which R is bromine, which reduced the tumor size by 31% at a dose of 100 mg / kg and by 25% at a dose of 50 mg / kg administered subcutaneously to Sa 37 tumor-bearing mice. Similarly, the compound of formula I in which R is an allyl group prolonged the survival of experimental animals with S 180 tumor at a dose of 100 mg / kg by 20% and by administering the same dose to animals (rats) with ascitic Yoshida tumor by 21%.

The compounds of the formula I in which R represents a chlorine or bromine atom are prepared according to the invention by halogenating compounds of the formula Π,

(II) by treatment with free or liberated halogen, in an aqueous medium, at room temperature.

The compounds of the formula I in which R is a propyl, allyl, propargyl, phenyl or 4-carboxybutyl group are prepared according to the invention by condensation of the triethyl ester of the tricarboxylic acid of the formula III,

WeC, OOC R s / η ₅ ο _ζ οοο ^{7 x} ch 2 -4 ^ -c ° ^oc 2h _s (III) in which R is as defined above, by condensation with guanidine or its adduct with inorganic or organic acids, preferably with hydrochloride, in the presence of sodium alcoholate, preferably sodium methylate, whereupon the crude condensation product is saponified and the substance is released from the solution by mineral acid.

Compounds of formula III, as defined above for R, can be prepared, mostly in very good yield, by the same method described for example for the synthesis of 2- (3-icarboxybenzyl) -1,3-propanedioic acid triethylested (Schaeffer JP et al .: J Org. Chem., 32, 1372 (1967) The compound of formula II is a substance known and readily obtainable according to the author's certificate No. 211196.

Further details of the method of manufacture of the materials will be apparent from the following non-limiting examples.

Example 1

4 - [(2-Amino-4,6-dioxo-5-chloro-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid

7.84 g (0.03 mol) of 4 - [(2-amino-4-oxo-6-hydroxy-3,4-dihydro-5-pyrimidinyl) methyl] benzoic acid are suspended in a mixture of 240 ml of 10% acid. hydrochloric acid and 48 ml of 30% hydrogen peroxide and the reaction mixture was allowed to stand at room temperature for 14 days with occasional shaking. The reaction product is filtered off, washed with water and dried. After purification by crystallization from dimethylformamide-methanol, a material having a melting point of up to 360 ° C is obtained.

Example 2

4 - [(2-Amino-4,6-dioxo-5-bromo-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid

5.22 g (0.02 mol) of 4 - [(2-amino-6-hydroxy-4-oxo-3,4'-dihydro-5-pyrimidinyl] methyl] benzoic acid is suspended in 200 ml of water and slowly stirred with stirring 2 ml of bromine was added dropwise, the reaction mixture was stirred at room temperature for 2 hours, the product was filtered off, washed with water and dried, after purification by crystallization from dimethylformaid-methanol, to give a substance of about 280 ° C without melting.

Example 3

2-Allyl-2- (4-carboxybenzyl) -1,3-propanedioic acid triethyl ester

To a solution of 2.3 g (0.1 mol) of sodium in 70 ml of ethanol was added dropwise 22.03 g (0.11 mol) of 2-allyl-1,3-propanedioic acid diethyl ester, refluxed for 10 minutes with stirring, then 26.8 g (0.11 mol) of 4-bromomethyl-benzoate are added dropwise and the reaction mixture is refluxed with stirring for 6 hours. After evaporating the ethanol in vacuo, water was added to the reaction mixture, the organic portion was taken up in ether, the extract was dried over anhydrous sodium sulfate and the ether was evaporated in vacuo. The crude product is purified by vacuum distillation. The fraction boiling at 174-179 ° C / 27 Pa was collected.

In the same manner, using the corresponding diethyl esters of 2-substituted 1,3-propanedioic acids, the following were prepared:

2-Propyl-2- (4-carboxybenzyl) -1H-propanedioic acid triethyl ester, boiling point 182-186 ° C / 27 Pa, 2-propargyl-2- (4-carboxybenzyl) -1,3-propanedioic acid triethyl ester, temperature boiling point 184-186 ° C / 27 Pa, 2-phenyl-2- (4-carboxybenzyl) -1,3-propanedioic acid triethyl ester, boiling point 198-204 ° C / 52 Pa, 2- (4-ethoxycarbonylbutyl) triethyl ester -2- (4-carboxybenzyl) -1,3-proipanedione, boiling point 246-251 ° C / 13 Pa.

Example 4

4 - [(2-Amino-4,6-dioxo-5-allyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid

To a solution of sodium methylate prepared by dissolving 2.76 g (0.12 moles) of sodium in 40 ml of methanol, 7.64 g (0.08 moles) of guanidine hydrochloride are added, the suspension is stirred for 10 minutes and 14.5 g are added. (0.04 mol) of 2-allyl-2- (4-carboxybenzyl) -1,3-propanedioic acid triethyl ester and the reaction mixture was stirred at room temperature for 4 hours. After distilling off the methanol under reduced pressure, the residue is saponified with 80 ml of 0.5 NaOH at 20-25 ° C, filtered and the filtrate is acidified with dilute hydrochloric acid (1: 1) to pH 2. The precipitate is filtered off, washed with water. and dried. The material obtained is purified by reprecipitation from dilute sodium hydroxide solution with hydrochloric acid. M.p. 335-337 ° C.

In the same manner as in Example 4, using the corresponding triethyl esters of 2- (4-carboxybenzyl) -1,3-propanedioic acid, 2- (4-carboxybenzyl) -1,2-propanedioic acid, the following were prepared:

4 - [(2-amino-4,6-dioxo-5-propyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid, m.p. 339-341 ° C, 4- [ (2-amino-4,6-dioxo-5-propargyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid, melting point above 360 ° C, 4 - [(2-amino-4) 6-dioxo-5-phenyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid, m.p. 324-327 ° C, 4 - [(2-amino-4,6-dioxo-) 5- (4-carboxybutyl) -3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzo, m.p. 317-319 ° C.

Claims (8)

SUBJECT What is claimed is: 1. A 5,5-disubstituted 2-aminobarbituric acid of the general formula I, in which R represents a chlorine, bromine, propyl, allyl, propargyl, phenyl or 4-carboxybutyl group. 2. 4 - [(2-Amino-4,6-dioxo-5-chloro-3,4,5,6-tetrahydro-5-pyrimidinyl) ethyl] benzoic acid. YNÁLEZU 3. 4 - [(2-Amino-4,6-dioxo-5-bromo-3,4,5,6-tetraihydro-5-pyrimidinyl) ethyl] benzoic acid. 4. 4 - [(2-Amino-4,6-dioxo-5-allyl-3,4,5,6-tetrahydro-5-pyrimidinyl) imethyl] benzoic acid. 5. 4 - [(2-Amino-4,6-dioxo-5-propyl-3,4,5,6-tetraihydro-5-pyrimidinyl) methyl] benzoic acid. 6. 4 - [(2-Amino-4,6-dioxo-5-propargyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid. 4 - [(2-Amino-4,6-dioxo-5-phenyl-3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid. 8. 4 - [(2-Amino-4,6-dioxo-5- (4-carboxybutyl) -3,4,5,6-tetrahydro-5-pyrimidinyl) methyl] benzoic acid.