CS211196B1 - 4- / omega- (2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) -alkyl / benzoic acid - Google Patents

Abstract

New 4-((®-/2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl/alkyl)benzoic acids of the general formula 1, lI) OH in which n and .Λ to 5, acting therapeutically in animals with certain transplantable tumors, and <o inhibiting tumor growth, and statistically significantly prolonging life span compared to control.

Description

The present invention relates to 4- (o - (2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidin) alkyl) benzoic acids of formula (I):

O

NH-f ^H 2 ^N -CCH ₂ ) _n - (I)

N— \

OH in which n = 1 to 5.

The compounds of formula I are 5- (2-aaino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) valeric acid analogs of formula II,

O

Η ₂ Ν-ζ VcH ₂ -CH ₂ -CH ₂ -CH ₂ -COOH ^N \

OH (II) which was selected for clinical development due to its extraordinary biological effects (MS AO No. 176 667). The compounds of formula I exhibit similar biological effects to: the compound of formula XII with the same or higher efficacy, while maintaining low toxicity. For example, 4 - ([2-amino-6-hydroxy-4-oxo-3,4-dlhydro-5-pyrimidinyl / methyl) benzoic acid showed a statistically significant increase in lifetime in S 180 by 44 56 and in Y by 35 16 after a sc dose of 100 mg / kg sc, and in Kr 2 at the same dose a tumor reduction of 27 56.

The c. Application in S mice reaches Θ00 mg / kg. 4- (2- / 2-amino-6-hydroxy-4-oxo-3,4-dlhydro-5-pyrimidinyl / ethyl) benzoic acid statistically significant increased the lifespan of experimental animals with tumor S 180 by 36 16 and Y by 24 16 after sc administration at a dose of 100 mg / kg and reduced tumor size by 36 16 in tumor S 37 and 32% in tumor Kr 2.

4- (3- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) propyl) benzoic acid exhibited a reduction in tumor size of S 37 and S 37 at a dose of 100 mg / kg s. Kr 2, o 36 16, resp. 50%. 4- (4- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / butyl) benzoic acid) showed efficacy in S 37 and Kr 2 tumors at the same dose and regimen, i. reduced tumor size S 37 by 67% and Kr 2 by 46 56. Similarly effective was also 4- (5- / 2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) pentyl acid. benzoové.

According to the invention, the compounds of the formula (I) can be prepared by the triethyl ester of the tricarboxylic acid of the formula (III), h ₅ c ₂ ooc _x (

/ h ₅ c ₂ ooc

CH- (GH ₂ ) _n - γ-COOC ₂ H ₅ (III) where η = 1 to 5, condenses with guanidine, respectively. with its addition product with inorganic or organic acids, preferably hydrochloride, in the presence of sodium alcoholate, preferably sodium methylate, whereupon the crude cohensate is saponified and the compound of formula I is liberated from the solution by mineral acid and purified by precipitation with alkali acid.

In addition to the compound of formula III in which n is 1 (Titley A. F .: J. Chem. Soc. 1928, 2571), the compounds of the formula III are not yet described. They can all be prepared, mostly in very good yield, by the same method as described for example for the synthesis of m-carboxybenzylmalonic acid triethyl ester (Schaeffer <J. P. et al .: J. Org. Chem. 32. 1372 (1967)). ie by condensing the sodium salt of diethyl malonate with the ethyl esters of ω-halogenated 4-alkylbenzoic acids, preferably ω-brominated, of the general formula IV,

Br- (CH ₂ ) _{n -,} COOC ₂ H ₅ where n = 1 to 5. Compounds of formula IV of the above-mentioned meaning n are partially known, partly not yet described. They can all be prepared by the same method as described for example for the synthesis of 4- (2-bromoethyl) benzoic acid ethyl ester (Forenam L. et al. J. Am. Chem. Soc. 62, 1435 (1940)).

Further details of the preparation of the compounds of formula (I) will be apparent from the following non-limiting example. 4- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) methyl) benzoic acid.

To a solution of sodium methylate prepared by dissolving 27.6 g (1.20 mol) of sodium in 400 ml of absolute methanol at 40-45 ° C, under stirring and under a nitrogen atmosphere, is added 76.4 g (0.80 mol) of guanidine hydrochloride and then 128.9 g (0.40 mol) of 4-carboxybenzylmalonic acid triethyl ester. The reaction mixture was stirred at room temperature for 4 hours and then stirred overnight.

After distilling off the methanol under reduced pressure, the residue is soaped with 800 ml of 0.5 N NaOH at 20-25 ° C, filtered and the filtrate is acidified with dilute hydrochloric acid (1: 1) to pH 3. The precipitate is filtered off, washed water and dried. The product obtained is purified by reprecipitation from dilute hydrochloric acid. Mp 352 ° C (dec.).

In the same manner as in the example, using the corresponding triethyl ω- (4-carboxyphenyl) alkylmalonic acid esters of formula III, the following compounds were prepared:

4- (2- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) ethyl) benzoic acid, m.p. about 300 ° C, melts to 360 ° C;

4- (3- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) propyl) benzoic acid, m.p. 323 DEG-325 DEG C. (dec.);

4- (4- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / butyl) benzoic acid, mp 333-355C (dec);

4- (5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) pentyl) benzoic acid, m.p. 286 DEG-288 DEG C. (dec.).

Acid 4 of the general formula I, in which η = 1 to 1

2. Acid 43. Acid 4 ·

4. Acid 45. Acid 46. Acid 43 '211196

Claims (3)

OBJECT OF THE INVENTION (o> - / 2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / alkyl) benzoic acid O ^H 2 ^N 4 (CH ₂ ) _n -> - COOH OH (I) ((2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl) methyl) benzoic acid. (2- / 2-amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / ethyl) benzoic acid. (3- / 2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / propyl) benzoic acid (4- / 2-amino-6-hydroxy-4-oxo-3,4-dihydro -5-pyrimidinyl / butyl) benzoic acid. (5- / 2-Amino-6-hydroxy-4-oxo-3,4-dihydro-5-pyrimidinyl / pentyl) benzoic acid