CS231636B1 - Pharmaceutically effective 2-/4-oxo-3,4-dihydropyrimidine-5/acid derivatives - Google Patents

Abstract

The invention relates to novel pharmacologically of the active derivatives of 2- (4-oxo- -3,4-Dihydropyrimidin-4-yl) propanoic acid, substituted at the 2 and 6 positions of the pyrimidine skeleton. Substances show prot is inflammatory activity at screening models.

Description

The invention relates to pharmacologically active 2- (4-oxo-3,4-dihydropyrimidin-5-yl) propanoic acid derivatives of the general formula I:

O

wherein R is amino, mercapto or methylthio and R is hydroxy or methyl.

The various substituted pyrimidine derivatives represent a group of substances with rich pharmacological activities, extending to virtually all therapeutic classes of drugs used or newly developed. Of particular interest is the use of pyrimidine derivatives as chemotherapeutic agents for invasive diseases and cancer chemotherapeutics. Compounds of the general vaorce I, the above meaning of R and R represent their structure analogues of the 4 / - (4-oxo-3,4-dihydropyrimidine-5-yl) alkanoic (Czechoslovak Author's Certificate No. 17666?) <.Tere ^of have shown some biological properties potentially useful in cancer chemotherapy. Above all, the pyrimidine part of the molecule (antimetabolite character) was the carrier of biological activity, whereas the alcaficarboxyl part represented a fragment affecting

chemical properties and distribution ratios. On the other hand, arylaliphatic and heteroarylaliphatic acids play an important role in the treatment.

inflammatory processes. 231 838

Compounds of formula I as defined above, when evaluated for antineoplastic activity in animals with experimental tumors, showed moderate antineoplastic activity in conventional screening screening schemes, resulting in a reduction in the size of experimental tumors in the range of 10-20%. However, when evaluated for anti-inflammatory activity, they showed p.o. administration of relatively low acute toxicity (indicative LD ^ q is greater than 1000 mg / kg) and statistically significant activity in conventional models. For example, 2- (2-amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) panic acid at 25 mg / kg p.o. inhibited adjuvant inflammation by 10%. 2- (2-mercapto-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) propanoic acid at 25 mg / kg inhibited kaolin inflammation by 12%, carragenine inflammation by 18% and at 100 mg / kg inhibited both carragenine and adjuvant inflammation by 20%. 2- (2-mercapto-6-methyl-4-oxo-3,4-dihydropyrimidin-5-yl) propanoic acid at 25 and 100 mg / kg induced inhibition of adjuvant inflammation in 20% and 2- (2-methylthio) -6-methyl-4-oxo-3,4-dihydropyrimidin-5-yl) propane at 100 mg / kg inhibited kaolin inflammation by 20% · * 12

The compounds of formula (I), as defined above for R and R, can be prepared by conventional procedures for the construction of substituted pyrimidine derivatives, in analogy to the earlier Czechoslovak author _Ό t mm. 2262-80, FA-1465-80 preferably by condensation of guanidine, thiourea or S-methylthiourea with 1,3-dioxo compounds of the general formula formula II, (II)

231,638 in which it is methyl or ethoxy, in methanol, in the presence of sodium methylate, followed by hydrolysis of the ester function of the condensate by the action of an aqueous alkaline medium on the carboxyl function.

The compounds of formula (II) are all readily obtainable by conditioning diethyl malonate or ethyl acetate with 2-bromopropanoate in the presence of alkaline agents.

Further details of the preparation of the compounds of formula I, as defined above for R and R, will be apparent from the following non-limiting Examples.

Example 1

2- (2-Amino-4-oxo-6-hydroxy-3,4-dihydro-pyrimidin-5-yl) for panic acid

To a solution of sodium methylate prepared by dissolving 6.90 g (0.3 mol) of sodium in 100 ml of methanol at 40-45 ° C, with stirring, is added 19.1 g (0.2 mol) of guanidine hydrochloride and then 26 ml. 03 g (0.1 mol) of 2-methyl-3-carboxysuccinic acid triethyl ester. The reaction mixture was stirred at 20-25 ° C for 4 hours and then allowed to stand at the same temperature for 12 hours. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in 200 ml of 0.5 M sodium hydroxide, stirred for 2 hours, then heated to boiling, filtered with activated carbon and the filtrate was acidified with dilute hydrochloric acid (1 s 1). The precipitate was filtered off, washed with water, dried and purified by crystallization from water. M.p. 287-289 (dec.).

In the same manner as in Example 1, 2- (2-mercapto-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) propanoic acid was prepared, m.p. 225-227 ° C (water). ), by reaction of thiourea with 2-methyl-3-carboxysuccinic acid triethyl ester.

Example ^2,838

2- (2-mercapto-6-methyl-4-oxo-3,4-dihydropyrimidin * 5-yl) propanoic acid

To the sodium methylate solution prepared according to Example 1, 22.8 g (0.3 mol) of thiourea and then 23 g (0.1 mol) of diethyl 2-methyl-3-acetylsuccinate are added and the reaction and working up of the reaction mixture is carried out as in Example 1, Crystallization of the crude product from water gave a melting point of 272 DEG-274 DEG C. (decomposition).

2- (2-Methylthio-6-methyl-4-oxo-3,4-dihydropyrimidin-5-yl) propanoic acid was prepared using the same procedure using S-methylisothiuronium hydrogen sulfate.

Claims (5)

OBJECT HAS A CLIMATE 231 838 Parmacologically active 2- (4-oxo-3,4-dihydropyrimidin-5-yl) propanoic acid derivatives of the general formula I in which R represents amino, mercapto or methylthio2 and R represents hydroxy or methyl. 2. 2- (2-Amino-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) propanoic acid. 3. 2- (2-Mercapto-4-oxo-6-hydroxy-3,4-dihydropyrimidin-5-yl) propanoic acid. 4. 2-C2-mercapto-6-methyl-4-oxo-3,4 * dihydropyrimidin-5-yl) propanoic acid. 5. 2- (2-Methylthio-6-methyl-4-oxo-3,4-dihydropyrimidin-5-yl) propanoic acid.