CS254620B1 - 5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives - Google Patents

Abstract

The solution relates to derivatives of 5- -(2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl)pentanoic acid of the general formula I in which R denotes a residue of amide-linked n-butylamine, cyclohexylamine, ethyl glycinate or ethyl 1-amino-1-cyclopentanecarboxylate. These substances show antineoplastic activity in animals with experimental transplanted tumors upon s.c. and p.o. application

Description

(54) Acid derivatives

5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanone

The present invention relates to 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives of the general formula I

wherein R is a residue of an amidically bonded n-butylamine, cyclohexylamine, ethyl glycinate or ethyl 1-amino-1-cyclopentanecarboxylate. These compounds exhibit antineoplastic activity in animals with experimentally transplanted tumors at s.c. and p.o. application

The present invention relates to 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives of the general formula I

wherein R is a residue of an amidically bonded n-butylamine, cyclohexylamine, ethyl glycinate or ethyl 1-amino-1-cyclopentanecarboxylate.

The compounds of the invention are novel potential cytostatics with a mechanism of action intervening in proteosynthesis and nucleic acid synthesis, in accordance with the results found in the antineoplastically active acids 5- (2-amino-4-oxo-6-alkyl-3,4-dihydropyromidine-5- yl) pentane (Czechoslovakian Authorial Certificate No. 226 946; Křepelka J. et al .: Czechoslovak. Farm., in print) and their esters (Czechoslovakian Authorial Certificate No. 242 050).

Compounds of formula (I) of the above-mentioned meaning of R, when tested in experimental tumors of mice and rats, exhibited a cancerostatic effect exhibiting either survival of animals with experimental tumors or reduced tumor mass compared to control groups of animals.

For example, 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid butylamide prolonged the life of Kr2 (Krebs) tumor H mice when administered orally at 200 mg / kg. ascitiocy tumor) at 123% versus untreated control (= 100%). Similarly, 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid cyclohexylamide at a dose of 100 mg / kg administered s.c. reduced the Kr 2 tumor size to 69% versus the untreated control and extended the life of the treated animals with Yoshid's tumor to 120%. Ethyl N- [5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoyl] glycinate when administered orally to 150 mg / kg to mice with solid form of Ehrlich's tumor prolonged animal survival to 115 and reduced the Kr 2 tumor size by 21 µ. Ethyl N- [5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoyl] aminocyclopentane-1-carboxylate at 200 mg / kg p.o. reduced the tumor size of Kr 2 by 16% while extending the life of the animals by 22%.

At the same time, the compounds of formula (I) as defined above for R may be considered as prodrugs of 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid,

The compounds of formula (I) as defined above R are prepared by converting an acid of formula (II) by reaction with 1 to 2 moles of thionyl chloride, in an indifferent solvent, preferably dimethylformamide, and then reacting the resulting acid chloride with 1 to 2 moles. 2 mol equivalents of compounds of formula III.

R-H (III), wherein R is as defined above, in the presence of 2 to 10 mol equivalents of triethylamine.

The substance of formula II is a substance known and easily transportable according to the Czechoslovak author's certificate. 226 946.

Further details of the preparation process will be apparent from the following non-limiting example.

Example

5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid cyclohexylamide

To a solution of 5.63 g (0.025 mol) of 5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid in 100 ml of dimethylformamide is added under stirring at 20-25 ° C. Thionyl chloride (3.57 g, 0.03 mol) was added and the reaction mixture was stirred for 1 h. Cyclohexylamine (2.48 g, 0.025 mol) and triethylamine (10.1 g, 0.1 mol) were added. The reaction mixture was stirred at 20-25 ° C for 4 hours. The volatile material was distilled off under water pump vacuum, the residue was stirred with water and the resulting suspension was filtered off with suction, dried and purified by crystallization from aqueous ethanol. M.p. 249-251 ° C.

The following compounds were prepared by the same procedure using the appropriate amino derivatives:

5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid n-butylamide, m.p. 182-184 ° C (water);

Ethyl N- [5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanol / glycinate, m.p. 204-207 ° C (aqueous ethanol);

Ethanol N- [5- (2-amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoyl] amino-1-cyclopentane carboxylate, m.p. 208-210 ° C (aqueous ethanol).

Claims (1)

SUBJECT OF THE INVENTION 5- (2-Amino-4-oxo-6-methyl-3,4-dihydropyrimidin-5-yl) pentanoic acid derivatives of formula I, 0 IH-γ in which R represents a residue of an amidically bound n-butylamine, cyclohexylamine, ethyl glycinate or ethyl 1-amino-1-cyclopentanecarboxylate.