CS217216B1 - Substituted omega- (4-oxo-4,5-dihydro-5-pyrimidinyl) alkanoic acids and their derivatives - Google Patents

Abstract

The invention relates to substituted ω _(4_ωχο-4,5-dihydro-5-pyrimidinyl)alkanoic acids, their derivatives of the general formula I (for the meaning of the substituents R, X, Y1, Y2 and Z see the description of the invention) and their pharmaceutically acceptable salts. The substances shown a mild cytostatic effect in experimental tumors in mice.

Description

(54) Substituted omega- (4-oxo-4,5-dihydro-5-pyrimidinyl) alkanoic acids and their derivatives

The invention relates to substituted acids _ω _ (4_οχο-4,5-dihydro-5-pyrimidinylJalkanových, derivatives of formula I (as R, X, Y ^1, Y ² and Z see description of invention), and their pharmaceutically acceptable salts.

The compounds showed a slight cytostatic effect in experimental mouse tumors.

217216 2

The present invention relates to substituted ω - (4-oxo-4,5-dihydro-5-pyrimidinyl) alkanoic acids and their derivatives of formula I and their pharmaceutically acceptable salts.

In formula (I), R is amino, hydroxy or mercapto, X is hydrogen or amino, is carboxymethyl, carboxybutyl or alkoxycarbonylmethyl, wherein the alkoxy group contains 1 to 4 carbon atoms, Y ² is hydrogen, and in the case where Y is ³ Y ² denote another karboxybutylskupinu and Z represents an oxo or imino group. Depending on the nature of substituents R, X, Y ^1, γ ^2, and z and the nature and pH of the medium may be those of formula I přísluget some of the corresponding tautomeric form, or may be a mixture of tautomers.

Compounds of formula I in which R, X, Y ³ , Y ² and Z are as defined above are prepared by the preparation of compounds of formula XI ^{r 2 '} , CR ⁴ - (CH ₂ ) _n -COOR ¹¹

R ^{3 /} . v.

2 wherein R is methyl or ethyl, R is methoxycarbonyl, ethoxycarbonyl or cyano group, R ³ represents cyano or formyl, R ^ is hydrogen or if R ² and R ³ represents a cyano group, then labeled ethoxykarbonylbutylskupinu n = 1 or 4 , condense with guanidine, respectively. with its editorial product with inorganic or organic acids, e.g. guanidine hydrochloride, thiourea or urea in the presence of sodium alcoholate, e.g. sodium ethylate, under conditions customary for the preparation of iminobarbituric, thiobarbituric or barbituric acids.

Compounds of formula I in which Y ³ is an alkoxycarbonylmethyl group, wherein p

Y is a hydrogen atom are prepared under conventional esterification conditions from the corresponding free carboxylic acids.

For the preparation of salts of the compounds of the formula I, either pharmaceutically acceptable acids with which the compounds of the formula X form addition salts or, in the case of the compounds of the formula I having a free carboxyl group, also pharmaceutically acceptable bases, e.g. alkali metal hydroxides or carbonates alkali metals.

The compounds of formula (I) and (II) respectively; their salts, administered orally or parenterally in the form of a microsuspension, respectively. in the form of a solution of their salts, they are mildly cytostatic in mice of strain H with sarcoma (induced by methylacridine), adenocareinoma of the mammary gland HK, with ascitic sarcoma S 37 and with Krebs ascitic carcinoma.

Further details of the preparation of the compounds of the formula I as well as the preparation of the compounds of the formula II which have not been described so far will be apparent from the following non-limiting examples.

Example i

5- (2,6-Diamino-4-oxo-4,5-dihydro-5-pyrimidinyl) pentanoic acid

To a solution of sodium methylene prepared from 0.7 g (0.03 mol) sodium and 40 ml methanol was added 1.91 g (0.02 mol) guanidine hydrochloride under a nitrogen atmosphere and after stirring for 10 minutes was added 2.41 g (0.01 mol) of diethyl 2-cyanoheptanedioate. The reaction mixture was stirred for one hour at room temperature and then allowed to stand overnight. The solvent was distilled off under reduced pressure, the crude aster was dissolved in 10 ml (0.01 mol) of 1M sodium hydroxide solution, the solution was allowed to stand overnight at room temperature and then acidified to pH 3 with hydrochloric acid. g (78% yield) after recrystallization from water gave the desired acid, mp 266-268 ° C (dec.).

Example 2

2- (2,6-Diamino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid

In the same manner as in Example 1, but using diethyl 2-cyanobutanedioate instead of diethyl 2-cyanoheptanedioate, 2- (2,6-diamino-4-oxo-4,5-dihydro-5-pyrimidinyl) was prepared. acetic. The crude product (87% yield) gave the desired acid by recrystallization from water, which decomposed at a temperature above 300 ° C without melting. UV / VIS (0.1 M HCl, 50% methanol)>. λ _max (log r.): 270 nm (4,238).

Example 3

5- (6-Amino-2-hydroxy-4-oxo-4,5-dihydro-5-pyrimidinyl) pentanoic acid

A mixture of sodium methylate prepared from 0,46 g (0,02 mol) of sodium and 25 ml of methanol,

1.2 g (0.02 mol) of urea and 2.41 g (0.01 mol) of diethyl 2-cyanoheptanedioate were heated to reflux for 4 hours with stirring. After working up the reaction mixture in the same manner as in Example 1, 1.47 g (yield 65%) of the product is obtained, which after recrystallization from water gives pure acid of m.p. Mp 293-295 ° C (dec.).

Example 4

5- (6-Amino-4-oxo-2-mercapto-4,5-dihydro-5-pyrimidinyl) pentanoic acid

In the same manner as in Example 3, but using 1.52 g (0.02 mol) of thiourea instead of urea, 1.8 g (yield 74%) of the product was obtained, which after recrystallization from water gave pure acid of m.p. Mp 288-290 ° C (dec.).

Example 5

5,5-Bis (4-carboxybutyl) -2,6-diamino-4-imino-4,5-dihydropyrimidine

To a solution of sodium methylate prepared by dissolving 2.76 g of sodium (0.12 mol) in 80 ml of methanol at 40 ° C was added 7.64 g (0.08 mol) of guanidine hydrochloride, and the reaction mixture was stirred for 10 min. 12.88 g (0.04 mol) of diethyl 6,6-dicyano-1,11-undecenedioate are added, the reaction mixture is refluxed for 3 hours and allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure, 60 ml of water and 1.7 g (0.04 mol) of sodium hydroxide were added to the residue, the mixture was stirred at room temperature for 2 hours, then filtered through a Slavia # 5 filter and the filtrate acidified. conc. hydrochloric acid to pH 4.2. After cooling, the precipitate formed is filtered off with suction, washed with 20 ml of cold water and dried. The crude product (8.3 g, 64% yield) gave a pure product after recrystallization from water. 304 DEG-306 DEG C. (dec.).

Example 6

5- (2,4,6-Triamino-5-pyrimidinyl) pentanoic acid

Using the same procedure as in Example 5, 5- (2,4,6-triamino-5-pyrimidinyl) -pentanoic acid was prepared using ethyl 6,6-dicyanehexanoate instead of diethyl 6,6-dicyano-1,11-undecenedioate. . The crude product (yield 66.7%) gave pure acid of m.p. Mp 276-278 ° C (dec.).

Example 7

2- (2-Amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid

In the same manner as in Example 5, but using dimethyl 2-formylbutanedioate instead of diethyl 6,6-dicyano-1,11-undecanedioate, 2- (2-amino-4-oxo-4,5-dihydro- 5-pyrimidinyl) acetic acid. The crude product (88.4% yield) after recrystallization from a mixture of dimethylsulfoxide, ethanol and water gave the desired acid, m.p. 317 DEG-319 DEG C. (dec.).

Example 8

Ethyl 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) -acetate

To 20 mL of absolute ethanol cooled to -70 ° C was added dropwise 2.02 g (1.23 mL;

Of thionyl chloride (0.017 mol) and 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid (2.54 g, 0.015 mol) were added portionwise at the same temperature. The mixture was then heated to 40 ° C and stirred at this temperature for 2 hours. Until now, the heterogeneous mixture has been made homogeneous. The temperature is then raised to reflux, which is maintained for a further 2 hours. The reaction mixture is then evaporated to dryness in vacuo, the residue is dissolved in 50 ml of water and, after filtration, the solution is basified with solid sodium bicarbonate. The crude product thus obtained (2.32 g, yield 78.4%) gave the desired ester after recrystallization from ethanol. Mp 212-214 ° C (dec.).

Example 9 n-Butyl-2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetate

Using the same procedure as in Example 8, but using n-butanol and 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid, n-butyl-2- (2-amino) was prepared. -4-oxo-4,5-dihydro-5-pyrimidinyl) acetate. The crude product (89% yield) after recrystallization from n-butanol gave the desired ester of m.p. Mp 217-218 ° C (dec.).

Example 10

2,6-Diamino-4-oxo-5- (4-carboxybutyl) -4,5-dihydropyrimidine hydrochloride

0.5 g of 2,6-diamino-4-oxo-5- (4-carboxybutyl) -4,5-dihydropyrimidine are dissolved in boiling 3.5 ml of concentrated hydrochloric acid and the solution is left to crystallize in a refrigerator for 4 hours. . There was obtained 0.53 g (91% yield) of the hydrochloride, m.p. 264 DEG-268 DEG C. (dec.).

Example 11

2- (2-Amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid, sodium salt

0.42 g (0.0025 mol) of 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid and 0.21 g (0.0025 mol) were dissolved in 35 ml of boiling water. sodium bicarbonate. After cooling, the sodium salt is precipitated by addition of ethanol. 0.39 g of salt is obtained (yield 81.5%), m.p. 260 DEG-265 DEG C. (dec.).

Example 12

Ethyl 6,6-dicyanehexanoate and diethyl 6,6-dicyano-1,11-undecanedioate

To a solution of sodium ethylate prepared by dissolving 12.7 g (0.55 mol) of sodium in

450 ml of ethanol heated to 40 DEG C. are added 36.3 g (0.55 mol) of melanodinitrile in 30 ml of ethanol, stirred for 10 minutes and then dropwise at the same temperature 104.6 g (0.5 mol) of ethyl- Of 5-bromopentanoate and the reaction mixture was refluxed for 5 hours and allowed to stand overnight.

After suctioning off the precipitated salt (NaBr), the filtrate is concentrated to a slurry, diluted with 500 ml of water and the organic portion is taken up in chloroform. After shaking with an equal volume of water, the chloroform phase is dried over sodium sulfate, the volatiles are removed in vacuo and the residue is distilled under vacuum. Between 155 and 160 ° C at 66 Pa, hexanoate is obtained and undecandioate at 200 to 210 ° C / 66 Pa. Redistillation gave 15.6 g (14.7% yield) of the hexanoate, m.p. 130-133 DEG C./40 mbar and 20.1 g (11.3% yield) of undecandioate, m.p. 185-190 ° C / Pa. Ethyl 6,6-dicyanehexanoate is unstable, decomposes rapidly and must be stored in the refrigerator.

Claims (12)

SUBJECT OF THE INVENTION Substituted o- (4-oxo-4,5-dihydro-5-pyrimidinyl) alkanoic acids and derivatives thereof of the general formula I (1) in which R represents amino, hydroxy or mercapto, X represents hydrogen or amino, Y R @ 1 is carboxymethyl, carboxybutyl or alkoxycarbonylmethyl, the alkoxy group having 1 to 4 carbon atoms, Y is hydrogen and, when Y is carboxybutyl, Y may be another carboxybutyl group, Z is oxo or thiomeric group, tautomeric forms, and pharmaceutically acceptable salts thereof. 2. 5- (2,6-Dlamino-4-oxo-4,5-dihydro-5-pyrymidinyl) pentanoic acid. 3. Acid 5- (6-amino-2-hydroxy-4-oxo-4,5-dihydro-5-pyrimidinyl) pentanoate. 4. 5. 6. 5- (6-Amino-4-oxo-2-mercapto-4,5-dihydro-5-pirimidinyl) pentanoic acid. 2- (2,6-Diamino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid. 2- (6-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid. 7. Ethyl 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetate. 8. n-Butyl 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetate. 9. 5- (2,4,6-Triamino-5-pyrimidinyl) pentanoic acid. 10. 5,5-Bis (4-carboxybutyl) -2,6-diamino-4-imino-4,5-dihydropyrimidine. 11. 2,6-Diamino-4-oxo-5- (4-carboxybutyl) -4,5-dihydropyrimidine hydrochloride. 12. Sodium salt of 2- (2-amino-4-oxo-4,5-dihydro-5-pyrimidinyl) acetic acid.