CS215554B1 - Esters of the 5-+l2-amino-6-hydroxy-4-oxo-3,4-dihydropyrimidine-5-yl+p valeric acid - Google Patents

Description

The present invention relates to novel 5- (2-amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) vsleric acid esters of formula I,

wherein R is propyl, isobutyl, ellyl, cyclopentyl, 2-hydroxyethyl or 2-methoxyethyl.

Compounds of formula (I) as defined above are esters derived from 5- (2-amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) butyric acid, i.e. compounds of formula II,

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oh ₂ ch ₂ ch ₂ ch ₂ coh (II) known under the designation DAMVAR, which shows a significant therapeutic effect in animals with some transplantable tumors and is a suitable drug, practically non-toxic, for the treatment of human cancer. The compound of formula II in combination with a number of clinically used cytostatics enhances their therapeutic effect without increasing the toxic effects of the used cytostatic in combination. It also enhances the antileukemic effect of cyclophosphamide and 5-fluorouracil and longer cytostatics (see, for example: Semonský M. et al. author's certificate No 176667; Pujmen, V. et al., Neoplesma 26, 85 (1979); Semonský 1 (et al., Cancer Chemotherapy, Pt. 2, g, 107 (1976)).

Compounds of formula I wherein R is as defined above showed a bioassay enhancing effect on 5-fluorouracil, tested using La leukemia, inoculated to male Black C ^ mice, weighing 18-25 g. Day 3 after leukemia cell transplantation ($ 20.10), in the form of aqueous suspensions. After administration of the compound, an aqueous solution of 5-fluorourscil, sc at a dose of 75 or 50 mg / kg was injected at 60 or 90 min. The efficacy of the substances was assessed by the change in median spillover in the experimental groups compared to the makeup control. The number of mice in the groups ranged from 8 to 11. The experimental groups were treated with certain doses of the compound alone, a combination of β 5 -fluoro-uroil at a certain dose ratio and 5-fluorouracil alone. Changes in median survival were expressed as% above 5-fluorouracil alone, whose median survival of 10 to 12 days was considered 100% · The median of untreated controls was 7 to 9 days. Compounds of formula I with the above-mentioned meaning of R in the dose range of 20 to 250 mg / kg did not affect the survival of the treated animals. Combination of substances with 5-fluorouracil, at the appropriate dose ratio, significantly increased the survival of the test animals by an average of 15 to 27% over 5-fluorouracil alone, ie the investigated compounds showed a potent effect on 5-fluorouracil in animals with Keukemia La. The allyl ester of 5- (2-amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) valeric acid showed the most pronounced effect from the study group, which strengthened the statistically significant effect of 5-fluorouracil (75 mg / kg, sc). ) at doses of 20 mg / kg by 27% and at doses of 60 mg / kg by 22% _t using the same combination regimen. The other agents showed a statistically significant survival in the dose range of 200 to 400 mg / kg, in combination with ee 75 mg / kg of 5fluoruraoil, ranging between 15 to 20%.

In the screening rank of compounds of formula I of the above-mentioned significance R for antineoplastic activity, they exhibited a mild anti-neoplastic effect in animals and experimental tumors in the dose range of 40 to 200 mg / kg, at s.c. administration resulting in a 10-20% reduction in tumors, without affecting the survival time of the test animals.

The esters of formula (I) may also be regarded as suitable transport forms from which the active compounds, i.e. the compound of formula (II), are gradually released from the metabolic processes.

The compounds of formula (I) of the above-mentioned meaning of R are at the same time valuable intermediates for the synthesis of other pharmacologically promising substances, in particular from the group of the antineoplastic β-potentiating effect of the years.

Compounds of formula (I) as defined above R are prepared by reacting formula (II) with a reactive adduct prepared by reacting compounds of formula R-OH (III) in which R is as defined above and thionyl chloride, at least 1 mol equivalent, preferably up to 20% in excess, in the temperature range of> 70 to> 10 ° C, the compounds of formula III being used as reaction medium, followed by the reaction of the adduct with the compound of formula II in a temperature range of -70 ° C to boiling point of the reaction mixture, preferably in a temperature range of > 10 ° C.

type of reactions, eg after distilling off the volatiles in the water pump, the resulting evaporators are stirred in water, basified with sodium bicarbonate and the precipitated suepense is filtered off with suction and washed with water and dried by recrystallization from suitable solvents or mixtures thereof. Other methods commonly used in organic preparative chemistry for ester synthesis may be used to prepare compounds of formula (I) as defined above, such as those employing special reagents for the preparation of reactive carboxylic acid derivatives, such as those of formula (II). N, N-dicyclohexylcarbodiimide, carbonyldiimidazole or mixed anhydride method, etc. However, these methods are less advantageous from an economic and purity point of view. The direct extinction of the carboxylic function in the compound of formula II is contemplated by the use of water scavengers such as sulfuric acid or p-toluenesulfonic acid. These substances cause oxidative cleavage, resp. transformation of the pyrimidine backbone of the starting material.

Compounds of formula (I) of the above-mentioned meaning of R, in an alkaline medium, are very easily hydrolyzed to a compound of formula (II) which, in the presence of an aqueous alkaline medium, is present ^. atmospheric oxygen readily transforms into a 2-imino-1,3-oxezolidin-4-one derivative.

Further details of the preparation of the compounds of formula I with the above-mentioned meaning of R will be apparent from the following non-limiting embodiment. The melting points of the substances refer to crystal-free substances and are not corrected.

Example

5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) valeric acid allyl ester

1.23 ml (2.02 g; 17 mmol) of freshly distilled thionyl chloride are added dropwise to 20 ml of allyl alcohol cooled to -70 DEG C. and then immediately added dropwise.

3.4 g (15 mmol) of 5- (2-emino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) valeric acid are added and the reaction mixture is stirred at the same temperature for 15 min. The mixture was warmed to room temperature, then heated at 40 ° C for 2 hours and refluxed for 2 hours. After concentrating the reaction mixture to dryness under reduced pressure on a vacuum rotary evaporator, the resulting residue was stirred in water, basified with acidic sodium carbonate and the precipitate was filtered off with suction. After washing with water and drying, the material was recrystallized from dimethylformamide-methanol (1: 2) to give a melting point of 263-265 ° C.

The following substances are prepared in an analogous manner using the appropriate alcohols:

5- 5- (2-8mino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) valeric acid propyl ester: m.p. 276-278 ° C (dimethylformamide-methenol, 1: 2).

5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) veleric acid tert -butyl ester: m.p.

282-284 (dimethylformamide-methenol, 1: 2).

5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -acrylic acid cyclopentyl ether: mp 288-290 ° C (dimethylformemide).

5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) veleric acid D2-hydroxyethyl ether: m.p. 233-234 ° C (water).

5- 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrrolidine-5-yl) -meric acid 2-methoxyethyl ester: m.p. 250-252 ° C (dimethylformemide-water, 1: 2).

Claims (7)

SUBJECT OF THE INVENTION 5- (2-emino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) C esters of CH ₂ CH ₂ CH ₂ CH ₂ COOR (1) wherein R represents propyl, i-butyl, ellyl, cyclopentyl, 2-hydroxyethyl or 2-methoxyethyl. 2. 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -verylic acid propyl ester. 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) veleric acid 3-i-butyl ester. 4. 5- (2-8mino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) butyl ester allyl ester. 5. 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) -meric acid cyclopentyl ester. 6. 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) veleric acid 2-hydroxyethyl ester. 5- (2-Amino-6-hydroxy-4-oxo-3,4-dihydropyrimidin-5-yl) veleric acid 2-methyl ethyl ester.