CH646715A5 - 2'-DESOXY-3 ', 5'-DI-O-ALKYLCARBONYL-5-FLUORURIDINE DERIVATIVES, METHOD FOR THEIR PREPARATION AND ANTITUARY AGENTS. - Google Patents

Description

The invention relates to new 2'-deoxy-3 ', 5'-di ~ O-alkylcarbonyl-5-fluorouridine derivatives of the general formula I.

in which R is an alkyl or alkoxy radical or a halogen atom, m is O or an integer from 1 to 3 and n is an integer from 1 to 14, with the proviso that if m is 2 or 3, the radicals R are the same or different, and that if m has the value 2 and the two radicals R are adjacent alkoxy radicals, the two alkyl units of the alkoxy radicals can be linked to one another and then together with the two oxa bridge atoms form an alkylenedioxy radical .

2. Compounds according to claim 1 of the general formula I, in which R represents a methyl, methoxy, ethoxy or propoxy group or a fluorine atom.

3. Compounds according to claim 1 of the general formula I, in which R represents a methoxy group and m has the value 2.

4. Compounds according to claim 1 of the general formula I, characterized in that n has the value 3, 4 or 5.

5. A process for the preparation of the compounds according to claim 1, characterized in that a 2'-deoxy-3 ', 5'-di-0-alkylcarbonyl-5-fluorouridine of the general formula II

0

HN

O ^ N-

CH3 (CÏÏ2) ^ COO.

0-

UD

y

CO - Hal

(III)

in which R and m have the meanings given above and Hai represents a halogen atom.

25th

(I)

CHs (CSOCOO-i / O ^

yy

CHsCCEb ^ COO

CBb (CH2) ", 00

in which n has the meaning given above, is reacted with a benzoyl halide of the general formula III,

35

in which R is an alkyl or alkoxy radical or a halogen atom, m is 0 or an integer from 1 to 3 and 40 n is an integer from 1 to 14, with the proviso that if m is 2 or 3 , the radicals R are the same or different, and that if m has the value 2 and the two radicals R represent adjacent alkoxy radicals, the two alkyl units of the alkoxy radicals can be connected to one another and then together with the two oxa bridge atoms Alkylenedioxyrest yield.

The invention further relates to a process for the preparation of the compounds of the general formula I and antitumor agents which contain a compound of the general formula I as the active ingredient.

In the field of chemotherapy, there is currently great interest in the development of new effective anti-tumor agents.

Different types of 5-fluorouridine derivatives have already been tested 55 as anti-tumor agents. However, all of these derivatives are very unsatisfactory because they either have little antitumor activity or high toxicity. 2'-Deoxy-5-fluorouridine (hereinafter referred to as FUDR) has been used as an anti-tumor agent. However, this compound has a very high toxicity for medical administration and a narrow safety range. In addition, the actual therapeutic utility of this compound is severely limited, since it can only be administered by intra-arterial injection, but not 65 orally (Physicians Desk Reference (1978), p. 1387). Known as the FUDR derivative is 2 '-deoxy-3', 5 '-di-O-acetyl-5-fluorouridine (hereinafter simply referred to as acetyl-FUDR). However, this connection is almost the same

toxic as FUDR and has little effectiveness (Biochem. Pharmacology, vol. 14 (1965), pp. 1605 ff .; Cancer Research, vol. 23 (1963) pp. 420 ff.).

3 ', 5'-dialkyl esters of FUDR have also been described as derivatives of FUDR, but are also still unsatisfactory in terms of their antitumor activity and toxicity (Biochem. Pharmacology, Vol. 14, (1965), p. 1605- 1619 and Vol. 15 (1966), pp. 627-644). More recently, FUDR and acetyl FUDR derivatives have been described in which the hydrogen atom bonded to the nitrogen atom in the 3-position of the uracil ring is substituted by a certain aroyl radical; see. British patent application 2 025 401 and European patent application No. 9882. However, an increase in the antitumor activity is also required for these compounds. There is therefore a great need for the development of new FUDR derivatives with strong antitumor activity and low toxicity which are suitable for oral administration and therefore do not require the troublesome intra-arterial or intravenous infection.

Surprisingly, the new compounds of general formula I have a superior anti-tumor activity compared to the known, structurally similar compounds, with approximately the same toxicity.

In the compounds of the invention, the benzoyl group which is introduced in the 3-position of the uracil ring can be ring-substituted with up to three radicals R. These radicals can be the same or different and each represent an alkyl or alkoxy radical or a halogen atom. If R is an alkyl radical, straight or branched alkyl radicals are preferably used with 1 to 20 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl -, n-Pentyl, isopentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-hexydecyl and n-octadecyl groups. Examples of the radical R in the case of the alkoxy radicals are unbranched or branched alkoxy radicals having 1 to 20 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert .-Butoxy, N-pentyloxy, n-hexyloxy, n-octyl-oxy, n-decyloxy, n-dodecyloxy, n-hexadecyloxy, and n-octadecyloxy groups.

If there are two adjacent lower alkoxy radicals as ring substituents in the benzoyl group (R means lower alkoxy radical and m has the value 2), then the alkyl units of the two lower alkoxy radicals can be linked to form an alkylene radical. In this case, the two neighboring lower alkoxy radicals result in an alkylenedioxy radical as a whole. Preferred examples of the alkylene-dioxy radicals are methylenedioxy, ethylenedioxy and propylenedioxy groups.

Examples of radicals R as halogen atoms are fluorine,

Chlorine, bromine and iodine atoms, with fluorine atoms being preferred.

Preferred compounds of the invention are listed below:

3-benzoyl-2'-deoxy-3 ', 5'-di-0-pentanoyl-5-fluorouridine, 3-benzoyl-2' -deoxy-3 ', 5' -di-O-hexanoyl-5-fluorouridine, 3- (2,3 or 4-methyl) benzoyl-2'-deoxy-3 ', 5'-di-0-buta-noyl-5-fluorouridine,

3- (2,3 or 4-methyl) benzoyl-2 'deoxy-3', 5 'di-O-penta-noyl-5-fluorouridine,

3- (2,3 or 4-methyl) benzoyl-2'-deoxy-3 ', 5'-di-0-hexa-noyl-5-fluorouridine,

3- (2,3 or 4-methoxy) benzoyl-2'-deoxy-3 ', 5'-di-0-penta-noyl-5-fluorouridine,

3- (2,3 or 4-methoxy) benzoyl-2'-deoxy-3 ', 5'-di-O-hexa-noyl-5-fluorouridine,

3- (3,5-dimethyl) benzoyl-2'-deoxy-3 ', 5'-di-0-pentanoyl-

646715

or -hexanoyl-5-fluorouridine,

3- (2,3 dimethoxy) benzoyl-2 'deoxy-3', 5 'di-O-pentanoyl or hexanoyl-5-fluorouridine,

3- (2,3 or 4-ethyl) benzoyl-2'-deoxy-3 ', 5'-di-0-penta-

noyl- or -hexanoyl-5-fluorouridine,

3- (2,3 or 4-ethoxy) benzoyl-2 '-deoxy-3', 5 '-di-O-penta-

noyl- or -hexanoyl-5-fïuoruridiri,

3- (2,3 or 4-propoxy) benzoyl-2'-deoxy-3 ', 5'-di-O-penta-

noyl- or -hexanoyl-5-fluorouridine,

3- (2,3 or 4-fluoro) benzoyl-2'-deoxy-3 ', 5'-di-O-pentanoyl or -hexanoyl-5-fiuoruridine and 3- (2,4-dichloro) benzoyl -2'-deoxy-3 ', 5'-di-O-pentanoyl or -hexanoyl-5-fluorouridine.

The compounds of general formula I can by reacting a 2'-deoxy-3 ', 5'-di-0-alkylcarbonyl-5-fluorouridine of general formula II

0

in which n represents an integer from 1 to 14, with a benzoyl halide of the general formula III

03)

m in which R, m and shark have the meaning given above, are produced. The reaction is usually carried out in the presence of a reaction medium (solvent) and an acid-binding agent.

The 2'-deoxy-3 ', 5'-di-O-alkylcarbonyl-5-fluorouridines of the general formula II are generally known or can easily be obtained by acylating one mole of FUDR with 2 moles of the corresponding fatty acid, preferably in the form of a reactive derivative , getting produced. The benzoyl halides of the general formula III are likewise generally known and are readily commercially available, or can be prepared in a manner known per se. The use of the corresponding chlorides or bromides of the general formula III is preferred.

The benzoyl halide of the general formula III is preferably used in 1 to 3 times the molar amount to the compound of the general formula II.

The reaction between the benzoyl halide of the general formula III and the 2'-deoxy-3 ', 5'-di-0-alkylcarbonyl-5-fluorouridine of the general formula II, i.e. the N-acylation of the fluorouridine with the benzoyl halide is usually carried out in the presence of an organic solvent which is inert to the N-acylation and enables the suitable reaction temperature. Examples of suitable organic solvents are aprotic solvents such as diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide and dimethyl sulfoxide.

3rd

5

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

646715

The reaction is usually carried out in the presence of an acid-binding agent. The reaction is usually promoted by neutralizing the hydrogen halide liberated from the N-acylation of the fluorouridine with the benzoyl halide. Accordingly, organic bases are generally used as acid-binding agents. Preferred examples of organic bases are aliphatic tertiary amines, such as triethylamine and similar lower trialkylamines, and aromatic and heterocyclic tertiary amines, such as N, N-dialkylanilines and pyridine, which can be substituted by one or more lower alkyl radicals. These organic bases are usually miscible with the organic solvent used as the reaction medium. However, they are precipitated during the reaction with the halogen hydrogen.

Therefore, these organic bases can be easily separated from the reaction mixture after the completion of the reaction.

The organic base is usually used in an amount of 1 to 5 moles per mole of benzoyl halide. Since the organic base as such can also be used as the reaction medium, an excess amount of this base, for example an amount of 5 to 20 moles per mole of benzoyl halide, can also be used, in which case part or all of the solvent is replaced for the reaction.

The reaction can be carried out in a relatively wide temperature range, for example with ice cooling or at the temperature up to the boiling point of the solvent used. As a rule, the implementation takes 30 minutes to 12 hours. The reaction time can be shortened by heating the reaction mixture at the end of the reaction. After the reaction is complete, the end product can be obtained by evaporation or concentration of the reaction mixture under reduced pressure. The reaction mixture can also be filtered first and then the filtrate can be evaporated under reduced pressure. Finally, the residue obtained can be recrystallized or chromatographed on silica gel. This latter purification treatment by chromatography or recrystallization can be repeated. If the product is isolated as a viscous oil, it can be obtained as a solid or crystalline substance by dissolving the oil in a small amount of dimethyl sulfoxide and pouring the resulting solution into water with vigorous stirring.

The compounds of the invention have high anti-tumor activity with low toxicity compared to known, structurally similar FUDR derivatives. The antitumor activity and toxicity of the compounds of the invention are evaluated according to the following tests:

(A) Pharmacological tests to determine antitumor activity

Approximately 10,000,000 Sarcoma 180 tumor cells (gradually incubated for several generations in the peritoneal cavity of a male mouse from the ICR strain) are subcutaneously transplanted into the groin area of five-week-old male mice from the ICR strain. After 24 hours, administration of the compounds of the invention is started. The compounds of the invention are administered orally once a day for 7 days. The body weight of each test animal is measured every day before administration. The compounds of the invention are dissolved or suspended in polyethylene glycol 400, administered to each test animal. Polyethylene glycol 400 alone is given to a control group of animals. In any case, the same volume of

0.1 ml / 10 g body weight administered to each animal. Although the exact dose of the compound of the invention will vary depending on the nature of the particular compound used, the doses will range from about 0.5 to 120 mg / kg. The cans are divided into three to twelve rows for each tested compound. In each row, the compound of the invention is administered to a group of 6 mice. 18 mice are used for the comparison group.

8 days after the transplantation of the tumor cells, the mice are anesthetized with ether and killed by drawing blood. Then the tumor tissue is removed and its weight is immediately determined and recorded. An average of the tumor weights in the treated group (referred to as T) for each compound and dose tested and an average of the tumor weights in the control group (referred to as (C)) are calculated to estimate a dose equal to T / C of 0.70 or 0.50 for each connection tested.

When evaluating the antitumor activity, a value T / C in the range from 0.70 to 0.51 is considered to be moderately effective, whereas a value below 0.50 is regarded as effective (Ohyo-Yakuri, Vol. 7, (1973), Pp. 1277 to 1292). Accordingly, the anti-tumor activity becomes stronger as the value indicating 0.70 or 0.50 as T / C becomes smaller.

(B) Test to measure toxicity:

Taking into account the effects achieved with the compounds of the invention, the toxicity values are measured according to the following method, whereby accumulative toxicity is taken into account.

Groups of 5 week old male mice of the ICR strain are used in this test, each group consisting of 10 animals. The compounds to be tested are forced orally administered once a day for 7 days. The body weight of each animal is determined every day before administration. The compounds of the invention are given in dissolved or suspended form in polyethylene glycol-400 to each test animal in the same volume of 0.1 ml / 10 g body weight. Although the exact dose of the compounds of the invention will vary according to the type of compound used, the doses will range from about 2 to 300 mg / kg. The cans are divided into five rows for each connection to be tested. In each row, the compound of the invention is administered to each group. The survival or death of the test animals is evaluated 14 days after the end of the administration and the values for LDio are calculated using the Litchfield-Wilcoxon method.

Tests (A) and (B) given above are also carried out with the following known compounds:

A: 2 / -deoxy-3 ', 5 / -di-0-n-propionyl-5-fluorouridine B: 2'-deoxy-3', 5'-di-0-n-butanoyl-5-fluorouridine C: 2'-Deoxy-3 ', 5' -di-On-heptanoyl-5-fluorouridine D: 2 '-Desoxy-3', 5 '-di-On-octanoyl-5-fluorouridine E: 2' -Desoxy-3 ', 5' -di-On-palmitoyl-5-fluorouridine F: 2 '-Desoxy-3', 5 '-di-On-pentanoyl-5-fluorouridine G: 2' -Desoxy-3 ', 5' -di -On-hexanoyl-5-fluorouridine H: 3- (3-methylbenzoyl) -2 '-deoxy-5-fluorouridine I: 3- (3-methylbenzoyl) -2'-deoxy-3', 5'-di-0 -acetyl-5-fluorouridine

J: 3- (2,3-DimethoxybenzoyI) -2'-deoxy-3 ', 5'-di-0-acetyl-5-fluorouridine

K: 3- (3,4-methylenedioxybenzoyl) -2'-deoxy-5-fluorouridine L: 3- (3,4-methylenedioxybenzoyl) -2'-deoxy-3 ', 5'-di-0-acetyl-5 -fluorouridine M: 5-fluorouracil.

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

646 715

(C) Results of the experiments:

The results of tests (A) and (B) and the therapeutic indices calculated therefrom are summarized in Tables I, II, III and IV below. The therapeutic indices are calculated according to the following equations:

Therapeutic index = LDio value divided by T / C 0.50 value.

Table I

Administered compound n

Value for T / C 0.70,

Value for T / C 0.50,

LDio mg / kg

Therapeutic index

In the general formula I, (R) m

mg / kg mg / kg

2,3-dimethoxy i

25th

44

90

2.05

C OD

2,3-dimethoxy

14

41

89

130

1.46

W> S

fi Prt

H (unsubstituted)

2nd

23

43

-

-

fi TD

1"

.s ^

h uj

3-methyl

2nd

8th

23

96

4.17

2-methyl

5

4th

11

-

-

2,3-dimethoxy

5

6

18th

33

1.83

0) (y

> -o

3-fluorine

5

1

8th

24th

3.00

2,3-dimethoxy

6

6

20th

36

1.80

3-fluorine

6

7

21st

41

1.95

0)

§.S

fi

-

rt A öö u G V <D 3

m> T3

A B C D E

22 19 6 5 18

72 45 15 12 55

108

70 24 19

71

1.50 1.55 1.60 1.58 1.29

Table!!

Administered compound

In the general formula I, (R) m means n

Value for T / C 0.50 mg / kg

LDio, mg / kg

Therapeutic index

H (unsubstituted)

3rd

1.0

8.6

8.60

2-methyl

3rd

2.0

9.5

4.75

3-methyl

3rd

3.6

8.1

2.25

M S

3,5-dimethyl

3rd

6.0

22

3.67

3rd

•O

3-fluorine

3rd

13

30th

2.31

C d

2-chlorine

3rd

13

33

2.54

IN THE

W

2,4-dichloro

3rd

14

31

2.21

U

O

H (unsubstituted)

4th

1.0

9.4

9.40

"Ö

2-methyl

4th

5.9

13

2.20

e a> w> fi

3-methyl

4th

5.7

16

2.81

4-methyl

4th

5.3

12

2.26

3 T3

2,4-dimethyl

4th

6.3

16

2.54

G

3-fluorine

4th

5.8

17th

2.93

u

<D

4-fluorine

4th

6.1

18th

2.95

>

3-chlorine

4th

8.6

23

2.67

4-bromine

4th

10th

26

2.60

3,5-dichloro

4th

13

37

2.85

F

28

28

1.00

c i fi c .S Ö

G

9.0

19th

2.11

C3 fi fai) ^ u fi

H

62

91

1.50

<ü 1) 3

oa> T3

I.

41

89

2.17

Table III

Compound administered n Value for T / C 0.70, value for T / C 0.50, LDio, mg / kg Therapeutic Index

In the general formula I, (R) m mg / kg mg / kg e jyj, 2-methoxy 3 3.6 10 36 3.60

3-methoxy 3 2.8 8.3 19 '2.29 § "§ 4-methoxy 3 2.5 7.6 17 2.24 c« 2-ethoxy 3 2.4 7.0 35 £ 5.00 « 4-ethoxy 3 1.2 5.3 27 5.09> | j 4-n-propoxy 3 1.8 7.4 24 3.24

4-n-butoxy 3 1.0 4.0 19 4.75

646 715

6

Table III (continued)

Administered compound

In the general formula I, (R) m means n

Value for T / C 0.70. mg / kg

Value for T / C 0.50 mg / kg

LDio, mg / kg

Therapeutic index

Compounds of the invention

2,3-dimethoxy 3,5-dimethoxy

2-methoxy

3-methoxy

4-methoxy 2-ethoxy 4-ethoxy 4-n-propoxy 4-n-butoxy 2,3-dimethoxy

3rd

3rd

4 4 4 4 4 4 4 4

2.0 3.0

2.0

2.1 0.9 0.8

1.1 2.4 2.3

8.1

9.7 7.6 9.5

4.2 4.1

2.8

4.3 8.0 8.0

23 36 17 26 12

22 16 20 20

23

2.84 3.71 2.24 2.74 2.86 5.37 5.71 4.65 2.50 2.88

Known connections

F G J

14 3.1 11

28 9.0 34

28 19 76

1.00 2.11 2.24

Table IV

Administered compound

In the general formula I, (R) m means n

Value for T / C 0.70 mg / kg

Value for T / C 0.50 mg / kg

LDio, mg / kg

Therapeutic index

Compounds of the invention

3,4-methylenedioxy 3,4-methylenedioxy

3rd

4th

1.8 2.7

7.4 7.6

12 15

1.62 1.97

Known connections

K L M

25 9 31

70 37 67

61 43 63

0.87 1.16 0.94

The results in Tables I to IV show that Example 1

Compounds of the invention have a strong antitumor activity 35 2.0 g of 2'-deoxy-3 ', 5'-di-O-propionyl-5-fluorouridine and relatively low toxicity are dissolved in 25 ml of anhydrous dioxane and with Have ice to known compounds. The invention brings chilled. Then the solution is mixed with 2 ml of triethylamine and thus an obvious advance in terms of the anti-1.7 g of 2-methylbenzoyl chloride and then 15 minutes of tumor activity and the reduction in toxicity. at room temperature and then 30 minutes at 70 ° C

The 4 # connections are implemented in clinical chemotherapy. The reaction mixture according to the invention is then preferably cooled in a daily dose and the triethylamine hydrochloride is filtered off. The Fil-1 administered to 1000 mg. Oral administration is preferred and is evaporated under reduced pressure. The conservation; however, the compounds of the invention can also be separated from the oily residue by column chromatography on parenteral, for example intravenously, or intrarectally by selgel with chloroform as the eluent. A suppository will then be administered. 4s the purified oily product is dissolved in about 15 ml of dimethyl sulfoxide as pharmaceutical preparations for oral administration, and the solution obtained is added with vigorous stirring, tablets, capsules (hard or soft), and liquid drops are dropped into about 400 ml of ice water. A sige preparations or granules in question arises, each precipitate, which is filtered off, washed with water and contains 0.5 to 500 mg of a compound of the invention as active substance at room temperature under reduced pressure. These formulations can be dried in addition to this. Yield: 1.5 g (56.4%) powdered active ingredient other common carriers, auxiliaries and additives 3- (2-methylbenzoyl) -2'-deoxy-3 ', 5'-di-0-propionyl-5- contains fluorine. Examples of suitable carriers are milk uridine.

sugar, corn starch, potato starch, various cane sugar esters of fatty acids, microcrystalline cellulose and UV absorption spectrum: 255.5 nm polyethylene glycol 4000. Acacia, ss NMR spectra: 5 (ppm, CDCb) are suitable as binders

Gelatin, hydroxypropyl cellulose and potato starch. For uridine unit: 7.80 (d, He), 6.19 (broad t, h'i), close to 2.5

Games for lubricants are magnesium stearate and talcum. (m, H'2), 5.10-5.30 (m, H'3), 4.16-4.42 (m, H'4, H's), 2.10-2.54

Calcium carboxymethyl cellulose, (m, 2 x COCH2), 0.98-1.26 (m, 2 x CH3) can be used as disintegrant.

Potato starch and corn starch can be used. Further benzoyl unit: 7.63 (d, Hò), 7.12-7.56 (m, H3, H4, Hs), 2.62

conventional solubilizers and suspending agents can be found in «> (s, CH3)

the preparations may be included, with polyethylene glycol 2000 to 600 being particularly preferred. Examples for suppo elementary analysis (for: C23H25FN2O8):

Basic ingredients are glycerin, cocoa butter, glyceroge-

latine, polyethylene glycol or laurin. Calc.%: C 57.98; H 5.29; N 5.88

In addition to the additives mentioned, other% s: C 57.82; H 5.49; N 5.99.

Substances usually used as carriers for pharmaceutical preparations are used. Example 2

The examples illustrate the invention. 2.0 g of 2'-deoxy-3 ', 5'-di-0-propionyl-5-fluorouridine

7

646 715

are dissolved in 25 ml of anhydrous dioxane. The solution obtained is cooled in ice and then mixed with 2 ml of triethylamine and 1.8 g of 3-fluoro-benzoyl chloride. The mixture is then reacted for 15 minutes at room temperature and then for 30 minutes at 60 ° C. The reaction mixture obtained is worked up according to Example 1. Yield: 2.5 g (71.5%) of powdered 3- (3-fluorobenzoyl) -2'-deoxy-3 ', 5'-di-O-propionyl-5-fluorouridine.

UV absorption spectrum: 251.5 nm NMR spectra: 8 (ppm, CDCÎ3)

Uridine unit: 7.81 (d, He), 6.18 (broad t, H '1), close to 2.5 (m, H2), 5.19-5.36 (m, H's), 4.24-4.48 (m, H'4, H's) ), 2.20-2.60 (m, 2 x COCH2), 1.05-1.32 (m, 2 x CHs)

Benzoyl unit: 7.28-7.76 (m, aromatic H)

Elemental analysis (for: C22H22F2N2O8):

Calc.%: C 55.00; Found%: C 55.28;

H 4.62; H 4.77;

N 5.83 N 6.02.

Example 3

2.0 g of 2'-deoxy-3 ', 5'-di-0-propionyl-5-fluorouridine are dissolved in 25 ml of anhydrous dioxane. The solution obtained is cooled in ice and 2 ml of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are then added. The mixture is then reacted at room temperature for 30 minutes and then at 50 ° C. for 30 minutes. The reaction mixture is then cooled and the triethylamine hydrochloride is filtered off. The filtrate obtained is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel using chloroform as the eluent. The purified oily product obtained is left to stand at room temperature for about 15 hours, part of which crystallizes out. A small amount of ethanol is then added to the mixture to completely crystallize the product. The crystalline precipitate obtained is filtered off. Yield: 2.3 g (79.0%) of 3- (2,3-dimethoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-propionyl-5-fluorouridine, mp 84.5 to 86 ° C.

UV absorption spectrum: 264.5.327 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.72 (d, He), 6.27 (broad t, H'i) close to 2.5 (m, H'2), 5.16-5.32 (m, H's), 4.18-4.48 (m, H'4, H's), 2.14-2.48 (m, 2 x COCH2), 1.05-1.32 (m, 2 x CH3)

Benzoyl unit: 7.46-7.64 (m, Ha), 7.10-7.26 (m, H4, Hs), 3.86 (s, OCHs), 3.84 (s, OCHs)

Elemental analysis (for: C24H27FN2O10):

%: C Found%: C

55.17; 55.27;

H H

5.21; 5.37;

N N

5.36 5.50

Yield: 1.25 g (35.4%) 3- (4-methylbenzoyl) -2'-deoxy-3 ', 5'-di-0-myristoyl-5-fluorouridine, melting point 76 to 77 ° C.

UV absorption spectrum: 263 nm 5 NMR spectra: 8 (ppm, CDCÎ3)

Uridine unit: 7.74 (d, Hó), 6.26 (broad t, H'i), close to 2.5 (m, H'2), 5.14-5.32 (m, H'3), 4.20-4.44 (m, H '4, H's), 2.20-2.54 (m, 2 x COCH2), 1.04-1.84 (m, 22 x CH2), 0.76-1.00 (m, 2 x CH3)

10 benzoyl unit: 7.78 (d, H2, Hó), 7.30 (d, H3, Hs), 2.42 (s, CH3)

Elemental analysis (for: C45H69FN2O8):

is Ber.%: C 68.85; H 8.86; N 3.57 Found%: C 68.76; H 8.55; N 3.79

Example 5

20 3.0 g of 2'-deoxy-3 ', 5'-di-0-palmitoyl-5-fluorouridine are dissolved in 25 ml of anhydrous dioxane. The solution obtained is cooled in ice and 2 ml of triethylamine and 1.9 g of 2,3-dimethoxybenzoyl chloride are then added. The mixture is then reacted at room temperature for 10 minutes and then at 70 ° C. for 90 minutes. The reaction mixture obtained is then cooled and the precipitated triethylamine hydrochloride is filtered off. The filtrate is evaporated under reduced pressure and the residue is dissolved in ethanol with heating. The solution is then left to stand, a crystalline precipitate separating out, which is filtered off and recrystallized from ethanol. Yield: 2.95 g (80.2%) 3- (2,3-dimethoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-palmitoyl-5-fluorouridine, melting point 77 to 78 ° C .

35

UV absorption spectrum: 264.5.327 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.76 (d, Hó), 7.31 (broad t, H '1), close to 2.4 (m, H'2), 5.18-5.34 (m, H'3), 4.22-4.48 (m, H '4, H's), 2.10-2.55 40 (m, 2 x COCH2), 1.08-1.80 (m, 26 x CH2), 0.76-1.06 (m, 2 x CHs)

Benzoyl unit: 7.59 (dd, Hó), 7.12-7.28 (m, H4, Hs), 3.90 (broad s, 2 x OCH3)

45 Elementary analysis (for: C50H79FN2O10):

Calc.%: C 67.69; H 8.89; N 3.16 Found%: C 68.09; H 9.11; N 2.99

Example 4

3.0 g of 2'-deoxy-3 ', 5'-di-0-myristoyl-5-fluorouridine are dissolved in 20 ml of anhydrous dioxane. The solution is then cooled in ice and 2.1 ml of triethylamine and 1.4 g of 4-methylbenzoyl chloride are then added. The mixture is then reacted for 3 hours at room temperature. The triethylamine hydrochloride formed is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel using chloroform as the eluent. The purified oily product obtained is then dissolved in ethanol and concentrated under reduced pressure. A crystalline precipitate is obtained, which is recrystallized from ethanol.

50

Example 6

3.0 g of 2'-deoxy-3 ', 5'-di-0-butanoyl-5-fluorouridine are dissolved in 20 ml of anhydrous dioxane. The solution obtained is cooled in ice and then 3 ml of triethylamine and 2.0 g of 55 benzoyl chloride are added. The mixture is then reacted for 2 hours at room temperature. The triethylhydrochloride formed is filtered off and the filtrate is evaporated under reduced pressure. The oily residue is purified by column chromatography on silica gel using chloroform as the eluent. Yield: 2.3 g (60.7%) of 3-benzoyl-2'-deoxy-3 ', 5'-di-0-butanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 253.5 nm NMR spectra: 8 (ppm, CDCÎ3)

65 uridine unit: 7.76 (d, Hó), 6.27 (broad t, H'i) near 2.5 (m, H'2), 5.15-5.32 (m, H's), 4.20-4.46 (m, H'4, H's), 2.20-2.52 (m, 2 x COCH2), 1.44-1.92 (m, 2 x CH2), 1.86-1.10 (m, 2 x CH3)

Benzoyl unit: 7.36-8.02 (m, aromatic H) Elemental analysis (for: C24H27FN2O8):

Calc.%: C 58.77; Found%: C 58.75;

H 5.55; H 5.82;

N 5.71 N 5.78

Examples 7 to 23 According to Example 6, a 2'-deoxy-3 ', 5'-di-O-alkylcarbonyl-5-fluorouridine is reacted with an aroyl chloride. Table V below shows the 2'-deoxy-3 ', 5'-di-0-alkylcarbonyl-5-fluorouridine derivatives obtained and their characteristic physical data.

Table V

Example In General No. Formula I

(R) m, n

Yield% elemental analysis Empirical formula Ber. %: C, H, N Found%: C, H, N

UV ?.

EtOH

(nm) NMR (CDCh) 8 (ppm)

Uridine unit

Benzoyl unit

7 3-methyl

2nd

8 4-methyl

2nd

71.6

71.6

9 3,4-dimethoxy 56.2 2

10 4-fluor 71

2nd

11 2-methyl 68.0

5

12 2,3-dimethoxy 89.0

5

13 3-fluorine 83.6

5

C25H29FN2O8 59.52; 5.79; 5.55 59.59; 6.09; 5.59

C25H29FN2O8 59.52; 5.79; 5.55 59.55; 6.82; 5.58

C26H31FN2O10 56.72; 5.68; 5.09 56.54; 5.60; 5.14

C24H26F2N2O8 56.69; 5.15; 5.51 56.74; 5.20; 5.56

C31H41FN2O8 63.25; 7.02; 4.76 63.31; 7.09; 4.79

C32H43FN2O10 60.56; 6.83; 4.41 60.60; 7.06; 4.36

C30H38F2N2O8 60.80; 6.46; 4.73 60.77; 6.48; 4.70

257

263.5

280.5 315.5

255

255.5

265 327

252

7.75 (d, H «), near 2.4 (m, H2 '), 4.20-4.44 (m, HU', Hs'), 1.44-1.92 (m, 2 x CH2)

7.74 (d, H '), near 2.4 (m, Ha'), 4.22-4.45 (m, H4 ', Hs'), 1.44-l.92 (m, 2x) CH2)

7.75 (d, H6), near 2.5 (m, H2 '), 4.20-4.46 (m, H4', H5 '), l, 50-l, 90 (m, 2 x CH2)

7.78 (d, H "), close to 2.5 (m, H" '), 4.22-4.48 (m, H4', Hs'), 1.46-l, 96 (m, 2 x CH2)

7.78 (d, H «), near 2.4 (m, H2 '), 4.18-4.44 (m, H4', Hs'), 1.08-l, 84 (m, 8 x CH2)

7.80 (d, H6), near 2.5 (m, H2 '), 4.20-4.50 (m, H4', H5 '), l, 16-l, 88 (m, 8 x CH2 )

7.85 (d (Hs), near 2.5 (m, H2 '), 4.20-4.48 (m, H4', Hs')> 1.10-1.84 (m, 8 x CH2 )

6.26 (broad-t, Hi '), 5.12-5.32 (m, H3'), 2.12-2.56 (m, 2 x COCH2), 0.84-l, 12 (m , 2x CH3)

6.26 (broad-t, hi '),

5.15-5.32 (m, H3 '),

2.16-2.52 (m, 2 x COCH2), 0.84-l, 08 (m, 2x CH3)

6.26 (broad-t, Hi '), 5.14-5.32 (m, H3'), 2.20-2.55 (m, 2 x COCH2), 0.84-l, 10 (m , 2 x CH3)

6.27 (broad-t, hi '),

5.17-5.34 (m, H3 '), 2.08-2.60 (m, 2 x COCH2), 0.84-l, 20 (m, 2xCH3)

6.27 (broad-t, Hi '), 5.14-5.32 (m, H3'), 2.16-2.52 (m, 2 x COCH2), 0.72-l, 04 (m , 2x CH3)

6.34 (broad-t, Hi '), 5.20-5.36 (m, H3'), 2.16-2.56 (m, 2 x COCH2), 0.76-l, 08 (m , 2x CH3)

6.28 (broad-t, Hi ') 5.16-5.35 (m, H3'), 2.20-2.56 (m, 2 x COCH2), 0.76-1.05 (m, 2 x CH3)

7.60-7.80 (m, H2, H6), 7.30-7.52 (m, H4, Hs), 2.40 (s, CH3)

7.79 (d, H2, Hs), 7.29 (d, H3, H5), 2.42 (S, CH3)

7.55 (broad-s, H2), 7.39 (d, H «), 6.88 (d, Hs), 3.91 (s, 2 x OCHs)

7.96 (dd, H2, Hó), 7.18 (t, H3, H5)

7.16-7.68 (m, aromatic H), 2.68 (s, CH3)

7.56-7.70 (m, H6), 7.18-7.32 (m, H4, H5), 3.90 (s, OCH3), 3.88 (s, OCH3)

7.28-7.90 (m, aromatic H)

Table V (continued)

Example In general yield% elemental analysis UVJi ^ [H (nm) NMR (CDCh) 8 (ppm)

No. Formally empirical formula

(R) m, n calc. %: C, H, N uridine unit, benzoyl unit

Found%: C, H, N

14 2-methyl 61.6

6

15 2,3-dimethoxy 67.9

6

16 3-fluorine 84.0

6

17 hydrogen 66.9 10

C33H45FN2O8 64.27; 7.35; 4.54 64.23; 7.31; 4.59

C34H47FN2O10 61.62; 7.15; 4.23 61.69; 7,02,4,09

C32H42F2N2O8 61.92; 6.82; 4.51 61.73; 6.72; 4.40

C40H59FN2O8 67.20; 8.32; 3.92 67.16; 8.30; 4.00

255.5

265 327

251.5

253

7.80 (d, Hó), close to 2.5 (m, H2 '), 4.22-4.48 (m, H4', H5 '), 1.16-1.90 (m, 10 x CH2 )

7.76 (d, height), near 2.5 (m, H2 '), 4.22-4.50 (m, H4', H5 '), 1.14-1.96 (m, 10 x CH2 )

7.86 (d, height), near 2.5 (m, H2 '), 4.26-4.50 (m, H4', H5 '), 1.14-2.00 (m, 10 x CH2 )

7.80 (d, Hô), near 2.5 (m, H2 '), 4.20-4.54 (m, H4', H5 '), l, 20-2.00 (m, 18 x CH2)

6.27 (broad-t, Hi '), 5.16-5.35 (m, H3'), 2.18-2.52 (m, 2 x COCH2), 0.76-l, 04 (m "2 x CH3)

6.29 (broad-t, Hi '), 5.16-5.33 (m, H3'), 2.16-2.54 (m, 2 x COCH2), 0.72-l, 04 (m , 2 x CH3)

6.30 (broad-t, Hi '), 5.20-5.36 (m, H3'), 2.22-2.58 (m, 2 x COCH2), 0.74-l, 06 (m , 2xCH3)

6.28 (broad-t, Hi '), 5.16-5.35 (m, H3'), 2.20-2.60 (m, 2 x COCH2), 0.76-l, 08 (m , 2 x CHs)

7.64 (d, Hó),

7.20-7.60 (m, H3, H4, Hs), 2.68 (s, CH3)

7.58 (dd, H6),

7.14-7.30 (m, H4, Hs) ,.

3.87 (s, OCH3), 3.85 (S, OCH3)

7.24-7.92 (m, aromatic H)

7.40-8.10 (m, aromatic H)

18 3-methyl 54.9

10th

C41H61FN2O8 67.56; 8.44; 3.84 67.59; 8.41; 3.81

257.5 7.79 (d, H6), close to 2.5 (m, H2 '),

4.20-4.48 (m, H4 ', H5'), l, 10-2.00 (m, 18 x CH2)

6.29 (broad-t, Hi '), 5.16-5.36 (m, H3'), 2.15-2.60 (m, 2 x COCH2), 0.70-1.10 (m , 2 x CH3)

7.30-8.00 (m, aromatic H)

19 2,4-dimethoxy 34 10

C42H63FN2O10 65.09; 8.19; 3.61 65.25; 8.65; 3.79

278 304

7.63 (d, H6), near 2.5 (m, H2 '), 4.16-4.44 (m, H4', H5 '), 1.04-180, (m, 18 x CH2 )

6.26 (broad-t, Hi '), 5.10-5.30 (m, H3'), 2.20-2.50 (m, 2 x COCH2), 0.78-l, 04 (m , 2xCH3)

8.01 (d, Hâ), 6.57 (dd, Hs), 6.36 (d, H3), 3.83 (s, OCH3), 3.74 (s, OCH3)

20 hydrogen 43.2 12

C44H67FN2O8 68.54; 8.76; 3.63 68.36; 8.75; 3.87

253

7.60 (d, H6), near 2.4 (m, H2 '), 4.05-4.35 (m, H4', H5 ') 1.00-80, 80 (m, 22 x CH2)

6.07 (broad-t, Hi '), 5.00-5.16 (m, H3'), 2.05-2.50 (m, 2 x COCH2), 0.70-l, 00 (m , 2 x CH3)

7.10-7.85 (m, aromatic H)

21 2-fluor

12

42.3

C44H66F2N2O8 66.98; 8.43; 3.55 66.89; 8.32; 3.81

250

7.62 (d, H6), near 2.4 (m, H2 '), 4.04-4.44 (m, H4', H5 '), 0.96-l, 80 (m, 22 x CH2)

6.06 (broad-t, Hi '), 5.00-5.20 (m, H3') j 2.04-2.48 (m, 2 x COCH2), 0.72-0.98) m , 2 x CH3)

6.80-7.92 (m, aromatic H)

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Example 24

A solution of 7.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of anhydrous dioxane is mixed with 3.7 ml of triethylamine and 2.7 g of benzoyl chloride. The mixture is then reacted for 2 hours at room temperature and then for 30 minutes at 60 ° C. The reaction mixture obtained is cooled and evaporated under reduced pressure. The residue is then dissolved in ethyl acetate, washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography on silica gel using chloroform as the eluent. The oily residue obtained is dissolved in about 80 ml of 15 ethanol and the solution is treated with activated carbon. The ethanol is then distilled off under reduced pressure and the residue is again purified by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained is dried at room temperature under 20 reduced pressure. Yield: 7.9 g (90%) of 3-benzoyl-2 '-deoxy-3', 5 '-di-0-n-pentanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 253 nm 25 NMR spectra: S (ppm, CDCh)

Uridine unit: 7.79 (d, Hó), 6.26 (broad t, H'i), close to 2.4 (m, H'2), 5.16-5.32 (m, H'3), 4.20-4.56 (m, H 't, H's), 2.08-2.64 (m, 2 x COCH2), 1.16-1.84 (m, 4 x CH2), 0.80-1.08 (m, 2 x CH3)

30 benzoyl unit: 7.36-8.02 (m, aromatic H)

Elemental analysis (for: C26H31FN2O8):

Calc.%: C 60.22; H 6.03; N 5.40 ss Found%: C 60.33; H 6.08; N 5.55

Examples 25 to 29 According to Example 24, the 2'-deoxy-3 ', 5'-di-O-n-alkylcarbonyl-5-fiorioruridine derivatives listed in Table VI below with their yields and physical data are prepared.

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Example 30

A solution of 7.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluoroururidine in 50 ml of anhydrous dioxane is mixed with 4.0 ml of triethylamine and 3.4 g of 3-methylbenzoyl chloride . 5 The mixture is then reacted for 5 hours at room temperature and then evaporated under reduced pressure. The residue obtained is dissolved in ethyl acetate, washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate 10. The solvent is then distilled off under reduced pressure and the residue obtained is purified twice by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained as a residue is dried under reduced pressure at room temperature. Yield: 6.0 g (66%) of 3- (3-methylbenzoyl) -2'-deoxy-3 /, 5'-di-0-n-pentanoyl-5-fluorouridine as an oil.

UV absorption spectrum: X ^ '° H 258 nm NMR spectra: 5 (ppm, CDCÎ3)

20 uridine unit: 7.76 (d, Hó), 6.26 (broad t, H '1) close to 2.4 (m, H'2), 5.16-5.32 (m, H'3), 4.20-4.56 (m, Ha , H's), 2.05-2.67 (m, 2 x COCH2), 1.16-1.84 (m, 4 x CH2), 0.80-1.06 (m, 2 x CH3)

Benzoyl unit: 7.26-7.56 (m, H <t, Hs), 7.64-7.88 (m, H2, H4), 25 2.38 (s, CH3)

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Calc.%: C 60.89; H 6.25; N 5.26 30 Found%: C 60.87; H 6.46; N 5.30

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Example 31

Using benzoyl chloride, 30.7.4 g (84%) of 3-benzoyl-2'-deoxy-3 ', 5'-di-0-n-35 pentanoyl-5-fluorouridine are obtained as an oil according to Example. The physical data of this compound are identical to that of the oil obtained in Example 24.

40 Example 32

A solution of 7.5 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of anhydrous dioxane is mixed with 10.7 ml of triethylamine and 3.6 g of benzoyl chloride. The mixture is then reacted for 4 hours at room temperature. The reaction mixture obtained is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The solution is then washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified twice by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained as a product is dried at room temperature under reduced pressure. Yield: 8.1 g (87%) of 55 3-benzoyl-2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil. The physical data of this compound are identical to that of the oil obtained in Example 25.

6o Example 33

A solution of 7.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of anhydrous dioxane is mixed with 3.7 ml of triethylamine and 3.4 g of 3.5- Dimethylbenzoyl chloride added. The mixture is then reacted for 1 hour at room temperature and 6 seconds afterwards for 30 minutes at 60 ° C. The reaction mixture obtained is cooled and then worked up according to Example 24. Yield: 6.6 g (71%) of 3 '- (3,5-dimethylbenzoyl) -2'-deoxy-3', 5'-di-0-n-pentanoyl-5-fluorouridine as an oil.

646715

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UV absorption spectrum: À, ®a ° H 263 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.79 (d, Hó), 6.28 (broad t, H'i), close to 2.4 (m, H'2), 5.16-5.32 (m, H's), 4.20-4.46 (m, H'4 , H's), 2.14-2.52 (m, 2 x COCH2), 1.16-1.84 (m, 4 x CHz), 0.82-1.04 s

(m, 2 x CHs)

Benzoyl unit: 7.54 (s, H2, Hó), 7.30 (s, Ht), 2.34 (s, 2 x CHs)

Elemental analysis (for: C28H35FN2O8):

Calc.%: C 61.53; Found%: C 61.69;

H 6.45; H 6.63;

N 5.12 N 5.31

10th

15

Example 34

Using 3-methylbenzoyl chloride, 6.6 g (73%) of 3- (3-methylbenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine are obtained as an oil according to Example 33 receive. The physical data of this compound are identical to that of the oil obtained in Example 30. 20th

Example 35

3.7 ml of triethylamine and 3.2 g of 3-fluorobenzoylchloride are added to a solution of 7.5 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of anhydrous dioxane. The mixture is then reacted for 4 hours at room temperature and then for 30 minutes at 60 ° C. The reaction mixture obtained is cooled and then worked up according to Example 30. Yield: 7.0 g (73%) of 3- (3-fluoro-benzoyl) -2 '-deoxy-3', 5 '-di-O-n-hexanoyl-5-fluorouridine as an oil.

25th

30th

UV absorption spectrum: 252 nm NMR spectra: S (ppm, CDCh)

Uridine unit: 7.77 (d, Hó), 6.24 (broad t, H '1), close to 2.4 (m, H'2), 5.14-5.30 (m, H's), 4.20-4.56 (m, H'4, H's), 2.04-2.68 (m, 2 x COCH2), 1.12-1.82 (m, 6 x CH2), 0.78-1.04 (m, 2 x CHs) benzoyl unit: 7.24-7.84 (m, aromatic H)

Elemental analysis (for: C28H34F2N2O8):

35

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S

Calc.%: C 59.57; Found%: C 59.69;

H 6.07; H 6.31;

N 4.96 N 5.02

Examples 36 to 43 According to Example 35, optionally with a modified reaction time, the 2'-deoxy-3 ', 5'-di-O-alkylcarbonyl-5-fluorouridine derivatives listed in Table VII with their yields and physical data are prepared.

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Example No.

In the general formula I (R) m, n

Yield,% shape

Elemental Analysis Empirical Formula Ber. %: C, H, N Found%: C, H, N

uv ^ a0xH

(nm) NMR (CDU) S (ppm)

Implementation period

Uridine unit

Benzoyl unit

Room temp., H

60 ° C, h

39

2,4-dichloro

(3)

71 oil

C26H29CI2FN2O8 53.16; 4.98; 4.77 53.23; 5.15; 4.53

263

7.76 (d, H6), near 2.4 (m, H2 '), 4.22-4.56 (m, H4', H5 '), l, 16-l, 82 (m, 4x CH2)

6.23 (broad-t, Hi ') »5.15-5.30 (m, H3'), 2.03-2.69 (m, 2 x COCH2), 0.82-l, 10 (m , 2 x CH3)

7.86 (d, H «), 7.22-7.54 (m, H3H5) 1

2nd

40

4-fluor (4)

59 oil

C28H31F2N2O8 59.57; 6.07; 4.96 59.42; 5.90; 5.03

256

7.77 (d, height), near 2.4 (m, H2 '), 4.20-4.56 (m, H4', H5 '), 1.14-1.84 (m, 6 x CH2 )

6.24 (broad-t, Hi '), 5.14-5.30 (m, H3'), 2.06-2.66 (m, 2 x COCH2), 0.78-l, 06 (m , 2 x CH3)

7.84-8.06 (m, H2, H6), 7.16 (t, H3H5)

1

2nd

41

3-chlorine (4)

68 oil

C28H34CIFN2O8 57.88; 5.90; 4.82 57.73; 5.78; 4.61

255

7.80 (d, Hó), near 2.4 (m, H2 '), 4.20-4.60 (m, H4', Hs'), 1.16-1.86 (m, 6 x CH2 )

6.26 (broad-t, Hi '), 5.16-5.32 (m, H3'), 2.06-2.70 (m, 2 x COCH2), 0.80-l, 06 (m , 2 x CH3)

7.24-7.94 (m, aromatic H)

1

1

42

4-bromine (4)

62 oil

C28H34BrFN2C> 8 53.77; 5.48; 4.48 53.71; 5.42; 4.30

267

7.78 (d, H6), near 2.4 (m, H2 '), 4.20-4.56 (m, H4', H5 '), l, 14-l, 84 (m, 6 x CH2 )

6.23 (broad-t, Hi '), 5.12-5.30 (m, H3'), 2.04-2.68 (m, 2 x COCH2), 0.76-l, 04 (m , 2 x CH3)

7.52-7.84 (m, aromatic H)

1

1

43

3,5-dichlor

(4)

73 oil

C28H33CI2FN2O8 54.64; 5.40; 4.55 54.61; 5.32; 4.46

258

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6.24 (broad-t, Hi '), 5.16-5.32 (m, H3'), 2.08-2.70 (m, 2 x COCH2), 0.80-l, 06 (m , 2 x CH3)

7.72-7.86 (m, H2H6), 7.60-7.72 (m, H4)

1

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Example 44

A solution of 7.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of anhydrous acetonitrile is mixed with ice cooling with 7.8 ml of triethylamine and 2.6 g of benzoyl chloride. The mixture is then reacted for 3 hours at room temperature and then for 10 minutes at 50 to 60 ° C. The reaction mixture obtained is cooled and then evaporated under reduced pressure. The residue is purified twice by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained is dried at room temperature under reduced pressure. Yield: 7.0 g (79%) of 3-benzoyl-2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine from oil. The physical data of this compound are the same as that of the oil obtained in Example 24.

Example 45

5.2 ml of triethylamine and 2.6 g of benzoyl chloride are added to a solution of 7.5 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of dioxane. The mixture obtained is then reacted at room temperature for 2 hours and then at 50 to 60 ° C. for 30 minutes. The reaction mixture obtained is then cooled and filtered to remove undissolved substances. The filtrate is worked up according to Example 44. Yield: 7.1 g (76%) of 3-benzoyl-2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that obtained in Example 25.

Example 46

Using 2-methylbenzoyl chloride, according to Example 45.6.8 g (75%) of 3- (2-methylbenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouride as Get oil. The physical data of this compound are the same as that of the oil obtained in Example 26.

Example 47

A solution of 1.0 g of 2'-deoxy-3 ', 5'-di-O-n-pentanoyl-5-fluorouridine in 10 ml of anhydrous dioxane is mixed with 0.52 ml of triethylamine and 0.54 g of benzoyl bromide while cooling with ice. The mixture is then reacted at room temperature for 15 minutes and then at 70 ° C. for 30 minutes. The reaction mixture obtained is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and then with saturated sodium chloride solution and worked up according to Example 30. Yield 0.75 g (60%) of 3-benzoyl-2'-deoxy-3 ', 5'-di-O-n-pentanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 24.

Example 48

A solution of 7.5 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 40 ml of ethyl acetate is mixed with 4.6 ml of triethylamine and 2.7 g of 3-fluorobenzoyl chloride. The mixture is then reacted for 3 hours at room temperature and then for 1 hour at 50 to 60 ° C. The reaction mixture is cooled and washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is worked up according to Example 30. Yield: 6.0 g (63%) of 3- (3-fluorobenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 35.

Example 49

A solution of 7.0 g of 2'-deoxy-3 ', 5' -di-on-pentanoyl-5-fluorouridine in 50 ml of anhydrous dioxane is mixed with 6.3 ml of triethylamine and 5.7 g of 3,5-dimethylbenzoyl chloride . The mixture is then reacted for 4 hours at room temperature. The reaction mixture obtained is then worked out in accordance with Example 30. Yield 5.9 g (63%) of 3- (3,5-dimethylbenzoyl) -2 '-deoxy-3', 5 '-di-O-n-pentanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 33.

Example 50

A solution of 4.1 g2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fiorioridine in 20 ml of anhydrous dioxane is mixed with 2.1 ml of triethylamine and 2.6 g of 2,3-dimethoxybenzoyl chloride transferred. The mixture is then reacted for 1 hour at room temperature and then for 1 hour at 60 ° C. The reaction mixture obtained is cooled and then evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography on silica gel using chloroform as the eluent. The oily compound obtained is dissolved in about 30 ml of ethanol and the solution is treated with activated carbon. The ethanol is then distilled off under reduced pressure and the residue is again purified by column chromatography on silica gel using chloroform as the eluent. Yield: 4.7 g (81.0%) of 3- (2,3-dimethoxybenzoyl) -2 '-deoxy-3', 5 '-di-O-n-pentanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 265.327 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.72 (d, Ho), 6.26 (broad t, H'i), close to 2.4 (m, H'2), 5.16-5.32 (m, H's), 4.20-4.46 (m, H'4 , H's), 2.02-2.68 (m, 2 x COCH2), 1.20-1.84 (m, 4 x CH2), 0.82-1.06 (m, 2 x CH3)

Benzoyl unit: 7.50-7.62 (m, He), 7.10-7.22 (m, H4, Hs), 3.88 (s, CH3O), 3.86 (s, CHsO)

Elemental analysis (for: C28H35FN2O10):

Calc.%: C 58.13; H 6.10; N 4.84 Found%: C 57.85; H 6.20; N 4.67

Examples 51-53

According to Example 50, the 2 '-deoxy-3', 5 '-di-O-alkylcarbonyl-5-fluorouridine derivatives listed in Table 8 with yields and physical data are prepared.

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Example 54

A solution of 2.0 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of chloroform is mixed with 0.95 ml of triethylamine and 1.08 g of 4-n-propoxybenzoyl chloride. Then the mixture is reacted for 1 hour at room temperature and then for 30 minutes at 50 to 60 ° C. The reaction mixture obtained is cooled, washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue obtained is purified by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained is dried at room temperature under reduced pressure. Yield: 2.1 g (77.8%) of 3- (4-n-propoxy-is-benzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil.

UV absorption spectrum: A, ® ° H 220.288 nm NMR spectra: 8 (ppm, CDCh)

20 uridine unit: 7.78 (d, Hó), 6.24 (broad t, H'i), close to 2.4 (m, H'2), 5.16-5.28 (m, H's), 4.24-4.52 (m, H ' 4, H'5), 2.24-2.46 (m, 2 x COCH2), 1.20-1.92 (m, 6 x CH2), 0.82-1.10 (m, 2x CHs)

Benzoyl unit: 7.86 (d, H2, Hó), 6.92 (d, Hs, Hs), 3.99 25 (t, CH2O), close (m, CH2), close 1.0 (m, CH3)

Elemental analysis (for: C31H41FN2O9):

Calc.%: C 61.58; H 6.83; N 4.63 30 Found%: C 61.35; H 6.98; N 4.43

Example 55

A solution of 2.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 30 ml of chloroform is mixed with 1.0 ml of diethyl-35 amine and 0.98 of 2-methoxybenzoyl chloride transferred. The mixture is then reacted for 5 hours at room temperature. The reaction mixture obtained is worked up according to Example 54. Yield: 2.1 g (79.8%) 3- (2-methoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine as an oil.

40

UV absorption spectrum: 259.322 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.69 (d, Hó), 6.16 (broad t, H'i), close to 2.4 (m, H'2), 5.14-5.28 (m, H's), 4.18-4.40 (m, H'4, H's), 2.18-2.46 (m, 45 2 x COCH2), 1.14-1.80 (m, 4 x CH2), 0.84-0.98 (m, 2 x CHs) Benzoyl unit: 8.06 (dd, Hó), 7.52 (td , H4), 7.04 (t, Hs), 6.92 (d, Hs), 3.78 (s, CHsO)

Elemental analysis (for: C27H33FN2O9):

50

Calc.%: C 59.12; Found%: C 58.68;

H 6.06; H 6.02;

N 5.11 N 4.80

Example 56

55 A solution of 2.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 30 ml of chloroform is mixed with 1.0 ml of triethylamine and 1.2 g of 2,3- Dimethoxybenzoyl chloride added. The mixture is then reacted at room temperature for 30 minutes and then at 50 to 60 ° C. for 2 hours. The reaction mixture obtained is cooled and then worked up according to Example 54. Yield: 4.6 g (79.3%) of 3- (2,3-dimethoxybenzoyl) -2 'deoxy-3', 5 'di-O-n-penta-noyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 50.

Example 57

A solution of 4.1 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-

646715

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5-fluorouridine in 10 ml of pyridine is mixed with 4.3 g of 4-n-butoxybenzoyl chloride. Then the mixture is reacted at 50 to 60 ° C for 12 hours. The reaction mixture obtained is evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography as in Example 50 and treated with activated carbon. Yield: 4.6 g (78.0%) of 3- (4-n-butoxybenzyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 221.289 nm NMR spectra: ô (ppm, CDCh)

Uridine unit: 7.76 (d, Hó), 6.27 (broad t, H 'i) close to 2.4 (m, H'2), 5.16-5.32 (m, H's), 4.20-4.58 (m, H'4, H's), 2.04-2.69 (m, 2 x COCH2), 1.15-1.96 (m, 4 x CH2), 0.82-1.12 (m, 2 x CH3)

Benzoyl unit: 7.88 (d, H2, Hó), 6.95 (d, H3, Hs), 4.06 (t, CH2O), close to 1.7 (m, 2 x CH2), close to 1.0 (m, CH3)

Elemental analysis (for: C30H39FN2O9):

%: C 61.01; H 6.66; N 4.74 Found%: C 61.00; H 6.74; N 5.16

Example 58

A solution of 4.1 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 20 ml of dioxane is cooled with ice with 2.1 ml of triethylamine and 2.1 g of 4-n -Butoxybenzoylchlorid added. The mixture is then reacted at room temperature for 30 minutes and at 50 to 60 ° C. for 2 hours. The reaction mixture obtained is worked up according to Example 50. Yield: 5.0 g (84.6%) of 3- (4-n-butoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 57.

Example 59

A solution of 2.0 g of 2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine in 40 ml of diethyl ether is mixed with 0.95 ml of triethylamine and 0.93 g of 3-methoxybenzoyl chloride. Then the mixture is reacted for 10 hours at room temperature. The reaction mixture obtained is cooled and worked up according to Example 54. Yield: 1.6 g (61.5%) 3- (3-methoxybenzoyl) -2 '-deoxy-3', 5 '-di-O-n-hexanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 220.261.318 nm NMR spectra: 5 (ppm, CDCh)

Uridine unit: 7.76 (d, Hó), 6.24 (broad t, H '1), close to 2.4 (m, H'2), 5.14-5.28 (m, H'3), 4.26-4.44 (m, H' 4, H's), 2.18-2.50 (m, 2 x COCH2), 1.20-1.74 (m, 6 x CH2), 0.82-0.96 (m, 2 x CH3) benzoyl unit: 7.12-7.50 (m, aromatic H) 3.86 (s,

CHsO)

Elemental analysis (for: C29H37FN2O9):

Calc.%: C 60.41; H 6.47; N 4.86 Found%: C 60.15; H 6.52; N 4.71

Example 60

A solution of 4.4 g of 2'-deoxy-3 ', 5'-di-0-n-hexanoyI-5-fluorouridine in 30 ml of acetonitrile is mixed with 3.5 ml of triethylamine and 3.4 g of 4-methoxybenzoyl chloride. Then the mixture is reacted for 6 hours at room temperature. The reaction mixture obtained is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The solution obtained is worked up according to Example 54. Yield: 4.5 g (78.0%) of 3- (4-methoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 221.287 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.75 (d, Hó), 6.24 (broad t, H '1) near 2.4 (m, H'2), 5.08-5.34 (m, H'3), 4.18-4.54 (m, H'4 , H's), 2.04-2.64 (m,

2 x COCH2), 1.16-1.90 (m, 6 x CH2), 0.76-1.06 (m, 2 x CHs) benzoyl unit: 7.87 (d, H2, Hó), 6.93 (d, H3, Hs), 3.86

(s, CH3O)

Elemental analysis (for: C29H37FN2O9):

Calc.%: C 60.41; H 6.47; N 4.86 Found%: C 60.78; H 6.59; N 4.69

Example 61

A solution of 4.4 g of 2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine in 30 ml of acetonitrile is mixed with 3.5 ml of triethylamine and 4.0 g of 2,3-dimethoxybenzoyl chloride transferred. The mixture is then reacted at room temperature for 2 hours and then at 50 to 60 ° C. for 1 hour. The reaction mixture obtained is evaporated under reduced pressure and the residue is dissolved in ethyl acetate. The solution obtained is worked up according to Example 54. Yield: 3.9 g (64.3%) of 3- (2,3-dimethoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 52.

Example 62

A solution of 4.4 g of 2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine in 20 ml of dioxane is mixed with 2.1 ml of triethylamine and 2.2 g of 4-n-propoxybenzoyl chloride. Then the mixture is reacted at room temperature for 30 minutes and then at 60 ° C. for 30 minutes. The reaction mixture obtained is cooled and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, the solution is washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by column chromatography on silica gel using chloroform as the eluent. The purified oil obtained is dried at room temperature under reduced pressure. Yield: 5.1 g (84.3%) of 3- (4-n-propoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine as an oil. The physical data of this compound are the same as that of the oil obtained in Example 54.

Examples 63 to 70 According to Example 62, the 2'-deoxy- listed in Table IX with yields and physical data

3 ', 5' -di-O-alkylcarbonyl-5-fluorouridine derivatives prepared.

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646 715

18th

Example 71

Using 2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine and 4-methoxybenzoyl chloride, the reaction and working up is carried out according to Example 60. The oil obtained is recrystallized from ethanol. Yield: 75% 3- (4-methoxybenzoyl) -2 '-deoxy-3', 5 '-di-O-n-hexanoyl-5-fluorouridine of melting point 81 to 82 ° C in the form of colorless needles.

UV absorption spectrum: 221.287 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.75 (d, Hó), 6.24 (broad t, H'i) close to 2.4 (m, H'2), 5.08-5.34 (m, H'a), 4.18-4.54 (m, H ' 4, H's), 2.04-2.64 (m, 2 x COCH2), 1.16-1.90 (m, 6 x CH2), 0.76-1.06 (m, 2 x CHs)

Benzoyl unit: 7.87 (d, H2, Hó), 6.93 (d, Hs, Hs), 3.86 (s, CHsO)

Elemental analysis (for: C29H37FN2O9):

Calc.%: C 60.41; H 6.47; N 4.86 Found%: C 60.30; H 6.73; N 4.80

Examples 72 to 74 The oils obtained in Examples 53, 64 and 69 are recrystallized from ethanol according to Example 71. You will receive:

3- (4-methoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine, mp 84-85 ° C; Yield: 74.0%; 3- (4-ethoxybenzoyl) -2'-deoxy-3 ', 5'-di-O-n-hexanoyl-5-fluorouridine, melting point 90 to 91 ° C, yield: 75.0%; 3- (4-ethoxybenzoyl) -2 '-deoxy-3', 5 '-di-O-n-pentanoyl-5-fluorouridine, melting point 88-89 ° C, yield 86.0%.

The physical data of these colorless needles are identical in the UV absorption spectrum, NMR spectrum and elemental analysis to those of the corresponding oils from Examples 53, 64 and 69.

Example 75

A solution of 3.0 g of 2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine in 30 ml of anhydrous dioxane is mixed with 2.0 ml of triethylamine and 1.6 g of 3,4- Methylenedioxybenzoyl chloride added. Then the mixture is reacted at 70 ° C for 1 hour. The reaction mixture obtained is cooled and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with 0.1N sodium hydroxide solution and then with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is dissolved in a small amount of chloroform and filtered to remove undissolved substances. The filtrate is purified by column chromatography on silica gel using chloroform as the eluent. Yield: 1.2 g (29.0%) of 3- (3,4-methylenedioxybenzoyl) -2 '-deoxy-3', 5 '-di-O-n-pentanoyl-5-fluorouridine as an oil.

UV absorption spectrum: 206.236.278.321 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.78 (d, Hó), 6.28 (broad t, H '1), close to 2.4 (m, H'2), 5.18-5.32 (m, H'3), 4.24-4.56 (m, H '4, H's), 2.20-2.52 (m, 2 x COCH2), 1.18-1.84 (m, 4 x CH2), 0.88-1.00 (m, 2 x CH3)

Benzoyl unit: 7.52 (dd, Hó), 7.38 (d, Hs), 6.86 (d, H2), 6.08 (s, CH2)

Example 76

Using 2'-deoxy-3 ', 5'-di-on-hexanoyl-5-fluorouridine and 3,4-methylenedioxybenzoyl chloride, 1.3 g (32.0%) of 3- is obtained by reaction and working up according to Example 75 (3,4-methylenedioxybenzoyl) -2'-deoxy-3 ', 5'-di-on-hexanoyl-5-fluorouridine obtained.

UV absorption spectrum: 206.236.278.321 nm NMR spectra: 8 (ppm, CDCh)

Uridine unit: 7.74 (d, Hó), 6.26 (broad t, H '1), close to 2.4 (m, H'2), 5.18-5.28 (m, H'3), 4.24-4.42 (m, H'4, H's), 2.18-2.50 (m, 2 x COCH2), 1.18-1.76 (m, 6 x CH2), 0.82-0.98 (m, 2 x CHs)

Benzoyl unit: 7.50 (dd, He), 7.36 (d, Hs), 6.86 (d, H2), 6.06 (s, CH2)

The production of the antitumor agents is to be explained below using the following typical formulation examples:

Hard capsule formulation:

Recipe 1:

3- (4-methoxybenzoyl) -2 'deoxy-3', 5 'di

O-n-hexanoyl-5-fluorouridine 100 mg

Milk sugar 160 mg crystalline cellulose 27 mg hydroxypropyl cellulose with low

Degree of substitution 10 mg

Magnesium stearate 3 mg together 300 mg

The capsules (No. 2) are manufactured in the usual way so that each capsule contains the aforementioned dose of the ingredients. Generally, three to nine capsules per day can be administered orally to adult patients.

Recipe 2:

Compound of the invention 80 mg

Cane sugar ester of fatty acids 20 mg

Milk sugar 165 mg

Crystalline cellulose 24 mg hydroxypropyl cellulose with low

Degree of substitution 8 mg

Magnesium stearate 3 mg together 300 mg

The following compounds can be used in the above recipe, for example:

3- (4-methoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine

3- (2,3-dimethoxybenzoyl) -2 'deoxy-3', 5 'di-O-n-pro-pionyl-5-fluorouridine

The capsules are manufactured in the usual way so that each capsule contains the above-mentioned dosage of the ingredients. Generally, three to nine capsules can be administered orally to adult patients.

Recipe 3:

Compound of the invention 80 mg

Polyethylene glycol 6000 20 mg

Milk sugar 161 mg crystalline cellulose 21 mg

Hydroxypropyl cellulose 8 mg

Carboxymethyl cellulose calcium 5 mg

Talc 5 mg together 300 mg s

10th

15

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35

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65

19th

646 715

The following compounds of the invention can be used, for example, in the prescription:

3- (4-methoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-hexanoyl-5-fluorouridine

3- (4-ethoxybenzoyl) -2'-deoxy-3 ', 5'-di-0-n-pentanoyl-5-fluorouridine

First, granules are produced in the usual way, for which the compound of the invention, the polyethylene glycol 6000, the milk sugar, the crystalline cellulose and the hydroxypropyl cellulose are used. The granules are then mixed with carboxymethyl cellulose calcium and talc and the mixture is processed into capsules (No. 2) in the usual way. Each capsule can contain the above dose of the ingredients. As a rule, three to nine capsules per day can be administered orally to adult patients.

(B) Soft Capsule Formulations:

Recipe:

Compound of the invention 50 mg

Polyethylene glycol 400 250 mg

Propylene glycol 10 mg bleached beeswax 10 mg together 320 mg

The following compounds of the invention can be used, for example, in the above recipe:

3- (4-methoxybenzoyl) -2 'deoxy-3', 5 'di-O-n-hexanoyl-5-fluorouridine

3- (3-fluorobenzoyl) -2 'deoxy-3', 5 'di-O-n-palmitoyl-5-fluorouridine

3- (2-methylbenzoyl) -2 'deoxy-3', 5 'di-O-n-pentanoyl-5-fluorouridine

3- (3-methylbenzoyl) -2 '-deoxy-3', 5 '-di-on-hexanoyl-5-fluorouridine 3-benzoyl-2' -deoxy-3 ', 5' -di-on-hexanoyl- 5-fluorouridine 3- (4-n-propoxybenzoyl) -2 '-deoxy-3', 5 '-di-on-penta-noyl-5-fluorouridine

The capsules are manufactured in the usual way so that each capsule contains the aforementioned dose of the components. As a rule, 3 to 9 capsules per day can be administered orally to adult patients.

(C) Syrup Formulations:

is recipe 1:

An ampoule with the following components:

3- (4-methoxybenzoyl) -2 '-deoxy-3', 5 '-di-O-

n-hexanoyl-5-fluorouridine 10 mg

20 calcium carboxymethyl cellulose 4 mg

White sugar 486 mg together 500 mg

Recipe 2:

25 ampoules with the following components:

Polyethylene glycol 400 300 mg

Pure water 1000 mg so together 4000 mg

When administered orally, the two solutions are carefully mixed together. The syrup obtained corresponds to a unit dose and can be administered orally three to nine times a day.

B

Claims (4)

646 715 1. 2 '-Desoxy-3', 5 '-di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula I (D CïïsCCBs ^ COO CHsCCEk ^ COO 6. The method according to claim 5, characterized in that one uses a benzoyl halide of the general formula III, in which shark represents a chlorine atom. 7. The method according to claim 5 or 6, characterized in 5 shows that the reaction is carried out under ice cooling or at a temperature up to 70 ° C. in dioxane and in the presence of triethylamine. 8. antitumor agent containing a compound according to claim 1 and carriers, auxiliaries and additives. 9. Anti-tumor agent according to claim 8, characterized in that it contains polyethylene glycol and cane sugar esters of fatty acids as carriers. 15