NL8302859A - DESOXYURIDINE DERIVATIVES AND METHODS FOR PREPARING THESE DERIVATIVES AND THEIR USE AS PHARMACEUTICS. - Google Patents

Description

* - v 7 i

V

- 1 -

Deoxyuridine derivatives and methods of preparing these derivatives and their use as pharmaceuticals.

The present invention relates to deoxyuridine derivatives, methods of their preparation, pharmaceutical preparations containing them and their use as pharmaceuticals, in particular as viricides, especially against Herpes viruses.

The invention particularly relates to compounds of formula I, wherein R 1 and R 1, independently of one another, are a hydrogen atom or a lower alkyl group, R 9 is a halogen atom, a C 1-6 or CF 8 group, R 9 is a hydrogen - or fluorine atom or a hydroxyl group and X represent an oxygen atom or an imino group, and wherein the sugar group - or - - glycosidically bound to the pyrimidine ring, in free form or in the form of an acid addition salt.

The compounds of the invention can be prepared according to the invention by a) reacting a compound of formula 2 with a compound of formula 3, or b) replacing the Rg 'group in the hydroxyalkyl side chain of a compound of formula la by an Rg group, wherein in formulas 1a, 2 and 3 Rj, Rp, Rg, Rg, Rx, 25X and n have the previously defined meanings, Rg a halogen atom or an acyloxy group and Rg 'a hydroxyl group in free or protected form and each hydroxyl group in the sugar portion may be protected, optionally removing any protecting group present from the compound thus obtained and recovering the compound thus obtained in free form or in the form of an acid addition salt.

Process a) can be carried out, for example, by converting a compound of formula 2 into its trimethylsilyl derivative in a conventional 8302359 \ 4-2 manner and using a compound of formula 3, the hydroxyl groups of which are protected, in a solvent, e.g. react halogenated hydrocarbon or acetonitrile.

According to method b), a compound of formula la in unprotected or protected form can be dissolved in a solvent which is inert under the reaction conditions, for example a low alkyl carboxylic acid amide such as dimethylformamide.

The conversion of R1 to halogen can be carried out with both free and protected hydroxyl groups in the sugar portion.

If R1 represents halogen, the reaction can be carried out using a conventional halogenation method, for example using carbon tetrachloride or bromosuccinimide. If it represents a CHF ^ group or CF ^ group, the reaction may be carried out using conventional fluorination methods, for example, from a compound of formula la after oxidation to an aldehyde with a dialkyl sulfur trifluoride or after oxidation to a carboxylic acid with sulfur tetrafluoride.

Examples of protecting groups are those commonly used in reactions of this type, such as p-toluyl, benzyl, p-nitrobenzoyl and trimethylsilyl. These can be entered and deleted according to usual methods.

The salt forms can be obtained from free forms in a usual manner and vice versa.

As mentioned above, the compounds of formulas 1 and 1a may be in the or configuration as to the binding to the sugar green. For the sake of convenience, the connection \ is denoted in the ^ form. .35 The pyrimidine group in the compounds with i? For example, "7 -l * v> - 3 - formulas 1 and 1a can exist in the tautomeric forms indicated on the formula sheet under A. The invention includes all tautomeric forms of the compounds.

The compounds of formulas I and Ia may also exist in the form of optical isomers or mixtures thereof, which isomers can be separated in a conventional manner. The invention includes isomeric forms and mixtures thereof, the compounds, unless otherwise indicated, being in the latter form.

The lower alkyl groups contain 1-4, preferably 1 or 2, carbon atoms.

The starting materials of the formula la are also new and are part of the invention. They can be obtained by reacting a compound 15 of formula 2a, wherein R 1, R 1, R 1 ', X and n have the meanings defined above, analogous to process a) 3 with a compound of formula 3.

The compounds of formulas 2, 2a and 3 are known or can be obtained analogously to known methods, for example as illustrated in the examples below.

The final products and intermediates can be separated and purified in a usual manner.

The compounds of formula 1 are chemotherapies, in particular anti-viral agents, as shown in particular by their activity against Herpes viruses, which can be demonstrated both in vitro and in vivo, for example by the reduction of the cytopathogenic effects (CPE) of various viruses, for example, Herpes simplex I and II in vitro at a concentration of about 0.003 µg / ml to about 300 µg / ml and in vivo in experiments conducted on mice and guinea pigs using systemic, local and encephalous infection models (see for example HE Renis and med.

J. Med. Chem. 16 (7) 754/19737). The compounds are therefore useful as chemotherapeutics, in particular 83 02 8 5 9 * f-4 - as agents for combating Herpes diseases and infections,

For this application, a suitable daily dose is between about 200 and 1200 mg, suitably in separated doses 2-4 times daily containing about 50-600 mg of the compounds, administered or given in a slow release form.

The compounds can be used in free form, or, if the compound is sufficiently basic, also in the form of a chemotherapeutically acceptable acid addition salt thereof, especially if X represents an imino group, which have the same degree of activity as the free possess shapes. Suitable salt forms include hydrogen chlorides, hydrogen fumarates and naphthalene-1,5-disulfates.

The compounds may, if desired, be mixed with conventional chemotherapeutically acceptable diluents and / or carriers and administered in such forms as tablets or capsules, or parenterally. Such preparations are also part of the invention.

Thus, the invention also relates to a method of controlling Herpes diseases or infections by providing an effective amount of one or more compounds of the invention of formula 1 to a patient in need of such treatment, and / or a chemotherapeutic acceptable acid addition salt thereof and to such compounds for use as chemotherapeutics, in particular as anti-viral agents, especially against Herpes diseases.

Examples of special substituent meanings are:

Rj, R2 = a) H

B) lower alkyl, preferably a methyl 83 02 8 5 9 T * - 5 - or ethyl group, = a) halogen b) chlorine, bromine or iodine X * oxygen 5 η - 1

R4 "a) H, OH, F

b) H, OH ·, in particular hydrogen, and combinations thereof.

Examples of special groups of compounds 10 are thus those of formula 1 a) in which R 1 and R 1 represent a hydrogen atom, R 1 a halogen atom, R 1 a hydrogen or fluorine atom or a hydroxyl group and X represent an oxygen atom or an imino group and η * 1, and b) wherein R 1 and R 1 have the meanings defined above, R 1 represents a halogen atom, X represents an oxygen atom, R 1 represents a hydrogen or fluorine atom or a hydroxyl group and n = 1.

A particularly recommended special compound 20 is 1- (2-deoxy-y4-D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione in free form or in the form of an acid addition salt.

Example I: 1- (2-Deoxy-4-D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method b).

200 mg of 1- (2-deoxy-1-D-etythro-pentofuranosyl) -5- (2-hydroxyethyl) - (1, 3 H) -pyrimidine-2,4-dione and 400 mg of triphenylphosphine were dissolved in 20 ml absolute dimethyl formamide, this mixture was reacted with 0.2 ml of tetrachloro-carbon and 0.2 ml of absolute pyridine and the reaction mixture was then left to stand at room temperature for 1 hour. Afterwards

* I

The solvent was removed under reduced pressure and - 83 0 2 2 "9 * * - 6 - addition of 1-butanol, chromatographed on a column of silica gel (mixture of chloroform and ethanol: 9: 1) to give the title compound as colorless crystals having a melting point of 166-167 ° C (from 5 absolute methanol).

Example II: 1- (2-Deoxy-6-D-erythro-pentofuranosyl) -5- (2-chloroethyl) -10 (1H, 3H) -pyrimidine-2,4-dione (Method b).

1.5 g of 1- (2-deoxy) -3,5-di-0-p-toluyl-O-D-erythro-pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) - were dissolved pyrimidine-2,4-dione in 20 ml of absolute dimethylformamide, this solution reacted with 2.3 g of triphenylphosphine, 1 ml of absolute carbon tetrachloride and 0.5 ml of absolute pyridine and kept the reaction mixture at 70 ° C for 10 minutes. the solvent was dissolved at 0.1 bar and the remaining syrup was chromatographed on silica gel (a mixture of 20 toluene and ethyl acetate 2: 1). There were thus obtained 0.5 g of 1- (2-deoxy-3,5-di-0-p-toluyl-D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine- 2,4-dione as colorless crystals (melting point: 142-144 ° C). To remove the p-toluyl groups, the compound was dissolved in 10 ml of absolute ethanol and reacted with 1.5 ml of a 1 N solution of sodium ethanolate in ethanol, the reaction mixture was allowed to stand at room temperature for 15 minutes and then reacted with 1.5 ml 1 N acetic acid. The solvent was removed under reduced pressure and the remaining syrup was treated with a mixture of diethyl ether and water. Chromatographing the aqueous phase over silica gel (a mixture of chloroform and methane 9: 1) gave the title compound as colorless crystals, m.p. 140-142 ° C (mixture of ethanol and chloroform).

83 0 2 3 5 9% * - 7 -

Example III: 1- (2-deoxy-β-D-erythro-pentofuranosyl) -5- (2-bromoethyl) - (1 Η, 3H) -pyrimidine-2,4-dione (method b).

5 1.14 g of 1 - (2-deoxy- ^ -D-erythropentofuranosyl) -5- (2-hydroxyethyl) - (1 Η, 3H) -pyrimidine-2,4-dione were dissolved in 30 ml absolute dimethylformamide, this solution reacted with 2.3 g of triphenylphosphine and 1.2 g of N-bromosuccinimide and kept the reaction mixture at room temperature for 90 minutes. The solvent was removed under reduced pressure and repeated evaporation after addition of n-butanol. A yellow syrup was obtained, from which, after crystallization from a mixture of ethanol and chloroform, the title compound was obtained as colorless crystals having a melting point of 161-162 ° C.

Example IV: 1- (2-deoxy-O -D-erythro-pentofuranosyl) -5- (2-bromoethyl) -20 (1H, 3H) -pyrimidine-2,4-dione (method b).

Analogous to Example III, 380 mg of I- (2-deoxy-4-D-erythro-pentafuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione were reacted, whereby the title product with a melting point of 131-133 ° C

(mixture of ethanol and chloroform).

Example V: 1- (2-deoxy-D-erythro-pentofuranosyl) -5- (2-iodethy1) - (1, 3 H) -pyrimidine-2,4-dione (method b).

550 mg of 1- (2-deoxy-3-D-erythro-pentofuranosyl) -5- (2-hydroxyethyl) - (1, 3 H) -pyrimidine-2,4-35 dione and 1.1 g of triphenylphosphine were dissolved in 25 ml of absolute dimethyl s' ^ Π O p «Ö y * V fj 'Zm' *** * 3 -— --- - * * - 8 - formamide, reacted this solution with 550 mg of N-bromo- succinimide and 3.3 g of tetrabutyl ammonium iodide and kept the resulting reaction mixture at room temperature for 90 minutes.

The solvent was then removed, after addition of 1 n-reduced pressure of n-butanol, and the residue was chromatographed on silica gel (a mixture of chloroform and methanol 9: 1) to give the title compound, m.p. 160. -161 ° C.

10

Example VI: 1- (2-Deoxy-4-D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione (Method a).

480 mg of 5- (2-chloroethyl) uracil were suspended in hexamethyldisalazane, reacted with 0.3 ml of trimethylchlorosilan and the mixture heated under reflux for 3 hours. The volatile material was then removed under reduced pressure and the evaporation repeated twice, after adding absolute xylene. The resulting syrup was dissolved in 30 ml of absolute chloroform and reacted at room temperature with 1.2 g of 3,5-di-Op-toluyl-2-deoxy-D-erythro-pentofuranosyl chloride and then with 0.5 ml of the trimethylsilyl ester of trifluoromethane-25 sulfonic acid. The reaction mixture was then kept at room temperature for 30 minutes and then shaken with 1.5 ml of a cold, saturated aqueous solution of potassium bicarbonate. Concentration of the organic phase under reduced pressure gave a syrup which was chromatographed on silica gel (a mixture of toluene and ethyl acetate 4: 1) to give 1- (2-desoxy-3,5-di-0-). p-toluy1 - (- D-erythro-pentofuranosyl) - 5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,5-dione (melting point: 167-169 ° C). The removal of the p-toluyl groups was carried out analogously to Example II, whereby 1— (2 - O wwi, -JO 1 - 9 - deoxy-jl -D-erythro-pentofuranosy1) -5- (2-chloroethyl 1 ) - (1Η, 3H) -pyrimidine-2,4-dione as colorless crystals, mp 165-166 ° C (from water).

5

Example VII: 1- (1-D-arabinofuranosyl) -5- (2-chloroethyl) - (1B, 3H) -pyrimidin-2,4-dione (method b).

10 400 mg! - (?-D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1,3H) -pyrimidine-2,4-dione was dissolved in 10 ml of absolute dimethylformamide, and this solution was reacted with 0 .7 g of triphenylphosphine, 0.3 ml of carbon tetrachloride and 0.3 ml of pyridine and kept the reaction mixture at room temperature for 1.5 hours. After adding 1-butanol, the mixture was evaporated to dryness with a Rotavapor and the resulting syrup-like residue was chromatographed on silica gel (mixture of chloroform and methanol 8: 1). Concentration of the appropriate fractions gave the title compound as colorless crystals, m.p. 182-183 ° C (from ethanol).

Example VIII: 1 - D-arabinofuranosyl) -5- (2-bromoethyl) - (1,3H) pyrimidine-2,4-dione.

320 mg of I- (γ-D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimicfin-2,4-dione were dissolved in 5 ml of ab-30 solute dimethylformamide and reacted with 650 mg triphenylphosphine and 300 mg N-bromosuccinimide and the reaction mixture was kept at room temperature for 1.5 hours. After adding 5 ml of 1-butanol, the mixture was evaporated to dryness on a rotary evaporator and the resulting syrup-like residue was chromatographed on silica gel (a mixture of 830: -1. - ♦ -10- chloroform and methanol 6: 1). Concentration of the fractions gave the title compound as colorless crystals, m.p. 166-167 ° C (from a mixture of acetone and chloroform).

5

Example IX: 1- (2-Deoxy-2-fluoro-ft-D-arabinofuranosyl) -5- (2-chloroethyl) ~ (1H, 3H) -pyrimidine-2,4-dione.

10

200 mg of 1- (2-deoxy-2-fluoro-β-D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1,3H) -pyrimidine-2,4-dione were dissolved in 5 ml of absolute dimethylformamide and reacted with 300 mg of triphenylphosphine and 0.3 ml of a mixture of equal parts absolute pyridine and carbon tetrachloride. The mixture was then stirred at room temperature for 4 hours. Then 10 ml of 1-butanol were added and the mixture was evaporated to dryness using an oil pump. The residue was chromatographed on silica gel (a mixture of chloroform and methanol 9: 1). Concentration of the fractions gave the title compound as a very hygroscopic colorless powder.

Example X: 4-Amino-5- (2-chloroethyl-1) -1- (2-deoxy-1-D-erythro-pento-furanosyl) -1H-pyrimidine-2-one.

Silence was carried out. 3.12 g of 4-amino-5- (2-hydroxy-30 ethyl) -1H-pyrimidin-2-one analogous to Example VI and reacted with 7.76 g of 2-deoxy-3,5-di-0 p-tolupyl-D-erythro-pentofuranosyl chloride. After shaking with 100 ml of a saturated aqueous solution of potassium hydrogen carbonate, the chloroform was removed under reduced pressure and the resulting residue was chromatographed on silica gel (a mixture of chloroform and methanol 9: 1). to give 4-amino-1- (2-deoxy-3,5-di-0-p-toluoyl-D-erythro-pento-furanosy 1) -5- (2-hydroxyethyl 1) -1 H-pyrimidine -2-on obtained,

1.4 g of this anomeric mixture were stirred in 20 ml of dimethyl-5-formamide for 2 hours at room temperature with 1.4 g of triphenylphosphine, 0.6 ml of absolute carbon tetrachloride and 0.6 ml of absolute pyridine. After adding 10 ml of 1-butanol, the solvents were removed under reduced pressure and the resulting residue was mixed with 20 ml of methanol and 5 ml of a 1 N solution of sodium methanolate in methanol.

At the completion of the reaction, the mixture was neutralized under reduced pressure.1 mixture with 1 N acetic acid and evaporated to dryness / Treatment of the residue with 30 ml of ethyl acetate and 10 ml of methanol gave the title compound as colorless crystals with a melting point of 174 ° C (from water).

For example, the necessary starting materials can be obtained as follows: 20 A) 1 - (2-deoxy-β, -D-erythro-pentofuranosy 1) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2 .4-dione (for Examples I, III and V).

10.5 g of 5- (2-hydroxyethyl) -25 uracil were suspended in 60 ml of hexamethyldisilazane, reacted with 3 ml of trimethylchlorosilan and the reaction mixture was refluxed for 2 hours. All the volatile material was removed under reduced pressure and the evaporation was repeated twice after adding absolute xylene. The remaining syrup was dissolved in 400 ml of absolute chloroform and this solution was reacted at room temperature with 26.2 g of 3,5-di-0-p-tolu-yl-2-deoxy-D-erythro-pento furanosyl chloride and then with 0.5 ml of the trimethylsilyl ester of trifluoromethanesulfonic acid. The reaction mixture was kept at room temperature for 1 hour and shaken with 8 µl of 100 ml of a saturated aqueous solution of potassium hydrogen carbonate. Concentration of the organic phase under reduced pressure gave a yellow syrup, from which 5- (2-hydroxyethyl) -3 ', 5'-5 di-Op-tolu-yl- ^ -D-2'- was crystallized. deoxyuridine (melting point: 176-178 ° G). The removal of the p-tolu-yl groups was carried out analogously to Example II, whereby, after crystallization from ethanol in a refrigerator, 1- (2-deoxy-2 -D-erythro-pentofuranosyl) -5- (2- hydroxyethyl) - (1H, 3H) -pyrim-10 midine-2,4-dione as colorless crystals, mp 160-161 ° C.

B) 1- (2-deoxy-3,5-di-0-p-tolu-yl-ot -D-erythro-pentofurano-syl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine -2,4-dione (for Example 2).

Using 5- (2-hydroxyethyl) -uracil and 3,5-di-0-p-tolu-yl-2-deoxy-D-ribofuranosyl chloride and analogous to A) obtained after fractional crystallization from ethanol the title compound.

C) 1- (2-deoxy-p-D-erythro-pentofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione (for example IV).

25

Obtained after removal of the tolyl groups analogous to Example II and chromatography on silica gel (a mixture of chloroform and methanol 3: 1). Colorless oil.

D) 5- (2-chloroethyl) - (1H, 3H) -pyrimidin-2,4-dione (for Example VI).

0.5 g of 5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione were dissolved in 20 ml of absolute dimethylformamide 35 and 2.5 g of triphenylphosphine and 30 ml of carbon tetrachloride were added 83 02 3 3 9 13 -13- and 1 ml of pyridine. The solution was kept at 80 ° C for 1.5 hours, concentrated and the oily residue was taken up in a mixture of chloroform and methanol (9: 1) to give the title compound as colorless crystals with a melting point of 260 -262 ° C (from ethyl acetate).

E) -D-arabinofuranosyl) -5- (2-hydroxyethyl) - (1H, 3H) -pyrimidine-2,4-dione (for Examples VII and VIII).

10 5 g of 2,3,5-tri-O-benzyl-1-O-p-nitro-benzoyl-D-arabinose were dissolved in 80 ml of absolute dichloromethane, which had been saturated with hydrogen at 0 ° C 1 hour before -chloride. The mixture was stirred at 0 ° C for 2 hours while passing through further hydrogen chloride and the precipitated p-nitrobenzoic acid was removed. The filtrate was evaporated to dryness and the oily residue was kept in a Rotavapor at 0.0013 bar for an additional 2 hours. The resulting residue was dissolved in absolute dichloromethane, reacted with a syrup containing 5- (2-hydroxyethyl) -uracil which did not contain hexamethylsilazane-20, to prepare 2.93 g of 5- (2-hydroxyethyl) uracil (analogous to AX7 and shaking in the presence of 10 g of a molecular sieve (4 A °) for 2 days at room temperature. After filtering and washing the molecular sieve, the filtrate was shaken with a cold, saturated solution of potassium bicarbonate water, wash the aqueous phase once with dichloromethane and concentrate the combined organic phases using a rotary evaporator to give a partly crystalline syrup 1 g of palladium chloride is suspended in 150 ml of methanol and hydrogenated in a Parr on palladium (water dust, room temperature and a pressure of 4 atmospheres, (duration: about 30 minutes). To this was added the aforementioned syrup dissolved in 100 ml of methanol and hydrogenated crumb overnight with hydrogen at 4 atmospheres. A white crystalline precipitate formed v v ij * 3 η -14- r.

in the hydrogenation vessel while the rest of the product was dissolved. The precipitate and palladium were filtered off, the product was dissolved in water and filtered off the palladium, and the filtrate was concentrated on a rotary evaporator and the residue crystallized from water. The methanolic residue of the hydrogenation is neutralized with an ion exchanger

Merck II (strongly basic), filtered over active carbon, concentrated and the resulting crystalline residue was recrystallized from water. The title compound was obtained in the form of colorless needles, melting point: 212-215 ° C.

F) 1- (2-deoxy-2-fluoro-D-arabinofuranosyl) -5- (2-hydroxy-15 ethyl) - (1H, 3H) -pyrimidine-2,4-dione (for Example IX) .

3.1 g of 5- (2-acetoxyethyl) -uracil analogous to A) were silenced and reacted after reaction with 4 g of 3-0-acetyl-5-0-benzoyl-2-deoxy-2-fluoro-D- arabinofuranosyl-20 bromide in absolute dichloromethane. After 14 days, the mixture was worked up by adding a few milliliters of methanol, filtering and separating over a column (a mixture of chloroform and methanol 9: 1). After removing the protecting groups (see Example II), the title compound was obtained in the form of colorless crystals, melting point: 177-178 ° C.

30 83 0 2? 3 9 -15-

NMR Spectra I.

KH = inaccurately indicated proton in the deoxyribose portion. I

KH-I 'ck, KH-Ifp = proton at C-1 of the deoxyribose portion, of which I

the bonding properties indicate monomers I.

enable. I

NMR device: Bruker WH-90- 90 MHz. I

Example Spectrum 2.10 (t, 2H, KH); 2.67 (C, 2H, CH 2 CH 2 Cl, 0 = 7 Hz); 3.4-3.9 1 (m, 5H, CH 2 CH 2 Cl, KH); 4.1-4.4 (m, 1H, KH); 5.03 (t, 1H, J = 5.1 Hz, 5'-OH); 5.24 (d, 1H, 3 = 4.3 Hz, 3'-OH); 6.17 (t, 1H, J = 6.7 Hz, KH-1'β); 7.83 (s, 1H, H-6); 11.4 (br, 1H, NH). 1.8-2.7 (m, 2H, KH); 2.66 (t, 2H, 3 = 7Hz, CH 2 CH 2 Cl); 3.43 (d, 2H, KH); 3.69 (t, 2H, J = 7Hz, CH 2 CH 2 Cl); 4.1-4.3 (m, 2H, KH); 4.82 (t, 1H, J = 5.7 Hz, 5'-OH); 5.30 (d, 1H, J = 3.1 Hz, 3'-OH); 6.10 (dubUd, 1H, 3 = 7.4 Hz, KH-1'α); 7.85 (a, 1H, H-6); 10.9 (br, 1H, NH).

2.14 (t, 2H, KH); 2.79 (t, 2H, 0 = 7.9 Hz, CH 2 CH 2 Br); 3.5-4.0 III (m, 5H, CH 2 CH 2 Br, KH); 4.29 (d, 1H, KH); 4.76 (br, 2H, 3 * -OH, 5'-OH); 6.20 (t, 1H, 3 = 6.7 Hz, KH-ΓΟ); 7.85 (s, 1H, H-6); 11.4 (s, 1H, NH).

1.7-2.5 (m, 2H, KH); 2.71 (t, 2H, 3 = 7Hz, CH2CH2Br); 3.3- IV 3.5 (m, 2H, KH); 3.53 (t, 2H, J = 7Hz, ΟΗ, ΟΗ, Βγ); 4.0-4.3 (m, 2H, KH); 4.80 (t, 1H, 3 = 5.1 Hz, 5'-OH); 5.27 (d, 1H, 3 = 3.2 Hz, 3 * -OH); 6.07 (dubi.d, 1H, 3 = 7.5 Hz, KH-1'α); 7.82 (s, 1H, H-6); 11.32 (s, 1H, NH).

2.06 (t, 2H, KH); 2.72 (t, 2H, 3 = 7Hz, CH 2 a-UJ); 3.4-3.9 v - 5H (CH 2 / 2J> * <H); 4.21 (br, 1H, KH); 4.99 (t, 1H, 3 = 2.5 Hz, 5'-OH); 5.20 (d, 1H, 3 = 4Hz, 3'-OH); 6.13 (t, 1H, J = 6.5 Hz, KH-1'Q); 7.77 (s, 1H, H-6); 11.35 (s, 1H, NH).

8302 553 -16-2.66 (t, 2H, 3 = 7.2 Hz, D 1 CH 2 1); 3.> 3.8 (m, 5H, CH2 Cl. Arid KH) 3.85-4.1 (m, 2H, KH); 5.0 (t, 1H, 3 = 5.4 Hz, 5'-OH); 5.36 and, 5.45 (je 1d, J = 5 Hz, 2H, 3'-OH and 3'-OH); 6.02 (d, 1H, J = 5.4 Hz, KH-1'G); 7.67 (a, 1H, H-6); 11.32 (a, 1H, NH).

, 2.75 (t, 2H, 3 = 7.4 Hz, CH 2 CH 2 Br); 3-4-3.8 Cm, 5H, CH 2 Br

ViIX and -KH); 3.85-4.1 (m, 2H, KH); 4.2-5.7 (br, 3H, 2 · -ΟΗ, 3 »-ΟΗ, 5'-OH); 6.01 (d, 1H, 3 = 4.5 Hz, KH-1fl); 7.66 (s, 1H, H-6); II, 32 (s, 1H, NH).

2.7 (t, 2H, J = 7Hz, CH 2 CH 2 Cl); 3.5-4.25 (m, 7H, Cl 2 Cl and KH); 4.25 (dt, 1H, H-3 ', JH-3, .F = 20.45 Hz, JH, H = 4 Hz); 5.05 (dt, 1H, H-2 ', = 52 * 2 Hz »JH-H = 4 Hz) 6.1 (dd, 1H, H-1', * 15.3 Hz, JHH = 4.1 Hz); 7.7 (s, 1H, H-6); 11.55 (s, 1H, NH).

2.0 (m, 2H, KH); 2.8 (t, 2H, 3 = 7Hz, CH 2 CH 2 Cl); 2.5-3.9 X (m, 5H, CH 2 Cl and KH); 4.2 (br 8.1H, KH); 5.0-5.2 (br s, 2H, 2 OH); 6.2 (t, 1H, J = 7Hz, KH-1-3); 7.3 (s, 2H, NH 2); 7.8 (a, 1H, H-6).

A 2.1 (t, 2H, KH); 2.3 (t, 2H, O ^ CH ^ H); 3.3-3.7 (m, 4H, CH2O2OH, KH); 3.7-3.85 (m, 1H, KH); 4.1-4.4 (m, 1H, KH); 4.54 (t, 1H, J = 5Hz, ΟΗ, Ο- ^ ΟΗ); 5.00 (t, 1H, J = 5Hz, 5'-OH); 5.23 (d, 1H, 3 = 4.3 Hz, 3 »-OH); 6.16 (t, 1H, 3 * 7Hz, ΚΗ-1Ό); 7.68 (s, 1H, H-6); 11-11.5 (br, 1H, NH).

2.1-2.4 (m, 10H, toluyl-CHl, Ο ^ Ο- ^ ΟΗ, KH); 3.32 (t, 2H, B 3 * 8 Hz, CHqCHqQH); 4.3-4.7 (m, 3H, KH, GH2CH2OH); 5.02 (m, 1H, KH); 5.56 (d, 1H, KH); 6.23 (dubl.d, 1H, J * '5 * 5 Hz, KH-lct); 7.28-7.40 (m, 4H, toluyl); 7.66 (s, 1H, H-6); 7.78-7.98 (m, 4H, toluyl); 11.32 (a, 1H, NH).

g f f \ 0 Λ C Λ 5 -17- • Λ C 1.7-2.5 (m, 2H, KH); 2.31 (t, 2H, J = 7Hz, CH2CH2C3H) 3.3 (m, 2H, KH); 4.1 (m, 2H, KH); 4.5 (br s, 1H, OH); 4.8 (br d, 1H, OH); 5.27 (br t, 1H, OH); 6.08 (dd, 1H, ΚΗ-Γα); 7.71 (s, 1H, H-6); 11.0 (br s, 1H, NH).

D 2.71 (t, 2H, J 8 Hz, CH 2 CH 2 Cl); 3.70 (t, 2H, J = 8Hz, CH 2 Cl); 746 (d, 1H, J = 7Hz, H-6); 1046 V 10J4 (2 br s, and 1H, 2NH).

É 2.36 (t, 6.3 Hz, 2H, CH 2 CH 2 OH); 3.4-3.8 (m, 5H, CH2CH2OH, KH); 3.85-4.1 (m, 2H, KH); 4.46 (t, J * 5.4 Hz, 1H, CH 2 CH 2 OH); 5.00 (t, J = 5.4 Hz, 1H, 5'-OH); 5.37 and 5.45 (2d, J = * 5 Hz, 2H, 2'-ΟΗ, 3'-OH); 6.01 (d, J * 4.5 Hz, 1H, KH-1 / 1fl); 7.54 (s, 1H, H-6); 11.95 (s, 1H, NH).

F 2.34 (t, 2H, J = 7Hz, CH 2 CH 2 OH); 3.3-4.0 (m, 5H, CH8OH, KH); 4.25 (br dt, 1H, 0H.3, _F = 22.5 Hz, H-3 '); 4.57 (t, 1H, CH 2 OH); 5.05 (dt, 1H, JH_2, _F = 514 Hz, JH H * 4 Hz, H-2 *); 54 (m, 1H, 5'-OH); 5.86 (d, 1H, JH_H * 4Hz, 3'-OH); 6.1 (dd, 1H, -16.4 Hz, JH_H * 4.1 Hz, Η-Γ); 7.57 (s, 1H, H-6); 11.41 (s, 1H, NH).

^ - - - · - ·, ----- -—— ^

Claims (10)

1. Compounds of formula 1, wherein R 1 and R 4, independently of one another, are a hydrogen atom or a lower alkyl group, R 1 a halogen atom or a CHF 1 or CF 1 group and R 1 a hydrogen or fluorine atom or a hydroxyl 5 represent group., X represents an oxygen atom or an imino group and n = 0 or 1, wherein the sugar group o (- or - - - glycosidically bound to the pyrimidine ring, in free form or in the form of an acid addition salt. Compounds according to claim 1, wherein R 1 and R 1 represent a hydrogen atom, R 1 a halogen atom, R 1 a hydrogen or fluorine atom or a hydroxyl group and X represent an oxygen atom or an imino group and n = 1, in free form or in the form of an acid addition salt. Compounds according to claim 1, wherein R 1 and R 1 have the meanings defined in claim 1, R 1 represents a halogen atom, X represents an oxygen atom and R 1 represents a hydrogen or fluorine atom or a hydroxyl group and n = 1, in free form or in the form of an acid addition salt. 4. 1 - (2-Desoxy- * 2 -D-erythro-pentofuranosyl) -20- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione. 5. A chemotherapeutic composition containing one or more compounds according to claim 1, in free form and / or in the form of a chemotherapeutically acceptable acid addition salt thereof, optionally together with a chemotherapeutically acceptable diluent and / or carrier. 6. A method for combating herpes diseases or infections, characterized in that a patient in need of such treatment is given an effective amount of one or more compounds according to claim 1, in free form and / or in the form of a 7. Compounds according to claim 1, in free form or in the form of a chemotherapeutically acceptable acid addition salt, for use as a pharmaceutical. 8. Process for preparing a heterocyclic compound, characterized in that a compound of formula 1 according to claim 1, in free form or in the form of an acid addition salt, is prepared by reacting a compound of formula 2 with a compound of formula 3, or b) by replacing the R 1 'group in the hydroxyalkyl side chain of a compound of formula 1a with a Back group, wherein in formulas 1a, 2 and 3 R 1, R 1, R 1', R 1, X and n have the meanings defined in claim 1, R 1. a halogen atom or an acyloxy group and R 1 'represent a hydroxyl group and any hydroxyl group present in the sugar group may be protected, and if desired remove any protecting group present from the compound thus obtained and the compound thus obtained in free form or in the form of winning an acid addition salt. 8. C 2 3; g -. Administer chemotherapeutically acceptable acid addition salt thereof. 9. Compounds of formula la, wherein R 1, R 1, R 1, X and n have the meanings defined in claim 1, wherein the sugar moiety or glycosidically bound to the pyrimidine ring. 10. Methods as described in the description and / or examples. 30 * ^ 83 0 2 3 5 9 -