NL8502794A - NEW NUCLEOSIDE DERIVATIVES WITH ANTI-HERPETIC PROPERTIES, PHARMACEUTICAL PREPARATIONS WITH SUCH DERIVATIVES THEREIN AND METHOD FOR PREPARING THE ACTIVE SUBSTANCES. - Google Patents

Description

V

* NL 33120-Kp / vD - 1 - * V

Novel nucleoside derivatives with antiherpetic properties, pharmaceutical preparations containing such derivatives and process for the preparation of the active ingredients.

The present invention relates to anti-veral pharmaceutical preparations, to methods of preventing viral multiplication, to novel nucleoside derivatives for use in such preparations, and to methods of their preparation.

More particularly, the invention relates to novel nucleoside derivatives of formula 1 of the formula sheet, as well as to their pharmaceutically acceptable acid addition salts, wherein 10 E and R 'are either the same or different from hydrogen or an optionally substituted acyl, preferably optionally substituted straight or branched alkanoyl, optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl. In addition, the invention relates to pharmaceutical compositions containing such compounds, to their use as antivirals, and to methods of preparing the compounds of the formula (I) and their pharmaceutically acceptable acid addition salts.

It is known in the art that the 21-deoxy nucleosides of the 5-substituted uracil base have a very good in vitro and in vivo antiviral activity. Meth. and Find. Exptl. Clin. Pharmacol. 2, 253 (1980) J7. In particular, of the known nucleosides, the (E) -5- (2-bromovinyl) -uracil-21-deoxynucleosides were active against Herpes simplex virus varieties / Proc. Natl, Acad. Sci. USA 76_, 2947 (1979) _7 It is also known in the prior art that these compounds have the disadvantage that they decompose very rapidly under in vivo conditions and that they thereby transform into inactive compounds due to the living organism occurring processes, in which the β-glycoside bond is broken / ^ Biomed. Biochem. Acta, 4 ^ 2. 35-38 (1983); Biochemical Pharmacology 32 (23) 3583-3590 (1983) J.

With these compounds, which are suitable against the 6592 794 s * 2 - Herpes simplex varieties, chemical modifications have been systematically made to increase their stability under in vivo conditions and thus increase their therapeutic activity.

It is known in the art that 2,2'-anhydride derivatives of said compounds are much less effective or biologically ineffective, as described for 5-ethyl, 5-n-propyl or 5-isopropyl-2 , 2'-anhydro-1-3-D-ara-binofuranoyluracil / J. Carbohydrates, Nucleoside, Nucleothi-10 des 6, 295-308 (1979) 7

The nucleoside derivatives of the invention exert the same or better in vitro antiviral activity than the known uracil derivatives, e.g. 5-ethyl-21-deoxyuridine or (E) -5- (2-bromovinyl) -2'-deoxyuridine, which compounds failure to decompose under in vivo conditions, while the in vivo tests conducted with the compounds of the invention have shown that their toxicity is much lower than that of the known nucleoside derivatives.

The preferred antiviral compounds of the formula (I) of the formula sheet are those wherein R and R 'independently represent hydrogen or an optionally substituted straight or branched alkanoyl and their acid addition salts.

The most preferred antiviral compounds of formula 1 of the formula sheet are: (E) -5- (2-bromovinyl) -2,2'-anhydro-1-3-D-arabinofuranosylura-cil, 30 (E ) -5- (2-bromovinyl) -2,2'-anhydro-3'-acetyl-1-β-D-arabino-furanosyluracil, (E) -5- (2-bromovinyl) -2,2'-anhydro -31,5'-diacetyl-1-β-D-arabinofuranosyluracil and its acid addition salts.

In the above formula 1 of the formula sheet, the straight or branched alkanoyl group is preferably a straight or branched alkanoyl group having 1-8 carbon atoms such as formyl, acetyl, propionyl, i-propionyl, buryryl, i-butyryl, valeryl, i-valeryl, caproyl, pivaloyl, heptanoyl, octanoyl.

1502 794 «* * * - 3 -

The "cycloalkanoyl" group is preferably a cycloalkanoyl group having 4-9 carbon atoms, such as, for example, the cyclohexanoyl group.

The "aroyl" group is preferably an aroyl group having 7-11 carbon atoms, such as, for example, the benzoyl or naphthoyl *

The "heteroaroyl" group is preferably an aroyl group having 4-11 carbon atoms and 1 or 2 oxygen, sulfur and / or nitrogen atoms as hetero atoms, such as, for example, furoyl, nicotinoyl or isonicotinoyl.

The said groups may be substituted by 1-3 substituents, preferably by alkyl and aryl.

The "alkyl" group is preferably an alkyl group of 1-6 carbon atoms, such as methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, i-pentyl, hexyl or i-hexyl.

The "aryl" group is preferably an aryl group with 6-10 carbon atoms, eg phenyl or naphthyl.

The most preferred substituents of the above substituents are methyl; and fe-20 nyl.

Salts of the compounds of formula 1 of the formula sheet which can usually be used in therapy are the physiologically acceptable salts of organic acids such as lactic acid, acetic acid, maleic acid or p-toluene-sulfonic acid as well as the physiologically acceptable salts of mineral acids, such as hydrochloric or sulfuric acid.

The new compounds of formula I of the formula sheet, wherein R and R 'independently represent hydrogen or a blocking group with the proviso that at least one of them is a blocking group, are suitable as intermediates for the preparation of the antiviral compounds of formula 1 of the formula sheet.

In the above formula, the blocking group can be any blocking group customary in organic chemistry, which can be cleaved without damaging the (E) -5- {2-bromovinyl) -2,2'-anhydro-1-3 -D-arabinofurano syluracil structure.

A preferred blocking group is the (4-methoxy-triphenyl) -methyl group.

85 0 2 79 4 ---- - 4 - * ί Η

The compounds of formula 1 of the formula sheet can be prepared by reacting a compound of formula 2 of the formula sheet with a compound of formula 3 of the formula sheet, wherein R has the above meanings 5, after which the compounds thus obtained can be optionally acylated , deacylated and re-acylated with an acylating agent of formula 4 of the formula sheet or formula 5 of the formula sheet, wherein Y has the same meanings as R or R 'with the exception of hydrogen.

For the preparation of the compounds of formula 1 of the formula sheet, wherein R = R '= H, a) a compound of formula 1 of the formula sheet, wherein R and R' are the same or different and an acyl group imagine, deacylated with sodium ethylate, or b) a compound of formula 1 of the formula sheet, wherein one of the groups R and R * is acyl, while the other is protecting group, is deacylated with sodium methylate, then the protecting group is split off.

For the preparation of the compounds of formula 1 of the formula sheet, wherein both R and R 'represent acyl, a) a compound of formula 1 of the formula sheet, wherein R' is hydrogen and R is acyl, is acylated with a compound of formula 4 or 5 of the formula sheet, wherein 25 Y has the above meanings, or b) a compound of formula 2 of the formula sheet is converted with a compound of formula 3 of the formula sheet, wherein R has the above meanings, after which the thus obtained compound of formula 1 of the formula sheet is reacted with a compound of formula 4 or 5 of the formula sheet, wherein Y has the above meanings, or c) becomes a compound of formula 1 of the formula sheet, in which one of the groups R and R 'represents hydrogen and the other is acyl, acylated with a compound of formula 4 or 5 of the formula sheet, wherein U has the above meanings.

For the preparation of the compounds of formula 1 of the formula sheet, wherein R is hydrogen and R 'represents acyl 8502 70 4 s - 5, a) a compound of formula 1 of the formula sheet, wherein both R and R' acyl, treated with methanolic ammonia, or b) a compound of formula 1 of the formula sheet wherein R is a protecting group and R 'acyl is the protecting group is removed.

For the preparation of the compounds of formula 1 of the formula sheet, wherein R is acyl and R 'represents hydrogen-10, a) a compound of formula 2 of the formula sheet is reacted with a compound of formula 3 of the formula sheet, wherein R has the above meanings, or b) the protecting group is removed from a compound of formula 1 of the formula sheet wherein R is acyl and R 'represents a protecting group.

The above reactions are represented by the reaction scheme of the reaction scheme sheet.

After the reaction is complete, the resulting compounds of the formula 1 of the formula sheet in the free base form are optionally converted to pharmaceutically acceptable acid addition salts or the free base is liberated from the salt.

The product can be obtained from the reaction mixture in a manner known per se, eg by means of solvent extraction, evaporation of the solvent, etc.

The crude product can be further purified by known methods, e.g., by recrystallization, chromatography or the like.

Results of the various biological tests to be described below show that the compounds according to the invention have the property of combating various virus varieties.

Two Herpes 35 simplex virus varieties were used in the experiments. HVS-1 has been designated "HILn, while HVS-2 has been designated" NAH "in international literature. Their time of one multiplication was 24-26 hours, while g was TCIDj-q value 10.

The viruses were grown on a fibroblast culture 350 2 79 4-6% of dipoloid chromosomes. The freshly isolated cells were stored in liquid nitrogen using the melted cells in the experiments. Both HVS-1 and HVS-2 were able to multiply rapidly on these cells. No mycoplasms were observed in the culture.

As culture broth in the experiments (pH = 7.4), use was made of "Minimal Essential Eagle" (MEM, GIBCO) with "Earles" salts supplemented with 10% aqueous swine gastric mucin, 10 NE / ml penicillin and 100 ml / ml streptomycin, The young almost confluent cultures of the cells were infected with a virus which multiplied very slowly (TCID / q = 0.01). After absorbing a virus (2 hours at 37 ° C), the unadsorbed virus was poured over the cell culture, after which a new culture broth was applied to the cell culture. When a 75% cytopathogenic activity could be observed, the cells were then frozen and melted three times. The broken fragments of the cells were removed by centrifugation (15 min, 30,000 rpm). The virus suspension was stored at -70 ° C for -20 before use.

A standard micro-dissolution method (Conrath, Theodore, B., Handbook of Microtiter Procedures, 1972, Dyna-tech Corporation, Cambridge, Massachusetts) was performed with the above broth to determine the 50% tissue culture infective dose (TCID ^ q). The value means the dose of the virus required to infect the inoculated cell cultures at 50%.

The effectiveness of the compounds according to the invention was determined on the basis of their influence on the TCID value of the viruses. The diluted virus suspensions were absorbed into the cell cultures at a temperature of 37 ° C for 2 hours. The unadsorbed virus was removed by washing with the phosphate buffered saline (PBS, pH = 2.4). A new culture broth was added to the cell cultures thus infected, in which the compounds according to the invention were used in different concentrations.

Each trial was repeated four times. The cell cultures were incubated until the maximum TCID ^ q value in the untreated infected cell cultures was reached.

The lowest active ingredient concentration was determined, which was able to decrease the TCid value of the virus by one log unit. These data are indicative of the effectiveness of the compounds, whereby the compounds can be compared with each other. The data thus obtained are shown in Table A.

TABLE A

Lowest inhibitory concentration of the compounds tyig / ml) compounds virus varieties HSV-1 HSV-2 (E) -5- (2-bromovinyl) -2,2'-anhydro- -1- (3-D-arabinofuranosyluracil 1.0 25 (E) -5- (2-bromovinyl) -2,21-anhydro-15 -3'-acetyl-1-6-D-arabinofuranosyluracil hydrochloride Ö, 5 (E) -5- (2-bromovinyl) - 2,21-anhydro-3 ', 51-diacetyl-1- -1-β-D-arahinafuranosyluracil 2.5 50 20 The in vivo antiviral efficacy of the compounds of the invention was determined using mice, which were inoculated with Herpes encephalitis Balb / C mice weighing 18 g were used in the experiments.

The mice were infected intracerebral (i.c.) 2 without anesthesia with a 10 ID ^ q dose of a virus, designated virus 667 (diluted with 0.05 ml MEM culture broth).

fr The ID50 value of virus 667 in mice is 10 / 0.1 ml. The contrd animals were treated with the culture broth only. Mice were administered intraperionally 140 mg / kg of the test compounds (0.2 ml, once a day) intraperionally on the day of infection and then every day after infection. The active ingredients were dissolved in physiological saline, the control group being treated only with physiological saline. The known (E) -5- (2-bromovinyl) -21-deoxy-uridine was used as a comparative compound. It is known in the art that the effective dose of (E) -5- (2-bromovinyl-2'-deoxy-uridine) is 140 mg / kg, reasons why the test compounds at the same dose - 8502 794 sec »V - 8 - were used (Antiviral Research, 2, 255/1983 /).

The data thus obtained are shown in Table B.

TABLE B

The action of the compounds of the invention on encephalitis induced by HSV-1 in mice.

days after the day ratio of the number of survivors of infection mice and: the infected mice _contrdle BrVdü 1155 * _1153 ** 10 1. 5/5 5/5 5/5 5/5 2. 5/5 5/5 5/5 5/5 3. 5/5 5/5 5/5 5/5 4. 5/5 5/5 5 / 5 5/5 5. 5/5 5/5 5/5 5/5 15 6. 5/5 4/5 5/5 5/5 7. 2/5 4/5 3/5 5/5 8. 1 / 5 3/5 2/5 5/5

BrVdü = (E) -5- (2-bromovinyl) -2'-deoxyuridine 2q * 1155 = (E) -5- (2-bromovinyl) -2,2'-anhydro-1-β-D-arabino-furanosyluracil ** 1153 * (E) -5- (2-bromovinyl) -2,2'-anhydro-3'-acetyl-1 - β-D-arabinofuranosyluracil The toxicity of the compounds in uninfected cell cultures was also assessed day determined, the results were compared to those of the untreated cell cultures. It could be established that the compounds according to the invention were non-toxic at the administered dose.

The antiviral agents of the invention can be administered by any method that contacts the active agent with the agent's site of action in the body. The antiviral agents can be administered by the usual methods for administration of pharmaceuticals, either as separate therapeutic agents or in combination with therapeutic agents. They can be administered alone, but they are generally administered in conjunction with a pharmaceutical carrier selected according to the route of administration chosen and standard pharmaceutical practice.

The dose to be administered, of course, depends on known factors such as the pharmacodynamic properties of the agent in question and the mode of administration; age, health and weight of the recipient; nature and extent of the symptoms, the type of concomitant treatment, frequency of treatment and the desired effect. Usually, a daily dose of the active ingredient may be about 100-500 mg / kg body weight, administered in separate doses 2-4 times a day or in delayed release form. These drugs can also be administered parenterally.

In the pharmaceutical preparations, the active ingredient is usually present in an amount of about 0.5-95% by weight, based on the total weight of the preparation.

The active ingredient can be administered orally in solid dosage forms such as capsules, tablets, powders etc. or as a liquid such as elixirs, syrups, suspensions etc. In addition, the drug can be administered parenterally in the form of sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powder carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be made as delayed release products to ensure that the drug is released continuously over several hours. Compressed tablets can be coated with sugar or a film to mask any unpleasant taste and protect tablets from the atmosphere, or tablets can be "enteric" coated for the selective disintegration in the digestive tract.

Liquid dosage forms for oral administration may contain dyes and flavors to promote patient acceptability.

Generally, water, a suitable oil, salt, water dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are used as suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, 8502794 * - 10 - suitable stabilizers and buffering agents if necessary. Antioxidants, such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference book in the field.

The compounds of the invention and their preparations are further illustrated by the following non-limiting examples.

EXAMPLE I

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-3 * - O-acetyl-1-β-D-arabinofuranosyluracil hydrochloride.

25 g (0.071 mol) (E) -5- (2-bromovinyl) -uridine was suspended in 250 ml of dry acetonitrile, after which 35.5 g (0.179 mol) of acetylsilicyl chloride was added and the reaction mixture was added for 10 min. stirring was carried out at an external temperature of 50-60 ° C. A clear solution was obtained after 10 min. The external heating was stopped and the reaction mixture was stirred at room temperature for an additional hour. The crystals precipitated after 15-20 min. The crystals were filtered off and the mother liquor was concentrated by external heating to 50 ° C. The remaining syrup was treated with 100 ml of ether, the crystals thus obtained were filtered off and washed with 20 ml of ether.

The weight of the crude product is 25 g. Melting point: 120-130 ° C. The crude product was dissolved in 50 ml of methanol containing 2-3% hydrochloric acid, filtered if necessary and saturated with a 5-fold amount of ether. The product thus obtained was stored in a refrigerator overnight, after which the precipitated crystals were filtered off and dried. The hydrochloride of the target compound was obtained. Yield: 20-22 g (74-81%). Melting point: 152-155 ° C.

Basic analysis: 8502 794 - 11 -

Calculated (%) Found (%) C 35.53 35.35 H 3.76 4.10 N 7.68 7.50 5 Br 21.32 21.62

Cl 9.46 9.50

EXAMPLE II

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-3 *, 5'-di-O-acetyl-1-6-D-arabinofuranosyluracil 10 to 7 g of the crude product, obtained according to example I, 40 ml of acetic anhydride, 2 ml of triethylamine and 20 mg of 4-dimethylaminopyridine catalyst were added. Most of the substances dissolved immediately. The reaction mixture was kept overnight, after which the mixture was concentrated under vacuum at a temperature of 50-60 ° C. The remaining syrup was taken up in 50 ml of chloroform and then extracted with 2 x 20 ml of saturated aqueous potassium hydrogen carbonate solution. The organic phase was separated, dried over anhydrous magnesium sulfate and evaporated in vacuo after removal of the desiccant. The remaining crystalline product was recrystallized from ethanol. Yield: 5-5.5 g (64-70%). Melting point: 177 ° C.

Elemental Analysis: 25 Calculated (%) Found (%) C 43.28 43.54 H 3.8 4.1 N 6.73 6.79

Br 19.19 19.20

EXAMPLE III

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-1-8-D-arabinofuranosyluracil

100 ml of 0.5 M sodium methylate was added to 10 g of the crude product obtained in Example I. A clear solution was obtained, which was stored at room temperature for 3 hours. The solution was neutralized by addition of Dowex 50 H resin, the resin was filtered off and washed while the mixture was evaporated under vacuum at 50 ° C. The crystalline product was recrystallized from water.

150 2, & - \ - 12 -

Yield: 5-6 g (63-79%). Melting point: 193 ° C.

Basic analysis:

Calculated (%) Found (%) C 39.66 39.80 5 H 3.33 4.1 N 8.60 8.59

Br 23.99 24.00

EXAMPLE IV

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-10 -31-propionyl-1-8-D-arabinofuranosyluracil 3.49 g (10 mmol) (E) -5- ( 2-bromovinyl) -uridine was suspended in 30 ml of dry acetonitrile, then 6.38 g (30 mmol) of propionylsalicylic acid chloride were added and the resulting reaction mixture was stirred at 5.0-60 ° C for 10 min. A clear solution was obtained after 10 min. The external heating was then stopped, while the solution was stirred at room temperature for an additional hour. The product thus obtained was concentrated under vacuum at 50 ° C. 20 ml of dry methanol were added to the residue, and the evaporation was repeated to decompose the excess acid chloride. 100 ml of ether were added to the remaining syrup and the solution was stirred at room temperature for 2 hours. The hydrochloride salt of the target compound is obtained, which is then filtered off and dried. The weight of the crude product was 3 g. Melting point: 150-160 ° C.

The crude product thus obtained was dissolved in 10-20 ml of methanol, after which sodium methylate was added until the pH of the solution was adjusted to a value of 30 (the pH was checked by means of an indicator paper). The solution thus obtained was evaporated in vacuo, after which the residue was taken up in 20 ml of ethyl acetate. The precipitate was filtered off, washed with 2 x 5 ml ethyl acetate and the combined solutions were concentrated under vacuum at an external temperature of 50 ° C. The residue thus obtained was dissolved in 5 ml of ethanol and then stored at room temperature. The final product crystallized slowly and the crystals were filtered off and dried the next day.

8502 79 4 * * - 13 -

Yield: 2.5 g (64.43%). Melting point: 191-T92 ° C.

= 0.56 in a 95: 5 mixture of ethyl acetate and methanol.

Elemental Analysis: (C ^ H ^ ^ Br ^ O ^; Mw = 387.19) 5 Calculated (%) Found (%) C 43.42 43.13 H 3.90 4.03 N 7.23 7.00

Br 20.63 20.40

10 EXAMPLES V - X

The compounds listed in Table C were prepared according to the method described in Examples I-IV and using the appropriate starting materials.

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EXAMPLE XI

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-5 (4-methoxytriphenylmethyl) -1-6-D-arabinofuranosyluracil 3, 31. gr (10; mmol) (E) -5- (2-bromovinyl) -2,2'-anhydro-1 -5 β-D-arabinofuranosyluracil was dissolved in 20 ml dry pyridine, after which 3.12 g (11.4 mmol) 4-methoxytriphenylmethyl chloride with stirring was added. The solution was stirred at room temperature for 20 hours and then evaporated to dryness. The residue was dissolved in chloroform and then extracted with water. After drying, the organic phase was evaporated, the residual residue was dissolved in methanol and then dried over 20 g of silica gel by vacuum distillation. The substance thus applied to the silica gel was then transferred to a silica gel column and eluted there with an 8: 2 mixture of ethyl acetate and petroleum ether and then with an 8: 2 mixture of ethyl acetate and methanol. The fractions containing the desired final product were evaporated and the resulting product recrystallized from a mixture of cyclohexane and methanol.

Yield: 2.5-2.8 g (80-90%). Melting point: 121 ° C.

Basic analysis:

Calculated (%) Found (%) C 61.7 62.2 25 H 4.51 4.39 N 4.64 4.80

EXAMPLE XII

Preparation of (E) -5- (2-bromovinyl) -2,2-anhydro-3,0-acyl-1-8-D-arabinofuranosyluracil 30 3.0 g (5 mmol) 5 '- (4- methoxytriphenylmethyl) -2,2'-anhydro- (E) -5- (2-bromovinyl) uridine was dissolved in 10 ml of dry pyridine and 11 mmoles of the appropriate carboxylic acid chloride were added dropwise with stirring and cooling with ice. The reaction mixture was stirred overnight, after which 50 ml of methanol was added. The solution was evaporated in vacuo, the residue was dissolved in chloroform and extracted with 3x5 ml of water. The organic phase was dried over anhydrous magnesium sulfate and then evaporated to dryness under vacuum. The residue was dissolved in 150 ml 80% acetic acid 8502 79 4-17 and the mixture was stored at room temperature for 4 hours. The homogeneous solution was evaporated to dryness. The residue crystallized by the addition of chloroform. The crystals were filtered and washed with chloroform. Yield: 2.5-4 mmol of the desired product (50-80%).

EXAMPLE XIII

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-31-benzoyl-1-3-D-arabinofuranosyluracil 10 3.02 g (5 mmol) 5 '- (4-methoxytriphenylmethyl) - 2,2'-anhydro- (E) -5- (2-bromovinyl) uridine was dissolved in 10 ml of dry pyridine and 1.28 ml (11 mmol) of benzoyl chloride was added dropwise to the solution with stirring and cooling with ice. The reaction mixture was stirred at room temperature overnight, after which 50 ml of methanol was added. The solution was evaporated in vacuo, the residue was dissolved in chloroform and then extracted three times with water. The organic phase was evaporated to dryness, after which the solid residue was dissolved in 150 ml of 80% rs acetic acid with stirring. After 4 hours, the reaction mixture was evaporated in vacuo and the entire water content was removed by repeated azeotropic distillations with ethanol. The residue was recrystallized from chloroform. The product was filtered off and dried.

Yield: 1.6 g (75%). Melting point: 240-241 ° C.

R @ 0.50 (in a 95: 5 mixture of ethyl acetate and methanol).

Basic analysis:

Calculated (%) Found (%) 30 C 49.67 49.78 H 3.47 3.38 N 6.44 6.41

The compounds of Examples VI-X were prepared according to the method described above. The physical constants of the compounds were the same as described in Table A, while the yields were as follows: Compound Yield (%) 6 80 7 63 85027 9 4 T t - 18 -

Compound Yield (%) 8 50 9 72 10 75

5 EXAMPLES XIV-XVI

Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-5'-0-acyl-1-f3-D-arabinofuranosyluracil 10 mmol (E) -5- (2-bromovinyl) -2 2'-anhydro-31,5'-di-0-acyl-1-8-D-arabinofuranosyluracil was dissolved in 100 ml of 10 methanolic ammonium hydroxide solution (methanol is saturated with ammonia at 0 ° C and diluted to one tenth of the ammonia concentration prior to use). The flask containing the reaction mixture and closed with a cork was stored at room temperature for 10-20 min and then evaporated to dryness. The solid product thus obtained was recrystallized from methanol.

The chemical structure of the products was verified by NMR spectroscopy, while their purity was checked by measuring the melting point and by thin layer chromatography. The TLC analysis was performed on a silica gel layer using a 9: 1 mixture of benzene and methanol as the eluent while detecting the spots in UV light.

The physical constants and yields of the (E) -5- (2-bromovinyl) -2,2'-anhydro-51-O-acyl-1-β-D-arabinofuranosyluracils thus obtained are shown in Table D.

TABLE D

No. Output connection end product melt-R »

Example R R 'R R' yield. point·

% ° C

XIV benzoyl benzoyl H benzoyl 82 228-229 0.4 XV β-phenyl- β-phenyl- H β-phenyl- 84 250-251 0.8 propionyl propionyl propionyl XVI furoyl furoyl H furoyl 80 193-195 0.44

EXAMPLES XVII - IXXX

35 Preparation of (E) -5- (2-bromovinyl) -2,2'-anhydro-3 ', 5'-di-0-acyl-1-8-D-arabinofuranosylura derivatives 1. Preparation of (E) -5 - (2-bromovinyl) -2,21-anhydro-3'-o-acyl-3-D-arabinofuranosyluracil by acylation of (E) -5- (2-bromovinyl) -2,2'-anhydro-1-^ -D-arabinofuranosyluracil 8502 794 - 19 -> f 9 a) Acylation with an acid anhydride

To 1 mmol (E) -5- (2-bromovinyl) -2,2 * -anhydro-1-3-D-arabinofuranosyluracil, 5 mmol of the appropriate acid anhydride (acetic anhydride, propionic anhydride etc.), 5 0.2 ml triethylamine and 4-5 mg of 4-dimethylaminopyridine catalyst added and the reaction mixture was heated to 60-80 ° C excluding moisture. A clear solution was obtained, which was stored at room temperature. Crystals started to form after 0.5 hours. After 5-6 hours, the resulting crystals were filtered and washed with a small amount of ether. The crude product was recrystallized from an alcohol.

b) Acylation with an acid chloride

To 1 mmol (E) -5- (2-bromovinyl) -2,2 * -anhydro-1-8-D-15 arabinofuranosyluracil was added 3 ml of dry pyridine and 2.5 mmol of the appropriate acid chloride. The reaction mixture was heated to a temperature of 60-80 ° C with the exclusion of moisture. A clear solution was obtained. The first crystals appeared after about 1 hour. The precipitated crystals were filtered after about 3-4 hours, washed with a small amount of cold ethanol and recrystallized from ethanol or dimethylformamide.

2. Preparation of the intended compound by acylation of (E) -5- (2-bromovinyl) -2,2 * -anhydro-3'-0-acyl-1-8-D-arabinofuranosyluracil a) Acylation with an acid anhydride.

The acylation can be carried out according to the above method 1a) using a lower carboxylic anhydride.

b) Acylation with an acid chloride.

The method described above under 1b) can be followed, however, instead of 2.5 mmol of acid chloride, 1.25 mmol of an acid chloride was used, calculated on 1 mmol of the starting compound.

The compounds prepared by the above methods, their physical constants, yield, basic analysis data and the starting materials used in the preparation are listed in Table E.

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Suitable pharmaceutical dosage forms of administration of the compounds of the invention are as follows:

Tablet 1 Compound of formula 1 of the formula sheet, wherein R = acetyl, R '= H 140 mg carrier q.s. for a tablet

Tablet 2

Compound of formula 1 of the formula sheet, where 10 in R = acetyl, R '= H 500 mg carrier q.s. for a tablet

Tablet 3

Compound of formula 1 of the formula sheet, wherein R = R '= H 140 mg of carrier q.s. for a tablet

Capsule

Compound of formula 1 of the formula sheet, wherein R = R '= H 300 mg sodium ascorbinate 30 mg 20 carrier q.s. for a capsule

Drops

The hydrochloride salt of the compound of formula 1 of the formula sheet, wherein R = R '= acetyl 600 mg vitamin C 3 mg 25 diluent q.s. 100 ml

Infusion solution

The hydrochloride salt of the compound of formula 1 of the formula sheet, wherein R = acetyl, R '= H 6 g dissolved in physiological saline, filled in 2.0-5.0 ml ampoules after filtration to sterile q.s. 1000 ml 8502794

Claims (11)

A compound of formula 1 of the formula sheet, wherein R and R 'represent the same or different from each other hydrogen or an optionally substituted acyl, preferably optionally substituted straight or branched alkanoyl, optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl as well as pharmaceutically acceptable acid addition salts thereof. 2. A compound of the formula 1 of the formula sheet according to claim 1, wherein R and R 'represent the same or different from each other hydrogen or an optionally substituted straight or branched alkanoyl having 1 to 8 carbon atoms, optionally substituted cycloalkanoyl having 4 to 9 carbon atoms, an optionally substituted aroyl of 7-11 carbon atoms or a heteroaroyl group of 4-11 carbon atoms and 1 or 2 of oxygen, sulfur and / or nitrogen atoms as hetero atoms, or pharmaceutically acceptable acid addition salts thereof. 3. A compound of formula 1 of the formula sheet according to claim 1, wherein R and R 'represent, optionally equal to each other, hydrogen or an optionally substituted straight or branched chain alkanoyl of 1-4 carbon atoms and pharmaceutically acceptable acid addition salts thereof. Compound of formula 1 of the formula sheet according to any one of the preceding claims, characterized in that the substituents optionally present are alkyl and / or aryl groups. A compound of formula 1 of the formula sheet according to any one of the preceding claims, characterized in that the substituents optionally present are alkyl with 1-6 carbon atoms and / or carbocyclic aryl with 6-10 carbon atoms. 02 734 i »ν '- 26 - 6. Compound selected from the group of: (E) -5- (2-bromovinyl) -2,2'-anhydro-1-gD-arabinofuranosyluracil, (E) -5- (2-bromovinyl) -2,2 ' -anhydro-3'-acetyl-1-gD-arabinofuranosyl-uracil, (E) -5- (2-bromovinyl) -2,21-anhydro-31,5'-diacetyl-1 rg-5 d-arabinofurano.s .yluracil. as well as pharmaceutically acceptable acid addition salts thereof. A compound of formula 1 of the formula sheet, wherein 10. and R 'represent the same or different from each other hydrogen or a suitable blocking group with the proviso that at least one of R and R' is a blocking group. 8. A compound of the formula (I) in the formula sheet wherein 15. and R 'are equal or different from each other to hydrogen or (4-methoxytriphenyl) -methyl provided that at least one of R and R' (4-methoxytriphenyl) - is methyl. 9. Process for the preparation of a compound of formula I of the formula sheet and pharmaceutically acceptable acid addition salts thereof, wherein R and R 'are equal or not to each other hydrogen or an optionally substituted acyl, preferably optionally substituted straight or branched alkanoyl optionally substituted cycloalkanoyl, optionally substituted aroyl or optionally substituted heteroaroyl, characterized in that a compound of formula II of the formula sheet is reacted with a compound of formula III of the formula sheet, wherein R has the above meanings, after which optionally one of the following 30 reactions is carried out: a) a compound of formula 1 of the formula sheet wherein at least one of R and R 'is hydrogen is acylated with a compound of formula 4 of the formula sheet or of formula 5 of the formula sheet, in which Y has the same meanings as R or R 'with the exception of hydrogen, b) a compound of formula 1 of the formula sheet wherein at least one of R and R 'is acyl is deacylated with a methanolic ammonia or sodium methylate, c) a blocking group is introduced in 8502 79 4 i φ - 27 - the compound of formula 1 of the formula sheet in which both R and R 'are hydrogen, after which the compound thus obtained is acylated with an acylating agent of formula 4 or 5 of the formula sheet and then the compound of formula 1 of the formula sheet thus obtained in the form of free base is converted into a pharmaceutically acceptable acid addition salt or the free base is released from the salt. An antiviral pharmaceutical composition consisting essentially of at least one compound of formula 10. of the formula sheet as defined in claims 1-6 and of a suitable pharmaceutical carrier. 11. A method of combating viral infections, characterized in that an appropriate amount of at least one compound of formula 1 of the formula sheet, as defined in claims 1-6, is administered. 8 5 0? 7 3 .1 V ij V * “v '