WO1993017651A2

WO1993017651A2 - Antiviral nucleoside analogues, their production and use

Info

Publication number: WO1993017651A2
Application number: PCT/DE1993/000213
Authority: WO
Inventors: Eckart Matthes; Martin Von Janta-Lipinski
Original assignee: Max-Delbrück-Centrum für Molekulare Medizin
Priority date: 1992-03-04
Filing date: 1993-03-03
Publication date: 1993-09-16
Also published as: WO1993017651A3; DE4207363A1

Abstract

New and known nucleoside analogues particularly effective against hepatitis B and HIV infections are disclosed, as well as their production and use.

Description

Antiviral nucleoside analogues, their preparation and their use

description

The invention relates to pyrimidine and purine nucleoside analogs, processes for their preparation and their use as pharmaceutical active substances or agents for the prophylaxis and / or treatment of infections, in particular those caused by the hepatitis B virus (HBV) or HIV (human immunodeficiency virus).

HBV is the triggering agent for hepatitis B, an infectious disease that affects around 200 million people worldwide and whose chronic form is associated with an increased risk of primary liver carcinoma, which in China alone has around one million new tumors leads to sick children every year.

An effective and tolerable antiviral therapy has so far been lacking. The use of adenine arabinoside monophosphate and acyclovir was limited to a few clinical studies, due to the currently considerable side effects and the only partial and temporary treatment success (Alexander et al. British Medical Journal 292, 915 (1986)). Only with interferon does a longer-term success in treatment appear to be emerging in around 50% of cases. This leads to the need to look for more effective and selective drugs.

The treatment of AIDS must be regarded as similarly unsatisfactory, as it leads to the collapse of the immunological defense as a late consequence of infection of T-4 lymphocytes with HIV. The previous antiviral therapy with azidothymidine and more recently with the better tolerated dideoxyinosine delayed the fatal outcome of the immunosensitive syndrome, but was unable to prevent it.

A number of nucleoside analogues point in the direction of new potentially effective agents, for which an activity against hepatitis B and / or HIV infections is claimed in the following patent applications: 1. 3 'fluomucleosides of adenine, guanine, cytosine and thymine (EP 0 277 151 and EP 0 254 268)

2. 2 ^1- fluoroarabinofuranosyl-5-ethyluracil (WO 89/01776)

3. 2 ', 3' dideoxynucleosides of various purine derivatives

(EP 0 302 760)

4. Sugar-modified purine and pyrimidine nucleosides (EP 0 322 384 and EP 0 409 227)

5. Cyclopentane derivatives of purines and pyrimidines (EP 0 330 992)

6. Carbocyclic nucleosides of purine derivatives (EP 0 434 450, EP 349 242, US 4 999 428 and WO 91/00282)

7. Oxetane derivatives of purines and pyrimidines (EP 433 898)

8. 3 "fluomucleosides (EP 0 442 757).

The invention has for its object to provide new pyrimidine and Purix nucleosides and their preparation, which are effective against hepatitis B and HIV infections and can be used as pharmaceutical agents for the prophylaxis and / or treatment of corresponding infections, and to show other compounds which good tolerance and low toxicity are highly effective against these infections.

The compounds according to the invention have the following general formulas:

in which mean:

B = thymine, uracil, 5-halouracil, 5-azidouracil, 5-hydroxymethyluracil, 5-formyluracil, 5-ethyluracil, 5-chloroethyluracil,

Cytosine, 5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, 5-ethylcytosine

Adenine, 2-fluoroadenine, 2-chloroadenine, N6-dialkyladenine (C1-C3),

8-azaadenine, 6-mercaptopurine Guanine, 6-chloroguanine, 6-thioguanine, 6-methoxyguanine, 2,6-

Diaminopurine, 8-azaguanine

R ¹ , R ² s H, OH; unless R ¹ = OH, then R ² - OH

R ³ = H, OH, F, N ₃ , NH ₂

R ⁴ = OH, O-acetyl, O-palmitoyl, alkoxycarbonyl, phosphonate,

Mono-, di-, triphosphate or another protective group which can be converted into the hydroxy group in a subsequent reaction,

R ⁵ = 0, C,

where R ^{5 is} C a) when B = thymine, uracil, cytosine, adenine, guanine and

R ¹ , R ² , R ³ = H and R ⁴ = OH, O-acetyl, O-palmitoyl, 0-alkoxyσarbonyl, mono-, di-, triphosphate and

1 b) if B = adenine, guanine,

R ¹ , R ² = H, R ³ = OH and R ⁴ = OH, O-acetyl, O-palmitoyl, 0-alkoxycarbonyl, mono-, di-, triphosphate,

wherein B 1, R1 and R4 are the above. Have meaning unless

B = thymine, uracil, cytosine, adenine or guanine and

R = H, then R is OH, O-acetyl, O-palmitoyl, 0-alkoxycarbonyl, mono-, di-, triphosphate,

III

wherein B 1, R1 and R2 deo g. Have meaning and

R, R = H, F, Cl, Br, NH ₂ , N3, SCN, phosphonate, phosphoamide mean.

These pyrimidine and purine nucleosides are active substances against viral infections, as are caused in particular by the hepatitis B virus (HBV) and HIV. They can be used advantageously as such and in the form of pharmaceutical agents together with suitable auxiliaries and / or carriers for the treatment and / or prophylaxis of hepatitis B and AIDS. The following were found to be particularly effective: 1- (4-fluoro-ß-D-arabinofuranosyl) cytosine (I) 1- (2-deoxy-4-fluoro-ß-D-glyceropentofuranosyl) thymine (I) 1- (2 -Desoxy-4-fluoro-β-D-glyceropentofuranosyl) guanine (I) 9- (2,3-dideoxy-4-fluoro-β-D-glyceropentofuranosyl) adenine (I) 1- (2,3 -Dideoxy-3,4-difluoro-ß-D-ribofuranosyl) guanine (I) 1- (2,3-dideoxy-4-fluoro-ß-D-glyceropentofuranosyl) cytosine (I) (*) -Iß- (3α-fluoro-4ß-hydroxymethylcyclopent-l-yl) 5-methylcytosine (II)

(±) -9ß- (3α-fluoro-4ß-hydroxymethylcyclopent-l-yl) 2,6-diamino-purine (II)

1- (3-Azido-2,3,5-trideoxy-5-fluoro-ß-D-glyceropentofuranosyl) thymine (III)

(*) -Iß- (3α-amino-4β-chloromethylcyclopent-l-yl) thymine (III). They are effective against the compounds of the prior art and have less toxicity and side effects. For example, 1- (2-deoxy-4-fluoro-ß-D-glyceropentofuranosyl) thymine as a highly effective inhibitor of HIV replication, which inhibits the cytopathic effect of HIV at 0.2 μM by 50% in MT-4 cells (ED50), while an equally strong effect on cell proliferation only occurs at 420 μM.

As an inhibitor of HBV replication, 1- (2-deoxy-4-fluoro-ß-D-glyceropentofuranosyl) guanine on HepG2 2.2.15 cells, for example, showed a strong activity: at a concentration of 0.15 μM, that of these The amount of HBV-DNA released into the medium was inhibited by 90%. Again, the impact was on that Cell proliferation is comparatively low (50% inhibition of cell proliferation at> 300 μM (CD50)).

They are produced using methods known per se. The compounds of the formula I are synthesized by oxidation of the optionally protected 5 * -deoxy-5 * -iodo-4 ^■ - fluorine derivatives or the ( ^± ) 4-α-fluoro-4β-iodomethylcyclopent-1-yl derivatives with silver (II) oxide, subsequent reduction with borohydride and removal of existing protective groups. Compounds of the formula II are prepared by treating the optionally protected 3β-hydroxycyclopent-l-yl derivatives of the corresponding heterocycles with DAST and then removing the protective groups present. Finally, compounds of the formula III are prepared by nucleophilic substitution of sulfonyloxy or other groups in the corresponding, optionally protected cyclopent-1-yl derivatives of the respective heterocycles and, if appropriate, modification by subsequent reactions, for example by hydrogenolysis and removal of existing protective groups. Treatment and / or prophylaxis of hepatitis B and HIV infections according to the invention consists in the administration of an effective amount of one or more compounds of the formulas I, II and / or III as such or in the form of suitable formulations.

The pharmaceutical preparations according to the invention, which are suitable for prophylaxis and / or therapy, in particular of infections caused by the hepatitis B virus or HIV, contain at least one pyrimidine or purine nucleoside of the formulas I, II and / or III , as defined above, as an active ingredient in addition to a pharmaceutically suitable auxiliary and / or carrier or several such additives and optionally other therapeutic agents or active ingredients. The agents are advantageously produced in the form of dosing units with one or more unit doses.

The invention further relates to the use of compounds of the following general formulas IV, V and VI against infections, in particular by the hepatitis B virus (IV and V) or by the hepatitis B virus and HIV (VI). The following connections are involved: O 93/17651

wherein

B = thymine, uracil, cytosine, adenine, guanine

R ⁸ , R ⁹ and R ¹⁰ = H or

B "_? = Adenine, guanine and R8, R ^J 9 = H and

R ¹⁰ = OH and

R ¹¹ = OH, O-acetyl, O-palmitoyl, alkoxycarbonyl, mono-, di-,

Triphosphate mean

where B _? and Rn the above Have meaning

wherein

B, R ¹ and R, R and R have the meaning given above with one

Limitation of claim to effectiveness against the

Hepatitis B virus replication when

B ¹ = thymine, uracil, cytosine, adenine, guanine and

R ¹ , R ² = H, R ⁶ = F, NH ₂ , N3 and R ⁷ = phosphonate or if

B ¹ = adenine, R ¹ = H, R ² = OH, R ⁶ = F and R ⁷ = NH.

Of particular importance are: 1) 1- (3,5-difluoro-2,3,5-trideoxy-β-D-glyceropentofuranosyl) thymine

2) 1- (3-chloro-5-fluoro-2,3,5-trideoxy-ß-D-glyceropentofuranosyl) thymine

3) (±) -Iß- (4α-fluoro-3α-hydroxy-4ß-hydroxymethylcyclopent-l-yl) guanine

4) (*) -9ß- (3α-fluoro-4ß-hydroxymethylcyclopent-l-yl) guanine

5) (±) -Iß- (3α-fluoro-4ß-hydroxymethylcyclopent-l-yl) cytosine

6) (*) -9ß- (4α-fluoro-3α-hydroxy-4ß-hydroxymethylcyclopent-l-yl) adenine

7) 9- (3-Azido-2,3,5-trideoxy-5-fluoro-β-D-glyceropentofuranosyl) adenine

8) 1- (3-amino-2,3,5-trideoxy-5-fluoro-ß-D-glyceropentofuranosyl) thymine

9) 1- (2,3,5-trideoxy-3-fluoro-ß-D-glycero-peιj.tofuranosyl) thymine

10) 1- (2,3,5-trideoxy-3,5-difluoro-β-D-glyceropentofuranosyl) 5-methylcytosine

11) 1- (3-chloro-5-fluoro-2,3,5-trideoxy-β-D-glyceropentofuranosyl) 5-methylcytosine

12) 1- (5-fluoro-2,3,5-trideoxy-3-rhodano-β-D-glyceropentofuranosyl) thymine.

The compounds of the formulas IV and V are particularly effective compounds for the treatment and / or prophylaxis of hepatitis B infections. Compounds of the formula VI with the stated restriction are also effective against HIV infections. They are used for the production of corresponding pharmaceutical agents. The pharmaceutical compositions are produced in the form of dosage units or multiples thereof. The auxiliaries and carriers used must be compatible, compatible with the other components of the agent and harmless to the patient. The pharmaceutical formulations or application forms of the pharmaceutical compositions according to the invention include those which are suitable for oral, rectal, nasal, topical, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. One or more active ingredients are combined with the carrier, which consists of several Accompanying components can be composed, brought into contact and, if necessary, converted into a corresponding pharmaceutical form.

The pharmaceutical compositions for oral administration are produced in the form of coated tablets, tablets, capsules, as a powder or as granules, each of which contains a certain amount of the active ingredient. They can also be formulated as solutions or as suspensions. If necessary, flavoring agents and / or other customary additives are added. Means for rectal administration are made as suppositories with a suitable basis. Medicines for vaginal administration are e.g. Formulated as pessaries, tampons, creams, gels, pastes, foams or spray products. The agents for parenteral administration can contain one dosage unit of the active ingredient or a multiple thereof and can be stored, for example, in ampoules, vials or in a freeze-dried state. Injection solutions and suspensions prepared immediately before use can be obtained from sterile powders, granules and tablets, e.g. B. by dissolving the substance in physiological saline, glucose or other media suitable for IV injection or infusion.

The invention is explained in more detail below by means of exemplary embodiments:

example 1

1- (4-fluoro-ß-D-arabinofuranosyl) cytosine

2.5 g (4.78 mol) of peracetylated 5 * -O-tosyl-ara C are first in the corresponding 5 'iodine compound and then with silver fluoride in pyridine (JPH VERHEYDEN and JG MOFFAT, J. Am. Chem. Soc. .88 _. (1966) 5684) converted into the corresponding 4-enofuranosyl derivative. After treatment with iodine / silver fluoride, the corresponding 5 * -deoxy-5'-iodo-4 • - fluorine compound is obtained, from which after oxidation with silver oxide on Celite, followed by reduction with borohydride (ID JENKINS, JPH VERHEYDEN and of the title compound are obtained JG MOFFAT, _Soc. J. Am. Chem., _98, (1976) 3346), and removal of the protective groups 37 mg. Example 2

(+) -9ß- (4g-fluoro-4ß-hvdroxymethylcvclopent-l-yl) guanine 104 mg (0.27 mmol) (*) -9- (4α-fluoro-4ß-iodomethylcyclopent-1-yl) guanine are used in 10 ml of dioxane with 1 g of silver (II) oxide, 5 ml of acetic acid (50%) and 0.5 g of sodium acetate. The reaction mixture is stirred for 24 hours at room temperature. The solution is then filtered, the filtrate i. Vac. evaporated to dryness. The residue is dissolved in 10 ml of aqueous dioxane (50%) and treated with 70 mg of sodium borohydride. After 1 hour the solution is mixed with acetic acid, then neutralized with sodium bicarbonate solution and concentrated to dryness. The residue is purified on silica gel 60 (0.063-0.2 mm, MERCK) with chloroform (7% methanol) as the eluent. 19.5 mg of the title compound are isolated from the corresponding fractions. MS (70 eV): m / z 267 (M ⁺ ).

Example 3

(+) -Iß- (3α-fluoro-4ß-hydroxymethylcvclopent-l-yl) 5-methylcvtosine 2 mmol (±) -Iß- (3ß-hydroxy-4ß-trityloxymethylcyclopent-l-yl) 5-methylcytosine are in 30 ml Dissolved dichloromethane and mixed with 3.5 mmol of DAST with stirring. The reaction mixture remains at room temperature for 2 hours. It is then neutralized with bicarbonate and the solvent removed in vacuo. The residue is heated in 50 ml of 80% acetic acid for 3 hours at 90 ° C. After the solvent has been removed in vacuo, the residue is purified by column chromatography on silica gel 40 (0.063-0.2 mm, Merck) with chloroform (5% methanol). 47 mg of the title compound are isolated.

Example 4

(+) -Iß- (4ß-fluoromethylcyclopent-l-yl) thymine

304 mg (*) -Iß- (4ß-p-toluenesulfonyloxymethylcyclopent-1-yl) thymin are dissolved in 30 ml of acetonitrile and 1 g of tetrabutylammonium fluoride is added. The reaction mixture remains at room temperature for 48 hours, then 100 ml of water are added, and the solution is poured over a cation exchange column (DOWEX W x 8, H ⁺ shape). The acidic eluate is collected in an aqueous calcium carbonate solution and i. Vac. evaporated to dryness. The resulting residue is purified on silica gel 40 (0.063-0.2 mm) by column chromatography using chloroform (1% methanol) as the eluent. 41 mg of (-) -Iß- (4ß-fluoromethyl-1-cyclopentyl) thymine are obtained from the corresponding fractions, m / z: 226 (M ⁺ ).

Example 5

2,3'-Anhγdro-1- (5-deoxy-5-fluoro-β-D-ribofuranosyl) thymine

To ^• a suspension of 1 g (4.1 mmol) of 5 '-deoxy-5' -fluorothymidine (K. Kowollik, K. Gaertner, G. Etzold and P. Langen,

Carbohyd. Res., 1970, 12, 301) in 100 ml dichloromethane, 0.7 ml DAST are added with stirring at room temperature. To

The starting nucleoside is completely converted within 90 minutes. The

Reaction solution is neutralized with sodium bicarbonate and i. Vac. evaporated to dryness. The residue is i. Vac.

(P2O5) dried and without further purification in the following

Reactions used.

MS: m / z 223 (Molpeak, C-LQ ^H llN2θ3F).

Example 6

1- (3-Azido-5-fluoro-2,3,5-trideoxy-ß-D-glvceropentofuranoεyl) thymine

670 mg (3 mmol) of the compound obtained in Example 1 are stirred in 25 ml DMF with 1.95 g (30 mmol) sodium azide 12

Heated to 120 ° C for hours. After cooling the

Reaction solution becomes the solvent i. Vac. away. The remaining residue is on silica gel G (0.063 - 0.2 mm,

Merck) with chloroform (2% methanol) separated by column chromatography. The corresponding fractions will become after

Removing the solvent obtained a residue from

Isopropanol / Eεεigeεter crystallized. After recrystallization from isopropanol, 476 mg (yield 59%) of l- (3-

Azido-5-fluoro-2,3,5-trideεoxy-ß-D-glyceropentofuranoεyl) thymine isolated. F. 195 ° C.

MS: m / z 269 (M ⁺ , C ₁₀ H ₁ N ₅ O ₃ F), 144 (sugar residue, C5H7N3OF), 126 (base + H, C ₅ H ₆ N ₂ 0). UV (methanol): A. _m χ ²⁶³ ' ⁸ 1 ™ (£ 12630).

Example 7

4-Amino-l- (3-azido-5-fluoro-2,3,5-trideoxy-ß-D-glvcero-pentofuranoεyl) 5-methyl- (1H) pyrimidin-2-one

880 mg (3.27 mmol) of 1- (3-azido-5-fluoro-2,3,5-trideoxy-ß-D-glyceropentofuranosäyl) thymine are dissolved in 35 ml of dry pyridine, with 1.55 ml ( 9.5 mmol) of phosphoric acid mono- (4-chlorophenyl ester) dichloride and 940 mg (16.6 mmol) of triazole (WING L. SUNG, J. Chem. Soc, Chem. Co mun., 1981, 1084). The reaction mixture remains at room temperature for 5 days. Then 100 ml of dioxane and 135 ml of aqueous ammonia solution (25%) are added. After 12 hours the solution is i. Vac. evaporated to dryness. The dark brown residue is fractionated using DOWEX W x 8 (100 ml, H ⁺ form). It is eluted with water (350 ml) and then with aqueous ammonia (3%; 500 ml). The ammonia-containing fraction is evaporated to dryness and the resulting residue on Celite (200 ml) with the upper phase of the mixture ethyl acetate / isopropanol / water (4/1/2) as eluent is separated by column chromatography. The title compound is obtained in crystalline form from the corresponding fractions and recrystallized from methanol. F. 116 - 118 ° C MS: m / z 268 (M ⁺ ),

144 (sugar residue, C5H7N3F),

125 (base + H, C ₅ HgN ₃ 0) UV (methanol): pH 7, λ _max = 278 nm (- 7800).

Example 8

9- (3-Azido-5-fluoro-2,3,5-tri-deoxy-ß-D-glvceropentofurano-εyl) adenine

1 g (3.6 mmol) 9- (3-azido-2,3-dideεoxy-ß-D-ribofuranoεyl) adenine (M. IMAZAWA and F. ECKSTEIN, J. Org. Chem., 43. (1978)

3044) is suspended in 50 ml dichloromethane and 10 mmol of DAST are added with stirring. The reaction mixture remains for 4

Hours at room temperature. Then the with aqueous

Bicarbonate neutralized solution evaporated to dryness and the residue obtained on silica gel using column chromatography

Chloroform (3% methanol) cleaned as eluent. 173 mg of the title compound are isolated from the corresponding fractions.

MS: m / z 278 (M ⁺ ).

Example 9

1- (3-amino-2,3,5-trideεoxy-5-fluoro-ß-D-glyceropentofurano-εyl) thymine

A solution of 1- (3-azido-2,3,5-trideoxy-5-fluoro-ß-D-glyceropentofuranoεyl) thymine (0.575 g) and triphenylphosphine (1.706 g) in 25 ml pyridine remains for 10 hours. with stirring at room temperature. The solvent is then removed and the residue is suspended in 13 ml of ethanol and 27 ml of 1N ammonia solution. After 24 hours, the reaction mixture is evaporated to dryness, the residue is partitioned between chloroform and water, and the aqueous phase is purified by chromatography on DOWEX 50 W x 8 (H ⁺ ) with water (300 ml) and 1 N ammonia solution. 265 mg of a crude product are obtained, which crystallize from methanol (125 mg). Mp 198-199 ° C. MS: m / z 243 (M ⁺ ),

126 (base + H),

118 (sugar residue, C5H9NOF).

Example 10

1- (2,3,5-trideoxy-3-fluoro-ß-D-glvcero-pentofuranoεyl) thymine 1- (2,3,5-trideoxy-3-fluoro-5-iodo-ß-D-glyceropentofuranosyl ) - thymine (0.87 g) is dissolved in a mixture of 40 ml of water, 80 ml of methanol and 20 ml of dioxane. The solution is brought to pH 10 with ammonia solution and treated with 3 g of Pd / BaSO 4 ( ⁵ %) hydrogenolytically. After 3 hours the catalyst is filtered off, the solution is evaporated to dryness and the residue on silica gel 60 (0.063-0.2 mm, Merck) with chloroform (1% methanol) as the eluent is purified by column chromatography. 390 mg of the title compound are obtained from the corresponding fractions. Mp 159-161.5 ° C. Example 11

1- (2,3,5-trideoxy-3,5-difluoro-ß-D-glvceropentofuranoεyl) - 5-methylcvtosine

1- (2,3,5-trideoxy-3,5-difluoro-β-D-glyceropentofuranosyl) thymin (0.88 g), triazole (0.5 g) and 4-chlorophenyl dichlorophosphate (0.86 ml) are dissolved in 25 ml pyridine and remain at room temperature for 5 days. 40 ml of dioxane / NH4θH conc. (3/1) are then added, and the mixture remains at room temperature for a further 24 hours. After the solvent has been removed, the residue is purified on silica gel 60 (0.063-0.2 mm) using chloroform (2% methanol) as the eluent. 430 mg of the title compound are obtained in crystalline form from i-propanol. F. 90-94 ° C.

Example 12

1- (3-chloro-5-fluoro-2,3,5-trideoxy-ß-D-glvceropentofurano-εyl) 5-methylcvtosine

A mixture of 0.49 1- (3-chloro-5-fluoro-2,3,5-trideoxy-ß-D-glyceropentofuranosyl) thymine, 0.37 g triazole and 0.8 ml 4-

Chlorphenyl dichlorophosphate in 10 ml pyridine remains for 1

Week at room temperature. Then 30 ml of dioxane and 30 ml of concentrated ammonia solution are added. After 10 hours it will

Solvent removed and the residue on DOWEX W x 8 (H ⁺ -

Form) with water (1 1) ml of 0.5% ammonia solution (0.5 1) and

1% ammonia solution (0.3 1) separated. 150 mg of the title compound are obtained from the corresponding elution volume and are recrystallized from isopropanol.

Mp 107-109 ° C. MS; m / z 261 (M ⁺ ).

Example 13

1- (3-chloro-5-fluoro-2,3,5-trideεoxy-ß-D-glyceropentofurano-εyl) thvmin lg 1- (2,5-dideεoxy-5-fluoro-ß-D-ribofuranoεyl) thymine and 0.7 ml

Diethylamino sulfur fluoride are used in 100 ml of dichloromethane

Stirred for 2 hours at room temperature. After neutralizing with NaHCO 3 solution, the solvent is removed in vacuo. The residue is suspended in 30 ml of dioxane, with 5 ml of one 0.4 N HCl-containing dioxane solution is added and remains overnight at room temperature. Then i.Vak. evaporated to dryness and the residue purified on silica gel 60 (0.063-0.2 mm) with chloroform (2% methanol). 0.49 g of the title compound are obtained from the corresponding fractions. Mp 157-158 ° C (methanol). MS: m / z 262 (M ⁺ ).

Example 14

1- (5-fluoro-2,3,5-trideoxy-3-rhodano-ß-D-glvceropentofurano-εyl) thymine

1- (2,5-dideoxy-5-fluoro-ß-D-ribofuranoεyl) thymine (1 g, 4 mmol) is suspended in 100 ml dichloromethane and mixed with 0.7 ml diethylaminosulfur trifluoride. The reaction mixture _'was stirred for 2 hrs. At room temperature, neutralized with NaHC03 anεchließend is i solution and the solvent. Vac. away. The residue is dissolved in 25 ml of dirnethylformamide, 2 g of finely powdered potassium rhodanide, 0.2 g of 18-crown-6 and 0.1 g of p-toluenesulfonic acid are added. The reaction mixture is heated to 120 ° C. for 10 hours. After cooling, the solvent is removed and the dark brown residue on silica gel 60 (0.063-0.2 mm, Merck) with chloroform (0.5 1) and chloroform (2% methanol; 0.9 1) as the eluent is purified by column chromatography. The title compound is obtained as a non-crystalline material from the corresponding fractions. MS: m / z 285 (M ⁺ ).

Claims

1. Pyrimidine and purine nucleosides of the general formula I,

wherein

B ^A = thymine, uracil, 5-halouracil, 5-azidouracil, 5-

Hydroxymethyluracil, 5-formyluracil, 5-ethyluracil, 5-

Chloroethyluracil;

Cytoεin, 5-methylcytoεin, 5-hydroxymethylcytoεin, 5-

For ylcytoεin, 5-ethylcytoεin;

Adenine, 2-fluoroadenine, 2-chloroadenine, N6-dialkyladenine (C ^ -

C3), 8-azaadenine, 6-mercaptopurine;

Guanine, 6-chloroguanine, 6-thioguanine, 6-methoxyguanine, 2,6-

Diaminopurine, 8-azaguanine,

R ¹ , R ² = H, OH; unless R ¹ = OH, then R ^{2 is} OH,

R ³ = H, OH, F, N ₃ , NH ₂ , = OH, O-acetyl, O-palmitoyl, alkoxycarbonyl, phosphonate,

Mono-, di-, triphosphate or another protective group which can be converted into the hydroxy group in a subsequent reaction, and

R = 0, C mean

where R < _r - C if a) B ¹ = thymine, uracil, cytosine, adenine, guanine and R ¹ , R ² , R ³ = H and = OH, O-acetyl, O-palmitoyl, 0-alkoxycarbonyl, Is mono-, di-, triphosphate or if b) B = adenine, guanine and R ¹ , R ² = H, R ³ = OH and

R ^ = OH, O-acetyl, O-palmitoyl, 0-alkoxycarbonyl, mono-, di-, triphosphate.

2. pyrimidine and purine nucleosides of the general formula II,

wherein

B, R ¹ and R have the above meaning, unless

B = thymine, uracil, cytose, adenine or guanine and

R- "ss H then is

ΕL - OK, O-acetyl, O-palmitoyl, -O-alkoxycarbonyl, mono-,

Di-, triphosphate.

3. pyrimidine and purine nuclides of the general formula III,

wherein

B, and R the above. Have meaning and

R, R ⁷ = H, F, Cl, Br, NH, N3, SCN, Phoεphonat, Phoεphoamid ε are.

4. 1- (4-fluoro-ß-D-arabinofuranoεyl) cytoεin (I)

5. 1- (2-Deεoxy-4-fluoro-ß-D-ribofuranosyl) thymine (I)

6. 1- (2-Deεoxy-4-fluoro-ß-D-ribofuranoεyl) guanine (I)

7. 9- (2,3-dideoxy-4-fluoro-β-D-glyceropentofuranoεyl) adenine (I)

8. 1- (2,3-Dideεoxy-3,4-difluoro-ß-D-ribofuranoεyl) guanine (I)

9. 1- (2,3-Dideεoxy-4-fluoro-ß-D-glyceropentofuranoεyl) cytoεin (I)

10. (*) -Iß- (3-α-fluoro-4ß-hydroxymethylcyclopent-l-yl) 5-methyl-cytosine (II)

11. (*) -9ß- (3-α_-fluoro-4ß-hydroxymethylcyclopent-l-yl) 2,6-dia inopurine (II)

12. (±) -lß (3-α-azido-4ß-fluoromethylcyclopent-l-yl) thymine (III)

13. (*) - Iß- (3-α-amino-4ß-chloromethylcyclopent-l-yl) thymine (III)

14.A process for the preparation of the compounds according to any one of claims 1 to 13, characterized in that for the preparation of the compounds of formula I, the protected or unprotected 5-deoxy-5-iodo-4'- fluorine derivatives or the (*) - 4α-fluoro-4ß-iodomethylcyclopent-1-yl derivatives, oxidized with silver (II) oxide, the products then reduced with borohydride and the protective groups present, if any, removed, for the preparation of the compounds of the formula II first the respective, optionally protected 3ß Hydroxycyclopent-1-yl derivatives of the corresponding heterocycles are treated with diethylamino sulfur trifluoride (DAST) and the protective groups present are subsequently removed, for the preparation of the compounds of the formula III sulfonyloxy or other groups in the corresponding, optionally protected cyclopent-1-yl derivatives of the respective heterocycles are substituted by corresponding nucleophiles and, if appropriate, the newly introduced Su substitutes by subsequent reactions, such as by hydrogenolysis, and cleaves off any protective groups that may be present.

15. Use of the compounds according to one of claims 1 to 13 and compounds of the general formula IV,

wherein

B ss thymine, uracil, cytose, adenine, guanine and

R ⁸ , R ⁹ and R ¹⁰ = H or

B = s adenine, guanine and

R ⁸ , R ⁹ = H and R ¹⁰ = OH and 1- "1- '= OH, O-acetyl, O-palmitoyl and alkoxycarbonyl, mono-,

Mean di-, triphosphate,

Compounds of the general formula V, l

in which B ^Λ _? -and

have the above meaning,

and compounds of the general formula VI,

in which B, R, R, R and R have the abovementioned meaning for the prophylaxis and / or treatment of infections caused by hepatitis B viruses, in particular in human medicine.

16.Pharmaceutical preparation for the prophylaxis and / or treatment of infections caused by hepatitis B viruses, characterized by at least one compound of the general formulas I and / or II and / or III and / or I and / or V and / or VI according to one or more of claims 1 to 13 and 15 as active substances in addition to conventional galenic auxiliaries, carriers and / or diluents.

17.Use of the compounds according to claims 1 to 13 and the compounds of the general formula VI, unless

B ¹ = thymine, uracil, cytose, adenine, guanine and

R ¹ , R ² = H

R ⁶ = F, NH ₂ , N ₃ and 7

R = phosphate or

B ¹ = adenine,

R ¹ = H, R ² = OH, R ⁶ = F and

R = NH ₂ mean for the prophylaxis and / or treatment of infections caused by HIV (human i munodeficiency viruε).

18.Pharmaceutical preparation for the prophylaxis and / or treatment of infections caused by HIV, marked by at least one compound of the general formulas I and / or II and / or III according to one of claims 1 to 13 and 17 as active ingredients in addition to conventional galenical auxiliary -, Carrier and / or Diluents.