IE921083A1

IE921083A1 - Substituted 2',3'-dideoxy-5-trifluoromethyluridines,¹processes for their preparation and their use in medicaments

Info

Publication number: IE921083A1
Application number: IE108392A
Authority: IE
Inventors: Dieter Habich; Rainer Neumann
Original assignee: Bayer Ag
Priority date: 1991-04-05
Filing date: 1992-04-03
Publication date: 1992-10-07
Also published as: CN1065462A; HU9201117D0; DE4110977A1; KR920019813A; NO921086D0; IL101482A0; HUT60748A; TW205043B; FI921456A0; CS92092A3; FI921456A; JPH05148261A; NZ242205A; AU640860B2; CA2064916A1; AU1219092A; EP0507188A1; NO921086L

Abstract

The invention relates to 2',3'-dideoxy-5-trifluoromethyluridines of the general formula I in which R<1> has the meaning stated in the description, to the method for preparing them and to their use as medicaments, especially as medicaments for hepatitis.

Description

BAYER AKTIENGESELLSCHAFT, a body corporate organised under the laws of the Federal Republic of Germany, at Leverkusen, Federal Republic of Germany.

The invention relates to 2 ’, 3 '-dideoxy-5-trif luoromethyluridines, processes for their preparation and their use as medicaments, in particular as medicaments against hepatitis .

About 300 million people worldwide are sick with hepatitis B, about 1 million new illnesses being recorded each year in the USA and Europe alone.

It is known that certain 2',3'-dideoxynucleosides which are unsubstituted in the 2'- and 3'-position act against hepatitis (B) viruses [cf. U.S. Pat. Appl. 351 502 (15.8.89); EP 302 760]. 2',3'-Dideoxy-cytidine (DDC) is explicitly described in WO 90/14,079 as a medicament against hepatitis B. It is additionally known by means of the publication [D.L.J. Tyrell et al., Biochem. Biophys.

Res. Commun. 156, 1144 - 1148 (1988)] that only 2',3'-dideoxypurine nucleosides, but not 2',3'-dideoxypyrimidine nucleosides, exhibit an activity against DHBV (duck hepatitis B virus). It is additionally indicated that in EP 217,580 the only correct starting compound for the process there, 2'-dideoxy-5-trifluoromethyluridine, was erroneously published with the wrong nomenclature 2',3'-dideoxy-5-trifluoromethyluridine - (Example 34) and thus also accepted by Chemical Abstracts under RN 108,441/81/2 as the structure, without this compound having previously been included by the scope of meaning of a published application or of a patent or mentioned as Le A 28 306 ft - 1 IE 921083 an actual representative substance.

The invention relates to 2 ',3 '-dideoxy-5-trifluoromethyluridines of the general formula (I) in which R1 represents hydrogen or a hydroxyl protective group, represents 4-methylbenzoyl or straight-chain or branched acyl having up to 18 carbon atoms, which is optionally substituted by carboxyl, represents an amino acid which is optionally substituted by an amino protective group customary in peptide chemistry, represents an ester radical which can be cleaved in vivo, or represents a radical of the formulae Le A 28 306 Ο II HO-P — OR2 O II O HO-P R< HO-P-f-O-PORk 0R4 in which R2, R3 and R4 are identical or different and denote hydrogen or an alkali metal or alkaline earth metal atom, n denotes the number 1 or 2, R5 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen, and their physiologically acceptable salts.

In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids.

Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, Le A 28 306 naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which can be mentioned are also salts with custom5 ary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyl10 diisopropylamine, procaine, N-methylmorpholine or Nmethylpiperidine or dihydroabietylamine.

The compounds according to the invention can exist in stereoisomeric forms, which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and the racemic forms and also the diastereomer mixtures. The racemic forms, like the diastereomers, can be separated in a known manner into the stereoisomerically uniform constituents [cf.

E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962].

Le A 28 306 L, β or (R,S) Amino protective groups in the context of the invention are the customary amino protective groups used in peptide chemistry.

These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarLe A 28 306 bonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexylcarbonyl, 1,1-dimethylethoxycarbonyl, adamantyl5 carbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2chloroacetyl, 2-bromoacetyl, 2,2,2-tri fluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl.

Amino acids (-NH-CHR-CO-) in the context of the abovemen15 tioned definition (R1) in general represent the natural amino acids from the series comprising alanine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, leucine, methionine, proline, threonine, tyrosine, arginine, cysteine, glycine, isoleucine, lysine, phenyl20 alanine, serine, tryptophan or valine, the linkage to the oxygen (Rx-0-) in the general formula (I) taking place via the carbonyl group while the terminal amino group is either present as a free NH2 group or optionally substituted by one of the abovementioned protective groups.

Hydroxyl protective group in the context of the abovementioned definition in general represents a protective group from the series comprising: trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyl-dimethylsilyl, Le A 28 306 tert-butyldiphenylsilyl, triphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, triphenylmethyl(trityl), monomethoxytrityl (MMTr), dimethoxytrityl (DMTr), benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxy5 carbonyl, 4-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyl, 2,4dimethoxybenzyloxycarbonyl, methoxymethyl, methyl10 thiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl ) ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl.

Ester radicals which can easily be eliminated in vivo in the context of the abovementioned definition R1 represent pharmaceutically tolerable ester radicals which can easily be eliminated in vivo with liberation of the OH group (R = H). Examples of such groups are disclosed in EP 357,495.

Preferred ester groups which can be cleaved in vivo are those of the following formulae: (CH3)3C-CO-O-CH2- , CH3-CO-O-CH-CH3 CH3-CH2O-CO-O-CH-CH3 Le A 28 306 - 7 IE 921083 Depending on the particular meaning of the radical R1, the compounds of the general formula (I) according to the invention can function as prodrugs, i.e. as pharmaceutically tolerable compounds which, on or after administra5 tion, if appropriate due to improved pharmacological and pharmacokinetic behaviour, provide further compounds of the general formula (I) which can be used according to the invention and in which, for example, R1 = H, as metabolic products or degradation products [cf. for this J. Pharm. Sci. 79, 531 (1990); EP 357,495; EP 362,967; EP 366,386 and WP 90/04,969].

Preferred compounds of the general formula (I) are those in which R1 represents hydrogen, tert-butyldimethylsilyl, 15 trimethylsilyl, triphenylmethyl, benzoyl, 4-methylbenzoyl or acetyl, or represents straight-chain or branched acyl having up to 16 carbon atoms, which is optionally substituted by carboxyl, or represents leucine (Leu), valine (Val), isoleucine (lie), phenylalanine (Phe), aspartic acid (Asp) or glutamic acid (Glu) , which are optionally substituted on the NH function by tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z), or represents an ester radical which can easily be cleaved in vivo, of the formulae Le A 28 306 (CH3)3C-CO-O-CH2- , CH3-CO-O-CH-CH3 ch3-ch2o-co-o-ch-ch3 or represents a radical of the formulae It HO - P — OR2 O O HO — P — O-P0R, OR, II HO - P — in which R2, R3 and R* are identical or different and denote hydrogen or a sodium metal atom, n denotes the number 1 or 2, R5 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine, and their physiologically acceptable salts.

Particularly preferred compounds of the general Le A 28 306 formula (I) are those in which represents hydrogen, tert-butyldimethylsilyl, 4methylbenzoyl or benzoyl, or represents straight-chain or branched acyl having up to 14 carbon atoms, which is optionally substituted by carboxyl, or represents leucine (Leu) or aspartic acid (Asp), which are optionally substituted on the -NH function by the protective group Boc, or represents an ester radical which can easily be cleaved in vivo, of the formulae (CH3)3C-CO-O-CH2CH3-CO-O-CH-CH3 CH3-CH2O-CO-O-CH-CH3 or represents a radical of the formulae O II HO-P HO — OR, O P OR O-P0R4 O II HO-P — R< Le A 28 306 - 10 IE 921083 in which R2, R3 and R* are identical or different and denote hydrogen or a sodium metal atom, n denotes the number 1 or 2, R5 denotes methyl, ethyl or chloromethyl, and their physiologically acceptable salts.

Processes for the preparation of the compounds of the general formula (I) according to the invention were additionally found, characterised in that [A] either 5-trifluoromethyluracil of the formula (II) or compounds of the general formula (III) Le A 28 306 (III) in which R6 represents one of the abovementioned silylhydroxyl protective groups, preferably trimethylsilyl, are first reacted with compounds of the general formula (IV) in which R7 represents one of the abovementioned hydroxyl protective groups, T represents a typical leaving group such as acetoxy, bromine, chlorine, iodine, azido, 4-nitrophenoxy, brosylate, tosylate, mesylate, Le A 28 306 trifluoromethanesulphonate or fluorosulphonate, preferably bromine, chlorine or acetoxy, in inert solvents, if appropriate in the presence of a base and/or of an auxiliary, to give compounds of the general formula (Ia) in which R7 has the abovementioned meaning, and which are either present as an α,/3-isomer mixture or 10 as a- and ^-isomers, or [B] either the compounds of the general formula (III) are reacted with the compounds of the general formula (IVa) Le A 28 306 (IVa) in which R7 and T have the abovementioned meaning, or 1-(£-D-ribofuranosyl)-5-trifluoromethyl-uracil of the formula (V) is reacted with compounds of the general formula (VI) R7-W (VI) Le A 28 306 R7 has the abovementioned meaning and in which W has the abovementioned meaning of T and is identical 5 to or different from this, in inert solvents, if appropriate in the presence of a base and/or of an auxiliary, and in the case of the compound of the formula (V) with simultaneous blocking of the vic-hydroxyl functions and/or of the primary hydroxyl function, and subsequent liberation of the vic-hydroxyl functions to give the compounds of the general formula (VII) (VII) in which R7 has the abovementioned meaning, Le A 28 306 and in a next step, by reaction with 1,1'-thiocarbonyldiimidazole or dimethyl orthoformate, these are converted into the corresponding 1,4-acetals or 1,3-thiocarbonates of the general formula (VIII) (VIII) in which R8 has the abovementioned meaning of R7 or represents hydrogen and X represents a radical of the formula =S or -OCH3, in inert solvents, in the presence of reducing agents and if appropriate of a catalyst, and in the case where R8 represents hydrogen, in one step, by reaction with acetic anhydride, the primary hydroxyl function is first blocked, the acetal radical is eliminated Le A 28 306 with formation of a double bond and the latter is then hydrogenated by customary methods, and in the case where X represents the radical of the formula =S, then reacted with trialkyl phosphites, such as trimethyl, triethyl or tripropyl phosphite, preferably with triethyl phosphite, and in the case of the elimination of the 1,3-thiocarbonate radical, first reduced in the presence of reducing agents and of a catalyst, the reaction with 1,1'-thiocarbonyldiimidazole is repeated, and reduction is finally carried out again, or [C] compounds of the general formula (IX) in which R7 has the abovementioned meaning, Le A 28 306 and R9 and R10 are different and represent hydrogen or hydroxyl, are first reacted with 1,1-thiocarbonyldiimidazole or phenylthiocarbonyl chloride by the method described under [B] to give the corresponding thiocarbonyl compounds of the general formula (X) in which R7 has the abovementioned meaning, L represents the radical Le A 28 306 — C-C.H or II s 6π5 and then, as described under [B], the blocked hydroxyl group is eliminated and the primary hydroxyl function is deblocked or in the case where R1 does not represent hydrogen or a phosphoric acid derivative, [D] α,/}-2 ', 3 '-dideoxy-5-trif luorouridine of the formula (lb) Le A 28 306 is reacted with compounds of the general formula (XI) R11-Y (XI) in which R11 has the abovementioned meaning of R1 but does not 5 represent hydrogen or a phosphoric acid derivative and Y has the abovementioned meaning of T and is identical to or different from this, in inert solvents, if appropriate in the presence of a base and/or of an auxiliary, or in the case where R1 represents one of the abovementioned phosphoric acid radicals, the compounds of the general formula (lb) are first phosphorylated with phosphorus trichloride, trisimida15 zolylphosphine or phosphorus oxychloride and then if appropriate with tributylammonium diphosphate or with compounds of the general formula (XII) O Rli- P(Z)2 (XII) Le A 28 306 in which R12 represents a radical of the formulae O ii HO - P — OR, O HO —PORr f Ο λ O- p 0 II HO - P — I R< in which R2, R3, R4, R5 and n have the abovementioned meaning, and Z represents halogen, preferably chlorine, in inert solvents, if appropriate in the presence of a base and of an alkali metal halide, such as, for example, sodium iodide, according to a customary method, and in the case of the free hydroxymethyl function (R1 = H), the respective protective group is eliminated according to a customary method and/or a chromatographic separation is optionally carried out.

The processes according to the invention can be illustrated 15 by way of example by the following reaction scheme: Le A 28 306 [A] CH, V HN. cf, Le A 28 306 [A) B. O-Bixtux·. laparation CHjOH / NH3 Le A 28 306 [A] CH, (CH,)C-Si -O CH, Cl ♦ r.t -► CH,CN / KOH / TDA-1 0, CL-mixture separation TDA-1: N(CHjCH,OCHjCHjOCH,)j tris-[2-{2-methoxyethoxy)eeiylJ«mln· Le A 28 306 [Β] C4H5-COO OCOCH, C.Hj-COO OCO-C.H (CH3),SO (CHjJjSIOSOjCF, --► CH,CN 1. ) BUjSnH / toluene AIBN / Δ 2. ) TCDI/CH3CN 3. ) BiijSnH / tolura· AIBN ▼ u HO OH TCOI: 1,1’-Thlocarbonyldlmiduol·: c=s Le A 28 306 [Β] 1. DMTr.-Cl, bau -> 2. TCDI/CH,CN S 1. Bu,SnrjA°J-“«i^AIBN / Δ 2. TCDI / CH,CN 1' 3. BujSnb^olurayAIBN / Δ OCH, DMTr-CI - CjHj-C-CI OCH, Le A 28 305 Le A 28 306 [CJ 1. C,HjCOCI / pyr Idin·· -► 2. TCDI/CH3CN S or BujSn-H toluan· AIBN / Δ (Bu3Sn)jO i Dioran· AIBN / Δ V o NH3 Z CHjOH ◄- Le A 28 306 [D] Le A 28 306 (D) 1. POCI, / PO(OCH,), ->. 2. (8ujNH)t P2OrHj / DMF 3. EtjNH* HCOO' 4. Nal / »c»ton· O [D] CF, 1. H3C-POCI2 / PO(OCH,), -► 2. NaOH / pH 7.5 Le A 28 306 [D] The processes for the preparation of the compounds of the general formula (I) according to the invention are partially carried out in analogy to those methods known Le A 28 306 from the literature listed in the following [cf. M. Okabe et al., J. Org. Chem. 53., 4780 (1980); V. Farina et al. , THL 29, 1239, (1988); F. Seela et al., Heterocycles 29, 2193 (1989); R.R. Webb et al., Nucleosides Nucleotides T_, 147 (1988); EP 357,495; EP 199,451; EP 362,967; L. Vrang et al., Antiviral Res. 7, 139 (1987); EP 366,385; EP 357,495; J.S. Driscoll, J. Med. Chem. 30, 862 (1987); H. Shiragami, J. Org. Chem. .53, 5170 (1988)].

Suitable solvents for process variants [A] - [D] accord10 ing to the invention are inert organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloromethane or tetrachloromethane, or amides such as dimethylformamide, dimethylacetamide or hexamethylphosphoric triamide, or hydrocarbons such as benzene, toluene or xylene, or acetonitrile, nitromethane, sulpholane, dimethyl sul20 phoxide, ethyl acetate, or alcohols such as methanol, ethanol, isopropanol, propanol or butanol, ethylene glycol or pyridine. Mixtures of the solvents mentioned can also be used. Methylene chloride and acetonitrile are preferred for process variant [A], pyridine and dimethyl25 formamide for process variants [B] and [C] and dimethylformamide and dimethyl phosphate for process variant [D].

Suitable auxiliaries for the reaction with the compounds of the general formula (IV) or (IVa) are, for example, Le A 28 306 trimethylsilyl trifluoromethanesulphonate or trimethylsilyl trifluoroacetate or Lewis acids such as, for example, tin(IV) chloride, titanium(IV) chloride, aluminium(III) chloride, mercury (II) chloride or zinc(II) chloride. Trimethylsilyl trifluoromethanesulphonate, tin(IV) chloride, titanium(IV) chloride, aluminium(III) chloride or mercury(II) chloride are preferred.

The auxiliaries are in general employed in an amount of 0.1 mol to 2.0 mol, preferably in molar amounts relative to 1 mol of the compounds of the general formulae (IV) and (IVa).

Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates such as sodium carbonate or potassium carbonate, or alkali metal alkoxides such as, for example, sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide, or organic amines such as triethylamine, pyridine, picoline, N-methylmorpholine, N-methylpiperidine, or tris-[2-(2methoxyethoxy)ethyl]amine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or ammonium sulphate.

The bases are in general employed in an amount from 1.0 mol to 3 mol, preferably from 1.0 mol to 1.2 mol, in each case relative to 1 mol of the compounds of the general formulae (IV), (IVa), (VI) or (IX).

Le A 28 306 The reaction temperatures can be varied within a broad range with respect to the particular process step. In general, the reaction is carried out in a range from -40°C to +170’C, preferably from -40°C to +150eC.

All reactions in processes [A] to [D] can be carried out at normal, elevated or at reduced pressure. The reactions are preferably carried out at a pressure of 0.5 to 5 bar.

The elimination of the silylhydroxyl protective groups (R6, if appropriate R7) in the compounds of the general formulae (III), (Ia) and (VII) is carried out by customary methods, for example under the action of fluorine salts such as, for example, tetrabutylammonium fluoride, if appropriate in the presence of acetic acid and/or in one of the abovementioned solvents, preferably in tetra15 hydrofuran, or in alcohols, preferably methanol, in the presence of p-toluenesulphonic acid.

The fluorine salts are employed in an amount from 1 to 3 mol and the acetic acid in an amount from 1 to 5 mol, in each case relative to 1 mol of the compounds of the general formulae (III) and (Ia).

In the case where R7 together with the oxygen atom forms an ester radical, the elimination is in general carried out in one of the abovementioned alcohols, such as methanol or ethanol, preferably in methanol in the presence of ammonia.

Le A 28 306 Th eliminations are preferably carried out in a temperature range from -10’C to +30 eC and under normal pressure.

Tin hydrides, such as, for example, tributyltin hydride, triphenyltin hydride or tin oxides such as, for example, tetrabutyltin oxide are suitable for reducing the compounds of the general formulae (VIII) and (X). Tributyltin hydride and tetrabutyltin oxide are preferred.

The reduction is carried out in one of the abovement ioned solvents, preferably in dioxane or toluene.

Suitable catalysts for the reduction are, for example, azobisisobutyronitrile (AIBN) and dibenzoyl peroxide. Azobisisobutyronitrile (AIBN) is preferred.

The catalyst is in general employed in an amount from 0.005 mol to 0.5 mol, preferably from 0.01 mol to 0.05 mol, in each case relative to 1 mol of the compounds of the general formulae (VIII) and (X).

The hydrogenation is carried out in one of the abovementioned alcohols, for example methanol, ethanol or propanol in the presence of a noble metal catalyst such as platinum, palladium, palladium on animal charcoal or Raney nickel, in a temperature range from 0eC to +50°C, preferably from room temperature to +40‘C at normal or elevated pressure.

Le A 28 306 Besides the abovementioned solvents, suitable solvents for the preparation of the corresponding mono-, di- or triphosphates and alkyl phosphonates [D] of the compounds of the general formula (I) according to the invention are also phosphoric acid esters such as, for example, trimethyl phosphate or triethyl phosphate.

Suitable bases for establishing a pH of 7.5 are preferably alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.

For the preparation of the phosphates, triethylammonium hydrogen carbonate is preferably employed as a buffer.

In the case of the preparation of the triphosphates of the general formula (I), the dichlorophosphate intermediate formed in the reaction with phosphorus oxy15 chloride is not hydrolysed to the monophosphate, but reacted directly with bis (tributylammonium) pyrophosphate to give the corresponding triphosphate.

The reactions of the compounds of the general formula (VIII) (X = =S) with trialkyl phosphites is carried out in analogy to methods known from the literature (cf. J. Org. Chem. 1989, 54, 4780).

The elimination or the replacement of hydroxyl protective groups and amino protective groups is in general carried out by customary methods, such as are described, for example, in Greene, Protective Groups in Organic Le A 28 306 Synthesis, John Wiley & Sons, 1981, 10 ff and 218 ff.

The preparation of the compounds of the general formula (I) according to the invention, in which R1 represents an amino acid radical [D], is carried out by elimination of the respective protective group, if appropriate with activation of the corresponding acid and esterification with the free hydroxymethyl function by the methods customary in peptide chemistry [cf. HoubenWeyl, Eugen Muller, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume XV/1 and XV/2, Georg Thieme Verlag, Stuttgart, 1974]. l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is preferably employed as the base in this case.

-Trifluoromethyluracil of the formula (II) is known.

The compounds of the general formula (III) are known per se or can be prepared by a method known from the literature (cf., for example, Khim Geterotsikl. Soedin, (8), 1128-31, (1), 101-10 and THL, 22 (11), 1029-32].

The compounds of the general formulae (IV) and (IVa) are known per se or can be prepared by processes known from the literature [cf., for example, J. Org. Chem. 53., 4780 (1988); THL 2£, 1239 (1988) and Heterocycles 2£, 2193 (1989); Khim. Geterotsikl. Soedin (1), 101-10 and (8), 1128-31] .

The compounds of the general formulae (Ia) and (lb) are Le A 28 306 new and can be prepared by the processes mentioned above.

The compounds of the general formulae (V) , (VII) and (IX) are known per se or can be prepared by a customary method [cf. J. Med. Chem. 30 (2), 440-4; JP 63,188,696].

Some of the compounds of the general formula (X) have been previously described in the case where L represents the radical -(C=S)-C6H5 (cf. JP 028,408) or are new and can then be prepared by the abovementioned process.

The compounds of the general formula (VI) are known [cf. Anal. Biochem. 60 , 608 (1974); MSD Book 2, 371 A].

The compounds of the general formulae (XI) and (XII) are known [cf. Houben-Weyl, Eugen-Miiller, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume XV/1 and XV/2, Georg Thieme Verlag, Stuttgart 1974 and Amino Acids, G.C. Barrett, London, New York, Chapman and Hall 1985] .

It has surprisingly been found that the compounds of the general formula (I) according to the invention have an extremely strong specific action against the hepatitis B Le A 28 306 virus (HBV). Detection was carried out in hepatoma cells (HEP G2.2.15) transfected with hepatitis B virus DNA.

The results of the examples listed below were determined for the HBV test system described in the following literature reference [Sells, M.A.; Chen, M.L., Acs, G., Proc. Natl. Acad. Sci. USA pp. 1005 - 1009, Vol. 84 (1987)]: Transfected hepatoma cells (HEP G2.2.15) were incubated with various concentrations of the respective compound.

By treatment of the transfected hepatoma cell line HEP G2.2.15 with the compounds according to the invention, it was possible to show the occurrence of virusspecific HBV DNA in the supernatant as well as a reduction in the HBsAg level. It was further found that the compounds according to the invention lead to a reduction of the replicative intermediates of the hepatitis viruses. The content of HBV DNA was determined in the supernatant of the cell cultures after PEG precipitation. This was carried out using a non-radioactively labelled HBV genomic DNA sample [Pauly, P., 1982, P.H.D. Thesis, University of Gbttingen, F.R.G.? KSchel et al., 1990, EMBL, Accession No. X 51790]. Determination of the influencing of HB,Ag formation was simultaneously carried out by means of a commercially available Elisa test. The IC5O values given relate to the substrate concentrations which, under the abovementioned test conditions, cause a 50 % inhibition of the HBV DNA concentration in the supernatant.

Le A 28 306 Ex. No.

IC50inMjL 0.01 5 > 0.25 The possibly present cytotoxic influence of the compounds 5 according to the invention took place simultaneously by means of crystal violet colouration or via the incorporation of radioactively labelled thymidine into the cellular DNA.

In comparison thereto, the substances DDA and DDC known 10 from the literature (cf. Ueda et al., Virology 169: 213-216 (1989) show the following IC50 values in the abovement ioned test system: DDA > 100 μπι and DDC = 5 μΐη.

The action of Example 2 on other cells was tested by incubation of HEL and MEF cells. No affect on the viabil15 ity of these cells was shown up to a concentration of 250 μΜ.

The compounds according to the invention are useful active substances in human medicine for the treatment of virus-induced hepatitis, caused by Hepdna viruses, such as hepatitis B viruses, hepatitis C viruses or hepatitis delta viruses, in particular hepatitis B viruses.

Examples of indication areas which can be mentioned in human medicine are: Le A 28 306 The treatment of chronic hepatitis B, C and delta virus infections and the treatment of acute hepatitis B, C and delta virus infections, in particular of chronic and acute hepatitis B virus infections.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active substances of the formula (I), and processes for the production of these preparations.

The active substances of the formula (I) should be present in the abovementioned pharmaceutical preparations, preferably in a concentration of about 0.1 to 99.5 % by weight, preferably of about 0.5 to 95 % by weight of the total mixture.

Apart from the compounds of the formula (I), the abovementioned pharmaceutical preparations can also contain further pharmaceutical active substances.

The abovementioned pharmaceutical preparations are 20 prepared in a customary manner by known methods, for example by mixing the active substance or substances with the excipient or excipients.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active substance or substances according to the invention in total amounts Le A 28 306 of about 0.5 to about 500, preferably 1 to 100, mg/kg of body weight per 24 hours, if appropriate in the form of several individual doses, to achieve the desired results.

An individual dose contains the active substance or substances preferably in amounts from about 1 to about 80, in particular 1 to 30, mg/kg of body weight. However, it may be necessary to depart from the dosages mentioned, in particular depending on the nature and the body weight of the subject to be treated, the nature and the severity of the disease, the type of preparation and of administration of the medicament and the time or interval within which administration takes place.

Starting compounds Example I 1-(2,3,5-Tri-O-benzoyl-M-D-ribofuranosyl) -5-(trifluorome t hy l)-ur ac i 1 O Le A 28 306 A stirred suspension of 5.0 g (27.8 mmol) of 5-(trifluoromethyl ) uracil in 139 ml (0.66 mol) of hexamethyldisilazane was treated with 211 mg (1.39 mmol) of anhydrous ammonium sulphate and heated to reflux for 5 h -under an atmosphere of nitrogen. The hexamethyldisilazane was then distilled off in a slight vacuum and the residue was dissolved in 370 ml of anhydrous acetonitrile. 13.31 g (26.40 mmol) of l-0-acetyl-2,3,5-tri-0-benzoyl0-D-ribofuranose were added, the mixture was cooled to 0°C and 7.0 ml (36.14 mmol) of trimethylsilyl trifluoromethanesulphonate were added dropwise in the course of 30 min. The cooling bath was removed, and the reaction solution was subsequently stirred at room temperature for a further 1 h. It was then stirred into a cold mixture of 170 ml of saturated NaHCO3 solution and 200 ml of ethyl acetate. The phases were separated and the water phase was extracted with 2 x 200 ml of ethyl acetate. The combined extracts were dried over MgSO<,, the solvent was evaporated in vacuo and the residue was chromatographed on 200 g of silica gel (toluene : ethyl acetate 4:1). .3 g (88 %) of the title compound were obtained as a colourless foam.

Rf = 0.35 (toluene : ethyl acetate 4:1) MS (FAB) m/z = 625 (M+H)+ Le A 28 306 Example II 1-( 5-O-Benzoyl-^-D-ribofuranoyl) -5-{trif luoromethyl)-uracil CF, In analogy to S.N. Shino et al., Tetrahedron 41, 5503 (1985), 10.90 g (17.50 mmol) of the dried compound from Example I were added in portions to a stirred suspension of 2.36 g (43.6 mmol) of sodium methoxide in 200 ml of anhydrous THF at O’C. The cooling bath was removed, and the reaction mixture was subsequently stirred at O’C for 1 h and neutralised (pH 6.5) by addition of Dowex 50 W-X 4 ion exchanger (H* form) . The ion exchanger was removed by filtration and washed with 3 x 20 ml of ethanol. The filtrate was concentrated to dryness in vacuo and chromatographed on 285 g of silica gel (dichloromethane : methanol 95:5). 4.48 g (62 %) of the title compound were obtained as colourless crystals, m.p.: 186’C Rf = 0.40 (dichloromethane : methanol 9:1) MS (FAB) m/z = 417 (M+H)+ Le A 28 306 Example III l-(5'-0-Benzoyl-0-D-ribofuranosyl)-5-trifluormethyl-uracil 2' ,3'-thionocarbonate C6H5-COO CF, A solution of 3.33 g (8.0 mmol) of the compound from Example II in 150 ml of anhydrous acetonitrile was treated in portions with 3.60 g (18.16 mmol) of 1,1'thiocarbonyldiimidazole and stirred at room temperature for 2 h. The solvent was then evaporated in vacuo and the residue was purified by filtration on 100 g of silica gel (toluene : ethyl acetate 3:2). 3.26 g (89 % of theory) of the title compound were obtained as a colourless powder, m.p.: 133°C (dec .) R IR { = 0.71 (ethyl acetate) MS KBr)= 3188, 1270, FAB) m/z = 459 3073 , 1144, M + H) + 1469 1697 , 1097 , 475 (M + Na 1012 , + 1379, 1326, 720 cm'1.

Le A 28 306 - 45 IE 921083 Example IV '-O-Benzoyl-2',3'-didehydro-2',3'-dideoxy-5-(trifluoromethyl )-uridine 3.00 g (6.55 mmol) of 1-(5'-O-benzoyl-^-D-ribofuranosyl)5 5-trifluoromethyl-uracil-2',3'-thionocarbonate (Example III) were added in one portion to 75 ml (66 equiv.) of freshly distilled triethyl phosphite preheated to 130“C under a nitrogen atmosphere and the mixture was heated at 130°C (exactly!) for 1.5 h. The reaction mixture was then cooled, 10 ml of toluene were added and it was concentrated to dryness on a rotary evaporator. This process was repeated twice more in order to remove the last residues of triethyl phosphite. 20 ml of ether were added to the still toluene-moist residual crystal magma, and it was well stirred, filtered off with suction, washed with a little ether and dried over Sicapent in a high vacuum. A further quantity of the title compound was obtained by concentration of the Le A 28 306 filtrate. Total yield 1.59 g (63 %) of colourless crystals. A further 230 mg (9 %) of the title compound were obtained by chromatography of the mother liquor on 40 g of silica gel (toluene : ethyl acetate 7:3). m.p.: 157°C Rf = 0.24 (toluene : ethyl acetate 7:3) MS (FAB-): m/e = 381 (M-H)'.

IR (KBr): v = 3434, 3181, 3065, 1703, 1462, 1327, 1280, 1147, 1120, 1098, 1043, 708 cm'1 Example V ' -Deoxy-5'-0-(4-methylbenzoyl)-5-(trifluoromethyl)uridine A solution of 290 μΐ (2.20 mmol) of p-toluoyl chloride in 12 ml of pyridine was added dropwise in the course of 2 h to a solution, cooled to O’C, of 593 mg (2.00 mmol) of 2'-deoxy-5-(trifluoromethyl)-uridine (Trif luridin*) in Le A 28 306 ml of anhydrous pyridine under a nitrogen atmosphere.

The mixture was then stirred at 0°C for 15 min and then 10 ml of anhydrous methanol were added dropwise to destroy excess p-toluoyl chloride. The cooling bath was removed and the reaction mixture was concentrated in vacuo and the residue was chromatographed on 85 g of silica gel (dichloromethane s methanol 9:1). 71 % of the title compound were obtained as colourless crystals, m.p.: 214°C Rf = 0.31 (dichloromethane : methanol 9:1) MS (FAB): m/e = 415 (M+H)+ Example VI ' -Deoxy-3 ' -0- ( imidazolyl-thiocarbonyl) -5' -0- (4-methylbenzoyl)-5-(trifluoromethyl)-uridine Le A 28 306 A suspension of 410 mg (0.99 mmol) of the compound from Example V in 15 ml of anhydrous acetonitrile was treated with 353 mg (1.98 mmol) of 1,1'-thionylcarbonyldiimidazole and stirred at room temperature for 25 h. The solvent was evaporated in vacuo without heating and the residue was stirred into a mixture of 10 ml of ethyl acetate, 10 ml of saturated NaCl solution, 5 ml of saturated NaHCO3 solution and 5 g of ice. The organic phase was separated off and the agueous phase was ex10 tracted with 10 ml of ethyl acetate. The combined extracts were dried over MgSO4, the solvent was evaporated in vacuo and the residue was triturated with a little ether. 474 mg (91 %) of thiocarbonylimidazolide were obtained as a colourless powder. m.p.: 87°C Rf = 0.30 (dichloromethane : THF 4:1) MS (FAB) m/e = 525 (M+H)+ IR (KBr): v = 3424, 1700, 1128 cm-1 Le A 28 306 Preparation Examples Example I a , β-5 ' -(tert-Butyldimethylsilyl)-2',3’-dideoxy-5-(trifluoromethyl) -uridine (Anomer mixture) A stirred mixture of 0.54 g (3.0 mmol) of 5-(trifluoromethyl ) -uracil (dried at 80°C for 24 h) and 21.1 ml (100 mmol) of hexamethyldisilazane was heated at 140 °C for 1 h under an atmosphere of nitrogen in the presence of 20 mg (0.15 mmol) of ammonium sulphate. The clear solution was allowed to cool and the volatile constituents were distilled off in vacuo. The residual oil was treated with 5 ml of anhydrous toluene and the volatile constituents were again distilled off in vacuo. The residual oil was dissolved in 40 ml of anhydrous acetonitrile, 0.82 g (3.0 mmol) of l-0-acetyl-5-(tert-butyldimethylsilyl ) -2 ' , 3 ' -dideoxyribose [M. Okabe et al., J. Org. Chem. 53, 4780 (1988)] was added and the mixture Le A 28 306 was cooled to -10 °C. 0.64 ml (3.3 mmol) of freshly distilled trimethylsilyl trifluoromethanesulphonate was added dropwise to this mixture and it was subsequently stirred at -10°C for 30 min. The reaction solution was then stirred into a mixture of 50 ml of saturated NaHC03 solution and 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with 25 ml of ethyl acetate (twice). The combined organic phases were dried over MgSO4. Evaporation of the solvent in vacuo gave 1.15 g (97 %) of the title compound as an oil (mixture of anomers) which was further reacted without further purification.

Rf = 0.83, 0.76 (ethyl acetate) MS (FAB) m/e = 395 (M+H)+.

Example 2 and Example 3 β-2 ' , 3 ' -Dideoxy-5-(trif luoromethyl)-uridine (Example 2) Le A 28 306 α-2 ' , 3 '-dideoxy-5-(trif luoromethyl)-uridine (Example 3) A solution of 1.15 g (3.0 mmol) of the anomer mixture obtained in Example 1 and 628 mg (3.3 mmol) of p-toluenesulphonic acid monohydrate in 8 ml of methanol and 1.2 ml of water was stirred at room temperature for 30 min. 0.84 ml (6.0 mmol) of triethylamine was then added. After evaporation of the solvent in vacuo and chromatography of the residue on 130 g of silica gel (toluene : ethyl acetate 1: 1), 303 mg (36 %) of the non-polar ^-isomer (Example 2) were obtained as colourless crystals, m.p.: 165 °C Rf = 0.46 (ethyl acetate); 0.27 (dichloromethane : methanol 9:1) HPLC purity > 99.5 % MS (DCI, NH3) m/e = 281 (M+H)\ 298 (M+NHJ + IR (KBr): 3466, 3192, 3074, 1706, 1461, 1410, 1334, 1286, 1141, 1092, 1066, 1040, 614 cm'1.

^-NMR (250 MHz, CD3OD) : δ = 1.90 - 2.50 (ra, 4H, H-2', H-3'); 3.70, 3.98 (AB, 2H, J = 12.5 Hz, 2.5 Hz, H-5'); 4.20 (m, 1H, H-4'); 6.01 (dd, 1H, J = 7.0 Hz, 1.5 Hz, Le A 28 306 H-l'); 8.98 (s, IH, H-6).

C10HuF3N2O4 (280.21) Calc.: C 42.87 H 3.96 N 10.00 Found: C 42.7 H 4.0 N 9.9 27 0 mg (32 %) of the polar a-isomer (Example 3) were additionally obtained as a colourless foam.

Rf = 0.36 (ethyl acetate) HPLC purity = 99 % MS (DCI, NH3) m/e = 281 (M+H) + , 298 (M+NH«) + 10 IR (KBr): 3448, 612 cm1 1702, 1473, 1412, 1334, 1276, 1129,1H-NMR (250 MHz, CD3OD) :6 = 1 .85 - 2.00 (m, 3H, H-2', H-3'); 2.51(m, IH, H-2'); 3.54 (dd, IH, J = 12.5 Hz, Hz, H-5'); 3.66 (dd, IH, J = 12.5 Hz, 3.5 Hz, H-5'); 4.50 (m, IH, H-4'); 6.00 (dd, IH, J = 6.5 Hz, 5.5 Hz, H-l'); 8.00 (s, IH, H-6).

The compound from Example 2 can additionally be prepared as follows: 150 mg (0.4 mmol) of 5'-0-benzoyl-2',3'-dideoxy-5-tri20 fluoromethyluridine were added to a solution of 25 mg (0.45 mmol) of sodium methoxide in 11 ml of anhydrous methanol and the mixture was stirred at room temperature for 1.6 h. The reaction mixture was then neutralised by addition of Dowex 50 X 4 ion exchanger (H+ form), the ion exchanger was removed by filtration and the filtrate was evaporated to dryness in vacuo. By trituration with ether/pentane, 104 mg (93 %) of the title compound were obtained as colourless crystals.

Le A 28 306 m.p.: 165’C Example 4 β-5' -(2,2-Dimethylpropanoyloxymethyl)-2',3'-dideoxy-5(tri f luoromethyl) - u r i d i n e (H3C)3c A solution of 150 mg (0.54 mmol) of ^-2',3'-dideoxy-5trifluoromethyluridine in 10 ml of anhydrous DMF was slowly added dropwise to a stirred suspension, cooled to 0°C, of 18 mg (0.59 mmol) of sodium hydride (80 % strength in oil) in 1 ml of anhydrous DMF. After evolu10 tion of hydrogen had ended (about 2 h) , a solution of mg (0.59 mmol) of pivaloyloxymethyl chloride in 1 ml of anhydrous DMF was added, the cooling bath was removed and the mixture was subsequently stirred at room temperature for 70 h. The largest part of the solvent was evaporated in vacuo, care being taken that the temperature did not exceed 35°C. The residue was taken up in a mixture of 10 ml of water and 10 ml of ethyl acetate. The organic phase was separated off and the water phase was Le A 28 306 extracted with 10 ml of ethyl acetate (twice) and the combined organic extracts were dried over MgSCh,. After evaporation of the solvent in vacuo and chromatography of the residue on 24 g of silica gel (toluene : ethyl acetate 7:3), 134 mg (66 %) of the title compound were obtained as a colourless foam.

Rf = 0.58 (ethyl acetate) MS (DCI, NH3) m/z = 395 (M+H)+, 412 (M+NH^p IR (KBr): γ = 3530, 2983, 1737, 1685, 1473, 1288, 1133, 785 cm'1.

Example 5 /3-5 ' - ( 1-Ethoxycar bo ny loxy-et h-1-yl) -2 ' , 3'-d i deoxy-510 (trif luoromethyl) - u r i d i ne As described for Example 4, 62 mg (47 %) of the title compound were obtained from 100 mg (0.36 mmol) of /32 ' , 3 ' -dideoxy-5-(trif luoromethyl) - ur i d i ne and 62 mg (0.40 mmol) of 1-chloro-l-ethoxycarbonyloxyethane after chromatography of the crude product on 8 g of silica gel (toluene : ethyl acetate 1:1) as colourless crystals, m.p.: 114 °C Rf = 0.33 (toluene: ethyl acetate 1:1) MS (DCI, NH3) m/z = 353 (Cj3HT5F3N^Og+ H ) + , 3 70 (M + NH4) + IR (KBr)3019, 1704, 1277, 1220, 1212 cm1.

Le A 28 306 Example 6 0-5-Hemisuccinyl-2 ', 3 ’ -dideoxy-5-(trif luoromethyl) -uridine A solution of 100 mg (0.36 mmol) of £-2',3'-dideoxy-5trifluoromethyluridine in 4 ml of anhydrous pyridine was treated with 54 mg (0.54 mmol) of succinic anhydride and the mixture was stirred at room temperature for 65 h. After evaporation of the solvent in vacuo and chromatography of the crude product on 30 g of silica gel (dichloromethane : methanol 9:1), 96 mg (70 %) of the title compound were obtained as a pale solid.

Rf = 0.19 (dichloromethane : methanol) MS (FAB) m/z = 381 (M+H)+.

Le A 28 306 Example 7 ' -O- [ (tert-Butoxycarbonyl)-L-leucyl)]-2',3'-dideoxy-5(tri fluoromethyl) -u r i d i ne A stirred solution of 150 mg (0.54 mmol) of β-2',3'5 dideoxy-5-trifluoromethyluridine and 634 mg (1.08 mmol) of (tert-butoxycarbonyl)-L-leucine-4-nitrophenyl ester [Houben-Weyl 15/2 p. 33] in 3 ml of anhydrous DMF was treated with 162 pi (1.08 mmol) of DBU and stirred at room temperature for 48 h. The solvent was then largely evaporated in vacuo and the residue was taken up in 40 ml of ethyl acetate. The organic phase was washed with 20 ml each of 10 % strength Na2CO3 solution, water and saturated NaCl solution and dried over MgSO,,. After evaporation of the solvent in vacuo and chromatography of the residue on 40 g of silica gel (toluene : ethyl acetate 1:1), 195 mg (73 %) of the title compound were obtained as a colourless foam.

Rf = 0.69 (ethyl acetate) MS (FAB) m/z = 494 (M+H)+ IR (KBr): p = 2965, 1703, 1470, 1369, 1275, 1162, 1091 , 1036 cm'1.

Le A 28 306 - 57 η- λ Rf = 0.69 (ethyl acetate) Example 8 ' -0- (L-Leucyl) -2 ' , 3 ' -dideoxy-5-(trif luoromethyl) -uridine hydrochloride CH3 A stirred suspension, cooled to +5°C, of 99 mg (0.2 mmol) of the compound from Example 7 in 1 ml of anhydrous dioxane was slowly treated with 1 ml of a 4 N solution of gaseous hydrogen chloride in anhydrous dioxane and stirred at +5°C for 30 min and at room temperature for 4 h. 5 ml of toluene were then added and the mixture was concentrated in vacuo. This process was repeated, then the residue was triturated with 5 ml of ether, filtered off with suction and dried over KOH in a high vacuum. 76 mg (96 %) of the title compound were obtained as a colourless powder.

Rf = 0.44 (acetonitrile : water 9:1) MS (FAB) m/z = 394 (M+H)+ IR (KBr): = 3433, 2965, 1701, 1472, 1413, 1276, 1132, 1090, 1038, 616 cm'1.

Le A 28 306 Example 9 ' , 3 ' -Dideoxy-5-(tri fluoromethyl) -uridine-51- mono-phosphate sodium salt A suspension, cooled to -10°C, of 100 mg (0.36 mmol) of β-2 ', 3 '-dideoxy-5-(trifluoromethyl)-uridine (Example 2) in ml of trimethyl phosphate was treated with 67 μΐ (0.71 mmol - 2 equiv.) of phosphorus oxychloride and stirred at 0°C for 24 h. It was then poured into 10 ml of ice-water and a pH of 7.5 was established using 2 N NaOH.

The aqueous solution was freed of organic material by extraction with dichloromethane and ether, concentrated in vacuo to a volume of about 1 ml and chromatographed on 40 ml of Diaion HP-20 (water). The product-containing fractions were collected, freeze-dried, taken up in 1 ml of water and chromatographed on a Lobar ready-to-use column size B (310-25) Lichroprep., RP-8 (40-63 gm) with water. The product-containing fractions were collected and freeze-dried. 129 mg (93 %) of the title compound Le A 28 306 were obtained as a colourless lyophilisate.

Rf = 0.33 (acetonitrile : water 8:2) IR (KBr): f = 3430, 1702, 1066, 860, 545 cm'1.

Example 10 ', 3 ' -Dideoxy-5-(trif luoromethyl)-uridine-5 ' -triphosphate, 5 trisodium salt O O II ll HO - P · O - P · O I I ONa ONa A solution, cooled to O’C, of 150 mg (0.54 mmol) of 2 ', 3 ' -dideoxy-5-(trifluoromethylj-uridine (Example 1) in 1 ml of trimethyl phosphate was treated with 0.11 ml (1.2 mmol) of phosphorus oxychloride and stirred at O’C for 18 h. 0.57 ml (2.40 mmol) of tributylamine and 6.7 ml (2.70 mmol) of a 0.4 M solution of bis-(tributylammonium)pyrophosphate [D.E. Hoard et al., J. Am. Chem. Soc., 87, 1785 (1965)] were then added dropwise at 0°C in DMF. After 25 min at O’C, the reaction was discontinued by addition of 9 ml of 1 M aqueous tributylammonium hydrogen carbonate (TEAB) buffer and a pH of 7.4 was established. The water phase was extracted with 5 x 50 ml of dichloromethane and then the mixture was adjusted to Le A 28 306 pH 1.5 by addition of 4 ml of Dowex 50 W-X 4 (H+ form).

The ion exchanger was removed by filtration and the clear filtrate solution was chromatographed on 40 ml of Sephadex A 25 (Pharmacia), which was equilibrated with 0.1 Μ TEAB. The column was eluted with an increasing gradient (0.1 M per 20 ml of eluate) of TEAB buffer of 0.1 M to 0.5 M. The product-containing fractions were concentrated to dryness on a rotary evaporator, treated with a little methanol and again concentrated to dryness.

This process was repeated a further 5 times, then a solution of the crude product in 3 ml of methanol was treated with 3 ml (3 mmol) of a 1 M solution of sodium iodide in acetone, as a result of which the triphosphate precipitated as the sodium salt. The precipitate obtained was washed a further 3 times with 5 ml of acetone (centrifuge) and then dried over P4O10 (phosphorus pentoxide) in a high vacuum. 169 mg (54 % of theory) of the title compound were obtained as a colourless solid. Rf = 0.18 (acetonitrile : water 4:1) IR (KBr):y= 3433, 1706, 1478, 1277, 1103, 997, 896, 769 cm1.

Le A 28 306 Example 11 ' , 3 ' -Dideoxy-5-{tri fluoromethyl)-uridine:-5 ' -methylphosphonate A solution, cooled to 0eC, of 100 mg (0.36 nunol) of 5 2',3'-dideoxy-5-trifluoromethyluridine (Example 1) in ml of trimethyl phosphate was treated with 71 mg (0.54 mmol) of methanephosphonyl dichloride and allowed to stand at -22 °C for 28 h. The reaction mixture was then treated with 8 ml of anhydrous dichloromethane, added to ml of cold water and adjusted to a pH of 8.0 by addition of IN NaOH solution. The water phase was extracted several times with dichloromethane and then freeze-dried. After chromatography of the crude product on Diaion HP 20 (water) and freeze-drying of the product15 containing fractions, 63 mg (48 %) of the title compound were obtained as a colourless lyophilisate.

Rf = 0.32 (acetonitrile : water 4:1) IR (KBr):y= 3448, 1629, 1467, 1201, 1029, 949, 808 cm'1 MS (SIMS) m/z = 369 (M+Na)+.

Le A 28 306 Example 12 β-2 ' , 3 ' -Dideoxy-5-(trif luoromethylj-uridine sodium salt A solution of β-2',3'-dideoxy-5-trifluoromethyl-uridine in 10 ml of THF was added dropwise to a stirred suspension, cooled to 0°C, of 105 mg (3.50 mmol) of sodium hydride (80 % in oil) in 5 ml of anhydrous THF. The cooling bath was removed and the mixture was stirred until evolution of gas was complete (about 10 min.). The solvent was then evaporated in vacuo and the residue was dissolved in ml of distilled water. The water phase was extracted with 10 ml of ethyl acetate (3 times), freed of solvent residues in vacuo, filtered through a Millipore membrane filter (0.22 μ) and freeze-dried. 971 mg (90 %) of the title compound were obtained as a colourless, highly water-soluble lyophilisate.

R£ = 0.46 (ethyl acetate) HPLC purity: > 99 % Le A 28 306 Example 13 ' -O-Benzoyl-2 ' , 3 ' -dideoxy-5-(trif luoromethy l)-uridine O CF, Other preparation possibilities: Method A: 410 mg (1.07 mmol) of the compound from Example IV were added in one portion to a suspension of 120 mg of prehydrogenated palladium on carbon (10 %) in 40 ml of THF (p.a.) and the mixture was hydrogenated for 1 h at 20°C and 1 atm of hydrogen (if required, a further 60 mg of the catalyst are added and the mixture is hydrogenated for a further 1 h at room temperature). After conclusion of the reaction (TLC), the catalyst was removed by filtration on about 10 g of kieselguhr washed with THF, the filtrate was concentrated in vacuo and the residue was chromatographed on 25 g of silica gel (toluene : ethyl acetate 3:2). 304 mg (74 %) of the title compound were obtained as a colourless foam which crystallised Le A 28 306 slowly from ether/pentane. m.p.: 93°C Rf = 0.35 (toulene : ethyl acetate 3:2); Rf = 0.56 (ethyl acetate) MS (DCI, NH3): m/e = 385 (M+H) + , 402 (M+NHJ + IR (KBr): υ = 3222, 3084, 1722, 1466, 1412, 1278, 1124, 1084, 1037, 713 cm*1 Method B: A suspension of 0.92 g (2.00 mmol) of the compound from example III 10 in 50 ml of anhydrous toluene was treated with 44 mg (0.27 mmol) of a, a' -azoisobutyronitrile and 3.90 ml (14.50 mmol) of tri-n-butyltin hydride and heated to reflux for 15 min. After cooling, the reaction mixture was concentrated to dryness in vacuo and the residue was filtered on 60 g of silica gel (toluene : ethyl acetate 1:1). 494 mg (62 % of theory) of a mixture of 1-(5-0benzoyl-2- and -3-deoxy-^-D-ribofuranosyl)-5-trifluoromethyluracil were obtained as a colourless powder.

Rf = 0.46 (ethyl acetate) IR (KBr): υ = 3393, 3062, 1720, 1677, 1482, 1282, 1122, 1056, 710 cm'1 This product was dissolved in 17 ml of anhydrous acetonitrile, treated with 429 mg (2.40 mmol) of 1,1'-thiocarbonyldiimidazole and stirred at room temperature for h. The solvent was evaporated in vacuo and the residue was chromatographed on 44 g of silica gel (toluene : ethyl acetate 1:1). 417 mg (68 % of theory) of the Le A 28 306 corresponding thiocarbonylimidazolide were obtained as a colourless foam.

Rf = 0.35 (ethyl acetate) MS (FAB) m/e = 511 (M+H)+ IR (KBr): υ = 1700, 1468, 1394, 1338, 1279, 1189, 1115, 1040, 970, 752, 710 cm'1 This product was suspended in 3 ml of anhydrous toluene, treated with 4 mg (0.02 mmol) of a,a'-azoisobutyronitrile and 293 pi (1.09 mmol) of tri-n-butyltin hydride and heated to reflux for 30 min. After cooling, the solvent was evaporated in vacuo and the residue was chromatographed on 250 g of silica gel (toluene : ethyl acetate 1:1). 262 mg (85 % of theory) of the title compound were obtained as a colourless foam. The physical data were identical with those of the compound obtained according to Method A.

Example 14 ', 3 ’ -Dideoxy-5'-0-(4-methylbenzoyl)-5-(trifluoromethyl)uridine Le A 28 306 A suspension of 347 mg (0.66 mmol) of the compound from Example VI in 15 ml of anhydrous toluene was treated with mg (0.09 mmol) of α,α'-azoisobutyronitrile and 1.30 ml (4.80 mmol) of tri-n-butyltin hydride and heated to reflux for 30 min. After cooling, the reaction mixture was concentrated to dryness in vacuo and the residue was filtered on 20 g of silica gel (toluene : ethyl acetate 3:2). 243 mg (70 % of theory) of the title compound were obtained as a colourless foam.

Rf = 0.30 (toluene : ethyl acetate 3:2) IR (KBr): u = 3422, 1720, 1466, 1281, 1123, 753, 616 cm1 MS (FAB) m/e = 399 (M+H)+

Claims

1. Patent Claims

1. 2',3'-Dideoxy-5-trifluoromethyluridines of the general formula (I) in which R 1 represents hydrogen or a hydroxyl protective group, represents 4-methylbenzoyl or straight-chain or branched acyl having up to 18 carbon atoms, which is optionally substituted by carboxyl, represents an amino acid which is optionally substituted by an amino protective group customary in peptide chemistry, represents an ester radical which can be cleaved in vivo, or represents a radical of the formulae Le A 28 306 68 IE 921083 II HO - Ρ OR 2 ο HO — Ρ — Ο - Ρ OR, 0R < II HO - Ρ — in which R 2 , R 3 and R* are identical or different and denote hydrogen or an alkali metal or alkaline earth metal atom, n denotes the number 1 or 2, R 5 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by halogen, and their physiologically acceptable salts.

2. Compounds of the general formula (I) according to Claim 1, in which R 1 represents hydrogen, tert-butyldimethylsilyl, trimethylsilyl, triphenylmethyl, benzoyl, 4-methylbenzoyl or acetyl, or represents straight-chain or branched acyl having up Le A 28 306 to 16 carbon atoms, which is optionally substituted by carboxyl, or represents leucine (Leu), valine (Val), isoleucine (lie), phenylalanine (Phe), aspartic acid (Asp) or glutamic acid (Glu), which are optionally substituted on the NH function by tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z), or represents an ester radical which can easily be cleaved in vivo, of the formulae (CH 3 ) 3 C-CO-O-CH 2 - , CH 3 -CO-O-CH-CH 3 CH 3 -CH 2 O-CO-O-CH-CH 3 or represents a radical of the formulae O II HO-P — OR 2 ° ( Ο Λ HO — P — O-POR OR; O HO-P in which R 2 , R 3 and R* are identical or different and denote hydrogen or a sodium metal atom, Le A 28 306 n denotes the number 1 or 2, R 5 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by chlorine, and their physiologically acceptable salts.

3. Compounds of the general formula (I) according to Claim 1, in which R 1 represents hydrogen, tert-butyldimethylsilyl, 4methylbenzoyl or benzoyl, or represents straight-chain or branched acyl having up to 14 carbon atoms, which is optionally substituted by carboxyl, or represents leucine (Leu) or aspartic acid (Asp), which are optionally substituted on the -NH function by the protective group Boc, or represents an ester radical which can easily be cleaved in vivo, of the formulae Le A 28 306 (CH 3 ) 3 C-CO-O-CH 2 - , ch 3 -co-o-ch-ch 3 ch 3 -ch 2 o-co-o-ch-ch 3 or represents a radical of the formulae It HO - P — OR 2 HO — P OR n II HO - P — in which R 2 , R 3 and R* are identical or different and denote hydrogen or a sodium metal atom, n denotes the number 1 or 2, R 5 denotes methyl, ethyl or chloromethyl, and their physiologically acceptable salts.

4. Medicament containing one or more compounds of Claims 1 to 3. Le A 28 306

5. Medicament for combating hepatitis B virus, containing one or more of the compounds of Claims 1 to 3.

6. A compound of the general formula (I) given and defined in Claim 1, or a physiologically acceptable salt thereof, substantially as hereinbefore described and exemplified.

7. A medicament according to Claim 4, substantially as hereinbefore described.

8. A medicament according to Claim 5, substantially as hereinbefore described.

9. A process for preparing a compound of the general formula (I) given and defined in Claim 1, or a physiologically acceptable salt thereof, substantially as hereinbefore described and exemplified.

10. A compound of the general formula (I) given and defined in Claim 1, or a physiologically acceptable salt thereof, whenever prepared by a process claimed in Claim 9.