WO1998016537A1 - Novel compounds - Google Patents

Abstract

This invention pertains to novel compounds which are derivatives of phosphonoformic acid, processes for their synthesis and their use as antiviral agents.

Description

NOVEL COMPOUNDS

Field of the invention

The present invention relates to novel compounds, novel methods for their preparation, novel intermediates, pharmaceutical compositions and to methods for combatting viral diseases caused by, for example, herpesviruses or retroviruses, which can occur in animals including man. Such diseases include both common viral infections and virus-related neoplastic diseases.

Background of the invention

Phosphonoformic acid (PFA) is a well known compound having antiviral activity.

Pharmaceutical formulations of PFA for the treatment of viral diseases have been described in U.S. Patent Nos. 4,215,113; 4,339,445; 4,665,062 and 4,771,041. PFA inhibits replication of all known herpesviruses in vitro including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV) and varicella-zoster virus (VZV) as well as certain retroviruses including the human immunodeficiency virus (HIV) types 1 and 2 (HIV-1 and HIV-2).

Alkyl derivatives of PFA are known from EP 0 003 007 and from Noren, J.-O. et al. (J. Med. Chem. 26 (1983) 264-270) and amide derivatives of PFA are known from EP 0 003 008, as are the antiviral effects in vitro and in vivo in animals of such compounds and of pharmaceutical compositions thereof. So far, however, no drug based on any of these alkyl or amide derivatives has become availiable. Phosphonoformic acid hydrazides are known from US 4,308,263 as are the antiviral effects against herpesviruses in vitro of such compounds. So far, however, no drug based on any of these hydrazides has become available.

Lipid derivatives of phosphonoacids for liposomal incorporation are known from WO 95/13682 and from Hostetler, K. Y. et al., Antiviral Research 31 (1996), 59-67, as are the antiviral effects in vitro of such compounds on viruses such as HIV, hepatitis B virus, EBV, and VZV.

P-monoesters of foscarnet with octadecyl substituted alditol moieties as well as with substituted derivatives of glycerol have been disclosed in WO 96/15132.

Treatment of CMV infections in AIDS patients infected with herpesvirus with foscarnet, i.e. trisodium phosphonoformate hexahydrate, is at present by intravenous injections. This mode of treatment is burdensome where foscarnet must be administered daily. Doses in the range of grams per day need to be administered. The development of a more effective drug is therefore very desirable since it would offer a more convenient method of treatment and result in improved quality of life for the patient.

Description of the invention

The compounds

According to the present invention we provide compounds of formula I

wherein the wavy line signifies a bond which is either in the α- or in the β-configuration;

n is 0 or 1 ;

Ri is Ci .₂₄-alkyl, C₂. -alkenyl, C₂ - ₂ -alkapolyenyl containing 2 to 6 double bonds, C₂. ₂ -alkynyl, C .₈-cycloalkyl, C₃.₈-cycloalkyl-Cι .₂₄-alkyl, or Ci . ι₂-alkoxy-Cι . ι₂-alkyl group, all of which may be branched or unbranched and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo;

R₂, R₃ and R₄ are each independently hydrogen, halogen, amino, acetylamino, azido, or a group XR_ό wherein X is O or S and R is hydrogen, or a branched or unbranched .₄- alkyl or C₂.₄-alkenyl group both of which may be optionally substituted with hydroxy, amino, halogen, or oxo, or

R2, R3, and R4 together with the respective geminal hydrogen represent an oxo group;

R₅ is hydrogen, or a group of the formula II or III,

π

wherein R and R₈ are the same or different and are bound to any two positions of the phenyl ring and each is selected from the group consisting of hydrogen, halogen, or Q .₄- alkyl, .₄-alkoxy, .₄-acyl, .₄-acyloxy, C .₅-alkoxycarbonyl all of which may be branched or unbranched; or R and R₈ together form an unbranched saturated alkylene chain having 3 or 4 carbon atoms bound to adjacent positions in the phenyl ring; or R and R₈ together form a methylenedioxy group, a 1,1-ethylidenedioxy group, or a 1,2- ethylenedioxy group bound to adjacent positions in the phenyl ring,

or R₅ is a group R₉COOCHR10 - or a group R9OCOOCHR₁₀ -

wherein R₉ is C_t .₆-alkyl, C₂.6-alkenyl, C₂.₆-alkynyl, C₃.₈-cycloalkyl, C₃.₈-cycloalkyl-Cι . -alkyl, or . _ό-alkoxy-Cj .₆-alkyl group all of which may be branched or unbranched, and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo; and Rio is hydrogen or a branched or unbranched .₄-alkyl group; and wherein the configurations of the substituents R₂, R₃, R and R₅OOCPO(OH)OCH₂- in I independently are D-gluco, L-gluco, D-galacto, L-galacto, D-manno, L-manno, D-talo, L- talo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-ido, or L-ido when n is 1, or that the configurations of the substituents R , R₃ and R₅OOCPO(OH)OCH - in I independently are D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D-lyxo, or L-lyxo when n is 0;

and physiologically acceptable salts and optical isomers thereof.

The configuration of the glycosidic bond of the compounds of the present invention is preferably α.

Preferred compounds of formula I are those wherein Rj is a Cc_24-alkyl, C9_24-alkenyl, Cg. 24-alkapolyenyl containing 2 to 6 double bonds, C9_24-alkynyl, C3 . g -cycloalkyl-Cg . 24- alkyl, or Cι_i2-alkoxy-C8_i2-alkyl group all of which may be branched or unbranched and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo.

Especially preferred compounds of formula I are those wherein R1 is n-tetradecyl, n- octadecyl, tra/ι.s-9-octadecen-l-yl, or w-9-octadecen-l-yl. Preferably also R2, R3, and R4 are each a hydroxyl group. It is also preferred for R5 to be H. Additionally, it is preferred for n to be 1. Even more preferred are compounds of formula I wherein the configuration of R₂, R3, R4, and R₅OOCPO(OH)OCH₂- is D-gluco.

The compounds of the invention are useful in therapeutic and /or prophylactic treatment of viral infections and may be useful in therapeutic and/or prophylactic treatment of virus- related neoplastic diseases in mammals.

The compounds of the present invention are particularly useful for the treatment of human herpesvirus infections and human retrovirus infections. They are also useful for the treatment of viral infections associated with acquired immunodeficiency syndrome (AIDS). The human herpesviruses include HSV-1 and HSV-2, VZV, CMV, EBV, human herpesvirus 6 and 7(HHV-6 and HHV-7), and human herpesvirus 8 (HHV-8) also known as Kaposi's sarcoma associated herpesvirus (KSHV). Human retroviruses include human immunodeficiency virus type 1 and 2 (HIV- 1 and HIV-2) and human T-cell leukaemia virus type 1 and type 2 (HTLV-1 and HTLV-2). Another important area of use of the compounds of the present invention is in the treatment of infections caused by orthomyxoviruses, e.g. influenza viruses of type A and type B. A further area of use is in the treatment of infections caused by viruses such as hepatitis B virus and hepatitis C virus, papillomaviruses, adenoviruses and poxviruses.

Other possible areas of use of the compounds of the present invention are in the treatment of infections caused by picornaviruses, arboviruses, arenaviruses, coronaviruses, rhabdoviruses, paramyxoviruses and bunyaviruses.

Pharmaceutical formulations

The compounds according to the invention may be used for the therapeutic and prophylactic control and treatment of diseases caused by virus infections. The compounds of the invention can be used alone or with other antiviral agents, e.g. acyclovir, valacyclovir, famciclovir, penciclovir, desciclovir, brivudine, carbovir, fiacitibine, ibacitabine, ganciclovir, idoxuridine, sorivudine, trifluridine, vidarabine, cidofovir, lobucavir, afovirsen, zidovudine, didanosine, stavudine, zalcitabine, dideoxyadenosine, lamivudine, FTC, fialuridine, adefovir, adefovir dipivoxil, nevirapine, delaviridine, loviride, saquinavir, indinavir, ritanovir, nelfinavir, 141W94, ribavirin, amantidine, rimantidine, sICAM-1, pirodavir, GG167, 1263W94, fomivirsen, GEM-132, RS-79070, SR-3775, or with immunological agents e.g. antiinflammatory agents including steroids, in particular glucocorticoids, and non-steroid antiinflammatory drugs (NSAID's), CMV neutraGAM, regavirumab, sevirumab, interferon, and growth factors e.g. granulocyte- macrophage (GM-CSF) and granulocyte -colony stimulating factors (G-CSF). The compounds of the present invention are suitably admixed with excipients to be formulated into capsules, tablets, suppositories and other formulations, e.g. ointments, suspensions, gels and solutions.

For clinical use the compounds of the invention may be formulated into pharmaceutical formulations for oral, parenteral, rectal and topical administration. The pharmaceutical formulation contains the compound of the invention normally in combination with a pharmaceutically acceptable excipient. The excipient may be in the form of a solid, semi- solid or liquid diluent. Usually the amount of active compound is between 0.1-99% by weight of the preparation.

In the preparation of pharmaceutical formulations containing the compounds of the present invention in the form of dosage units for oral administration the compound may be mixed with a solid, powdered carrier, e.g. lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable carrier; stabilizing substances, e.g. alkaline compounds, e.g. bicarbonates, carbonates, and hydroxides of sodium, potassium, calcium, magnesium, as well as magnesium oxide and the like as well as with lubricating agents e.g. magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethyleneglycol waxes. The mixture may then be processed into granules or pressed into tablets. Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach. The enteric coating is chosen among pharmaceutically acceptable enteric- coating materials e.g. beeswax, shellac or anionic film-coating polymers and the like, if preferred in combination with a suitable plasticizer. To the coating various dyes may be added in order to distinguish among tablets or granules with different active compounds or with different amounts of the active compound present.

Soft gelatin capsules may be prepared with capsules containing a mixture of the active compound of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Soft gelatin capsules may also be enteric-coated as described above. Hard gelatin capsules may also contain the active compound in combination with a powdered carrier as described above. The hard gelatin capsules may be enteric-coated as described above. Hard gelatin capsules may contain granules or enteric-coated granules of the active compound.

Dosage units for rectal administration may be prepared in the form of suppositories with the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatin capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules, or they may be prepared in the form of enemas, e.g. dry micro enemas, or they may be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of solutions, syrups, emulsions or suspensions, e.g. containing from 0.1 % to 50% by weight of the active ingredient and the remainder consisting of for example sugar or an alditol and/or a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharin or carboxy methyl cellulose or other thickening agents. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

In addition, using known pharmaceutical procedures, sustained release preparations at doses of 1 mg to 2000 mg may be formulated.

For topical application, especially for the treatment of herpes virus infections on skin, genitals and in mouth and eyes the preparations are suitably in the form of a solution, ointment, gel, suspension cream or the like. The amount of active substance may vary, for example between 0.05% to 20% by weight of the preparation . Such preparations for topical application may be prepared in known manner by mixing the active substance with known carrier materials e.g. isopropanol, glycerol, paraffin, stearyl alcohol, polyethylene glycol, etc. The pharmaceutically acceptable carrier may also include a known chemical absorption promotor. Examples of absorption promotors are e.g. dimethylacetamide, trichloroethanol or trifluoroethanol, certain alcohols and mixtures thereof.

Liposomal formulations based on lipid substances, e.g. phospholipids, sphingolipids, glycolipids, and galactolipids can be used for formulations for oral, topical or parenteral administration.

The typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, doses will be in the range of 1 mg to 2000 mg per day, preferably 5 mg to 1000 mg of active substance per day. Unit doses of 0.25 mg to 2000 mg can be given e.g. 1 to 4 times a day.

Methods of preparation of the compounds of the invention, starting materials and intermediates.

Some of the compounds of the formula I may be prepared from triesters or P,C-diesters of phosphonoformic acid in which suitably protected glycoside moieties are present as P,P- diesters or P-monoesters, respectively, which are deprotected in a final step to give the compounds of formula I. The compounds of the formula I may be prepared by methods analogous to known methods for the synthesis of either diesters or monoesters of phosphonic acids, for example as described in Houben-Weyl, Methoden der Organischen Che ie, Auflage 4, Band XII, Teil 1, Organischen Phosphorverbindungen, p. 408-414 and 423-463. Examples of such methods are the following.

A. Reacting an alkoxycarbonylphosphonic dihalide or an aryloxycarbonylphosphonic dihalide with at least two equivalents of a glycoside ProtGlycoside-OH, which may if necessary be suitably protected, with a free hydroxyl group at the 6-position if a hexose or at the 5-position if a pentose in the presence of a base such as, for example, pyridine or triethylamine, according to the formula:

O

Hal . base ProtGlycoside-O. I I

-COOR' + 2 ProtGlycoside-OH -COOR'

Hal ProtGlycoside-O'

+ 2 base.HHal

followed by selective removal of one of the glycoside groups, e.g. by reaction with iodide or bromide anion according to the formula:

+ ProtGlycoside-X

The resulting intermediate compound of the formula

IVa

is then, where necessary, subjected to deprotection of the glycoside moiety, if desired with concomitant or subsequent removal of R' , to give a compound of the formula IVb, e.g. in the form of a salt thereof

IVb

wherein n, R\, R2, R3, and R4 have the meaning given above, R' has the meaning given above for R5 with the exception of hydrogen, or R' is branched or unbranched

alkyl, Rl8 is R' or hydrogen,

X is Br or I and Hal is CI, Br or I

In the case where Ris is R5, the compounds of the formula IVb correspond to compounds of the formula I.

ProtGlycoside-OH corresponds to a compound of the formula V

V wherein n and Ri are as defined above, and Rι₅, R₁₆ and R_l7 each correspond to the groups R₂, R₃ and R₄, respectively, which have, when necessary or desired, been derivatized by suitable protective groups. Preferred protective groups are methoxy methyl, methylthiomethyl, benzyloxymethyl,/?-methoxybenzyloxymethyl, tetrahydropyranyl, 1- ethoxyethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl,t-butyl, allyl, but-2-enyl, 3- methylbut-2-enyl, p-methoxyphenyl, benzyl, /?-methoxybenzyl, 3 ,4-dimethoxybenzyl, p- nitrobenzyl, diphenylmethyl, trimethylsilyl, triethylsilyl,r-butyldimethylsilyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, isobutyryl, pivaloyl, benzoyl, -methoxybenzoyl, p- chlorobenzoyl, -bromobenzoyl, 2,2,2-trichloroethoxycarbonyl, methanesulfonyl oxp- toluenesulfonyl in the case where at least one of the groups R₂, R₃ and P is a hydroxyl group or R is substituted by a hydroxyl group, or ethylidene, isopropylidene, cyclohexylidene, benzylidene, -methoxybenzylidene, methoxymethylene, ethoxymethylene, di-t-butylsilylene, or tetraisopropyldisiloxane-l,3-diylidene in the case where at least two of groups R₂, R₃ and R₄ are hydroxyl groups, or methoxy methyl, benzylthiomethyl, phenylthiomethyl, tetrahydropyranyl, 2-cyanoethyl, benzyl^- methoxybenzyl, ?-nitrobenzyl, diphenylmethyl, t-butyl, acetyl, benzoyl, 2,2,2- trichloroethoxycarbonyl, r-butoxycarbonyl or benzyloxycarbonyl in the case where at least one of the groups R , R and R is a thiol group, or ethoxycarbonyl, 9- fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, r-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl,/?-methoxybenzyloxycarbonyl,/?- nitrobenzyloxycarbonyl, formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phthaloyl, allyl, 2-trimethylsilylethoxymethyl, benzyl, benzylidene orp-methoxybenzylidene in the case where at least one of the groups of the groups R₂, R₃ and R4 is an amino group or R6 is substituted by an amino group, or finally, in the case where one of the groups R?, R₃ and R together with the respective geminal hydrogen represent oxo, or R5 is substituted by an oxo group, then the group is derivatized as e.g. a dimethyl ketal, a bis(2,2,2-trichloroethyl) ketal, a dibenzyl ketal, a diacetyl ketal, a 1,3-dioxane, a 5-methylene-l,3-dioxane, a 1,3- dioxolane, a S,S'-dimethyl dithioketal, a S,S'-dibenzyl dithioketal, a S,S'-diacetyl dithioketal, a 1,3-dithiane, a 1,3-dithiolane, a 1,3-oxathiolane, an O-acetyl cyanohydrin, an O-trimethylsilyl cyanohydrin, an N,N-dimethylhydrazone, a 2,4-dinitrophenylhydrazone, an oxime, or an O-methyloxime and salts and optical isomers thereof. Further examples of suitable protective groups for the functional groups of the glycoside moiety are given in Protective Groups in Organic Synthesis, Ed. T. W. Greene and P.G. M Wuts, John Wiley & Sons, Inc., New York, 1991 (Ref. 1).

Novel starting materials are compounds of the formula ProtGlycoside-OH corresponding to formula V, wherein R\ is a C9_24-alkyl, C9_24-alkenyl, C9_24-alkapolyenyl containing 2 to 6 double bonds, C9_24-alkynyl, C3 . s-cycloalkyl- .24-alkyl, or Cι_i2- lkoxy-C8-i2-alkyl group, all of which may be branched or unbranched and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo;

provided that in the case where the configuration of the substituents R₁₅, Rι₆ , R_l7 and HOCH2- is D-gluco,

i) Ri is not rc-decyl, n-dodecyl, or n-octadecyl at the same time as each of Rι₅, Rι₆ and Rπ is benzyloxy, and

ii) Ri is not l-ethenyl-l,5-dimethyl-4-hexen-l-yl at the same time as each of R₎₅, R₁₆ and Rπ is benzoyloxy, and

iii) Ri is not 8-hydroxy-l-(4-hydroxy-2-methyl-2-butenyl)-3,7-dimethyl-2,6-octadienyl at the same time as R1₅ is 2-methyl-2-butenoate and each of Rι₆ and Rι₇ is acetoxy, and

provided that, in the case where the configuration of the substituents R₁₅, Rι₆ , R_]7 and HOCH₂- is D-galacto,

iv) Ri is not n-octadecyl at the same time as each of R₁₅ , Rι₆ and Rj₇ is acetoxy, and

provided that, in the case where the configuration of the substituents R₁₅, Rι₆ , Rι and HOCH₂- is D-manno, v) Ri is not rc-hexadecyl at the same time as each of Rι₅ , Rι₆ and Rι₇ is trimethylsilyloxy, and

vi) Ri is not 3,7,1 l-trimethyl-2,6,10-dodecatrienyl at the same time as each of Rι₅ , Rι₆ and Rι₇ is acetoxy,

and salts and optically active isomers thereof.

Said preferred starting materials for the first step of the synthesis are novel and comprise part of the present invention.

The compounds of the formula IVa which correspond to compounds of the formula VI, wherein n, Rj, R15, Ri6, R17 and R'are as above, and physiologically acceptable salts and optical isomers thereof are novel and comprise part of the present invention.

VI

The first step of the synthesis is performed by methods known er se for the phosphorylation of alcohols by phosphoric and phosphonic dihalides. Examples of such methods are described for example in Slotin, L.A. in Synthesis 1977, 737 (Ref. 2) and Seliger, H. and Kossel, H., Progress in the Chemistry of Organic Natural Products 32 (1975) 297 (Ref. 3). The alkoxycarbonyl- and aryloxycarbonylphosphonic dihalides are prepared by methods known er se for the synthesis of dihalides of phosphoric acids and phosphonic acids. References for these methods are found, for example, in the two publications above and in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII/1, p. 387-406 and Band XII/2, p. 212-225.

The second step of the synthesis is preferably carried out with sodium iodide in a suitable solvent, e.g. tetrahydrofuran or acetone. Preferably the reaction is carried out at a temperature from 20°C to the boiling point of the solvent for from 2 hours to 7 days.

The protective groups of the glycoside moiety, if present, may be removed according to the methods described in Ref. 1. If desired, the group R' may be removed by hydrolysis with base such as, for example, 0.5M - 2M sodium hydroxide, lithium hydroxide or potassium hydroxide in water, methanol, ethanol, or aqueous tetrahydrofuran. If R' is benzyl, it may be removed by catalytic hydrogenation in the presence of a catalyst, such as palladium on charcoal.

The suitably protected glycosides required as starting materials for the first step of the synthesis may be prepared from the corresponding unprotected glycosides, which may be obtained according to known methods for the synthesis of such compounds as described, for example, in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band E14a, Teil 3, Acetale in, p. 761-816. The methods for the preparation of the suitably protected glycosides involve the judicious use of protective group strategy, as illustrated in Ref. 1. For example selective protection of the primary hydroxyl group at the 6-position if a hexose or at the 5 -position if a pentose may be achieved with a group such as, for example, triphenylmethyl or tert-butyldimethylsilyl. Such compounds with protected primary hydroxyl groups may then be derivatized at the remaining groups, where appropriate, by choosing a suitable group, e.g. from the list of groups given above. Selective removal of the protective group at the 6-position if a hexose or at the 5-position if a pentose then affords the suitably protected glycosides. B. In a modification of the first step of the procedure described above in A, a phosphonoformate which is monosubstituted at the phosphonate group with a glycoside moiety, which may if necessary be suitably protected, may be obtained directly without the intermediacy of the phosphonoformate which is disubstituted at the phosphonate group with a glycoside moiety, which may if necessary be suitably protected. This may be achieved by reacting an alkoxycarbonylphosphonic dihalide or an aryloxycarbonylphosphonic dihalide with a glycoside ProtGlycoside-OH, which may if necessary be suitably protected, with a free hydroxyl group at the 6-position if a hexose or at the 5-position if a pentose followed by aqueous hydrolysis according to the formula:

Hal ProtGlycoside-O. II -COOR' + ProtGlycoside-OH ► ^- p COOR' Hal HO

H-Hal

followed as under A above by deprotection, if necessary, of the glycoside moiety, if desired with concomitant or subsequent removal of R', to give a compound of the formula IVb, e.g. as a salt, which in the case where R _$ is R5 corresponds to a compound of the formula I.

ProtGlycoside-OH, Hal, R', R5 and RJS each have the same meaning as given above in A.

The first step of the synthesis is performed using more than one equivalent, preferably 1 to 2 equivalents, more preferably about 1.6 equivalents, of the alkoxycarbonylphosphonic dihalide or the aryloxycarbonylphosphonic dihalide per equivalent of glycoside, which may if necessary be suitably protected, in a solvent such as dichloromethane, dichloroethane, ethyl acetate or acetonitrile in the absence of base. Preferably the reaction is carried out at a temperature of -20°C to +5°C for 30 minutes to 2 hours followed by stirring at room temperature for 1 hour to 5 hours. Following removal of the solvent, the residue from the reaction mixture may be stirred vigorously for 5 to 30 minutes with a 1 : 1 mixture of water and an organic solvent, for example, ethyl acetate or diethyl ether. The reaction may also be performed by using a glycoside, which may if necessary be suitably protected, in which an acid labile group such as a trisubstituted silyl ether group, for example a tert- butyldimethylsilyl ether group, is present at the 6-position if a hexose or at the 5-position if a pentose.

The protective groups of the glycoside moiety may be removed according to the methods described in Ref. 1, and the group R' may be removed, if desired, as described above in A.

The modified procedure described in the first step of the above synthesis affords a convenient general method for the preparation of phosphonoformate diesters from e.g. alkoxycarbonylphosphonic dihalides or aryloxycarbonylphosphonic dihalides and alcohols or their trisubstituted silyl ethers without the need to first isolate a phosphonoformate triester.

C. Reacting a salt of an alkoxycarbonylphosphonate or an aryloxycarbonylphosphonate with a glycoside, which may if necessary be suitably protected, with a halogen at the 6- position if a hexose or at the 5-position if a pentose, ProtGlycoside-Hal, according to the formula:

+ 2 ⁺ Hal^"

followed by selective removal of one of the protected glycoside groups as described above under A.

ProtGlycoside-Hal corresponds to a compound of the formula

VII

wherein n, Hal, Rj, R15, R\^, R17, and R' have the meanings given above in A.

M⁺is a cation, e.g. Ag⁺, Li⁺, Na⁺, K⁺, Cs⁺, Et₃NH⁺ or ( -Pr)₂NEtH⁺.

The first step of the synthesis is carried out in a solvent, for example, ethanol or dimethylformamide, at a temperature from 25°C to 100°C for 1 to 50 hours.

The second step of the synthesis is preferably carried out as above in A.

The protective groups of the glycoside moiety may be removed according to the methods described in Ref. 1, and the group R' may be removed, if desired, as described above in A.

D. Reacting an alkoxycarbonylphosphonic acid or an aryloxycarbonylphosphonic acid with a suitably protected glycoside ProtGlycoside-OH with a free hydroxyl group at the 6- position if a hexose or at the 5-position if a pentose, according to the formula:

followed by selective removal of one of the glycoside groups, which may be suitably protected, and finally, if necessary, by deprotection of the glycoside moiety, if desired with removal of the group R', as above in A.

ProtGlycoside-OH, and R' are as above in A.

The first step of the synthesis may be performed through the intermediary of activating agents known per se for the phosphorylation of alcohols. Examples of such methods are described for example in Refs. 2 and 3.

The second step of the synthesis is preferably carried out as above in A.

The protective groups of the glycoside moiety may be removed according to the methods described in Ref. 1 , and the group R' may be removed, if desired, as described above in A.

E. Reacting a suitably activated formate with suitably substituted phosphite triesters in which two of the ester groups are glycosides, which may be suitably protected if necessary, which are substituted at the 6-position if a hexose or at the 5-position if a pentose by the phosphite group according to the formula:

+ R" Y

followed by selective removal of one of the glycoside groups, which may be suitably protected, and then, where necessary, subjecting the resulting compound to deprotection of the glycoside moiety, if desired with removal of the group R' as above in A.

ProtGlycoside-O- corresponds to a group derived from a compound of the formula V. R' is as above in A.

R" is a C i .₆-alkyl, a C₃.₈-cycloalkyl, a benzyl, an allyl or any phosphite esterifying group suitable for participation in an Arbuzov type reaction, and

Y is a leaving group suitable for Arbuzov type reactions, e.g. CI, Br, I, sulphonate, carboxylate, or alkoxide.

The first step of the synthesis may be performed at a temperature from 0°C to 150°C for 1 to 50 hours.

The second step of the synthesis is preferably carried out as above in A.

The protective groups of the glycoside moiety may be removed according to the methods described in Ref. 1, and the group R' may be removed, if desired, as described above in A.

The starting materials for the first step of the synthesis may be prepared by known methods commonly used for the synthesis of phosphite triesters and formates. Examples of methods used for the synthesis of phosphite triesters may be found in Houben-Weyl, Methoden der Organischen Chemie, Auflage 4, Band XII, Teil 2, Organische Phosphorverbindungen, p. 5-78. Examples of methods used for the synthesis of haloformate esters may be found in, or referred to in M. Matzner et al., Chem. Rev. 64 (1964) 645.

F. Reacting a suitably activated formate with a suitably substituted phosphite diester salt in which the ester groups are protected glycosides, which may be suitably protected if necessary, which are substituted at the 6-position if a hexose or at the 5-position if a pentose by the phosphite group according to the formula: o o

ProtGlycoside-O. || ProtGlycoside-O.

,P^' M⁺ + Y COOR' ► P COOR'

ProtGlycoside-O ProtGlycoside-O

+ M⁺ Y^"

followed by selective removal of one of the protected glycoside groups as above in A.

ProtGlycoside-O- corresponds to a group derived from a compound of the formula V, and R' is as above in A. M⁺ is a cation, preferably a metal ion, e.g. Li^4-, Na⁺ or K⁺ and Y has the meaning given above.

The first step of the synthesis is preferably performed at 0°C to 100°C for 1 to 50 hours in a solvent for example toluene, ether or tetrahydrofuran.

The second step of the synthesis is preferably carried out as above in A.

The protective groups of the glycoside moiety and the group R'may be removed, if desired, as described above in A.

The phosphite diester salts are prepared by treating the phosphite diester with a suitable proton extracting compound, such as a metal alkoxide, suitably free from the alcohol, e.g. as lithium, sodium, or potassium methoxide, ethoxide, or rert-butoxide, or with a hydride e.g. sodium or potassium hydride, or with a base such as butyllithium.

Experimental part

General description of the methods

Η-, ¹³C- and ³¹P-NMR spectra were recorded on a Varian Unity 400 MHz spectrometer at 25 °C. The following reference signals were used: CDC1₃ δ 77.0 (¹³C in CDC1₃); tetramethylsilane δ 0.00 (1H in CDC1₃); 3-(trimethylsilyl)-propanesulfonic acid sodium salt δ 0.00 (Η in D₂O); Me₂CO δ 31.00 (¹³C in D₂O); the middle line of CD₃OD δ 49.0 (¹³C in CD₃OD); the middle line of DMSO-d6 δ 39.5 (¹³C in DMSO-d6); DMSO-d6 δ 2.5 (1H in DMSO-d6). NMR-spectra recorded for all compounds were in agreement with the postulated structures and only selected data are reported. Thin layer chromatography (TLC) was performed on Merck DC- Fertigplatten® (Kieselgel 60 F₂s₄, 0.25 mm) and on Merck DC-Alufolien® (Kieselgel 60 F₂₅₄ 0.2 mm) and on Merck RP®-18 F₂₅ (0.25 mm). Spots were visualized by UV and/or spraying with 8% aqueous sulfuric acid and charring. Merck Silica gel 60®(40-63 μm) was used for column chromatography in the flash mode. Merck LiChroprep® RP-18 (40-63 μm) was used for reversed phase chromatography. All solvents used were analytical grade (acetone and diethyl ether/Prolabo, dichloromethane/Fluka and the remaining from Merck) dried with 3A (methanol) or 4A molecular sieves, except tetrahydrofuran used for Birch reductions (Labscan of Anhydroscan grade).

Below is a detailed description of the synthesis of the intermediate and final compounds according to the present invention. The synthesis is performed stepwise to produce the compounds of the invention. The following abbreviations are used in the chemical formulas: Bn denotes a benzyl group, Bz denotes a benzoyl group, Tr denotes a triphenylmethyl group, Ac denotes an acetyl group, and Et denotes an ethyl group. Glycosidations

In the figure above either R\ ι=Ri2=Rl3=Rl4 = OBn or Ri ι= i2=Rl3=Ri4 = OAc, and R\ has the meaning stated above.

To a solution under argon, of the glycosyl donor (mixture of anomeric acetates) (5 mmoles) and the alcohol, (1.5 eq.) in CH₂Cl₂ Et₂O (1/2, 40 ml) was added activated 4 A crushed molecular sieves. The mixture was stirred for 20 minutes, cooled to 0°C in an ice/water bath, and trimethylsilyl triflate (TMSOTf) (1.05 eq.) was added. The reaction was kept for 30 minutes at 0°C, and then allowed to warm up to room temperature. After 3 hours the reaction mixture was neutralized by addition of triethylamine (1.2 eq.) diluted with CH C1₂ (40 ml), filtered, and evaporated. Flash chromatography of the residue gave the glycoside.

Preparation of the unprotected glycosides

For deprotection of benzyl ethers by hydrogenolysis with palladium on charcoal, see e.g. McCloskey, CM. in Wolfrom , M.L.(ed), Adv Carbohydr. Chem., Academic Press Inc., New York, 12, 137-153, (1957).

For deprotection of benzyl ethers by Birch reduction, see e.g. Philips, K.D., Zemlicka, J. and Horowitz, J.P., Carbohydr. Res., 30 (1973) 281.

For deprotection of benzoyl esters by basic hydrolysis, see e.g. Conchie, J. and Levvy, G.A. in Whistler, R.L. and Wolfrom, M. L. (eds), Methods in Carbohydrate Chemistry, Academic Press Inc., New York and London, Vol. II, 345-347, (1963).

Tritylation and benzoylation

A solution of the glycoside (3 rnmoles), triphenylmethyl chloride (1.1 eq.) and, a catalytic amount of 4-dimethylaminopyridine (DMAP) in 120 ml of pyridine was stirred overnight (14 hours) at 70° C. The solution was brought to room temperature, diluted with 60 ml of CH₂C1₂ and benzoyl chloride (8 eq.) was added. After 12 hours at room temperature the reaction mixture was diluted with 60 ml of CH₂C1₂ and washed with a saturated solution of NaHCO₃, then with H₂O and finally dried over MgSO . Filtration and evaporation (rotavapor, coevaporation of the traces of pyridine with toluene) followed by flash chromatography gave the title compounds. Detritylation

To a solution of the trityl derivative (2 rnmoles) in CHCl₃/MeOH (2/1, 90 ml) was added para- toluenesulfonic acid monohydrate to pH 1-2. After 3 hours the solution was diluted with 50 ml of CH₂C1₂, washed with a saturated solution of NaHCO₃, then with H₂O and finally dried over MgSO Filtration and evaporation followed by flash chromatography gave the title compounds.

Preparation of diesters of phosphonoformic acid

A solution of the hydroxy compound (1 mmol) in dry CH₂C1₂ (20 ml) was added drop wise to an ice cold solution of the ethoxycarbonylphosphonic dichloride (1.6 mmol) in dry CH₂C1₂ (15 ml). The reaction was stirred at 0°C for an hour, and then for 3 hours at room temperature. The solvent was removed under reduced pressure, dried in high vacuum for 5 min., and redissolved in AcOEt (20 ml). 20 ml of H₂O were added and the two phases were vigorously stirred for 10 min. (emulsion). The organic phase was separated, and washed with H₂O. The aqueous phases were extracted twice with AcOEt (5% of MeOH was added when the phases separation was difficult). The combined organic phases were dried (MgSO ), and evaporated. Flash chromatography of the residue gave the diesters.

Preparation of monoesters of phosphonoformic acid

The diester of foscarnet (1 mmol) was suspended in H₂O (25 ml) at room temperature. A 0.4 M solution of NaOH (25 ml) was added (insoluble product stuck to the walls of the flask was washed down with THF (10 ml)). The suspension was left 3 hours at room temperature., brought to pH 5-5.3 by addition of cation exchange resin (Dowex® 50W-X8 (H) standard grade, paricle size 0.39-1.00 mm), filtered, and the solvent was removed under reduced pressure (10 mm Hg, 30° C). If the solution could not be concentrated by drying in a rotavapor (due to rapid formation of a foam), the THF was removed by a continuous current of air overnight. The residue was purified by reverse phase chromatography, gradient: H_∑O/MeOH 1/0 to 1/4). The fractions containing the monoester were collected, the MeOH evaporated (rotavapor, 20°C) and lyophilisation gave the title compounds. The invention is further illustrated by the following non-limiting examples according to the procedures described above.

Examples of glycosidations according to the procedure described above under "Glycosidations":

Example 1

n-OctadecyI 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside: 3.240 g of acetyl 2,3,4,6-tetra-O-benzyl-D -glucopyranoside (5.56 mmoles) and octadecanol gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/11) 3.097 g

(71%) of the title compound.

Rf = 0.46 (AcOEt/petroleum ether 40°-60° C : 1/5).

Η-NMR (CDC1₃): 7.37-7.12 (m, 20 H-arom.); 5.01-4.44 (m, 9H); 3.99 (t, J= 9.2 Hz); 3.76- 3.40 (m, 7H); 1.62-1.58 (m, 2H); 1.32-1.19 (m, 30H); 0.86 (t, J= 6.7Hz, 3H).

¹³C -NMR (CDCI₃): 139.0-126.7 (C arom.); 96.9 (C(l)); 82.1; 80.1; 77.8; 75.6; 75.0; 73.4;

73.1; 70.1; 68.5; 68.2; 31.8-14.0 (C alkyl).

Example 2

cw-9-Octadecen-l-yl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside:

4 g of acetyl 2,3,4,6-tetra-O-benzyl^D-glucopyranoside (6.865 mmoles) and c/s-9-octadecen-l- ol gave after flash chromatography 3 times (eluent AcOEt/petroleum ether 40°-60° C : 1/11) 3.719 g (68%) of the title compound.

Rf = 0.33 (AcOEt/petroleum ether 40°-60° C : 1/8).

Η-NMR (CDCI3): 7.36-7.12 (m, 20 H-arom.); 5.36-5.34 (m, 2H); 4.99 (d, J= 10.9 Hz); 4.84-

4.44 (m, 8H); 3.99 (t, J= 9.2 Hz); 3.80-3.59 (m, 5H); 3.56 (dd, J= 9.6, 3.6 Hz, H-C(2)); 3.42 (dt, J= 9.8, 6.7 Hz); 2.03-1.99 (m,4H); 1.64-1.60 (m, 2H); 1.29-1.26 (m, 22H); 0.88 (t, J= 6.6 Hz, 3H).

¹³C -NMR (CDC1₃): 138.9-137.9 (4C arom.); 129.-127.4 (C arom., 2C olef); 96.8 (C(l)); 82.1; 80.1; 77.7; 75.6; 75.0; 73.4; 73.0; 70.0; 68.5; 68.2; 31.8-14.1 (C alkyl).

Example 3

trαn^-9-Octadecen-l-yl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside:

4 g of acetyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside (6.865 mmoles) and tra/25-9-octadecen- l-ol gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/11) 3.3 g

(61%) of the title compound.

Rf = 0.30 (AcOEt/petroleum ether 40°-60° C : 1/10).

1H-NMR (CDC1₃): 7.36-7.12 (m, 20 H-arom.); 5.39-5.37 (m, 2H); 4.99 (d, J= 11 Hz); 4.84-

4.44 (m, 8H); 4.00 (t, J= 9.2 Hz); 3.80-3.59 (m, 5H); 3.56 (dd, J= 9.6, 3.6 Hz, H-C(2)); 3.42 (dt, J= 9.7, 6.7 Hz); 1.98-1.94 (m, 4H); 1.64-1.59 (m, 2H); 1.35-1.26 (m, 22H); 0.88 (t, J= 6.8

Hz, 3H).

¹³C -NMR (CDC1₃): 138.9-137.9 (4C arom.); 130.3-127.4 (C arom., 2C olef); 96.8 (C(l));

82.0; 80.1; 77.7; 75.5; 74.9; 73.4; 73.0; 70.0; 68.5; 68.1; 32.5-14.0 (C alkyl).

Example 4

Eicosyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside:

3.5 g of 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranoside (8.967 mmoles, purchased from Senn Chemicals AG) and eicosanol gave after a reaction time of 15 h, work up and flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/4) 1.45 g (26%) of the title compound.

Rf = 0.24 (AcOEt/petroleum ether 40°-60° C : 1/4).

Η-NMR (CDC1₃): 5.39 (br.d, J= 2.6Hz, H-C(4)); 5.21 (dd, J= 9.4, 7.9 Hz, H-C(2)); 5.02 (dd, J= 10.4, 3.4 Hz, H-C(3)); 4.46 (d, J= 7.9 Hz, H-C(l)); 4.21-4.11 (m, 2H)); 3.92-3.86 (m, 2H); 3.47 (dt, J= 9.6, 6.9 Hz); 2.15, 2.05, 2.04, 1.98 (4s, 4 x 3H, Ac); 1.60-1.55 (m, 2H); 1.33-1.16 (m, 34H); 0.88 (t, J= 6.8 Hz, 3H).

¹³C -NMR (CDC1₃): 170.3-169.2 (4 CO); 101.3 (C(l)); 70.9; 70.5; 70.2; 68.9; 67.0; 61.2; 31.9-14.0 (C alkyl and acetyl).

Examples of preparation of the unprotected glycosides (see the references given above under "Preparation of the unprotected glycosides"):

Example 5

n-Octadecyl α-D-glucopyranoside:

A suspension of 1.28 g of n-octadecyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (1.615 mmoles) and 250 mg of 10% Pd/C in AcOEt/EtOH (1/1, 30 ml) was shaken 3 hours under an atmosphere of 3 bars of H₂ to give the title compound. The reaction mixture was filtered, and washed twice with 40 ml of AcOEt/MeOH/H₂O (7/2/1). The combined filtrates were evaporated, dried (high vacuum, 594 mg, 85%) and directly used in the next reaction step without further purification. Rf = 0.19 (AcOEt/MeOH: 5/1).

Example 6

cw-9-Octadecen-l-yl α-D-glucopyranoside:

A solution 2.184 g of cw-9-octadecen-l-yl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (2.76 mmoles) in THF (15 ml) was added dropwise over a period of 30 minutes to a solution of 1.01 g of sodium (43.9 mmoles) in 200 ml of liquid ammonia. The mixture was left stirring at - 35°C. After 5 hours, MeOH (20 ml) and 2.34 g of NFLC1 were added and the reaction mixture was left to warm up to room temperature. The ammonia was removed by a continuous current of air overnight. The solid residue was suspended in AcOEt/MeOH (3/1, 100 ml) and filtered.

Concentration of the filtrate, followed by flash chromatography (AcOEt/MeOH: 10/1) gave

642 mg (54 %) of cw-9-octadecen-l-yl α-D-glucopyranoside.

Rf = 0.23 (AcOEt/MeOH: 10/1). Η-NMR (CD₃OD, (ref. 3.24 ppm)): 5.29-5.26 (m, 2H olef); 4.70 (d, J= 3.8 Hz, H-C(l)); 3.72

(dd, J= 11.8, 2.3 Hz, H-C(6)); 3.66 (dt, J= 9.6, 6.9 Hz); 3.61 (dd, J= 11.8, 5.5 Hz, H-C(6));

3.56 (t, J= 9.3 Hz); 3.50 (ddd, J= 9.7, 5.4, 2.3 Hz, H-C(5)); 3.37 (dt, J= 9.6, 6.6 Hz); 3.31 (dd,

J= 9.6, 3.8 Hz, H-C(2)); 3.22 (t, J= 9.5 Hz); 1.97-1.94 (m ,4H); 1.59-1.54 (m, 2H); 1.33-1.17

(m, 22H); 0.89 (t, J= 6.8 Hz, 3H). ¹³C -NMR (CD₃OD): 130.8 (2C olef); 100.1 (C(l)); 75.1 ; 73.6 (2C); 71.8; 69.1; 62.7; 33.1-

13.4 (C alkyl).

Example 7

frα7W-9-Octadecen-l-yl α-D-glucopyranoside:

A solution 2.4 g of tom.ϊ-9-octadecen-l-yl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (3.03 mmoles) in THF (15 ml) was added dropwise over a period of 30 minutes to a solution of 1.4 g of sodium (60 mmoles) in 200 ml of liquid ammonia. The mixture was left stirring at -35°C.

After 5 hours, MeOH (20 ml) and 3.21 g of NH4CI were added and the reaction mixture was left to warm up to room temperature. The ammonia was removed by a continuous current of air overnight. The solid residue was suspended in AcOEt/MeOH (3/1, 100 ml) and filtered.

Concentration of the filtrate and followed by flash chromatography (AcOEt/MeOH: 10/1) gave

728 mg (56%) of trøn.y-9-octadecen-l-yl α -D-glucopyranoside.

Rf = 0.23 (AcOEt/MeOH: 10/1). Η-NMR (CDCl₃/CD₃OD: 2/1 (ref. 3.35 ppm)): 5.39 (m, 2H olef); 4.82 (d, J= 3.8 Hz, H-

C(D); 3.79-3.65 (m, 4H); 3.59 (dt, J= 9.7, 3.6 Hz); 3.48-3.38 (m, 3H); 1.98-1.95 (m ,4H);

1.65-1.61 (m, 2H); 1.34-1.27 (m, 22H); 0.89 (t, J= 6.9 Hz, 3H).

¹³C -NMR (CDCI3 CD3OD: 2/1, (ref. 77.0 ppm)): 130.0, 129.9 (2C olef.); 98.2 (C(l)); 73.6;

71.8; 71.3; 69.9; 69.1; 67.8; 61.1; 32.1-13.4 (C alkyl). Example 8

Eicosyl β-D-galactopyranoside:

To a solution of 1.38 g of eicosyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (2.194 mmoles) in MeOH (50 ml) was added a solution of MeO^"Na⁺ in MeOH (0.01 M, 20 ml). After 3 hours the reaction mixture was neutralized by addition of cation exchanger resin (Dowex 50W-X8 (H) standare grade, particle size 0.39-1.00 mm) and diluted by CHCI3 (100 ml). Filtration, evaporation gave 990 mg of a residue (98 %) consisting of the title compound, which was directly used in the next reaction step without further purification. Rf = 0.21 (AcOEt/MeOH: 5/1).

Examples of tritylation and benzoylation according to the procedure described above under "Tritylation and benzoylation":

Example 9

rt-Octadecyl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside:

660 mg of rt-octadecyl α-D-glucopyranoside (1.37 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/8) 965 mg (72%) of the title compound. Rf = 0.25 (AcOEt/petroleum ether 40°-60° C : 1/8).

Η-NMR (CDCI₃): 8.01-7.07 (m, 30 H-arom.); 6.10 (t, J= 9.8 Hz); 5.56 (t, J= 10 Hz); 5.40 (d, J= 3.7 Hz, H-C(l)); 5.30 (dd, J= 10.1, 3.8 Hz, H-C(2)); 4.26 (dt, J= 10, 3.9 Hz, H-C(5)); 3.88 (dt, J= 9.7, 6.4 Hz); 3.51(dt, J= 9.7, 6.6 Hz); 3.29-3.28 (m, 2H, H-C(6)); 1.68-1.61 (m, 2H); 1.35-1.18 (m, 30H); 0.85 (t,3H). Example 10

cis-9-Octadecen-l-yl 2,3,4-tri-O-benzoyI-6-O-trityl-α-D-glucopyranoside:

642 mg of c j^,-9-octadecen-l-yl α-D-glucopyranoside (1.5 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/9) 1.148 mg (78%) of the title compound.

Rf = 0.23 (AcOEt/petroleum ether 40°-60° C : 1/9).

Η-NMR (CDC1₃): 8.01-7.07 (m, 30 H-arom.); 6.11 (t, J= 9.8 Hz); 5.56 (t, J= 9.9 Hz); 5.40 (d, J= 3.8 Hz, H-C(l)); 5.37-5.33 (m, 2H); 5.30 (dd, J= 10.1, 3.8 Hz, H-C(2));4.26 (dt, J= 10.1, 4 Hz, H-C(5)); 3.88 (dt, J= 9.8, 6.4 Hz); 3.52 (dt, J= 9.7, 6.6 Hz); 3.29-3.28 (m, 2H, H-C(6)); 2.02-1.96 (m, 4H); 1.66-1.60 (m, 2H); 1.35-1.17 (m, 22H); 0.86 (t, J= 6.7Hz, 3H). ¹³C -NMR (CDCI3): 165.8-164.9 (3 C, CO); 146-126.8 (C arom.); 95.7 (C(l)); 86.6; 72.3; 71; 69.7; 69.3; 68.4; 62.6; 31.8-14 (C alkyl).

Example 11

trαπs-9-Octadecen-l-yI 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside:

728 mg of trarc.s-9-octadecen-l-yl α-D-glucopyranoside (1.69 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/9) 1.590 mg (95 %) of the title compound.

Rf = 0.23 (AcOEt/petroleum ether 40°-60° C : 1/9).

Η-NMR (CDCI3): 8.01-7.07 (m, 30 H-arom.); 6.11 (t, J= 9.9 Hz); 5.56 (t, J= 9.9 Hz); 5.40- 5.37 (m, 3 H); 5.32 (dd, J= 10.1, 3.7 Hz, H-C(2)); 4.26 (dt, J= 10.1, 4 Hz, H-C(5)); 3.88 (dt, J= 9.8, 6.5 Hz); 3.51 (dt, J= 9.7, 6.6 Hz); 3.29-3.28 (m, 2H, H-C(6)); 1.99-1.91 (m, 4H); 1.66- 1.60 (m, 2H); 1.35-1.17 (m, 22H); 0.87 (t, J= 6.8 Hz, 3H).

¹³C -NMR (CDCI3): 165.8-164.9 (3 C, CO); 146-126.8 (C arom.); 95.7 (C(l)); 86.6; 72.3; 71; 69.7; 69.3; 68.4; 62.6; 32.6-14.1 (C alkyl). Example 12

n-Dodecyl 2,3,4-tri-O-benzoyl-6-O-trityI-α-D-gIucopyranoside:

1 g of n-dodecyl α-D-glucopyranoside (3.52 mmoles) gave after flash chromatography (eluent AcOEt petroleum ether 40°-60° C : 1/8) 2.52 g (79 %) of the title compound. Rf = 0.21 (AcOEt/petroleum ether 40°-60° C : 1/9).

1H-NMR (CDC1₃): 8.15-7.07 (m, 30 H-arom.); 6.12 (t, J= 9.7 Hz); 5.57 (t, J= 9.9 Hz); 5.40 (d, J= 3.6 Hz, H-C(l)); 5.32 (dd, J= 10.1, 3.6 Hz, H-C(2)); 4.27 (dt, J= 10.1, 3.9 Hz, H-C(5)); 3.88 (dt, J= 9.8, 6.5 Hz); 3.52 (dt, J= 9.8, 6.8 Hz); 3.30-3.29 (m, 2H, H-C(6)); 1.67-1.63 (m, 2H); 1.38-1.17 (m, 18H); 0.88 (t, J= 6.8 Hz, 3H).

¹³C -NMR (CDCI₃): 165.8-164.9 (3 C, CO); 143.6-126.8 (C arom.); 95.7 (C(l)); 86.6; 72.3; 71.0; 69.7; 69.3; 68.4; 62.6; 31.9-14.1 (C alkyl).

Example 13

Eicosyl 2,3,4-tri-O-benzoyl-6-O-trityl-β-D-galactopyranoside :

990 mg of eicosyl β-D-galactopyranoside (2.15 mmoles) gave after flash chromatography

(gradient AcOEt/petroleum ether 40°-60° C : 1/12 to 1/8) 1.98 g (84 %) of the title compound.

Rf = 0.19 (AcOEt/petroleum ether 40°-60° C : 1/10). 1H-NMR (CDCI3): 7.95-7.09 (m, 30H); 6.06 (d, J= 3.1 Hz, H-C(4)); 5.67 (dd, J= 10.4, 7.6 Hz,

H-C(2)); 5.61 (dd, J= 10.4, 3.2 Hz, H-C(3)); 4.72 (d, J= 7.5 Hz, H-C(l)); 4.12-3.90 (m, 3H);

3.53-3.47 (m, 2H); 3.29 (dd appearing as t, J= 8.5 Hz); 1.56-1.47 (m, 2H); 1.35-1.01 (m, 34H);

0.87 (m, 3H).

¹³C -NMR (CDCI3): 165.2-165.1 (3 C, CO); 143.3-126.9 (C arom.); 101.6 (C(l)); 86.9; 72.5; 71.9; 70.3; 70.0; 68.1; 61.0; 31.9-14.1 (C alkyl). Examples of detritylation according to the procedure described above under "Detritylation":

Example 14

n-Octadecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside:

1.29 g of n-octadecyl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside (1.3 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/4) 730 mg (75%) of the title compound. Rf = 0.25 (AcOEt/petroleum ether 40°-60° C : 1/4).

Η-NMR (CDC1₃): 8.01-7.24 (m, 15 H-arom.); 6.26 (t, J= 9.8 Hz); 5.53 (t, J= 9.9 Hz); 5.39 (d,

J= 3.8 Hz, H-C(l)); 5.31 (dd, J= 10.1, 3.8 Hz, H-C(2)); 4.11 (m, H-C(5)); 3.83-3.73 (m, 3H);

3.48 (dt, J= 9.9, 6.6 Hz); 2.85 (dd, J= 7, 5.8 Hz, HO-C(6)); 1.62-1.56 (m, 2H); 1.31-1.14 (m,

30H); 0.88 (t, J= 6.9 Hz, 3H). ¹³C -NMR (CDCI₃): 166.2-165.6 (3 C, CO); 133.5-126.8 (C arom.); 95.9 (C(l)); 72.0; 70.3;

69.8; 69.6; 68.7; 61.0; 31.8-14.1 (C alkyl).

Example 15

cis-9-Octadecen-l-yI 2,3,4-tri-O-benzoyl-α-D-glucopyranoside:

1.08 g of c/.ϊ-9-octadecen-l-yl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside (1.1 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/3.5) 590 mg (72%) of the title compound. Rf = 0.23 (AcOEt/petroleum ether 40°-60° C : 1/3.5). Η-NMR (CDCI3): 8.00-7.24 (m, 15 H-arom.); 6.26 (t, J= 9.9 Hz); 5.53 (t, J= 9.8 Hz); 5.39 (d, J= 3.7 Hz, H-C(l)); 5.36-5.33 (m, 2H); 5.31 (dd, J= 10.1, 3.7 Hz, H-C(2)); 4.11-4.08 (m, H- C(5)); 3.84-3.72 (m, 3H); 3.48 (dt, J= 9.9, 6.6 Hz); 2.84 (br.s, HO-C(6)); 2.02-1.96 (m, 4H); 1.64-1.56 (m, 2H); 1.26-1.14 (m, 22H); 0.87 (t, J= 6.8 Hz, 3H). ¹³C -NMR (CDCI3): 166.2-165.6 (3 C, CO); 133.5-128.2 (C arom.); 95.9 (C(l)); 72.0; 70.3; 69.8; 69.6; 68.7; 61.0; 31.8-14.0 (C alkyl).

Example 16

frα/ι.s-Octadecen-1-yI 2,3,4-tri-O-benzoyl-α-D-glucopyranoside:

1.653 g of tran5-octadecen-l-yl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside (1.68 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/3.5) 919 mg (74%) of the title compound. Rf = 0.23 (AcOEt/petroleum ether 40°-60° C : 1/3.5).

Η-NMR (CDCI₃): 8.00-7.25 (m, 15 H-arom.); 6.25 (t, J= 9.9 Hz); 5.51 (t, J= 9.8 Hz); 5.38- 5.37 (m, 3H); 5.30 (dd, J= 10.1, 3.7 Hz, H-C(2)); 4.09 (br.d, J= 9.8 Hz, H-C(5)); 3.84-3.73 (m, 3H); 3.47 (dt, J= 9.8, 6.6 Hz); 2.80 (br.s, HO-C(6)); 1.99-1.91 (m, 4H); 1.64-1.54 (m, 2H); 1.38-1.14 (m, 22H); 0.88 (m, 3H). ¹³C -NMR (CDCI₃): 166.3-165.7 (3 C, CO); 133.6-128.2 (C arom.); 95.9 (C(l)); 72.1; 70.3; 69.8; 69.6; 68.7; 61.1; 32.5-14.0 (C alkyl).

Example 17

n-Tetradecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside:

The 6-O-trityl derivative of the title compound was prepared as follows.2,3,4,6-Tetra-O- benzyl-α-D-glucopyranosyl chloride (5g, 8.9 mmol), obtained by treatment of commercially available 2,3,4,6-tetra-O-benzyl-α-D-glucopyranose

dimethylformamide and oxalyl chloride in dichloromethane, «-tetradecanol (13.4 mmol) and tetrabutylammonium bromide (13.4 mmol) were dissolved in CH2CI2 containing molecular sieves (4A) and stirred at room temperature for three days. TLC (toluene: EtOAc 6: 1) indicated that only about half of the starting material was consumed. Silver trifluoromethanesulfonate (8.9 mmol) dissolved in toluene was therefore added. After 1 h triethylamine (26.8 mmol) was added to the reaction mixture, which then was applied directly on top of a silica gel column and eluted to give the α- and the β-anomer in a mixture. The mixture was dissolved in EtOAc and hydrogenolyzed over palladium on charcoal at 60 psi in a Parr apparatus overnight. The catalyst was filtered off and the filtrate concentrated. Flash chromatography was performed to separate the anomeric mixture, giving the anomers in a ratio of 3: 1 (α:β). The β-anomer was used in Example 18. The residue was dissolved in pyridine and triphenylmethyl chloride (9.8 mmol) and dimethylaminopyridine (catalytic amount) was added. The mixture was heated at 55 °C and stirred for three days, then diluted with CHCI3 and the organic phase washed with Na2S2θ3 (twice), NaHCO3 (3 times) and water (twice), then dried (Na2SO4) and concentrated. The residue was dissolved in pyridine and cooled in an ice-bath. Benzoyl chloride (44.5 mmol) was added dropwise. The mixture was allowed to attain room temperature and stirred for an additional hour whereafter ice was added to the mixture. After another hour the mixture was diluted with toluene and the organic phase was separated and washed with water, NaHCO3 and water, dried (Na2SO4) and concentrated. The residue was purified on a silica gel column to give rc-tetradecyl 2,3,4-tri-O-benzoyl-6- O-trityl-α-D-glucopyranoside. Detritylation of n-tetradecyl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside was performed with stirring for 1 hour only, giving after flash chromatography 300 mg (48%) of the title compound.

^I3C -NMR (CDCI₃ (ref.77.17 ppm), JEOL GX-270): 166.2-165.7 (3 C, CO); 133.5-128.2 (C arom.); 95.9 (C(l)); 72.1; 70.5; 69.9; 69.6; 68.7; 61.1; 31.9-14.1 (C alkyl).

Example 18

n-Tetradecyl 2,3,4-tri-O-benzoyl-β-D-glucopyranoside:

In order to prepare the 6-O-trityl derivative of the title compound, n-tetradecyl β-D- glucopyranoside (produced as in Example 17) was dissolved in pyridine and triphenylmethyl chloride (9.8 mmol) and dimethylaminopyridine (catalytic amount) were added. The mixture was heated at 55 °C and stirred for three days, then diluted with CHCI3 and the organic phase washed with Na2S2θ3 (twice), NaHCO3 (3 times) and water (twice), then dried (Na2SO4) and concentrated. The residue was dissolved in pyridine and cooled in an ice-bath. Benzoyl chloride (44.5 mmol) was added dropwise. The mixture was allowed to attain room temperature and stirred for an additional hour whereafter ice was added to the mixture. After another hour the mixture was diluted with toluene and the organic phase was separated and washed with water, NaHCO3 and water, dried (Na2SO4) and concentrated. The residue was purified on a silica gel column to give n-tetradecyl 2,3,4-tri- O-benzoyl-6-O-trityl-β-D-glucopyranoside.

Detritylation of ra-tetradecyl 2,3,4-tri-O-benzoyl-6-O-trityl-β-D-glucopyranoside was performed with stirring for 1 hour only, giving after flash chromatography 56 mg (9%) of the title compound.

¹³C -NMR (CDC1₃ (ref. 77.17 ppm), JEOL GX-270): 166.2-165.7 (3 C, CO); 133.5-128.2 (C arom.); 95.9 (C(l)); 72.1; 70.5; 69.9; 69.6; 68.7; 61.1; 31.9-14.1 (C alkyl).

Example 19

DodecyI 2,3,4-tri-O-benzoyl-α-D-glucopyranoside:

2.8 g of n-dodecyl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-glucopyranoside (3.1 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/3.5) 1.564 g (76%) of the title compound. Rf = 0.17 (AcOEt/petroleum ether 40°-60° C : 1/4).

1H-NMR (CDCI₃): 8.01-7.25 (m, 15 H-arom.); 6.26 (t, J= 9.9 Hz); 5.52 (t, J= 9.8 Hz); 5.38 (d, J= 3.8 Hz, H-C(l)); 5.30 (dd, J= 10.1, 3.8 Hz, H-C(2)); 4.10 (ddd, J= 9.8, 3.5, 2.1 Hz, H- C(5)); 3.82-3.73 (m, 3H); 3.48 (dt, J= 9.9, 6.6 Hz); 2.81 (br.s, HO-C(6)); 1.62-1.58 (m, 2H); 1.31-1.15 (m, 18H); 0.88 (t, J= 6.9 Hz, 3H). ¹³C -NMR (CDCI₃): 166.3-165.7 (3 C, CO); 133.5-128.2 (C arom.); 95.9 (C(l)); 72.0; 70.3; 69.8; 69.6; 68.7; 61.0; 31.8-14.0 (C alkyl).

Example 20

Eicosyl 2,3,4-tri-O-benzoyI-β-D-galactopyranoside:

1.5 g of eicosyl 2,3,4-tri-O-benzoyl-6-O-trityl-α-D-galactopyranoside (1.48 mmoles) gave after flash chromatography (eluent AcOEt/petroleum ether 40°-60° C : 1/3) 901 mg (79%) of the title compound. Rf = 0.24 (AcOEt/petroleum ether 40°-60° C : 1/3). Η-NMR (CDCI₃): 8,15-7.23 (m, 15H); 5.84 (dd, J= 10.4, 7.9 Hz, H-C(2)); 5.82 (d, J= 3.3 Hz,

H-C(4)); 5.59 (dd, J= 10.4, 3.3 Hz, H-C(3)); 4.79 (d, J= 7.9 Hz, H-C(l)); 4.03 (t, J= 6.9 Hz);

3.96 (dt, J= 9.6, 6.1 Hz); 3.84 (dt, J= 11.9, 7.0 Hz, H-C(6)); 3.66 (dt, J= 11.9, 6.9 Hz, H-C(6));

3.56 (dt, J= 9.6, 6.8 Hz); 2.65 (t, J= 7.2 Hz, HO-C(6)); 1.63-1.50 (m, 2H); 1.39-1.00 (m, 34H);

0.88 (dd, J= 6.7, 6.1 Hz, 3H).

¹³C -NMR (CDCI₃): 166.9-165.3 (3 C, CO); 133.8-128.3 (C arom.); 101.8 (C(l)); 74.0; 71.8;

70.6; 70.0; 69.1; 60.6; 31.9-14.1 (C alkyl).

Examples of preparation of diesters of phosphonoformic acid according to the procedure described above under "Preparation of diesters of phosphonoformic acid"

Example 21

n-OctadecyI 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate: 700 mg of octadecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (0.94 mmoles) gave after flash chromatography (gradient AcOEt/MeOH : 5/1 to AcOEt/MeOH/H₂O: 8/1.5/0.5) 580 mg

(70%) of the title compound.

Rf = 0.31 (AcOEt/MeOH : 5/1).

Η-NMR (DMSO-d6): 7.96-7.47 (m, 15 H-arom.); 6.03 (t, J= 9.7 Hz); 5.59 (t, J= 9.8 Hz); 5.39 (d, J= 3.4 Hz, H-C(D); 5.34 (dd, J= 10.1, 3.4 Hz, H-C(2)); 4.37-4.33 (m, H-C(5)); 4.09-3.86

(m, 5H); 3.55 (m, 1H); 1.66-1.62 (m, 2H); 1.35-1.23 (m, 30H); 1.14 (t, J= 7.1 Hz, 3H); 0.92 (t,

J= 6.7 Hz, 3H).

¹³C -NMR (DMSO-d6): 174 (d, J_CO-p = 249 Hz); 165.2-164.5 (3 C, CO); 133.7-128.6 (C arom.); 94.9 (C(l)); 71.4; 70.9; 69.0; 68.7 (d, J_C._P = 5.6 Hz); 67.5; 63.6 (d, J_C._P = 3.2 Hz); 58.4 (br.d); 31.3-13.9 (C alkyl). Example 22

cw-9-Octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxy carbony l)phosphonate : 590 mg of cw-9-octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (0.794 mmoles) gave after flash chromatography (gradient AcOEt/MeOH : 5/1 to AcOEt/MeOH/H_O:

8/1.5/0.5) 600 mg (86%) of the title compound.

Rf = 0.23 (AcOEt/MeOH : 5/1).

Η-NMR (CDCl₃/CD₃OD: 2/1, (ref. 3.36 ppm)): 7.96-7.26 (m, 15 H-arom.); 6.16 (t, J= 9.7 Hz); 5.64 (t, J= 9.8 Hz); 5.34-5.31 (m, 3H); 5.24 (dd, J= 10.3, 3.4 Hz, H-C(2)); 4.32-4.09 (m,

5H); 3.86-3.82 (m, 1H); 3.48-3.43 (m, 1H); 2.02-1.95 (m, 4H); 1.58-1.54 (m, 2H); 1.27-1.10

(m, 25H); 0.88 (m, 3H).

¹³C -NMR (CDCl₃/CD₃OD: 2/1, (ref. 49.0 ppm)): 173.6 (d, J_CO-p = 250 Hz); 166.4-165.9 (3 C,

CO); 133.9-128.6 (C arom.); 96.2 (C(l)); 72.4; 71.3; 69.5; 69.3 (d, J_C._P = 7.5 Hz); 69.1; 64.9 (d, J_c-_P = 5.3 Hz); 61.3(d, J_C._P = 3.8 Hz); 32.2-14.1 (C alkyl).

Example 23

tr ns-9-Octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate:

919 mg of traτw-9-octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (1.237 mmoles) gave after flash chromatography (gradient AcOEt/MeOH : 5/1 to AcOEt/MeOH/ffcO: 8/1.5/0.5) 872 mg (80%) of the title compound. Rf = 0.23 (AcOEt/MeOH : 5/1). 1H-NMR (CDC1₃/ CD₃OD: 2/1, (ref. 3.35 ppm)): 7.97-7.27 (m, 15 H-arom.); 6.15 (t, J= 9.7 Hz); 5.63 (t, J= 9.8 Hz); 5.39-5.36 (m, 2H); 5.32 (d, J= 3.7 Hz, H-C(l)); 5.24 (dd, J= 10.1, 3.7 Hz, H-C(2)); 4.33-4.09 (m, 5H); 3.86 (dt, J= 9.8, 6.3 Hz); 3.47 (dt, J= 9.8, 6.1 Hz); 2.00-1.90 (m, 4H); 1.58-1.54 (m, 2H); 1.27-1.10 (m, 25H); 0.88 (t, J= 6.7 Hz, 3H). ¹³C -NMR (CDCI3 CD₃OD: 2/1, (ref. 77.0 ppm)): 172.7 (d, J_CO-_P = 250 Hz); 165.6-165.1 (3 C, CO); 133.1-127.8 (C arom.); 95.4 (C(l)); 71.6; 70.5; 68.6; 68.3 (d, J_C-_P = 6.9 Hz); 68.2; 64.1 (d, J_C._P = 5.2 Hz); 60.4 (d, J_C-p = 3.8 Hz); 32.0-13.2 (C alkyl).

Example 24

n-Tetradecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxy carbonyI)phosphonate :

Deviation from the general procedure: Stirring at room temperature only one extra hour, and after extraction dried with Na SO₄. 1 g of n-tetradecyl 2,3,4-tri-O-benzoyl-α-D- glucopyranoside (1.45 mmoles) gave after flash chromatography (AcOEt/MeOH ^O:

10/1.5/0.5) 413 mg (34%) of the title compound.

Rf = 0.25 (AcOEt/MeOH/H₂O: 10/1.5/0.5).

Η-NMR (DMSO-d6): 7.9-7.4 (m, 15 H-arom.); 5.92 (t, J= 9.8 Hz); 5.47 (t, J= 9.8 Hz); 5.29 (d, J= 3.6 Hz, H-C(l)); 5.25 (dd, J= 10.4, 3.6 Hz, H-C(2)); 1.14 (t); 0.92 (t).

¹³C -NMR (DMSO-d6): 176.2 (d, J_C0-_P = 232 Hz); 165.2-164.5 (3 C, CO); 133.8-128.5 (C arom.); 94.8 (C(l)); 71.4; 70.9; 69.0; 68.8 (d, J_C._P = 6.9 Hz); 67.5; 63.5 (d, J_C._P = 5.3 Hz); 58.2

(d, J_c-_P = 3.0 Hz);); 31.3-13.9 (C alkyl).

Example 25

n-Tetradecyl 2,3,4-tri-O-benzoyl-β-D-glucopyranosid-6-yl (ethoxy carbony l)phosphonate :

Deviation from the general procedure: Stirring at room temperature only one extra hour, and after extraction dried with Na₂SO₄. 561 mg of tetradecyl 2,3,4-tri-O-benzoyl-β-D- glucopyranoside (0.81 mmoles) gave after flash chromatography (AcOEt/MeOH/H₂O: 10/1.5/0.5) 305 mg (45%) of the title compound. Rf = 0.5 (AcOEt/MeOH/H₂O: 8/1.5/0.5). 1H-NMR (DMSO-d6): 8.2-7.0 (m, 15 H-arom.); 5.92 (t, J= 9.6 Hz); 5.43 (t, J= 9.6 Hz); 5.27 (t, J= 9.6 Hz); 5.10 (d, J= 9.1, H-C(l)); 4.4-3.68 (m).

¹³C -NMR (DMSO-d6): 165.0-164.5 (3 C, CO); 135.1-127.4 (C arom.); 99.5 (C(l)); 73.3; 72.1 (d, Jc-_P = 6.9 Hz); 71.7; 69.0; 64.3; 59.6 (d, J_C._P = 3.8 Hz); 31.3-13.5 (C alkyl).

Example 26

n-Dodecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate:

1.3 g of n-dodecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranoside (1.97 mmoles) gave after flash chromatography (gradient AcOEt/MeOH : 5/1 to AcOEt/MeOH/H₂O: 8/1.5/0.5) 1.345 mg

(86%) of the title compound.

Rf = 0.20 (AcOEt/MeOH : 5/1).

Η-NMR (CDC1₃/ CD₃OD: 2/1): 7.96-7.24 (m, 15 H-arom.); 6.18 (t, J= 9.8 Hz); 5.66 (t, J= 9.7

Hz); 5.34 (d, J= 3.5 Hz, H-C(l)); 5.26 (dd, J= 10.1, 3.5 Hz, H-C(2)); 4.33-4.11 (m, 5H); 3.86 (m, IH); 3.47 (dt, J= 9.8, 6.7 Hz); 1.64-1.55 (m, 2H); 1.32-1.14 (m, 21H); 0.88 (t, J= 6.8 Hz,

3H).

¹³C -NMR (CDC1₃/ CD₃OD: 2/1, (ref. 77.0 ppm)): 172.8 (d, J_C0-_P = 251 Hz); 165.6-165.1 (3

C, CO); 133.1-127.8 (C arom.); 95.4 (C(l)); 71.6; 70.5; 68.7; 68.3 (d, J_c-P = 7.7 Hz); 68.2;

64.1 (d, J_c-_P = 4.9 Hz); 60.4 (d, J_c-P = 3.8 Hz); 31.4-13.3 (C alkyl).

Example 27

Eicosyl 2,3,4-tri-O-benzoyI-β-D-galactopyranosid-6-yl (ethoxycarbonyl)phosphonate:

854 mg of eicosyl 2,3,4-tri-O-benzoyl-α-D-galactopyranoside (1.1 mmoles) gave after flash chromatography (gradient AcOEt/MeOH : 5/1 to AcOEt/MeOH/H₂O: 8/1.5/0.5) 803 mg (80%) of the title compound. Rf = 0.25 (AcOEt/MeOH : 5/1).

Η-NMR (CDC1₃/ CD₃OD: 2/1): 8.06-7.24 (m, 15 H-arom.); 5.96 (d, J= 3.2 Hz, H-C(4); 5.74 (dd, J= 10.2, 7.9 Hz, H-C(2)); 5.62 (dd, J= 10.4, 3.2 Hz, H-C(3)); 4.89 (d, J= 7.9 Hz, H-C(l)); 4.34-3.96 (m, 6H); 3.62-3.56 (m, IH); 1.56-1.49 (m, 2H); 1.32-1.00 (m, 37H); 0.88 (t, J= 6.7 Hz, 3H).

¹³C -NMR (CDC1₃/ CD₃OD: 2/1, (ref. 77.0 ppm)): 172.7 (d, J_C0-_P = 249 Hz); 165.7-165.3 (3 C, CO); 133.3-127.9 (C arom.); 101.1 (C(l)); 72.0 (d, J_C-_P = 6.9 Hz); 71.7; 70.1; 69.7; 67.9; 63.1 (d, J_C-P = 5.3 Hz); 60.60 (d, J_c-P = 3.8 Hz); 31.5-13.4 (C alkyl).

Examples of preparation of monoesters of phosphonoformic acid according to the procedure described under "Preparation of monoesters of phosphonoformic acid":

Example 28

Disodium n-octadecyl α-D-glucopyranosid-6-yI carboxyphosphonate:

500 mg of n-octadecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl

(ethoxycarbonyl)phosphonate (0.568 mmoles) gave after reverse phase chromatography (gradient H₂O, H₂O/ MeOH: 1/4) 190 mg (57%) of the title compound.

Rf = 0.06 (AcOEt/MeOH/H₂O: 7/2/1).

Η-NMR (D₂O): 4.84 (d, J= 2.8 Hz, H-C(l)); 4.24 (t, J= 9.8); 3.94 (m, IH); 3.73-3.52 (m, 5H);

3.39 (m, IH); 1.56 (m, 2H); 1.35-1.18 (m, 30H); 0.82 (m, 3H).

¹³C -NMR (D₂O): 178.5 (d, J_C0-p = 230 Hz); 99.7 (C(l)); 73.4; 72.4; 71.9 (br.s); 69.6; 69.5 (br.s); 67.5; 64.1 (br.s); 33.0-14.9 (C alkyl).

Example 29

Disodium cw-9-octadecen-l-yl α-D-glucopyranosid-6-yl carboxyphosphonate: 500 mg of cw-9-octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl

(ethoxycarbonyl)phosphonate (0.569 mmoles) gave after reverse phase chromatography (gradient H₂O, H₂O/ MeOH: 1/4) 176 mg (53%) of the title compound. Rf = 0.06 (AcOEt/MeOH/H₂O: 7/2/1). Η-NMR (D₂O): 5.28 (m, 2H olef.); 4.81 (br.s, H-C(l)); 4.22 (m, IH); 3.93 (m, IH); 3.68-3.49 (m, 5H); 3.38 (m, IH); 1.95 (m, 4H); 1.54 (m, 2H); 1.24-1.16 (m, 22H); 0.83 (m, 3H). ¹³C -NMR (D₂O): 177.7 (d, J_Co-p = 232 Hz); 100 (C(l)); 73.7; 72.8; 70.2 (d, J_C._P = 6.9 Hz); 69.8 (2C); 64.4 (d, J_C-_P = 3.8 Hz); 35.4-15.2 (C alkyl).

Example 30

Disodium rαns-9-octadecen-l-yl α-D-glucopyranosid-6-yl carboxyphosphonate:

737 mg of tn s-9-octadecen-l-yl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate (0.838 mmoles) after reverse phase chromatography (gradient

H₂O, H₂O/ MeOH: 1/4) 153 mg (31%) of the title compound.

Rf = 0.06 (AcOEt/MeOH/H₂O: 7/2/1).

1H-NMR (D₂O): 5.30 (m, 2H olef); 4.82 (br.s, H-C(l)); 4.22 (m, IH); 3.93 (m, IH); 3.69-3.38

(m, 6H); 1.94-1.89 (m, 4H); 1.55 (m, 2H); 1.27-1.18 (m, 22H); 0.79 (m, 3H). ¹³C -NMR (D₂O): 187.7 (d, J_C0-_P = 232 Hz); 100 (C(l)); 73.7; 72.8; 70.2 (d, J_C-_P = 6.9 Hz);

69.8 (2C); 64.4 (d, J_C._P = 3.8 Hz); 35.4-15.2 (C alkyl).

Example 31

Disodium n-tetradecyl α-D-glucopyranosid-6-yl carboxyphosphonate:

(35 ml THF was used) 413 mg of n-tetradecyl 2,3,4-tri-O-benzoyl-α-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate (0.50 mmoles) gave, after flash chromatography, (MeOH/FfeO : 3/1) 180 mg (71%) of the title compound. Rf = 0.34 (MeOH/H₂O 3/1). Η-NMR (D₂O): 4.82 (d, H-C(l)); 4.24 (t, IH); 3.97 (m, IH); 3.74-3.50 (m, 6H); 3.41 (IH); 1.59 (m, 2H); 1.4-1.2 (m, 22H); 0.82 (m, 3H). ^I3C-NMR (D₂O, (ref. CD₃OD 49.0 ppm)): 178.4 (d, J_CO-_P= 232 Hz); 99.6 (C(l)); 73.4; 72.4;

71.9 (d, J_C-_P =6.9 Hz); 69.4; 69.5; 64.2 (d, J_c-P =4.6 Hz); 32.7-14.7 (C alkyl). ³¹P-NMR (D₂O, H-coupled, (ref. H₃PO₄0 ppm)): 1.49 (s). Example 32

Disodium n-tetradecyl β-D-glucopyranosid-6-yl carboxyphosphonate:

(8 ml THF was used) 303 mg of n-tetradecyl 2,3,4-tri-O-benzoyl-β-D-glucopyranosid-6-yl (ethoxycarbonyl)phosphonate (0.37 mmoles) gave after flash chromatography (MeOU/HO: 3/1) 174 mg (93%) of the title compound. Rf = 0.19 (MeOH/H₂O: 3/1)

Η-NMR (D₂O): 4.43 (d, J= 2.8 Hz, H-C(l)); 4.24 (t, J= 9.8); 3.90 (m, IH); 3.64-3.42 (m, 6H); 3.29 (m, IH); 1.6 (m, 2H); 1.4-1.2 (m, 22H); 0.82 (m, 3H).

¹³C -NMR (D₂O): 178.5 (d, J_C0-_P = 232 Hz); 100.0 (C(l)); 72.6; 72.3 (d, J_C._P = 6.1 Hz); 70.7; 68.2; 66.2; 60.7 (d, J_C-_P =5.4 Hz); 28.9-11.0 (C alkyl).

Example 33

Disodium n-dodecyl α-D-glucopyranosid-6-yl carboxyphosphonate:

1.285 mg of rt-dodecyl 2,3,4 tri-O-benzoyl-α-D-glucopyranosid-6-yl

(ethoxycarbonyl)phosphonate (1.612 mmoles) gave after reverse phase chromatography

(gradient H₂O, H₂O/ MeOH: 1/4) 532 mg (66 %) of the title compound.

Rf = 0.06 (AcOEt/MeOH/H₂O: 7/2/1).

1H-NMR (D₂O): 4.78 (d, J= 3.6 Hz, H-C(l)); 4.10 (m, IH); 3.92 (br.dd, J= 11.1, 3.7 Hz, H-

C(6)); 3.63-3.49 (m, 4H); 3.46 (dd, J= 9.8, 3.6 Hz, H-C(2)); 3.38 (dt, J= 9.7, 6.6 Hz); 1.50-

1.46 (m, 2H); 1.16 (m, 18H); 0.75 (t, J= 6.8 Hz, 3H).

¹³C -NMR (D₂O): 176.2 (d, J_C0-_P = 233 Hz); 97.2 (C(l)); 71.4; 70.2; 69.7 (d, J_C-P = 6.9 Hz);

67.5; 67.3; 62.0 (d, J_C._P = 5.4 Hz); 30.2-12.4 (C alkyl). Example 34

Disodium eicosyl β-D-galactopyranosid-6-yl carboxyphosphonate:

700 mg of eicosyl 2,3,4-tri-O-benzoyl-β-D-galactopyranosid-6-yl

(ethoxycarbonyl)phosphonate (0.77 mmoles) gave after reverse phase chromatography

(gradient H₂O, H₂O/ MeOH: 1/4) 170 mg (36 %) of the title compound.

Rf = 0.06 (AcOEt/MeOH/H₂O: 7/2/1).

'H-NMR (D₂O): 4.91 (d, J= 7.1 Hz, H-C(l)); 4.31 (m, H-C(6)); 4.03 (m, H-C(6)); 3.79-3.46

(m, 6H); 1.61-1.55 (m, 2H); 1.48-1.38 (m, 34H); 0.85 (t, J= 6.8 Hz, 3H).

¹³C -NMR (D₂O): 178.8 (d, J_C0-_P = 231 Hz); 101.1 (C(l)); 73.7; 72.7; 72.2 (d, J_C._P = 6.9 Hz);

69.8 (2C); 64.5 (br.s); 33.9-15.2 (C alkyl).

Tests for antiviral activity

The antiviral activity of the compounds of the invention may be determined according to the method of Wahren, B. et al. J. Virol. Methods 6, (1983) 141-149. Thus confluent human lung fibroblast cells are infected with Herpes simplex virus type 1 (HSV-1). After absorption for one hour at 37°C, virus is removed and antiviral drugs diluted in cell media were added, at concentrations of 800 μM down to 3 μM. Cells are incubated at 37 °C in a humidified atmosphere of 5% CO2 in air until characteristic cytopathic effect is seen in control wells (24-48 h). Cells are lysed by addition of Triton X-100, and viral antigen content of the supernatants measured by enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody.

The title compounds of Examples 28 to 34 were tested according to this test method for antiviral activity and were all found to be active.

Claims

Claims

1. A compound of the formula I

wherein the wavy line signifies a bond which is either in the α- or in the β-configuration;

n is 0 or 1 ;

Ri is Ci .₂4-alkyl, C₂.₂ -alkenyl, C₂.₂₄-alkapolyenyl containing 2 to 6 double bonds, C₂. ₂₄-alkynyl, C₃.₈-cycloalkyl, C₃. g-cycloalkyl-Q .₂4-alkyl, or . ₁₂-alkoxy-Cι . ₁₂-alkyl group, all of which may be branched or unbranched and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo;

R₂, R₃ and R₄ are each independently hydrogen, halogen, amino, acetylamino, azido, or a group XRe wherein X is O or S and Rό is hydrogen, a branched or unbranched 0 .₄-alkyl or C₂.4-alkenyl group both of which may be optionally substituted with hydroxy, amino, halogen, or oxo, or

R2, R3 and R4 together with the respective geminal hydrogen represent an oxo group; R₅ is hydrogen, or R₅ is a phenyl group of the formula II or III,

II

wherein R and R₈ are the same or different and are bound to any two positions of the phenyl ring and each is selected from the group consisting of hydrogen, halogen, or .₄- alkyl, d .₄-alkoxy, .₄-acyl, .₄-acyloxy, C₂.₅-alkoxycarbonyl all of which may be branched or unbranched; or R₇ and R₈ together form an unbranched saturated alkylene chain having 3 or 4 carbon atoms bound to adjacent positions, i.e. 2,3- or 3,4- in the phenyl ring; or R₇ and R₈ together form a methylenedioxy group, a 1,1-ethylidenedioxy group, or a 1,2-ethylenedioxy group bound to the 2,3- or 3,4-positions of the phenyl ring,

or R₅ is a group R₉COOCHR₁₀- or a group R₉OCOOCHRι₀-

wherein R₉ is Ci .₆-alkyl, C₂.₆-alkenyl, C₂.₆-alkynyl, C₃.₈-cycloalkyl, C₃.₈-cycloalkyl-Cι ₆-alkyl, or . -alkoxy-C! .₆-alkyl group all of which may be branched or unbranched, which is optionally substituted with hydroxy, amino, halogen, or oxo; and Rι₀ is hydrogen or a branched or unbranched Q . -alkyl group; and wherein the configurations of the substituents R₂, R₃, R₄ and R₅OOCPO(OH)OCH₂- in I independently are D-gluco, L-gluco, D-galacto, L-galacto, D-manno, L-manno, D-talo, L- talo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-ido, or L-ido when n is 1, or that the configurations of the substituents R₂, R₃ and R₅OOCPO(OH)OCH₂- in I independently are D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D-lyxo, or L-lyxo when n is 0;

and physiologically acceptable salts and optical isomers thereof.

2. A compound according to claim 1 wherein R\ is a C9_24-alkyl, C9_24-alkenyl, C9.24- alkapolyenyl containing 2 to 6 double bonds, C9.24- lkynyl, C3 . s-cycloalkyl-Cg .24-alkyl, or Cι_i2- lkoxy-C8- 12-alkyl group.

3. A compound according to either of claims 1 or 2 wherein R₂, R₃ and R₄ are each a hydroxyl group.

4. A compound according to any one of claims 1 to 3 wherein R₅ is hydrogen.

5. A compound according to any one of claims 1 to 4 wherein the configuration of the glycosidic bond is α-.

6. A compound according to any one of claims 1 to 4 wherein the configuration of the glycosidic bond is β-.

7. A compound according to any one of claims 1 to 6 wherein n is 1.

8. A compound of the formula I according to any one of claims 1 to 7 wherein the configuration of the substituents R₂, R₃, R4 and R₅OOCPO(OH)OCH₂- is D-gluco.

9. A compound according to any one of claims 1 to 8 wherein Rj is n-tetradecyl; n-octadecyl; tra w-9-octadecen-l-yl, orcw-9-octadecen-l-yl.

10. A process for the preparation of a compound of formula I according to claim 1, carrying at least one group capable of protection, characterized by

deprotection of a compound of the formula

wherein R' has the meaning given above for R5 with the exception of hydrogen, or R' is branched or unbranched .g-alkyl, and ProtGlycoside-O- corresponds to a group of the formula

wherein n is 0 or 1, Ri has the meaning given above and R₁₅, R₁₆ and R[₇ each correspond to the groups R₂, R₃ and R4, respectively, which have been derivatized by suitable protective groups where appropriate.

11. A process according to claim 10 wherein R₁₅, Rι and R₁ each correspond to the groups R₂, R₃ and R4, respectively, at least one or more of which have been derivatized where appropriate by methoxymethyl, methylthiomethyl, benzyloxymethyl,/?- methoxybenzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 2,2,2-trichloroethyl, 2- trimethylsilylethyl, t-butyl, allyl, but-2-enyl, 3-methylbut-2-enyl,/?-methoxyphenyl, benzyl, /7-methoxybenzyl, 3,4-dimethoxybenzyl,/?-nitrobenzyl, diphenylmethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, isobutyryl, pivaloyl, benzoyl, -methoxy benzoyl, /?-chlorobenzoyl, /?-bromobenzoyl, 2,2,2- trichloroethoxycarbonyl, methanesulfonyl or -toluenesulfonyl in the case where at least one of the groups R₂, R₃ and R4 is a hydroxyl group, or R5 is substituted by a hydroxyl group, or ethylidene, isopropylidene, cyclohexylidene, benzylidene,/?-methoxybenzylidene, methoxymethylene, ethoxymethylene, di-r-butylsilylene, or tetraisopropyldisiloxane-1,3- diylidene in the case where at least two of groups R₂, R₃ and R4 are hydroxyl groups, or methoxy methyl, benzylthiomethyl, phenylthiomethyl, tetrahydropyranyl, 2-cyanoethyl, benzyl, -methoxybenzyl,/?-nitrobenzyl, diphenylmethyl, t-butyl, acetyl, benzoyl, 2,2,2- trichloroethoxycarbonyl, r-butoxycarbonyl or benzyloxycarbonyl in the case where at least one of the groups R₂, R₃ and R₄ is a thiol group, or ethoxycarbonyl, 9- fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, t-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, -methoxybenzyloxycarbonyl, - nitrobenzyloxycarbonyl, formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phthaloyl, allyl, 2-trimethylsilylethoxymethyl, benzyl, benzylidene or -methoxybenzylidene in the case where at least one of the groups of the groups R₂, R3 and R4 is an amino group, or Rg is substituted by an amino group, or finally, in the case where one of the groups R₂, R₃ and R₄ together with the respective geminal hydrogen represents oxo, or R5 is substituted by an oxo group, then the group is derivatized as e.g. a dimethyl ketal, a bis(2,2,2-trichloroethyl) ketal, a dibenzyl ketal, a diacetyl ketal, a 1,3-dioxane, a 5-methylene-l,3-dioxane, a 1,3- dioxolane, a S,S'-dimethyl dithioketal, a S,S'-dibenzyl dithioketal, a S,S'-diacetyl dithioketal, a 1,3-dithiane, a 1,3-dithiolane, a 1 ,3-oxathiolane, an O-acetyl cyanohydrin, an O-trimethylsilyl cyanohydrin, an N,N-dimethylhydrazone, a 2,4-dinitrophenylhydrazone, an oxime, or an O-methyloxime.

12. A process for the preparation of compounds of the formula I as defined in claim 1, characterized by A. Selective removal of one of the protected glycoside groups of a compound of the formula

ProtGlycoside-O

wherein R' has the meaning given above for R₅ with the exception of hydrogen, or R' is branched or unbranched .₆-alkyl;

ProtGlycoside-O- corresponds to a group of the formula

wherein n is 0 or 1, R_\ has the meaning given above and R₁₅, R_f6 and R₁₇ each correspond to the groups R₂, R₃ and R₄, respectively, which have been derivatized where appropriate by methoxymethyl, methylthiomethyl, benzyloxymethyl,/7-methoxybenzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl,t-butyl, allyl, but-2-enyl, 3-methylbut-2-enyl, -methoxyphenyl, benzyl, -methoxybenzyl, 3,4- dimethoxybenzyl,/?-nitrobenzyl, diphenylmethyl, trimethylsilyl, triethylsilyl,r- butyldimethylsilyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl, isobutyryl, pivaloyl, benzoyl, p-methoxybenzoyl, p-chlorobenzoyl, -bromobenzoyl, 2,2,2- trichloroethoxycarbonyl, methanesulfonyl or/?-toluenesulfonyl in the case where at least one of the groups R₂, R₃ and R4is a hydroxyl group, or Rg is substituted by a hydroxyl group, or ethylidene, isopropylidene, cyclohexylidene, benzylidene,/?-methoxybenzylidene, methoxymethylene, ethoxymethylene, di-t-butylsilylene, or tetraisopropyldisiloxane-l,3-di- ylidene in the case where at least two of groups R₂, R₃ and R₄ are hydroxyl groups, or methoxymethyl, benzylthiomethyl, phenyl thiome thy 1, tetrahydropyranyl, 2-cyanoethyl, benzyl, -methoxybenzyl,/?-nitrobenzyl, diphenylmethyl, t-butyl, acetyl, benzoyl, 2,2,2- trichloroethoxycarbonyl, t-butoxycarbonyl or benzyloxycarbonyl in the case where at least one of the groups R₂, R₃ and R4 is a thiol group, or ethoxycarbonyl, 9- fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, r-butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl , -methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, formyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, phthaloyl, allyl, 2-trimethylsilylethoxymethyl, benzyl, benzylidene or -methoxybenzylidene in the case where at least one of the groups of the groups R₂, R₃ and R₄ is an amino group, or R is substituted by an amino group, or finally, in the case where one of the groups R₂, R₃ and R4 together with the respective geminal hydrogen represents oxo, or R5 is substituted by an oxo group, then the group is derivatized as a dimethyl ketal, a bis(2,2,2-trichloroethyl) ketal, a dibenzyl ketal, a diacetyl ketal, a 1,3-dioxane, a 5-methylene-l,3-dioxane, a 1,3- dioxolane, a S,S'-dimethyl dithioketal, a S,S'-dibenzyl dithioketal, a S,S'-diacetyl dithioketal, a 1,3-dithiane, a 1,3-dithiolane, a 1,3-oxathiolane, an O-acetyl cyanohydrin, an O-trimethylsilyl cyanohydrin, an N,N-dimethylhydrazone, a 2,4-dinitrophenylhydrazone, an oxime, or an O-methyloxime;

to give a compound of the formula

and, optionally, final deprotection with or without removal of R' to give, except where R' is branched or unbranched .₆-alkyl, a compound of the formula I.

B. Reaction of one equivalent of a compound of the formula

wherein R' has the meaning given above for R₅ with the exception of hydrogen, or R' is branched or unbranched .₆-alkyl and Hal is CI, Br, or I with one equivalent or less of a glycoside ProtGlycoside-OH, which may be suitably protected, with a free hydroxyl group at the 6-position if a hexose or at the 5-position if a pentose, wherein ProtGlycoside-O- is defined as above in A, in the absence of base to give a compound of the formula

and, optionally, final deprotection with or without removal of R' to give, except where R' is branched or unbranched .₆-alkyl, a compound of the formula I.

13. A compound according to any one of claims 1 to 9 for use in therapy.

14. A compound according to any one of claims 1 to 9 for use in the treatment of viral infections in mammals.

15. A compound according to any one of claims 1 to 9 for use in the treatment of human herpesvirus or human retrovirus infections.

16. A compound according to any of claims 1 to 9 for use in the treatment of viral infections in humans caused by HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8, fflV-1, HIV-2, HTLV-1 or HTLV-2.

17. Use of a compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical formulation for the treatment of viral infections in mammals.

18. Use of a compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical formulation for the treatment of human herpesvirus or retrovirus infections.

19. Use of a compound according to any one of claims 1 to 9 in the manufacture of a pharmaceutical formulation for the treatment of viral infections in humans caused by HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8, HIV-1, HIV-2, HTLV-1 or HTLV-2.

20. A pharmaceutical composition containing as an active ingredient a compound as defined in any one of claims 1 to 9.

21. A pharmaceutical composition according to claim 20 which is suitable for oral administration.

22. A pharmaceutical composition according to claim 20 which is suitable for parenteral administration.

23. A pharmaceutical composition according to claim 20 which is suitable for rectal administration.

24. A pharmaceutical composition according to claim 20 which is suitable for topical administration.

25. A method of treatment of virus infections wherein a therapeutically active amount of a compound according to any one of claims 1 to 9 is administered to a patient in need of such treatment.

26. A compound of the formula V

V

wherein the wavy line signifies a bond which is either in the α- or in the β-configuration;

wherein n is 0 or 1, R\ is C9.24- alkyl, C9_24-alkenyl, C9_24-alkapolyenyl containing 2 to 6 double bonds, C9_24-alkynyl, C3 . g-cycloalkyl- .24-alkyl, or Cι_i2-alkoxy-C8- 12-alkyl group, all of which may be branched or unbranched and all of which may be optionally substituted with hydroxy, amino, halogen, or oxo;

and wherein R₁₅, Rι₆ and R₁₇ each correspond to the groups R₂₎ R₃ and R₄, respectively, which have been derivatized by suitable protective groups,

provided that in the case where the configuration of the substituents R₁₅, Rι₆ , R₁ and HOCH₂- is D-gluco,

i) Ri is not n-decyl, n-dodecyl, or n-octadecyl at the same time as each of R₁₅, R₁₆ , and R₁₇ is benzyloxy, and

ii) Ri is not l-ethenyl-l,5-dimethyl-4-hexen-l-yl at the same time as each of R₁₅, R₁₆ and R₁ is benzoyloxy, and iii) Ri is not 8-hydroxy-l-(4-hydroxy-2-methyl-2-butenyl)-3,7-dimethyl-2,6-octadienyl at the same time as R₁₅ is 2-methyl-2-butenoate and each of R_[6 and Rι₇ is acetoxy, and

provided that, in the case where the configuration of the substituents Rι₅, Rι₆ , R_i7 and HOCH₂- is D-galacto,

iv) Ri is not rc-octadecyl at the same time as each of R1₅ , R₎₆ and R₁₇ is acetoxy, and

provided that in the case where the configuration of the substituents R15, Rig, R 7 and HOCH2- is D-manno,

v) Ri is not n-hexadecyl at the same time as each of Rι₅ , Rι₆ and Rπ is trimethylsilyloxy, and

vi) Ri is not 3,7,1 l-trirnethyl-2,6,10-dodecatrienyl at the same time as each of R₁₅ , Rι₆ and R[ is acetoxy,

and salts and optically active isomers thereof.

27. A compound of the formulaVI

VI wherein the wavy line, n, and Ri are as defined in Claim 1 ,

and wherein R15, R₁₆ and R_]7 each correspond to the groups R₂, R₃ and R₄, respectively, as defined in Claim 1, which have been derivatized by suitable protective groups,

R' is as defined in Claim 10,

and physiologically acceptable salts and optical isomers thereof.