HK1097550B - Antiviral nucleoside analogues as inhibitors of retroviral reverse transcriptase and dna polymerase - Google Patents

Description

Nucleoside analogs as antiviral agents for retroviral reverse transcriptase and DNA polymerase inhibitors

The present application is a divisional application of an invention patent application, the filing date of which is 14/8/1998, application No. 03157988.4, entitled "nucleoside analogs of antiviral agents useful as inhibitors of reverse transcriptase and DNA polymerase of retroviruses".

Technical Field

The present invention relates to nucleoside analogs which are antiviral agents that are inhibitors of the reverse transcriptase and DNA polymerase of retroviruses including Hepatitis B Virus (HBV). The present invention provides novel compounds having good pharmacodynamic parameters, methods for their preparation, pharmaceutical compositions containing these compounds and methods for their use in the inhibition of viruses and neoplasms, including HBV and HIV.

Background

International patent application WO88/00050 describes the antiretroviral and anti-HBV activity of a range of 3 ' -fluoronucleosides, including the compounds 2 ', 3 ' -dideoxy-3 ' -Fluoroguanosine (FLG) and 3 ' -Fluorothymidine (FLT). The latter compound was clinically identified as an anti-HIV agent, which, despite its good antiviral activity and pharmacokinetics, showed unexpected toxicity (Flexner et al, J Inf Dis 170(6) 1394-. The former compound FLG has good activity in vitro, but the present inventors have detected that its bioavailability is very low, about 4%, so that the use of this compound in vivo has hitherto been limited to animal models administered intraperitoneally or subcutaneously.

U.S. patent 4,963,662 discloses a series of 3 '-fluoronucleosides and the corresponding triphosphate compounds, and specifically describes 5' -O-palmitoyl derivatives of FLT, but does not report any improvement in bioavailability. International patent application WO9313778 describes FLG derivatives modified in the 6 position of the matrix, in particular with n-propoxy, cyclobutoxy, cyclopropylamino, piperidinyl or pyrrolidinyl groups. International patent application 9314103 describes FLG derivatives in which the oxygen at the 6-position of guanine is substituted by an amino group, an ether, a halogen or a sulfonate.

Brief description of the invention

In one aspect, the invention provides a compound of formula I:

wherein:

R₁selected from hydroxyl, amino or carboxyl; saturated or unsaturated C optionally esterified/amidated thereon₄-C₂₂Optionally substituted fatty acids or alcohols, or aliphatic L-amino acids;

R₂is a residue of an aliphatic L-amino acid;

L₁is a trifunctional linker;

L₂is absent or a bifunctional linking group;

and pharmaceutically acceptable salts thereof.

The invention also provides a pharmaceutical composition containing the compound of formula I or a salt thereof and a pharmaceutically acceptable carrier or diluent. In another aspect, the invention provides a method of inhibiting HBV and retroviruses, such as HIV, comprising contacting a compound or salt of formula I with a retrovirus or HBV, for example by injecting an effective amount of the compound or salt into a human infected with the retrovirus or HBV.

In the treatment of conditions caused by retroviruses such as HIV or HBV, the compound or salt of formula I is preferably administered in an amount of 50-1500 mg once, twice or three times daily, preferably 100-700 mg two to three times daily. It is desirable that the serum concentration of the active metabolite be in the range of 0.01-100. mu.g/ml, preferably 0.1-5. mu.g/ml.

When R is₁For the fatty acid residue, preferably having an even number of carbon atoms in total, decanoyl (C) is advantageous₁₀) Lauroyl (C)₁₂) Myristoyl (C)₁₄) Palmitoyl (C)₁₆)、

Stearoyl (C)₁₈) Eicosanoyl (C)₂₀) Or behenyl (C)₂₂). The fatty acid preferably has a total of 10 to 22 carbon atoms, more preferably 16 to 20 carbon atoms, particularly 18 carbon atoms. The fatty acid may be unsaturated and have one to three double bonds, in particular one double bond. The unsaturated fatty acids preferably belong to the n-3 or n-6 series, the unsaturated R commonly used₁Groups include those derived from the mono-unsaturated carboxylic acids myristoleic acid, myristoelaidic acid, palmitoleic acid (palmiteladic acid), n 6-octadecenoic acid, oleic acid, elaidic acid, gandoic acid, erucic acid, brassidic acid or from polyunsaturated fatty acids such as linoleic acid, gamma-linolenic acid, arachidonic acid and alpha-linolenic acid. However, when these compounds are to have greater stability and pot life, R1 as a fatty acid is preferably saturated.

R as fatty alcohol₁The residues preferably correspond to the fatty acids mentioned above. The fatty alcohol may also contain residues of short chain alcohols such as methanol, ethanol or propanol.

R₁When the fatty acid or the alcohol is saturated or unsaturated, the fatty acid or the alcohol can be optionally substituted by at most five same or different substituents which are respectively selected from hydroxyl and C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical C₁-C₆Alkoxy radical C₁-C₆Alkyl radical, C₁-C₆Alkyl acyl, amino, halogen, cyano, azido, oxo, mercapto, nitro, and the like.

Is suitable for R₂And R₁(if R is present)₁If) aliphatic amino acids include L-alanineL-isoleucine, L-leucine and L-valine, and R is preferred for ease of synthesis₂And R₁Are all aliphatic amino acid residues, preferably identical residues.

First linking group L₁The expression trifunctional means that the linking group has at least three functional groups, including at least two groups derived from the corresponding hydroxyl, amino or carboxyl groups. Wherein the amino and hydroxy functions are for reacting with R₁And R₂Esterification/amidation of the carboxyl function; the carboxyl function of the linking group being for reaction with R₂In the form of a free alpha-amino group or, as the case may be, with R₁Amidating the free alpha-amino group; or R₁In the case of fatty alcohols, with R₁Esterification takes place. When R is₁By itself, hydroxyl, amino or carboxyl is defined, with hydroxyl being most preferred over three, in which case a functional group on the trifunctional linker is the hydroxyl, amino or carboxyl.

The trifunctional linker also contains a third functional group that is linked to an optional second linker L, as described in more detail below₂A hydroxyl group at the 5 'position of the linked or parent nucleoside, such as 2', 3 '-dideoxy-3' -fluoroguanosine. The suitable third functional group depends on the optional linking group L₂The nature of the functional group attached (if present) and may include amino, hydroxyl, carbonyl, sulfonyl, phosphoryl, phosphonyl, carbamoyl, and the like. If there is no L₂First linking group L₁The third functional group above generally contains a carboxyl group which can be esterified with the 5' -O group of the nucleoside analogue.

And R₁And R₂The functional group on the attached trifunctional linker is preferably a hydroxyl functional group, and the attachment is to R₁Fatty acid (if any) and R₂A further preferred embodiment is that there is a free hydroxyl group as R on the linker₁And one and R₂In another embodiment, the linking group contains an (optionally protected) carboxyl group R₁To do so byAnd one and R₂The carboxyl esterified hydroxyl functional group of (a).

Useful trifunctional L' s₁A group, particularly a group capable of direct esterification with a nucleoside, comprises a linking group of formula IIa or IIb:

wherein A and A' are defined as hydroxy and R on the linking group₁Or R₂Or a carboxyl group on the linking group with a fatty alcohol R₁Or an amino group on the linking group and at R₁Or R₂Or a carboxyl group in the linker with R₁Or R₂Amide linkage between amino groups of (a), or when R is₁When the hydroxyl, amino or carboxyl groups are themselves free, one of A and A' is as defined above and the other is hydroxyl, amino or carboxyl,

rx is H or C₁-C₃An alkyl group, a carboxyl group,

t is a bond, -O-or-NH-;

alk is absent, C₁-C₄Alkyl or C₂-C₄Alkenyl, optionally substituted as described above;

and

m and n are independently 0, 1 or 2.

In a preferred embodiment of this aspect of the invention, R₁Or R₂The radicals are each esterified (via A and A') to the leftmost different functional hydroxyl groups of the formula IIa, while the right carbonyl moiety is optionally linked via a second linking group L₂Esterified with the 5' -O-group of a nucleoside.

L₁The group may also contain a linker group of formula IIb:

wherein Ar is a saturated or unsaturated, preferably 5 or 6 ring atoms, mono-or heterocyclic ring; A. a', T, Alk, m and n are as defined above.

In formula IIb, Ar is preferably an aryl radical, such as pyridine or, in particular, phenyl, as aryl moiety with R₁And R₂The arms of (a) are each para and ortho, meta and ortho, both ortho, or preferably para and meta, both para or both meta with respect to the remainder of the linker.

In formulae IIa and IIb, the following combinations of m, n and Alk are advantageous:

m n Alk

10 methylene group

101, 2-ethylene radical

11 is absent

11 methylene group

111, 2-ethylene radical

111, 2-propylene radical

12 is absent

12 methylene group

111, 2-ethylene radical

111, 2-propylene radical

Due to R₁And R₂Having different structures, it is apparent that many L₁The group, in particular of formula IIa, will be defined as a chiral structure>80% enantiopure, preferably>A 95% enantiomerically pure compound preparation.

Particularly preferred trifunctional linkers contain glycerol derivatives of formula IIc

Wherein A is hydrogen, an acyl residue of an aliphatic L-amino acid ester, or an acyl residue of a fatty acid ester, A' is an acyl residue of an aliphatic amino acid residue, and D is a saturated or unsaturated C₂-C₆Dicarboxylic acid residues. The trifunctional linkage shown in formula IIc is hydrolyzed or decomposed in vivo to release a property-invariant compound such as glycerol, an L-amino acid, a fatty acid (if any) and a dicarboxylic acid, each of which is generally metabolically and/or excretory safe for the body.

When the dicarboxylic acid moiety of the derivative of formula IIc is directly esterified with the 5' hydroxyl functionality (or equivalent) of the nucleoside, the glycerol moiety can be defined analytically as a trifunctional link L₁The dicarboxylic acid moiety is defined as a difunctional linkage L₂。

Particularly preferred dicarboxylic acid residues include those derived from oxalic acid, malonic acid, tartronic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, glutaric acid, glutaconic acid, citraconic acid, itaconic acid, ethylidene malonic acid, mesaconic acid, adipic acid, allylmalonic acid, propylidene malonic acid, hydrogenated muconic acid, dioctadec acid, muconic acid, and the like. The dicarboxylic acid residues may optionally be substituted, e.g. by the fatty acids R mentioned above₁The substituents listed. The hydroxy substituent may be further esterified with another L-amino acid or fatty acid residue.

Some of the above dicarboxylic acids may themselves be defined as trifunctional linkers. For example, hydroxy-substituted dicarboxylic acids such as tartaric acid or maleic acid provide a number of configurations within the scope of the present invention. In the case of tartaric acid, the carboxyl function can be esterified with the 5' -hydroxyl function of the nucleoside (optionally via a bifunctional linker L)₂). The hydroxy function may be reacted with R₂And R₁The various carboxyl groups on the fatty acids or amino acids are esterified while the remaining carboxyl groups may be free or optionally protected, for example with commonly used pharmaceutically acceptable esters such as methyl or ethyl esters. Optional protection of the free carboxylic acid function is with R₁Esters of fatty alcohols containing one or two of the groups R₂Esterified hydroxyl functional group:

advantageous linkers in the above tartaric acid series are generally as described in formula IIe:

and wherein R₁And R₂Interchangeable isomers wherein R₁And R₂As indicated above, p, q and R are each 0 to 5, preferably 0 or 1, and Ry is a free acid, R₁Esters or customary pharmaceutically acceptable carboxyl protecting groups, such as methyl, benzyl or, in particular, ethyl esters.

An advantageous linkage of the maleic series has the formula IIf:

wherein Ry, p, q and R₂As defined above, p and q are preferably zero.

Preferred compounds of this aspect of the invention include:

5 '-O- [ 3-methoxycarbonyl-2-valyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 3-benzyloxycarbonyl-2-valyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 3-methoxycarbonyl-2-isoleucyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 3-benzyloxycarbonyl-2-isoleucyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-methoxycarbonyl-2, 3-divalinyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-benzyloxycarbonyl-2, 3-divalinyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-methoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-benzyloxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

particularly preferred are compounds derived from L-maleic acid and L-tartaric acid; and derivatives of the esters which are accordingly capable of constituting the usual pharmaceutically acceptable esters on the terminal carboxyl function.

Particularly advantageous compounds include:

5 '-O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 3-ethoxycarbonyl-2-isoleucyloxy-propionyl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

5 '-O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -2', 3 '-dideoxy-3' -fluoroguanosine,

in particular isomers derived from L-maleic acid and L-tartaric acid.

In another related aspect of the invention, R₁And R₂May be deleted.

Typical compounds of this aspect of the invention include formula Ia:

wherein Alk is optionally substituted C₁-C₄Alkyl or C₂-C₄Alkenyl radical, R₂Is the above-mentioned R₁And R₂Ester residues of defined aliphatic L-amino acids or of fatty acids. The linker in this aspect of the invention may conveniently be prepared from an alpha-hydroxy omega-carboxylic acid such as carbonic acid, glycolic acid, hydroxypropionic acid, hydroxybutyric acid, hydroxyvaleric acid or hydroxyhexanoic acid.

Typical compounds of formula Ia include:

2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [3- (L-valyloxy) -propionyl ] guanosine,

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (L-valyloxy) -pentanoyl ] guanosine,

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [6- (L-valyloxy) -hexanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [3- (L-isoleucyloxy) -propionyl ] guanosine,

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (L-isoleucyloxy) -pentanoyl ] guanosine,

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [6- (L-isoleucyloxy) -hexanoyl ] guanosine,

and pharmaceutically acceptable salts thereof.

Particularly advantageous compounds of formula Ia include:

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [4- (L-valyloxy) -butyryl ] guanosine, and

2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [4- (L-isoleucyloxy) -butyryl]Guanosine, and pharmaceutically acceptable salts thereof. In vivo R in these compounds₂The groups are hydrolyzed and removed, leaving behind a living end group that can cyclize and promote efficient release of the parent nucleoside.

In one aspect of the invention, the fatty acid residue R₁Can be used as a linker per se₂Is esterified/amidated at the amino, hydroxyl or carboxyl group of the fatty acid alkyl chain, for example at the beta carbon. In this embodiment, R₁The fatty acid is esterified directly with the 5' -hydroxy group (or equivalent) of the nucleoside, which usually has the R esterified/amidated₂A group. Functionalized fatty acids (with carboxyl/hydroxyl/amino functionality suitably protected) can also be esterified first onto nucleosides and then reacted with R₂According to a preferred embodiment of this aspect the linker has the structure shown in formula IId:

wherein R is₂Is an aliphatic L-amino acid residue, p is 0, 1 or 2-20 (optionally including double bonds), q is 0-5, preferably 0. Typical compounds include:

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -butyryl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -hexanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -octanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -decanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -dodecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -tetradecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -hexadecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -octadecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -eicosanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-valyloxy) -docosanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -butyryl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -hexanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -octanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -decanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -dodecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -tetradecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -hexadecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -octadecanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -eicosanoyl ] guanosine,

2 ', 3 ' -dideoxy-3 ' -5-O- [2- (L-isoleucyloxy) -docosanoyl ] guanosine,

and corresponding n-3 and n-6 monounsaturated analogs, such as 6 or 9-octadecenoyl derivatives.

In formula IId, p and q are preferably 0 and are therefore defined as lactic acid derivatives, preferably L-lactic acid derivatives, such as

2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [2- (L-valyloxy) -propionyl ] guanosine; and

2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [2- (L-isoleucyloxy) -propionyl ] guanosine and pharmaceutically acceptable salts thereof, decomposition products thereof, lactic acid and amino acids are physiologically well acceptable.

At the second linking group L₂The expression difunctional refers to a linking group having two functional groups such that it is at the first linking group L₁And the 5' -O-group of the nucleoside as a spacer or bridge. For example optional groups L₂May contain a linker of formula IIIa:

wherein R is₄And R₄' is hydrogen or C₁-C₄In the alkyl group IIIa, R₄Preferably hydrogen, methyl, ethyl or isopropyl, R₄The linker of formula IIIa is advantageous because various nucleosides, such as FLG parent compounds, must first be phosphorylated by cellular enzymes before they inhibit viral polymerase. Primary or subsequent hydrolysis of the compounds of the invention releases in vivo a monobasic phosphorylated nucleoside which can be rapidly converted to di-and triphosphates.

Optionally bisFunctional linking group L₂May also contain a structure of formula IIIb:

wherein R is₄And R₄' independently of one another are H or C₁-C₄An alkyl group.

The other group of the bifunctional linker has the structure shown in formula IIIc:

as mentioned above, preferred difunctional linking groups contain alpha, omega-dicarboxylic acids C₂-C₆Alkyl derivatives, e.g. succinic acid, which are optionally substituted (e.g. with fatty acids R as described above₁Defined substituents) and/or are optionally mono-or polyunsaturated, such as n-3 or n-6 monounsaturated. Such preferred groups are as described above.

Although the above disclosure focuses on the reaction with dicarboxylic acids L₂Glycerol L with attached radicals₁Groups, it being understood that a large number of trifunctional linkers are suitable for use with dicarboxylic acids L₂Together, the groups are, for example, structures of formulae IIa and IIb described above without the rightmost carbonyl group.

The invention also includes R containing conventional FLG prodrugs₁(R₂)L₁L₂Dual prodrugs of derivatives, which are commonly used to release FLG in vivo, such as prodrug derivatives at the 2 and 6 positions of the guanosine substrate of FLG. Examples of such commonly used FLG prodrugs include compounds of formula IV:

wherein R is₁、R₂、L₁And L₂As defined above; and

R₃is H, N₃、NH₂Or OH or a pharmaceutically acceptable ether or ester thereof; and

R₃' is an aromatic bond or hydrogen.

R₃Wherein the possible pharmaceutically acceptable esters include the above R₁Related fatty acids, e.g. stearoyl or oleoyl esters and the like or shorter esters, e.g. acetyl or butyryl esters₂Esters may also include the corresponding fatty acids or alkyl aryl carbonates, carbamates or sulfonates.

R₃Suitable pharmaceutically acceptable ethers of (a) include C₁-C₆Alkyl, cycloalkyl, C₆-C₁₂Alkylaryl radicals such as benzyl or methylpyridyl, any of which may be substituted by R as defined above₁The substituent is substituted. Advantageous ethers include the ethers mentioned in the above-mentioned WO9313778, such as n-propoxy, cyclobutoxy, cyclopropylamino, piperidino or pyrrolidinyl and the like.

The invention is described primarily with reference to the monohydroxylated nucleoside FLG, however, it will be apparent that the corresponding derivative may be prepared from other monohydroxylated nucleoside analogues, particularly where the hydroxyl group corresponds to the 5' hydroxyl function of the nucleoside. Thus according to a further aspect of the invention there is provided a compound of formula Ic:

wherein R is₁、R₂、L₁And L₂Exemplary nucleosides according to this aspect of the invention include acyclic nucleoside analogs such as acyclovir, and cyclic nucleoside analogs such as ddI (2 ', 3' -dideoxyinosine), ddC (2 ', 3'-dideoxycytidine), d4T (2 ', 3' -dideoxythymidine), FTC, lamivudine, 2 '-deoxy-3' -thiocytidine (-) enantiomer (3TC), 1592U89(4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl)]-2-cyclopentene-1-methanol), AZT (azidothymidine), DAPD (D-2, 6-diaminopurine dioxolane), F-ddA, and the like, each of which is known in the nucleoside art. A large number of monohydroxy L-nucleosides are under development, and the present inventors have also found use of these compounds. The compounds of this aspect of the invention will have the corresponding uses shown for the parent compounds, e.g. herpes virus infection corresponds to acyclovir derivatives, HIV corresponds to ddI, dideoxythymidine, ddC, lamivudine, AZT&1592U89, HBV corresponds to lamivudine, FTC, etc.

An advantageous subgroup of formula Ic contains derivatives of monohydroxynucleosides of formula Ic':

wherein A, A', Alk and O-nuc are as defined above. Formula Ic 'above describes A and A' in the 1 and 3 positions of the glycerol moiety, and L₂A compound at the 2-position of glycerol. Possible isomers are A and A' in the 1 and 2 or 2 and 3 positions of glycerol, respectively, L₂In position 3 or 2, respectively.

Typical compounds of this aspect of the invention include:

4' -O- [3- ((2, 3-di-L-valyloxy) -1-propoxycarbonyl) propionyl ] acycloguanosine (acyclovir),

4' -O- [3- ((2-hydroxy-3-L-valyloxy) -1-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((2-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((1, 3-di-L-valyloxy) -2-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((1-hydroxy-3-L-valyloxy) -2-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((1, 3-di-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] acycloguanosine,

4' -O- [3- ((1-hydroxy-3-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] acycloguanosine,

5' -O- [3- ((2, 3-di-L-valyloxy) -1-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((2-hydroxy-3-L-valyloxy) -1-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((2-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((1, 3-di-L-valyloxy) -2-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((1-hydroxy-3-L-valyloxy) -2-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((1, 3-di-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((1-hydroxy-3-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] lamivudine,

5' -O- [3- ((2, 3-di-L-valyloxy) -1-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((2-hydroxy-3-L-valyloxy) -1-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((2-hydroxy-3-L-valyloxy) -1-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((1, 3-di-L-valyloxy) -2-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((1 hydroxy-3-L-valyloxy) -2-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((1, 3-di-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] DAPD,

5' -O- [3- ((1-hydroxy-3-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] DAPD,

5 ' -O- [3- ((2, 3-di-L-valyloxy) -1-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((2-hydroxy-3-L-valyloxy) -1-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((2-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((1, 3-di-L-valyloxy) -2-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((1-hydroxy-3-L-valyloxy) -2-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((1, 3-di-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5 ' -O- [3- ((1-hydroxy-3-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] -2 ', 3 ' -dideoxyinosine,

5' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((2-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((2, 3-di-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((2-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((1, 3-di-L-valyloxy) -2-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((1-hydroxy-3-L-valyloxy) -2-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((1, 3-di-L-isoleucyloxy) -2-propoxycarbonyl) propionyl ] dideoxythymidine,

5' -O- [3- ((1-hydroxy-3-L-isoleucyloxy) -1-propoxycarbonyl) propionyl ] dideoxythymidine,

4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol corresponding derivatives and pharmaceutically acceptable salts thereof.

A subset of the compounds of this aspect of the invention may also contain compounds of formula Id:

wherein R is₂And Alk is as defined in formula Ia, and O-nuc is as defined above.

Typical compounds of formula Id include:

4' -O- [4- (L-valyloxy) -propionyl ] acyclovir,

4' -O- [5- (L-valyloxy) -valeryl ] acyclovir,

4' -O- [6- (L-valyloxy) -hexanoyl ] acyclovir,

4' -O- [4- (L-isoleucyloxy) -propionyl ] acyclovir,

4' -O- [5- (L-isoleucyloxy) -valeryl ] acyclovir,

4' -O- [6- (L-isoleucyloxy) -hexanoyl ] acyclovir,

5' -O- [4- (L-valyloxy) -propionyl ] ddI,

5' -O- [5- (L-valyloxy) -valeryl ] ddI,

5' -O- [6- (L-valyloxy) -hexanoyl ] ddI,

5' -O- [4- (L-isoleucyloxy) -propionyl ] ddI,

5' -O- [5- (L-isoleucyloxy) -valeryl ] ddI,

5' -O- [6- (L-isoleucyloxy) -hexanoyl ] ddI,

5' -O- [4- (L-valyloxy) -propionyl ] dideoxythymidine,

5' -O- [5- (L-valyloxy) -valeryl ] dideoxythymidine,

5' -O- [6- (L-valyloxy) -hexanoyl ] dideoxythymidine,

5' -O- [4- (L-isoleucyloxy) -propionyl ] dideoxythymidine,

5' -O- [5- (L-isoleucyloxy) -valeryl ] dideoxythymidine,

5' -O- [6- (L-isoleucyloxy) -hexanoyl ] dideoxythymidine,

5' -O- [4- (L-valyloxy) -propionyl ] DAPD,

5' -O- [5- (L-valyloxy) -pentanoyl ] DAPD,

5' -O- [6- (L-valyloxy) -hexanoyl ] DAPD,

5' -O- [4- (L-isoleucyloxy) -propionyl ] DAPD,

5' -O- [5- (L-isoleucyloxy) -valeryl ] DAPD,

5' -O- [6- (L-isoleucyloxy) -hexanoyl ] DAPD,

5' -O- [4- (L-valyloxy) -propionyl ] lamivudine,

5' -O- [5- (L-valyloxy) -valeryl ] lamivudine,

5' -O- [6- (L-valyloxy) -hexanoyl ] lamivudine,

5' -O- [4- (L-isoleucyloxy) -propionyl ] lamivudine,

5' -O- [5- (L-isoleucyl-oxy) -valeryl ] lamivudine,

5' -O- [6- (L-isoleucyloxy) -hexanoyl ] lamivudine,

and 4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol.

Particularly preferred compounds of formula Id include:

4' -O- [4- (L-valyloxy) -butyryl ] acyclic bird nuclei,

4' -O- [3- (L-isoleucyloxy) -butyryl ] acyclic bird nuclei,

5' -O- [4- (L-valyloxy) -butyryl ] ddI,

5' -O- [3- (L-isoleucyloxy) -butyryl ] ddI,

5' -O- [4- (L-valyloxy) -butyryl ] dideoxythymidine,

5' -O- [3- (L-isoleucyloxy) -butyryl ] dideoxythymidine,

5' -O- [4- (L-valyloxy) -butyryl ] DAPD,

5' -O- [3- (L-isoleucyloxy) -butyryl ] DAPD,

5' -O- [4- (L-valyloxy) -butyryl ] lamivudine,

5' -O- [3- (L-isoleucyloxy) -butyryl ] lamivudine,

and 4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol corresponding derivatives, and pharmaceutically acceptable salts thereof.

In these compounds R₂After hydrolysis and removal of the group in vivo, the remaining reactive end groups can cyclize and facilitate efficient release of the parent nucleoside.

Also provided by the present invention are compounds of formula If:

wherein R is₁、R₂Ry, p, q, r and o-nuc are as defined above.

Advantageous compounds of this aspect of the invention include:

5' -O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -ddI,

5' -O- [ 3-ethoxycarbonyl-2-isoleucyloxy-propionyl ] -ddI,

5' -O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -ddI,

5' -O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -ddI,

4' -O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -acyclovir,

4' -O- [ 3-ethoxycarbonyl-2-isoleucyloxy-propionyl ] -acycloguanosine,

4' -O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -acyclovir,

4' -O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -acyclovir,

5' -O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -DAPD,

5' -O- [ 3-ethoxycarbonyl-2-isoleucyloxy-propionyl ] -DAPD,

5' -O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -DAPD,

5' -O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -DAPD,

5' -O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -dideoxythymidine,

5' -O- [ 3-ethoxycarbonyl-2-isoleucyloxy-propionyl ] -dideoxythymidine,

5' -O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -dideoxythymidine,

5' -O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -dideoxythymidine,

5' -O- [ 3-ethoxycarbonyl-2-valyloxy-propionyl ] -lamivudine,

5' -O- [ 3-ethoxycarbonyl-2-isoleucyl-oxy-propionyl ] -lamivudine,

5' -O- [ 4-ethoxycarbonyl-2, 3-divalinyloxy-butyryl ] -lamivudine,

5' -O- [ 4-ethoxycarbonyl-2, 3-diisoleucyloxy-butyryl ] -lamivudine,

and 4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol corresponding malic and tartaric acid derivatives, and pharmaceutically acceptable salts thereof; in each case, the isomers derived from L-tartaric and L-malic acid are preferred.

The present invention provides compounds of formula Ig:

wherein R is₂P, q and O-nuc are as defined above.

Preferred compounds of formula Ig include:

4' -O- [2- (L-valyloxy) -propionyl ] acyclovir,

4' -O- [2- (L-isoleucyloxy) -propionyl ] acyclovir,

5' -O- [2- (L-valyloxy) -propionyl ] ddI,

5' -O- [2- (L-isoleucyloxy) -propionyl ] ddI,

5' -O- [2- (L-valyloxy) -propionyl ] dideoxythymidine,

5' -O- [2- (L-isoleucyloxy) -propionyl ] dideoxythymidine,

5' -O- [2- (L-valyloxy) -propionyl ] lamivudine,

5' -O- [2- (L-isoleucyloxy) -propionyl ] lamivudine,

5' -O- [2- (L-valyloxy) -propionyl ] DAPD,

5' -O- [2- (L-isoleucyloxy) -propionyl ] DAPD,

and 4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol corresponding derivatives, and pharmaceutically acceptable salts thereof. The decomposition products of these compounds, lactic acid and amino acids, are physiologically well acceptable.

The compounds of the invention may form salts and thus form a further aspect of the invention. Suitable pharmaceutically acceptable salts of compounds of formula I include salts of organic acids, particularly carboxylates, including but not limited to acetates, trifluoroacetates, lactates, gluconates, citrates, tartrates, maleates, malates, pantothenate, isethionates, adipates, alginates, aspartates, benzoates, butyrates, digluconates, cyclopentanoate, glucoheptonates, phosphoglycerates, oxalates, heptanoates, hexanoates, fumarates, nicotinates, palmitates, pectinates, 3-phenylpropionates, picrates, pivalates, propionates, tartrates, lactobionates, pivolates, camphorates, undecanoates and succinates, organic sulfonates such as methanesulfonates, ethanesulfonates, 2-isethionates, camphorsulfonates, 2-naphthalenesulfonates, camphorsulfonates, and succinates, Benzene sulfonate, p-chlorobenzene sulfonate, and p-toluene sulfonate; and inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphate and sulfonate. In some cases, the compound of formula I may be isolated as a hydrate.

The commonly used N protecting groups are disclosed in Greene, "protecting groups in organic synthesis" (John Wiley & Sons, New York, 1981), incorporated herein by reference; sulfonyl such as benzenesulfonyl, p-toluenesulfonyl and the like, carbamate-forming groups such as benzyloxycarbonyl, p-chlorophenoxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc.; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N protecting groups include formyl, acetyl, allyl, F-moc, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-Butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).

Hydroxyl and/or carboxyl protecting groups are also widely discussed in Green's above literature and include ethers such as methyl ether, substituted methyl ether groups such as methoxy methyl ether, methylthio methyl ether, benzyloxy methyl ether, t-butoxy methyl ether, 2-methoxyethoxy methyl ether and the like, silicon ethers such as Trimethylsilylether (TMS), t-butyldimethylsilylether (TBDMS), tribenzylsilyl ether, triphenylsilyl ether, t-butyldiphenylsilyl ether, triisopropylsilyl ether and the like, substituted ethyl ethers such as 1-ethoxymethyl ethyl ether, 1-methyl-1-methoxyethyl ether, t-butyl ethyl ether, allyl ethyl ether, benzyl ethyl ether, p-methoxyphenylmethyl ethyl ether, diphenylmethyl ethyl ether, triphenylmethyl ethyl ether and the like, aralkyl groups such as trityl and pixyl (9-hydroxy-9-phenylxanthene derivative, particularly chloride). Ester hydroxy protecting groups include formate, benzyl formate, chloroacetate, methoxyacetate, phenoxyacetate, pivalate, adamantanecarboxylate, ketoester, benzoate and the like. Carbonate hydroxy protecting groups include methyl esters, vinyl esters, allyl esters, cinnamyl esters, benzyl esters, and the like.

In keeping with the conventional use of retroviral and HBV inhibitors, it may be advantageous to administer one to three or more antivirals simultaneously, such as AZT, ddI, ddC, d4T, 3TC, H2G, foscarnet, ritonavir, indinavir, saprenavir, nevirapine, delavirdine, Vertex VA478 or Agouron AG1343 in the case of HIV, or lamivudine, interferon, famciclovir, etc. in the case of HBV. These additional antivirals will be administered in dosages that generally reflect their respective therapeutic value. The molar ratio is advantageously generally from 100:1 to 1:100, in particular from 25:1 to 1:25, relative to the compound or salt of the formula I. For antiviral nucleosides to treat herpes infections, it is not common to use other antivirals simultaneously.

Although the active agent may be administered alone, it is preferred as a component in a pharmaceutical formulation. Such formulations comprise an active agent as defined above together with one or more acceptable carriers/excipients and optionally other therapeutic ingredients. The carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), intrathecal or parenteral (including subcutaneous, intramuscular, intravenous and intraepidermal) administration, but oral formulations are preferred. The formulations are generally presented in unit dosage forms, such as tablets and sustained release capsules, and may be prepared by any method known in the art of pharmacy.

These methods comprise bringing into association the active agents defined above with carriers, usually by preparing the formulation by first bringing into intimate and intimate association the active agent with the liquid carrier or the finely divided solid carrier or both, and then, if necessary, shaping the product. If the manufacture of the formulation involves intimate mixing of the active ingredient in salt form with a pharmaceutical excipient, it is often preferred to use a non-basic excipient, i.e., an acidic or neutral excipient.

Oral formulations of the present invention may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active agent; can be in the form of powder or granule; may be present as a solution or suspension of the active agent in an aqueous or non-aqueous liquid; or in the form of oil-in-water emulsion or water-in-oil emulsion and pill.

For oral compositions (e.g., tablets and capsules), the term "carrier" suitably includes carriers such as conventional excipients, for example, binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricating agents such as magnesium stearate, sodium stearate and other metal stearates, glyceryl stearate, stearic acid, silicone fluids, talc, waxes, oils and colloidal silica, flavoring agents such as peppermint, oil of wintergreen, cherry flavoring, and the like may also be employed. Tablets may also be coated by methods known in the art, if desired, or with a colorant to make the formulation easily identifiable.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active agent in any flowable form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. The tablets may optionally be coated or labelled and may be formulated so as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include: lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia, and mouthwashes comprising the active agent in a suitable liquid carrier.

In another aspect, the invention provides a process for the preparation of a compound of formula I or Ic, which process comprises acylation of a nucleoside, here FLG of formula V, typically at the 5' hydroxy group

Wherein R is₁(R₂)L₁X represents an activated acid, a carboxylic acid derivative of formula IIa or IIb, wherein R₁、R₂And L₁As defined above or a protected derivative thereof. In addition, an activating acidMay also include the formula R₁(R₂) Compounds of glycerol-D-X, wherein R₁，R₂And D is as defined for formula IIc, or in the case of compounds of formula Ia, the activated acid comprises activated R_zIn the latter, the linker may be constructed sequentially by: first esterification of a moderately protected D or omega-hydroxycarboxylic acid onto a nucleoside, deprotection of the terminal carboxyl or hydroxyl group, and then esterification of a moderately protected glycerol or R thereon_zAnd (4) partial.

The activated derivative used in the acylation reaction contains, for example, an acid halide, an acid anhydride, an activated acid ester, or an acid present as a coupling agent, such as dicyclohexylcarbodiimide. Typical activated acid derivatives include acid halides, alkoxycarbonyl halide derived anhydrides such as isobutoxycarbonyl chloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy-5-norbornene-2, 3-diimide derived esters, 2, 4, 5-trichlorophenol derived esters and the like. The activating acid may also include compounds of the formula RX, wherein X represents an OR' moiety, wherein R is R₂As defined, R' is, for example, COCH₃、COCH₂CH₃Or COCF₃Or X is benzotriazole.

When the invention is applied to other monohydroxylated nucleosides, the corresponding method can be employed, i.e., the activated derivative is esterified accordingly to the free 5' hydroxyl group (or equivalent) of a monohydroxylated nucleoside such as acyclovir, ddI, FTC, lamivudine, 1592U89, DAPD, F-ddA, etc.

The intermediates used in the above process define themselves novel compounds, in particular those of formula IIc':

wherein A, A 'and Alk are as defined above (A and A' are preferably protected with commonly used protecting groups) and X represents the free acid or the activated acid mentioned above.

Typical compounds of formula IIc' include:

malonic acid 2, 3-di- (L-valyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-CBZ-L-valyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-Fmoc-L-valyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-Boc-L-valyloxy) -propyl ester

Malonic acid 2, 3-di- (L-isoleucyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-CBZ-L-isoleucyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-Fmoc-L-isoleucyloxy) -propyl ester

Malonic acid 2, 3-bis- (N-Boc-L-isoleucyloxy) -propyl ester

Succinic acid 2, 3-di- (L-valyloxy) -propyl ester

Succinic acid 2, 3-di- (N-CBZ-L-valyloxy) -propyl ester

Succinic acid 2, 3-di- (N-Fmoc-L-valyloxy) -propyl ester

Succinic acid 2, 3-di- (N-Boc-L-valyloxy) -propyl ester

Succinic acid 2, 3-di- (L-isoleucyloxy) -propyl ester

Succinic acid 2, 3-di- (N-CBZ-L-isoleucyl-oxy) -propyl ester

Succinic acid 2, 3-bis- (N-Fmoc-L-isoleucyloxy) -propyl ester

Succinic acid 2, 3-di- (N-Boc-L-isoleucyl-oxy) -propyl ester

Glutaric acid 2, 3-di- (L-valyloxy) -propyl ester

Glutaric acid 2, 3-di- (N-CBZ-L-valyloxy) -propyl ester

Glutaric acid 2, 3-bis- (N-Fmoc-L-valyloxy) -propyl ester

Glutaric acid 2, 3-di- (N-Boc-L-valyloxy) -propyl ester

Glutaric acid 2, 3-di- (L-isoleucyloxy) -propyl ester

Glutaric acid 2, 3-di- (N-CBZ-L-isoleucyloxy) -propyl ester

Glutaric acid 2, 3-bis- (N-Fmoc-L-isoleucyloxy) -propyl ester

Glutaric acid 2, 3-di- (N-Boc-L-isoleucyloxy) -propyl ester

And the corresponding acid halides, especially acid chlorides, acid anhydrides, and diesters of the above compounds, e.g.

Succinic acid 2, 3-di- (N-CBZ-L-valyloxy) -propyl ester, 4-methoxybenzyl ester

Succinic acid 2, 3-di- (N-CBZ-L-valyloxy) -propyl ester, 1, 1-dimethylethyl ester,

preferred groups of the intermediates also contain a group of the formula IIa':

wherein Rx, Alk, m, N and T are as defined above, A and A 'represent acyl residues of L' -aliphatic amino acids esterified with a hydroxyl group on the linking group (protecting N, if necessary), or one of A and A 'is an acyl residue and the other is a free hydroxyl group, X represents the above-mentioned free acid or activated acid, and A' are preferably the same amino acid residue.

Other novel intermediates include free or activated acid precursors of compounds of formula Ia, such as:

3-N-Boc-L-valyloxy propionic acid, 3-N-Fmoc-L-valyloxy propionic acid, 3-N-CBZ-L-valyloxy propionic acid, 3-N-Boc-L-isoleucyloxy propionic acid, 3-N-Fmoc-L-isoleucyloxy propionic acid, 3-N-CBZ-L-isoleucyloxy propionic acid, 4-N-Boc-L-valyloxy butyric acid, 3-N-Fmoc-L-valyloxy butyric acid, 4-N-CBZ-L-valyloxy butyric acid, 4-N-Boc-L-isoleucyloxy butyric acid, 3-N-Fmoc-L-isoleucyloxy butyric acid, 3-N-, 3-N-CBZ-L-isoleucyloxybutyric acid, and the like, as well as activated derivatives, such as acyl halides.

Novel intermediates also include precursors to the compounds of formulae IIe and IIf above, particularly those derived from the "natural" configuration (e.g., L-malic and L-tartaric acids), for example:

3-ethoxycarbonyl-2-valyloxy-propionic acid

3-ethoxycarbonyl-2-isoleucyloxy-propionic acid

4-ethoxycarbonyl-2, 3-di-valyloxy-butyric acid

4-ethoxycarbonyl-2, 3-di-isoleucyloxy-butyric acid

3-benzyloxycarbonyl-2-valyloxy-propionic acid

3-benzyloxycarbonyl-2-isoleucyloxy-propionic acid

4-benzyloxycarbonyl-2, 3-di-valyloxy-butyric acid

4-benzyloxycarbonyl-2, 3-di-isoleucyloxy-butyric acid and the like;

and the corresponding activated derivatives, such as anhydrides.

The novel intermediates also include precursors corresponding to the structure shown in formula IId, such as: 2- (L-valyloxy) propionic acid, 2- (N-Boc-L-valyloxy) propionic acid, 2- (N-Fmoc-L-valyloxy) propionic acid, 2- (N-CBZ-L-valyloxy) propionic acid, 2- (L-isoleucyloxy) propionic acid, 2- (N-Boc-L-isoleucyloxy) propionic acid, 2- (N-Fmoc-L-isoleucyloxy) propionic acid, N- (CBZ-L-isoleucyloxy) propionic acid, 2- (L-valyloxy) butyric acid, 2- (N-Boc-L-valyloxy) butyric acid, 2- (N-Fmoc-L-valyloxy) propionic acid, 2- (N-Boc-L-, 2- (N-CBZ-L-valyloxy) butyric acid, 2- (L-isoleucyloxy) butyric acid, 2- (N-Boc-L-isoleucyloxy) butyric acid, 2- (N-Fmoc-L-isoleucyloxy) butyric acid, N- (CBZ-L-isoleucyloxy) butyric acid, etc.; and activated derivatives thereof, such as acyl halides.

Processes for the preparation of 3' fluoronucleosides, such as compounds of formula V, have been described in detail by Herdiwijn et al, nucleosides and nucleotides 8(1), 65-96(1989), which are incorporated herein by reference. Other monohydroxy nucleosides such as acyclovir, ddI (2 ', 3' -dideoxyinosine), ddC (2 ', 3' -dideoxycytidine), D4T (2 '3' -dideoxythymidine), FTC, lamivudine (3TC), 1592U89(4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol), AZT (azidothymidine), DAPD (D-2, 6-diaminopurine dioxolane), F-ddA, and the like are known and are discussed in detail in this document.

R₁(R₂)L₁L₂The reactive derivative of the X group may be prepared beforehand or generated in situ by using reagents such as dicyclohexylcarbodiimide (DDDC) or O- (1H-benzotriazol-1-yl) N, N, N ', N' tetramethyluronium tetrafluoroborate (TBTU). When an acid halide, such as an acid chloride, is used, a tertiary amine catalyst, such as triethylamine, N' -dimethylaniline, pyridine or dimethylaminopyridine, may be added to the reaction mixture to bind the liberated hydrohalic acid.

The reaction is preferably carried out in a non-reactive solvent such as N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile or a halogenated hydrocarbon such as dichloromethane, and any of the tertiary amine catalysts mentioned above may be used as the solvent if desired, taking care to maintain a suitable excess. The reaction temperature is generally varied from 0 to 60 ℃ but is preferably kept at 5 to 50 ℃. After 1 to 60 hours, the reaction is usually substantially complete and the course of the reaction is followed by Thin Layer Chromatography (TLC) and a suitable solvent system, typically when the reaction is complete as determined by TLC, the product is extracted with an organic solvent and purified by chromatography and/or recrystallised from a suitable solvent system.

The side products produced by acylation reactions on nucleoside substrates can be separated chromatographically, but such misdirected acylation can be minimized by controlling the reaction conditions. For example by controlling the reagent concentration or feed rate, especially the acylating agent; the control conditions can be achieved by lowering the temperature or by selecting the solvent. Follow the reaction by TLC to monitor control conditions. Protection of the 6-oxyl group, especially the 2-amino group, on the substrate with commonly used protecting groups prevents the acylation of dislocations.

R₃When hydrogen is present, the compounds of formula IV can be prepared as follows: activating the corresponding guanine compound of formula I with an activating group such as halogen at the 6-position (wherein R is₂The naked amino function in an amino acid residue is optionally protected with a commonly used N protecting group). The resulting activated 6-purine is then reduced to a purine, for example using a palladium catalyst, and then deprotected to provide the desired compound of formula IV or formula V.

R₃Is R₁Or other ester compounds may be prepared by esterification (analogous to the esterification reaction described above) of the corresponding hydroxy compound of formula I or formula IV, optionally at R₂And/or R₃After the naked amino function in the amino acid residue is protected by N. R₃The compounds in the case of ethers can be prepared by a process analogous to that disclosed in the above-mentioned WO9313778, optionally also with N protection of the naked amino group₃In the case of azides, they are prepared as described in WO 9709052.

Intermediates of formula IId can be prepared using appropriately activated and N-protected R₂Derivatives, such as N-CBZ valyl or isoleucyl derivatives, in combination with a common coupling agent such as DMAP/DCC; or by acylating a carboxy-protected hydroxyalkanoic acid, typically a 2-hydroxy-1-alkanoic acid, using an amino acid chloride. The carboxyl protecting group is then removed, for example by acidolysis. The resulting intermediate is activated as described above, or the free acid and coupling agent together esterify the nucleoside under the usual esterification conditions.

Compounds of formula Ia can generally be prepared by the methods described in the preceding paragraph, i.e., carboxy-protected α -hydroxy, ω -carboxylic acids such as glycolic acid, lactic acid, hydroxybutyric acid and the like and suitableN protected R₂And (4) esterifying the derivative. The carboxyl protecting group may also be removed with the free acid and coupling agent together or with an activated acid, such as the corresponding acid halide, and the resulting intermediate may be esterified using the methods and nucleosides described above.

Compounds containing the structure of formula IIe or IIf can be prepared by carboxy-protecting the terminal carboxy group of a different dicarboxylic acid, such as L-tartaric or L-malic acid, with a common carboxy-protecting group, such as benzoyl. The free hydroxyl group is then esterified using conventional esterification techniques, such as DMAP in DMF&DCC, R protected with an appropriate N₂The benzoyl carboxyl protecting group is removed and the resulting product is esterified with the 5' -hydroxy function of the monohydroxynucleoside using conventional procedures, such as those described in the examples. Finally, the free carboxyl function with R₁The groups are esterified, or more preferably, esterified to commonly used pharmaceutically acceptable esters-such as ethyl esters.

Compounds containing a phosphorylated moiety III can be prepared by reacting 2 ', 3 ' -dideoxy-3 ' -fluoroguanine-5-monophosphate with a compound of formula VIa,

wherein Ha is a halogen, such as chlorine, iodine or bromine, under conditions similar to those described in US 4337201, US 5227506, WO 94/13682 & WO94/13324, Starret et al, J Med Chem 371857-. The monophosphates can be prepared by phosphorylation of FLG in general, for example, as described in Herdwyn et al, supra.

Another esterification reaction to give a phosphate ester can also be carried out in two steps, including a first step of reaction between FLG-monophosphate and a compound of formula VII

Wherein R is₄And R₄' As defined above, PG is a conventional carboxyl protecting group as defined above, then deprotected and linked to a third, rightmost functional group L which is a hydroxyl group₁Two examples of such linking groups are described in scheme 1 below (penultimate compounds in each series). in this embodiment, the leftmost carbonyl group of formula Va is the same as the carbonyl group of the linking group to which formula IIa is attached.

Containing optional linking groups L₂The compound of (3) can also be prepared by a two-step process. In particular of the formula ClC (═ O) OC (R)₄)(R₄') Cl can be reacted with the 5' hydroxyl of FLG, optionally protected with a conventional protecting group on the substrate, as is known in the cephalosporin art. The obtained FLG-5' -O-C (═ O) OC (R)₄)(R₄') hydrochloride salt with R₁And R with trifunctional linker₂A reaction is carried out in which the third functional group contains a carboxyl functional group, such as a potassium salt.

It is understood that trifunctional L of the formula IIa₁Groups wherein n and m are 1 and Alk is absent can be prepared from glycerol by a regioselective esterification reaction as shown in scheme 1 below, see the combination stearoyl/L-valyl. In brief, R₁And R₂Optionally esterified in the 1 and 3 positions with glycerol and then converted in the 2 position to the appropriate-T-C (═ O) -group, which is then esterified with the 5' position of the fluoronucleoside, or with L₂(not shown) with a synergistic group the hydroxyl group in position 2 of the glycerol derivative may also be reacted with L containing a synergistic carbonyl function at its left-hand end₂The groups are esterified.

L of the formula IIa₁Where m is 1, n is 0 and Alk is methylene, it is also possible to regioselectively react R₁And R₂Prepared by esterification to the 1 and 2 positions of glycerol as shown in scheme 1 below, followed by conversion of the hydroxyl group at the 3 position to the appropriate-T-C (═ O)) A series of reactions at the far right end of scheme 1 show R₁Esterification of position 1 with Glycerol and R₂With the 2-position. Wherein R is₁With esterification in the 2-position, R₂The corresponding arrangement with esterification in position 1 can be obtained by the following process: first glycerol was treated with CBz-L-valine/DCC/DMAP/DMF and then at fatty acid R₁Before esterification with glycerol at position 2, position 3 is protected with pixyl chloride and finally deprotected, if necessary, to convert position 3.

Although line 1 has been referred to by reference R₁Is stearyl radical, R₂For the purpose of the combination of L-valinyl groups, it is believed that this basic scheme is applicable to other amino acids, where other fatty acids may be used; or with conventional protecting groups, also for R₂Is an amino acid derivative, R₁Is a combination of hydroxyl groups. When T contains an-NH-group, the linker can be prepared by a similar regioselective esterification reaction, followed by conversion of the free hydroxyl group to an amino group, reduction to an azide, and finally reaction with phosgene to yield the corresponding carbamoyl chloride.

In this modification, the phosgene reaction step described above is replaced by a reaction with an activated dicarboxylic acid such as succinic anhydride. This gives the triglyceride (containing the (optionally protected) R₁Esters, protected R₂Esters and esters of dicarboxylic acids) and then activating the free carboxyl group on the dicarboxylic acid and esterifying it onto the nucleoside in the usual manner the linker group of formula IIc may also be generated in situ on the nucleoside, in which modification the dicarboxylic acid is esterified to an appropriately protected glycerol derivative. This succinic acid monoester is then esterified to the 5' -hydroxy function of the nucleoside in the usual manner one or both protecting groups in the final glycerol moiety are replaced by an L-amino acid ester. In addition, if present, the remaining protecting groups are replaced by fatty acid esters, or removed and the remainder remainsA free hydroxyl group. Scheme IA illustrates an embodiment wherein the nucleoside is cyclic guanosine (FLG in phantom), the dicarboxylic acid is succinic acid, R₁And R₂Are all CBZ-protected valinyl groups, although it is also applicable to other variations of formula Ic. In each case, coupling conditions refer to conventional esterification conditions, such as the coupling agents DMAP, DCC, and the like, or the conversion of the carboxyl functionality of interest to a reactive derivative, such as an acid chloride, or the inclusion of an anhydride in the activated succinic acid moiety.

In a modification of scheme IA, succinic anhydride is reacted directly with the nucleoside, thereby avoiding the first protection and deprotection process. Another approach is to regioselectively esterify the glycerol moiety with an N-protected amino acid moiety, typically while protecting the hydroxyl group coupled to the nucleoside, which is then deprotected and coupled to the nucleoside.

Where m and n are 1, Alk is an alkylene or alkenylene group, and T is a single bond, the linking group may be prepared as shown in scheme II above. A trifunctional linking group L of the formula IIa₁Other combinations of m, n, Alk and various functional groups in (a) can be prepared by methods similar to those described above using the corresponding starting materials. The raw materials include 1, 2, 4-trihydroxybutane (CA accession No. 3968-00-6), and 3, 4-dihydroxybutyric acid (1518-61-2)&22329-74-4), (S) -3, 4-dihydroxybutyric acid (51267-44-8), (R) -3, 4-dihydroxybutyric acid (158800-76-1), 1, 2, 5-pentanetriol (51064-73-4)&14697-46-2), (S) -1, 2, 5-pentanetriol (13942-73-9), (R) -1, 2, 5-pentanetriol (171335-70-9), 4, 5-dihydroxypentanoic acid (66679-29-6)&129725-14-0), 1, 3, 5-pentanetriol (4328-94-3) and 3- (2-hydroxyethyl) -1, 5-pentanediol (53378-75-9). The preparation of each starting material is referred to the respective accession number. OhThe control of the stereochemistry of trifunctional linkers with lipase P is described by sawa et al in chem.pharm.Bull.41(11)1906-1909(1993) and Terao et al in chem.pharm.Bull.39(3)823-825 (1991).

R₂Amino acid derivative of (1) and R₁The esterification onto the linker group, if present, may also be carried out by the 2-oxa-4-aza-cycloalkane-1, 3-dione method, which is described in International patent application WO94/29311, which is incorporated herein by reference.

By conventional peptide chemistry, R₁And/or R₂The carboxyl function of (a) is attached to the amino group derived from the linker, typically while protecting the alpha-amino group with a commonly used N protecting group. Carboxyl and R at the linking group₂The protection of the alpha-carboxyl function is generally carried out simultaneously with the formation of an amide bond between the alpha-amino groups of (a) by conventional peptide chemistry. Fatty alcohol R₁Analogous to R above for the carboxyl function esterified to the linker₁Is a method of esterification of fatty acids, but the esterification is reversed.

Drawings

Various aspects of the present invention will now be illustrated, by way of example only, with reference to the following examples and accompanying drawings, in which:

FIG. 1 shows the treated and untreated serum virus-DNA concentrations of DHBV infected ducks as a function of time, as shown in biological example 3;

FIG. 2 shows the weight gain of treated ducks infected with DHBV as a function of time, as shown in biological example 3.

Example 1

2- (stearoyloxymethyl) -2- (N- (fluorenylmethoxycarbonyl) -L-valyloxymethyl Yl) -propionic acid

To a solution of 2, 2-bis (hydroxymethyl) propionic acid (28.16 g,210 mmol) in water (50 ml) was added potassium hydroxide (11.78 g, 210 mmol). After 5 min, the solution was evaporated in vacuo and the residue co-evaporated three times with anhydrous DMF. The residue was then dissolved in DMF (500 ml) and benzoyl bromide (3.57) was added to the solutionMilliliter (ml)30 ml.) after stirring for 30 minutes, the reaction mixture was filtered through Celite, poured into aqueous sodium bicarbonate, and extracted with dichloromethane. The organic phase was collected and then washed with an aqueous solution of sodium bicarbonate. Subsequent evaporation in vacuo afforded benzyl 2, 2-bis (hydroxymethyl) propionate (4.37 g),

¹H-NMR(CDCl₃)：7.35(s，5H)，5.20(d，2H)，3.91-3.71(m，4H)，1.10(s，3H).

to a solution of benzyl 2, 2-bis (hydroxymethyl) propionate (4.37 g, 19.5 mmol) in pyridine (50 ml) was added dropwise a solution of stearoyl chloride (4.13 g, 13.6 mmol) in dichloromethane over a period of 40 minutes. The reaction was then held for 16 hours and poured into aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was collected and evaporated in vacuo. The product, benzyl 2- (hydroxyethyl) -2- (stearoyloxymethyl) propionate (1.97 g), was isolated by column chromatography on silica gel,

¹H-NMR(CDCl₃)：7.34(s，5H)，5.17(d，2H)，4.28(dd，2H)，3.69(dd，2H)，2.24(t，2H)，1.57(m，2H)，1.25(s，28H)，1.22(s，3H)，0.87(t，3H)。

benzyl 2- (hydroxyethyl) -2- (stearoyloxymethyl) propionate (1.86 g, 3.8 mmol) was dissolved in pyridine (30 ml) to the solution was added toluene sulfonic acid (73 mg, 0.39 mmol), N-fluorenylmethoxycarbonyl-L-valine (3.94 g, 11.6 mmol) and DCC (3.58 g, 17.4 mmol). The reaction was maintained at 4 ℃ for 16 hours and then filtered through Celite, the filtrate was poured into aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was collected and evaporated in vacuo. The product, benzyl 2- (N-fluorenyl-methoxycarbonyl) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate, was isolated by chromatography on a silica gel column in a yield of 2.38 g,

¹H-NMR(CDCl₃)：7.78-7.25(m，13H)，5.29(m，1H)，5.15(d，2H)，4.38-4.23(m，7H)，2.19(t，2H)，2.10(m，1H)，1.55(m，2H)，1.24(m，31H)，0.94-0.83(m，9H)。

to a solution of benzyl 2- (N-fluorenyl-methoxycarbonyl) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate (1.86 g, 3.8 mmol) in a THF/methanol (16 ml/8 ml) mixed solvent was added ammonium formate (376 mg, 6 mmol), formic acid (1.87 ml) and palladium black (40 mg), the reaction was maintained at room temperature for 16 hours, then filtered through Celite, and after evaporation, the product was isolated by silica gel column chromatography in a yield of 1.05 g.

Example 2

1-O-stearoyl-2-O- (N-CBz-L-valyl) glycerol

a) Preparation of 1-O-stearoyl glycerol

To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 ml) dissolved in DMF (300 ml) was added stearoyl chloride (10 g, 33 mmol) dissolved in DMF (100 ml) dropwise. The mixture was cooled on an ice bath until the dropwise addition was complete. Reaction in N₂Held overnight under atmosphere, after 15 hours CH was added₂Cl₂(300 mL) and saturated NaHCO₃(aqueous solution). The phases were separated and the organic phase was washed with water (50 ml), Na₂SO₄Drying and evaporation of the solvent and pyridine under vacuum, chromatography on a silica Column (CH)₂Cl₂MeOH, 20:1) crude product and recrystallisation of (CH)₂Cl₂-diethyl ether) yield about 7 g.

b) Preparation of pixyl chloride

Acetyl chloride (150 ml, 2.1 mol) was added to a magnetically stirred suspension of 9-hydroxy-9-phenylxanthene (20 g, 72 mmol) in benzene to give a homogeneous dark red solution which was stirred at 20 ℃ for 30 minutes. Volatiles were removed under reduced pressure, ethanol was carefully added to neutralize excess AcCl. The residue was co-evaporated with toluene (2X 30 ml) and cyclohexane (2X 30 ml) to give a crystalline residue which was stored under sealed conditions. Pixyl chloride is also available from Aldrich.

c) Preparation of 1-O-stearoyl, 3-O-pixyl glycerol

The product from a) above (2.28 g) and pyridine (25 ml) were mixed and heated until dissolved after cooling in an ice bath pixyl chloride (1.92 g) from step b) was added. The mixture was kept in an ice bath for half an hour under argon with stirring and then at room temperature for 1.5 hours, pyridine was evaporated under vacuum and the residue was dissolved in CH₂Cl₂(70 ml) and washed with 0.5M citric acid to remove remaining pyridine. With Na₂SO₄The residue was dried, evaporated and chromatographed (ether-hexanes 1:3) to give 1.25 g of pure product, TLC Rf about 0.2.

d) Preparation of 1-O-stearoyl, 2-O- (N-CBz-L-valyl), 3-O-pixyl glycerol

The product of step c) (237 mg, 0.39 mmol), CBz-L-valine (116 mg, 0.46 mmol), DCC (96 mg, 0.46 mmol) and DMAP (4.7 mg, 0.04 mmol) were dissolved in CH₂Cl₂(4 ml). The mixture was kept under nitrogen overnight with stirring. After 18 h the mixture was filtered through a glass filter and chromatographed on a silica gel column (ether-hexane 1:4) to give a yield of 230 mg and a TLC Rf of 0.2.

e) Preparation of 1-O-stearoyl-2-O (N-CBz-L-valyl) glycerol

Removal of the pixyl group from the product of step d) by selective deprotection using the method described for example 3 gives the title compound,

¹H-NMR(CDCl₃)：δ7.35(m，5H)，5.3-4.9(m，4H)，4.35-4.25(m，3H)，3.8-3.6(m，2H)，2.31-2.25(m，2H)，2.20-2.10(m，1H)，1.60(m，2H)，1.02-0.86(m，9H)。

example 3

1-O- (N-CBz-L-valyl) -2-O-stearoyl glycerol

a) Preparation of 1-O- (N-CBz-L valyl) glycerol

CBz-L-valine (4.35 g, 17.3 mmol), dicyclohexylcarbodiimide (4.29 g, 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) were added together to a five-fold excess of glycerol (8 ml, 86.9 mmol) at room temperature. After stirring overnight, the suspension was filtered and the DMF was removed from the filtrate in vacuo. Dissolving the residue in CH₂Cl₂In the middle, continuously using saturated NaHCO₃Brine and water, then dried. The crude product was chromatographed on silica gel with 4/1 EtOAc-hexane as eluent, yield 2.465 g, Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH)₂Cl₂Methanol) 0.12.

b) Preparation of 1-O- (N-CBz-L-valyl) -3-O-pixyl glycerol

The product of step a) (0.672 g, 20.1 mmol) was dissolved in dry pyridine (3.5 ml) under nitrogen 9-chloro-9-phenylxanthene (pixyl chloride, prepared as above, 0.65 g, 22.0 mmol, 1.1 eq) was added and the mixture stirred at room temperature for 1.5 h MeOH (1.5 ml) was added and the mixture was taken up in 10 ml Et₂O and 10 ml of saturated NaHCO₃Are distributed among the devices. The aqueous layer was extracted with more ether and the organic layers were combined, dried and concentrated several times with toluene to give a white solid. The crude product was chromatographed on silica gel with 3/1 hexanes-EtOAc as eluent to give 0.681 g.

The pixyl group may also be supported on PxOH and acetic acid by Gaffney et al, in Tetrahedron Lett 1997, 38, 2539-.

c) Preparation of 1-O- (N-CBz-L-valyl) -2-O-stearoyl-3-O-pixyl glycerol

To a solution of the product of step b) (0.658 g, 1.13 mmol) in 11 ml of pyridine was added dropwise, with stirring, 1.5 ml of CH in an ice bath under nitrogen₂Cl₂Stearoyl chloride (496 ml, 1.3 eq). After 15 minutes, the mixture is stirred at room temperatureThe mixture was taken up in 20 ml Et₂Diluted with O and saturated NaHCO 10 ml₃Wash with more Et₂The aqueous layer was O extracted, the organic layers combined, washed with brine (20 mL), Na₂SO₄Dried and concentrated several times with toluene and the crude product (1.37 g) chromatographed on 130 g silica gel with 6/1 hexane-EtOAc. 500 ml in the first stage and then 100 ml in each stage, the desired substance was eluted in 2-5 stages with a yield of 0.748 g.

d) Preparation of 1-O- (N-CBz-L-valyl) -2-O-stearoyl glycerol

To CH dissolved in 35 ml at room temperature₂Cl₂To a 0.025M solution of the product of step c) (0.748 g, 872 mmol) were added pyrrole (16.5 molar equivalents) and dichloroacetic acid (5.5 molar equivalents). TLC after 5 minutes showed the reaction was complete. The mixture was diluted with 300 ml of CH₂Cl₂Diluted and diluted with 30 ml of saturated NaHCO₃And (6) washing. More CH is used for the water layer₂Cl₂And (4) extracting. The combined organic phases were washed with brine (30 ml), Na₂SO₄Dried and concentrated. The crude product was chromatographed on silica gel with 2/1 hexane-EtOAc (containing 0.3% acetic acid) as eluent, yielding 0.363 g, Rf (2/1 hexane-EtOAc) 0.21,

¹H NMR(CDCl₃)δppm0.86-0.99(m，9H)，1.25(s，28H)，1.61(m，2H)，2.16(m，1H)，2.32(m，2H)，3.74(br s，2H)，4.28-4.44(m，3H)，5.09(m，1H)，5.11(s，2H)，5.22(d，1H)，7.36(m，5H)。

example 4

1-O-stearoyl-3-O- (N-CBz-L-valyl) glycerol

The product of example 2 part a) (2.86 g, 7.99 mmol), DCC (0.9 g, 4.36 mmol), 4- (N, N-dimethyl) aminopyridine (DMAP) (0.048 g, 0.39 mmol) and N-CBz-L-valine (1 g, 3.98 mmol) were dissolved in CH₂Cl₂(60 ml) and DMF (6 ml). The reaction was left at ambient temperature for 18 hours, then filtered and the solvent evaporated under reduced pressureThe residue is dissolved in CH₂Cl₂(100 ml) and filtered. Chromatography of the crude title Compound [ SiO₂Ether/hexane (1:2)]Purification gives 1.3 g of the desired product, the unreacted 1-stearoyl glycerol may be replaced by CH₂Cl₂the/MeOH (20:1) is eluted and recovered,

¹H-NMR(CDCl₃)：δ5.25(d，1H)，5.11(s，2H)，4.30-4.05(m，6H)，2.65(d，1H)，2.35(t，2H)，2.06(m，1H)，1.62(m，2H)，1.26(s，28H)，1.00-0.84(m，9H).

example 5

To ice-cooled 1-chloroethyl chloroformate (1.89 g, 13.2 mmol) in anhydrous CH₂Cl₂(5 ml) solution was added to CH₂Cl₂(20 ml) of the compound of example 4, then anhydrous pyridine (1.2 ml, 29.6 mmol) is added. The reaction mixture was stirred under cooling under an argon atmosphere until TLC (ether/hexane 1:2) indicated exhaustion of the starting material. After 1.5 h, the mixture was washed with water (3X 5 mL), saturated NaHCO₃Washed (5 ml) and dried (Na)₂SO₄). By chromatography [ SiO ]₂Ether/hexane (1:2)]Purification gave the title compound (4.0 g),

¹H-NMR(CDCl₃)：δ7.36-7.32(m，5H)，6.40(m，1H)，5.24(m，1H)，5.11(s，2H)，4.30(m，6H)，2.32(m，2H)，2.15(m，1H)，1.82(m，3H)，1.60(m，2H)，1.25(br s，28H)，0.97(m，3H)，0.86(m，6H).

example 6

To the compound of example 5 (3.4 g,4.87 mmol) in anhydrous acetonitrile (47 ml) was added sodium iodide (3.65 g, 24.3 mmol). The resulting solution was refluxed under argon atmosphere until NMR indicated exhaustion of the starting material 4.5 h, ether (50 ml) was added and the mixture was filtered, the solvent was removed by evaporation, the crude product was dissolved in ether (50 ml), the ether solution was washed with water (2X 10 ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. By chromatography [ SiO ]₂Ether/hexane (1:2)]Purification gave the title compound (2.15 g),

¹H-NMR(CDCl₃)：δ7.37(m，5H)，6.75(m，1H)，5.22(m，1H)，5.15(s，1H)，4.3(m，6H)，2.32(m，1H)，2.22(m，2H)，1.6(m，2H)，1.25(s，28H)，0.95(m，9H).

example 7

A solution of the compound from example 3 (810 mg, 1.37 mmol) in 2.2 ml of dry dichloromethane was cooled under stirring in an ice bath under argon. 1-chloroethyl chloroformate (298. mu.l, 2.74 mmol) was added and 2.5 ml of pyridine in dichloromethane (665. mu.l, 8.22 mmol) were added dropwise. After 2.5 hours, the mixture was diluted with 25 ml of dichloromethane and washed successively with 10 ml of water and 10 ml of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated several times with toluene to give a yellow oil. Purification by flash column chromatography on silica gel with 40/1 dichloromethane-diethyl ether gave the title compound as an oil (96 mg, quantitative yield).

¹H-NMR(CDCl₃)：δppm 0.85-0.98(m，9H)，1.25(s，28H)，1.60(m，2H)，1.83(d，3H，J＝5.8Hz)，2.17(m，1H)，2.31(t，2H)，4.19-4.48(m，5H)，5.11(s，2H)，5.22(d，1H)，5.27(m，1H)，6.38-6.43(m，1H)，7.36(m，5H)。

Example 8

Under nitrogen, a solution of the compound of example 7 (1.896 g, 2.71 mmol) and sodium iodide (1.80 g, 12.0 mmol) in acetonitrile (27 ml) was refluxed at 80 ℃ after 4.5 h, the reaction mixture was diluted with 100 ml of 1/1 hexane-diethyl ether and washed with 25 ml of water. The aqueous phase was extracted with more solvent (25 ml), the organic phases combined, washed successively with 5% aqueous sodium thiosulfate (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate and concentrated under vacuum purification by flash column chromatography on silica gel with 80/1 dichloromethane-methanol as eluent to give an oil (1.45 g) containing 90% of the title compound and 10% of the compound of example 7,

¹H-NMR(CDCl₃)：δppm0.85-0.99(m，9H)，1.25(s，28H)，1.60(m，2H)，2.17(m，1H)，2.23(d，3H，J＝6Hz)，2.31(t，2H)，4.16-4.49(m，5H)，5.10(s，2H)，5.20-5.29(m，2H)，6.69-6.79(m，1H)，7.36(m，5H)。

example 9

4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -1-stearoyloxybutane

a) Synthesis of diethyl-2- (2-benzyloxyethyl) malonate

To a solution of freshly prepared sodium (0.95 g, 41.4 mmol) in 50 ml ethanol was added a solution of diethyl malonate (6.4 g, 40 mmol) in 10 ml ethanol and the mixture was stirred for 15 min. Then a solution of 2-benzyloxy-1-iodoethane (11.5 g, 41.35 mmol) was added dropwise. The mixture was refluxed for 4 hours and evaporated in vacuo. 100 ml of water are added, the mixture is extracted three times with 50 ml of diethyl ether, the organic phase is dried over sodium sulfate and evaporated in vacuo, and the product is isolated by column chromatography on silica gel in yield: 8.6 g of the total weight of the powder,

¹H-NMR(CDCl₃)：1.26(m，6H)2.26(m，2H)3.54(m，3H)4.16(m，4H)4.57(s，2H)7.32(m，5H)。

b) synthesizing 4-benzyloxy-2-hydroxymethyl-butanol-1.

To a stirred suspension of lithium aluminium hydride (3.0 g, 80 mmol) in 100 ml of diethyl ether at about 15 ℃ is added dropwise a solution of diethyl-2- (2-benzyloxyethyl) malonate (8.5 g, 28.8 mmol) in 20 ml of diethyl ether. The mixture was refluxed for 2 hours, about 4 ml of water were added dropwise with cooling, and the mixture was filtered and washed with dioxane. The filtrate was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel in a yield of 3.4 g,

¹H-NMR(CDCl₃)：1.60(m，2H)1.82(m，1H)3.00(m，2H)3.56(t，2H)3.69(m，4H)4.50(s，2H)7.32(m，5H)。

c) synthesis of 4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -butanol-1

To a solution of N-trityl-L-valine (4.66 g, 13 mmol) and 4-benzyloxy-2-hydroxymethyl-butanol-1 (3.3 g, 15.6 mmol) in 50 ml dichloromethane were added DCC (3.0 g, 14.5 mmol) and DMAP (0.18 g, 1.45 mmol). The mixture was stirred for three days, the mixture was cooled to 5 ℃ and the urethane was filtered, the solution was evaporated under reduced pressure, the product was isolated by column chromatography on silica gel with a yield of 2.5 g,

¹H-NMR(CDCl₃)：1.00(m，6H)1.55(m，4H)1.72(m，1H)2.18(m，1H)2.70(m，1H)3.27(m，2H)3.43(m，3H)4.50(s，2H)7.26(m，20H).

d) synthesis of 4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -1-stearoyloxybutane

To a solution of 4-benzyloxy-2- (N-trityl-L-valyloxymethyl) -butanol-1 (2.4 g, 4.35 mmol) in 50 ml dichloromethane was added pyridine (1.72 g, 21.7 mmol). The solution was cooled to 10 ℃, stearoyl chloride (2.64 g, 8.7 mmol) in 10 ml dichloromethane was added dropwise between 10-15 ℃, the mixture was stirred at room temperature overnight, 100 ml 5% sodium bicarbonate solution was added, the mixture was stirred for 30 minutes, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over sodium sulfate and concentrated in vacuo, the product was isolated by silica gel column chromatography with a yield of 3.0 g,

¹H-NMR(CDCl₃)：0.98(m，9H)1.26(m，28H)1.54(m，2H)1.94(m，1H)2.25(m，2H)3.23(m，2H)3.44(m，2H)3.58(m，1H)3.91(m，2H)4.10(m，1H)4.47(s，2H)7.28(m，20H)。

example 10

5- (N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoic acid

a preparation of 2-allyl-1, 3-propanediol

Diethyl allylmalonate (20 ml, 101 mmol) in anhydrous ether (100 ml) was added dropwise to a stirred solution of lithium aluminium hydride (9.6 g, 253 mmol) at 0 deg.c the reaction was warmed to room temperature and held for 5 hours. Cooled to 0 ℃ and water (12 ml) was added dropwise. After stirring for 30 minutes, the mixture was filtered through Celite, then washed with ethanol (2 × 500 ml), and the solution was dried under vacuum to give 9.5 g of product,

¹H-NMR(CDCl₃)：5.78(m，1H)，5.03(m，2H)，3.78(m，2H)，3.69(m，2H)，2.06(t，2H)，1.87(m，1H)。

b) preparation of 1-O- (N-trityl-L-valyl) -2-allyl-1, 3-propanediol

To a solution of N-trityl-L-valine (5.5 g, 15.2 mmol), 2-allyl-1, 3 propanediol (4.4 g, 38 mmol), N-dimethylaminopyridine (183 mg, 1.5 mmol) in dichloromethane (120 ml) was added DCC (3.5 g, 16.7 mmol). The reaction was maintained at reflux overnight. After filtration through Celite, the organic phase is washed with aqueous sodium hydrogencarbonate solution and dried. Silica gel column chromatography gave 4.6 g of intermediate 1-O- (N-trityl-L-valyl) -2-allyl-1, 3-propanediol.

c) Preparation of 1-O- (N-trityl-L-valyl) -2-allyl-3-stearoyl-1, 3-propanediol

Stearoyl chloride (3.62 g, 12 mmol) in dichloromethane was added dropwise to a solution of 1-O- (N-trityl-L-valyl) -2-allyl-1, 3-propanediol (1.83 g, 4 mmol) in dichloromethane (40 ml) and pyridine (3.2 ml, 40 mmol) at 0 ℃. The solution was warmed to room temperature and held for 3 hours, washed with an aqueous sodium bicarbonate solution and dried, and the product was isolated by silica gel column chromatography (1.9 g),

¹H-NMR(CDCl₃)：7.30(m，15H)，5.70(m，1H)，4.99(m，2H)，3.93(m，2H)，3.55(m，1H)，3.27(m，2H)，2.68(m，1H)，2.30(m，2H)，2.33(m，1H)，2.01(m，2H)，1.85(m，1H)，1.62(m，2H)，1.3(m，28H)，0.98(dd，6H)，0.91(t，3H)。

d) preparation of 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxy-butyraldehyde

1-O- (N-trityl-L-valyl) -2-allyl-3-stearoyl-1, 3-propanediol (580 mg, 0.8 mmol) was dissolved in dioxane (5 mL). Osmium tetroxide (20 mg, 0.08 mmol) and pyridine (0.05 ml, 0.64 mmol) were added to the solution. A solution of sodium periodate in water (3.5 ml) was added to the reaction mixture. The reaction was held overnight and then cooled to 0 ℃. An aqueous solution of sodium bisulfite was added, and the mixture was extracted with dichloromethane. The organic phase was dried and purified by column chromatography on silica gel in a yield of 250 mg,

¹H-NMR(CDCl₃)：9，68(s，1H)，7.25(m，15H)，3.92(m，2H)，3.58(m，1H)，2.32(m，2H)，2.68(m，1H)，2.34(m，7H)，1.58(m，2H)，1.53(m，28H)，0.96(dd，6H)，0.86(t，3H)。

f) preparation of benzyl 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxyhexene-2-oate

To a solution of 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxy-butyraldehyde (15.8 g, 21.8 mmol) in dichloromethane were added (benzyloxycarbonylmethyl) triphenylphosphonium bromide (10.7 g, 21.8 mmol) and triethylamine (2.21 g, 21.8 mmol). The reaction was kept at room temperature overnight and the mixture was evaporated. Diethyl ether (200 ml) was added to the residue and held at 4 ℃ for two hours. Then filtered, the filtrate is evaporated and the product is purified by chromatography on a silica gel column with a yield of 10 g,

¹H-NMR(CDCl₃)：7.30(m，20H)，6.89(m，1H)，5.88(d，1H)，5.19(d，2H)，3.95(m，2H)，3.57(m，1H)，3.29(2H)，2.68(m，1H)，2.23(m，5H)，1.93(m，1H)，1.60(m，2H)，1.32(m，28H)，0.95(dd，6H)，0.89(t，3H).

g) preparation of 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxyhexanoate

To a solution of benzyl 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxyhexene-2-oate (70 mg, 0.08 mmol) in methanol (3 ml) and ethyl acetate (1 ml) was added sodium bicarbonate (10 mg) and palladium black (20 mg). The reaction was maintained under hydrogen at atmospheric pressure for 2 hours. The mixture was filtered and evaporated. The residue was dissolved in dichloromethane and washed successively with aqueous EDTA solution and cold 2% aqueous lemon solution, the organic phase was evaporated to give 61 mg of product,

¹H-NMR(CDCl₃)：7.30(m，15H)，3.93(m，2H)，3.57(m，1H)，3.25(m，2H)，2.30(dt，4H)，2.20(m，1H)，1.70(m，1H)，1.62(m，4H)，1.30(m，28H)，0.95(dd，6H)，0.87(t，3H)。

example 11

3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyric acid

a) Preparation of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-1, 3-propanediol

To a solution of 2-allyl-1, 3-propanediol (4.6 g, 40 mmol) and N-benzyloxycarbonyl-L-valine (5.02 g, 20 mmol) in dichloromethane was added dimethylaminopyridine (244 mg, 2 mmol) and DCC (4.5 g, 22 mmol). after two hours, the mixture was filtered through Celite and evaporated to isolate the product 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-1, 3-propanediol in 5.01 g yield.

¹H-NMR(CDCl₃)：7.36(m，5H)，5.78(m，1H)，5.26(d，1H)，5.11(s，2H)，5.06(d，2H)，4.22(m，3H)，3.59(m，2H)，2.13(m，3H)，1.98(m，2H)，0.94(dd，6H)。

b) Preparation of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1, 3-propanediol

Stearoyl chloride (7.8 g, 26 mmol) was added to a solution of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-1, 3-propanediol (4.46 g, 12.7 mmol) in dichloromethane (70 ml) and pyridine (6.1 ml, 76 mmol) in an ice bath. The reaction mixture was warmed to room temperature and held for one hour, then poured into aqueous sodium bicarbonate, the organic phase was dried, and the product, 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1, 3-propanediol, was purified by silica gel column chromatography (6.7 g),

¹H-NMR(CDCl₃)：7.34(m，5H)，5.77(m，1H)，5.30(d，1H)，5.11(s，2H)，5.08(d，2H)，4.32(m，1H)，4.10(m，4H)，2.29(t，2H)，2.13(m，4H)，1.62(m，3H)，1.25(m，28H)，0.90(m，9H)。

c) preparation of 3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyric acid

Potassium permanganate (756 mg, 4.8 mmol) was dissolved in water (7.5 ml). The solution was kept under vigorous stirring for 10 minutes. A solution of 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1, 3-propanediol (1 g, 1.6 mmol) and tetrabutylammonium bromide (77 mg, 0.24 mmol) in benzene (5 mL) was added and the slurry stirred for 1.5 h and dichloromethane was added. An aqueous sodium bisulfite solution was added to the slurry until the mixture faded. The organic phase was acidified with acetic acid and washed with water. After evaporation, the product, 3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyric acid (390 mg) was isolated by column chromatography on silica gel,

¹H-NMR(CDCl₃)：7.33(m，5H)，5.38(d，1H)，5.11(s，2H)，4.14(m，5H)，2.60(m，1H)，2.45(m，2H)，2.29(t，2H)，2.18(m，1H)，1.58(m，2H)，1.25(m，28H)，0.90(m，9H).

example 12

2′3′-dideoxy-3′-fluoro-5′-O- [5- (L-valyloxymethyl) -6-stearoyloxyhexanoyl Base of]Guanosine

a) Preparation of 2 '3' -dideoxy-3 '-fluoro-5' -O- [5- (N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoyl ] guanosine

To a solution of 5- (N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoic acid (462 mg, 0.6 mmol) and 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (340 mg, 1.25 mmol) in DMF (3 ml) was added dimethylaminopyridine (7 mg, 0.06 mmol) and DCC (136 mg, 0.66 mmol). The reaction was kept at room temperature overnight and then at 40 ℃ for 2 hours. The reaction mixture was filtered through Celite and poured into dichloromethane, washed with aqueous sodium bicarbonate, and the product, 2 '3' -dideoxy-3 '-fluoro-5' -O- [5- (N-trityl-L-valyloxymethyl) -6-stearoyloxyhexanoyl ] guanosine (93 mg), was isolated by column chromatography on silica gel,

¹H-NMR(DMSO d-6)：7.88(s，1H)，7.29(m，15H)，6.52(s，2H)，6.17(dd，1H)，5.45(m，1H)，4.35(m，1H)，4.20(m，2H)，3.82(m，2H)，3.502.60(m，5H)，2.30(m，4H)，2.10(m，1H)，1.70(m，1H)，1.50(m，4H)，1.22(m，28H)，0.85(m，9H)。

b) preparation of 2 '3' -dideoxy-3 '-fluoro-5' -O- [5- (L-valyloxymethyl) -6-stearoyloxyhexanoyl ] guanosine

The compound of step b) (90 mg, 0.088 mmol) was deprotected by treatment with 80% acetic acid (5 ml) for 30 min at room temperature, evaporated and the product purified by silica gel column chromatography to give 72 mg of the title compound,

¹H-NMR(DMSO d-6)：7.88(s，1H)，6.54(s，2H)，6.18(dd，1H)，5.48(dd，1H)，4.27(dt，1H)，4.19(m，2H)，3.98(m，4H)，3.17-2.55(m，4H)，2.29(m，4H)，1.95(m，1H)，1.75(m，1H)，1.50(m，4H)，1.21(m，28H)，0.84(m，9H).

example 13

2′3′-dideoxy-3′-fluoro-5′-O- [3- (L-valyloxymethyl) -4-stearoyloxybutyryl Base of]Guanosine

a) Preparation of 2 '3' -dideoxy-3 '-fluoro-5' -O- [3- (N-benzyloxycarbonyl-L-valyloxy) -4-stearoyloxybutyryl ] guanosine

To a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (113 mg, 0.42 mmol) and 3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyric acid (140 mg, 0.21 mmol) in DMF (2 ml) was added dimethylaminopyridine (3 mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol), two days later dichloromethane (10 ml) and a few drops of acetic acid were added and the organic phase was filtered over Celite. The filtrate was washed with an aqueous sodium hydrogencarbonate solution, and the product, 2 '3' -dideoxy-3 '-fluoro-5' -O- [3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyryl ] guanosine, was isolated by silica gel column chromatography in a yield of 51 mg,

¹H-NMR(CDCl₃)：7.79(d，1H)，7.26(m，5H)，6.38(s，2H)，6.23(t，1H)，5.44(m，2H)，5.08(s，2H)，4.50-4.10(m，8H)，3.15-2.40(m，5H)，2.30(t，2H)，2.14(m，1H)，1.58(m，2H)，1.24(m，28H)，0.87(m，9H)。

b) preparation of 2 '3' -dideoxy-3 '-fluoro-5' -O- [3- (L-valyloxymethyl) -4-stearoyloxybutyryl ] guanosine

The product of step a) (76 mg, 0.084 mmol) was dissolved in a mixed solvent of methanol (3 ml), ethyl acetate (0.5 ml) and acetic acid (0.01 ml). To this solution, palladium black (10 mg) was added, and after 2 hours, 10 mg of palladium black was added. After 3 hours, the mixture was filtered and evaporated, and the residue was dissolved in dichloromethane and washed with aqueous EDTA. The organic phase was dried and co-evaporated with toluene to give the title compound as the acetate salt in 65 mg yield,

¹H-NMR(DMSO d-6+D₂O)：7.87(s，1H)5.16(dd，1H)，5.37(dd，1H)，4.24(m，3H)，4.01(m，4H)，3.10-2.60(m，3H)，2.40(m，2H)，2.24(t，2H)，1.70(m，1H)，1.48(m，2H)，1.25(m，28H)，0.82(m，9H)。

example 14

Chloroformic acid 3- [1- (N-CBz-L-valyl) -2-stearoyl ] propyl ester

1- (N-CBz-L-valyl) -2-stearoyl glycerol (300 mg, 0.5 mmol) was dissolved in 20% phosgene in toluene (15 mL). After 18 hours, the solution was evaporated and the residue and toluene were co-evaporated several times to give the title product quantitatively. The product and the target nucleoside are formed into carbonate by conventional methods, such as reaction at 0 deg.C in 10:1 DMF/pyridine for 3-24 hours, injection into NaHCO₃Deprotection of the amino acid, for example, with palladium black in methanol, ethyl acetate, acetic acid, to give the nucleoside-O- [1- (L-valyl) -2-stearoyl-3-propoxycarbonyl]，

¹H-NMR(CDCl₃)：7.40(m，5H)，5.28(m，2H)5.10(s，2H)，4.35(m，5H)，2.35(m，2H)，2.17(m，1H)，1.56(m，2H)，1.30(m，28H)，0.95(m，9H)。

Example 15

5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoic acid

a)4, 5-dihydroxy-2-pentenoic acid benzyl ester

A mixture of DL-glyceraldehyde (4.5 g, 50 mmol) and (benzyloxycarbonylmethyl) -triphenyl-phosphonium bromide (24.57 g, 50 mmol) in 100 ml of 1, 2-epoxybutane was refluxed overnight. The mixture was evaporated under vacuum and the product was isolated by column chromatography on silica gel in 8 g to 71%,

¹H-NMR(CDCl₃)：2.50(s，1H)2.96(s，1H)3.54(m，1H)3.70(m，1H)4.38(m，1H)5.12(s，2H)6.14(m，1H)6.90(m，1H)7.30(m，5H)。

b) benzyl 5- (N-FMOC-L-valyloxy) -4-hydroxy-2-pentenoate

A 100 ml dichloromethane mixture of benzyl 4, 5-dihydroxy-2-pentenoate (4.4 g, 20 mmol), N-FMOC-L-valine (5.8 g, 17 mmol) and DMAP (0.21 g, 1.7 mmol) was cooled to about 10 ℃. A solution of DCC (4.2 g, 20 mmol) in 25 ml of dichloromethane was added dropwise at the same temperature, and the mixture was stirred at room temperature overnight. The mixture was cooled to 5 ℃ and the urethane was filtered. The filtrate was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel, yield: 6.6 g-71%,

¹H-NMR(CDCl₃)：0.91(m，6H)2.12(m，1H)4.38(m，5H)，5.14(s，2H)5.24(m，1H)6.20(m，1H)6.92(m，1H)7.30(m，13H)。

c) benzyl 5- (N-FMOC-L-valyloxy) -4-stearoyloxy-2-pentenoate

To a solution of benzyl 5- (N-FMOC-L-valyloxy) -4-hydroxy-2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmol) in 100 ml dichloromethane at 10 ℃ was added dropwise a solution of stearoyl chloride (4.55 g, 15 mmol) in 25 ml dichloromethane, the mixture was stirred overnight, 100 ml of 5% sodium bicarbonate solution was added, the mixture was stirred for 30 min, the organic phase was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography. Yield: 7.8 g to 80%,

¹H-NMR(CDCl₃)：0.88(m，9H)1.25(m，28H)1.58(m，2H)2.14(m，1H)2.32(m，2H)4.22(m，5H)5.19(s，2H)5.25(m，1H)6.12(m，1H)6.85(m，1H)7.35(m，13H)。

d)5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoic acid

A solution of benzyl 5- (N-FMOC-L-valyloxy) -4-stearoyloxy-2-pentenoate (3.8 g, 4.69 mmol) in 50 ml of ethyl acetate was hydrogenated with 10% palladium on charcoal (0.5 g) for 5 h at room temperature under normal pressure, the catalyst was filtered, washed with ethyl acetate and 1, 4-dioxane, the solution was evaporated under reduced pressure, yielding 3.3 g ═ 99%

¹H-NMR(CDCl₃)：0.92(m，9H)1.25(m，28H)1.54(m，2H)1.98(m，2H)2.18(m，1H)2.28(m，2H)2.41(m，2H)4.32(m，5H)5.13(m，1H)5.33(m，1H)7.50(m，8H)。

Example 16

3- (N-FMOC-L-valyloxy) -2-stearoyloxy propanoic acid

a)2, 3-Dihydroxypropionic acid benzyl ester

A mixture of D, L-glyceric acid calcium salt dihydrate (2.9 g, 10 mmol) and benzyl bromide (3.8 g, 22 mmol) in 25 ml DMF was stirred at 60 ℃ overnight, the mixture was evaporated under reduced pressure, the product was isolated by silica gel column chromatography in 4 g to 100% yield,

¹H-NMR(CDCl₃)：3.26(s，1H)3.90(m，2H)4.32(m，1H)5.25(s，2H)7.28(m，5H)。

b)3- (N-FMOC-L-valyloxy) -2-hydroxypropionic acid benzyl ester

A solution of benzyl 2, 3-dihydroxypropionate (4.0 g, 20 mmol), N-FMOC-L-valine (5.4 g, 16 mmol) and DMAP (0.2 g, 1.6 mmol) in 80 mL of dichloromethane was cooled to about 10 ℃. A solution of DCC (4.12 g, 20 mmol) in 25 ml of dichloromethane was added dropwise at the same temperature, and the mixture was stirred at room temperature overnight. The mixture was cooled to 5 ℃ and the urethane was filtered. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel. Yield 4.7 g ═ 45%

¹H-NMR(CDCl₃)：0.88(m，6H)2.05(m，1H)4.40(m，6H)5.23(m，3H)7.50(m，13H)

c)3- (N-FMOC-L-valyloxy) -2-stearoyloxy propanoic acid benzyl ester

To a stirred solution of benzyl 3- (N-FMOC-L-valyloxy) -2-hydroxypropionate (4.6 g, 8.89 mmol) and pyridine (1.41 g, 17.8 mmol) in 80 ml of dichloromethane was added dropwise a solution of stearoyl chloride (3.64 g, 12 mmol) in 20 ml of dichloromethane, and the mixture was stirred at room temperature overnight. 100 ml of 5% sodium bicarbonate solution were added and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography in 6.1 g 87%,

¹H-NMR(CDCl₃)：0.88(m，9H)1.26(m，28H)1.56(m，2H)2.06(m，1H)2.34(m，2H)4.36(m，6H)5.19(s，2H)5.32(m，1H)7.50(m，13H)

d)3- (N-FMOC-L-valyloxy) -2-stearoyloxy propanoic acid

A solution of benzyl 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionate (0.78 g, 1 mmol) in 20 ml of ethyl acetate was hydrogenated over 10% palladium on charcoal (0.2 g) at room temperature under normal pressure for 3 hours. The catalyst was filtered and washed with ethyl acetate and 1, 4-dioxane. The solution was evaporated under reduced pressure, yielding 0.63 g to 90%,

¹H-NMR(CDCl₃)：0.88(m，9H)1.24(m，28H)1.40(m，2H)2.12(m，3H)4.30(m，5H)5.16(m，1H)5.60(m，1H)7.40(m，8H)。

example 17

1- (N-benzyloxycarbonyl-L-valyloxy)Ylmethyl) -2-stearoyloxyethoxycarbonyl chloride Article (A)

Bis (trichloromethyl) carbonate (160 mg, 0.54 mmol) was added to a solution of 1- (N-benzyloxycarbonyl-L-valyl) -3-stearoylglycerol/1- (N-benzyloxycarbonyl-L-valyloxy) -3-stearoyloxy-2-propanol/the (660 mg, 1.12 mmol) prepared in example 4 and triethylamine (200 mg, 2.0 mmol) in dichloromethane (5 ml) at room temperature with stirring. After 1h, n-hexane (10 ml) was added, the precipitated triethylamine hydrochloride was filtered off through a short silica gel column, the product was eluted with n-hexane and the solvent was evaporated in vacuo to yield 650 mg (89%) of the title compound,

13C NMR(CDCl₃，62.975MHz)：δ172.8(stea-COO)，171.2(Val-COO)，155.9(CONH)，154.1(COCl)，136.0(Ph-Cl-Val)，128.1-127.7(Ph)，67.2(CHOH)，66.7(PH CH2)，63.1(ValCOOCH₂)，61.8(stea-COOCH₂) 58.7 (Val-. alpha.C), 33.7 (Stea-C2), 31.6 (Stea-C16), 31.0 (Val-. beta.C), 29.3-28.8 (Stea-C4-15), 24.5 (Stea-C3), 18.6 and 17.1(Val 2 CH)₃)，13.8(stea -C18)。

Example 18

Chloroformic acid 3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutyl ester

a)3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutanol

To a stirred solution of 4-stearoyloxy-3- (N-CBz-L-valyloxymethylbutanal (prepared analogously to example 6, step d protected valine with CBz) (2.0 g, 3.2 mmol) in 25 ml of methanol was added sodium borohydride (0.6 g, 16 mmol) in small portions at 10 ℃, the mixture was stirred for 30 minutes, then acidified with acetic acid, the mixture was diluted with water and extracted three times with dichloromethane, the organic phase was dried with sodium sulfate and concentrated in vacuo, the product was chromatographed on a silica gel column at 1.5 g 75%,

¹H-NMR(CDCl₃)0.88(m，9H)1.25(m，28H)1.52(m，4H)2.24(m，3H)3.68(m，2H)4.12(m，1H)4.24(m，1H)5.08(s，2H)5.22(m，1H)7.36(m，5H)

b) chloroformic acid 3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutyl ester

Step intermediate a) was stirred overnight in 20 ml of 20% phosgene in toluene. The mixture was evaporated under reduced pressure to give the title compound in a yield of 1.5 g 97%,

¹H-NMR(CDCl₃)0.88(m，9H)1.28(m，28H)1.58(m，2H)1.72(m，2H)2.15(m，1H)2.31(m，2H)4.08-4.42(m，5H)5.10(s，2H)5.22(m，1H)7.36(m，5H)。

example 19

2′，3′-dideoxy-3′-fluoro-5′-O- [1- (L-valyloxy) -2-stearoyloxy-3-propoxy Radical carbonyl]Guanosine

a) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [1- (N-CBz-L-valyloxy) -2-stearoyloxy-3-propoxycarbonyl ] guanosine

To a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (270 mg, 1 mmol) in DMF (10 mL) and pyridine (1 mL) was added 3- {1- (N-CBz-L-valyl) -2-stearoyl } propyl chloroformate (619 mg, 0.5 mmol) at 0 ℃. After 3 hours, the reaction mixture was poured into sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried in vacuo, and 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [1- (N-CBz-L-valyloxy) -2-stearyloxy-3-propoxycarbonyl ] guanosine (195 mg) was separated by silica gel column chromatography,

¹H-NMR(CDCl₃)：7.69(s，1H)，7.31(m，5H)，6.50(m，2H)，6.32(m，1H)，5.3(m，2H)，5.09(m，2H)，4.35(m，7H)，2.60(m，2H)，2.31(t，2H)，2.20(m，1H)，1.58(m，2H)，1.23(m，28H)，0.92(m，9H)。

b) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [1- (L-valyloxy) -2-stearoyloxy-3-propoxycarbonyl ] guanosine

2 ', 3' -dideoxy-3 '-fluoro-5' -O- [1- (N-CBz-L-valyloxy) -2-stearoyloxy-3-propoxycarbonyl ] guanosine (190 mg) was dissolved in a mixed solvent of methanol (6 ml), ethyl acetate (2 ml) and acetic acid (1 ml). To the solution was added palladium black (30 mg), the reaction mixture was kept under hydrogen for 2 hours, followed by filtration, evaporation of the filtrate, separation of the title product by silica gel column chromatography (110 mg),

¹H-NMR(DMSO-δ6)：7.86(ds，1H)，6.51(s，2H)，6.17(dd，1H)，5.48(m，1H)，5.20(m，1H)，4.25(m，7H)，2.70(m，2H)，2.27(m，2H)，1.72(m，1H)，1.47(m，2H)，1.22(m，28H)，0.84(m，9H).

example 20

2′，3′-dideoxy-3′-fluoro-5′-O- [5- (L-valyloxy) -4-stearoyloxy-pentanoyl] Guanosine

DMAP (16 mg, 0.13 mmol), HOBT (0.176 g, 1.3 mmol) and DCC (0.248 g, 1.2 mmol) were added to a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (0.27 g, 1 mmol) and 5- (N-FMOC-L-valyloxy) -4-stearoyloxypentanoic acid (0.94 g, 1.3 mmol) in 30 mL of DMF. The mixture was stirred at room temperature for three days. 4 g of silica gel were added and the mixture was evaporated in vacuo. The product, 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (FMOC-L-valyloxy) -4-stearoyloxy-pentanoyl ] guanosine, was isolated by chromatography on a silica gel column with a yield of 0.45 g,

¹H-NMR(DMSO-δ6)：0.88(m，9H)1.20(m，28H)1.45(m，2H)1.78(m，2H)2.18(m，2H)2.36(m，1H)2.62(m，2H)3.88(m，1H)4.22(m，6H)4.92(m，1H)5.45(m，1H)6.19(m，1H)6.52(s，2H)7.26-7.88(m，8H)。

deprotection of the protected intermediate as described above affords the title compound.

Example 20

2′，3′-dideoxy-3′-fluoro-5′-O- [3- (N-FMOC-L-valyloxy) -2-stearoyloxy- Propionyl group]Guanosine

To a stirred mixture of 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionic acid (0.61 g, 0.88 mmol) in 5 ml of anhydrous diethyl ether was added a drop of DMF and thionyl chloride (0.52 g, 4.4 mmol). The mixture was refluxed for two hours and then evaporated under reduced pressure. The product was dissolved in anhydrous dichloromethane and a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (0.215 g, 0.8 mmol) and pyridine (0.35 g, 4.4 mmol) in 20 ml of DMF was added dropwise. The solution was stirred overnight. Two grams of silica gel were added and the mixture was evaporated in vacuo. The product was isolated by silica gel column chromatography in 0.19 g 25% yield,

¹H-NMR(CDCl₃)：0.88(m，9H)1.25(m，28H)1.62(m，2H)2.12(m，1H)2.38(m，2H)2.58(m，2H)4.12-4.76(m，6H)5.32(m，2H)6.12(m，1H)6.26(m，1H)6.44(m，1H)7.12-7.78(m，8H)。

example 21

Succinic acid 1- (N-CBz-L-valyl) -3-stearoyl-2-propyl monoester

1- (N-CBz-L-valyl) -3-stearoylglycerol (886 mg, 1.5 mmol) and succinic anhydride (450 mg, 4.5 mmol) were dissolved in a mixed solvent of DMF (15 mL) and pyridine (1 mL). The reaction was held at room temperature for 3 hours and then at 60 ℃ for 5 hours. The reaction mixture was poured into a solution of acetic acid and water and extracted with dichloromethane. The organic phase is washed with water and evaporated, and the product is isolated by column chromatography on silica gel in a yield of 900 mg,

¹H-NMR(CDCl₃)：7.43(m，5H)，5.27(m，1H)，5.09(m，2H)，4.21(m，5H)，2.54(m，4H)，2.29(t，2H)，2.13(m，1H)，1.59(m，2H)，1.25(m，28H)，0.90(m，9H)。

example 22

2′，3′-dideoxy-3′-fluoro-5′-O- {3- [1- (L-valyloxy) -3-stearoyloxy-2- Propoxycarbonyl radical]-propionyl } guanosine

To a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (351 mg, 1.3 mmol) and 1- (N-CBz-L-valyl) -3-stearoyl-2-propyl succinate (900 mg, 1.3 mmol) in DMF (15 ml) was added dimethylaminopyridine (24 mg, 0.2 mmol), 1-hydroxybenzotriazole (175 mg, 1.3 mmol), DCC (321 mg, 1.56 mmol). After 48 hours, the reaction mixture was filtered, the filtrate was poured into sodium bicarbonate solution and extracted with dichloromethane. The product, 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1- (N-CBz-L-valyl) -3-stearoyl-glyceroxycarbonyl ] -propionyl } guanosine, 780 mg, was isolated by silica gel column chromatography,

¹H-NMR(DMSO-d6)：7.89(s，1H)，7.34(m，5H)，6.50(s，2H)，6.17(dd，1H)，5.46(m，1H)，5.38(m，1H)，5.02(s，2H)，4.22(m，7H)，3.32(s，4H)，2.80(m，2H)，2.57(m，2H)，2.31(t，2H)，2.05(m，1H)，1.48(m，2H)，1.21(m，28H)，0.84(m，9H)。

to a solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1- (N-CBz-L-valyl) -3-stearoyl-2-propoxycarbonyl ] -propionyl } guanosine (460 mg, 0.5 mmol) in a mixed solvent of methanol (10 ml), ethyl acetate (3 ml) and acetic acid (2 ml) was added palladium black (50 mg), after reacting for 2 hours under a hydrogen atmosphere, the mixture was filtered, the filtrate was dried, and 360 mg of the objective product was isolated by silica gel column chromatography,

¹H-NMR(DMSO-d6)：7.89(s，1H)，6.51(s，2H)，6.16(dd，1H)，5.48(m，1H)，5.17(m，1H)，4.28(m，7H)，2.90(m，2H)，2.58(m，4H)，2.28(t，2H)，1.85(m，1H)，1.49(m，2H)，1.22(m，28H)，0.85(m，9H).

example 23

Stearoyl chloride (12.1 g, 40 mmol, 1.0 eq) in CH at room temperature₂Cl₂The solution (100 ml) was added slowly (1 h) to a solution of 2, 2-bis (hydroxymethyl) propionic acid (26.8 g, 200 mmol, 5.0 eq) in pyridine (400 ml). The reaction mixture was stirred at room temperature overnight and then concentrated under vacuum (100 ml). The reaction mixture was slowly diluted with saturated NaHCO₃(400 ml) treatment followed by CH₂Cl₂(3X 300 ml) was extracted. The combined organic phases were washed with brine, Na₂SO₄Dried and concentrated in vacuo. The crude product was purified on silica gel (500 g) at 19/1-4/1 CH₂Cl₂Chromatographic separation with MeOH as eluent to give the stearic acid monoester, Rf (9/1 CH)₂Cl₂MeOH)0.33, yield 12.5 g (78%).

N-Cbz-L valine (18.85 g, 75 mmol, 2.4 equiv.) and DMAP (855 mg, 7 mmol, 0.22 equiv.) in CH₂Cl₂The solution (800 ml) was cooled to 0 ℃ and treated with DCC (14.4 g, 70 mmol, 2.2 eq). The reaction mixture was stirred at room temperature for 30 minutes, then slowly (1 hour) with the above stearic acid monoester (12.5 g, 31.2 mmol, 1 equivalent) in CHCl₃(200 ml, no alcohol) solution. After stirring overnight, the suspension was filtered and the filtrate was washed with brine, Na₂SO₄Dried and concentrated in vacuo. The crude product was purified on silica gel (500 g) at 19/1-4/1 CH₂Cl₂Chromatographic purification with MeOH as eluent to give the above diester, Rf (9/1 CH)₂Cl₂MeOH)0.46, yield 13.8 g (70%),

¹H-NMR(250MHz，CDCl₃)：δ7.35-7.3(m，5H，ArH)，5.32(d，1H，CH)，5.10(s，2H，CH₂Ph)，4.33-4.18(m，4H，CH₂)，2.28(t，2H，CH₂)，2.22-2.05(m，1H，CH)，1.65-1.50(m，2H，CH₂)，1.35-1.15(m，31H)，1.00-0.82(m，9H，Me)。

example 24

2′，3′-dideoxy-3′-fluoro-5′-O- [5- (L-valyloxy) -4-stearoyloxy-pentanoyl] Guanosine

a) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoyl ] guanosine

2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (269 mg, 1.0 mmol), 5- (N-FMOC-L-valyloxy) -4-stearoyloxy-pentanoic acid (940 mg, 1.3 mmol), DMAP (16 mg, 0.13 mmol) and HOBT (176 mg, 1.3 mmol) were coevaporated twice with DMF down to 30 mL. DCC (248 mg, 1.2 mmol) was added and the mixture stirred at room temperature overnight the mixture was filtered and the solution was evaporated under reduced pressure ethyl acetate (50 ml) was added and washed twice with 5% acetic acid, 5% sodium bicarbonate and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. The yield was 450 mg of the product,

¹H-NMR(DMSO d-6)0.88(m，9H)1.22(m，28H)1.45(m，2H)1.83(m，2H)2.21(m，2H)2.37(m，1H)3.90(m，1H)5.36-5.58(m，1H)6.18(m，1H)6.50(s，2H)7.28-7.91(m，10H)。

b) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (L-valyloxy) -4-stearoyloxy-pentanoyl ] guanosine

A mixture of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (N-CBZ-L-valyloxy) -4-stearoyloxy-pentanoyl ] guanosine (300 mg, 0.308 mmol) in 5 ml of N, N-diisopropylethylamine and 5 ml of DMF was stirred at room temperature for three days. Acetic acid (5 ml) was added, the mixture was evaporated under reduced pressure, the product was isolated as acetate by silica gel column chromatography in a yield of 90 mg,

¹H-NMR(DMSO d-6)0.88(m，9H)1.24(m，28H)1.55(m，2H)1.91(m，2H)2.31(m，2H)2.44(m，1H)2.56-3.08(m，2H)3.15(m，1H)4.00-4.49(m，5H)5.08(m，1H)5.40-5.62(m，1H)6.24(m，1H)6.54(s，2H)7.96(s，1H)。

example 25

2′，3′-dideoxy-3′-fluoro-5′-O- [3- (L-valyloxy) -2-stearoyloxy-propionyl] Guanosine

a) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (N-CBz-L-valyloxy) -2-stearoyloxy-propionyl ] guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (404 mg, 1.5 mmol), 3- (N-CBZ-L-valyloxy) -2-stearoyloxy-propionic acid (1.06 g, 1.75 mmol), DMAP (24 mg, 0.2 mmol) and HOBT (264 mg, 1.82 mmol) was coevaporated twice with DMF down to about 30 ml. DCC (372 mg, 1.8 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure, the product was isolated by column chromatography on silica gel in 0.73 g yield,

¹H-NMR(DMSO d-6)0.82(m，9H)1.22(m，28H)1.48(m，2H)2.31(m，2H)2.50-3.00(m，2H)3.91(m，1H)4.18-4.52(m，5H)5.00(s，2H)5.30-5.61(m，2H)6.16(m，1H)6.50(s，2H)7.32(m，5H)7.71(m，1H)7.92(s，1H)10.18(s，1H)。

b) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (L-valyloxy) -2-stearoyloxy-propionyl ] guanosine

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (N-CBz-L-valyloxy) -2-stearoyloxy-propionyl ] guanosine (350 mg, 0.4 mmol) in ethyl acetate (25 ml), methanol (5 ml) and acetic acid (5 ml) was hydrogenated with palladium black (300 mg) at normal pressure for three hours, the catalyst was filtered off, washed with ethyl acetate and methanol, the solution was evaporated under reduced pressure, the product was isolated as acetate by silica gel column chromatography in a yield of 120 mg,

¹H-NMR(DMSO d-6)0.84(m，9H)1.22(m，28H)1.50(m，2H)2.32(m，2H)2.50-3.00(m，2H)3.07(m，1H)4.21-4.59(m，5H)5.38-5.59(m，2H)6.17(m，1H)6.0(s，2H)7.90(s，1H)。

example 26

2′，3′-dideoxy-3′-fluoro-5′-O- [3, 3-bis (L-valyloxymethyl) -propionic acid]Guanosine

a) Synthesis of 4, 4-bis (N-CBZ-L-valyloxymethyl) but-1-ene

DCC (9.08 g, 44 mmol) was added portionwise to a solution of 2-allyl-1, 3-propanediol (2.32 g, 20 mmol), N-CBZ-L-valine (10.06 g, 40 mmol) and DMAP (0.488 g, 4 mmol) in 120 ml of dichloromethane, the mixture was stirred at room temperature overnight, the mixture was cooled to 5 ℃, the urethane was filtered off, the filtrate was evaporated, the product was isolated by column chromatography on silica gel, yield 9.0 g,

¹H-NMR(CDCl₃)0.89(m，12H)5.11(s，2H)5.73(m，1H)

b) synthesis of 3, 3-bis (N-CBZ-L-valyloxymethyl) propionic acid

To a cooled solution of 4, 4-bis (N-CBZ-L-valyloxymethyl) -but-1-ene (14.6 g, 25 mmol) and tetrabutylammonium bromide (1.3 g, 4 mmol) in 120 ml benzene was added 100 ml water potassium permanganate (15.8 g, 100 mmol) was added in portions with vigorous stirring and the mixture was stirred for 2 hours at 15-20 ℃. An aqueous bisulfite solution was added to the slurry until the mixture faded, the mixture was acidified with 2N hydrochloric acid and extracted four times with ethyl acetate. The organic phase was washed twice with water, dried over sodium carbonate and evaporated under reduced pressure. The product was chromatographed on a silica gel column with a yield of 7.5 g,

¹H-NMR(CDCl₃)0.89(m，12H)2.05(m，2H)2.46(m，2H)2.62(m，1H)4.20(m，6H)5.11(s，4H)5.30(m，2H)7.35(m，10H)

c) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3, 3-bis (N-CBZ-L-valyloxymethyl) -propionyl ] guanosine

A solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (1.35 g, 5 mmol), 3-bis- (N-CBZ-L-valyloxymethyl) -propionic acid (3.6 g, 6 mmol), DMAP (0.061 g, 0.5 mmol) and HOBT (0.81 g, 6 mmol) was co-evaporated twice with DMF down to about 120 ml. DCC (1.24 g, 6 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield 2.7 g.

¹H-NMR(DMSO d-6)0.88(m，12H)2.00(m，2H)2.50-3.00(m，2H)3.90-4.43(m，10H)5.08(s，4H)5.32-5.59(m，1H)6.17(m，1H)6.50(s，2H)7.28(m，10H)7.72(m，2H)7.90(s，1H)

d) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3, 3-bis (L-valyloxymethyl) -propionic acid ] guanosine

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3, 3-bis (N-CBZ-L-valyloxymethyl) -propionyl ] guanosine (2.6 g, 3.1 mmol) in 80 ml ethyl acetate, 20 ml methanol and 20 ml acetic acid was hydrogenated with palladium black (0.3 g) at atmospheric pressure for two hours. The catalyst was filtered off and washed with ethyl acetate and methanol. The solution was evaporated under reduced pressure and the product isolated as diacetate by column chromatography on silica gel in a yield of 1.2 g.

¹H-NMR(DMSO d-6)0.90(m，12H)1.78(m，2H)2.50-3.00(m，2H)3.09(m，2H)4.02-4.45(m，8H)5.34-5.59(m，1H)6.17(m，1H)6.62(s，2H)7.88(s，1H).

Example 27

2′，3′-dideoxy-3′-fluoro-5′-O- [3- (L-valyloxymethyl) -4-stearoyloxy-butan Oxyacyl group]Guanosine

a) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (N-CBz-L-valyloxymethyl) -4-stearoyloxy-butoxycarbonyl ] guanosine

To a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (269 mg, 1.0 mmol) in absolute DMF was added pyridine (198 mg, 2.5 mmol) and 3- (N-CBZ-L-valyloxymethyl) -4-stearoyloxy-butoxycarbonylchloride (750 mg, 1.1 mmol) in 5 ml dichloromethane, the mixture was stirred at room temperature for three days, the solution was evaporated under reduced pressure, the product was isolated by column chromatography on silica gel with a yield of 120 mg,

¹H-NMR(DMSO d-6)0.88(m，9H)1.24(m，28H)5.08(，2H)6.24(m，1H)8.00(s，1H).

b) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (L-valyloxymethyl) -4-stearoyloxy-butoxycarbonyl ] guanosine

A mixture of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (N-CBz-L-valyloxymethyl) -4-stearoyloxy-butoxycarbonyl ] guanosine in 15 ml ethyl acetate, 2 ml methanol and 2 ml acetic acid was hydrogenated with palladium black (40 mg) under normal pressure for two hours. The catalyst was filtered off, washed with ethyl acetate and methanol, the solution was evaporated under reduced pressure, the product was chromatographed on a silica gel column in the form of the acetate salt with a yield of 78 mg,

¹H-NMR(DMSO d-6)0.87(m，9H)1.22(m，28H)1.48(m，2H)1.68(m，2H)2.12(m，1H)2.26(m，2H)2.50-3.00(m，2H)4.00-4.42(m，10H)5.34-5.58(m，1H)6.18(m，1H)6.52(s，2H)7.82(s，1H)。

example 28

2′，3′-dideoxy-3′-fluoro-5′-O- [2- (L-valyloxy) stearoyl]Guanosine

a) Synthesis of benzyl 2-hydroxystearate

To a stirred solution of DL-2-hydroxystearic acid (3.0 g, 10 mmol) in 20 ml of anhydrous DMF was added potassium tert-butoxide (1.23 g, 11 mmol), the mixture was stirred at 60 ℃ for one hour, benzyl bromide (2.14 g, 12.5 mmol) was added, the mixture was stirred at 80 ℃ for six hours, the mixture was evaporated under reduced pressure and 100 ml of ethyl acetate was added. The organic phase is separated and washed four times with water, the organic phase is dried over sodium sulphate and concentrated in vacuo, the product is isolated by chromatography on a silica gel column with a yield of 3.3 g,

¹H-NMR(CDCl₃)0.88(m，3H)1.26(m，28H)1.62(m，2H)4.20(m，1H)5.20(s，2H)7.36(m，5H).

b) synthesis of benzyl 2- (N-FMOC-L-valoylamino-oxy) stearate

To a solution of benzyl 2-hydroxystearate (3.2 g, 8.2 mmol), N-FMOC-L-valine (3.4 g, 10 mmol) and DMAP (0.12 g, 1 mmol) in 80 ml of dichloromethane was added a solution of DCC (2.5 g, 12 mmol), the mixture was stirred at room temperature overnight, the mixture was cooled to 5 ℃, and the urethane was filtered off. The filtrate was evaporated and the product was isolated by silica gel column chromatography with a yield of 4.5 g,

¹H-NMR(CDCl₃)0.90(m，6H)1.26(m，6H)1.82(m，2H)2.16(m，1H)4.21(m，1H)4.36(m，2H)5.10(m，1H)5.18(s，2H)5.28(m，1H)7.20-7.80(m，13H).

c) synthesis of 2- (N-FMOC-L-valoylaminoxy) stearic acid

A solution of benzyl 2- (N-FMOC-L-valoyloxy) stearate (4.4 g, 6.2 mmol) in 50 ml of ethyl acetate was hydrogenated with 10% palladium on charcoal (0.5 g) at atmospheric pressure for two hours. The catalyst is filtered off, washed with ethyl acetate and 1, 4-dioxane, the solution is evaporated under reduced pressure, the product is isolated as acetate by chromatography on a silica gel column in a yield of 3.4 g,

¹H-NMR(CDCl₃)0.88(m，6H)1.26(m，28H)1.82(m，2H)2.28(m，1H)4.20(m，1H)4.40(m，2H)5.00(m，1H)5.41(m，1H)7.26-7.82(m，8H)。

d) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [2- (N-FMOC-L-valyloxy) stearoyl ] guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (404 mg, 1.5 mmol), 2- (N-FMOC-L-valyloxy) -stearic acid (1.24 g, 2 mmol), DMAP (24 mg, 0.2 mmol) and HOBT (264 mg, 1.95 mmol) was coevaporated twice with DMF down to about 30 ml. DCC (372 mg, 1.8 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure, the product was isolated as acetate by chromatography on a silica gel column in a yield of 1.2 g,

¹H-NMR(DMSO d-6)0.80-0.90(m，9H)1.22(m，28H)2.12(m，1H)2.50-3.00(m，2H)3.98(m，1H)4.96(m，1H)6.17(m，1H)6.50(s，2H)7.32-7.95(m，10H)

e) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [2- (L-valyloxy) stearoyl ] guanosine

To a solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [2- (N-FMOC-L-valyloxy) stearoyl ] guanosine (800 mg, 0.89 mmol) in 15 ml of DMF was added DBU (1.35 g, 8.9 mmol) and the mixture was stirred at room temperature for 5 minutes. Acetic acid (2 ml) was added and the mixture was evaporated under reduced pressure water (20 ml) was added and the mixture was extracted three times with dichloromethane. The organic phase was dried over sodium sulfate and evaporated under reduced pressure, the product was isolated by column chromatography on silica gel in a yield of 165 mg,

¹H-NMR(DMSO d-6)0.87(m，9H)1.22(m，28H)1.70(m，2H)1.88(m，1H)2.50-3.00(m，2H)3.20(m，1H)4.32(m，3H)4.94(m，1H)5.32-5.54(m，1H)6.14(m，1H)6.49(s，2H)7.89(s，1H)

example 29

2′，3′-dideoxy-3′-fluoro-5′-O-3- [1, 3-bis- (L-valyloxy) -2-propoxycarbonyl Propionyl group]Guanosine

a) Synthesis of succinic acid 1, 3-dibenzyloxy-2-propyl monoester

1, 3-dibenzyloxypropan-2-ol (6.8 g, 25 mmol) and succinic anhydride (7.5 g, 75 mmol) and DMAP (12.2 g, 100 mmol) were stirred for one hour at 60 ℃. The mixture was evaporated under reduced pressure, acidified with 2N HCl and extracted twice with ethyl acetate. The combined organic phases are washed three times with water, the organic phase is dried over sodium sulfate and evaporated under reduced pressure, the product is isolated by chromatography on a silica gel column in a yield of 7.8 g,

b) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (1, 3-dibenzyloxy-2-propoxycarbonyl) propionyl ] guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (1.61 g, 6 mmol), HOBT (0.972 g, 7.2 mmol), DMAP (73.3 mg, 0.6 mmol) and 1, 3-dibenzyloxy-2-propyl succinate (2.68 g, 7.2 mmol) was coevaporated twice with DMF down to about 150 ml. DCC (1.55 g, 7.5 mmol) was added and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. Ethyl acetate (200 ml) was added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure and the product was isolated by silica gel column chromatography in 3.3 g yield.

c) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (1, 3-dihydroxy-2-propoxycarbonyl) propionyl ] guanosine

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (1, 3-dibenzyloxy-2-propoxycarbonyl) propionyl ] guanosine (3.2 g, 5.13 mmol) in 50 ml ethyl acetate, 50 ml methanol and 10 ml acetic acid was hydrogenated with palladium black (0.6 g) at 40psi pressure overnight. The catalyst was filtered off, washed with methanol, the solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel in a yield of 1.64 g.

d) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis (N-CBZ-L-valyloxy) -2-propoxycarbonyl ] propionyl } guanosine

A mixture of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (1, 3-dihydroxy-2-propoxycarbonyl) propionyl ] guanosine (1.93 g, 2.93 mmol), N-CBZ-L-valine (1.76 g, 7 mmol), HOBT (0.95 g, 7 mmol), and DMAP (85.5 mg, 0.7 mmol) was coevaporated with DMF twice, reduced to about 60 ml DCC (1.55 g, 7.5 mmol) was added, the mixture was stirred at room temperature overnight, the mixture was incubated at 60 ℃ for four hours, then cooled to 10 ℃, the mixture was filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate (150 ml) was added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure and the product was isolated by silica gel column chromatography in 1.6 g yield.

e) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis (L-valyloxy) -2-propoxycarbonyl ] propionyl } guanosine

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis (N-CBZ-L-valyloxy) -2-propoxycarbonyl ] propanoyl } guanosine (1.6 g, 1.75 mmol) in 80 ml ethyl acetate, 20 ml methanol and 20 ml acetic acid was hydrogenated with palladium black (0.3 g) at room temperature and pressure for two hours. The catalyst was filtered off and washed with methanol. The solution is evaporated under reduced pressure and the product is chromatographed on a silica gel column in the form of the diacetate with a yield of 1.02 g,

¹H-NMR(DMSO d-6)0.84(m，12H)1.85(m，2H)2.58(m，4H)2.60-3.10(m，2H)3.11(m，2H)3.61-4.39(m，7H)5.19(m，1H)5.35-5.56(m，1H)6.16(m，1H)，6.62(s，2H)7.89(s，1H).

example 30

2′，3′-dideoxy-3′-fluoro-5′-O- {3- [1- (L-valyloxy) -3-hydroxy-2-propoxycarbonyl Base of]Propionyl guanosine

a) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1- (N-CBZ-L-valyloxy) -3-hydroxy-2-propoxycarbonyl ] propionyl } guanosine

A mixture of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [3- (1, 3-hydroxy-2-propoxycarbonyl) propionyl ] guanosine (1.3 g, 2.93 mmol), N-CBZ-L-valine (1.00 g, 4 mmol), HOBT (0.54 g, 4 mmol) and DMAP (48.8 mg, 0.4 mmol) was coevaporated twice with DMF, reducing to about 60 ml. DCC (0.91 g, 4.4 mmol) was added and the mixture was stirred at room temperature for 72 hours. The mixture was filtered and the solution was evaporated under reduced pressure ethyl acetate (150 ml) was added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography in a yield of 0.99 g.

b) Synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1- (L-valyloxy) -3-hydroxy-2-propoxycarbonyl ] propionyl } guanosine

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1- (N-CBZ-L-valyloxy) -3-hydroxy-2-propoxycarbonyl ] propanoyl } guanosine (0.82 g, 1.21 mmol) in 30 ml of ethyl acetate, 15 ml of methanol and 15 ml of acetic acid was hydrogenated with palladium black (0.15 g) at room temperature and normal pressure for two hours, the catalyst was filtered off, the solution was washed with methanol, the product was evaporated under reduced pressure, the product was isolated as acetate by silica gel column chromatography, yield 0.5 g,

¹H-NMR(DMSO d-6)0.84(m，6H)1.86(m，1H)2.58(m，4H)2.63-3.02(m，2H)3.10-4.38(m，9H)5.34-5.55(m，1H)6.16(m，1H)6.56(s，2H)7.90(s，1H)。

example 31

5′-L-valyl-2′，3′-dideoxy-3′-fluoroguanosine

To a solution of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (810 mg, 3 mmol) and 4-dimethylaminopyridine (73 mg, 0.6 mmol), N-CBz-L valine (1.5 g, 6 mmol) and 1-hydroxybenzotriazole (810 mg, 6 mmol) in DMF (20 ml) was added DCC (1.36 g, 6.6 mmol). After 72 hours, the reaction mixture was filtered and concentrated in vacuo. 5 '- (N-CBz-L-valyl) -2', 3 '-dideoxy-3' -fluoroguanosine (1.15 g) was isolated by silica gel column chromatography.

This intermediate (503 mg, 1 mmol) was dissolved in a mixed solvent of ethyl acetate (10 ml), methanol (20 ml) and acetic acid (2 ml). Palladium black (100 mg) was added to the mixture, and the reaction mixture was kept under hydrogen at normal pressure for 3 hours. After filtration and concentration, the objective product (370 mg) was isolated by silica gel column chromatography,

¹H-NMR(DMSO d-6)7.94(s，1H)，6.52(s，2H)，6.17(dd，1H)，5.47(dd，1H)，4.15(m，3H)，3.15(d，1H)3.01-2.62(m，2H)1.80(m，1H)0.82(dd，6H)。

example 32

2′，3′-dideoxy-3′-fluoro-5-O- [2- (L-valyloxy) propanoyl]Guanosine

a) Synthesis of 4-methoxybenzyl 2-hydroxypropionate

To a stirred solution of DL-2-hydroxypropionic acid (9.0 g, 100 mmol) in 100 mL of anhydrous DMF was added potassium tert-butoxide (12.34 g, 110 mmol), the mixture was stirred at 60 ℃ for one hour, 4-methoxybenzoyl chloride (18.8 g, 120 mmol) was added, and the mixture was stirred at 60 ℃ for 8 hours. The mixture is evaporated under reduced pressure, 250 ml of ethyl acetate are added, the organic phase is washed four times with water, dried over sodium sulfate and concentrated in vacuo to yield 16.8 g,

¹H-NMR(CDCl₃)1.40(m，3H)3.81(s，3H)4.26(m，1H)5.14(s，2H)6.90(d，2H)7.28(d，2H).

b) synthesis of 4-methoxybenzyl 2- (N-CBZ-L valyloxy) propionate

To a solution of 4-methoxybenzyl 2-hydroxypropionate (4.2 g, 20 mmol), N-CBZ-L valine (5.02 g, 20 mmol) and DMAP (0.24 g, 2 mmol) in 100 ml of dichloromethane was added a solution of DCC (4.54 g, 22 mmol), the mixture was stirred at room temperature overnight, the mixture was cooled to 5 ℃ and the urethane was filtered off. The filtrate was evaporated and the product was isolated by column chromatography on silica gel, giving a yield of 7.9 g,

¹H-NMR(CDCl₃)0.88(m，6H)1.50(m，3H)2.26(m，1H)3.81(s，3H)4.34(m，1H)5.04-5.30(m，6H)6.88(d，2H)7.26(m，7H)。

c) synthesis of 2- (N-CBZ-L-valyloxy) -propionic acid

To a solution of 4-methoxybenzyl 2- (N-CBZ-L valyloxy) propionate (7.8 g, 17.5 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml), and the solution was stirred at room temperature for one hour. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography, yield 5.0 g,

¹H-NMR(CDCl₃)0.94(m，6H)1.56(d，3H)2.30(m，1H)4.42(m，1H)5.12-5.30(m，4H)7.28(m，5H).

d) synthesis of 2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [2- (N-CBZ-L-valyloxy) propionyl ] guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (404 mg, 1.5 mmol), 2- (N-CBZ-L valyloxy) propionic acid (0.582 g, 1.8 mmol), DMAP (22 mg, 0.18 mmol) and HOBT (243 mg, 1.8 mmol) was coevaporated twice with DMF down to about 30 ml. DCC (412 mg, 2.0 mmol) was added and the mixture was stirred at room temperature overnight the mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate were added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel with a yield of 0.72 g,

¹H-NMR(DMSO d-6)0.92(m，6H)1.40(d，3H)2.10(m，1H)2.50-3.06(m，2H)4.03(m，1H)4.20-4.44(m，3H)5.04(s，2H)5.12(m，1H)5.44-5.58(m，1H)6.18(t，1H)6.52(s，2H)7.36(m，5H)7.70(d，2H)7.92(s，1H)

e) synthesis of 2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [2- (L-valyloxy) propionyl ] guanosine

A solution of 2 ', 3 ' -dideoxy-3 ' -fluoro-5-O- [2- (N-CBZ-L-valyloxy) propionyl ] guanosine (0.6 g, 1.04 mmol) in 20 ml ethyl acetate, 10 ml methanol and 10 ml acetic acid was hydrogenated with palladium black (0.1 g) at room temperature and pressure for two hours. The catalyst is filtered off, washed with methanol and the solution is evaporated under reduced pressure to give the title compound as acetate in a yield of 0.5 g,

¹H-NMR(DMSO d-6)0.88(m，6H)1.40(d，3H)1.92(m，4H)2.52-3.04(m，2H)3.18(m，1H)4.18-4.42(m，3H)5.06(m，1H)5.32-5.58(m，2H)6.18(m，1H)6.52(s，2H)7.90(s，1H)。

example 33

2′，3′-dideoxy-3′-fluoro-5′-O-3- [2, 3-bis- (L-valyloxy) -1-propoxycarbonyl] Propionyl guanosine

a) Synthesis of succinic acid 4-methoxybenzyl monoester

To a mixture of succinic anhydride (75 g, 750 mmol) and 4-methoxybenzyl alcohol (69.1 g, 500 mmol) in 1, 4-dioxane (300 ml) was added pyridine (79.1 g, 1000 mmol) and the mixture was stirred at 80 ℃ for 5 hours. The mixture is evaporated under reduced pressure, 600 ml of ethyl acetate and 60 ml of acetic acid are added, the organic phase is washed three times with water, dried over sodium sulfate and evaporated under reduced pressure, the product is recrystallised from toluene, yield 104 g,

¹H-NMR(DMSO d-6)2.48(m，4H)3.72(s，3H)5.00(s，2H)6.90(d，2H)7.28(d，2H)。

b) synthesis of succinic acid 2, 3-dihydroxy-propyl ester, 4-methoxybenzyl ester

To a solution of glycerol (23.0 g, 250 mmol), 4-methoxybenzyl succinate (5.96 g, 25 mmol) and DMAP (0.36 g, 3 mmol) in DMF (200 ml) was added DCC (6.2 g, 30 mmol), the mixture was stirred at room temperature overnight, the mixture was evaporated under reduced pressure and 150 ml dichloromethane was added. The mixture was filtered and the solution was washed twice with water. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with a yield of 3.0 g,

¹H-NMR(CDCl₃)2.65(m，4H)3.61(m，2H)3.80(s，3H)3.90(m，1H)4.18(m，2H)5.05(s，2H)6.89(d，2H)7.26(d，2H)。

c) synthesis of succinic acid 2, 3-bis- (N-CBZ-L-valyloxy) -propyl ester, 4-methoxybenzyl ester

To a stirred solution of 2, 3-dihydroxy-propyl succinate, 4-methoxybenzyl ester (2.9 g, 9.28 mmol), N-CBZ-L-valine (5.03 g, 20 mmol) and DMAP (0.244 g, 2 mmol) in dichloromethane (60 ml) was added DCC (4.5 g, 22 mmol), the mixture was stirred at room temperature overnight, the mixture was filtered, the solution was evaporated under reduced pressure, the product was isolated by silica gel column chromatography in 2.5 g yield,

¹H-NMR(CDCl₃)0.90(m，12H)2.16(m，2H)2.62(m，4H)3.80(s，3H)4.32(m，4H)5.05-5.52(m，9H)6.89(d，2H)7.30(m，12H)。

d) synthesis of succinic acid 2, 3-di- (N-CBZ-L-valyloxy) -propyl ester

Trifluoroacetic acid (2.5 ml) was added to a solution of the above intermediate (2.3 g, 2.95 mmol) in dichloromethane (25 ml), and the solution was stirred at room temperature for two hours. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel in a yield of 1.8 g,

¹H-NMR(CDCl₃)0.92(m，12H)2.12(m，2H)2.64(m，4H)4.32(m，4H)5.10(s，4H)5.22-5.50(m，3H)7.34(m，10H).

e) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [2, 3-bis- (N-CBZ-L-valyloxy) -1-propoxycarbonyl ] propionyl } guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (0.538 g, 2 mmol), HOBT (0.327 g, 2.42 mmol), DMAP (29.3 mg, 0.24 mmol) and 2, 3-bis- (N-CBZ-L-valyloxy) -1-propyl succinate (1.6 g, 2.42 mmol) was coevaporated twice with DMF down to about 50 ml. DCC (0.536 g, 2.6 mmol) was added and the mixture was stirred at room temperature for 72 hours. The mixture is filtered and the solution is evaporated under reduced pressure 100 ml of ethyl acetate are added, the organic phase is washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase is dried over sodium sulfate and evaporated under reduced pressure, the product is isolated by chromatography on a silica gel column in a yield of 0.65 g,

¹H-NMR(DMSO d-6)0.88(m，12H)2.08(m，2H)2.58-3.04(m，6H)3.92(m，2H)4.10-4.46(m，7H)5.00(s，4H)5.22(m，1H)5.32-5.56(m，1H)6.17(m，1H)6.50(s，2H)7.32(m，10H)7.70(d，2H)7.92(s，1H)。

f) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [2, 3-bis- (L-valyloxy) -1-propoxycarbonyl ] propionyl } guanosine

A solution of the above intermediate (0.57 g, 0.626 mmol) in 20 ml of ethyl acetate, 10 ml of methanol and 10 ml of acetic acid was hydrogenated with palladium black (0.1 g) at room temperature and pressure for two hours. The catalyst was filtered off and washed with methanol. The solution was evaporated under reduced pressure, the product was isolated by silica gel column chromatography, dissolved in dichloromethane and 1M hydrochloric acid in ether (1.1 ml) was added the mixture was evaporated under reduced pressure and dried in vacuo to give the title compound as the dihydrochloride salt in yield 0.37 g,

¹H-NMR(DMSO d-6)0.92(m，12H)2.12(m，2H)2.58-3.04(m，6H)3.75(m，2H)4.16-4.50(m，7H)5.19-5.60(m，2H)6.18(m，1H)6.76(s，2H)7.92(s，1H)。

example 34

2′，3′-dideoxy-3′-fluoro-5′-O-3- [1, 3-bis- (L-valyloxy) -2-propoxycarbonyl] Propionyl guanosine dihydrochloride

a) Synthesis of 1, 3-dibromo-2-propyl succinate, 4-methoxybenzyl ester

DCC (24.8 g, 120 mmol) was added portionwise to a solution of 1, 3-dibromopropan-2-ol (21.8 g, 100 mmol), 4-methoxybenzyl succinate (28.6 g, 120 mmol) and DMAP (1.22 g, 10 mmol) in dichloromethane (400 ml) at about 10 ℃. The mixture was stirred at room temperature overnight and cooled to about 5 ℃. The mixture was filtered and the solution was evaporated under reduced pressure. 600 ml of ethyl acetate were added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the solution was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel, yield 34.8 g,

¹H-NMR(CDCl₃)2.69(m，4H)3.57(m，4H)3.81(s，3H)5.07(s，2H)5.14(m，1H)6.88(d，2H)7.26(d，2H)。

b) synthesis of 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl succinate, 4-methoxybenzyl ester

To a solution of N-CBZ-L-valine (58.5 g, 232.8 mmol) in anhydrous DMF (300 ml) was added potassium tert-butoxide (24.68 g, 220 mmol), and the mixture was stirred at room temperature for one hour. A solution of 1, 3-dibromo-2-propyl succinate, 4-methoxybenzyl ester (34 g, 77.6 mmol) in anhydrous DMF (50 ml) was added, and the mixture was stirred at 60 ℃ for 18 hours. The potassium bromide was filtered off and the solution was evaporated under reduced pressure. 600 ml of ethyl acetate were added, the organic phase was washed twice with 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel with a yield of 45 g,

¹H-NMR(CDCl₃)0.90(m，12H)2.16(m，2H)2.61(m，4H)3.80(s，3H)4.12-4.42(m，6H)5.02(s，2H)5.10(s，4H)5.43(m，3H)6.88(d，2H)7.32(m，12H)。

c) synthesis of 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl succinate

Trifluoroacetic acid (50 ml) was added to a solution of the above cooled intermediate (44.5 g, 57.1 mmol) in dichloromethane (500 ml) at 5-10 ℃ and the solution was stirred at 10 ℃ for two hours. The solution was evaporated under reduced pressure and co-evaporated with toluene twice. 400 ml of ethanol were added, the mixture was stirred at 40 ℃ for 30 minutes, the mixture was cooled and the by-products were filtered off. The solution was evaporated under reduced pressure and the product was isolated by column chromatography on silica gel in a yield of 33 g,

¹H-NMR(DMSO d-6)0.88(m，12H)2.04(m，2H)2.46(m，4H)，3.94-4.40(m，6H)5.02(s，4H)5.18(m，1H)7.32(m，10H)7.74(d，2H)。

d) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis- (N-CBZ-L-valyloxy) -2-propoxycarbonyl ] propionyl } guanosine

A mixture of 2 ', 3 ' -dideoxy-3 ' -fluoroguanosine (17.8 g, 66 mmol), HOBT (10.64 g, 78.8 mmol), 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl succinate (52 g, 78.8 mmol) and DMAP (0.96 g, 7.88 mmol) was coevaporated twice with DMF down to about 500 ml. DCC (17.3 g, 84 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was incubated at 60 ℃ for 6 hours and then cooled to about 10 ℃. The mixture was filtered and the solution was evaporated under reduced pressure. 1200 ml of ethyl acetate were added, the organic phase was washed twice with 5% acetic acid, 5% sodium bicarbonate and water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel, yield 42 g,

¹H-NMR(DMSO d-6)0.90(m，12H)2.02(m，2H)2.5-3.02(m，6H)3.94(m，2H)4.22(m，7H)5.02(s，4H)5.18(m，1H)5.22-5.50(m，1H)6.16(m，1H)6.50(s，2H)7.32(m，10H)7.72(d，2H)7.92(s，1H)。

e) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis- (L-valyloxy) -2-propoxycarbonyl ] propionyl guanosine dihydrochloride

A solution of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- {3- [1, 3-bis- (N-CBZ-L-valyloxy) -2-propoxycarbonyl ] propionyl } guanosine (5.0 g, 5.9 mmol) in 75 ml ethyl acetate and 75 ml methanol was hydrogenated with 10% palladium on activated carbon (1 g) at room temperature and atmospheric pressure for one hour. The catalyst was filtered off and washed with methanol. The solution is evaporated under reduced pressure, the product is dissolved in dichloromethane and 1M aqueous diethyl ether of hydrochloric acid (6 ml) is added with cooling the mixture is evaporated under reduced pressure, yield 3.5 g,

¹H-NMR(DMSO d-6)0.94(m，12H)2.18(m，2H)2.5-3.04(m，6H)4.20-4.54(m，7H)5.24(m，1H)5.34-5.64(m，1H)6.22(m，1H)6.92(s，2H)8.30(s，1H)8.62(s，6H)。

example 35

Synthesis 2′，3′-dideoxy-3′-fluoro-5′-O-3- [1, 3-bis- (L-valyloxy) -2-propoxy Carbonyl radical]Propionyl guanosine

a) Synthesis of 1, 3-dibromo-2-propyl succinate, 1, 1-dimethylethyl ester

DCC (12.4 g, 60 mmol) was added portionwise to a solution of 1, 3-dibromopropan-2-ol (10.9 g, 50 mmol), 1-dimethylethyl succinate (j.org. chem 59(1994)4864) (10.45 g, 60 mmol) and DMAP (0.61 g, 5 mmol) in dichloromethane (180 ml) at about 10 ℃, the mixture was stirred at room temperature overnight and cooled to about 5 ℃. The mixture was filtered and the solution was evaporated under reduced pressure. 250 ml of ethyl acetate were added and the organic phase was washed twice with 5% citric acid, 5% sodium bicarbonate and water. The solution was dried over sodium sulfate and evaporated under reduced pressure. The product was distilled in vacuo (bp 0.5135-140 ℃ C.) to yield 16.8 g,

¹H-NMR(CDCl₃)1.45(s，9H)2.58(m，4H)3.61(m，4H)5.12(m，1H)。

b) synthesis of 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl succinate, 1, 1-dimethylethyl ester

To a solution of N-CBZ-L-valine (18.85 g, 75 mmol) in anhydrous DMF (100 ml) was added potassium tert-butoxide (7.85 g, 70 mmol), and the mixture was stirred at room temperature for one hour. 1, 3-dibromo-2-propyl succinate, 1, 1-dimethylethyl ester (9.35 g, 25 mmol) in anhydrous DMF (20 ml) was added to the solution, and the mixture was stirred at 60 ℃ for 18 hours. The potassium bromide was filtered off and the solution was evaporated under reduced pressure. 300 ml of ethyl acetate were added and the organic phase was washed twice with 5% sodium bicarbonate and water. The organic phase was dried over sodium sulfate and evaporated under reduced pressure the product was isolated by column chromatography on silica gel in 14 g yield.

¹H-NMR(CDCl₃)0.90(m，12H)1.42(s，9H)2.14(m，2H)2.52(m，4H)4.32(m，6H)5.10(s，4H)5.32(m，3H)7.26(m，10H)

c) Synthesis of succinic acid 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl monoester

Trifluoroacetic acid (20 ml) was added to the cooled solution of 1, 3-bis- (N-CBZ-L-valyloxy) -2-propyl succinate, 1, 1-dimethylethyl ester (13 g, 18.18 mmol) in dichloromethane (100 ml), and the solution was stirred at room temperature for six hours. The solution is evaporated under reduced pressure, 200 ml of ethyl acetate are added, the organic phase is washed with 5% sodium bicarbonate and water, the solution is evaporated under reduced pressure, yield 11.7 g,

¹H-NMR(DMSO d-6)0.88(m，12H)2.04(m，2H)2.46(m，4H)，3.94-4.40(m，6H)5.02(s，4H)5.18(m，1H)7.32(m，10H)7.74(d，2H)。

d) synthesis of 2 ', 3' -dideoxy-3 '-fluoro-5' -O-3- [1, 3-bis- (L-valyloxy) -2-propoxycarbonyl ] propionyl guanosine

The intermediate of step c) is esterified to FLG as in step b) of example 34 and the N protecting group on the valyl moiety is removed using conventional techniques, such as step e) of example 35 or step e) of example 29.

Biological examples

Pharmacokinetics

It can be confirmed that the oral prodrug of the present invention releases FLG in vivo in a mouse model, which is considered to be a useful model for evaluating pharmacokinetic parameters of nucleoside drugs. Oral compositions can be administered with a pharmaceutical excipient including propylene glycol, or for more soluble compounds, such as the compounds described in example 26 or example 34, with water, and the experiment repeated at a dose of 0.1 mmole/kg against the diet animal. For comparison, one group of mice was intravenously injected with 0.01 mmol/kg metabolite 2 ', 3 ' -dideoxy-3 ' fluoroguanosine. After 0.5-12 hours of administration (5 minutes-6 hours for FLG), the concentration of serum metabolites was monitored by continuously collecting serum from each animal.

Metabolites were analyzed by HPLC with UV detection at 254 nm in analogy to Stahle et al 1995, J Pharm, biomed.anal, 13,369-376, based on a 0.05M ammonium dihydrogen phosphate buffer solution containing 1.2% 2-propanol solvent at a buffer value of pH4.5 or a 30mM sodium dihydrogen phosphate buffer solution containing 2% acetonitrile solvent at a buffer value of pH 7.0. The column was a 100X 2.1 mm BAS C185 micron particle size or 150X 4.6 mm Zorbax SB-CN C18, 5 micron column with a 7 micron C18 guard column. The protein binding capacity of the compounds of the invention is negligible, as is the binding capacity of the metabolites, and ultrafiltration with Amicon or Microcon 30 filters is useful for serum samples. Advantageously, the main peak can be subjected to column chromatography again, to better improve the resolution of FLG for low molecular weight serum components. The iv value is multiplied by 10 to arrive at an AUC value comparable to the oral value. Absolute oral bioavailability in^0→∞AUC_ivAnd^0→∞AUC_{is administered orally}The ratio of (a) to (b) is determined.

TABLE 1

	Absolute bioavailability after 6 hours%	Absolute bioavailability after 12 hours%
			FLG EXAMPLE 22 EXAMPLE 13 EXAMPLE 12 EXAMPLE 25 EXAMPLE 28 EXAMPLE 24 EXAMPLE 26 EXAMPLE 29	39％37％29％81.5％47.5％60.5％51％	9％>80％67.5％

Measured value document value

In particular, the compounds are released in a relatively sustained manner in the blood, rather than in an interpeak (intermodal peak) manner. This means that an effective amount of active metabolite in the blood can last many hours, thus facilitating a once-a-day dose. In addition, sustained release avoids acute toxicity problems associated with rapid release of the compound.

Although rats may be considered as a good animal model for predicting the bioavailability of nucleosides in humans, the respective bioavailabilities of the compounds of the invention (example 34) were determined by ≈ 11.5 kg male and female police dogs, orally as an aqueous 0.05 mmol/kg (38 mg/kg) compound or intravenously as an aqueous 0.005 mmol/kg (1.35 mg/kg) metabolite. Plasma collection and analysis was as described above.

Absolute bioavailability of 51% after 12 hours for male dogs

Absolute bioavailability of 74% after 12 hours for female dogs

Biological example 2

Antiviral Activity-retroviruses

The compound of the present invention was demonstrated to release the metabolite 2 ' 3 ' -dideoxy-3 ' -fluoroguanosine in vivo by the method described in biological example 1, therefore, the antiviral activity of the metabolite measured in vitro would reflect the actual activity of the compound of the present invention.

The XYY dye uptake assay of MT4 cells was used in the XTT dye uptake assay described by Koshide et al in Antitirob Agents Chemother 33778-780 (1989), and the metabolites determined in biological example 1 above showed the following anti-retroviral activity in vitro.

TABLE 2

HIV or retrovirus strains	IC*
		HIV-1HIV-1AZTHIV-1TIBOHIV-IHIV-2SIV	1. mu.g/ml 0.7. mu.g/ml 2. mu.g/ml 1. mu.g/ml

Concentration of metabolite that caused 50% inhibition of viral replication.

It is therefore clear that the ingestion of the compounds of the present invention results in potent antiviral activity against the retroviruses HIV-1, HIV-2 and SIV. Simultaneously according to HIV-1²⁴⁴¹AZT^rAnd HIV-1_IIIBTIBO^rAs a result, it should be noted that the antiviral activity of the compounds of the invention does not show cross-resistance against HIV strains which are resistant to other HIV agents such as the nucleoside AZT or the non-nucleoside reverse transcriptase inhibitor TIBO.

Biological example 3

Antiviral Activity-HBV

The antiviral activity against Duck Hepatitis B Virus (DHBV) in duck is a well-established animal model for verifying the activity of hepatitis B virus in humans. The activity of the in vivo metabolite determined in biological example 2 above has been determined according to the DHBV model described by Sherker et al (1986) Gastroenterology 91, page 818-824. The results are shown in figures 1 and 2, where 4 control ducks were treated with Phosphate Buffered Saline (PBS) and 4 other ducks ingested the active metabolite at 5 mg/kg/day, the ducks were alive for two days when the DHBV was inoculated, and the treated ducks were alive for 18 days. Intraperitoneal injections of metabolite and PBS (control) were administered twice daily for ten days, 8 am and 4 pm, treatment continued for 33 days, and animals survived for 5 weeks after treatment was completed.

Efficacy tracking was performed by dot blot hybridization of DHBV DNA using a radioactive probe, and the amount of DHBV was taken as the amount of radioactive hybridization determined. Figure 1 plots the amount of DHBV DNA in serum before, during and after treatment at various time points.

As shown in fig. 1, there was no decrease in the amount of DHBV during treatment with PBS (control, solid line). Animals given the metabolites determined in biological example 2 (dashed line) showed a dramatic decrease in serum DHBV during the first ten days of treatment, after which the DHBV concentration administered at 5 mg/kg/day was below the limit of detection for the remainder of the treatment. The same results were obtained in the previously infected ducks (not shown) by repeating the experiments at 30 and 3 mg/kg/day doses, i.e. the DHBV DNA in the serum dropped dramatically below the limit of detection. The metabolites produced considerable DHBV inhibition in vivo, despite low doses of 3 mg/kg/day. After the treatment, the virus reappeared in the serum, as shown in figure 1, HBV reappearance was observed in humans and animals infected with chronic hepatitis b virus long after short-term treatment with the commonly used antiviral agents.

As shown in FIG. 2, the weight of the duck was increased as compared to the control (treated with PBS) animals. The weight increase from about 270 grams to about 800 grams was observed during the treatment period, which was so great that one would consider that there would be a noticeable change in growth rate if toxicity was present. The metabolite is therefore clearly non-toxic. Since the compound of the present invention is hydrolyzed in vivo to generate such a metabolite, as described in example 2 above, and a fatty acid of the same nature and being easily metabolized, it can be concluded that administration of the compound of the present invention does not cause long-term toxicity problems.

Oral administration of the compounds of the present invention without causing acute (short-term) toxicity was demonstrated in biological example 2 above.

Formulation example 1

Tablet formulation

Sieving the following components with a 0.15 mm sieve, and dry mixing

10 g of 2 ', 3' -dideoxy-3 '-fluoro-5' -O-3- [1, 3-bis- (L-valyloxy) -2-propoxycarbonylpropionyl ] guanosine

40 g lactose

49 g of crystalline cellulose

1 g magnesium stearate

The mixture was compressed with a tabletting machine to tablets containing 250 mg of active ingredient.

Formulation example 2

Enteric coated tablet

The tablets of formulation example 1 were spray coated in a tablet coater with a solution containing the following components:

120 g of ethylcellulose

30 g propylene glycol

10 g of sorbitan monooleate

1000 ml of distilled water was added

Formulation example 3

Controlled release formulations

50 g of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (L-valyloxymethyl) -6-stearoyloxyhexanoyl ] guanosine

12 g hydroxypropyl methylcellulose (Methocell K15)

4.5 g lactose

Dry mixing and granulating with a water paste of povidone. Magnesium stearate (0.5 g) was added and the mixture was formed into 13 mm diameter tablets containing 500 mg of active agent in a tabletting machine.

Formulation example 4

Soft capsule

50 g of 2 ', 3' -dideoxy-3 '-fluoro-5' -O- [5- (L-valyloxymethyl) -6-stearoyloxyhexanoyl ] guanosine

100 g lecithin

100 g peanut oil

The compounds of the invention are dispersed in lecithin and peanut oil and filled into soft gel capsules.

Claims (2)

1. 5 '-L-valyl-2', 3 '-dideoxy-3' -fluoroguanosine.
2. Use of a compound referred to as 5 '-L-valyl-2', 3 '-dideoxy-3' -fluoroguanosine for the preparation of a medicament for the treatment or prevention of HBV or reverse transcriptase virus infection.