KR20000053226A - Nucleosides - Google Patents

Abstract

PURPOSE: Pharmaceutical compositions comprising these compounds, methods for their manufacture and methods for the treatment or prophylaxis of cancers and viral infections employing these compounds are provided. CONSTITUTION: Mixed esters of antiviral nucleosides such as compounds of Formula (I), where B is natural or unnatural nucleotide base, X is O or CH2, Y and Z are each H, or together form a bond, or Y is methylene or -CH(OH)- and Z is a bond thereto; n is 0 or 1; one of R1 and R2 is the acyl residue of an aliphatic amino acid and the other is -C(=O)C5-C21 saturated or monounsaturated alkyl; and pharmaceutically acceptable salts thereof have advantageous pharmacokinetic and other properties.

Description

Nucleosides

The practical use of many acyclic nucleosides is limited by their relatively suitable pharmacokinetics. Many prodrug methods have been developed to improve the bioavailability of acyclic nucleosides. One of these methods involves the preparation of ester derivatives, in particular aliphatic esters, having at least one hydroxy group in the acyclic side chain.

See Harnden, et al., J. Med. Chem. 32, 1738 (1989) describe many short-chain aliphatic esters of acyclic nucleoside 9- [4-hydroxy- (3-hydroxymethyl) butyl] guanine, also known as phencyclovir, and their 6-deoxy homologs thereof. Was studied. Famcyclovir, a definite antiviral agent, is a diacetyl derivative of 6-deoxy phencyclovir.

See Benjamin, et al., Pharm. Res. 4 No. 2, 120 (1987), describes short-chain aliphatic esters of 9-[(1,3-dihydroxy-2-propoxy) -methyl] guanine, also known as gancyclovir. Dipropionate esters are described as preferred esters.

See, Lake-Bakaar, et al., Antimicrob. Agents Chemother. 33 No. 1, 110-112 (1989) describe diacetate and dipropionate derivatives of acyclic nucleoside H2G and monoacetate and diacetate derivatives of 6-deoxy H2G. It has been reported that H2G and diacetate and and dipropionate derivatives have only moderately improved bioavailability compared to H2G.

International Patent Application WO94 / 24134, published October 27, 1994, includes di-pivaloyl, di-valeroyl, mono-valeroyl, mono-oleoryl and mono-stearoyl esters. Aliphatic ester prodrugs of the 6-deoxy N-7 homologue of gancyclovir are described.

International Patent Application WO93 / 07163, published April 15, 1993 and International Patent Application WO94 / 22887, published October 13, 1994, both contain mono-unsaturated C18, including araT, araA, and ribavirin. Or mono-ester derivatives of nucleoside homologs derived from C20 fatty acids are described. U.S. Patent No. 5,216,142, issued June 1, 1993, also describes long chain fatty acid mono-ester derivatives of nucleoside homologs. The preparation and esterification of ribavirin is described in WO 94/22887 and US 3984396.

Rubas et al., Int J cancer 37 No 1 149-154 (1986) describe N ⁴ and O ⁴ oleyl and palmityl esters of araC, with N ⁴ oleyl derivatives being the most effective. I conclude. Schott et al., Biol Chem Hoppe Seyler 368, No 7, 773 (1987) report that N ⁴ -acyl araCs exhibit 2 to 8 fold antitumor activity in comparison to araC in vivo. International patent application WO92 / 01456 describes 6-alkoxy araG derivatives with enhanced bioavailability. However, modified bases have many disadvantages. One of these possible problems arises in nucleosides, particularly where the 3 'and 5' hydroxy groups of sugar residues are affected by phosphorylation and polymerase enzymes, and these modified bases are sometimes incorporated into DNA and damage DNA. And in worst cases, carcinogenic or hereditary mutations. Another disadvantage is that when the base is hydrolyzed from saccharides, the modified base thus separated is sometimes significantly more toxic than the corresponding neutral base.

A second method of providing prodrugs of acyclic nucleosides involves the preparation of amino acid esters having one or more hydroxy groups in the acyclic side chain. European patent EP 99 493 generally describes amino acid esters of acyclovir, and European patent application EP 308 065 published March 22, 1989 describes valine and isoleucine esters of acyclovir. have.

European Patent Application EP 375 329, published June 27, 1990, describes amino acid ester derivatives of gancyclovir, including di-valine, di-isoleucine, di-glycine and di-alanine ester derivatives. . International Patent Application WO95 / 09855, published April 13, 1995, describes amino acid ester derivatives of fencyclovir, including mono-valine and di-valine ester derivatives.

DE 19526163, published February 1, 1996 and US Pat. No. 5,543,414, issued August 6, 1996, describe the achiral amino acid esters of gancyclovir.

European patent application EP 694 547, published January 31, 1996, describes its preparation from the mono-L-valine esters of gancyclovir and di-valyl-gancyclovir. International patent application WO97 / 27194-27197 describes another preparation of monovalyl gancyclovir.

European Patent Application EP 654 473, published May 24, 1995, describes many bis amino acid ester derivatives of 9- [1 ', 2'-bishydroxymethyl) -cyclopropane-1'yl] methylguanine. It is.

International Patent Application WO95 / 22330, published August 24, 1995, describes aliphatic esters of acyclic nucleoside 9- [3,3-dihydroxymethyl-4-hydroxy-but-1-yl] guanine. , Amino acid esters and mixed acetate / valinate esters are described. This document describes that bioavailability decreases when one valine ester of a trivalin ester derivative is replaced with an acetate ester.

International patent application WO89 / 03837 has claims that include nucleosides 2 ', 3' and / or 5 'amino acid / fatty acid esters, but nucleosides with mixed esters are not specifically described.

See Dae-Kee Lim et al., Bioorg. & Med. Chem. Lett. Vol 6 No 15 pp 1849-1854, 1996, describes a series of phencyclovir derivatives with valine / isoleucine in combination with acetyl, propionyl and butyryl esters. The best pharmacokinetic performance of the mixed esters in this study is the use of acetyl. That is, this is the shortest possible alkyl ester component. Performance is significantly reduced by extending the alkyl chain with only one or two methylene units.

See, eg, Starret et al., J. Med. Chem. (1994) 37 No 12 1857-1884], an acyclic antiviral 9- [2- (phosphonomethoxy)-comprising mixed alkyl (acyloxy) alkyl esters which are absorbed but incompletely hydrolyzed to monoethyl esters. The preparation of a series of phosphonate prodrugs of ethyl] adenine is described.

The applicant's co-pending International Patent Applications WO97 / 30051 and WO97 / 30052, published August 21, 1997 (ie after the priority date of the present application), disclose acyclic nucleoside 9- [4-hydrides. Fatty acid / amino acid esters of oxy- (2-hydroxymethyl) butyl] guanine and 6-deoxy derivatives thereof are described.

The present invention relates to the field of nucleosides and nucleoside analogs. The present invention provides novel compounds, pharmaceutical compositions comprising these compounds, methods for their preparation and methods for treating or preventing cancer and viral infections using these compounds.

We now find that acylated antiviral nucleosides comprising two or more free hydroxy groups with combinations of specific amino acids and specific fatty acid esters produce nucleosides with good bioavailability and other useful properties. Revealed.

Combination esters of the invention can normally be applied to nucleosides which have at least two free hydroxy groups, preferably at the saccharide or acyclic moiety of the nucleoside, provided that the nucleoside is a 9- [4-hydride Oxy- (2-hydroxymethyl) butyl] guanine or a 6-deoxy derivative thereof.

However, particularly preferred kinds of compounds within the scope of the present invention are compounds of formula (I) and pharmaceutically acceptable salts thereof:

In the above formula,

B is a natural or unnatural nucleotide base,

X is O or -CH _2- ,

Y and Z are each H or Y is methylene or -CH (OH)-, Z is a bond to it or Y and Z are a bond together,

n is 0 or 1,

One of R ₁ and R ₂ is an acyl residue of an aliphatic amino acid and the other is —C (═O) C ₅ -C ₂₁ monounsaturated or saturated, optionally substituted alkyl.

In compounds wherein Y is -CH (OH)-, one of R ₁ and R ₂ may also be acylated in addition or additionally to 2'-hydroxy, while R ₁ and R ₂ are 3 'of the nucleoside or homologue. And 5 'position.

Another kind of compound within the scope of the present invention is a compound of formula la:

In the above formula,

B, R ₁ and R ₂ are as defined above.

Representative examples of this class include: 9- [1'-valyloxymethyl-2'-dodecanoyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-valyloxymethyl -2'-tetradecanoyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-valyloxymethyl-2'-hexadecanoyloxymethyl) -cyclopropane-1'yl] methylguanine , 9- [1'-valyloxymethyl-2'-octadecanoyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-valyloxymethyl-2'-eicosanoyloxymethyl) -Cyclopropane-1'yl] methylguanine, 9- [1'-valyloxymethyl-2'-docosanoyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-dodecanoyl Oxymethyl-2'-valyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-tetradecanoyloxymethyl-2'-valyloxymethyl) -cyclopropane-1'yl] methylguanine , 9- [1'-hexadecanoyloxymethyl-2'-valyloxymethyl) -cyclopropane-1'yl] methyl 9- [1'-octadecanoyloxymethyl-2'-valyloxymethyl) -cyclopropane-1'yl] methylguanine, 9- [1'-eicosanoyloxymethyl-2'-valyloxymethyl ) -Cyclopropane-1'yl] methylguanine, and the corresponding isoleucyl homologues.

Another kind of compound within the scope of the present invention is a compound of formula Ib:

In the above formula,

B, R ₁ and R ₂ are as defined above,

R6 is fluoro and R7 is hydrogen, or R6 and R7 are both fluoro or R6 and R7 together represent an exo-methenyl group.

A preferred base for this other class is guanine.

Another kind of nucleoside within the scope of the present invention is a compound of formula

In the above formula,

B, R ₁ and R ₂ are as defined above,

R8 and R9 are fluoro (one of which is fluoro and the other is hydrogen), and R8 and R9 together represent exomethenyl or exomethenyl mono- or disubstituted by fluoro.

These nucleosides have anticancer activity.

The invention also relates to phosphonylated antiviral agents, such as (s) -1-3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (sidofovir, as described in US Pat. No. 5,142 051). , HPMPC). In this case, one of R ¹ and R ² is ^a hydroxy group on the phosphonyl moiety, preferably via an intermediate —CH (R ^a ) —O— group where R ^a is hydrogen, methyl, isopropyl, and the like. While other of R ¹ and R ² may be esterified to the hydroxy group on the 3-hydroxy group. In addition, both R ¹ and R ² can be esterified to the respective hydroxy groups on the phosphonyl moiety, preferably via the respective intermediate —CH (R ^a ) —O— groups. The latter arrangement also applies to phosphonylated nucleosides, for example 9- [2- (phosphono-methoxy) ethyl] adenine (adepovir, PMEA) as described in US Pat. No. 5,476,938. can do. If a 3-hydroxy group is present, it can be optionally acylated by further R ¹ or R ² . When applied to such phosphonylated nucleosides, the saturated or monounsaturated alkyl component may contain 5 to 21 carbon atoms via fatty acid esters having 6 to 22 carbon atoms including carbonyl.

Preferred compounds of the embodiments of the invention described above include the following: 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monohexanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monooctanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monodecanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monododecanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monotetradecanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monohexadecanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monooctadecanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monoeicosanoyloxymethyl ester; 9- [2- (phosphonomethoxy) ethyl] adenine, monovalyloxymethyl, monodocosanoyloxymethyl ester; And each corresponding isoleucyl homologue.

Another use of the formulated fatty acid and amino acid esters of the invention is to apply these esters to conventional linker groups, which linker groups are hydroxyl functional groups of the dehydroxylated nucleosides or nucleoside homologs, for example the It may be self esterified to R ¹ or R ² represented by the hydroxyl functional group in formula (I), (la), (lb) or (Ic). The other of R ¹ and R ² is usually hydrogen, but may include additional linker structures as defined herein or may be acylated as for R ¹ or R ² . Typical linker groups may be compounds of formula II:

In the above formula,

One of R ₃ and R ₄ is an acyl residue of an aliphatic amino acid, the other is —C (═O) C ₅ -C ₂₁ monounsaturated or saturated, optionally substituted alkyl,

R ₅ is H or C ₁ -C ₃ alkyl,

T is a bond, O or NH,

m and m 'are independently 0, 1 or 2,

n is 0 to 5;

Preferably m is 1 and / or n is 0, 1 or 2 and / or T is a bond or -O-. In particular, when T is a bond, n is preferably 0 or 1. Conveniently both n and m are not zero. R ₅ is preferably H. The residue represented by () n preferably includes an alkane chain, but may contain unsaturated bonds.

This embodiment of the invention provides a linker group, such as a compound of formula (II), having nucleosides having at least two hydroxy groups but outside the range of formula (I), (la), (lb) or (c), for example described in WO95 / 22330. -[3,3-dihydroxymethyl-4-hydroxy-but-1-yl] guanine and 9- [4-hydroxy- (2-hydroxymethyl) butyl] guanine described in EP 343 133 Consider applying to.

The invention also relates to compounds of the invention, for example compounds of formula I, Ia, Ib, Ic or I / II (ie compounds of formula I, Ia, Ib or Ic in combination with compounds of formula II) or phospho Provided is a pharmaceutical composition comprising a mixed ester of a nilated antiviral agent and a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. Another aspect of the present invention provides the use of these compounds and salts in the preparation of the compounds of the present invention and pharmaceutically acceptable salts thereof for use in therapy and medicaments for treating or preventing cancer and viral infections in humans or animals. to provide.

The invention also relates to optionally substituted saturated or monounsaturated fatty acid esters having 6 to 22 carbon atoms (ie, -C (= 0) C ₅ -C ₂₁ saturated or monounsaturated, optionally substituted alkyl residues) and aliphatic amino acids. Nucleoside homologues (9- [4-hydroxy- (2-hydroxymethyl) butyl] guanine and 6-deoxy derivatives thereof) having two or more hydroxy groups on saccharide or acyclic moieties of the combination of esters And / or (if present) and / or the pharmacokinetics of the phosphonate residues. Another aspect of the invention provides an optionally substituted, saturated or monounsaturated fatty acid ester having 6 to 22 carbon atoms (ie, —C (═O) C ₅ -C ₂₁ monounsaturated or saturated, optionally substituted alkyl residues). And use of the pharmacokinetics of nucleoside homologs having two or more hydroxy groups on saccharide or acyclic moieties of linker groups in which aliphatic amino acid esters are esterified.

Compounds of the invention, in particular guanine derivatives in which X is O or CH ₂ and Y and Z are H, in particular are varicella zoster virus, herpes simplex virus type 1 & 2, Epstein-Barr virus, herpes type 6 (HHV-6 And antiviral agents for herpes infections such as those caused by type 8 (HHV-8).

Compounds of the invention, in particular cytosine or guanine derivatives in which X is oxygen, n is 1 and Y and Z are rings, are also known to certain retroviral infections, in particular SIV, HIV-1 and HIV-2, and hepatitis B viruses. Active against.

Compounds of the invention, in particular cytosine, guanosine or 6-methoxyguanosine derivatives, in which X is oxygen, n is 0 and Y and Z represent arabinose rings, are potent anticancer compounds.

Compounds of the invention, in particular comprising 1,2,4-triazole-3-carboxamide bases wherein X is O, Y is -CH (OH)-, Z is a bond to it and n is 0 Derivatives (ribavirin) are expected to be active against hepatitis C virus (HCV). A compound comprising a substituted benzimidazole base wherein X is O, Y is -CH (OH)-, Z is a bond to it, and n is 0. For example, the base is 2-isopropylamine-5,6. 1263W94 of Glaxo Wellcome, -dichloro-benzimidazol-3-yl, is expected to be active against CMV. Compounds containing adenine bases where X is O, Y is -CH (OH)-, Z is a bond to it, and n is 0 (Vidarabine) are expected to be active against HSV encephalitis. Compounds comprising 2-chloroadenine base and 2'-deoxyribose sugar are expected to have anticancer activity.

Accordingly, another aspect of the present invention provides a human or animal with an effective amount of a compound of the invention, for example a mixed ester of a compound of formula (I), (la), (I / II) or a phosphonylated antiviral agent or a pharmaceutically acceptable salt thereof Provided are methods for preventing or treating cancer or viral infections in humans or animals, including administering.

The nucleoside derivatives of the present invention are particularly useful for guanine nucleosides and homologues which tend to have poorer absorption than pyrimidine nucleosides. Thus, B is preferably a guanine or guanine derivative. Guanine bases represent a much more readily soluble 6-deoxy derivative that can be advantageously modified at position 6 and oxidized to guanine form in vivo (eg, by xanthine oxidase). Guanine bases may also be present in the 6-alkoxy form.

Preferred bases when Y and Z are hydrogen or they form a bond together include adenine and in particular guanine. Other preferred bases are cytosine, especially when X is oxygen, n is 1, Y and Z represent a ring, or n is 0 and Y is -C (OH)-.

Compounds in which Y is -C (OH)-may represent a rixofuranosyl or xylopuranosyl derivative, but more preferably an arabinose or ribose derivative.

Preferably the amino acid esters of groups R ₁ or R ₃ are derived from L-amino acids, for example leucine, alanine and especially L-valine or L-isoleucine. The amino acid ester R ₁ is preferably located at the 5 'position of the nucleoside.

Advantageous fatty acid esters for R ₂ and R ₄ represent the formula —C (═O) C ₁₁ -C ₂₁ and preferably have an even number of carbon atoms, in particular lauryl (C ₁₂ ), myristoyl (C ₁₄ ), palmi Toil (C ₁₆ ), stearoyl (C ₁₈ ), eicosanoyl (C ₂₀ ) or behenoyl (C ₂₂ ). Other useful R ₂ groups include esters of myristoleic acid, mystelideic acid, palmitoleic acid, palmitlideic acid, n6-octadecenoic acid, oleic acid, elideic acid, liver acid, erucic acid or brasidic acid do. Fatty acids are hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl amino, halo, cyano, azido, oxo , May be optionally substituted with up to 5 substituents independently selected from the group consisting of mercapto, nitro and the like. It is preferred if the fatty acid ester is unsubstituted.

Preferred compounds include the following:

9- [4- (L-isoleucineoxy) -3- (dodecanoyloxymethyl) butyl] guanine,

9- [4- (L-isoleucineoxy) -3- (tetradecanoyloxymethyl) butyl] guanine,

9- [4- (L-isoleucineoxy) -3- (hexadecanoyloxymethyl) butyl] guanine,

9- [4- (L-isoleucineoxy) -3- (octadecanoyloxymethyl) butyl] guanine,

9- [3- (eicosanoyloxymethyl) -4- (L-isosiloxy) butyl] guanine,

9- [3- (docosenoyloxymethyl) -4- (L-isosilyloxy) butyl] guanine,

2-amino-9- [4- (L-isoleucineoxy) -3- (dodecanoyloxymethyl) butyl] purine,

2-amino-9- [4- (L-isoleucineoxy) -3- (tetradecanoyloxymethyl) butyl] purine,

2-amino-9- [4- (L-isosiloxy) -3- (hexadecanoyloxymethyl) butyl] purine,

2-amino-9- [4- (L-isoleucineoxy) -3- (octadecanoyloxymethyl) butyl] purine,

2-amino-9- [4- (L-isosilyloxy) -3- (eicosanoyloxymethyl) butyl] purine,

2-amino-9-[(3- (eicosanoyloxymethyl) -4- (L-isoleucineoxy) butyl] purine,

2-amino-9- [3- (docosanoyloxymethyl) -4- (L-isosilyloxy) butyl] purine,

9- [3- (L-isoleucineoxy) -4- (dodecanoyloxymethyl) butyl] guanine,

9- [3- (L-isoleucineoxy) -4- (tetradecanoyloxymethyl) butyl] guanine,

9- [3- (L-isoleucineoxy) -4- (hexadecanoyloxymethyl) butyl] guanine,

9- [3- (L-isoleucineoxy) -4- (octadecanoyloxymethyl) butyl] guanine,

9- [4- (eicosanoyloxymethyl) -3- (L-isosilyloxy) butyl] guanine,

9- [3- (docosanoyloxymethyl) -3- (L-isosiloxy) butyl] guanine,

2-amino-9- [3- (L-isoleucineoxy) -4- (dodecanoyloxymethyl) butyl] purine,

2-amino-9- [3- (L-isoleucineoxy) -4- (tetradecanoyloxymethyl) butyl] purine,

2-amino-9- [3- (L-isoleucineoxy) -4- (hexadecanoyloxymethyl) butyl] purine,

2-amino-9- [3- (L-isoleucineoxy) -4- (octadecanoyloxymethyl) butyl] purine,

2-amino-9- [3- (L-isoleucineoxy) -4- (eicosanoyloxymethyl) butyl] purine,

2-amino-9- [4- (eicosanoyloxymethyl) -3- (L-isoleucineoxy) butyl] purine,

2-amino-9- [4- (docosanoyloxymethyl) -3- (L-isosilyloxy) butyl] purine,

And pharmaceutically acceptable salts thereof.

Another preferred compound includes:

9- [3- (dodecanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (tetradecanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (hexadecanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (octadecanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

9- [3- (docosanoyloxymethyl) -4- (L-valyloxy) butyl] guanine,

2-amino-9- [3- (dodecanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

2-amino-9- [3- (tetradecanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

2-amino-9- [2- (hexadecanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

2-amino-9- [3- (octadecanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

2-amino-9- [2- (eicosanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

2-amino-9- [3- (docosanoyloxymethyl) -4- (L-valyloxy) butyl] purine,

9- [4- (dodecanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

9- [4- (tetradecanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

9- [4- (hexadecanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

9- [4- (octadecanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

9- [4- (eicosanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

9- [4- (docosanoyloxymethyl) -3- (L-valyloxy) butyl] guanine,

2-amino-9- [4- (dodecanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

2-amino-9- [4- (tetradecanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

2-amino-9- [4- (hexadecanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

2-amino-9- [4- (octadecanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

2-amino-9- [4- (eicosanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

2-amino-9- [4- (docosanoyloxymethyl) -3- (L-valyloxy) butyl] purine,

And pharmaceutically acceptable salts thereof.

Preferred compounds include the following:

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-dodecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-tetradecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-hexadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-octadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-eicosanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-docosanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-isoleucineoxymethyl-5'-dodecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-(9-tetradecanoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-(9-hexadecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-(9-octadecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-(11-eicosenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-isoleucineoxymethyl-5'-(11-docosenoyl) cytosine.

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-dodecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-tetradecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-hexadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-octadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-eicosanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-docosanoylcytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(9-dodecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(9-tetradecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(9-hexadecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(9-octadecenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(11-eicosenoyl) cytosine,

2 ', 3'-dideoxy, 3'-C-L-valyloxymethyl-5'-(11-docosenoyl) cytosine.

2 ', 3'-dideoxy, 3'-C-dodecanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C-tetradecanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C-hexadecanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C-octadecanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C-eicosanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C-docosanoyloxymethyl-5'-L-isocylatecytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-dodecanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-tetradecanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-hexadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-octadecanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-eicosanoylcytosine,

2 ', 3'-dideoxy, 3'-C- (L-valyloxymethyl) -5'-docosanoylcytosine,

2 ', 3'-dideoxy, 3'-C-dodecanoyloxymethyl-5'-L-valylcytosine,

2 ', 3'-dideoxy, 3'-C-tetradecanoyloxymethyl-5'-L-valylcytosine,

2 ', 3'-dideoxy, 3'-C-hexadecanoyloxymethyl-5'-L-valylcytosine,

2 ', 3'-dideoxy, 3'-C-octadecanoyloxymethyl-5'-L-valylcytosine,

2 ', 3'-dideoxy, 3'-C-eicosanoyloxymethyl-5'-L-valylcytosine,

2 ', 3'-dideoxy, 3'-C-docosanoyloxymethyl-5'-L-valylcytosine,

And pharmaceutically acceptable salts thereof.

Another preferred compound includes:

1- (3'-O-dodecanoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-tetradecanoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-hexadecanoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-stearoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-eicosanoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-docosanoyl-5'-O-valyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-dodecanoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-tetradecanoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-hexadecanoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-stearoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-eicosanoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-docosanoyl-5'-O-isoleucine) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-dodecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-tetradecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-hexadecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-stearoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-eicosanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-valyl-5'-O-docosanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-dodecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-tetradecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-hexadecanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-stearoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-eicosanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

1- (3'-O-isoleucine-5'-O-docosanoyl) -β-D-ribofuranosyl) -1,2,4-triazole-3-carboxamide,

And pharmaceutically acceptable salts thereof.

Another preferred compound includes:

9-((1-dodecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-tetradecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-hexadecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-octadecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-eicosanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-docosanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) guanine,

9-((1-dodecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) guanine,

9-((1-tetradecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) guanine,

9-((1-hexadecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) guanine,

9-((1-octadecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) guanine,

9-((1-eicosanoyloxy-3- (L-isoleuxyoxy) -2-propoxy) -methyl) guanine,

9-((1-docosanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) guanine,

2-amino-9-((1-dodecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-tetradecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-hexadecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-octadecanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-eicosanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-docosanoyloxy-3- (L-valyloxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-dodecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-tetradecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-hexadecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-octadecanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-eicosanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

2-amino-9-((1-docosanoyloxy-3- (L-isoleucineoxy) -2-propoxy) -methyl) purine,

And pharmaceutically acceptable salts thereof.

Another preferred compound includes:

3-O'-dodecanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-tetradecanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-hexadecanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-octadecanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-eicosanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-docosanoyl, 5'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-dodecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-tetradecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-hexadecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-octadecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-eicosanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

5-O'-docosanoyl, 3'-O-valyl-9-β-D-arabinofuranosylguanine,

3-O'-dodecanoyl, 5'-O-valyl-9-β-D-arabinofuranosylcytosine,

3-O'-tetradecanoyl, 5'-O-valyl-9-β-D-arabinofuranosyltocin,

3-O'-hexadecanoyl, 5'-O-valyl-9-β-D-arabinofuranosyltocin,

3-O'-octadecanoyl, 5'-O-valyl-9-β-D-arabinofranosylcytosine,

3-O'-eicosanoyl, 5'-O-valyl-9-β-D-arabinofuranosyltocin,

3-O'-docosanoyl, 5'-O-valyl-9-β-D-arabinofuranosylcytosine,

5-O'-dodecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylcytosine,

5-O'-tetradecanoyl, 3'-O-valyl-9-β-D-arabinofranosylcytosine,

5-O'-hexadecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylcytosine,

5-O'-octadecanoyl, 3'-O-valyl-9-β-D-arabinofuranosylcytosine,

5-O'-eicosanoyl, 3'-O-valyl-9-β-D-arabinofuranosyltocin,

5-O'-docosanoyl, 3'-O-valyl-9-β-D-arabinofuranosylcytosine,

And corresponding isoleucyl homologs thereof.

Compounds of the invention, for example compounds of formula (I), (Ia), (Ib), (Ic), (I / II) or mixed esters of phosphonylated antiviral agents, may form salts that constitute a further aspect of the invention. Suitable pharmaceutically acceptable salts of the compounds of the invention are salts of organic acids, in particular carboxylic acids, for example acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, pantothenate, ise Thionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotine Of nates, palmoates, pectinates, 3-phenylpropionate, picrates, pivalates, proprionates, tartrates, lactobionates, pivolates, camphorates, undecanoates and succinates, organic sulfonic acids Salts, for example methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2- Program talren sulfonate, benzenesulfonate, p- chlorobenzene sulfonate, and p- toluenesulfonate; And salts of inorganic acids, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric acid and sulfonic acid. Compounds of formula (I), (Ia), (Ib), (Ic), (I / II) and the like may be isolated as hydrates.

The compounds of the invention are particularly suitable for oral administration, but can also be administered rectally, vaginally, intranasally, topically, transdermally or parenterally, for example intramuscularly, intravenously or dural. The compounds may be administered alone, for example in capsules, but are usually administered in admixture with a pharmaceutically acceptable carrier or diluent. The present invention extends to a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (I / II) or a pharmaceutically acceptable salt thereof in admixture with or with a pharmaceutically acceptable carrier or vehicle. do.

Oral formulations may conveniently be prepared in unit dose form, such as capsules or tablets, using conventional carriers or binders such as magnesium stearate, chalk, starch, lactose, wax, gum or gelatin. . Liposomes or synthetic or natural polymers such as HPMC or PVP can be used to provide sustained release formulations. In addition, the formulations may include solutions, suspensions, emulsions, oil-in-water or water-in-oil formulations in conventional vehicles (e.g., water, saline, ethanol, vegetable oils or glycerin), optionally with fragrances and / or preservatives and / or emulsifiers. May be present as a nose or eye drop, syrup, gel or cream.

For antiviral use the compounds of the invention are usually 0.1 to 200 mg / kg / day, advantageously 0.5 to 100 mg / kg / day, more preferably 10 to 50 mg / kg / day, for example 10 to 25 mg / It may be administered in a daily dose in the range of kg / day. Representative dosages for normal adults are approximately 50-500 mg, eg 300 mg, once or twice a day for herpes infections and 2-10 times for HIV infection. In each case, irrespective of whether the compound is an antiviral or anticancer compound, suitable doses for the compounds of the invention are determined by the techniques of the derivatives of the invention against the established dosage regimen of the parent compound by techniques well known in the pharmaceutical art. It can be calculated by mentioning kinetic performance.

As contemplated for antiviral treatment, the antiviral compounds of the present invention may be used in combination with other antiviral agents, such as acyclovir, valcyclovir, phencyclovir, famcyclovir, gancyclovir or poscarnet for the treatment of herpes and AZT, ddI, ddC, d4T, 3TC, poscarnet, ritonavir, indinavir, aquinavir, delaviridine, Vertex VX 478, Agouron AG1343, etc. have. Additional antiviral agents for the treatment of hepatitis B include 2 ', 3'-deoxy-3'-fluoroguanosine, lamivudine and various interferons.

The compounds of the present invention can be esterified from freshly prepared or commercially available antiviral agents such as phencyclovir or gancyclovir. The preparation of compounds in which X is O, n is 1 and Y / Z represents a ring can be prepared as described in WO95 / 32983. The preparation of compounds in which X is 0, n is 0 and Y / Z represents -C (OH)-, in particular arabinose compounds such as araC and araG, is described in British Patents GB 1386584, EP 002192, Germany Patent Application DE 2156637, International Patent Application WO9201456, Nucleosides Nucleotides (1982) 1 (3) 233-7 & (1983), 2 (3) 221-9, Synthesis (1978) (12) 908-910, J Heterocycl. Chem. (1988) 25 (6) 1899-903 and Chattopadihaya et al., Nuc Acids Res (Spec Publ) (1978) and Tetrahedron Lett (1980) 21 (5) 479-82.

The preparation of phosphonylated compounds is described in US Pat. No. 5,142,051, US Pat. No. 5,476,938 and J. Med Chem (1944) 37 1857-1864. Compounds in which Y and Z show a bond together are described in Antiviral Res. 1994; Suppl 1:44 and J Med Chem (1990) 33 1281-1285. The preparation and esterification of ribavirin is described in WO 94/22887 and US 3984396 and references.

The term ″ N-protected group ″ or ″ N-protected ″ as used herein refers to a group for protecting the N-terminus of an amino acid or peptide or for protecting an amino group against undesirable reactions during the synthesis process. Commonly used N-protective groups are described in Greene, ″ Protective Groups in Organic Synthesis (John Willey & Sons, New York, 1981), which is incorporated herein by reference. N-protective groups include acyl groups (e.g., formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, etc.); Sulfonyl groups (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.), carbamate forming groups (e.g. benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro Benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- Dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α, α-dimethyl-3,5-dimeth Oxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2 , 2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclo Hexyloxycarbonyl, phenylthiocarbon And the like); Alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; Silyl groups such as trimethylsilyl and the like. Advantageous N-protecting groups include trityl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBz).

Hydroxy and / or carboxy protecting groups are also extensively reviewed in Greene's literature, including ethers such as methyl, substituted methyl ethers such as methoxymethyl, methylthiomethyl, benzyl Oxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), tribenzylsilyl, triphenylsilyl, t-butyl Substituted ethyl ethers such as diphenylsilyl triisopropyl silyl, for example 1-ethoxymethyl, 1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, diphenylmethyl Aralkyl groups such as trityl, and pisyl (9-hydroxy-9-phenylxanthine derivatives, in particular chlorides). Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate, adamantatoate, mesitoate, benzoate and the like.

Bases in these starting materials (e.g. 2-amino groups of guanine or carboxamide groups of ribavirin derivatives) are optionally customary protecting groups (e.g. acetyl BOC (t-BuO-CO-), Z or CBz (BnO-CO -) Or Ph ₃ C-). Fmoc may be useful for cytosine. Compounds of formula (I) can be prepared from starting materials as follows.

Direct acylation methods are particularly suitable for achiral or symmetric compounds such as fencyclovir or gancyclovir. Scheme A is phencyclo wherein G is guanine or 6-deoxyguanine, PG is any protecting group or hydrogen, R ₁ ^* is a fatty acid chain, and R ₂ ^* is a side chain of valine, isoleucine, leucine, alanine and the like. Acylation of bir derivatives is shown. The nucleosides (derivatives) are preferably reacted with the activated R ₁ fatty acid derivative to provide the monoacylation product, as further described below in a solvent (eg dimethylformamide or pyridine) in the first step. Acylation first with fatty acids rather than amino acids is convenient because the lipophilic properties of acyl facilitate subsequent handling.

After purification, the R ₁ monoacylated compound is further acylated with a suitable activating amino acid derivative at the R ₂ position to provide a diacylation product using a similar method as in the first esterification step. R ₁ α-amino acid may be suitably N-protected with N-BOC, Fmoc, N-CBz and the like. The diester product is then subjected to conventional deprotection treatment, for example with trifluoroacetic acid, HCl (aq) / dioxane or hydrogenated in the presence of a catalyst to give the desired compound of formula (I). The compound may exist in salt form depending on the deprotection conditions.

It is clear that the fatty acid esters in Scheme A-1 are acylated first to nucleosides, but may also be acylated first to amino acid esters as shown in Scheme A-2.

Activated R ₁ / R ₂ acid derivatives used in various acylations can include acids in the presence of, for example, acid halides, acid anhydrides, activated acid esters or coupling agents such as dicyclohexylcarbodiimide, Where in each case ″ acids ″ represents the corresponding R ₁ amino acid or R ₂ fatty acid. Representative activated acid derivatives include acid chloride, formic acid and acetic acid derived mixed anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride, N-hydroxysuccinamide derived esters, N-hydroxy Phthalimide derived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters, and the like.

When the nucleosides are chiral or hydroxy groups are not the same, the reaction conditions are carefully controlled, for example by adjusting the reagent concentration or rate of addition of the acylating agent, by lowering the temperature or by selecting the solvent, for example. First acylation may be preferentially performed on the hydroxy group. The reaction can then be subjected to TLC to check the controlled conditions.

Scheme A-2 shows that arabinose nucleosides are preferentially acylated with fatty acids or aliphatic amino acid esters or with linker groups such as compounds of formula II.

By greater reactivity of the primary hydroxyl in Scheme A-2, the linker or first acylation of R ₁ / R ₂ is first carried out without requiring protection of the secondary hydroxyl group. The rightmost series first shows the addition of amino acid esters, but fatty acid esters can also be introduced first in this primary hydroxyl.

In the above formula,

C is cytosine (optionally N-protected),

R ₁ ^* , R ₂ ^* and the like are as described in Scheme A.

This technique is particularly suitable for chiral or asymmetric nucleosides where it is desirable to apply fatty acids and amino acid esters to specific hydroxy groups.

Scheme B is a bulky protective group followed by the regioselective protection of one of the hydroxy groups. In Scheme B, this is shown as t-butyldiphenylsilyl, but other regioselective protecting groups such as trityl, 9- (9-phenyl) xenyl, 1,1-bis (4-methylphenyl) -1 ' -Pyrenylmethyl) may also be suitable. The 2′-hydroxy group, if present, is usually sufficiently blocked by base, but may also be protected by conventional hydroxy protecting groups. The product obtained is acylated in a free hydroxy group using reagents and methods similar to those described in Scheme A above, wherein the activated acid derivatives are R ₁ fatty acids such as myristic acid, stearic acid, oleic acid, elide Acid chlorides and the like. Protective groups that can be carried out using these reagents in a highly selective manner by appropriately deprotecting the thus acylated compounds include, but are not limited to, regioselective protecting groups such as HF / pyridine and the like, the reagent concentration rates, temperatures and solvents added. According to the manipulation of the reaction conditions by, the removal is carried out as synthesized above. Current free hydroxy positions are acylated with activated α-amino acids in a similar manner as described in Scheme A above.

Other methods of introducing amino acid esters in Schemes A or B include the 2-oxo-4-aza-cycloalkanes-1,3-dione method described in WO 94/29311.

In addition, conventional linker groups, such as compounds of formula (II) having R ³ and R ⁴ fatty acids and amino acids already acylated, usually associate similarly with the above-mentioned esterification / carbonyl / amide linkage techniques. Can be introduced into nucleoside derivatives. It is usually necessary to protect the free amino group on the amino acid ester with a common protecting group such as CBz or BOC.

The esterification of phosphonylated antiviral agents having R ¹ and R ² groups linked via the intermediate —CH (R ^a ) O— is described in J. Med Chem. 37 1857-1864 (1994), where stepwise esterification for Schemes A and B is preferably a corresponding activated acyloxyalkyl, optionally using a free hydroxy group with a protecting group such as benzyl. Used in the Preferably R ^a is methyl, thereby producing a nontoxic ethanol metabolite.

Compounds in which Y comprises a —C (OH) — group may be theoretically acylated at the 2 ′ position with R ₁ , R ₂ or a structure of Formula II. Bases, however, usually stericly block the 2'hydroxy position, requiring strong protecting groups for 3 ', 5' and / or bases, usually with strong acylation conditions.

Conventional linker groups of formula (II) are in the 3 'or 5' position or less advantageously in the 2 'position, esterifications / carbonates / as indicated generally similarly to the above reactions A or B associated with the corresponding activating derivatives of formula (II) It can be introduced using amide binding techniques and suitable protection of unassociated hydroxy functional groups on sugars and acyclic moieties.

Compounds prepared by one of the above techniques can be post-modified as in conventional nucleoside chemistry. This usually requires protection by a protecting group (eg BOC) of the amino functional group of the amino acid ester.

A typical linker group of formula (II), wherein m is 1 and m 'is 0, regioselectively esterifies R ₃ and R ₄ from glycerol to the 1 and 2 positions of glycerol, as shown in Scheme I, and then hydroxy Can be prepared by converting to the appropriate -TC (= 0)-group at the 3 position. The reaction in the leftmost series in Scheme I represents the situation where R ₃ is esterified to the 1 position of glycerol and R ₄ is esterified to the 3 position. The corresponding arrangement, in which R ₄ is esterified to position 2 and R ₃ to position 1, treats glycerol first with CBz-L-valine / DCC / DMAP / DMF, then protects position 3 with pixyl chloride, and then the fatty acid. Can be obtained by esterifying to the 2-position of glycerol and deprotecting and converting to the 3-position if necessary.

Scheme I is shown with reference to the combination where R ₃ is stearoyl and R ₄ is L-valyl, but this basic scheme also applies when other fatty acids and amino acid derivatives or R ₄ is a fatty acid ester and R ₃ is an amino acid ester. can do. Linkers in which T comprises an -NH- group can be prepared by similarly regioselective esterification followed by conversion of the free hydroxyl to an azide, reduction with an amine and reaction with phosgene to form the corresponding chlorocarbamate.

Linkers in which m is 1, n is alkylene or alkenylene and T is a bond can be prepared as shown in Scheme II above. Other substituents, such as m, m 'and n, in the linker group of formula (II) are the corresponding starting materials [e.g. 1,2,4-trihydroxybutane (CA reg. No. 3968-00-6), 3,4- Dihydroxybutanoic acid (1518-61-2 & 22329-74-4), (S) -3,4-dihydroxybutanoic acid (51267-44-8), (R) -3,4-dihydroxy Roxybutanoic acid (158800-76-1), 1,2,5-pentane triol (51064-73-4 & 14697-46-2), (S) -1,2,5-pentane triol (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-pentanetriol (53378-75-9)]. Can be. The preparation of each of these starting materials is described with reference to the respective registration number.

Other linker structures of formula (II) and their arrangement via acylation or carbonate linkages on nucleoside homologs are shown in the following examples.

Thus, another aspect of the invention

a) optionally protecting the base of the compound of formula I wherein R ₁ and R ₂ are each hydrogen,

b) i) acylation with an optionally protected aliphatic amino acid group or C ₅ -C ₂₁ COOH derivative;

ii) reacting with a regioselective protecting group to regioselectively react a compound of formula (I) at the R ₁ or R ₂ position,

c) acylating with a C ₅ -C ₂₁ COOH derivative or an aliphatic amino acid outside of the R ₁ or R ₂ position,

d) when present, replaces the regioselective protecting group at R ₁ / R ₂ with an optionally protected aliphatic amino acid acyl or C ₅ -C ₂₁ COOH derivative,

e) if necessary, a process for the preparation of the compound of the first aspect of the invention comprising deprotecting the obtained compound.

The acylation in step b) or the substitution in step d) is the substitution of the amino acid ester via 2-oxo-4-aza- (5-isopropyl or 5-isobutyl) -cycloalkane-1,3-dione derivative It may include.

Another aspect of the invention

a) optionally protecting the base of the compound of formula I wherein R ₁ and R ₂ are each hydrogen,

b) i) acylating / carbonate bonding / amide bonding the activating structure of formula II;

ii) reacting with a regioselective protecting group to regioselectively react a compound of formula (I) at the R ₁ or R ₂ position,

c) if present, the regioselective protecting group at R ₁ / R ₂ is substituted by acylating / carbonate bonding / amide bonding the activating structure of formula II,

d) if necessary, a process for the preparation of another compound of the invention comprising deprotecting the obtained compound.

The invention is now illustrated by way of example with reference to the following non-limiting examples.

Example 1

9- (1-stearoyloxy-3- (L-valyloxy) -2-propoxy) methyl guanine

i) Preparation of 9- (1-stearoyloxy-3-hydroxy-2-propoxy) methyl) guanine

Pyridine (1.3 ml, 16 mmol) is added to a solution of 9- (1,3-dihydroxy-2-propoxy) -methyl) guanine (1.02 g, 4 mmol) in DMF (120 ml). Next, stearoyl chloride (1.62 g, 4.8 mmoles) is added in small portions to the reaction mixture. The reaction is left overnight and an additional portion of stearoyl chloride (214 mg, 0.8 mmole) is added. After 3 hours, methanol (3 ml) is added to the reaction mixture and the temperature is raised to 45 ° C. The reaction is left at this temperature for 2 hours. The mixture is evaporated in vacuo and the product is separated by silica gel column chromatography (1.17 g).

¹ H NMR (DMSO-d6): 10.6 (s, 1H, NH), 7.78 (s, 1H, H-8), 6.58 (s, 2H NH ₂ ), 5.40 (s, 2H, CH ₂ ), 3.96 ( m, 2H, CH ₂ ), 3.82 (m, 1H, CH), 3.39 (m, 2H), 2.10 (t, 2H, stear), 1.40 (m, 2H, stear), 1.23 (m, 28H, stear) , 0.88 (t, 3H, stearic).

ii) Synthesis of 9-((1-stearoyloxy-3- (N-t-butoxycarbonyl-L-valyloxy) -2-propoxy) methyl) guanine

9-((1-stearoyloxy-3-dihydroxy-2-propoxy) -methyl) guanine (521 mg, 1 mmole) and Nt-butoxycarbonyl-L-valine (651 mg, in DMF (20 ml) To a solution of 3 mmoles 4-dimethylaminopyridine (18.3 mg, 0.15 mmoles) and DCC (618 mg, 3 mmoles) are added. The reaction is left overnight and filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution, the organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography (271 mg).

¹ H NMR (DMSO-d6): 10.62 (s, 1H, NH), 7.80 (d, 1H, H-8), 6.47 (s, 2H, NH ₂ ), 5.40 (s, 2H, CH ₂ ), 4.04 (m, 6H), 2.10 (m, 2H, stearic), 1.95 (m, 1H), 1.67 (m, 2H), 1.36 (s, 9H, Boc), 1.22 (m, 28H, stearic), 0.84 (m , 9H).

iii) Synthesis of 9-((1-stearoyloxy-3- (L-valyloxy) -2-propoxy) methyl) guanine

9-((1-Stearoyloxy-3- (Nt-butoxycarbonyl-L-valyloxy) -2-propoxy) methyl) guanine (200 mg, 0.277 mmol) with trifluoroacetic acid (5 ml) After 20 min at 0 ° C., the reaction mixture is evaporated in vacuo. The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (237 mg).

¹ H NMR (DMSO-d6): 10.4 (s, 1H, NH), 8.40 (b, 3H, NH ₃ ), 7.96 (d, 1H, H-8), 5.45 (s, 2H, CH ₂ ), 4.11 (m, 6H), 2.27 (m, 2H), 2.03 (m, 1H, Val), 1.46 (m, 2H), 1.20 (m, 9H).

Example 2

9-((1-stearoyloxy-3- (L-alanyloxy) -2-propoxy) methyl) guanine

i) Synthesis of 9-((1-stearoyloxy-3- (N-t-butoxycarbonyl-L-alanyloxy) -2-propoxy) methyl) guanine

9-((1-stearoyloxy-3-hydroxy-2-propoxy) methyl) guanine (365 mg, 0.7 mmol) and Nt-butoxycarbonyl-L-alanine (396 mg, 2.1 in DMF (15 ml) 4-dimethylaminopyridine (12 mg, 0.1 mmol) and DCC (432 mg, 2.1 mmol) were added to the solution of mmole). The reaction is left overnight and filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution, the organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography. Yield: 164 mg.

¹ H NMR (DMSO-d6): 10.61 (s, 1H, NH), 7.81 (s, 1H, H-8), 6.48 (s, 2H, NH ₂ ), 5.41 (s, 2H, CH ₂ ), 4.04 (m, 6H), 2.10 (t, 2H, stear), 1.35 (m, 11H), 1.22 (m, 31H), 0.85 (t, 3H, stear).

iii) Synthesis of 9-((1-stearoyloxy-3- (L-alanyloxy) -2-propoxy) methyl) guanine

9-((1-Stearoyloxy-3- (Nt-butoxycarbonyl-L-alanyloxy) -2-propoxy) methyl) guanine (150 mg, 0.21 mmole) trifluoroacetic acid (5 ml) 30 minutes at 0 ° C. and then evaporate the reaction mixture in vacuo. The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (177 mg).

¹ H NMR (DMSO-d6): 10.77 (s, 1H, NH), 8.30 (b, 3H, NH ₃ ), 7.93 (d, 1H, H-8), 4.11 (m, 6H), 2.15 (t, 2H, stear), 1.42 (m, 2H), 1.23 (m, 31H), 0.85 (t, 3H, stear).

Example 3

9- (1-stearoyloxy-3- (L-isoleucineoxy-2-propoxy) methyl) guanine

i) Synthesis of 9- (1-stearoyloxy-3- (N-t-butoxycarbonyl-L-isosiloxy) -2-propoxy) methyl) guanine

In a solution of 9- (1-stearoyloxy-3-hydroxy-2-propoxy) methylguanine (365 mg, 0.7 mmole) and Nt-butoxycarbonyl-L-isoleucine (485 mg, 2.1 mmole), DCC ( 432 mg, 2.1 mmol) is added. The reaction is left overnight and filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution. The organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography. Yield: 208 mg.

¹ H MMR (DMSO-d6): 10.61 (s, 1H, NH), 7.80 (d, 1H, H-8), 6.47 (b, 2H, NH ₂ ), 5.40 (s, 2H, CH ₂ ), 4.01 (m, 6H), 2.11 (m, 2H), 1.58 (m, 1H, Ile), 1.36 (m, 11H), 1.23 (m, 28H), 0.81 (m, 9H).

ii) Synthesis of 9- (1-stearoyloxy-3- (L-isoleuxyoxy) -2-propoxy) methyl) guanine

9- (1-Stearoyloxy-3- (Nt-butoxycarbonyl-L-isosiloxy) -2-propoxy) methyl) guanine (190 mg, 0.26 mmole) trifluoroacetic acid (5 ml) 20 minutes at 0 ° C. and then evaporate the reaction mixture in vacuo. The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (225 mg).

¹ H NMR (DMSO-d6): 10.77 (s, 1H, NH), 7.91 (d, 1H, H-8), 6.55 (b, 2H, NH ₂ ), 5.44 (s, 2H, CH ₂ ), 4.12 (m, 6H), 2.16 (m, 2H, stearic), 1.78 (m, 1H, Ile), 1.42 (m, 2H), 1.23 (m, 28H), 0.84 (m, 9H).

Example 4

9- [4-stearoyloxy-3- (L-valyloxymethanyl) butyl] guanine

i) Synthesis of 9- (4-stearoyloxy-3-hydroxymethyl-butyl) guanine

Pyridine (1 ml, 11 mmol) is added to a solution of 9- (4-hydroxy-3-hydroxymethyl-butyl) guanine (1.01 g, 4 mmol) in DMF (120 ml). Stearoyl chloride (1.51 g, 5 mmole) is then added to the reaction mixture. The reaction is left overnight and then diluted with dichloromethane and the mixture is washed with aqueous sodium hydrogen carbonate solution. The organic phase is evaporated in vacuo and the product is separated by silica gel column chromatography (1.22 g).

¹ H NMR (DMSO-d6): 7.68 (s, 1H, H-8), 6.60 (b, 2H, NH ₂ ), 4.05 (m, 6H), 2.23 (t, 2H), 1.75-1.40 (m, 5H), 1.20 (m, 28H), 0.83 (t, 3H).

ii) Synthesis of 9- (4-stearoyloxy-3- (N-t-butoxycarbonyl-L-valyloxymethyl) butyl) guanine

4-into a solution of 9- (4-stearoyloxy-3-hydroxymethyl-butyl) guanine (519mg, 1mmole) and Nt-butoxycarbonyl-L-valine (651mg, 3mmole) in DMF (20ml) Dimethylaminopyridine (18.3 mg, 0.15 mmol) and DCC (618 mg, 3 mmole) are added. The reaction is left for 5 hours and then filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution. The organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography (239 mg).

¹ H-NMR (DMSO-d6): 10.58 (s, 1H, NH), 7.68 (s, 1H, H-8), 6.49 (b, 2H, NH ₂ ), 4.03 (m, 6H), 3.82 (m , 1H), 2.38 (t, 2H), 1.80 (m, 4H), 1.50 (m, 2H), 1.32 (m, 9H), 1.22 (m, 28H), 0.82 (m, 9H).

iii) Synthesis of 9- (4-stearoyloxy-3- (L-valyloxymethyl) butyl) guanine

Treated 9- (4-stearoyloxy-3- (Nt-butoxycarbonyl-L-valyloxymethyl) butyl) guanine (225 mg, 0.312 mmol) with trifluoroacetic acid (5 ml) at 0 ° C. for 40 minutes. The reaction mixture is then evaporated in vacuo. The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (266 mg).

¹ H NMR (DMSO-d6): 10.85 (s, 1H, NH), 8.31 (b, 3H, NH ₃ ), 8.06 (s, 1H, H-8), 4.08 (m, 7H), 2.28 (t, 2H), 2.12 (m, 1H), 1.99 (m, 1H), 1.82 (m, 2H), 1.50 (m, 2H), 1.23 (m, 28H), 0.92 (m, 6H), 0.85 (t, 3H ).

Example 5

9-((4-stearoyloxy-3- (L-alanyloxymethyl) butyl) guanine

i) Synthesis of 9- (4-stearoyloxy-3- (N-t-butoxycarbonyl-L-alanyloxymethyl) butyl) guanine

Solution of 9- (4-stearoyloxy-3- (hydroxymethyl) butyl) guanine (200 mg, 0.38 mmol) and Nt-butoxycarbonyl-L-alanine (218 mg, 1.15 mmol) in DMF (6 ml) To 4-dimethylaminopyridine (7mg, 0.06mmole) and DCC (238mg, 1.15mmole) are added. The reaction is left for 3 hours and then filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution. The organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography. Yield: 98 mg.

¹ H-NMR (CDCl ₃ + CD ₃ OD): 7.57 (d, 1H, H-8), 4.10 (m, 7H), 2.33 (t, 2H), 2.05 (m, 1H), 1.90 (m, 2H ), 1.61 (m, 2H), 1.45 (s, 9H), 1.38 (d, 3H), 1.30 (m, 28H), 0.89 (t, 3H).

ii) Synthesis of 9-((4-stearoyloxy-3- (L-alanyloxymethyl) butyl guanine

9- (4-stearoyloxy-3- (Nt-butoxycarbonyl-L-alanyloxymethyl) butyl guanine (90 mg, 0.13 mmole) with trifluoroacetic acid (3 ml) at 50 ° C. for 50 minutes The reaction mixture is evaporated under vacuum The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (100 mg).

¹ H-NMR (DMSO-d ₆ ): 10.78 (s, 1H, NH), 8.30 (b, 3H, NH ₃ ), 8.01 (s, 1H, H-8), 6.53 (b, 2H, NH ₂ ) , 4.10 (m, 7H), 2.30 (t, 2H), 1.97 (m, 1H), 1.80 (m, 2H), 1.49 (m, 2H), 1.32 (q, 3H), 1.23 (m, 28H), 0.83 (t, 3 H).

Example 6

9- (4-stearoyloxy-3- (L-isosiloxyoxy) butyl) guanine

i) Synthesis of 9- (4-stearoyloxy-3- (N-t-butoxycarbonyl-L-isoleucineoxymethyl) butyl) guanine

To a solution of 9- (4-stearoyloxy-3-hydroxymethyl) butyl) guanine (200 mg, 0.38 mmol) and Nt-butoxycarbonyl-L-isoleucine (263 mg, 1.15 mmol) in DMF (5 ml). 4-dimethylaminopyridine (7 mg, 0.06 mmole) and DCC (237 mg, 1.15 mmole) are added. The reaction is left for 3 hours and an additional portion of DCC (118 mg, 0.57 mmole) is added. The reaction is left overnight and filtered through celite. The filtrate is diluted with dichloromethane and then washed with aqueous sodium hydrogen carbonate solution, the organic phase is concentrated in vacuo and the product is separated by silica gel column chromatography. Yield: 201 mg.

¹ H-NMR (DMSO-d6): 10.51 (s, 1H, NH), 7.68 (s, 1H, H-8), 6.40 (b, 2H, NH ₂ ), 4.05 (m, 6H), 3.82 (t , 1H), 2.37 (t, 2H), 1.95 (m, 2H), 1.83 (m, 2H), 1.48 (m, 2H), 1.36 (m, 9H), 1.25 (m, 28H), 0.82 (m, 9H).

ii) Synthesis of 9- (4-stearoyloxy-3- (L-isosilyloxymethyl) butyl) guanine

9- (4-stearoyloxy-3- (Nt-butoxycarbonyl-L-isosiloxymethyl) butyl) guanine (190mg, 0.26mmole) with trifluoroacetic acid (5ml) for 50 minutes at 0 ° C After treatment, the reaction mixture is evaporated in vacuo. The residue is successively co-evaporated with toluene, methanol and lyophilized to give the desired product (217 mg).

¹ H-NMR (DMSO-δ6): 10.93 (s, 1H, NH), 8.34 (b, 3H, NH ₃ ), 8.12 (s, 1H, H-8), 6.66 (b, 2H, NH ₂ ), 4.08 (m, 6H), 3.95 (m, 1H), 2.50 (t, 2H), 2.18 (m, 1H), 1.98 (m, 1H), 1.86 (m, 2H), 1.48 (m, 2H), 1.22 (m, 28H), 0.87 (m, 6H), 0.84 (t, 3H).

Example 7

3'-O-stearoyl-5'-O-valyl-ribavirin

Boc-Val-OH (5.47 g, 25.2 mmol) and DCC (3.05 g, 14.8 mmol) in CH ₂ Cl ₂ (240 ml) are stirred at room temperature under nitrogen for 3 hours. The mixture is filtered and the solvent is evaporated. Anhydride is dissolved in DMF (300 ml). Ribavirin (3.0 g, 12.3 mmol) and DMAP (226 mg, 1.85 mmol) are added to this solution and stirred at room temperature for 24 hours. DMF was evaporated and the residue was purified by chromatography by eluting with MeOH / CH ₂ Cl ₂ 5/95 on silica gel to give 2.5 g of 5′-Boc-valine-ribavirin.

¹ H NMR (250 MHz, DMSO) δ 8.90 (s, 1H), 7.87 (br s, 1H), 7.66 (br s, 1H), 7.20 (d, 1H), 5.88 (m, 2H), 5.20 (m, 1H), 5.24 (t, 1H), 4.72 (m, 1H), 4.10 (m, 1H), 4.02 (m, 1H), 3.57 (m, 2H), 2.10 (m, 1H), 1.37 (s, 9H ), 0.91 (t, 3 H).

Stearoyl chloride (1.34 g, 4.4 mmoles) in CH ₂ Cl ₂ (60 ml) is added dropwise onto ice to a solution of the intermediate (2.17 g, 4.9 mmoles) in pyridine (60 ml). The mixture is stirred at the same temperature for 15 minutes and then cooling is stopped. The stirring is continued for 2 hours. The mixture is treated with 1M sodium hydrogen carbonate and the organic layer is washed with water and brine and dried over sodium sulfate. The solution was concentrated and eluted with 5% MeOH in CH ₂ Cl _2, CH ₂ Cl and 2.5% MeOH in CH ₂ Cl _{2 2} on silica gel and purified by chromatography to give the product 0.6g, and this, in TFA (20ml) Deprotection on ice for 2 hours, evaporation and drying in vacuo yields 560 mg of 3'-0-stearoyl, 5'-0-valyl-ribavirin.

¹ H NMR (250 MHz, DMSO) δ 8.89 (s, 1H), 8.53 (br s, 2H), 7.87 (br s, 1H), 7.71 (br s, 1H), 6.01 (d, 1H), 5.43 ( t, 1H), 4.78 (t, 1H), 4.42-4.02 (m, 4H), 2.40-2.10 (m, 3H), 1.46 (m, 2H), 1.23 (br s, 28H), 1.02 (t, 6H ), 0.84 (t, 3 H).

Example 8

3'-O-stearoyl-5'-O-valyl-arabinoshitocin

a) N- (benzyloxycarbonyl) araC

A mixture of araC (243 mg, 1.00 mmol), trimethylchlorosilane (1.00 g, 9.2 mmol), N, N-dimethylformamide (1 ml) and pyridine (6 ml) was stirred at room temperature for 1 hour and then iced at -15 ° C. Cool in a salt bath. A 50% solution of benzyl chloroformate (680 mg, 2.0 mmol) in toluene is added three times below the surface of the reaction mixture, which is left at room temperature for 0.5 hours and then cooled with ice water. Water (5 ml) is added (first very slowly) followed by 5 ml of ethyl acetate. After stirring for 10 minutes, the aqueous phase is extracted 5 times with 5 ml of ethyl acetate and the combined organic phases are evaporated in small amounts. The crude product is purified by chromatography on 8 g of silica gel with ethyl acetate + methanol + water (15 + 2 + 1) as eluent, with slight warming of the column for chromatography. Yield of the title compound is 267 mg (71%).

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 171.9 (COO); 162.6 (C4); 156.7 (C2); 156.3 (CONH-Val); 152.4 (CONH-4); 146.3 (C6); 136.0 (Ph-Cl-Val); 134.9 (Ph-Cl-cyt); 128.4-128.0 (2 Ph); 95.1 (C5); 88.9 (C1 '); 83.3 (C4 '); 77.1 (C3 '); 75.0 (C2 '); 67.8 (Ph CH ₂ -Val); 67.0 (Ph CH ₂ -cyt); 64.7 (C5 '); 59.5 (Val-aC); 31.5 (Val-bC); 19.0 / 18.8 and 17.9 / 17.7 (Val 2 CH ₃ ).

b) N- (benzyloxycarbonyl) -5 '-(N-benzyloxycarbonyl-L-valyl) araC

A mixture of N-benzyloxycarbonyl-L-valine (302 mg, 1.20 mmol), cyclohexylcarbodiimide (136 mg, 0.66 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) in dichloromethane (3 ml) was added to room temperature. Stirred for 1 h, filtered and evaporated in small amounts in vacuo to afford crude N-benzyloxycarbonyl-L-valine anhydride. The intermediate of step a) (174 mg, 0.46 mmol), triethylamine (100 mg, 1.0 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and N, N-dimethylformamide (2 ml) were added and the mixture was allowed to stand at room temperature. Stir. After a few minutes, a new product can be detected by TLC. After 2 hours, the mixture is evaporated in small portions in vacuo and purified on a silica gel column (8 g; ethyl acetate + methanol + water, 15 + 2 + 1). The first fraction contains a lipophilic byproduct, and then the pure title compound is eluted (yield 97.5 mg; 34.6%); Finally, unreacted intermediate compounds can be recovered.

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 171.9 (COO); 162.6 (C4); 156.7 (C2); 156.3 (CONH-Val); 155.5 (C2); 152.4 (CONH-4); 146.3 (C6); 136.0 (Ph-Cl-Val); 134.9 (Ph-Cl-cyt); 128.4-128.0 (2 Ph); 95.1 (C5); 88.9 (C1 '); 83.3 (C4 '); 77.1 (C3 '); 75.0 (C2 '); 67.8 (Ph CH ₂ -Val); 67.0 (Ph CH ₂ -cyt); 64.7 (C5 '); 59.5 (Val-αC); 31.5 (Val-βC); 19.0 / 18.8 and 17.9 / 17.7 (Val 2 CH ₃ ).

c) N- (benzyloxycarbonyl) -5 '-(N-benzyloxycarbonyl-L-valyl) -3'-stearoyl-araC

Intermediate (97.5 mg, 0.16 mmol), stearoyl chloride (isomer-free; 97 mg, 0.32 mmol) in step b), triethylamine (50 mg, 0.40 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and The mixture of N, N-dimethylformamide (3 ml) is stirred at room temperature for 2 hours and evaporated in small amounts in vacuo. The residue is suspended in a small amount of ethyl acetate and added to Pasteur pipette 'column' (silica gel 1 cm; ethyl acetate as eluent) (with insoluble amine salts). Fractions containing some purified product are evaporated to dryness and the residue is dissolved in 5 ml of a 50:50 mixture of ethyl acetate-hexane, washed with aqueous potassium carbonate solution and run through another 1 cm silica gel 'column'. The aqueous phase containing salt is extracted twice with 1 ml portion of ethyl acetate-hexane eluted through the 'column'. The combined fractions were evaporated to dryness to give 118 mg of a colorless oil which was further purified on a small silica column (ethyl acetate-hexane, 1 + 1) to give 66.5 mg (47.4%) of the pure title compound.

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 172.5 (Stear-COO); 171.8 (Val-COO); 162.6 (C4); 156.0 (CONH-Val); 154.2 (C2); 152.2 (CONH-4); 145.2 (C6); 136.0 (Ph-Cl-Val); 134.9 (Ph-Cl-cyt); 128.4-127.9 (2 Ph); 94.4 (C5); 88.5 (C1 '); 81.3 (C 4 ′); 77.4 (C3 '); 73.8 (C2 '); 67.9 (Ph CH ₂ -Val); 67.0 (Ph CH ₂ -cyt); 63.0 (C5 '); 59.1 (Val-αC); 33.8 (stear-C2); 31.7 (stear-C16); 31.0 (Val-βC); 29.5-29.2 (stear-C4-15); 24.5 (stear-C3); 22.5 (stear-C17); 19.0 and 17.5 (Val 2 CH ₃ ); 13.9 (stear-C18).

d) 3'-stearoyl-5'-L-valyl-araC

The intermediate (67 mg, 0.076 mmol) of step c) in 4 ml of EtOH and 0.4 ml of acetic acid was hydrogenated through Celite for 0.5 hours at room temperature and atmospheric pressure using 20 mg of Pd / C 10%, evaporated in vacuo and dioxane Lyophilization gave 50 mg (99%) of the title compound as a white powder.

¹³ C NMR (CDSO-d ₆ , 62.975 MHz): δ 171.7 (Stear-COO); 170.7 (Val-COO); 165.5 (C4); 156.5 (CONH-Val); 155.5 (C2); 141.8 (C6); 92.4 (C5); 87.0 (C1 '); 80.5 (C 4 ′); 78.8 (C3 '); 72.6 (C2 '); 63.0 (C5 '); 57.8 (Val-αC); 33.5 (stear-C2); 31.3 (stear-C16); 29.8 (Val-βC); 29.0-28.4 (stear-C4-15); 24.1 (stear-C3); 22.0 (stear-C17); 18.8 and 18.0 (Val 2 CH ₃ ); 13.7 (Steaar-C18).

Preparation Example 1

2- (Stearoyloxymethyl) -2- (N- (fluorenylmethoxycarbonyl) -L-valyloxymethyl) propionic acid

Potassium hydroxide (11.78 g, 210 mmol) is added to a solution of 2,2-bis (hydroxymethyl) propionic acid (28.16 g, 210 mmol) in water (50 ml). After 5 minutes, the solution is evaporated in vacuo and the residue is co-evaporated three times with anhydrous DMF. The residue is then dissolved in DMF (500 ml) and benzyl bromide (3.57 ml, 30 ml) is added to this solution. After stirring for 30 minutes, the reaction mixture is filtered through celite, poured into an aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is collected and then washed with aqueous sodium hydrogen carbonate solution. Then evaporate in vacuo to yield benzyl 2,2-bis (hydroxymethyl) propionate (4.37 g).

¹ H-NMR (CDCl ₃ ): 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 (58 ml) was added dropwise stearoyl chloride (4.13 g, 13.6 mmol) in dichloromethane over 40 minutes. . Next, the reaction was left for 16 hours, poured into an aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic phase is collected and evaporated in vacuo. The product benzyl-2- (hydroxymethyl) -2- (stearoyloxymethyl) propionate is isolated by silica gel column chromatography (1.97 g).

¹ H-NMR (CDCl ₃ ); 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, 3 H), 0.87 (t, 3 H).

Benzyl 2- (hydroxymethyl) -2- (stearoyloxymethyl) propionate (1.86 g, 3.8 mmol) is dissolved in pyridine (30 ml). Toluenesulfonic acid (73 mg, 0.39 mmol), N-fluorenylmethoxycarbonyl-L-valine (3.94 g, 11.6 mmol) and DCC (3.58 g, 17.4 mmol) were added to this solution. The reaction is left at 4 ° C. for 16 hours and then filtered through celite. The filtrate is poured into an aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is collected and evaporated in vacuo. The product benzyl-2- (N-fluorenylmethoxycarbonyl) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate is separated by silica gel column chromatography. Yield: 2.38 g.

¹ H-NMR (CDCl ₃ ): 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).

Benzyl 2- (N- (fluorenylmethoxycarbonyl) -L-valyloxymethyl) -2- (stearoyloxymethyl) propionate (1.86 g) in a mixed solvent of THF / methanol (16 ml / 8 ml) Ammonium formate (376 mg, 6 mmole), formic acid (1.87 ml) and palladium black (40 mg) were added to a solution of 3.8 mmol). The reaction is left at room temperature for 16 hours and then filtered through celite. After evaporation, the product is separated by silica gel column chromatography. Yield: 1.05 g.

Preparation Example 2

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

a) Preparation of 1-O-Stearoylglycerol

To a mixture of glycerol (30 g, 326 mmole) and pyridine (25 ml) dissolved in DMF (300 ml) is added dropwise stearoyl chloride (10 g, 33 mmole) dissolved in DMF (100 ml). The mixture is cooled in an ice bath until the addition is complete, then the reaction is kept under nitrogen atmosphere overnight. After 15 h, CH ₂ Cl ₂ (300 ml) and saturated sodium bicarbonate (aq) are added. The phases are separated and the organic phase is washed with water (50 ml) and dried over sodium sulfate. Solvent and pyridine are evaporated in vacuo. The crude product is chromatographed on silica column (CH ₂ Cl ₂ -MeOH, 20: 1) and recrystallized (CH ₂ Cl ₂ -ether) to give about 7 g.

b) preparation of pisyl chloride

Acetyl chloride (150 ml, 2.1 mole) is added to a magnetic stirred suspension of 9-hydroxy-9-phenylxanthene (20 g, 72 mmol) in benzene (100 ml). A homogeneous deep red solution is obtained. The solution is stirred at 20 ° C. for 30 minutes. The volatiles are removed under reduced pressure. Excess AcCl is neutralized by careful addition to ethanol. The residue is co-evaporated with toluene (2 x 30 ml) and cyclohexane (2 x 30 ml) to give a crystalline residue, which is airtight stored. Pixyl chloride can also be obtained from Aldrich.

c) preparation of 1-O-stearoyl, 3-0-picylglycerol

The product from a) (2.28 g) and pyridine (25 ml) are mixed and heated until dissolved. After cooling in an ice bath, pixyl chloride (1.92 g) from step b) is added. The mixture is kept for half an hour in an ice bath under an argon atmosphere with stirring, followed by 1.5 hours at room temperature. Pyridine is evaporated in vacuo and the residue is dissolved in CH ₂ Cl ₂ (70 ml) and washed with 0.5 M citric acid to remove residual pyridine. The residue is dried over sodium sulfate, evaporated and chromatographed (ether-hexane 1: 3) to give 1.25 g of pure product having a TLC Rf of about 0.2.

d) Preparation of 1-O-Stearoyl, 2-O- (N-CBz-L-Valyl), 3-O-Pixylglycerol

Dissolve 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) in CH ₂ Cl ₂ (4 ml) Let's do it. The mixture is kept overnight in a nitrogen atmosphere with stirring. After 18 hours, the mixture is filtered through a glass filter and chromatographed on a silica gel column (ether-hexane 1: 4) to give 230 mg of TLC Rf of 0.2.

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

The title compound is obtained by selective deprotection and removal of the pixyl group in the product of step d) by the method described in Example 3, step d).

¹ H-NMR (CDCl ₃ ): δ 7.35 (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).

Preparation Example 3

1-O- (N-CBz-L-valyl) -2-O-stearoylglycerol

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

CBz-L-valine (4.35 g, 17.3 mmol) was added to a 5-fold excess of glycerol (8 ml, 86.9 mmol) with dicyclohexylcarbodiimide (4.29 g, 20.8 mmol) and 4-dimethylaminopyridine (0.212 g). Add at room temperature. After stirring overnight, the suspension is filtered and the DMF is removed from the filtrate in vacuo. The residue is redissolved in CH ₂ Cl ₂ , washed successively with saturated sodium bicarbonate, brine and water and then dried. The crude material is chromatographed on silica gel with 4/1 EtOAc-hexane as eluent to afford 2.465 g. Rf (4/1 EtOAc-hexane) 0.17, (20/1 CH ₂ Cl ₂ -methanol) 0.12.

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

The product of step a) (0.672 g, 20.1 mmol) is dissolved in anhydrous pyridine (3.5 ml) under nitrogen. 9-Chloro-9-phenylxanthene (pixyl chloride, 0.65 g, 22.0 mmol, 1.1 equiv-prepared as above) is added and the mixture is stirred at room temperature for 1.5 hours. MeOH (1.5 ml) is added and the mixture is partitioned between 10 ml of Et ₂ O and 10 ml of saturated sodium bicarbonate. The aqueous layer is extracted with a large amount of ether. The organic layers are combined, dried and concentrated several times with toluene to give a white solid. The crude material is chromatographed on silica gel with 3/1 hexanes-EtOAc as eluent to afford 0.681 g.

Pixyl groups can also be bound using PxOH and acetic acid by the method described in Gaffney et al, Tetrahedron Lett 1997, 38, 2539-2542.

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

Stearoyl chloride (496 ml, 1.3 equiv) in 1.5 ml CH ₂ Cl ₂ is added dropwise with stirring in an ice bath under nitrogen to a solution of the product of step b) (0.658 g, 1.13 mmol) in 11 ml of pyridine. After 15 minutes, the mixture is stirred overnight at room temperature. The mixture is diluted with 20 ml of Et ₂ O and washed with 10 ml of saturated sodium hydrogen carbonate. The aqueous layer is extracted with a large amount of Et ₂ O. The organic layers are combined, washed with brine (20 ml), dried over sodium sulphate and concentrated several times with toluene. The crude material (1.37 g) is chromatographed on 130 g silica gel with 6/1 hexanes-EtOAc. 500 ml of fraction are initially obtained followed by 100 ml of fraction. The desired material eluted in fractions 2-5 to yield 0.748 g.

d) preparation of 1-O- (N-CBz-L-valyl) -2-O-stearoylglycerol

Pyrrole (16.5 mol equivalent) and dichloroacetic acid (5.5 mol equivalent) are added to a solution of the product of step c) (0.748 g, 872 mmol) dissolved in 35 ml of CH ₂ Cl ₂ making 0.025 M at room temperature. After 5 minutes TLC showed complete reaction. The mixture is diluted with 300 ml of CH ₂ Cl ₂ and washed with 30 ml of saturated sodium hydrogen carbonate. The aqueous layer is extracted with a large amount of CH ₂ Cl ₂ . The organic phases are combined, washed with brine (30 ml), dried over sodium sulphate and concentrated. The crude material is chromatographed on silica gel with 2/1 hexane-EtOAc as eluent (with 0.3% acetic acid) to give 0.363 g of Rf (2/1 hexane-EtOAc) 0.21.

¹ H-NMR (CDCl ₃ ) δ ppm 0.86-0.99 (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).

Preparation Example 4

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

Product of Preparation Example 2, step a) (2.86 g, 7.99 mmol), DCC (0.9 g, 4.36 mmol), 4- (N, N-dimethyl) aminopyridine (DMAP) (0.048 mg, 0.39 mmol) and N -CBz-L-valine (1 g, 3.98 mmol) is dissolved in CH ₂ Cl ₂ (60 ml) and DMF (6 ml). The reaction is left at ambient temperature for 18 hours and then filtered. The solvent is evaporated under reduced pressure. The residue is dissolved in CH ₂ Cl ₂ (100 ml) and filtered. The crude title compound is purified by chromatography [SiO 2, ether / hexanes (1: 2)] to afford 1.3 g of the desired product. Unreacted 1-stearoylglycerol can be recovered by eluting with CH ₂ Cl ₂ / MeOH (20: 1).

¹ H-NMR (CDCl ₃ ): δ 5.25 (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).

Preparation Example 5

A solution of stearoyl chloride (12.1 g, 40 mmol, 1.0 equiv) in CH ₂ Cl ₂ (100 ml) was converted to 2,2-bis (hydroxymethyl) propionic acid (26.8 g, 200 mmol, 5.0 equiv) in pyridine (400 ml). To the solution is added slowly (1 hour) at room temperature. The reaction mixture is stirred overnight at room temperature and then concentrated in vacuo (100 ml). The reaction mixture is slowly treated with saturated sodium hydrogen carbonate (400 ml) and then extracted with CH ₂ Cl ₂ (3 × 300 ml). The organic layers are combined, washed with brine, dried over sodium sulphate and concentrated in vacuo. Crude was chromatographed on silica gel (500 g) using 19/1 to 4/1 CH ₂ Cl ₂ -MeOH as eluent to monostearoyl with 0.33 Rf (9/1 CH ₂ Cl ₂ -MeOH) 12.5 g of ester are obtained (78%).

A solution of N-CBz-L-valine (18.85 g, 75 mmol, 2.4 equiv) and DMAP (855 mg, 7 mmol, 0.22 equiv) in CH ₂ Cl ₂ (800 mL) was cooled to 0 ° C. and DCC (14.4 g, 70 mmol, 2.2 equivalents). The reaction mixture is stirred at room temperature for 30 minutes and then treated slowly (1 hour) with a solution of the monostearoyl ester (12.5 g, 31.2 mmol, 1 equivalent) in CHCl ₃ (200 ml, ethanol free). After stirring overnight, the suspension is filtered and the filtrate is washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude material was chromatographed on silica gel (500 g) using 19/1 to 4/1 CH ₂ Cl ₂ -MeOH as eluent to give Rf (9/1 CH ₂ Cl ₂ -MeOH) 0.46 above. 13.8 g of ester are obtained (70%).

¹ H-NMR (250 MHz, CDCl ₃ ) δ 7.35-7.3 (m, 5H, ArH), 5.32 (d, 1H, CH), 5.10 (s, 2H, CH ₂ Ph), 4.33-4.18 (m, 4H , CH ₂ ), 2.28 (t, 2H, CH ₂ ), 2.22-2.05 (m, 1H, CH), 1.65-1.50 (m, 2H, CH ₂ ), 1.35-1.15 (m, 31H), 1.00-0.82 (m, 9H, Me).

Preparation Example 6

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 at 0 ° C. to a stirred solution of lithium aluminum hydride (9.6 g, 253 mmol). The reaction is allowed to warm to room temperature and left for 5 hours. It is cooled to 0 ° C. and water (12 ml) is added dropwise carefully. After stirring for 30 minutes, the mixture is filtered through celite and then washed with ethanol (2 x 500 ml). The solution is dried under vacuum to yield 9.5 g of product.

¹ H-NMR (CDCl ₃ ): 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

N-trityl-L-valine (5.5 g, 15.2 mmol), 2-allyl-1,3-propanediol (4.4 g, 38 mmole), N, N-dimethylamino pyridine (183 mg, 1.5) in dichloromethane (120 ml) Add DCC (3.5 g, 16.7 mmol) to the solution of mmole). The reaction is left under reflux overnight. After filtration through celite, the organic phase is washed with an aqueous sodium hydrogen carbonate solution and dried. Silica gel column chromatography yields 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

0 ° C. in a solution of 1-O- (N-trityl-L-valyl) -2-allyl-1,3-propanediol (1.83 g, 4 mmole) in dichloromethane (40 ml) and pyridine (3.2 ml, 40 mmol) Is added dropwise stearoyl chloride (3.62 g, 12 mmol) in dichloromethane. The solution is allowed to warm to room temperature and left to stand for 3 hours. Next, it is washed with an aqueous sodium hydrogen carbonate solution and dried. The product is isolated by silica gel column chromatography (1.9 g).

¹ H-NMR (CDCl ₃ ): 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), 2.23 (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) is dissolved in dioxane (5 ml). Osmium tetraoxide (20 mg, 0.08 mmol) and pyridine (0.05 ml, 0.64 mmol) are added to this solution. A solution of sodium periodate in water (3.5 ml) is added to the reaction mixture. The reaction is left overnight and then cooled to 0 ° C. An aqueous sodium hydrogen sulfite solution is added and the mixture is extracted with dichloromethane. The organic phase is dried and purified by silica gel column chromatography. Yield 250 mg.

¹ H-NMR (CDCl ₃ ): 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-valyloxamethyl) -4-stearoyloxyhexene-2-oate

(Benzyloxycarbonylmethyl) triphenylphosphonium bromide (10.7 g) in a solution of 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxy-butyraldehyde (15.8 g, 21.8 mmol) , 21.8 mmol) and triethylamine (2.21 g, 21.8 mmol) were added. The reaction is left overnight at room temperature and the mixture is evaporated. Diethyl ether (200 ml) was added to the residue, and the mixture was left to stand at 4 ° C for 2 hours. It is then filtered and the filtrate is evaporated and the product purified by silica gel column chromatography. Yield 10 g.

¹ H-NMR (CDCl ₃ ): 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 (m, 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, 3 H).

g) Preparation of 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxyhexanoic acid

Hydrogen carbonate in a solution of benzyl 3- (N-trityl-L-valyloxymethyl) -4-stearoyloxyhexene-2-oate (70 mg, 0.08 mmole) in methanol (3 ml) and ethyl acetate (1 ml) Sodium (10 mg) and palladium black (20 mg) are added. The reaction is left under hydrogen at atmospheric pressure for 2 hours. The mixture is filtered and evaporated. The residue is dissolved in dichloromethane and washed successively with aqueous EDTA solution and cold 2% citric acid solution. The organic phase is evaporated to yield 61 mg of product.

¹ H-NMR (CDCl ₃ ): 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).

Preparation Example 7

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

a) Preparation of 1-0- (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-benzyloxycarbonylvaline (5.02 g, 20 mmol) in dichloromethane, dimethylaminopyridine (244 mg, 2 mmole) and DCC (4.5 g, 22mmole). After 2 hours, the mixture is filtered through celite and evaporated to separate the product, 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-1,3-propanediol. Yield 5.01 g.

¹ H-NMR (CDCl ₃ ): 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 1-0- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1,3-propanediol

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) To the solution is added stearoyl chloride (7.8 g, 26 mmol) in an ice bath. The reaction mixture is allowed to warm to room temperature and left for 1 hour. Then, it was poured into an aqueous sodium hydrogen carbonate solution and the organic phase was dried and the product 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1 , 3-propanediol is purified by silica gel column chromatography (6.7 g).

¹ H-NMR (CDCl ₃ ): 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 mmoles) is dissolved in water (7.5 ml). The solution is left for 10 minutes with vigorous stirring. 1-O- (N-benzyloxycarbonyl-L-valyl) -2-allyl-3-O-stearoyl-1,3-propanediol (1 g, 1.6 mmol) and tetrabutyl in benzene (5 ml) A solution of ammonium bromide (77 mg, 0.24 mmole) is added. The slurry is stirred for 1.5 hours and dichloromethane is added. An aqueous sodium bisulfite solution is added to the slurry until the mixture decolorizes. The organic phase is acidified with acetic acid and washed with water. After evaporation, the product 3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxy-butyric acid (390 mg) was separated by silica gel column chromatography.

¹ H-NMR (CDCl ₃ ): 7.33 (m, 5H), 5.38 (d, 1 H), 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).

Preparation Example 8

3- [1- (N-CBz-L-valyl) -2-stearoyl] propyl chloroformate

1- (N-CBz-L-valyl) -2-stearoyl) glycerol (300 mg, 0.5 mmol) is dissolved in 20% phosgene in toluene (15 ml). After 18 hours, the solution is evaporated and the residue is co-evaporated several times with toluene to afford the title product in quantitative yield. This product is reacted using a standard method, for example, in a 10: 1 DMF / pyridine solution at 0 ° C. for 3 to 24 hours, poured into sodium hydrogen carbonate solution and extracted with dichloromethane to give the target nucleoside and carbamate Form. The amino acid is deprotected, for example with palladium black in methanol, ethyl acetate, acetic acid solution to nucleoside-O- [1- (L-valyl) -2-stearoyl-3-propyloxy carbonyl] To obtain.

¹ H-NMR (CDCl ₃ ): 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).

Preparation Example 9

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

a) benzyl 4,5-dihydroxy-2-pentenoate

A mixture of DL-glycerinaldehyde (4.5 g, 50 mmol) and (benzyloxycarbonylmethyl) -triphenyl-phosphonium bromide (24.57 g, 50 mmol) in 100 ml of 1,2-epoxybutane is refluxed overnight. The mixture is evaporated in vacuo and the product is separated by silica gel column chromatography. Yield: 8 g = 71%.

¹ H-NMR (CDCl ₃ ): 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, 1 H), 6.90 (m, 1 H), 7.30 (m, 5 H).

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

A 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) in 100 ml of dichloromethane Cool to about 10 ° C. A solution of DCC (4.2 g, 20 mmol) in 25 ml of dichloromethane is added dropwise at the same temperature and the mixture is stirred overnight at room temperature. The mixture is cooled to 5 ° C. and the urethane is filtered off. The filtrate is evaporated under reduced pressure and the product is separated by silica gel column chromatography. Yield: 6.6 g = 71%.

¹ H-NMR (CDCl ₃ ): 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, 1 H), 7.30 (m, 13 H).

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

In a solution of benzyl-5- (N-FMOC-L-valyloxy) -4-hydroxy-2-pentenoate (6.5 g, 12 mmoles) and pyridine (2.0 g, 25 mmoles) in 100 ml of dichloromethane in 25 ml of dichloromethane A solution of stearoyl chloride (4.55 g, 15 mmol) is added dropwise at 10 ° C. The mixture is stirred overnight. 100 ml of 5% sodium hydrogen carbonate solution is added and the mixture is stirred for 30 minutes. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in vacuo. The product is separated by silica gel column chromatography. Yield: 7.8 g = 80%.

¹ H-NMR (CDCl ₃ ): 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 diluted to 10% palladium (0.5 g) on charcoal. Hydrogenate at room temperature for 5 hours at atmospheric pressure. The catalyst is filtered off and washed with ethyl acetate and 1,4-dioxane. The solution is evaporated under reduced pressure. Yield: 3.3 g = 99%.

¹ H-NMR (CDCl ₃ ): 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).

Preparation Example 10

3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionic acid

a) benzyl 2,3-dihydroxypropionate

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 of DMF is stirred at 60 ° C. overnight. The mixture is evaporated under reduced pressure and the product is separated by silica gel column chromatography. Yield: 4 g = 100%.

¹ H-NMR (CDCl ₃ ): 3.26 (s, 1 H), 3.90 (m, 2 H), 4.32 (m, 1 H), 5.25 (s, 2 H), 7.28 (m, 5 H).

b) benzyl 3- (N-FMOC-L-valyloxy) -2-hydroxypropionate

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 Cool to ° C. A solution of DCC (4.12 g, 20 mmol) is added dropwise at the same temperature and the mixture is stirred overnight at room temperature. The mixture is cooled to 5 ° C. and the urethane is filtered off.

The solution is evaporated under reduced pressure and the product is separated by silica gel column chromatography. Yield: 4.7 g = 45%.

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

c) benzyl 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionate

Stea in 20 ml of dichloromethane in a stirred solution of benzyl 3- (N-FMOC-L-valyloxy) -2-hydroxypropionate (4.6 g, 8.89 mmole) and pyridine (1.41 g, 17.8 mmole) in 80 ml of dichloromethane A solution of loylchloride (3.64 g, 12 mmole) is added dropwise and the mixture is stirred at rt overnight. 100 ml of 5% sodium hydrogen carbonate solution is added and the mixture is stirred for 30 minutes. The organic phase is separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The product is separated by silica gel column chromatography. Yield: 6.1 g = 87%.

¹ H-NMR (CDCl ₃ ): 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, 2 H), 5.32 (m, 1 H), 7.50 (m, 13 H).

d) 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionic acid

A solution of benzyl 3- (N-FMOC-L-valyloxy) -2-stearoyloxypropionate (0.78 g, 1 mmole) in 20 ml of ethyl acetate was charged with 10% palladium (0.2 g) on charcoal at normal pressure for 3 hours. Hydrogenate at room temperature. The catalyst is filtered off and washed with ethyl acetate and 1,4-dioxane. The solution is evaporated under reduced pressure. Yield: 0.63 g = 90%.

¹ H-NMR (CDCl ₃ ): 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, 1 H), 7.40 (m, 8 H).

Preparation Example 11

1- (N-benzyloxycarbonyl-L-valyloxymethyl) -2-stearoyloxyethoxycarbonyl chloride

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

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 172.8 (Stear-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 CH ₂ ); 63.1 (ValCOOCH ₂ ); 61.8 (stear-COOCH ₂ ); 58.7 (Val-αC); 33.7 (stear-C2); 31.6 (stear-C16); 31.0 (Val-βC); 29.3-28.8 (stear-C4-15); 24.5 (stear-C3); 18.6 and 17.1 (Val 2 CH ₃ ); 13.8 (stear-C18).

Preparation Example 12

3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutylchloroformate

a) 3- (N-CBz-L-valyoxymethyl) -4-stearoyloxy-butanol

4-stearoyloxy-3- (N-CBz-L-valyloxymethylbutyraldehyde (prepared in analogy to Preparation Example 6, step d) using CBz protected valine at 10 ° C.) in 25 ml of methanol A small amount of sodium borohydride (0.6 g, 16 mmol) is added to a stirred solution of (2.0 g, 3.2 mmol) The mixture is stirred for 30 minutes and then acidified with acetic acid The mixture is diluted with water and 3 with dichloromethane Extraction times The organic phase is dried over sodium sulfate and concentrated in vacuo The product is separated by silica gel column chromatography Yield: 1.5 g = 75%.

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

b) 3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutyl chloroformate

The intermediate solution of step a) in 20 ml of a 20% phosgene solution in toluene is stirred overnight. The mixture is evaporated under reduced pressure to afford the title compound. Yield: 1.5 g = 97%.

¹ H-NMR (CDCl ₃ ): 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 9

5'-O- (5-valyloxymethyl-6-stearoyloxy) hexanoyl ribavirin

5'-O- (5-N-trityl-valyloxymethyl-6-stearoyloxy) hexanoic acid (0.97 g, 1.26 mmol) in DMF (10 ml), DCC (0.303 g, 1.47 mmol), ribavirin ( A mixture of 0.256 g, 1.05 mmol) and DMAP (14 mg, 0.11 mmol) is stirred at room temperature for 24 hours. After evaporation, the purification by chromatography on silica gel eluting the residue with CH ₂ Cl _2, CH ₂ Cl ₂ 2.5% MeOH and 5% MeOH in CH ₂ Cl ₂ in. Deprotection of the product at room temperature in acetic acid (10ml), evaporated, CH ₂ Cl _2, CH ₂ Cl ₂ and purified by chromatography on silica gel by eluting with 5% MeOH and 20% MeOH in CH ₂ Cl ₂ in the title 72 mg of product is obtained as an acetate salt.

¹ H-NMR (250 MHz, MeOD-d ₄ ) δ 8.70 (s, 1H), 5.84 (d, 1H), 4.19-4.02 (m, 6H), 3.78-3.55 (m, 2H), 3.40 (br s, 1H), 2.37 (t, 2H), 2.25 (t, 2H), 2.00 (m, 2H), 1.87-1.32 (m, 6H), 1.20 (s, 28H), 0.96-0.73 (m, 9H).

Example 10

4'O- [2-stearoyloxy-1- (L-valyloxymethyl) ethoxycarbonyl] gancyclovir

a) 4'O- [1- (N-benzyloxycarbonyl-L-valyloxymethyl) -2-stearoyloxyethoxycarbonyl] gancyclovir

1- (N-benzyloxycarbonyl-L-valyloxymethyl) -2-stearoyloxyethoxycarbonyl chloride (654 mg, 1.0 mmol) in N, N-dimethylformamide (10 ml), gancyclovir ( A mixture of 220 mg, 0.86 mmol), triethylamine (200 mg, 2.0 mmol) and 4-dimethylaminopyridine (30 mg, 0.25 mmol) is stirred at room temperature for 24 hours. Undissolved salts are filtered off and the solution is evaporated in small amounts in vacuo. The residue is purified by chromatography on silica gel (8 g). Elution of the column with ethyl acetate + methanol + water (15 + 2 + 1) with slight warming to prevent crystallization and evaporation in vacuo followed by 9- {1- [1- (N-benzyloxycarbonyl- 149 mg (20%) of L-valyloxymethyl) -2-stearoyloxyethoxycarbonyloxymethyl] -2-hydroxyethoxymethyl} guanine are obtained.

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 173.0 (Stear-COO); 171.5 (Val-COO); 158.6 (C6); 156.1 (CONH); 154.5 (OCOO); 154.1 (C2); 151.1 (C4); 137.9 (C8); 136.3 (Ph-Cl-Val); 128.4-127.8 (Ph); 116.5 (C5); 78.7 (CHOCH ₂ ); 73.2 (CHOCO); 72.4 (OCH ₂ N); 67.3 (ValCOOCH ₂ ); 67.0 (PhCH ₂ ); 66.0 (stear-COOCH ₂ ); 62.5 (OCOOCH ₂ ); 61.5 (CH ₂ OH); 58.7 (Val-αC); 33.7 (stear-C2); 31.6 (stear-C16); 31.0 (Val-βC); 29.3-28.8 (stear-C4-15); 24.5 (stear-C3); 22.5 (stear-C17); 18.6 and 17.1 (Val 2 CH ₃ ); 13.8 (stear-C18).

b) 4'O- [2-stearoyloxy-1- (L-valyloxymethyl) ethoxycarbonyl] gancyclovir

The product of step a) (149 mg, 0.17 mmol) in 5 ml of EtOH and 0.5 ml of acetic acid was hydrogenated overnight at room temperature and atmospheric pressure using 10 mg Pd / C 100 mg, filtered through celite and evaporated in vacuo and then as a solid. 110.5 mg (81%) of the title product 9- {1- [2-stearoyloxy-1- (L-valyloxymethyl) ethoxycarbonyloxymethyl] -2-hydroxyethoxymethyl} guanine with acetate To obtain.

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 173.0 (Stear-COO); 171.5 (Val-COO); 158.6 (C6); 154.5 (OCOO); 154.1 (C2); 151.1 (C4); 137.9 (C8); 115.5 (C5); 78.5 (CHOCH ₂ ); 73.4 (CHOCO); 72.5 (OCH ₂ N); 67.5 (ValCOOCH ₂ ); 66.1 (stear-COOCH ₂ ); 62.2 (OCOOCH ₂ ); 61.6 (CH ₂ OH); 59.0 (Val-αC); 33.7 (stear-C2); 31.7 (stear-C16); 30.7 (Val-βC); 29.3-28.8 (stear-C4-15); 24.6 (stear-C3); 22.5 (stear-C17); 19.0-17.2 (Val 2 CH ₃ ); 13.9 (stear-C18).

Example 11

9- {1- [4-stearoyloxy-3- (L-valyloxymethyl) butyryloxymethyl] -2-hydroxyethoxymethyl} guanine

a) 9- {1- [3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxybutyryloxymethyl] -2-hydroxyethoxymethyl} guanine

3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxybutyric acid; Preparation Example 7 (634 mg, 1.00 mmol) was dissolved in dichloromethane (5 ml), thionyl chloride (400 mg, 3.36 mmol) and 4 drops of N, N-dimethylformamide were added, and the mixture was left at room temperature for 2 hours. Then carefully evaporate in small amounts in vacuo to afford crude acid chloride. Gancyclovir sodium salt (280 mg, 1.00 mmol) is suspended in N, N-dimethylformamide (5 ml), triethylamine (100 mg, 1.0 mmol), 4-dimethylamino in a small amount of N, N-dimethylformamide. Pyridine (20 mg, 0.16 mmole) and crude acid chloride are added. The mixture is stirred effectively at room temperature for 2 days. After filtration through a small amount of silica gel, the filtrate is evaporated in small amounts in vacuo. Chromatography on silica gel using ethyl acetate + methanol + water (15 + 2 + 1) as eluent, followed by chromatography on alumina to 4'O- [3- (N-benzyloxycarbonyl-L-valyl 168 mg (19%) of oxymethyl) -4-stearoyloxybutyryl] gancyclovir are obtained.

¹ H NMR (CDCl ₃ ): δ 12.0 (br s, 1H, 1-NH); 7.8 (s, 1 H, 8-H); 7.3 (br, 5H, Ph); 6.7 (br s, 2H, 2-NH ₂ ); 5.6 (d, 1 H, OCONH); 5.5 (s, 2H, OCH ₂ N); 5.1 (br, 2H, PhCH ₂ ); 4.3 (d, 1 H, Val-α C); 4.2-4.0 (m, 7H, 3 × COOCH ₂ , CHO); 3.7 (m, 2H, CH ₂ OH); 2.5 (m, 1H, CHCH ₂ COO); 2.4 (d, 2H, CHCH ₂ COO); 2.3 (t, 2H, stear-2-CH ₂ ); 2.15 (m, 1 H, ValβC); 1.55 (pentine, 2H, stear-3-CH ₂ ); 1.3-1.2 (m, 28H, stear-CH ₂ ); 1.0-0.8 (dd, 6H, Val CH ₃ ); 0.85 (t, 3H, stear-18-CH ₃ ).

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 173.6 (stear-COO); 172.0 (CHCH ₂ COO); 171.4 (Val-COO); 158.4 (C6); 156.3 (CONH); 154.0 (C2); 151.6 (C4); 138.9 (C8); 136.0 (Ph-C1); 128.4-127.9 (Ph); 116.8 (C5); 77.6 (CHOCH ₂ ); 72.5 (OCH ₂ N); 67.0 (PhCH ₂ ); 64.1 (ValCOOCH ₂ ); 63.0 (stear-COOCH ₃ ); 62.0 (COOCH ₂ CH); 61.6 (CH ₂ OH); 59.0 (Val-αC); 34.1 (CHCH ₂ COO); 33.9 (stear-C2); 32.7 (CHCH ₂ COO); 31.8 (stear-C16); 30.9 (Val-βC); 29.6-28.9 (stear-C4-15); 24.7 (stear-C3); 22.5 (stear-C17); 18.9 and 17.4 (Val 2 CH ₃ ); 14.0 (stear-C18).

b) 9- {1- [4-stearoyloxy-3- (L-valyloxymethyl) butyryloxymethyl] -2-hydroxyethoxymethyl} guanine

The title compound is the same as Example 10, b) above from 4'O- [3- (N-benzyloxycarbonyl-L-valyloxymethyl) -4-stearoyloxybutyryl] gancyclovir (100 mg) Synthesis using the method yields 80 mg (87%) of 4'O- [4-stearoyloxy-3- (L-valyloxymethyl) butyryl] gancyclovir as an acetate salt, white crystalline product.

¹³ C NMR (CDCl ₃ , 62.975 MHz): δ 173.5 (Stear-COO); 171.7 (CHCH ₂ COO); 171.2 (Val-COO); 158.4 (C6); 156.3 (CONH); 154.0 (C2); 151.5 (C4); 138.2 (C8); 115.5 (C5); 79.0 (OCH ₂ N); 64.4 (ValCOOCH ₂ ); 63.2 (stear-COOCH ₂ ); 61.7 (COOCH ₂ CH and CH ₂ OH); 58.7 (Val-αC); 34.2 (CHCH ₂ COO); 34.0 (stear-C2); 32.6 (CHCH ₂ COO); 31.8 (stear-C16); 30.9 (Val-βC); 29.6-28.9 (stear-C4-15); 24.7 (stear-C3); 22.6 (stear-C17); 18.9 and 17.5 (Val 2 CH ₃ ); 14.0 (stear-C18).

Example 12

9- {5-O- [3- (L-Valyloxymethyl) -4-stearoyloxybutanoyl] arabinofuranosyl} guanine

a) 9- {5-O- [3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutanoyl] arabinofuranosyl} guanine

Dimethylamino in a solution of 9-arabinofuranosyl guanine (110 mg, 0.42 mmol) and 3- (N-CBz-L-valyloxymethyl) -4-stearoylbutyric acid (355 mg, 0.55 mmol) in DMF (15 ml) Pyridine (7 mg), 1-hydroxybenzotriazole (73 mg, 0.55 mmole) and DCC (135 mg, 0.65 mmole) are added. After 2 days, the reaction mixture is filtered, the filtrate is poured into sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is dried and the product 9- {5-O- [3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutanoyl] arabinofuranosyl} guanine is used with a silica gel column Isolated (41 mg).

¹ H-NMR (DMSO-δ6): 7.70 (s, 1H), 7.42 (m, 5H), 6.48 (s, 2H), 5.40 (d, 1H), 4.30-3.0 (m, 9H), 2.45 (m , 3H), 2.37 (t, 2H), 2.05 (m, 1H), 1.47 (m, 2H), 1.22 (m, 28H), 0.85 (m, 9H).

9- {5-O- [3- (N-CBz-L-valyloxymethyl) -4-stearoyloxybutanoyl in a mixed solvent of methanol (3 ml), ethyl acetate (1 ml) and acetic acid (0.5 ml) Add palladium black (30 mg) to a solution of arabinofranosyl} guanine. After reacting for 18 hours under a hydrogen atmosphere, the reaction mixture is filtered and the filtrate is dried. The title product is separated by silica gel column (18 mg).

¹ H-NMR (DMSO-d6): 7.57 (s, 1H), 6.59 (s, 2H), 6.05 (d, 1H), 4.40-3.90 (m, 9H), 2.45 (m, 3H), 2.26 (t , 2H), 1.70 (m, 1H), 1.47 (m, 2H), 1.22 (m, 28H), 0.82 (m, 9H).

Formulation Example 1

Tablet formulation

The following ingredients are filtered through 0.15 mm sieve and dry mixed:

10 g of 9- (4-stearoyloxy-3- (L-valyloxymethyl) butyl) guanine

Lactose 40g

Crystalline Cellulose 49g

1 g magnesium stearate

Using a tablet press, the mixture is compressed into tablets containing 250 mg of the active ingredient.

Formulation Example 2

Enteric coating tablets

The tablets of Formulation Example 1 are sprayed in a tablet depilator with a solution comprising 120 g of ethyl cellulose, 30 g of propylene glycol, 10 g of sorbitan monooleate and distilled water in an amount of 1000 ml.

Formulation Example 3

Sustained Release Formulations

Dry mix 50 g of 9- (4-stearoyloxy-3- (L-isosiloxyoxy) butyl) guanine, 12 g of hydroxypropylmethylcellulose (Methocell K15) and 4.5 g of lactose, and granulate with an aqueous paste of povidone Make up. Magnesium stearate (0.5 g) is added and the mixture is compressed into tablets of 13 mm diameter containing 500 mg of active agent in a tablet press.

Formulation Example 4

Soft capsules

250 g of 9-((1-stearoyloxy-3- (L-isosiloxy) -2-propoxy) methyl) guanine

100 g of lecithin

Arakis Oil 100g

The compounds of the present invention are dispersed in lecithin and arachis oil and filled into soft gelatin capsules.

Biological Example 1

Bioavailability Test

The bioavailability of representative compounds of the present invention is compared with each parent compound in a rat model. The compound of the present invention and the comparative compound are administered orally several times to three animals of different weights to obtain 0.1 mmoles / kg of prodrug dissolved in a propylene glycol vehicle. Comparative Example 1 (Pencyclovir) and Comparative Example 2 (Gancyclovir) are from the same batch used for the preparation of the Examples. The animals are fasted from 5 hours before the administration to 17 hours after the administration and placed in metabolic cages. Urine is collected for 24 hours after dosing and frozen until analysis. Parent compounds are analyzed using HPLC / UV analysis in urine, as follows. Stahle & Oberg, Antimicrob Agents Chemother. 36 No 2, 339-342 (1992)]: The sample is diluted 1: 100 with distilled water upon thawing and filtered at 3000 rpm for 10 minutes while centrifuged with an Amicon filter. Two 30 μl samples are chromatographed on an HPLC column; Zorbax SB-C18; 75 x 4.6 mm; 3.5μ; Mobile phase 0.05M NH ₄ PO ₄ , 3-4% methanol, pH 3.3-3.5; 0.5 ml / min; Retention time for PCV / GCV at 254 nm, MeOH 4% and pH 3.33 about 12.5 minutes. Bioavailability is calculated as the parent compound recovery measured from each animal averaged over three or more animals, and as described above by intravenous injection of 0.1 mmole / kg of parent compound in each body weight and in a Ringer buffer vehicle, respectively, as described above. It is shown as the average compound recovery of 24 hours urine from the group of four rats analyzed. The results are shown in Table 1.

compound R ₁ R ₂ Bioavailability Comparative Example 1 Hydrogen Hydrogen 1.5% Example 4 Ballyl Stearoyl 22.7% Example 6 Isoryu room Ballyl 26.3% Comparative Example 2 Hydrogen Hydrogen 10.6% Comparative Example 3 Ballyl Ballyl 29.6% Example 1 Ballyl Stearoyl 47.8%

Comparison of the bioavailability of the compounds of the present invention with the compounds of the comparative examples shows that the bioavailability is significantly greater than that of each parent compound and significantly greater than the prior art divalyl prodrugs in this assay system by the specific combination of fatty acids and amino acids. Indicates.

While many embodiments of the invention have been illustrated using stearoyl and valel as the respective fatty acid and amino acid esters, the same properties of the fatty acids and aliphatic amino acids specified in the claims are expected to result from the corresponding modifications of the corresponding methods and implementations respectively. It is understood that it can. Likewise, it is clear that the present invention is applicable to many nucleoside homologs as this synthesis is understood both in the pharmacy field as cyclic and acyclic.

Claims (11)

One or more hydroxy functional groups on a sugar or acyclic moiety, one of which is esterified with an aliphatic amino acid, the other monounsaturated or saturated, optionally substituted fatty acids having 6 to 22 carbon atoms A nucleoside homologue esterified with only 9- [4-hydroxy- (2-hydroxymethyl) butyl] guanine or a 6-deoxy derivative thereof; A nucleoside homolog wherein aliphatic amino acids and fatty acid esters are esterified with a conventional linker group wherein the linker group is bonded to one of the hydroxy functional groups. The nucleoside homolog of claim 1 according to claim 1. Formula I In the above formula, B is a natural or unnatural nucleotide base, X is O or CH ₂ , Y and Z are each H, or together form a bond, or Y is methylene or -CH (OH)-, Z is a bond to it, n is 0 or 1, One of R ₁ and R ₂ is an acyl residue of an aliphatic amino acid, the other is an acyl residue of a fatty acid, or One of R ₁ and R ₂ is hydrogen or an acyl moiety of the aliphatic amino acids or fatty acids described above, and the other is a structure of formula II. Formula II In the above formula, One of R ₃ and R ₄ is an acyl residue of an aliphatic amino acid, the other is an acyl residue of a fatty acid, R ₅ is H or C ₁ -C ₃ alkyl, T is a bond, -O- or -NH-, m and m 'are independently 0, 1 or 2, n is 0 to 5; The compound of claim 1, wherein the aliphatic amino acid ester is L-valyl or L-isoleucine. The compound of claim 1, wherein the fatty acid ester has 12 to 22 carbon atoms, including carbonyl. The compound of claim 4, wherein the fatty acid is stearoyl, eicosanoyl or behenoyl, or n9-octadecenoyl, n9-eicosenoyl or n11-docosenoyl. The compound of claim 2, wherein B is guanine or guanine modified at the 6 position. The compound of claim 2, wherein B is cytosine, substituted benzimidazol-3-yl or 1,2,4-triazole-3-carboxamide. The compound of claim 2, wherein X is O or CH ₂ and Y and Z are H. 4. 3. Compounds according to claim 2, wherein formula I is arabinose, ribose, 2-deoxyribose or 2 ', 3'-hydroxymethylcyclobutyl moiety. 3. A compound according to claim 2 wherein T is -O- or a bond, m 'is 1 and n is 0 to 2. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 together with a pharmaceutically acceptable carrier or diluent.