GB1561380A

GB1561380A - Esters of hydroxyalkoxyalkyl purines their preparation and pharmaceutical compositions containing them

Info

Publication number: GB1561380A
Application number: GB7988/76A
Authority: GB
Original assignee: Wellcome Foundation Ltd
Current assignee: Wellcome Foundation Ltd
Priority date: 1976-03-01
Filing date: 1976-03-01
Publication date: 1980-02-20
Also published as: NO770698L; RO71410A; ZM2577A1; NO145339C; NO145339B; SU980623A3; DK147596B; DK88876A; DK147596C

Description

(54) ESTERS OF HYDROXYALKOXYALKYL PURINES, THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (71) We, THE WELLCOME FOUND ATION LIMITED, of 183-193 Euston Road, London N.W.l a company incorporated in England, do hereby declare the invention which was communicated from Burroughs Wellcome Co., of 3030 Cornwallis Road, Research Triangle Park, North Carolina 27709, being incorporated in the state of North Carolina, United States of America, for which we pray that a Patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to substituted purine compounds and their pharmaceutically acceptable salts, and to methods of preparing them. In particular this invention relates to the esters of the 9 (2-hydroxyethoxymethyl)derivatives of guanine and 2.6-diaminopurine, and the pharmaceutically acceptable salts of these compounds.

It has now been discovered that substituted purines of formula (I)

wherein Rl is a hydroxy or amino group, R2 is hydrogen, straight or branched chain alkyl group having from 2 to 16 carbon atoms, an unsubstituted aryl group having 10 carbon atoms, or a substituted aryl group having 6 to 18, preferably less than 10, carbon atoms, have antiviral activity against various families of DNA and RNA viruses in vitro and against DNA viruses in vivo. In particular, the compounds are especially active against herpes, vaccinia, and rhino viruses, the herpes viruses include simplex, zoster and varicella in mammals, which cause such diseases as for example herpetic keratitis in rabbits and herpetic encephalitis in mice.

According to the present invention there is provided a compound of formula (I) wherein R' and R2 are defined above, or a salt thereof especially in the form of a pharmaceutically acceptable salt.

The compounds of formula (I) wherein R' is hydroxy, or a salt thereof, are preferred, as are compounds wherein R2 is hydrogen or a straight or branched chain alkyl group having from 2 to 8 carbon atoms, the most preferred have from 2 to 4 carbon atoms.

when R2 is a substituted aryl group having 6 to 18 carbon atoms, preferably less than 1), the preferred substituents on the aryl group are halogen atom, amino, nitrile, suphamido group, or alkanoyl or alkyl group having from 1 to 4 carbon atoms.

The most preferred compounds are 9-(2formyloxyethoxymethyl) guanine, 9 (2)propionoyloxyethoxymethyl)guanine, 9 [2-(2,2-dimethylpropionoyloxy)ethoxymethyllguanine and 2-amino-9-(2-formloxy ethoxymethyl)adenine, particularly because of their extremely high antiviral activity against Herpes.

Salts which are especially convenient for therapeutic use are salts of pharmaceutically acceptable organic acids such as lactic, acetic, malic or ptoluenesulphonic acid as well as salts of pharmaceutically acceptable mineral acids such as hydrochloric or sulphuric acid.

When R' is hydroxy the salts of pharmaceutically acceptable alkali metal salts may be used, most preferably the sodium salt. Other salts may also be prepared and then converted into salts directly suitable for the purposes of treatment.

In a second aspect of the present invention there is provided a method of preparing a substituted purine of formula (I), as hereinbefore defined, characterised in that: a) a compound of formula (II)

is reacted with a compound of formula (III)

wherein A is a leaving atom or group and Q is a hydrogen atom or an alkali metal, or b) a compound of formula (IV)

wherein R2 is defined above, and either or both M and G represent an azido group, is converted into a compound of formula (I) by methods known per se: or c) an alcohol of formula (V):

is esterified by reaction with an acylating agent, or d) a blocking group is linked to R' and/or the 2-amino group, the blocking group or groups being removed by solvolysis or alcoholvsis: and optionally converting the compound of formula (I) formed by any of the methods a) to d) to another compound of formula (I) by transesterification; and where the product of any one of the above-mentioned reactions is a base, optionally converting the product into an acid addition salt or an alkali metal salt thereof, or where the product is a salt of a compound of formula (i), optionally converting said salt into its base or another salt thereof In method a) the leaving atom or group A is preferably a reactive residue of an organic or inorganic acid, and may therefore be a halogen atom, or sulphonate group, and Q is hydrogen or an alkali metal preferably sodium. The preferred method comprises the condensation of a purine having the desired 2- and 6- substitution with an acyl blocked 2halomethoxyethanol, or acyl blocked acyloxymethoxyethanol, for instance 2propionyloxyethoxymethyl chloride or butyryloxyethoxymethyl acetate, in a strong polar solvent such as dimethylformamlde (DMF), and in the presence of a base, e.g.

sodium hydride. The reaction is preferably carried out at room temperature over an extended period of time, i.e. several hours or even days may be required to give reasonable yields.

Conversion of a compound of formula (IV), by method b), can be achieved in several ways, for example the azide groups can be converted to amino groups by reduction using a suitable catalyst such as palladium.

These methods, together with other well known processes can be found in "Heterocyclic compounds-Fused Pyrimidines Part II Purines ed. by D. J.

Brown (1971) published by Wiley Interscience Those compounds that contain the precursor substituents G and M and can be converted into compounds of formula (I), can be considered as intermediates in the synthesis of those compounds, and can be analogously prepared according to method (a).

In method c) an alcohol of formula (V) is reacted with a suitable carboxylic acylating agent such as a carboxylic acid, an aliphatic or aromatic carboxylic anhydride, an aliphatic or aromatic carboxylic halide, a mixed carbonic-carboxylic anhydride, or carboxylic acid ester. Compounds of formula (V) can be prepared according to the processes described in German Offenlegungsschrift No. 2 539 963.

In method d) one or both of the amino group in the 2-position and the substitution at the 6-position may be reversibly blocked by a blocking group for example a trialkylsilyl group, an activated acyl group, or a benzyloxycarbonyl group, however these latter two types of groups will only block R1 when it is amino. When both the amino groups in the 2-position and the substitution in the 6-position are blocked by a trialkylsilyl group such a compound will be the product of the condensation of a trialkylsilylated purine and an ester or diester similar to method a). Such blocking groups are very labile and can be removed by solvolysis with alcoholic or aqueous ammonia, or by alcoholysis.

One or both of the 2- and 6-positions on the purine ring may be blocked by an activated acyl group such as a trihaloalkanoyl group, e.g. trichloroacetyl, which together with the amino group it is blocking forms a trichloroacetamido gro'up. The 6-position on the purine ring is blocked only when it is substituted by an amino group. Such groups can be reductively cleaved: if a benzyloxycarbonyl group is the blocking group this too can be removed by reductive cleavage.

Methods a) to d) all rely on intermediates which can be prepared from simply substituted purines. Such purines are of course readily available according to techniques well known per se which are disclosed in the literature, and text books such as "Heterocyclic compounds-Fused Pyrimidines Part II Purines ed. by D. J.

Brown (1971) published by Wiley lnterscience A compound of formula (I) made by any of methods a) to d) may be optionally converted to another compound of formula (I) by transesterification. Such interconversion can be achieved by reacting a compound of formula (I) with a suitable carboxylic acid, for example to prepare 9 (2- propionyloxyethoxymethyl)guanine, reaction with propionic acid is required. In certain cases the acid may also act as an acid catalyst, but in others an additional acid catalyst is required, e.g. paratoluene sulphonic acid.

In another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor. In a particular aspect the pharmaceutical composition comprises a compound of formula (I) in effective unit dose form.

As used herein the term "effective unit dose" is denoted to mean a predetermined antiviral amount sufficient to be effective against the viral organisms in vivo.

Pharmaceutically acceptable carriers are materials useful for the purpose of administering the medicament, and may be solid, liquid or gaseous materials, which are otherwise inert and medically acceptable and are compatible with the active ingredients.

In a further aspect of the invention there is provided a method of preparing a pharmaceutical composition comprising bringing into association a substituted purine of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

These pharmaceutical compositions may be given parenterally, orally, used as a suppository or pessary, applied topically as an ointment, cream, aerosol, powder, or given as eye or nose drops etc., depending on whether the preparation is used to treat internal or external viral infections.

For internal infections the compositions are administered orally or parenterally at dose levels calculated as the free base, of about 0.1 to 250 mg per kg, preferably 1 to 50 mg/kg, of mammal body weight, and are used in man in a unit dosage form.

administered a few times daily in the amount of 1 to 250 mg per unit dose.

For oral administration, fine powders or granules may contain diluting, dispersing and/or surface active agents, and may be presented in a draught, in water or in a syrup; in capsules or sachets in the dry state or in a non-aqueous solution or suspension, wherein suspending agents may be included; in tablets, wherein binders and lubricants may be included; or in a suspension in water or a syrup. Where desirable or necessary, flavouring, preserving, suspending, thickening or emulsifying agents may be included. Tablets and granules are preferred, and these may be coated.

For parenteral administration or for administration as drops, as for eye infections, the compounds may be presented in aqueous solution in a concentration of from about 0.1 to 10 /O more preferably 0.1 to 1 ,O, most preferably 0.20/n w/v. The solution may contain antioxidants, buffers, etc.

Alternatively for infections of the eye, or other external tissues, e.g. mouth and skin, the compositions are preferably applied to the infected part of the body of the patient as a topical ointment or cream. The compounds may be presented in an ointment, for instance with a water soluble ointment base, or in a cream, for instance with an oil in water cream base, in a concentration of from about 0.1 to 10 ,O preferably 0.3 to 3%, most preferably 1 , w/v.

In yet a further aspect of the invention there is provided a method of treating viral infections in mammals which comprises the administration of an effective unit dose, as hereinbefore defined, of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Administration is preferably by topical application or by the oral or parenteral route.

The invention will now be illustrated with reference to the following Examples.

Example I A solution of 9-(2-hydroxyethoxymethyl)guanine (4.73 g) prepared according to the processes described in German Offenlegungsschrift No. 2 539 963 in 97 formic acid (24 ml) was stirred at room temperature overnight. The amber solution was diluted with about 200 ml of dried ether and chilled.

The resulting white precipitate was filtered, dried and recrystallized from dry dimethylformamide to give 9-(2-formyloxyethoxymethyl)guanine (3.6 g, m.p. 225--275"C).

Example 2 A solution of 2-amino-9 (2-hydroxyethoxymethyl)adenine (0.5 g) prepared according to the processes described in German Offenlegungsschrift No. 2 539 963 in 97 /O formic acid (2.5 ml) was stirred in an ice bath for 3 hours, and then at room temperature overnight. Dry ether (80 ml) was added and the mixture chilled. The solid was removed by filtration and dissolved in hot acetonitrile (125 ml); residual solids were removed by filtration.

The filtrate was applied to a column containing silica gel (14 g) in acetonitrile.

The column was eluted with dry acetone.

The eluant was evaporated and the residual solid recrystallized from acetonitrile to give 2-amino-9-(2-formyloxyethoxymethyl)- 2 - amino - 9 - (2 - formyloxyethoxymethyl) adenine (93 mg, m.p. 238-2400C).

Example 3 Preparation of 9-(2-Hexanoyloxyethoxy methyl)guanine 9-(2-Hydroxyethoxymethyl)guanine (1.0 g) prepared according to the processes described in German Offenlegungsschrift No. 2 539 963 was dissolved in dry dimethylformamide (70 ml) by heating on a steam bath, the solution was cooled to room temperature and dry pyridine (10 ml) and hexanoic anhydride (9.4 g) added. After stirring at room temperature for four days, TLC (silica gel in 10% methanol chloroform) showed that the reaction was completed.

The yellow reaction solution was diluted with ethyl acetate to a volume of 800 ml and chilled for several days. The fine white powder which precipitated was filtered off, dried and recrystallized from dry acetonitrile to give 400 mg (28%) of white granules, m.p. 221-2230C.

Example 4 Preparation of 9-(2-Propionyloxyethoxy methyl)guanine (A) Ethylene glycol (31 g), propionic acid (18.5 g) and 7.5 g of strong hydrogen ion resin, Bio, Rod AG 50 WX-4 in 100 ml of toluene are refluxed with stirring under a Dean Stark trap for eighteen hours.

The toluene is removed by flash evaporation and the residual liquid distilled.

The initial forerun of ethylene glycol is followed by distillation of the desired product, ethylene glycol mono-propionate.

NMR assay is used to determine the purity.

Yield--70o.

(B) Dry hydrogen chloride gas is passed into the chilled (0 C) suspension of ethylene glycol monopropionate (7.1 g) prepared above and paraformaldehyde (1.8 g) in dichloromethane (50 ml) until the solid is dissolved and the mixture saturated with hydrogen chloride. After drying over molecular sieves and calcium chloride, the mixture is filtered and the solvent is removed by flash evaporation at 300 C.

The residual oil of 2propionyloxyethoxymethyl chloride is used directly. Yield-60%.

(C) Sodium hydride (2.53 g) of a 57 mineral oil dispersion is washed with dry hexane and added to a solution of guanine (4.53 g) in 100 ml of dry dimethyl sulfoxide and the mixture stirred at 300C for 23 hours.

2-Propionyloxyethoxymethyl chloride (5.5 g) is added and the reaction mixure is stirred ar 20"C for 18 hours. The solution is filtered and the solvent is removed by flash evaporation in vacuo. The residue is cooled in an ice bath, dissolved in water and neutralized with acetic acid.

After one hour standing, the product is filtered off, washed with water and dried.

Recrystallization (3 times) from boiling acetonitrile gives 9-(2-propionyloxyethoxy methyl)guanine. Yield-35%, m.p.

223--226"C.

Example 5 Preparation of 9-(2-Tridecanoyloxyethoxy methyl)guanine 9-(2-Hydroxyethoxymethyl)guanine (300 mg) prepared according to the processes described in German Offenlegungsschrift No. 2 539 963 was heated in dry dimethyl formamide (20 ml) and dry pyridine (30 ml) on a steam bath until dissolved. The solution was cooled to room temperature and tridecanoyl chloride (0.93 g) was added. The solution was stirred at ambient temperature until thin layer chromatography showed the reaction was completed by disappearance of the starting material. (18 hours).

The solution was flash evaporated and a residual yellow oil crystallised from acetonitrile to give a creamy yellow solid (375 mg). N.m.r. analysis of the crude product indicated presence of several compounds. The cleared mixture was purified by column chromatography.

Example 6 Preparation of 9-(2-Dodecanoyloxyethoxy methyl)-2,6-diaminopurine I. Dry hydrogen chloride gas is passed into a chilled (0 C) suspension of ethylene glycol monododecanate (14.66 g) and paraformaldehyde (1.8 g) in dichloromethane (50 ml) until the solids dissolve and the mixture is saturated with hydrogen chloride.

After drying the solution over molecular sieves and calcium chloride, the mixture is filtered and the solvents are removed by flash evaporation at 300 C.

The residual oil of 2dodecanoyloxyethoxymethyl chloride is used directly. Yield-75%.

II. An anhydrous solution of 2.6- diaminopurine in dimethylformamide is prepared by heating 3.54 g of the monhydrate in 250 ml of the solvent on a steam bath until dissolved, cooling and allowing to stand over fresh molecular sieves for 18 hours.

To this mixture is added 0.95 g of a 57 mineral oil dispersion of sodium hydride.

After stirring the slurry overnight 2dodecanoyloxyethoxymethyl chloride (6.35 g) is added dropwise and the reaction mixture is stirred at ambient temperature overnight.

The solids are filtered off, washed with chloroform and the combined washings and mother liquor flash were evaporated at 60"C.

The residual oil is recrystallized from ethanol. Yield--200i.

Example 7 9-(2-Propionyloxyethoxy methyl)guanine A mixture of 9-(2-hydroxyethoxymethyl)guanine (1.0 g) and dry dimethylformamide (50 ml) was heated on a steam bath until most of the solid had dissolved. It was then cooled to room temperature. Dry pyridine (10 ml) and propionic anhydride (2.9 ml) was added and the mixture stirred at room temperature overnight. Additional propionic anhydride (1.0 ml) was added and the mixture stirred for an additional 18 hours. The reaction mixture was diluted with ethyl acetate, chilled and the resulting solid removed by filtration. This was recrystallized from dimethylformamide to give 9-(2-propionyloxyethoxymethyl)guanine (0.9 g), m.p. 223--226"C.

Example 8 9-[2-(2-Dimethylpropiony loxy)ethoxymethyliguanine A mixture of 9-(2hydroxyethoxymethyl)guanine (2.46 g), dry pyridine (400 ml), and pivalic anhydride (6.5 ml) was heated on a steam bath for a total of 33 days. On day 11 additional pyridine (150 ml) was added, and on day 27 dimethylformamide (50 ml) was added.

Volatiles were removed under reduced pressure. and the residue was triturated with ethyl acetate. The insoluble solid was removed by filtration and dissolved in methanol-acetone. Silica gel (3 g) was added and the solvent evaporated. The residue was added to a column of silica gel (180 g) in acetone. Elution with acetone yielded an initial fraction of N,O-diacylated material followed by a fraction containing the desired monoacylated product. The acetone was evaporated from this latter fraction, and the residue was recrystallized from dimethylformamide-acetonitrile ether acetate to give 9-[2-(2,2-dimethylpropionvl- oxy)ethoxymethyl]guanine (0.5 g), m.p.

245--246"C.

Example 9 Preparation of 9-(2-Palmitoyloxyethoxy methyl)guanine 9-(2-Hydroxyethoxymethyl)guanine (0.3 g) prepared according to the processes described in German Offenlegungsschrift No. 2 539 963 was partially dissolved in dry dimethylformamide (15 ml) and dry pyridine (30 ml) by heating on a steam bath for hour. the mixture was chilled in an ice bath and (4.00) palmitoyl chloride (1.1 g) was added with stirring. The mixture was allowed to come to room temperature and stirred for 20 hours during which all the solid material dissolved. Thin layer chromatography shows quantitative conversion of the starting material.

The solution was diluted with ethyl acetate to a volume of 300 ml and chilled over night. Filtration yielded a white solid.

0.49 g.

The crude material was recrystallized once from ethyl acetate and once from acetone to give analytically pure 9-(2 Palmitoyloxyethoxymethyl)guanine 190 mg (31 ) m.p.t 190--2100C.

The NMR, u.v. and Mass Spectre were consistent with the desired product.

Example 10 Preparation of 9-(2-Butyryloxyethoxy methyl)guanine A solution of sodium methoxide in dry methanol (10 ml) was added to methanolic solution of 9-(2-hydroxyethoxymethyl)guanine at room temperature. Removal of the solvent in vacuo gave the sodium salt of the purine as a white powder.

The above sodium salt was suspended in a mixture of ethyl butyrate and dry DMF (20 ml) and brought to reflux with stirring. After 3t days most of the solid had dissolved so the reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in 2N acetic acid (25 ml). Removal of the solvent on vacuo gave a semi-solid mass which solidified after treatment with water (15 ml) and SD3A (15 ml) with removal of the solvents in vacuo. This product was slurred with SD3A (25 ml), filtered, and air-dried to give 195.2 mg of a tan solid.

Example 11 A tablet formulation containing a mixture of 9-(2-formyloxyethoxymethyl)guanine (100 mg). lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation.

Example 12 A tablet formulation containing a mixture of 2-amino-9-(2-formyloxyethoxymethyl)- adenine (100 mg), lactose (200 mg, starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation.

Example 13 A tablet formulation containing a mixture of 9-(2-propionoyloxyethoxymethyl)guanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation.

Example 14 A tablet formulation containing a mixture of 9-2-(2,2-dimethyl-propionoyloxy)ethoxymethyl guanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation.

WHAT WE CLAIM IS: 1. A substituted purine of formula (I)

wherein Rl is a hydroxy or amino group, R2 is hydrogen, straight or branched chain alkyl group having from 2 to 16 carbon atoms, an unsubstituted aryl group having 10 carbon atoms, or a substituted aryl group having 6 to 18 carbon atoms, or a salt thereof.

2. A substituted purine of formula (I) as claimed in claim 1 wherein R1 is hydroxy, or a salt thereof.

3. A substituted purine of formula (I) as claimed in either claim 1 or claim 2 wherein R2 is hydrogen or a straight or branched chain alkyl group having from 2 to 8 carbon atoms.

4. A substituted purine as claimed in either claim 1 or claim 2 wherein the aryl group is substituted with a halogen atom, amino, nitrile, sulphamido group or alkanoyl or alkyl group having from I to 4 carbon atoms.

5. A substituted purine as claimed in any one of claims 1, 2 or 4 wherein when R2 is a substituted aryl group it has less than 10 carbon atoms 6. A substituted purine of formula (I) as claimed in claim 1 which is 9-(2 formyloxyethoxymethyl)guanine.

7. A substituted purine of formula (I) as claimed in claim 1 which is 9-(2propionyloxyethoxymethyl)guanine.

8. A substituted purine of formula (I) as claimed in claim 1 which is 9-[2-(2,2- dimethyl - propionoyloxy)ethoxymethyl]guanine.

9. A substituted purine of formula (I) as claimed in claim 1 which is 2-amino-9-(2formyloxyethoxymethyl)adenine.

10. A salt of a substituted purine of formula (I), as claimed in any one of the preceding claims wherein the salt is a pharmaceutically acceptable salt.

11. A pharmaceutical composition which comprises a substituted purine of formula (I) as defined in Claim 1, together with a pharmaceutically acceptable carrier therefor.

12. A composition as claimed in claim 11 which comprises a substituted purine as claimed in any one of claims 6 to 9, together with a pharmaceutically acceptable carrier therefor.

13. A composition as claimed in either claim 11 or claim 12 which is in the form of an ointment or cream.

14. A composition in either claim 11 or claim 12 which is in the form of a tablet.

15. A pharmaceutical composition for oral or parenteral administration as claimed in any one of claims 11, 12 or 14 comprising the compound of formula (I) in an amount of I to 250 mg per unit dose.

16. A pharmaceutical composition as claimed in claim 15 for parenteral administration as eye or nose drops comprising the compound of formula (I) in a concentration from 0.1 to 10% in a suitable medium.

17. A pharmaceutical composition for topical administration as claimed in any one of claims 11 to 13 comprising the compound of formula (I) in a concentration from 0.1 to 10%.

18. A pharmaceutical composition as

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 3t days most of the solid had dissolved so the reaction mixture was concentrated to dryness in vacuo and the residue was dissolved in 2N acetic acid (25 ml). Removal of the solvent on vacuo gave a semi-solid mass which solidified after treatment with water (15 ml) and SD3A (15 ml) with removal of the solvents in vacuo. This product was slurred with SD3A (25 ml), filtered, and air-dried to give 195.2 mg of a tan solid. Example 11 A tablet formulation containing a mixture of 9-(2-formyloxyethoxymethyl)guanine (100 mg). lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation. Example 12 A tablet formulation containing a mixture of 2-amino-9-(2-formyloxyethoxymethyl)- adenine (100 mg), lactose (200 mg, starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation. Example 13 A tablet formulation containing a mixture of 9-(2-propionoyloxyethoxymethyl)guanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation. Example 14 A tablet formulation containing a mixture of 9-2-(2,2-dimethyl-propionoyloxy)ethoxymethyl guanine (100 mg), lactose (200 mg), starch (50 mg), polyvinylpyrrolidone (5 mg) and magnesium stearate (4 mg) was prepared by wet granulation. WHAT WE CLAIM IS:

1. A substituted purine of formula (I)

5. A substituted purine as claimed in any one of claims 1, 2 or 4 wherein when R2 is a substituted aryl group it has less than 10 carbon atoms

6. A substituted purine of formula (I) as claimed in claim 1 which is 9-(2 formyloxyethoxymethyl)guanine.

18. A pharmaceutical composition as

claimed in claim 17 comprising the compound in a concentration of 1 Ó.

19. A method of preparing a substituted purine of formula (I) as defined in claim 1, characterised in that: a) a compound of formula (II):

is reacted with a compound of formula (III):

wherein A is a leaving atom or group and Q is a hydrogen atom or alkali metal; or b) a compound of formula (IV):

wherein R2 is defined above and either or both of M and G represent an azido group converted into a compound of formula (I) by methods known per se; or c) an alcohol of formula (V):

is esterified by reaction with an acylating agent.

d) a blocking group is linked to Rl and/or the 2-amino group, the blocking group or groups being removed by solvolysis or alcoholysis and optionally converting the compound of formula (I) formed by any of methods a) to d) to another compound of formula (I) by transesterification; and where the product of any one of the abovementioned reactions is a base optionally converting the product into an acid addition salt or an alkali metal salt thereof, or where the product is a salt of a compound of formula (I) optionally converting said salt into its base or another salt thereof.

20. A process as claimed in Claim 19 for preparing compounds of formula (I) wherein R' is hydroxy.

21. A process as claimed in either claim 19 or claim 20 for preparing compounds of formula (I) wherein R2 is hydrogen or a straight or branched chain alkyl group having from 2 to 8 carbon atoms.

22. A process as claimed in either claim 19 or claim 20 for preparing compounds of formula (I) wherein R2 is a substituted aryl group wherein the aryl group is substituted with a halogen atom, amino, nitrile sulphamido group or alkanoyl or alkyl group having from 1 to 4 carbon atoms.

23. A process as claimed in any one of claims 19, 20 or 22 for preparing compounds of formula (I) wherein R2 is a substituted aryl group with less than 10 carbon atoms.

24. A process as claimed in claim 19 for preparing 9-(2-formyloxyethoxymethyl)guanine.

25. A process as claimed in claim 19 for preparing 9-(2-propionoyloxyethoxy methyl)guanine.

26. A process as claimed in claim 19 for preparing 9-[2-(2,2-dimethylpropionoyloxy)ethoxymethyllguanine.

27. A process as claimed in claim 19 for preparing 2-amino-9-(2-formyloxyethoxy methyl)adenine.

28. A process as claimed in any one of claims 19, 20 to 27 wherein the leaving atom or group A is a reactive residue of an organic or inorganic acid and Q is hydrogen or an alkali metal.

29. A process as claimed in claim 28 wherein A is halogen or sulphonate.

30. A process as claimed in claim 29 wherein when A is halogen and Q is hydrogen the reaction is carried out in the presence of a base.

31. A process as claimed in any one of claims 19, 20 to 27 wherein M and G are both azide groups and are converted to amino groups by catalytic reduction.

32. A process as claimed in any one of claims 19, 20 to 27 wherein the acylating agent is a carboxylic acid, an aliphatic or aromatic carboxylic anhydride, an aliphatic or aromatic carboxylic acyl halide, a mixed carbonic-carboxylic anhydride or a carboxylic acid ester.

33. A process as claimed in any one of claims 19, 20 to 27 wherein R' and the 2amino group is blocked by a trialkylsilyl group and said blocking group is removed by solvolysis or aloholysis.

34. A process as claimed in any one of claims 19, 20 to 27 wherein when in formula (I) R' is amino, both RX and the 2-amino group are blocked by an activated acyl group, or a benzyloxycarbonyl group, said blocking groups being removed by reductive cleavage.

35. A process as claimed in any one of claims 19, 20 to 27 wherein when in formula (I) R' is hydroxy, the 2-amino group is blocked by an activated acyl group, or a benzyloxycarbonyl group, said blocking group being removed by reductive cleavage.

36. A process as claimed in either claim 34 or claim 35 wherein the activated acyl group is a trihaloalkanoyl group.

37. A process as claimed in any one of claims 19 to 36 wherein the compound of formula (I) so formed is converted into another compound of formula (I) by reaction with a carboxylic acid.

38. A method of preparing a pharmaceutical composition as claimed in any one of claims 11 to 18 which comprises bringing into association a substituted purine of formula (I) as defined in any one of claims I to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

39. A method of treating viral infections in mammals other than humans comprising the administration of an effective unit dose, as hereinbefore defined, of a compound of formula (I), as defined in claim 1 or a pharmaceutically acceptable salt thereof.

40. A method as claimed in claim 39 wherein administration is by the oral or parenteral route.

41. A method as claimed in claim 39 wherein administration is by topical application.

42. A substituted purine of formula (I) substantially as hereinbefore described with reference to any one of the foregoing Examples.

43. A pharmaceutically composition substantially as hereinbefore described with reference to any one of Examples 11 to 14.

44. A method of preparing a compound of formula (I) substantially as hereinbefore described with reference to any one of Examples 1 to 10.