MC869A1 - Furanosyl-aminopurines and medicines containing these substances - Google Patents

Description

1

10

15

The present invention relates to purine and sugar derivatives, which can be used as immunosuppressants and as antiviral agents, and the preparation of these substances.

It includes the compounds that are represented by formula I below and their salts usable in pharmacy.

hooh2

(I)

1

In this formula, the symbol R represents a radical p

amino or lower alkylamino and R an amino radical or a

1

hydrogen atom, with the condition that if R is a

2

amino or methylamino radical, R being an amino radical. These 20 compounds have the p configuration with respect to the bond between the purine: and D-arabinofuranose. Particular preference is given to compounds of formula I in which 2

R is an amino radical.

In this description, the qualifier 25 "lower" applies to an alkyl radical having

1 to 4 carbon atoms, preferably 1 to 3 and, even better, 1 or 2 carbon atoms.

The salts of these compounds that are particularly suitable for therapeutic uses are those of carboxylic acids usable in pharmacy such as lactic acid, acetic acid and malic acid, as well as salts of mineral acids usable in pharmacy,

such as hydrochloric acid and sulfuric acid.

The activity of any salt lies in the

35 base.

Toxic salts can also be prepared and transformed either into a base or into salts for therapeutic uses, by the usual methods, for example by a metathesis reaction.

2

Formula I compounds are particularly useful for treating viral infections caused by DNA viruses such as smallpox and herpes. Other uses for these compounds include suppressing the immune response, in animals or humans, to the transplantation of foreign cells into their bodies, as well as treating autoimmune diseases in mammals, such as lupus erythematosus, hemolytic anemias, ulcerative colitis, and nephrosis.

10 This invention also includes medicinal products which contain as active substance a compound of formula I' below, or a salt of such a compound usable in pharmacy.

E1

15

-N\ \N

E

20

2X ir F (I • )

H

H0CH2 h'\H °0H^

' \

's

OH H

1

In this formula I', the symbol E represents a radical

2

amino or a lower alkylamino radical and E a radical

25 amino or a hydrogen atom, with the condition that if E

2

is an amino radical, E is also an amino radical.

These medicinal products include the active substance combined with a vehicle for pharmaceutical uses and/or in the form of an effective unit dose.

30. Certain medications include a compound

of formula I as defined above and of pre-

2

In the compound with formula I' or I, E is an amino group.

In this description, the term "effective unit dose" refers to a specific quantity of the antiviral agent sufficient to be effective against the organism in vivo. Vehicles for pharmaceutical uses are materials recommended for administering the drug; these materials may be liquid, solid, or vapor, and are otherwise inert or usable for other purposes.

3

medical and which are compatible with the active ingredient. In this regard, an aqueous solution of 6-methylamino-9-(P-D-arabinofuranosyl)-purine, other than in sterile form and presented in a sealed container, is not part of the invention.

These medications can be administered parenterally or orally, or as suppositories, or they can be applied as an ophthalmic solution or eye drops, or locally as an ointment, cream, powder, etc., depending on whether they are used to treat internal or external viral infections or as immunosuppressants or autoimmunosuppressants.

For the treatment of internal viral infections, the drug is given orally or parenterally at doses, calculated on a basis, of about 5 to 250 mg, preferably 20 to 100 mg, per kg of mammal and, in humans, it is preferably used in unit doses of 10 to 250 mg each, which are administered a small number of times per day.

20 As an immunodepressant, the drug is given

by internal route a small number of times per day, at doses which are preferably about 3 to 10 mg per kg of mammal.

For oral administration, fine powders or granules may be used, which may contain diluents, dispersants, or surfactants and may be presented as liquids, in water or syrup, in capsules or sachets, either dry or as a non-aqueous suspension, possibly with suspending agents, as tablets, possibly containing binders and lubricants, or suspended in water or syrup. If desirable or necessary, flavoring agents, preservatives, suspending agents, thickeners, or emulsifiers may be added. Tablets or granules, which may be coated, are preferable.

For parenteral administration, the active compounds may be presented as injectable aqueous solutions at concentrations of 0.1 to 10%, preferably 4-0 to 1%, solutions which may contain antioxidants.

4

buffering agents etc...

For the treatment of viral infections of the eye or other external tissues, the drug is preferably applied topically to the infected area, in the form of an ointment or eye drops, at a dose that is about half that used for internal use, i.e., which may be up to 125 mg/kg, or 5 to 125 mg per unit dose.

Among the compounds of formula I, 2,6-diamino-10 9-((3-D-ara"binofuranosyl)-purine is by far the most interesting, particularly due to its very strong antiviral activity, for example against the herpes virus. This substance has also shown significant and unexpected activity against the smallpox virus and has proven to have an equally unexpected benefit in reducing the immune response to cell transplantation.

Compounds of formula I', and in particular those of formula I, can be conveniently prepared by reducing a suitable compound of formula II.

20

,1

25

zoch

(ii)

50 in which z represents a blocking group such as an alkyl group, preferably a para-phenylbenzyl group, a fi- or p-naphthylmethyl group, or, better still, a benzyl group. This group Z must, when bonded to the oxygen atom at the second position of the sugar, 35 not interfere with the reaction at the carbon atom 1 of the sugar,

and it must be able to be eliminated under mild conditions.

However, one or two of the three possible radicals z, for example in the third and fourth positions, may

5

to be a hydrogen atom.

The reduction can be carried out catalytically, that is, with hydrogen in the presence of a hydrogenation catalyst such as palladium, palladium-coated carbon, platinum black, or Raney nickel. Some of these substances are rather weak catalysts, and it may then be necessary to carry out the hydrogenation under pressure or to prolong it; in this respect, platinum oxide and platinum black have proven to be the best catalysts.

10 The compound of formula II can also be reduced by means of a reducing agent, in particular an agent which gives atomic hydrogen within the reaction mixture itself, such as an alkali metal, preferably sodium, in liquid ammonia.

15

1 2

Compounds of formula II in which R and R are both amino groups can in turn be prepared by one of the following methods:

I. A compound of formula III is reacted with an alkali metal azide, preferably sodium azide

20

25

ZOCH

(III)

1 2

50 in which the symbols X and X represent halogen atoms, preferably chlorine or bromine, and Z a blocking group as defined previously, preferably the benzyl group, then the 2,6-diazide thus formed is catalytically hydrogenated into 2,6-diamine of formula II, 55 hydrogenation which is done by also forming a small amount of the corresponding compound of formula I.

By then continuing the reduction of the compound of formula II under the conditions indicated above,

6

that is to say by catalytic hydrogenation or, preferably, with a reducing agent such as sodium in liquid ammonia, the desired final product, of formula I, is obtained. It may be advantageous to combine the two operations into one by using the most efficient catalysts such as platinum oxide or platinum black and operating preferably under pressure or by extending the duration of the hydrogenation, so as to form the intermediate product of formula II and to reduce it immediately to the compound of formula I.

10 II. A compound of formula IV is deacylated by hydrolysis in a basic medium.

15

zoch2

20

(IV)

1 2

in which the symbols Q and Q each represent a YCONH group, Y being an alkyl radical of 1 to 6 carbon atoms, preferably the methyl radical, and Z a blocking group as defined above, preferably the benzyl group, which can be done, for example, by dissolving this compound in a lower alcohol such as methanol and adding to the solution an alkali metal hydroxide, for example sodium hydroxide.

To obtain the compound of formula III, a 2,6-dihalopurine, preferably 2,6-dichloropurine, can be condensed with an arabinose halide in which one or more of the hydroxyl groups are blocked by 35 eliminable Z groups as defined above, according to the method described by Keller and his collaborators in the publication J. Org. Chem., (1967), 32, 1644, the sugar preferred for this purpose being 2,3,5-tri-O-benzyl-a-D-arabinofuranosyl chloride.

7

Acylation of 2,6-diaminopurine, preferably with acetic anhydride, followed by a similar condensation with sugar, gives the compound of formula IV.

The compounds of formula IV are novel compounds 5 which constitute interesting intermediate products for the preparation of the final products according to the invention.

The compounds of formula II, in which R is a lower alkylamino radical and R2 is a hydrogen atom, can be prepared by dissolving a halogenated arabinose derivative 10 at position 6, suitably protected as before, preferably 6-chloro-9-(2,3,5-tri-O-benzyl-j3-D-arabino-furanosyl)-purine, in a solvent such as methanol, which has been previously saturated with the desired alkylamine, and then removing the solvent under reduced pressure. 15 The halogenated arabinose derivative at position 6 can

in turn be obtained by condensation of the corresponding 6-halopurine with the appropriate and suitably protected arabinose halide, in a solvent such as methylene chloride and in the presence of a molecular sieve (see 20 Keller et al., Ibid).

Compounds of formula I' and in particular those of formula I, in which R is an alkylamino radical

2 ^

lower and R a hydrogen atom, can also be prepared by reaction of the corresponding halogenated derivative in position 6, preferably the chlorinated derivative, with the appropriate lower alkylamine, for example in an aqueous medium.

The halogenated derivative at position 6 can be obtained by halogenation of the corresponding thiol, which can be prepared from the amino derivative, i.e. 9-(f3-arabino-50 furanosyl)-adenine, by diazotization and hydrolysis followed by acylation of the hypoxanthine derivative formed, reaction with phosphorus pentasulfide and finally deacylation, in the manner described by Reist and his collaborators in J. Org. Chem., 1962, 27, 5274.

1

35. Compounds of formula I' in which R is

2

an amino radical or a lower alkylamino radical and R an amino radical or a hydrogen atom can be prepared from anomeric xylosides, via lyxosides, following the general processes described by Reist and his collaborators, Ibid, and in Biochemistry,

8

1964, 3, 15-18.

The final stage in the formation of these compounds of formula I' by this method is the ring opening of the corresponding 2,3-anhydro-p-D-lyxofuranosyl derivative by treating it with sodium acetate in an inert solvent such as aqueous dimethylformamide. The lyxofuranosyl derivative is in turn obtained by converting the appropriate 9-(2-O-methane-sulfonyl-p-D-xylofuranosyl) derivative to an epoxide with an alcoholic solution of a suitable alkoxide, for example, a methanolic solution of sodium methoxide. The starting xylofuranosyl compound can then be formed by the following reactions.

9-(p-D-xylofuranosyl)-purine, bearing the desired substituents at positions 2 and 6, is reacted with 15 of acetone containing ethanesulfonic acid to form the corresponding derivative 9-(3,5-O-isopropylidene-6-D-xylofuranosyl), which is then reacted with methanesulfonyl chloride to obtain the compound 2-methanesulfonyl. This compound is subsequently hydrolyzed, for example in aqueous acetic acid, to remove the protecting isopropylidene group. The resulting derivative 9-(2-O-methanesulfonyl-p-D-xylofuranosyl) is then reacted in the manner described above.

The xylofuranosylpurine from which we started can be obtained by condensation of 1,2,3,5-tetra-O-acetyl-D-xylofuranose with the appropriate purine whose free amino group is protected by acylation, preferably by acetylation. For example, 2-amino-6-ethylamino-xylofuranosylpurine can be prepared by condensation of xylofuranose with 2-acetylamino-6-chloropurine, followed by the addition of ethylamine and then hydrolysis of the acetylamino group.

Thus, the present invention also includes the above-described processes for preparing compounds of formula I and their salts for pharmaceutical uses.

2

35 In these compounds, R is preferably an amino group, in

"1

particular when R is already 'the amino group'.

The invention further includes a method for preparing the compounds of formula II which have been defined above, a method according to which a compound of formula IV is desacylated in a basic medium.

9

This invention provides a means of treating infections caused by adenoviruses in mammals, for example in mice, rats, dogs, humans, etc., by administering a non-toxic antiviral dose of a compound of formula I' to infected animals or to animals that may be exposed to infection, in particular by administering a compound of formula I.

The following examples, which in no way limit the scope of the invention, describe it in more detail. 10 EXAMPLE 1:

2,6-diazido-9- (2,5,5-tri-0-benzyl-f3~D-ar abinofur ano syl) -

purine.

A solution of 2.1 g of 2,6-dichloro-9-(2,3,5-tri-O-benzyl-3-D-arabinofuranosyl)-purine (III) is heated for 6 hours under reflux in 8 mL of methanol and 2 mL of acetone with 440 mg, or 2 molecular equivalents, of sodium azide, and then the sodium chloride precipitate is separated by filtration. The yellow filtrate, which contains 2,6-diazido-9-(2,3,5-tri-O-benzyl-P-D-arabinofuranosyl)-purine, exhibits absorption maxima at 245, 270 (protrusion), and 300 mFi in 95% ethanol. This filtrate is used directly for the reduction in the following step.

EXAMPLE 2:

2,6-diamino-9-(2,3,5-tri-O-benzyl-p-D-arabinofurano syl)-25 purine (II).

The product obtained in Example 1 is reduced with hydrogen and a 5% palladium-containing carbon catalyst at 25°C under a pressure of 2 atmospheres. After 4 hours of hydrogenation, the catalyst is separated, and the filtrate is evaporated to dryness under reduced pressure. The remaining material (1.88 g) is then recrystallized in 95% ethanol, yielding 1 g of pale yellow crystals melting at 158–159°C. Thin-layer chromatography shows that these crystals have a homogeneous composition. The analysis corresponds to 2,6-diamino-9-(2,3,5-tri-O-benzyl-|3-D-arabinofuranosyl)-purine.

EXAMPLE 3:

2,6-diamino-9-(f3-D-arabinofuranosyl)-purine (I).

To 1 g of product II, add 200 ml of liquid ammonia 40, then small pieces of sodium until the

10

The blue color persists for several minutes, representing a total of 350 mg of sodium, and the blue color is removed with a few crystals of ammonium chloride. The ammonia is then evaporated in a stream of nitrogen, and the remaining material is triturated with 50 mL of benzene. The insoluble residue is then dissolved in a few mL of water and neutralized with acetic acid. The product, representing 500 mg, melts at 257–259°C, decomposing after recrystallization in water. 2,6-Diamino-9-(P-L-arabinofuranosyl)-10-purine (I) exhibits a maximum concentration (Xmax) of 253.290 mJ at pH 1 and a maximum concentration (Xmax) of 257.279 mJ at pH 11.

EXAMPLE 4:■

2,6-diacetylaminopurine.

A well-shaken suspension of 10 g of anhydrous 2,6-diaminopurine is heated to 70-80°C in 150 ml of fresh acetic anhydride. The solid material is then isolated by vacuum dewatering and thoroughly washed with ether. This solid material is a mixture of diacetylated and triacetylated substances, with a melting point of 244-250°C and decomposition. This material is placed in 1 liter of absolute methanol containing 100 ml of concentrated ammonium hydroxide. The flask is kept at room temperature for 15 minutes, shaking occasionally. The insoluble material is then separated by vacuum filtration and dried at 100°C. 25 We obtain 10.6 g of product, i.e. a total yield of 68%, melting point 296-300°C, the structure of which is confirmed by RHfT spectroscopy.

EXAMPLE 5:

2,6-diamino-9-(2,5,5-tri-O-benzyl-,0-D-ar abinof urano syl) -30 purine (II).

A suspension of 16 g of 2,6-diacetylamino-purine and molecular sieves is shaken for two weeks at room temperature in dry methylene chloride containing 20.6 g of 2,3,5-tri-O-benzyl-α-D-35 arabinofuranosyl chloride. The solution is then filtered through Celite buffer and the solvent removed under reduced pressure. Extraction of the crude oily material with cyclohexane gives 10.3 g (47% yield) of crude 2,6-diacetylamino-9-(2,3,5-tri-O-benzyl-α-D-arabinofuranosyl)-purine. This substance is then deacetylated by treating

11

an ethanolic solution (a) with 2 molecular equivalents of normal aqueous sodium hydroxide or (h) with a large excess of this base, the solution being stirred for half an hour at 70-80°C.

5 (a) The product is extracted from the solution with chloroform, dried over magnesium sulfate, and then the chloroform is removed under reduced pressure, to obtain product II either directly or after crystallization.

(b) When deacetylation has taken place, the precipitated product II is isolated from the solution by vacuum filtration. Recrystallization of this product in methanol gives 2,6-diamino-9-(2,3,5-tri-O-benzyl-f3-D-arabinofuranosyl)-purine, melting point 161-162°C.

EXAMPLE 6:

15. We react the 6-chloro-9-(3-D-(arabinofuranosyl)-

purine, obtained according to the methods described by Reist, Ibid, with a strong aqueous solution of methylamine, by heating under pressure for a few hours, then recrystallizing the remaining dry matter obtained in water, 20 melting point 201-203°C.

EXAMPLE 7:

6-ethylamino-9-((3-D-arabinôfuranosyl)-purine.

A mixture of 12 g of 6-chloro-25-purine, 15.1 g of 2,3,5-tri-O-benzyl-α-D-arabino-furanosyl chloride and 200 ml of methylene chloride is shaken for 12 days at room temperature with 4A molecular sieves, then the mixture is filtered and the solvent is removed under reduced pressure, leaving the 6-chloro-9-(2,3,5-tri-O-benzyl-β-D-arabino-furanosyl)-purine in the form of an oily substance, of which 15.2 g is obtained. \max = 263 mp. in methanol.

This crude oily material is dissolved in methanol that has been previously saturated with ethylamine, and the bottle is sealed. After one week at room temperature, the bottle is opened, and the solvent is removed under reduced pressure. The oily material is then purified by chromatography on a silica gel column, using a mixture of benzene and ethyl acetate as the eluent. Evaporation of the solvent leaves 6-ethylamino-9-(2,3,5-tri-O-benzyl-P-D-arabinofuranosyl)-purine.

40 The release of this compound is done either (A) by

12

chemical reduction or (B) by catalytic reduction.

(A) The tribenzyl compound is dissolved in ether and the solution is added to liquid ammonia; small pieces of sodium are added until the endpoint is

At point 5, the reaction is stopped with solid ammonium chloride, and the ammonia is evaporated. The remaining material is triturated with ether, and the residue is dissolved in a small amount of water. Neutralization yields the desired product.

(B) A suspension of PdCl2 10 is first reduced in methanol using a Parr apparatus, then a methanolic solution of 6-ethylamino-9-(2,3,5-tri-O-benzyl-p-D-arabinofuranosyl)-purine is added. After the theoretical amount of hydrogen has been fixed, the solution is neutralized with Dowex 1 in the form of bicarbonate, then the mixture is filtered and the solvent is evaporated under reduced pressure - EXAMPLE 8:

2-amino-6-ethylamino-9-((3-D-ar abino furano syl)-purine.

A suspension formed with 22.3 g of 2-amino-6~20 chloro-purine, 700 ml of fresh acetic anhydride and 2 ml of 85% H^PO^ phosphoric acid is heated to 95°C for 3 and a half hours while stirring. After cooling, the insoluble material is separated by filtration, the filtrate is brought to dryness under reduced pressure and the remaining material is thoroughly washed with ether.

25 This material is placed in 1.5 liters of methanol containing 150 ml of concentrated NH^OH. After 15 minutes, the insoluble material is separated by filtration and the filtrate is brought to dryness under reduced pressure. The solid material is then taken up in normal sodium hydroxide, treated with Darco's product, filtered, and neutralized with dinormal hydrochloric acid, giving 2-acetylamino-6-chloropurine, melting point 500°C.

1,2,3,5-Tetra-O-acetyl-D-xylofuranosyl is first condensed with 2-acetylamino-6-chloropurine and then with ethylamine. The condensation product is hydrolyzed to obtain 2-amino-6-ethylamino-9-(3-D-xylofuranosyl)-purine, which is reacted with acetone containing ethanesulfonic acid to form 2-amino-6-ethylamino-9-(3,5-O-isopropylidene-(3-D-xylofuranosyl)-purine. This substance is then reacted with methanesulfonyl chloride.

'15

to obtain 2-amino-6-ethylamino-9-(3,5-O-isopropylidene-2-methanesulfonyl-|3-D-xylofuranosyl)-purine, which is hydrolyzed in aqueous acetic acid to form 2-amino-6-ethylamino-9-(2-O-methanesulfonyl-B-D-xylofuranosyl)-purine, which is then treated with sodium methyl oxide in methanolic solution to obtain 2-amino-6-ethylamino-9-(2,3-anhydro-B-D-lyxofuranosyl)-purine. This substance is then converted to 2-amino-6-ethylamino-9-(@-D-arabinofuranosyl)-purine by heating with sodium acetate in aqueous dimethylformamide. The reaction mixture is evaporated to dryness and then the remaining material is dissolved and crystallized in water.

EXAMPLE 9:

Sterile injectable solution (unit dose) 15 Active ingredient 10 mg NaCl 0.09 mg Water qs per 1 ml

Tablet (total weight 200 mg)

Active ingredient: 10 mg 20 Lactose: 134 mg

Polyvinylpyrrolidone: 5 mg Corn starch: 50 mg Magnesium stearate: 1 mg.

Capsule (total weight of contents 200 mg) 25 Active ingredient: 10 mg Lactose: 50 mg Corn starch: 138 mg Magnesium stearate: 2 mg (hard gelatin capsule in 2 parts). 50 Tablets and capsules may have an enteric coating to prevent disintegration in the stomach. They may also be sugar-coated.

Syrup (dose for one 5 ml spoonful)

Active ingredient: 10 mg

35

Liquid sucrose: 3 mg Glycerol: 1 mg Flavouring agent: 0.001 mg Distilled water q.s» for 5 ml.

14

Ophthalmic solution or eye drops. Active ingredient: 1 mg. Distilled water qs per 10 ml. Buffered solution at pH 5.5-7*.

5 Ointment for local applications

Active ingredient: 10 mg Vaseline: 90 g

In the above medicines, the active substance may be any of the compounds of formula I', preferably 2,6-diamino-9-(|3-D-arabinof urano syl)-purine.

Claims (1)

15 SUMMARY The present invention includes in particular 1°) the compounds which are represented by formula I below and their salts 10 HO-CH. (I) 15 formula in which the symbol R represents an amino radical or a lower alkylamino radical and the symbol R an amino radical or a hydrogen atom, with the condition that 1 2 If R is an amino or methylamino radical, then R is a radical 20 amino. 2°) Varieties of the compounds specified under 1°), exhibiting the following characteristics: 25 a) R is an amino radical, b) R is a lower alkylamino radical having from 1 to 3 carbon atoms, more specifically 1 2 carbon, and R a radical arnmo. or 2 atoms of 3°) 2-6-diamino-9-((3-D-arabinofuranosyl)purine, 6-ethylamino-9-(3-D-arabinofuranosyl)purine and 2-amino-30 6-ethylamino-D-(3-D-arabinofuranosyl)purine. 4°) The compounds specified under 1°), 2°) or 3°) in the form of a salt with a carboxylic acid, more especially with lactic, acetic or malic acid. 5°) A process for preparing the compounds of formula I defined under 1°), a process according to which a suitable compound of formula II is reduced (See formula II on the following page). r-' 16 ZOCH 10 (II) H 15 in which Z represents a blocking group. 6°) Methods of carrying out the process specified under 5°) having the following characteristics, taken separately or according to the various possible combinations: a) The blocking group is a benzyl group, b) the reduction is carried out with hydrogen in the presence of a hydrogenation catalyst, c) the reduction is carried out with a reducing agent, d) the reducing agent comprises an alkali metal in ammonia, which e) The alkali metal is sodium, 1 2 f) R and R are both amino groups. 7°) A process for preparing compounds of formula II 1 2 2^ defined under 5°), in which R and R are amino groups, a process by which a compound of formula IV is desacylated 20 30 35 Q ZOCH. y (IV) H 1 2 (in which Q and Q each represent a YCONH group, Y being an alkyl radical of 1 to 6 carbon atoms and Z a block group) by hydrolysis in basic medium. 17 8°) Execution methods of the process specified under 7®)» exhibiting the following characteristics, taken separately or according to the various possible combinations: a) Y is a methyl group, 5 b) z is a benzyl group, c) Hydrolysis is carried out in an alcoholic medium, preferably in methanol, with a base derived from an alkali metal, for example sodium hydroxide or alkoxide; 9) A process for preparing the compounds of 10 formula II defined under 5°), in which R is a group 2 lower alkylamino and R a hydrogen atom, process by which a compound of formula VII is reacted Hal 15 zoch, 20 (vii) in which Hal designated a halogen atom, in particular 1 25 a chlorine atom, with the amine R within a solvent. 10°) A process for preparing the compounds of formula I defined under 1°), according to which a corresponding derivative of (2,3-anhydro-f3-D-lyxofuranosyl)purine, of formula VI, is reacted 30 ho-ch 35 (VI) H H with a base such as sodium acetate, in an inert solvent such as dimethylformamide, especially when hot. 18 11°) A process for preparing fojN compounds 1 mule I defined under 1°), in which R is a group 2 lower alkylamino and R a hydrogen atom, according to which the amine R Mg is reacted with the corresponding derivative 5 halogenated in position 6, in particular with the chlorinated derivative. 12°) Compounds of formula IV defined under 7°), in particular 2,6-diacetylamino-9-(2,3,5-tri-O^benzyl-p-D-arabinofuranosyl)purine. 13°) A process for preparing 2,6-diacetylamino-10 9-(2,3 ,5-tri-O-benzyl-p-D-arabinofuranosyl)purine, according to which 2,6-diacetylamino-purine is reacted with a halide of 2,3,5-tri-O-benzyl-ce-D-arabinofuranosyl, in particular with chloride. P. The Welcome Foundation Ltd. ORIGINAL Eighteen pages, without line spacing or overwriting, P. The Welcome Foundation Ltd If—<