AU602464B2 - 2-aminopurines substituted in the 6- and 9-position, their use, medicaments containing these purines, and processes for the preparation of the purines - Google Patents

Description

Seal of Company and Signaturesof0 Its Officers as Pre'eribed by Its Articles of Association, L~~IbAn Re4~ied aten Atorney Ti-iF Com miqqnN PR r)1 P.%TPNTI Form COMMONWEALTH OF AUSTRA LIA PATENTS ACT 1952-69 COMPLETE

SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Loeaged: C 3c)5' Complete Specification Lodged: Accepted: Published: Priority: IThis document contains the amendments made under SSection 49 and is correct for ~prntinga Related Art: C t.

Name of Applicant: Address of Applicant: Actual Inventor: X8 ddress for Service: HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-623O Frankfurt/Main Federal Republic of Germany ERHARDT WINKELMANN, HEINRICH ROLLY and IRVIN WINKLER EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Cbim6~plete Specification for the invention entitled: a 2-AMINOPURINES SUBSTITUTED IN THE 6- AND 9-POSITION, THEIR USE, MEDICAMENTS CONTAINING THESE PURINES, AND PROCESSES FOR THE PREPARATION OF THE PURINES The following statement is a full description of this invention, including the best method of performing it known to US PAT 510 UU11151 1kb 2twgIrdrahft( V fwisrt Authorized sg ppa. Reuter i.V. Lapice -la- HOECHST AKTIENGESELLSCHAFT HOE'86/F 194 JK Dr.Klr/St t I t I t

(III

IL

1 I t 2-Aminopurines substituted in the 6- and 9-position, their use, medicaments containing these purines, and processes for the preparation of the purines Medicaments containing as active compound 2-amino-6hydroxy-9-(2-hydroxyethoxymethyl)purine (Acyclovir cf.

Figure 1, formula ACV depicted in the tautomeric oxo form) are known. These are good antiherpes agents (cf.

Podent oLpflicca4on EuropeanP blihode -pea 4f:ti- 72 027).

Subsequently, there has been development of medicaments to counter viral infections, which differ from those of the formula ACV in that they contain an additional hydroxymethyl group in the position adjacent to the ether group in the hydroxyethyl radical, which are thus glycerol derivatives, it additionally being possible for the cxygen in the 6-position to be replaced by sulfur. (cf. J. Med.

Chem. 28, 358 (1985)). Finally, compounds of this type have been further modified in that the hydroxymethyl group 20 has additionally been etherified by a benzyl group and, where appropriate, the oxygen in the 6-position has been replaced by an imino group (cf. European aP4ubli44. pe.4ica-tion 152 965).

The invention now relates to compounds of the formula I (see patent claim 1) and to medicaments which contain them as active compound, in which R 1 is hydrogen, halogen, hydroxyl, mercapto, azido, amino or Z-R 5 Z being oxygen, sulfur, sulfinyl, sulfonyl or NH, and R 5 being an acyclic 30 aliphatic hydrocarbon radical which has 1 to 6 carbon atoms and is a) unsubstituted or b) modified by at Least one of the features that it contains an alkoxy group having 1 to 3 carbon atoms, or contains a double bond, or is at least partially fluorinated, or represents cycloalkyl having 3 to 6 carbon atoms, or phenylalkyL having one alkylene group of 1 to 3 carbon atoms, or phenyl, it S being possible for each phenyl ring to be substituted 11 II It I aL It I I I I i U lil-: -1 tt ft t C t ft ft t *t C *t ft *t L1C

I

tt

CL

*E CC ft V It 2 a maximum of twice, preferably a maximum of once, by a substituent from the group comprising halogen, trifluoromethyl, alkoxy and alkylthio, each having 1 to 3 carbon atoms, R 2 is hydrogen or has the meaning of R 5 or is an acyl group CO-R R being alkyl having 1 to 6 carbon atoms, benzyl or phenyl, R 3 denotes halogen, azido, unsubstituted amino or the radical Y-R 4 X and Y denoting oxygen, sulfur, sulfinyl or sulfonyl and possibly being identical or 4 5 different, and R has the s me meaning as 5 an exception 9-fl!-bit 5 f5opro-oxu Prpy| -Ofy- e f %)qsrte r.4a 1 10 being made ofthose compoun s in which simultaneously R is OH or SH, R 2 is H, R 3 is YR 4 X is 0 or S, Y is O, and R is alkyl having 1 to a carbon atoms other than isopropyl and 1 2 sec.-butyl, or in which simultaneously R is OH or HN 2

R

3 4 4 is benzyl, R 3 is Y-R where Y O and R benzyl, and X 0.

In the radicals R 4 to R the acyclic hydrocarbon radical preferably contains 3 to 5 carbon atoms, and the cycloaliphatic radical usually contains 4 to 6, and in particular 5 to 6, carbon atoms. Of course, it is possible 20 for the radicals R 4 to R the substituents contained in the 1 3 phenyl radicals, the radicals R and R and X and Y to be identical or different in each case. Aliphatic hydrocarbon radicals, alkoxy radicals and alkylene groups in the phenylalkyl radicals can each be straight-chain or branched, but in the phenylalkyl radicals they are preferably straightchain. Halogen in the radicals R and R denotes fluorine, chlorine, bromine or iodine. Halogen in the radical R 1 is preferably chlorine or bromine and in the radical R 3 is preferably fluorine or chlorine. The alkyl radicals which are at least partially fluorinated in the radical R 3 have, for example, 1 to 4, preferably two, carbon atoms, the partially fluorinated radicals being particularly preferred,

L,

I--mrrr- -r 3 for example -CH2-CF 3 tf CC I IIt II I1 r I If I *e I

I,

I I *IP iI

I

IC

I cs The compounds in which R 1 represents OH or SH, R 2 represents H, R 3 inter alia represents O-R 4 X represents O or S, and

R

4 inter alia represents alkyl having 1 to 8 carbon atoms, are disclosed in claim 8 of European patent application 145 207, as is their use as medicaments for the treatment of autoimmune diseases such as arthritis, multiple sclerosis etc., and of viral infections and cancer. In detail there are disclosed only those alkyl compounds in which R 4 is 10 ethyl, n-butyl, n-hexyl and n-octyl. Apart from these compounds, the said European patent application 145 207 additionally describes and claims, principally in fact, those which contain in the 8-position a bromine atom or a

NH

2 or NHCOR group, it being possible for R 6 to represent a '5 C 1

-C

4 -alkyl radical, an aryl radical or an aralkyl radical.

Although the compounds which contain hydrogen in the 8position are also attributed with the abovementioned effects, they are described and required as, especially, intermediates for the preparation of the compounds 20 substituted in the 8-position (cf. scheme 1, reaction steps 22(2), 23(2), 24(3), 25(4) and 11(5) and scheme 2, reaction steps 34(2), 33(2), 36(3), 37(4) and 26(5)).

Pharmacological data relating to the mode of action are given in European patent application 145 207 neither for the compounds substituted in the 8-position nor for the compounds unsubstituted in the 8-position. (European patent application 145 207 corresponds to Australian patent application 34 747/84.) According to scheme 1 of European patent application 145 207 reaction step 22(2) to 23(2), the benzyl radical as protective group is eliminated by catalytic hydrogenation.

Reactions of this type are not possible with an alkyl group, such as the isopropyl group, because although it is possible under the reaction conditions described there to eliminate x/xPAALIA 17 N T L- .IW WO11 Wh" 3a the benzyl group as toluene, it is not possible with aliphatic ether groups.

Compared with the compounds which are disclosed in European patent application 145 207 and are substituted in the 8position and unsubstituted in the 8-position, and compared with the compound of the formula Z, the compounds according to the invention have the advantage of con iderably greater efficacy. This means that, while the toxicity is the same or improved, it is possible to use substantially smaller 10 amounts of the active compounds.

a l The compounds of the general formula 1, according to the a S94 *0 4

PS

I yl 4 invention, can be prepared by various methods, the meaning of the radical R 1 determining the selection of the various starting materials and suitable protective groups. Some embodiments (A to D) and the formulae names given below are depicted in the reaction scheme (Figure 2) in which HMDS denotes hexamethyldisilazane, Pyr denotes pyridine and Ac denotes acetyl, and it would also be possible for the formulae in which R' denotes OH, SH or NH2 to be depicted in the tautomeric form shown by formulae 3' and 6' (see Figure In the cases where reaction takes place with halogen compounds, the halogen is preferably chlorine, although it can also be another, such as bromine.

The purines used as starting material are known, and most of them can be bought, for example: 2-amino-6-hydroxypurine guanine, 2-amino-6-mercaptopurine and 2-amino-6chloropurine (both in J. Med. Chem. 28 358 (1985)), 2,6-diaminopurine (Synthesis 11, 963 (1984), European pa&en'r- cpph;c.cion Published pee if iat iol138 683) and 2-aminopurine poen' 3pei'c( P eri D" (EuropeankP.ubli.C d eSpec iiati 108 285). Most of the starting materials of the formulae 13 and 14 are known and can be prepared by known methods (see Examples la-d and 3a-g).

SProcess A) When R1 is hydroxyl (or oxo in the tautomeric form) (formula amino (or imino) (formula 6), i hydrogen (formula 7) or R Z-R 5 (formula 21) see S. Figure 2 in each case it is expedient to react 2,6,9tris(trimethylsilyl)- or 2,9-bis(trimethylsilyl)-2-aminopurines as shown in one of formulae 8, 11 and 12 with halogen, in particular chlorine, compounds of the formula 2 3 13 in which R acyl, and X and R have the indicated m eaning, to eliminate the trimethylsilyl protective groups, and thus to obtain compounds of the formula I substituted in the 9-position, specifically of the formulae 15, 19, and 22. During this, the halogen, in particular chlorine, located in the a-position to X in formula 13 is distinguished by a particular reactivity. Of course, it 77 it cT 5 is also possible to use in place of the trimethylsilyl protective group other trialkylsilyl protective groups in which the alkyL radical has, for example, 1 to 6, preferably 1 to 3, carbon atoms and is straight-chain or branched.

Compounds 15, 19 and 20 according to the invention are, where appropriate, hydrolyzed to give other compounds of the formula 1 in which R 2 is hydrogen in place of acyl (see Figure 2).

Process B) When R1 is hydroxyl (or oxo) (formula 9), mercapto (or thio) (formula 10), amino (or imino) (formula 6a) or hydrogen (formula 7a) see Figure 1 in each case appropriate diacyl or triacyl compounds of the formulae 9, 10, 6a or 7a are reacted with reactive acetoxy compounds of the formula 14 in which R is acyl, and X and rrr 3 E R have the indicated meaning. In this way, compounds of t ,t the formulae 16, 17, 6b and 7b which are substituted in 20 the 9-position are obtained. These compounds according 4* Ct to the invention are, where appropriate, hydrolyzed to give other compounds of the formula 1 in which R is hydrogen.

t 1, 25 Process C) When R is halogen, in particular chlorine (formula it is possible C 1 to react this compound with active halogen compounds of the formula 13 to give t compounds of the formula 18 substituted in the 9-position and C 2 to hydrolyze the latter where appropriate to give other compounds of the formula 1 in which R 2 is H, or C 3 to exchange, before or after the hydrolysis, the halogen to prepare other compounds of the formula 1, for example if

R

1 is to be hydroxyl (or oxo) by acid hydrolysis, for example with aqueous hydrochloric acid, R is to be mercapto (or thio) by reaction with hydrogen sulfide, R is to be azido by reaction with alkali metal azides,

R

1 is to be amino (or imino) by reaction with ammonia, -|m 6 R is to be hydrogen by catalytic dehalogenating hydrogenation, for example with palladium charcoal/hydrogen triethylamine,

R

1 is to be ZR 5 by reaction with alcohols or phenols, mercaptans or thiophenols, or amines or anilines, R being acyl or, where appropriate after hydrolysis, being hydrogen, and R 3 and X having the indicated meaning.

Compounds which are often preferred for process C are those in which R 1 is H, OH or NH 2

R

2 is acyl, in particular acetyL, and X is 0 or S, R 3 and hence also Y and R 4 having the meaning indicated in claim 1.

The reactions according to processes A to C, and process D which is mentioned hereinafter, which are analogous processes, are carried out under the usual conditions.

The reaction temperatures in processes A) to C) are gener- ,ally between 0 and 150 0 C, preferably between 50 and 100 0

C.

Atmospheric pressure is usually employed, but it is also o"0 20 possible to employ elevated or reduced pressure, although Sthis is not normally associated with any advantages. The Ssolvents and dispersants can, of course, be used both in the form of homogeneous substances and in the form of mixtures. The following details of the individual pro- 25 cesses are also given: The reactions according to process A) are expediently carried out in a solvent or dispersant. Suitable for this purpose are, in particular, aprotic solvents such as benzene, toluene, the various xylenes, as well as 1,2dichloroethane, chlorobenzene, 1,2-dimethoxyethane and dioxane. It is advisable to use a base, such as triethylamine or N-ethylmorpholine, to capture the hydrohalic acid which is formed. The reaction times depend on the reaction temperature and reactants and range from a few minutes to several hours, usually 12-24 hours.

Because of the sensitivity to moisture of the trialkylsilyl-protected purines 8, 11 and 12 which are used as 7 starting materials, it is advisable to use a protective gas in the reaction vessel, for example nitrogen or argon.

The elimination of the trialkylsilyl protective groups can be carried out by, for example, boiling the intermediate compound with an alcohol, such as methanol or ethanol.

The reactions according to process B) are likewise expediently carried out in a solvent or dispersant. Particularly suitable for this purpose are sulfones as aprotic solvents, such as sulfolane (tetramethylene sulfone) or dipropyl sulfone. It is advisable to use an acid catalyst in this reaction, such as methane-, ethane-, benzene- or toluene-sulfonic acid. The reaction times depend on the reaction temperature and reactants and usually range from several hours up to some days.

The reactions according to process C 1 are likewise expediently carried out in a solvent or dispersant. Particu- Larly suitable for this purpose are polar aprotic solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, hexamethylphosphoric triamide or dimethyl sulfoxide. It is advisable to use a base, for example those mentioned hereinafter for the hydrolysis, such as triethylamine, N-ethylmorpholine or alkali metal carbonates, such as sodium or potassium carbonate, to capture the hydrohalic acid which is formed. The reaction times depend on the reaction temperature and reactants and range from several minutes to several hours.

The halogen exchange according to process C 2 is carried out, for example, in the following manner: C2a) When R 1 is hydroxyl (or oxo) it is possible to hydrolyze compound 18, for example, with 1 molar aqueous hydrochloric acid, by boiling under reflux for 2-3 hours, to give compound 15; reaction conditions of this type are, just as are those for process C 1 described in detail in International Application PCT/SE83/00254.

8

C

2 b) When R 1 is mercapto (or thio) it is possible to carry out the reaction of compound 18 with hydrogen sulfide gas in the presence of a base, such as triethylamine or pyridine, which can simultaneously serve as the solvent, or in an alcohol such as methanol, ethanol, one of the propanols or butanols, or ethylene glycol monomethyl ether or monoethyl ether, for example at 20-60°C, to give compound 17.

C

2 c) When R is azido it is possible to carry out the reaction with alkali metal azides in polar, and possibly in non-polar, solvents which are inert towards the reactants, such as dimethylformamide or dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide, Nmethylpyrrolidone, acetonitrile and tetramethylurea, under customary conditions, for example between 20 and 120, preferably between 60 and 90, °C.

'I1

C

2 d) When R is amino (or imino) it is possible to react compound 18, for example, with ammonia (liquid or in alco- Sholic solution), where appropriate using a solvent which is inert towards the reactants, such as ethanol, generally at temperatures between 20 and 120 0 C, preferably 50-100°C, for example within 12 hours.

C

2 e) When R is hydrogen it is possible to carry out the dehalogenating hydrogenation of compound 18 advantageously with palladium charcoal/hydrogen under atmospheric pressure in the presence of a base suitable for this purpose, such as triethylamine, under customary conditions, for example in the course of 12 hours at room temperature, to give compound 1 5

C

2 f) When R is Z-R Z is oxygen, sulfur or NH, and

R

5 has the indicated meaning, it is possible to react Scompound 18 with corresponding hydroxyl, mercapto or amino compounds. The hydroxyl or mercapto compounds are reacted in the form of their alkali metal salts, and the amino compounds are reacted in the presence of an inorganic or, preferably, organic base such as triethylamine or pyridine. It is possible to use as solvents in the case of hydroxyl compounds an excess of the alcohol which is used, and in the case of amino compounds the auxiliary 9 -9base pyridine, for example. In general, the solvents used are alcohols such as propanols and butanols, and alkylene glycols or their monoalkyl or dialkyl ethers.

The temperatures are generally between 25 and 130 0 C, preferably between 80 and 100 0 C. The reaction times depend on the temperature and the reactants and are usually between 6 and 24 hours. It is possible by analogous reaction of compound 3 or 5 with appropriate hydroxyl, mercapto or amino compounds, and further reaction with compound 13 or 1 by process A) to prepare compounds with R

Z-R

5 (compound 21 or 22) as shown in Figure 2.

Process D) Where compounds according to the invention, such as 15 to 20, 6b and 7b, are obtained by one of processes A to C, the latter can be hydrolyzed, for example by the action of bases, such as ammonia, alkylamines such as methylamine or ethylamine or the various propylamines or butylamines, or alkali metal hydroxides or carbonates,

I

t such as sodium hydroxide, potassium hydroxide, sodium 20 carbonate or potassium carbonate, in aqueous or alcoholic (methanol or ethanol) solution, generally at temperatures of 0-100 0 C, preferably at 20-50 0

C.

Most of the compounds of the formulae 15 to 19 result j 25 from processes A to D as a mixture of purine 7- and 9isomers in varying ratios of amounts, which can, where appropriate, be separated by fractional crystallization.

J i c In general, the isomers are separated by column chromatography, for example on silica gel. The characterization of the isomers and determination of their percentage contents are carried out by, for example, high-pressure Liquid chromatography (HPLC) using Li-Chrosorb Si 60/5 pm supplied by Merck, Darmstadt, Germany.

The compounds according to the invention have, where Y is not oxygen and R 2 is not identical to R 4 an optically active (chiral) center at carbon atom 2 in the ether side-chain. The compounds exist as racemates (DL form).

It is possible to prepare or isolate the optically active 10 antipodes (enantiomers).

The compounds of the formula 1, according to the invention, have valuable pharmaceutical properties. They are active in vitro and in vivo against various viruses and are thus suitable for controlling various diseases caused by DNA viruses, such as herpes, for example simplex types 1 and 2, and cytomegalovirus, and RNA viruses, for example retroviruses, as well as autoimmune diseases and for the treatment of cancer. Medicaments which contain them can be administered enterally (orally), parenterally (intravenously), rectally or Locally (topically). They can be administered in the form of solutions, powders (tablets, capsules including microcapsules), ointments (creams or gels) or suppositories. Auxiliaries suitable for formulations of these types are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, masking flavors, colorants and/or buffer substances. The dosage which is expediently ad- 20 ministered is 0.1-10, preferably 0.2-8, mg/kg of body weight. They are expediently administered in dosage units which contain at least the effective daily amount of the compounds according to the invention, for example 30-300, preferably 50-250, mg.

The compounds according to the invention can also be administered in combination with other antivirus agents and immunostimulants, such as interferons.

The action of compounds according to the invention was S tested as follows: A. In vitro tests: Cell cultures, for example HeLa and vero cells, were introduced into microtiter plates and infected with viruses, for example Herpes simplex 1. 2 hours after the infection various dilutions of the compounds to be tested were added to the infected cell cultures. 48-72 hours I- F 11 after the infection the result of treatment was determined on the basis of the cytopathogenic effect under the microscope, and by photometry after uptake of neutral red.

B. In vivo tests: Specific pathogen free NMRI mice weighing about 15 g were infected intraperitoneally with Herpes simplex type 1, and then treated intraperitoneally with the compounds described. Acyclovir (ACV) was always used for comparison. Treatment was administered twice a day for 5 days, starting after the infection. The result of treatment was determined on the basis of the course of the disease and the survival rate compared with the untreated infected controls. The latter received, in place of the compounds to be tested, administration of a water-soluble methylhydroxyethylcellulose (viscosity 300 Pa.s in 2% strength solution) ((R)Tylose MH 300 P).

Table 1 shows the chemotherapeutic action of compounds according to the invention.

Examples 1) Products according to the invention: 4 0 4 48 41 6f *l I 4 41 la) 9-(1-Chloromethyl-2-acetoxyethoxymethyl)guanine (Compound 6) 36.73 g (0.1 mole) of 2,6,9-tris(trimethylsilyl)guanine, crude product (prepared according to U.S. Patent 4,287,188), a .re dissolved in 100 mL of toluene, 20 mL of triethylamine are added, and 22.0 g (0.1 mole 10X excess) of 1chloro-2-chloromethoxy-3-acetoxypropane, dissolved in a Little toluene, are added dropwise at room temperature, with stirring and under nitrogen protective gas. The reaction mixture is then heated at 90°C under nitrogen, with stirring, for 20 hours. The toluene solvent is then removed by evaporation, the residue is dissolved in 500 ml of methanol, and the solution is heated under reflux for ll~ll L W__il II~ U~ C( ~XIII~ D1 ^~IUIIIIIIMO~ 12 minutes. After addition of charcoal, the solution is filtered hot with suction, evaporated, and the residue is recrystallized twice from water. 16 g 50% of theory are obtained; white crystals; melting point 166 0

C.

lb) 9-(1-Chloromethyl-2-hydroxyethoxymethyL)guanine (Compound 2) 31.55 g (0.1 mole) of the compound obtained according to la are introduced into a solution of 500 mL of liquid ammonia in 500 ml of methanol. The solution is stirred at room temperature for 12 hours and, after addition of a little active charcoal, is filtered with suction, evaporated, and the residue is recrystallized twice from a little water. 19 g 70% of theory are obtained; white crystals; melting point 178°C.

Starting materials *oo ic) 1-Chloro-2-chloromethoxy-3-acetoxypropane a0 20 1.25 g (0.1 mole) of 1-chloro-2-hydroxy-3-acetoxypropane are dissolved in 70 ml of methylene chloride, 3 g (0.1 mole) of paraformaldehyde are added and, while stirring and cooling in ice/water at about 5 C, hydrogen chloride gas is passed in for 2 hours. After addition of 10 g of 25 magnesium sulfate (anhydrous) as water-absorbing agent, hydrogen chloride gas is passed in once more at 5 0 C for 4 hours. The magnesium sulfate is then removed by filtration with suction, and the solvent is removed by evaporation at the Lowest possible temperature. The liquid residue is immediately reacted further. 17 g 85% of theory are obtained; Liquid; decomposes on distillation.

Id) 1-ChLoro-2-hydrovy-3-acetoxypropane The compound used as starting material was prepared according to Liebig's Annaten 402, 137 (1914) by reaction of epichlorohydrin with glacial acetic acid in the presence of iron(III) chloride at room temperature. Liquid; b;oiing point (17 mm) 1180C.

1.

13 2) Products according to the invention 2a) 9-(1-Azidomethyl-2-acetoxyethoxymethyl)guanine (Compound 9) 36.73 g (0.1 mole) of 2,6,9-tris(trimethylsiytl)guanine, crude product, are dissolved in 100 ml of toluene, 20 ml of triethylamine are added, and 22.8 g (0.1 mole excess) of 1-azido-2-chloromethoxy-3-acetoxypropane, dissolved in a little toluene, are added dropwise, initially at room temperature, with stirring and under nitrogen protective gas. The reaction mixture is then heated at 80 0

C

with stirring and under nitrogen, for 20 hours. The toluene is then removed by evaporation, and the residue is dissolved in 500 ml of methanol and heated under reflux for 30 minutes. After addition of charcoal to the solution it is filtered hot with suction, evaporated, and the residue is dissolved in a mixture of methylene chloride and methanol 5:1 (ratio by volume) and purified on a chromatography column packed with silica gel (Grace Matrex L C 60 The eluate is evaporated, and the residue is mixed with ethanol, filtered with suction and washed with a Little ethanol and ether. 13.7 g 38% of theory are obtained; white crystals, melting point 198 0

C.

2b) 9-(l-Aminomethyl-2-acetoxyethoxymethyl)guanine (Compound The compound obtained according to 2a) is catalytically reduced with Raney nickel/hydrogen in ethylene glycol monomethyl ether at 40 0 C. White crystals; melting point 144 0

C.

Jl Starting materials 2c) 1-Azido-2-chloromethoxy-3-acetoxypropane 15.9 g (0.1.mole) of 1-azido-2-hydroxy-3-acetoxypropane are dissolved in 100 ml of methylene chloride, 3 g (0.1 mole) of paraformaldehyde are added and, while stirring and cooling in ice/water at 0-5 0 C, hydrogen chloride gas is passed in for 2 hours. After addition of 10 g of sodium sulfate (anhydrous), hydrogen chloride gas is passed in for a further 4 hours at 5 0 C. Then the sodium t 14 sulfate is removed by filtration with suction, and the solvent is removed by evaporation at the Lowest possible temperature. The liquid residue is immediately reacted further. 1-Azido-2-chloromethoxy-3-acetoxypropane is ob'-" tained. This is used as crude product for the preparation of compound 9 as in Example 2a.

2d) 1-Azido-2-hydroxy-3-acetoxypropane 13.55 g (0.1 mole) of 1-azido-2-hydroxy-3-chloropropane are mixed with 10.7 g (0.1 mole 10% excess) of anhydrous potassium acetate, and the mixture is heated at 150 0

C,

with stirring, for 1 hour. After cooling, the mixture is poured on to 200 ml of ice/water and extracted by shaking 3 times with ether. The ether extracts are dried over sodium sulfate, evaporated, and the residue is distilled under water pump vacuum. The compound is obtained as a yellowish oil; boiling point (1 mm) 2e) 1-Azido-2-hydroxy-3-chloropropane V' 20 This compound was prepared according to J. Org. Chem. 21, 373 (1956) by reaction of 12.0 g (0.13 mole) of epichlorohydrin with 11.7 g (0.18 mole) of sodium azide in the presence of 17.9 g (0.08 mole) of magnesium perchlorate in water at 0 to 5 0 C. The compound is a colorless liquid of boiling point (1 mm) 62°C.

Products according to the invention 3a) 9-(1-Isopropoxymethyl-2-acetoxyethoxymethyl)guanine 30 (Compound 36.73 g (0.1 mole) of 2,6,9-tris(trimethylsilyl)guanine, t. crude product (prepared according to U.S. Patent 4,287,188), are dissolved in 100 ml of toluene, 20 ml of triethylamine are added, and 24.6 g (0.1 mole 10% excess) of 1isopropoxy-2-chloromethoxy-3-acetoxypropane, dissolved in a Little toluene, is added dropwise at room temperature, with stirring and under nitrogen protective gas. The reaction mixture is initially treated as described in Example 2 and is evaporated. The residue from evaporation 15 contains the 7- and 9-isomers in ratios of amounts which vary according to the batch. Hence the melting points vary between 209 and 225°C. It is possible to separate these isomers on a B6chi chromatography column packed with Grace Matrex LC 60A silica gel and using the eluent mixture methylene chloride/cyclohexane/methanol/glacial acetic acid (ratio by volume 100:20:10:1). After the eluate has been evaporated, the residue is mixed with water, filtered with suction and washed with water and a little cold ethanol, and dried. In this way, from a residue of melting point 212 0 C, 9 g 26% of theory) of white crystals of melting point 232 0 C (95% 9-isomer according to HPLC analysis on Merck Li-Chrosorb Si 60/5 pm) are obtained.

3b) 9-(1-Isopropoxymethyl-2-hydroxyethoxymethyl)guanine (Compound 14) 33.9 g (0.1 mole) of 9-(1-isopropoxymethyl-2-acetoxyethoxymethyl)guanine are introduced into a solution of 500 ml of Liquid ammonia in 500 ml of methanol. The solution is stirred at room temperature for 12 hours and, after addition of a Little active charcoal, is filtered with suction, evaporated, and the residue is recrystallized twice from water. 17 g 57% of theory are obtained; white crystals, melting point 191 0

C.

The same compound 14 can also be prepared by process B as follows. For this purpose, 23.5 g (0.1 mole) of 2,9diacetylguanine are heated together with 27.3 g (0.1 mole 10% excess) of 1-isopropoxy-2-acetoxymethoxy-3-acetoxypropane and 0.2 g of 4-toluenesulfonic acid in 60 ml of t anhydrous sulfolane at 95 0 C, with stirring, for 60 hours.

The cooled reaction mixture is diluted with 500 ml of toluene, filtered and chromatographed on silica gel.

ELution is carried out with a mixture of methylene chloride and methanol (ratio by volume 10:1). The eluate is evaporated, and the residue (2-acetyl-7(9)-(1-isopropoxymethyl-2-acetoxthothoxymethy)guanine isomer mixture) is introduced into a solution of 500 ml of Liquid ammonia in

A

77 -16- 500 ml of methanol, and the mixture is stirred at room temperature for 12 hours. After addition of a Little active charcoal, the mixture is filtered with suction, the filtrate is evaporated, and the residue is recrystaLLized from water. 9 g 37% of theory of white crystaLs are obtained, melting point 190 0

C.

Starting materials 3c) 1-Isopropoxy-2-choromethoxy-3-acetoxypropane 17.6 g (0.1 mote) of 1-isopropoxy-2-hydroxy-3-acetoxypropane are reacted with formaldehyde and hydrogen chloride gas in analogy to Example 2c). 20 g of the compound are obtained as a liquid (90% of theory); decomposes on distillation.

3d) 1-Isopropoxy-2-hydroxy-3-acetoxypropane S 15.25 g (0.1 mole) of 1-isopropoxy-2-hydroxy-3-chloropropane are reacted with anhydrous potassium acetate in analogy to Example 2d). 15 g 85% of theory are obtained; 20 Liquid; boiling point (22 mm) 128 0

C.

3e) 1-Isopropoxy-2-hydroxy-3-chloropropane The compound used as starting material was prepared according to J. Org. Chem. 12, 831 (1947) by reaction of 25 epichlorohydrin with isopropanol in the presence of con- .centrated sulfuric acid at room temperature. Liquid; A boiling point (22 mm) 89 0

C.

3f) 2,9-Diacetylguanine This compound was prepared in analogy to Bull. Chem. Soc.

SJap. 37 1389 by reaction of guanine with acetic anhydride in the presence of a Little concentrated sulfuric acid (30 minutes refLux). MeLting point 265 0

C.

3g) 1-Isopropoxy-2-acetoxymethoxy-3-acetoxypropane This compound was prepared by reaction of 1-isopropoxy-2chLoromethoxy-3-acetoxypropane (3c) with excess potassium acetate in acetone (12 hours at room temperature) in analogy to J. Med. Chem. 26, 759 (1983) and immediately A lp 39b ecino unn ihaei n

-U

17 reacted further as the crude product.

Products according to the invention l ll oo o I

I

o 0 00

I

0 4a) 2-Amino-6-isopropoxy-9-(1-isopropoxymethyl-2-acetoxyethoxymethyl)purine (Compound 44) 19.3 g (0.1 mole) of 2-amino-6-isopropoxypurine and 13.2 g (0.1 mole) of ammonium sulfate are introduced into 200 ml of hexamethyldisilazane under nitrogen, and the mixture is heated at 130 0 C for 4 hours. After cooling, the excess hexamethyldisilazane is removed by distillation under water pump vacuum, and the solid residue (6-isopropyl- 2,9-bis(trimethylsilyl)guanine) is dissolved in 100 ml of toluene, 20 ml of triethylamine are added, and 24.6 g (0.1 mole 10% excess) of 1-isopropoxy-2-chloromethoxy- 3-acetoxypropane, dissolved in a little toluene, are added dropwise, with stirring and under nitrogen, at room temperature. The reaction mixture is then heated at with stirring and under nitrogen, for 12 hours. The 20 toluene is then removed by evaporation, and the residue is dissolved in 200 ml of methanol and heated under reflux for 20 minutes. The methanol is removed by evaporation, and the residue is dissolved in methylene chloride/methanol (ratio by volume 40:1) and purified on a chromato- 25 graphy column packed with silica gel (supplied by Grace, Matrex LC 60A). The eluate is evaporated, and the oily residue is induced to crystallize by mixing with ethyl acetate/cyclohexane (ratio by volume The crystals are filtered with suction and washed with ethyl acetate/ 30 diethyl ether and dried in a desiccator. 19 g 50% of theory are obtained; white crystals; melting point 137 0 C (98X of 9-isomer according to HPLC analysis on Merck Li-Chrosorb Si 60/5 um).

0900 *e 0 0* 0 00 0 Io Starting materials 4b) 2-Amino-6-isopropoxypurine This compound was prepared in high yields by reaction of 2-amino-6-chloropurine with sodium isopropylate in isodistinguished by a particular reactivity. Of course, it co I O I 18 propanol (boiling under reflux for 12 hours) in analogy to J. Org. Chem. 25, 1573 (1960). Melting point 206 0

C.

Products according to the invention 5a) 9-(1,3-Bis(isopropoxy)propyl-2-oxymethyl)guanine (Compound 49) 36.73 g (0.1 mole) of 2,6,9-tris(ris(trimethysilyl)guanine, crude product, are reacted with 24.7 g (0.1 mole excess) of 1,3-bis(isopropoxy)-2-chloromethoxypropane in the presence of 20 ml of triethylamine in toluene as in Example 2b). Then the toluene is removed by evaporation, and the residue is dissolved in 200 ml of methanol and heated under reflux for 20 minutes. The methanol is removed by evaporation, and the residue is dissolved in methylene chloride/methanol (ratio by volume 9:1) and chromatographed on silica gel Matrex LC 60A supplied by I Grace. The eluate is evaporated, and the crystalline residue is recrystallized from ethanol. 9.5 g 42% of r theory are obtained; white crystals; melting point 20 222 0 C (96% of 9-isomer according to HPLC analysis on Merck Li-Chrosorb Si 60/5 nm).

Starting materials C C f 5b) 1,3-Bis(isopropoxy)-2-chloromethoxypropane 25 17.6 g (0.1 mole) of 1,3-bis(isopropoxy)-2-hydroxypropane were prepared with 3 g (0.1 mole) of formaldehyde and hy- A drogen chloride gas at 0 to 5 0 C and immediately reacted further as the crude product.

y "tt30 5c) 1,3-Bis(isopropoxy)-2-hydroxypropane 11.6 g (0.1 mole) of. 2,3-epoxypropyl isopropyl ether were reacted with isopropanol in the presence of catalytic amounts of tin(IV) chloride, initially at room temperature and then slowly increasing the temperature to Colorless Liquid; boiling point mm) 80 0

C.

6ff) The compounds listed in Table 2 can be prepared by the processes described under 1 to In this table, these compounds are identified by the NMR spectra in addition to their melting points.

followed by page 18a 18ia- Compound 40 is 2-amino-9- (1-isopropoxymethyl-2-acetoxyethoxymethyl)-purine, compound 48 is 2-amino-9-C(1,3-bis-(isopropoxy) Propyl-2-oxymethyl)-purine and compound 52 is 2-amino-6-isopropoxy-9-: ,3-.bis- (isopropoxy) -propyl-2-oxymethyl17-purine.

4t 4 19 Table 1 Herpes simplex Type I in the NMRI mouse Mean Mean Product Dose survival Dose survival No. mg/mouse i.p. x/10 mg/mouse i.p. x/l0 6 10 x 0.6 9/10 10 x 0.2 8/10 7 9/10 118/10 9 9/10 9/10 411t11 5/10 2/10 of: 9, 12 7/10 5/10 13 7/10 5/10 14 10/10 8/10 3/10 1/10 16 9/10 9/10 10/10 10/10 22 10/10 9/10 24 tI10/10 8/10 8 10/0 /1 *28 10/10 8/10 10/10 8/10 31 9/10 7/10 39 10/10 8/10 10/10 8/10 42 10/10 8/10 44 10/10 9/10 48 10/10 9/10 49 10/10 9/10 52 10/10 9/10 Acyclovir 9/10 8/10 Infected 10 x 0.5 ml 2/10 10 x 0.5 ml 2/10 controls Tylose Tylose@n igA D 4 4, Acyclovir 9- (2-hydroxyeathoxymethyl )guanine Sac 71 0*S Formula I No. R R X R 3 Table 2 M.p* s2 2 OC NH2 C-2 nl +qr rr il-D1 4 C* n"r" I**e n i o r

F

tM 6 vaLues in dim~ethyL sulfoide. (Me 2So- 6 27 Mz)) sIH C-6 CH C-8 9,2H NM 2X MiH

XCH

m,2ff CH 2 R2 8,31R OCOCH3 m,211 CH 2 R3 I OH H 0 F i 8o 6.45 10.6 7.8 5.3 4.15 3.7 4-1 2 cl 178 6.45 10.6 798 5.3 4.15 3.7 4.1 3 Br 158 6.45 10.6 7.8 5.3 4.15 3.7 4.1 4 i 15 6.45 10.6 7.8 5.3 015 3.7 4,1 CH Ac 0 IV7 6-45 10.6 7.8 5.4 4.15 3.6 2.0 4.1 6 cl 166 6.45 10.6 7.8 5.4 4.15 3.7 2.0 4.1 7 Ar 151 6,45 10.6 7.8 5.4 4.15 3.7 2.0 8 1 145 6s4 10-55 7.8 5.4 4.15 3.,75 2,0 4.1 9 N 319 6.45 10.6 7.8 5.4 4.1.5 3.7 2.0 NH 2 144 6.45 10.6 7.8 5.4 4.15 3-1 2.0 3.45 9,2H N0H20 m,IH m,2H n(CH2)2 11 Off H 0 OCJ194 6.4 10.6 7.8 5.35 4.15 3.5 4.0 OCH3 37.15 12 (C2 H 190 6.45 10.6 7.8 5.3 4.1-5 3,5 4.0 OC A 3-3/1-0 13 O(CH 197 6.45 10.6 7.8 5.3 4.15 3.5 4, o(Cff2)2Cff31.40.8 14 ocH(cH3)2 196 6.45 10.6 7.8 5.3 4.15 3.5 4-0 OCH(CH3)2 .35/1.02 O(CH 2Y-GH3 207 6.45 10.6 7.8 5.3 4.15 3.5 4.n, O(CH2) 3 C3 1-5/0-8 .M OCH(CH )C2 H 5 20 6.45 M-.6 7.8 5.3j 4,15 3.9. 4-0 OCH(rH3C2H5 3-4/1.0j~ O *ne *r h o n r o k ~O CI+ C Table 2 (continuation) Fornuta I No. R' R2 X NMR 6 vaLues ih dinethyl sulfoxide (Me 2 69270 MHz) 4Ip. e,2H sC NH2 C-2 s,lH 9,IH 0-6 CH C-8 8,2H m,1H m,2H NCH20 OCH(CH2)2 CH20AO e,3 ococ013 m,2H CH 2R3 CHI Ac 0 CH22CH3 OCH( CH 3

)C

2 e 5 214 6.4 10.55 7.8 5.3 4Ai1 3.6 1.9 4.0 OCH 3 3.15 220 6.45 10.6 7.75 5,3 4.15 3.6 1,9 4.0 OC, 3.31.0 216 6.45 10.6 7.8 5.3 4.15 3,6 1.9 4.0 0(011)2011 1.4/0.8 232 6.45 10,6 7.7 5.35 4.15 3.55 1.9 3.9 OCr(c 3 2 3.35/1-02 213 6.45 10.6 7.8 5.3 4.15 3s6 1.9 3"9 O(C 3 C 1.5/0.8 219 6.45 10.55 7.8 5.3 4.15 3.55 1.9 3.9 OC(CI)C 2

H

5 3.4/1.0 CH33.1 217 6.45 10.6 7.8 5.35 4,15 3.6 2.0 4.0 OCR CHR 3.4 2- 185 6.45 10.6 7.8 5.3 4.15 3.6 1.9 4.0 OC(CH 3 Y3 11 210 6.45 10.6 7.8 5.3 4.15 3.6 1.9 4.0 O(CH 2 4

CT

3 1.7/0,8 e-CA 3.4 221 6.45 10.6 7.8 5.35 4.15 3.45 1.85 4.0 0M1 1.2 NCR 5 0.8 OC(CH3)3 O(CR2)4CH OGH( C2H5)2 27 0-0 212 6.5 10.6 7.8 5.4 4,1'5 3.6 1.9 4.0 j c~i- O ,rr r n n nR* ni C r C C

C*

D

I

CIClaer~9P lll~ (BE~j~Si~l~ Tabte 2 (continuation) FormuLa l No. R 1

R

2 X M.P. 9,2H OC W 2 Cs,1H C-6 NMR 6 vabLes in dimethyL sutfoxide .(rqeSO-d, 270 (eHz) e,1H e,2I ni,H m,2H ,3H ,,2H CH C8 NCHOC(CH) 2CH2OAc OCOCH3 CR 3 OCR C

H

28 OR Ac 0 OCH CH 2 OCH(c)6H 5 209 6.4 10.6 7.8 186 6.5 10.65 7.8 180 6.45 10.6 7.7 5.3 4.15 3.4 1.95 3.9 OCH 2

CH=CH

2 5.0-6.0 5.35 4.15 3.4 1.95 4.0 OCR,-Ck 4.45 6 -C6H 5 7.3 1.25 5.35 415 3.55 1.85 4.0 OCH 4.4

"C

6

H

5 7.3 OC CF 208 6.45 10.6 7.8 5.3 4.1'5 3.6 1.95 3.9 OCHO2CP r* a. ali nr Fr TabLe 2 (continuation) NMR 6 vaLues in dimethyl sulfoxide (Me 2 30-%6 70 MHO FormuLa No. R 1 R2 x R 3 M.p.

9C s,21 NH2 C-2 8,11 0-6 s,IH CH C8 e,211 NCH2X m, H XcH(CH2)2 m, 2H C"2

OR

2 m, 2H

CHR

3 m,lH

H(CH

3 2 d,6:! 32 CH H 0 CH(CH3)2 187 6.45 10.6 7.8 5.35 4.15 2.8 3.5 3.2 1.1 33 SOCH(C1 3 2 118 6.45 10.6 7.8 5.4 4.15 2.8 3.7 3.4 1.1 34 02CH(C)2 146 6.45 10.6 7.8 5r4 4-15 2.8 3.8 3.5 1.1 I AC 0 sc11H3)2 198 6.45 10.6 7.8 5,4 4.15 3.6 1.9 4.0 3.2 1.2 36 1SO(CH 3 2 127 6.45 10.6 7.8 5.4 4.3 3.7 1.9 4.2 3.4 1.2 37 302CH(CH3)9 157 6.45 10.6 7.8 5.4 4.3 3.7 1.9 4.3 3.5 1.2 38 (H H S OCH(CH)2 196 6.4 10.5 7.7 5.1 4.15 2.7 3.5 3.35 1.1 39 H IC S OCH(C3)2 205 6.4 10.5 7.7 5-1 4.15 3.6 1.9 3.35 3.35 1.1 s,1-2H s,2H m,1H 8,31 m,2H C-6 WH210 'O(CH)2 OCOCH, CH 2or3" H AD 0 OdH(CH3) 2 89 5.53" 8.72 7.88 5.13 4.3 3.5 2.05 3.72 3.4 1.08 41 Ql AC 0 122 4.8 7.9 5.45 4.3 3.5 2.1 3,7 3.4 1.05 42 NH2 AC 0 168 6.68 7.75 8.02 5.38 4.15 3.6 1.98 3.9 3.4 43 SH e 0 0 192 6.9 13.1 8.2 5.35 4.15 3.5 1.85 3.9 3.4

I

Table 2 (continuation) No. R -Formula 1 R2 X R3

M.P.

oc S2H N; -ta v sl'in diffethyL suLfoxide (He SO-d s,114 s,1H s,2H *,1H *,2H s,3H C-6 CH C-8 NCH2 0 OCH(CH 2)2 CH 2 OCOCH3 270 M64z) m,2H nIH 3 CH2 R OCH(CH 3)21 OCH(CH 3)2 44 OCH(CH )2 Ac 0 OCH(CH 3)2 137 6.4

OCH(CH)

5 ,3 8.0 0C14(CH 3) 5.5 4.15 3.4 1.8 4.0 3.6

OCH

46 OCH(CH3)2 OCH(CH OCII(CH )2 3 2 96 6.4 61 5.0 116 8.4 81 6.5 1.35 7.4 R3 7.9 5.4 4.0 3,4 1.9 3.9 OCH(C14 3.35/1.0 7.8 5.5 4.1 3.7 2.0 3.7 0CH(CH3) 33512 47 N 48 N' Ac CH(CH 3)2 8.3 5.6 4.1 8.7 8,.2 5.6 3.8 1.9 3.7 OCH(CH 3) 11 -S 20 C H( H3 2 .2(114)

OCH(CH)

3.6 3,35/0.9 3.35/1.0 d2(6H) OCH(CH 2 49 ON CH(CN 3)2 OCH(CH 3)2 222 6.4 10.55 7.75 5.35 4.15 pm- 0.1 a a Table'2 (continuation) Fnrfmll aI 'vI-z~I No.R FormuLa R 2 3 Table 2 (continuation) N ,R values in dimetyl suLfoxide (Me 2SO-d6 MPp. s,2H s,lH s,IH s,2H *,lH *,2H s,3;1 OC NH 2 C-2 C-6 CH C-8 NCH 2 0 OCH(CH 2)2 CH%~c OCOCH3 270 MHz) m,2H m,1IH CH R 3OCH(CH 3)2 d, 6H OCH(CH 3)2 m,4M 2+3m CH 2OR R3 so a" 51 ON -2 2=C -M 2 C1I=CH2 216 6.45 10.65 7.8 5.4 4,1 3.9/3.4 CH CF 2 3 0 -OCH CF 2 3 212 6.4 10.6 7.8 5.4 4.3 3.7 20cC C= 20CH CF 2 3 m

R

3 3OCH(CH 3)2 5.0-6.0 52-OcH(CN 32 CH('3H -OM(CH 3)2#v10 6.35 7.95 5,6 4,1 3.8/3.4 3,35/1,0

V.-

Claims (2)

1. 2-6 HOE 86/F 194 JK ?beendxCbatmagxx THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Compounds of the formula 1 R 1 N 7 >8 HNN N N X CH2 2 CH 2 CH OR CH R3 wherein R 1 is hydrogen, halogen, OH, SH, azido, NH 2 or Z-R 5 Z being 0, S, SO, S0 2 or NH and R 5 being an acyclic aliphatic hydrocar- bon group having 1 to 6 carbon atoms which a) is un- substituted or b) is modified by at least one of the fea- .t tures that it contains an alkoxy group of from 1 to 3 car- *r /bon atoms or an olephinic bond or is at least partially fluorinated, or R 5 being cycloalkyl having from 3 to 6 Scarbon atoms, or phenyl bound directly to Z or via an alkylene group of from 1 to 3 carbon atoms, the phenyl ring being unsubstituted or substituted by at most two substituents of the group halogen, trifluoromethyl, alkoxy and alkylthio, each alkyl having from 1 to 3 carbon atoms, 2 5 R is hydrogen or has the meaning of R 5 or is an acyl group 4Ct-R 6 6 CO-R R being alkyl having from 1 to 6 carbon atoms, benzyl or phenyl, R is halogen, azido, unsubstituted amino or the group Y-R 4 R 4 having the same meaning as R 5 and Y being, as S: X 0, S, SO or S02 and X and Y being equal or different from each other, -bise anc with the exception of-compounds in which at the same time R 1 is OH or SH, R 2 is H, R is Y-R 4 X is 0 or S, Y is 0 and S0-othr than Isopropyl, an s'ec boiyl R is alkyl having from 1 to 8 carbon atoms, or in which at 1 2 3 4 the same time R is OH or NH 2 R 2 is benzyl, R is Y-R 4 Y being 0 and R 4 being benzyl, and X is 0. LL introduced into a solution of 500 ml of Liquid ammonia in t
2. 27- 2. Compounds according to claim 1, wherein R is hydrogen, halogen, OH, SH or NH2, R is hydrogen or acyl, R is halogen or Y-R 4 X and Y are 0, S, SO or SO 2 and are equal or different and R 4 is an acyclic aliphatic hydrocarbon group having from 1 to 6 carbon atoms, alkyl having from 1 to 4 carbon atoms being at least partially fluorinated or cycloalkyl having from 3 to 4 carbon atoms, however, with the exception of such compounds, in which simultaneously R i is OH or SH, R 2 is hydrogen, R 3 is Y-R 4 X is 0 or S, Y is 0 and R 4 is alkyl having from 1 to 4 carbon o herS+Am s roppy l a n see. bsey atoms. 3. Compounds according to claim 1 or 2, wherein R 4 is par- Stially fluorinated alkyl having from 1 to 4 carbon atoms or is cycloalkyl having from 3 to 4 carbon atoms. 4. Compounds according to claim 1 or 2, wherein Y is S, SO or S02. Compounds according to one or more of claims 1 to 4, wherein R is hydrogen, halogen, SH or NH 2 6. Compounds according to one ore more of claims 1 to 4, 1 2 wherein R is hydrogen, OH or NH 2 R 2 is acyl, in particular acetyl, and X is 0 or S. St, 7. Compounds according to one or more of claims 1 to 4 6 f wherein in groups R to R the acyclic aliphatic hydrocarbon group has from 3 to 5 carbon atoms and the cycloaliphatic group has from 4 to 6 carbon atoms and in particular 5 to 6 carbon atoms, and wherein halogen which may be present in R is chlorine or bromine and wherein halogen which may be present in R 3 is fluorine or chlorine. 8. A compound according to claim 1, which is 9-(1-isopropoxy- RAL%4 methyl-2-acetoxyethoxymethyl)-guanine, 2-amino-9-(1-isoprop- 77 1 analogy to J. Med. Chem. 26, 759 (1983) and immediately zV. oxymethyl-2-acetoxyethoxymethryl)-purine, 2-amino-6-isoprop- oxy-9-(1-isopropoxymethyl-2-acetoxyethoxymethyl)-purine, 2- amino-9-l ,3-bis-(isopropoxy)-propyl-2-oxymethylJ-purine, 9- [i,3-bis-(isopropoxy)-propyl-2-oxymethyl]-guanine or 2-amino- 6-isopropoxy-9-[ 3-bis-(isopropoxy)-propyl-2-oxymethylj- purine. 9. A pharmaceutical composition containing as an essential ingredient an effective amount of at least one compound according to one or more of claims 1 to 8. A process for the manufacture of compounds according to one or more of claims 1 to 8, wherein there is reacted under conventional conditions A) for the manufacture of a compound in which R is hydroxy, 2 amino or hydrogen, a 2,6,9-tris-(trialkylsilyl)- or 2,9- bis-(trialkylsilyl)-2--amino-purine of one of the formulae A., 8, 11 or 12 NH-SiC M 3 0-si(CH3 3 ')3 HN (033 HN SC 3 3 HN Si(Ci 3 3 H3)3 (H3)3 SI(CH3)3 8 11 12 with a halogen, in particular chlorine compound of the formula 13 wherein R 2 is acyl and X and R 3 have the meaning indicated in any one of claims 1 to 8, and the trialkylsilyl protec- tive groups are then split off, or B) for the manufacture of a compound, in which R1 is hydroxy, mercapto, amino or hydrogen, the corresponding di- or tri- A 2.9 acyl compound of the formulae 9, 10, 6a or 7a, respective- ly 0 NH (Ac) .9 10 7a 6a with a reactive acetoxy compound of the formula 14 AJ x .CH4 IA C .7 N C 2 14 Si t; in which R 2 is acyl and X and R 3 have the meaning indica- *I ted in any one of claims 1 to 8 or C) for the manufacture of a compound in which R is halogen, u a compound of the formula Hal u is reacted with an active halogen compound of formula 13 as shown under and the compound 18 thus obtained is iso- S' lated or is converted by acid saponifiation to a compound in which R is hydroxy, or is converted by reaction with hydrogen sulfide to a compound in which R is mercapto, or is converted by reaction with an alkaliazide to a compound in which R I is azido, or is converted by reaction with ammonia to a compound in which R is amino, or is conver- ted by a catalytic dehalogenating hydrogenation to a com- I_ pound in which R 1 is hydrogen, Or is converted by reaction with an alcohol or a phenol, a mercaptan or a thiophenol, or an amine or an aniline to a compound in which R is ZR 5 or D) a compound obtained according to any one of the processes A) to C) is saponified to yield a compound in which R is hydrogen. 114 Use of a compound a co-ding to one or more-of-r*Ia mns=--to f=J ht' *reat'ent.- of -a viru s.-d i seas 11 A method of treating a patient suffering from a virus disease which comprises administering to a person suffering from a virus disease an effective amount of a pharmaceutical composition containing as an essential ingredient an effec- tive amount of at least one compound as claimed in one or more of claims I to 8. DATED this 22nd day of September 1986. Si' HOECHST AKTIENGESELLSCHAFT EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000. 1 i