AU644414B2

AU644414B2 - Substituted purines, processes for their preparation and their use as antiviral agents

Info

Publication number: AU644414B2
Application number: AU73514/91A
Authority: AU
Inventors: Matthias Helsberg; Gerhard Jahne; Manfred Rosner; Thomas Scholl; Irvin Winkler
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1990-03-20
Filing date: 1991-03-19
Publication date: 1993-12-09
Anticipated expiration: 2011-03-19
Also published as: PT97080A; CA2038589A1; EP0452680B1; FI911310L; ATE144984T1; ZA912015B; CN1054982A; ES2093651T3; DE59108319D1; CS70891A2; EP0452680A1; GR3021591T3; DE4008858A1; DK0452680T3; HU910928D0; JP3146423B2; NO911081D0; IL97586A0; FI911310A7; KR910016751A

Abstract

Purine derivs. of formula (I) and their salts are new. R1 = H, halo, NH3, OH, 1-6C alkoxy, -O-CH2Ph, -OPh, SH, 1-6C alkylthio, -S-CH2Ph, -SPh, NH2, 1-6C alkylamino, -NH-CH2Ph, -NH-Ph, 2-12C dialkylamino, -N(CH2Ph)2, cyclic dialkylamino, -N(Ph)2, 1-8C acylamino, 2-16C diacylamino, (N-alkyl-2-pyrrolidin-yliden)amino or 2-10C dialkylaminomethylidenamino; R2 = H, halo, N3, OH, SH, NH2, 1-6C alkylamino, 2-12C dialkylamino, -NH-CH2Ph, -N-(CH2Ph)2, cyclic dialkylamino, -NH-Ph, -N(Ph)2, 1-8C acylamino or thioacylamino, 2-16C diacylamino or di(thioacyl)amino; R3 = H, 1-6C alkyl (opt. substd.) or R8, where R8 is a phosphate ester-contg. gp.; R4 = H, 1-6C alkyl, OH, SH, NH2, halo, N3, 1-6C alkoxy, alkylthio or alkylamino, 2-12C dialkylamino, -O-CH2Ph, -S-CH2Ph, -NH-CH2Ph, -N(CH2Ph)2, -NHPh, -N(Ph)2, -OPh, -SPh, 1-8C acyloxy, 1-8C acylthio, 1-8C acylamino, 2-16C diacylamino, -O-(1-4C alkyl)-P(O)(OR6)(OR7) or -O(1-4C alkyl)-P(1-6C alkyl)(=O)(OR6); R5 = H, 1-6C alkyl (opt. substd.). A number of provisos are given in the specification.

Description

~_CC~

644414 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class In Application Number: Lodged: Form it. Class Complete Specification Lodged: Accepted: Published: P'iority Related Art Name of Applicant Address of Applicant Actual Inventor Address for Service HOECHST AKTIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main Republic of Germany 80, Federal GERHARD JAHNE, MANFRED ROSNER, IRVIN WINKLER, MATTHIAS HELSBERG and THOMAS SCHOLL WATERMARK PATENT TRADEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the invention entitled: SUBSTITUTED PURINES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS ANTIVIRAL AGENTS The following statement is a full description of this invention, including the best method of performing it known to Us r e I -L L- X- HOECHST AKTIENGESELLSCHAFT HOE 90/F 093 Dr.WN/PP Description Substituted purines, processes for their preparation and their use as antiviral agents The present invention relates to derivatives of purine, which carry an alkoxymethyl radical in the 7-position, to processes for the preparation of these compounds and to their use as antiviral agents.

The invention in particular relates to purines such as adenine, guanine, 6-chloro-2-aminopurine, 2-aminopurine, 6-isopropoxy-2-aminopurine, 2,6-diaminopurine, purine and thioguanine which carry an unsubstituted or acyl- and/or alkyl- and/or benzyl-substituted 2-hydroxyethoxymethyl radical or 1,3-dihydroxy-2-propoxymethyl radical or 2,3-dihydroxy-l-propoxymethyl radical in the 7-position.

The invention further relates to the physiologically tolerable salts of said compounds.

While the antiviral activity and the preparation of purine nucleosides which carry an acyclic radical in the 9-position are already long-known (see, for example, DE-OS 2,539,963 or K.K. Ogilvie et al., Can.J.Chem. 62, 241 (1984) or C.K. Chu and S.J. Cutler, J. Heterocyclic Chem. 23, 289 (1986)), to date nothing is known about a specific synthesis of acyclic purines substituted in the 7-position or their antiviral activity.

Only J. Kjellberg et al., J. Heterocyclic Chem. 23, 625 (1986) and J. L. Sessler et al., Nucleosides Nucleotides 8, 431 (1989) describe a more or less selective method for the preparation of carboacyclic guanines and 2-aminopurines substituted in the 7-position. However, the compcunds prepared in this way were not investigated for their antiviral activity or were inactive in in vitro -2investigations.

In individual cases, the acyclic purine derivatives substituted in the 7-position were separated from the desired acyclic purine derivatives substituted in the 9-position and investigated for their antiviral activity in vitro K. Ogilvie et al. Can. J. Chem. 62., 2702 (1984), K. K. Ogilvie et al., Can. J. Chem. 62, 241 (1984)) and found to be inactive.

It has now surprisingly been found that certain 7-substituted purines and their physiologically tolerable salts have antiviral properties against various DNA viruses, RNA viruses and retroviruses.

The invention accordingly relates to compounds of the formula I

R

3

R

4 ,j CH 2

-O-CH-CH-R

I I I

R

2

N

in which R, is hydrogen, halogen, azide, hydroxyl, C 1

-C

8 -alkoxy, benzyloxy, phenoxy, mercapto, C,-C-alkylthio, benzylthio, phenylthio, amino, Cl-C 6 -alkyl amino, benzylamino, phenylamino, C 2

-C

2 -dialkyl amino, dibenzylamino, cyclic dialkylamino, diphenylamino, Cl-C 8 -acyl amino. C 2

-C

6 d iacyl amino, (N-alkyl- 2-pyrrolidinylidene) amino or C 2 -C-dialkylaminomethylidene amino, Rz is hydrogen, halogen, azide, hydroxyl, mercapto, amino, Cl-C 8 -alkylamino, C 2 -C 1 2 -dia lkyl amino, benzylamino, dibexnzylamino, cyclic dialkylamino, -3 phenylainino, diphenylainino, Cl-C-acylamino and thicacylamino, C 2

-C

1 6 di acyl amino or di (thioacyl) amino,

R

3 is hydrogen, 4 Cl-C 6 -alkyl, optionally supstituted by halogen or by a hydroxyl, amino,~teo, r- akoy Cl-C.C-alkylthio, C-C 6 -alkylamino, benzyloxy, benzylamino, benzylthio, C 2

-C

2 -dialkylamino, dibenzylamino,. diphenylamino, Cl-C-acyloxy, Cl-C-acylamino, C-C 1 -diacyl amino or C,-C-acylthio group or a radical where R, is (OR 6

(OR

7

(C

1

-C

4 -alkyl) -P (OR 6

(ORA),

(Cl-C 4 -alkyl) -P (OR 7

),I

-NH- (Cl-C 4 -alkyl) -P (OR 6

(OR

7 -N Cl-C 6 -alkyl) -C,-c 4 -alkyl-P (ORB) (OR 7 ),1 -P (Cl-Cr-alkyl) (RB), 0- (Cl-C 4 -alkyl -P (C 1

-C

6 -alkyl) (ORB), (C,-C-alkyl) -P (C,-C-alkyl) (OR 6

),I

(C-C

4 -alkyl) -P (C-C-alkyl) (OR 6 ),j -N (C,-C-alkyl -Cl-C 4 -alkyl-P (CI-C-alkyl) (OR 6 in which R 6 and R 7 are independently of one another hydrogen or a Cl-C-alkyl radical or amnmoniumi, tr iethyl ammoniumn or an alkali metal or alkaline earth metal ion,

R

4 is hydrogen, C,-C-alkyl,jAhydroxyl, mercapto, amino, halogen, azide, C-C 6 -alkoxy, C-C 6 -alkylthio

C-C

6 -alkylaxuino, C 2 -C 12 -dialkyl amino, benzyloxy, benzylthio, benzylaznino, dibenzylamino, phenylamino, diphenylainino, phenoxy, phenylthio, Cl-C-acyloxy,

C-C

8 -acylthio, C -Ce-acyl amino I C 2 -C 1 -diacyl amino or

-O-(C

1

-C

4 -alkyl)-P(O) (OR 8

(OR

7 or 4 -alkyl)- P(O) (ORB)(OR,) o r C-C 4 -alkyl)

P(C

1

-C

6 -alkyl)(0)(0R 6 where the radicals R 6 and R7 are as defined above, and RS is hydrogen, C 1

-C

6 -alkyl, optionally substituted by Wa hydroxyl, thio, amino, C 1

-C

6 -alkoxy, 4 C,-C-alkylthio, C-CB-alkylamino, C 2

-C

12 -dialkylamino, Cl-C.-acyloxy, Cl-C-acylthio, C,-C.-acylamino,

C

2

-C

1 6 -diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino or diphenylamino group or a radical R 8 where R. is

(OR

7

(C-C

4 -alkyl) P (OR) (OR 7 -S-(Cl-C 4 -alkyl)-P(O) (OR) (OR 7

-NH-(C-C

4 -alkyl) -P (OR) (OR 7 -N (C,-C-alkyl) -C--C 4 -alkyl-P (OR 6

(OR

7

-P(C

1 -C,-alkyl)(0)(ORB), 4 -alkyl)-P(Cl-C 6 -alkyl)(0)(OR 6 (Cl-C 4 -alkyl) -P (C,-C-alkyl) (OR) -NH- (Cl-C 4 -alkyl) -P (Cl-C-alkyl) (OR 6 N(Cl-C 6 -alkyl)-Cl-C-alkyl-P(C-C-alkyl)(0)(OR), in which R, and R, are independently of one another hydrogen or a CI-C 6 -alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable salts and obvious chemical equivalents, with the proviso that, at the same time, R, is not hydroxyl and R 2 is not amino or R, is not hydroxyl, R 2 is not acetamido, R 3 is not benzyloxymethyl, R4 is not benzyloxy and R, is not hydrogen or R, is not chlorine or methoxy, R 2 is not amino, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R, is not hydrogen or R, is not hydroxyl, R, is not acetamido, R 3 is not acetoxymethyl, R 4 is not acetoxy and R. is not hydrogen or R, is not methoxy, R 2 is not amino, R 3 is not hydroxymethyl, R 4 is not hydroxyl and RS is not hydrogen or R, is not chlorine or amino, R 2 is not hydrogen, R 3 is not hydroxymethyl or benzyloxymethyl, R 4 is not hydroxy. or benzyloxy and R 5 is not hydrogen or R, is not amino, R 2 is not mercapto, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and RS is not hydrogen or R, is not benzyloxy, R 2 is not chlorine, R, is not benzyloxynethyl, R 4 is not benzyloxy and R 5 is not hydrogen or R, is not chlorine, R 2 is not amino, R, is not acetoxymethyl, R 4 is not acetoxy and R 5 is not hydrogen or R, is not benzyloxy, R 2 is not chlorine, R 3 is not hydrogen, R 4 is not benzyloxy and R. is not benzyloxymethyl or R, and R 2 are not chlorine, R 3 is not benzyloxyinethyl, R 4 is not benzyloxy and R. is not hydrogen or R, is not amino, R 2 is not mercapto, R 3 and R 5 are not hydrogen and R 4 is not acetoxy or R, is not hydrogen, R 2 is not amino, R 3 and R5 are not hydrogen and R4 is not hydroxyl or acetoxy or R, and R 2 are not chlorine, R 3 and R. are not hydrogen and

R

4 is not benzyloxy or R, is not iodine, R 2 is not chlorine, R 3 and R 5 are not hydrogen and is not hydroxyl.

Preferred compounds of the formula I are those in which R, is hycarogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms, amino, C-C-al kyl amino or

C

2

-C

6 -di (alkyl) amino, or C-C-alkylthio,

R

2 is hydrogen, halogen, hydroxyl, amino,

CI-C

6 alkyl amino, C 2

-C

8 -di (alkyl) amino or CI-C-acyl amino,

R

3 is hydrogen, Cl-C-alkyl, optionally substituted by a hydroxyl, amino or C 1 -C-alkoxy group or halogen or a C-C-acyloxy, C-C-acylamino or C 1 -C-alkyl amino group or a group R 8 1 where Re is

-O-(C

1

-C

4 -alkyl)-P(O) (ORO) (R 7 -P(O)(0RB)(OR7) or

-P(C

1

-C

4 -alkyl)(O)(0R 6 in which R6 and R7 are independently of one another hydrogen or a C-C-alkyl radical or an alkali metal or alkaline earth metal ion, -6

R

4 is hydrogen, hydroxyl, amino, mercapto, Cl-C 6 -alkoxy, C,-C-acyloxy, Cj- C 6 alkyl amino or an

(C

1

-C

4 -alkyl) -P (OR 6

(OR

7 or (Cl-C 4 -alkyl) -P (Cl-C-alkyl) radical having the meanings R 6 and R 7 as described above and

R

5 is hydrogen or C,-C 4 -alkyl, optionally substituted by hydroxyl, C,-C.-acyloxy, benzyloxy, Cl-C 6 -alkoxy,, amino, C -C 6 -alkyl amino or a radical R 8 where R8 is (ORB) (ORA or -P(Cl-C-alkyl) (R 6 in which

R

6 and R 7 are defined as described above.

Particularly preferred compounds of the formula I are those in which R, is hydrogen, hydroxyl, chlorine, mercapto, benzyloxy, Cl-C-alkoxy, amino, Cl-C 3 -alkylamino or

C

2

-C

6 -dialkylamino,

R

2 is hydrogen, hydroxyl, amino or C 1 -C8- acyl amino,

R

3 is hydrogen, Cl-C 3 -alkyl, optionally substituted by a hydroxyl, CI-C-acyloxy or Cl-C 6 -alkoxy group or a 0 0- CH 2 A OR 6

OR

7 or -P (RB) (ORA group, where RB and R 7 have the above meanings,

R

4 is hydrogen, hydroxyl or C-C-acyloxy or 0 11 CI-Ce-alkoxy or -CH 2

R

6 and

OR

7

R

5 is hydrogen or C 1

-C

4 -alkyll optionally substituted by hydroxyl, CI-C-acyloxy or C-C-alkoxy or -P (0RB)(ORA), where R 6 and R 7 have the abovementioned meanings.

Very particularly preferred compounds of the formula I -7 are those in which is hydrogen, hydroxyl, chlorine, Cl-C 4 -alkoxy, amino, Cj-C 3 -alkyl amino or C 2 -C-dia lkyl amino,

R

2 is hydrogen, hydroxyl, amino or C 1

-C

3 acyl amino,

R

3 is C-C 3 -alkyl, optionally substituted by hydroxyl or by Cl-C-acyloxy or by C 1

-C

6 -alkoxy or by -P(O)(0R,)(0R 7 where and R 7 have the abovementioned meanings, R4 is hydroxyl or Cl-C-acyloxy or Cl-C-alkoxy and

R

5 is hydrogen.

Compounds of the formula I furthermore have particular significance, in which

R

2

R

is hydrogen, chlorine or amino, is amino or Cl-C 3 -acylamino, is Cl-C-alkyl, optionally substituted by hydroxyl or by Cl-C.-acyloxy or by C 1

-C

5 -alkoxy or by -P (ORB)(OR7) where R. and R 7 have the abovementioned meanings, is hydroxyl or C-C 5 -acyloxy or CI-C-alkoxy and is hydrogen; and compounds of the formula I have very particular significance, in which

R

3 in

R

2 is hydrogen, is amino, is Cl-C 3 -alkyl, optionally substituted by hydroxyl or by Cl-C 4 -acyloxy or by C 1

-C

4 -alkoXY, is hydroxyl or C 1

-C

4 -acyloxy or Cl-C 4 -alkoxy and is hydrogen, particular the compound of the formula I in which is hydrogen, is amino, 1 8

R

3 is hydroxymethyl,

R

4 is hydroxyl and

R

5 is hydrogen.

Said alkyl groups as substituents of the abovementioned formula I can be branched, unbranched or cyclic. Examples of alkyl groups are the methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. Examples of alkoxy groups are the methoxy, ethoxy, propoxy, isopropoxy, butoxy or cyclopentyloxy group.

Examples of cyclic dialkylamino groups are the pyrrolidino, piperidino, morpholino, N-methylpiperazino or 1,2,4-triazolo group.

The preferred halogen substituent is chlorine. Particularly suitable alkali metal or alkaline earth metal substituents are sodium and calcium.

The compounds of these inventions are all substituted acyclic purine nucleosides, which carry the acyclic substituent in the 7-position of the purine ring system.

Salts of the compounds according to the invention particularly suitable for therapeutical purposes are salts of physiologically tolerable organic and inorganic acids such as acetic acid, lactic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, isethionic acid, hydrochloric acid or sulfuric acid.

Obvious chemical equivalents of the compounds according to the invention are in particular derivatives thereof which can be converted into the compounds according to the invention without problem, for example under physiological conditions.

Of the compounds of the formula I according to the invention 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine compound of the formula I in which R, H, R 2

NH

2 9 R3 CH 2 -OH, R 4 OH and R 5 H (Example 6.12.), 2-amino-7-(l-hydroxy-3-isopropoxy-2-propoxymethyl)purine compound of the formula I in which R, hydrogen, R 2 amino, R 3 hydroxymethyl, R 4 isopropoxy and Rs hydrogen (Example 6.10.) and 2-amino-7-(1,3-bis(isopropoxy)-2-propoxymethyl)purine compound of the formula I in which R, H, R 2

NH

2

R

3

CH

2

-O-CH(CH

3 2

R

4

O-CH(CH

3 2 and R, H (Example 6.7.) are particularly preferred, in particular because of their particularly high antiviral activity against herpes viruses.

Other compounds of the formula I where R, hydrogen, R2 amino and an acyclic side chain whose hydroxyl function or hydroxyl functions is/are esterified with Ci-C 6 -alkyl radicals or esterified with Ci-C-acyl radicals show particularly high antiviral activity.

The invention furthermore relates to the use of said compounds as antiviral agents, the compounds classified above as excluded not being excluded. The compounds according to the invention are particularly active against herpes simplex viruses type 1 and type 2, cytomegaloviruses, varicella zoster viruses, Epstein Barr viruses and human herpes viruses 6 (HHV6).

The present invention furthermore relates to processes for the preparation of substituted purines of the formula I or a physiologically tolerable salt thereof, which comprise 1) if in the compound of the formula I R 4 is hydroxyl, amino, alkylamino or mercapto, replacing a protecting group (blocking group) Ai in a compound of the formula II -1 -1 1 I 1 1,

A

IT_ _L*l 10 H 3

R

R1 CH-- 0- CH- CH-A I

I

C N C

N

by a hydroxyl, amino, alkylarino or mercapto group, 2) if in the compound of the formula I R 3 is hydroxya- Ikyl, aminoalkyl, alkylaminoalkyl or thioalkyl, replacing a protecting group A 2 in a compound of the formula III H alkyl-A 2

R

1 T- c C N R4 C C by a hydroxyl, amino, alkylamino or mercapto group, 3) if in the compound of the formula I R 5 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl, replacing a protecting group A 3 in a compound of the formula IV H R 3 alkyl-A 3

II

RC C 2 by a hydroxyl, amino, alkylamino or mercapto group, 4) if in the compound of the formula I R 3 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl and/or R 4 is hydroxyl, amino, alkylamino or mercapto and/or R 5 is hydroxyalkyl, aminoalkyl, L 11 monoalkylaminoalkyl or thicalkyl, replacing a protecting group A 4 and/or A5 and/or A. in a compound of the formula V R alkyl-A 4 S 0H--CH-CH- AS III -I WlC N 1 N N alkyl-A6 I I

(V)

by a hydroxyl, amino, alkylamino or mercapto group, 5) converting a compound of the formula VI Rr 1 11 z11C N C N7

(VI)

in which Y and Z are precursors of the groups R, and R. into a compound of the formula I in which R, and R. have the meanings described above, 6) reacting a compound of the formula VII N C C C N C 7

R

2

N

(VII)

with a compound of the formula VIII

R

3

R

4 i I

L--CH

2 CH- -CH

RS

(VI II) in which L 2 is a leaving group and L, is hydrogen or I_ 12 a leaving group, 7) removing a .locking group from a compound of the formula I in which one or both radicals R 1 and R 2 are blocked, and if the product of the reaction is a base of the formula I, optionally converting it into an acid addition product of this base of the formula I, or if the product of the reaction is a salt of a base of the formula I, optionally converting it into its base or into another salt of this base.

In the cases of processes 1) hydroxyl, mercapto, amino and monosubstituted amino functions of the acyclic side chain in the 7-position of the purine system, if present, are modified at the end by a blocking group D and, if appropriate, a further blocking group E, where D can be identical to or different from E.

These blocking groups can be esters for example acyloxy groups and/or benzyloxy groups and/or Ci-C 6 -alkyloxy groups for example isopropoxy groups.

In the first case, the acyloxy group can be aliphatic for example acetoxy or pivaloyloxy or aromatic for example benzoyloxy.

Both types of acyl groups can be removed, for example, by mild basic hydrolysis; in general warming with aqueous or alcoholic methylamine is adequate in order to achieve removal of the blocking group.

In the second case, the benzyloxy blocking group can be removed by hydrogenolysis, either catalytically or by means of hydrogen and Raney nickel or palladium/carbon or by means of ammonium formate and palladium/carbon or by means of a transfer hydrogenolysis with palladium hydroxide and cyclohexene or cyclohexadiene or chemically by reaction with boron halides for example boron trichloride at low temperatures for example at degrees Celsius or by means of sodium in liquid ammonia, the liquid ammonia being used as solvent.

r' i lr "~pEij' ~e 1 13 In the case of catalytic hydrogenolysis, the preferred solvent is an alkanol; however, a series of inert solvents can also be used if the substrate is at least partially soluble therein. Examples of these are benzene, toluene, tetrahydrofuran or dioxane.

For chemical reaction by means of boron trichloride, in which a solution of boron trichloride in n-hexane or in dichloromethane or alternatively gaseous boron trichloride is used, dichloromethane is the preferred solvent.

In the third case, deblocking of the Ci-C 6 -alkyloxy groups can be achieved if boron trihalides for example boron trichloride are reacted with the substrate at temperatures which are not quite so low for example at to 0°C, preferably at -40 0 C to -20 0 C. The preferred solvent for this is dichloromethane and the boron trichloride can be employed in gaseous form, as a solution in n-hexane or as a solution in dichloromethane.

The conversion of a compound of the formula VI into a compound of the formula I can be achieved in a very different manner by process For example, one of the two radicals R, or R 2 or both the radicals Ri and R 2 can be converted into a halogen by halogenation, into a hydroxyl group by hydrolysis, into a C,-Cs-alkoxy group by conversion with a Ci-C 6 -alkanolate, into a mercapto group by sulfurization, into a Ci-C-alkylthio group by reaction with a Ci-C-alkylthiolate, into an amino group by ammonolysis, into an amino group by deblocking a Ci-C.acylamino, CI-C-thioacylamino, benzylamino or Ci-C 6 -alkylamino group, into a C-Cs-alkylamino group or

C

2 -Cz 1 -dialkylamino group by aminolysis, or into hydrogen by hydrogenolysis or desulfurization or formation of the azide.

All these processes are known and can be found, for example, in: Heterocyclic Compounds Fused Pyrimidines Part II, Purines, editor: D.J. Brown, published by L. i rr~Lr~l i -L -i I-L- :li_ _r The following statement is a full description of this invention, including the best method of performing it known to us 1.

p.- 14 Wiley-Interscience, 1971.

In process the leaving group L 2 of a compound of the formula VIII is either a reactive radical of an inorganic acid and can thus be a) halogen, preferably chlorine, or b) a C-C-alkylthio or Ci-C-alkylsulfinyl or Ci-C 6 -alkylsulfonyl group, preferably the methylthio or the methylsulfinyl or the methylsulfonyl group, or it is a reactive radical of an organic acid and can thus be c) Ci-C.-acyloxy or benzoyloxy, preferably acetoxy.

In process 6a), the leaving group L, in a compound of the formula VII is hydrogen or trialkylsilyl, preferably trimethylsilyl.

In process 6b), the leaving group Li in a compound of the formula VII is a Ci-C.-acyloxy group, preferably the acetoxy group, or a trialkylsilyl group, preferably the trimethylsilyl group.

In process 6c), the leaving group L, in a compound of the formula VII is a Ci-Ce-acyloxy group or alternatively preferably a trialkylsilyl group, in particular the trimethylsilyl group.

The preferred process according to 6a) comprises the condensation of a purine with the desired substitution in the 2- and 6-position with a Cl-C.-acyl- or benzyl- or C,-C-alkyl-blocked l-(halomethoxy)ethanol, for example 1-(chloromethoxy)-2-acetoxyethane or l-(chloromethoxy)-2-benzyloxyethane or 1-(chloromethoxy) .2-isopropoxyethane, or an acyl- and/or arylalkyl- and/or alkyl-blocked 2-(halomethoxy)-1,3-propanediol, for example 2-(chloromethoxy)-l,3-bis(acetoxy)propane or 2-(chloromethoxy)-1,3-bis(benzyloxy)propane or V- -L

P

15 2-(chloromethoxy)-1,3-bis(isopropoxy)propane, or 1-(halomethoxy)-2,3-propanediol blocked by a Cl-C.-acyl and/or benzyl and/or C,-C.-alkyl, for example l-(chloromethoxy)-2,3-bis(acetoxy)propane or 1-(chloromethoxy)-2,3-bis(benzyloxy)propane or 1-(chloromethoxy)-2,3-bis(isopropoxy)propane, in a strongly polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolid-2 -one, tetramethylurea or dimethyl sulfoxide, in the presence o- a base, such as triethylamine, N-ethylmorpholine or of an alkali metal carbonate, such as, for example, potassium carbonate, at room temperature for 1 72 hours, if L, in a compound of the formula VII is hydrogen, or in aprotic solvents such as benzene, toluene, xylene, 1,2-dichloroethane, chlorobenzene, 1,2-dimethoxyethane, dioxane or acetonitrile, in the presence of a base such as triethylamine or N-ethylmorpholine, at a reaction temperature of 0 to 150 0 C, preferably at room temperature, for 1 72 hours, if L, in a compound of the formula VII is trimethylsilyl.

It is known that alkylthioalkyl ethers, in particular methylthiomethyl ethers such as, for example, compounds of the formula VIII where L, methylthio, can be reacted with oxygen nucleophiles and Lewis acids such as mercury(II) chloride Corey, M.G. Bock, Tetrahedron Letters 1975, 3269 or K. Yamada, K. Kato, H. Nagase, Y. Hirata, Tetrahedron Letters 1976, 65) or alkylsulfinylalkyl ethers, in particular methylsulfinylmethyl ethers such as, for example, compounds of the formula VIII where L 2 methylsulfinyl, can be reacted with carbon nucleophiles and Lewis acids such as zinc iodide (J.A.

Schwindeman, P.D. Magnus, Tetrahedron Letters 1981, 4925).

The preferred process according to 6b) comprises the condensation of a purine with the desired substitution in the 2- and 6-.position with a C-C-acyl- or benzyl- or Cl-CG-alkyl-blocked 1-(alkylthioalkoxy) ethanol, for 16 example 1- (methyithiomethoxy) -2-acetoxyethane or l-(methylthiomethoxy)-2-beflzyloxyethane or l-(methylthiomethoxy)-2-isopropoxyethane or 2 -(alkylthioalkoxy) 1, 3-propanediol or with a Cl-C 8 -acyland/or benzyl- and/or C,-C-alkyl-blocked, for example 2-(methylthiomethoxy)-1,3-bis(acetoxy)propane or 2-(methylthiomethoxy)-1,3-bis(benzyloxy)propane or 2- (methyithiomethoxy) 3-bis isopropoxy) propane, orwith a Cl-C.-acyl-* and/or benzyl- and/or C-C 6 -alkyl- blocked l-(alkylthioalkoxy)-2,3propanediol, for exaimple l-(methylthiomethoxy)-2,3-bis(acetoxy)propane or l-(methylthiomethoxy)-2,3-bis(benzyloxy)propane or 1- (methylthiomethoxy) 2, 3-bis (isopropoxy)propane, where in each case instead of the alkylthioalkoxy group the alkylsulfinylalkoxy or alkylsulfonylalkoxy group can advantageously also be employed, in a strongly polar solvent or solvent mixture such as dimethylformamide, dimethylacetamide, N-methylpyrrolid- 2-one, tetramethylurea and/or dimethyl sulf oxide, in the presence of a protonic acid or Lewis acid, such as iron trichloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride, but preferably tin tetrachloride, or iodine or trialkylsilyl.

trifluoromethanesulfonate, preferably trimethylsilyl trifluoromethanesulfonate, at a temperature of -40*C to +100 0 C, preferably between -20'C and +80 0 C, for several hours, if L, in a compound of the formula VII is

C

1

-C

8 -acyl, preferably acetyl, or in a less polar solvent or solvent mixture such as dichloromethane or 1,2dichloroethane in the presence of a Lewis acid such as iron(III) chloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride or tin tetrachloride or of a trialkylsilyl trifluoromethanesulfonate, preferably trimethylsilyl. trifluoromethanesulfonate, at a temperature of -40 0 C to +100 0

C,

preferably between -30 0 C and +20 0 C, for 0.5 to 8 hours, preferably for 1 to 4 hours, if L, in a compound of the formula VII is trialkylsilyl, preferably trimethylsilyl or in a polar aprotic solvent such as acetonitrile in the 17 presence of a Lewis acid such as iron (III) chloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride, but preferably tin tetrachloride, at a temperature of -40"C to 100 0 C, preferably between -30*C and +20*C, for 0.5 to 8 hours, perferably for 1 to 4 hours, if L, in a compound of the formula VII is trialkylsilyl, preferably trimethylsilyl.

The preferred process according to 6c) comprises the condensation of a purine having the desired substitution in the 2- and 6-position, preferably an expediently modified 2-amino-6-chloropurine, in particular per-trimethylsilylated 2-acetamido-6-chloropurine, with a

C

1 -C.-acyl- or benzyl- or Cl-C-alkyl- blocked 1- (Cl-C.-acyloxymethoxy) ethanol, for example 1-acetoxymethoxy-2-acetoxyethane or 1-acetoxymethoxy-2-benzyloxyethane or l-acetoxymethoxy-2-isopropoxyethane, or with a

C,-C

8 -acyl- and/or benzyl- and/or C-C-alkyl-blocked 2-(C-Co-acyloxymethoxy)-1,3-propanediol, for example 2-acetoxymethoxy-1,3-bis(acetoxy)propane or 2-acetoxymethoxy-1,3-bis(benzyloxy)propane or 2-acetoxymethoxy-1,3-bis(isopropoxy)propane, or with a C 1

-C

8 -acyl- and/or benzyl- and/or Cl-C 6 -alkylblocked 1-(Cl-C-acyloxymethoxy)-2,3-propanediol, for example l-acetoxymethoxy-2,3-bis(acetoxy)propane or l-acetoxymethoxy-2, 3-bis (benzyloxy)propane or 1-acetoxymethoxy-2,3-bis(isopropoxy)propane, in an aprotic solvent such as benzene, toluene, xylene, acetonitrile, dichloromethane or 1,2-dichloroethane or mixtures thereof, in the presence of an acid, preferably a Lewis acid such as aluminum trichloride, boron trifluoride, iron trichloride, gallium trichloride, tin tetrachloride or titanium tetrachloride or in the presence of iodine or preferably trialkylsilyl trifluoromethanesulfonate, particularly trimethylsilyl trifluoromethanesulfonate, the amounts of these reagents being 0.1 to 10, preferably 0.8 to 7 equivalents, relative to the amount of the acetoxymethoxy 18 compound employed in each case, at temperatures between -70 0 C and +80 0 C, preferably between -40"C and +30 0 C, for 2 to 24 hours, preferably for 2 to 6 hours, if Li in a compound of the formula VII is trialkylsilyl, particularly trimethylsilyl.

This process yields in high regioselectivity, as a rule preferably the 7-isomer of the respective acyclic purine derivative.

If product mixtures are formed by processes 6a) 6c), these are separated into the pure components, if necessary after conversion into another purine derivative, by chromatography or by fractional crystallization.

Compounds of the formula VIII where L 2 halogen can be prepared by reacting an expediently modified and protected alkanol, for example l-acetoxyethanol or 1,3-bis- (acetoxy)propan-2-o' or 2,3-bis(acetoxy)propanol or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2,3-bis(benzyloxy)propanol or 1-isopropoxyethanol or 1,3-bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)propanol with paraformaldehyde and a gaseous hydrogen halide, for example hydrogen chloride, in an inert solvent, for example dichloromethane, at room temperature or below.

The preparation of halomethyl ethers is a generally utilizable reaction; a detailed description can be found, for example, in: Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, 1965, volume VI/3, pp. 125 et eq.

Compounds of the formula VIII where L 2 a methylthio can be prepared by reacting an expendiently modified and protected alkanol, for example 1-acetoxyethanol or i,3-bis(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2,3-bis(benzyloxy)propanol or 1-isopropoxyethanol or 19 1,3-bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)propanol with dimethyl sulfoxide, Ci-Ce-acid anhydride and Ci-C 8 -carboxylic acid in a temperature range between 0 C and +40"C, preferably at room temperature, for several days, as a rule 2 to 4 days.

A detailed description of the preparation of methylthiomethyl ethers of primary, secondary and tertiary alcohols can be found in P.M. Pojer and S.J. Angyal, Aust. J. Chem., 31, 1031 (1978).

The corresponding methylsulfinylmethyl compounds and methylsulfonylmethyl compounds can be obtained in a simple manner by oxidation by means of peracids, for example m-chloroperbenzoic acid or peracetic acid.

Compounds of the formula VIII where L 2 Ci-Ce-acyloxy can be prepared either from a compound of the formula VIII where L 2 halogen, which is accessible as described above, by reaction with an alkali metal carboxylate, preferably sodium or potassium acetate, in acetone or dimethylformamide, or by converting an expediently modified and protected alkanol into the alkoxyalkyl ether, preferably the methoxymethyl ether, which is then in turn converted into the Ci-Cs-acyloxy compound, preferably the acetoxy compound, by reaction with a Ci-C-carboxylic acid anhydride, preferably acetic anhydride, under protonic or Lewis acid catalysis, preferably boron trifluoride etherate catalysis (for both processes see: Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, 1965, volume VI/3, pp. 286 et seq).

However, the compounds of the formula VIII where L 2 CI-CO-acyloxy are particularly simply and effectively prepared by combining an expediently modified and protected alkanol, for example 1-acetoxyethanol or 1,3-bis(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol 20 or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2,3-bis(benzyloxy)propanol or l-isopropoxyethanol or 1,3-bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)propanol with a carboxylic acid, preferably acetic acid, and the anhydride pertaining to it, preferably acetic anhydride, in dimethyl sulfoxide, preferably about 60 ml of acid, about 50 ml of anhydride and about 100 ml of dimethyl sulfoxide being used per 0.1 mol of alkanol, below room temperature, preferably at 0°C, and stirring for several hours, preferably 4 to 6 hours, at elevated temperature, preferably at 40 to 100 degrees Celsius.

In process the substituents Ri and R 2 can be blocked by, for example, trialkylsilyl groups, preferably trimethylsilyl groups.

Compounds of this type will be the product of the condensation of a per-trimethylsilylated purine and a compound of the formula VIII as in process 6).

These blocking groups are labile and can be removed by solvolysis with water, with aqueous or alcoholic ammonia or with aqueous hydrogen carbonate solution or by alcoholysis.

A further process combines processes 1) or 2) or 3) or 4) with process in this case, deblocking can be achieved by solvolysis at the same time as the replacement of a group leaving the purine system, for example halogen, such as, for example, by reaction with liquid ammonia. In this case, in addition to the deblocking of the side chain, if this was protected by a Ci-Ca-acyloxy group (see processes 1) the leaving group in the purine system is at the same time replaced by the amino group.

In addition here, a Cl-C 8 -acyl-blocked group in the purine system can be deblocked.

The compounds of the formula I according to the invention can have one or more chiral centers in the acyclic side j z, 21 chain. The compounds are as a rule racemates; preparation or isolation of the pure enantiomers is possible. The invention therefore relates both to the pure enantiomers and to mixtures thereof, such as, for example, the respective racemate.

The present invention in addition relates to pharmaceuticals containing at least one compound according to the invention.

The pharmaceuticals according to the invention can be administered enterally (orally) parenterally (intravenously), and rectally or locally (topically).

They can be administered in the form of solutions, powders (tablets, capsules including microcapsules), ointments (creams or gel) or suppositories. Suitable auxiliaries for formulations of this type are the pharmaceutically customary liquid or colid fillers and extenders, solvents, emulsifiers, lubricants, flavor correctants, colorants and/or buffer substances.

0.1 10, preferably 0.2 8 mg/kg of body weight, are administered as an expedient dosage. The compounds 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 250 mg.

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

In vitro tests and results: The antiviral activity of the compounds according to the invention was tested in in vitro tests. To do this, the compounds according to the invention were added in various dilutions to cell cultures of Vero cells in microtiter plates. After 3 hours, the cultures were infected with different viruses. Vero cells were infected Ily_ 22 with various human pathogenic herpes viruses, HeLa cells were infected with vaccinia virus and MDBK cells with vesicular stomatitis virus. 48 72 hours after infection, the result of treatment was determined microscopically by the cytopathic effect and photometrically (Finter, in "Interferons" Pinter et al.), North Holland Publishing Co., Amsterdam (1966), by neutral red absorption (color test according to Finter).

The minimum concentration at which about half the cells show no cytopathogenic effect is considered as the minimum inhibitory concentration (MIC). The results are summarized in Table 1.

23 Table 1 Substance from Exampl.e TMD (pg/mi) MIC (pg/mi) HSV-1 HSV-2 Vaccinia vsv 7-(1,3-dihydroxy- 2isopropoxymethyl )guanine >400 >400 6.7 >400 >400 >400 >400 133.3 1.65 >400 >400 >400 >400 >400 >400 133.3 1.65 >400 1.65 >400 >400 >400 >400 >400 >400 44.4 4.94 >400 >400 >400 >400 >400 >400 >400 >400 >400 >400 >133.3 133.3 6.10.

6.12.

Standard: 9-(1,3-dihydroxy-2isopropoxyiethyl)guanine >400 4.94 HSV- 1 HSV-2

MIC

TMD

VSV

Herpes simplex virus 1 Herpes simplex virus 2 Minimum inhibitory concentration TolerateI maximum dose Vesicular stomatitis virus 24 In vivo tests and results: NMRI mice, specifically pathogen-free, with a weight of about 15 g were infected intraperitoneally with herpes simplex virus 1 and then treated intraperitoneally or orally with the compound according to the invention (see Table 2 or Table Treatment was carried out for the first time 3 hours after infection and was continued twice daily for 4 days. The result of treatment was determined by the course of the disease and the survival rate compared to untreated infection controls. The latter received physiological saline solution instead of the compound according to the invention. The observation period was two weeks.

L r -r 25 Table 2: Antiviral action against HSV-1 in intraperitoneal administration NMRI mice on Example Dosage Mean survival time (days) Surviving/ total 6.7.

6. 10.

9 x 10 100 9 x 10 100 9 x 100 9 X 10 30 100 7 .0 0 10.0 ±1.4 6. 12.

7-(1,3-dihydroxy- 2isopropoxymethyl)guanine 10.0 10.0 9.3 1.4 0.0 2.1 Control Cnrol0 8. 3 2. 81 5 1 26 Table 3: Example Antiviral action against HSV-1 in NMRI mice on oral administration Dos age (pmol/kg) Mean survival time (days) Surviving/ total 6 .7.

6.10.

9 x 100 9 x 10 100 9 x 10 100 9 x 10 30 100 10 .0 0 0.0 8.3 6 .12.

7-(1,3-dihydroxy-2 isopropoxyxnethyl) guanine 6.5 8.5 9.0 2.1 0.7 1.4 Control Cotrol0 7 .7 1.52 5 2 ~I 27 Examples: Process according to 6b): 1. Compound of the formula VIII in which L 2 methylthio, R 3 isopropoxymethyl, R 4 isopropoxy and

R

5 hydrogen: 300 ml of anhydrous dimethyl sulfoxide are slowly added dropwise with stirring and cooling to about to a mixture of 180 ml of glacial acetic acid and 150 ml of acetic anhydride. After the addition is complete, the mixture is subsequently stirred for min. 52.8 g (0.3 mol) of 2,3-bis(isopropoxy)propan-2-ol (prepared by reaction of sodium isopropylate with 2,3-epoxypropyl isopropyl ether in isopropanol) are then added dropwise at about The reaction mixture is allowed to stand at room temperature for 4 days with periodic stirring. The reaction mixture is then stirred into about 1 1 of ice-water and extracted several times by shaking with diethyl ether or hexane. The organic phase is washed several times with water, dried over sodium sulfate and evaporated. The oily residue is fractionated in vacuo.

The yield is 53.5 g (75.5% of theory) of 1,3-bis(isopropoxy)-2-methylthiomethoxypropane.

Colorless oil of boiling point 68-74C at a pressure of 2 mm Hg.

2. Compound of the formula I in which R, hydroxyl,

R

2 acetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R, hydrogen: 5.7 g (0.0218 mol) of the methylthiomethyl ether from Example 1 are combined with 4.9 g of anhydrous dimethyl sulfoxide and 4.9 g (0.0209 mol) of 2N,9Ndiacetylguanine (prepared from guanine and acetic anhydride in N-methylpyrrolid-2-one) in 20 ml of 28 anhydrous dimethylformamide. The mixture is cooled to -20 0 C and 5.5 g (0.0209 mol) of tin tetrachloride are added dropwise to the suspension with stirring.

After addition is complete, the reaction mixture is stirred at 80°C for 5 hours. It is then allowed to cool, the reaction mixture is treated with dichloromethane and ice-water, extracted several times with dichloromethane, and the combined organic phases are first shaken with water, then with aqueous sodium hydrogen carbonate solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated.

HPLC analysis (RP 18 (LiChrospher 100 RP 18, pm, 125-4), water/methanol 1:1 0.1% of trifluoroacetic acid, ammonium acetate) shows a ratio of 7-isomer/9-isomer of 47.5:47.7. The crude yield is 7.5 g (94.4% of theory) of a pale oil. The isolation of the 7-isomer is carried out by means of column chromatography on neutral alumina using a mixture of ethyl acetate/methanol 9:1 and yields g (44% of theory) of 2N-acetyl-7-[l,3-bis- (isopropoxy)-2-propoxymethyl]guanine of melting point 162 163 0

C.

IH-NMR (60 MHz, d6-DMSO), ppm: 11.93 broad, 2H), 8.35 1H), 5.73 2H), 3.83 1H), 3.55 3.17 6H), 2.20 3H), 0.93 12H).

3.1. Compound of the formula I in which R, chlorine,

R

2 acetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 6.9 g (0.033 mol) of 2-acetamido-6-chloropurine (for preparation see under 5a.) are heated to reflux under argon for 3 hours with 28 ml of hexamethyldisilazane (HMDS) and 0.2 g of ammonium sulfate in 28 ml of dry xylene. The solvent and excess HMDS are then distilled off, the residue is dissolved in ml of dry 1,2-dichlozoethane and the solution is I_ 1_ 29 added at -30 0 C to a solution of 6.3 g (0.024 mol) of the methylthiomethyl ether from Example 1 in 85 ml of dry 1,2-dichloroethane. 5 ml (0.026 mol) of trimethylsilyl trifluoromethanesulfonate are then added and the mixture is stirred at -30"C for 2 hours.

The reaction product is poured into 150 ml of icewater and filtered, and the residue is washed with 1,2-dichloroethane. The aqueous phase is extracted by shaking with 1,2-dichloroethane; the combined organic phases are extracted by shaking with water, then with dilute sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated. HPLC analysis (RP 18 (LiChrospher 100 RP 18, 125 x 4), water/acetonitrile 3:1 0.1% TEA) shows the presence of 73% of 2-acetamido-6-chloro- -7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine in addition to 2% of the corresponding 9-isomer.

3.2. The analogous conversion in acetonitrile and using 3.8 equivalents of tin tetrachloride gives 73% of the 7-isomer and 23% of the 9-isomer (HPLC analysis of the crude product as in the preceding example).

Process according to 6c): 4.1. Compound of the formula VIII in which L 2 acetoxy,

R

3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 200 ml of anhydrous diniaethyl sulfoxide are added dropwise with stirring to a mixture of 120 ml of glacial acetic acid and 100 ml of acetic anhydride in such a way that the temperature of the mixture does not rise above 35°C. The mixture is stirred for a further 30 minutes before 35.2 g (0.2 mol) of 1,3-bis(isopropoxy)propan-2-ol (prepared as described above) are added dropwise. After completion of the addition, the mixture is heated at I00 0 C for 7 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether several tim~es by shaking. The organic phase is then washed with water and subsequently with aqueous hydrogen carbonate solution, dried over sodium sulf ate and evaporated. A pale yellow oil remains, which is subjected to fractional distillation. A forerun of boiling point 46 47*C at a pressure of 15 mmn Hg is composed of thiomethylmethyl acetate.

The reaction product, 2-acetoxymethoxy-1,3-bis- (isopropoxy)propane, boils at 87 92*C at a pressure of 1 nun Hg. The yield is 27.3 g (55% of theory).

'H-NIMR (60 MHz, CDCl 3 ppm: 5.43 2H), 4.0 3.33 (in, 7H), 2.12 3H), 1.33 12H).

The followiLng were prepared in this manner: 2-acetoxymethoxy-1, 3-bis (nethoxy)propane 4.3. 2-acetoxyinethoxy-1,3-bis(ethoxy)propane 4.4. 2-acetoxymethoxy-1, 3-bis (propoxy)propane 2-acetoxymethoxy-1,3-bis(benzyloxy)propane 4.6. 2-acetoxymethoxy-1, 3-bis (cyclopentyloxy) propane 4.7. 2-acetoxyinethoxy-1,3-bis(prop-2-en-1-oxy) propane 4.8. 2-acetoxymethoxy-1-benzyloxy-3-(isopropoxy) propane 4 2-acetoxymethoxy-1-isopropoxy-ethane 4.10. 1-acetoxyinethoxy-2-benzyloxy-3-isopropoxypropane 4 .11. 2-acetoxymethoxy-l-benzyloxyr-3-pivaloyloxypropane 4.12. 2-acetoxymethoxy-l,3-bis (pivaloyloxy)propane 5. Compound of the formula I in which R, chlorine, R= aeamd, R 3 isopropioxyinethylt R 4 31 isopropoxy and R 5 hydrogen: 3.17 g (0.015 mol) of 2-acetamido-6-chloropurine (prepared according to E.M. Acton and R.H. Iwamoto in W.W. Zorbach and R.S. Tipson (editors) Synthetic Procedures in Nucleic Acid Chemistry, Volume 1, Interscience Publishers, John Wiley Sons, New York, 1968, pp. 25 et seq.) are heated under reflux in an inert gas atmosphere for 3-4 hours with 11.3 ml of hexamethyldisilazane and 100 mg of ammonium sulfate in 13 ml of anhydrous xylene and thus converted into the bis-trimethylsilyl compound.

After the reaction is complete, the solvent and excess hexamethyldisilazane are evaporated in vacuo.

The residue is dissolved in 10 ml of anhydrous acetonitrile and added dropwise with stirring to a solution of 2.8 g (0.01 mol) of 2-acetoxymethoxy- 1,3-bis(isopropoxy)propane in 70 ml of anhydrous acetonitrile. 13 g (0.05 mol) of tin tetrachloride are then added slowly at -20 0 C and under an inert gas atmosphere and the mixture is stirred at -20 0

C

for 3 hours. The reaction mixture is stirred into a mixture of ice-water and dichloromethane and filtered. The aqueous phase is extracted several times with dichloromethane and the combined organic phases are then washed twice with sodium chloride solution, dried over sodium sulfate, and filtered and evaporated. A pale syrup remains whose HPLC analysis (RP 18 (Nucleosil 5 C18) water/acetonitrile 3:1 0.1% TEA) gives a content of 86% of the 7-isomer and 4% of the 9-isomer. Chromatographic purification on silica gel using ethyl acetate/methanol 20:1 gives 1.8 g (45% of theory) of 2-acetamido-6-chloro-7-[l,3-bis(isopropoxy)-2propoxymethyl]purine of melting point 73-75'C.

'H-NMR (270 MHz, d6-DMSO), ppm: 10.68 1H), 8.84 1H), 5.81 2H), 3.71 1H), 3.46 3.24 (m, 6H), 2.18 3H), 0.90 12H).

~~1~1 32 Reaction procedure as in 5a., with the difference that the silylated 2-acetamido-6-chloropuzine (0.015 mol) dissolved in 10 ml of anhydrouz 1,2-dichloroethane is added dropwise to a solution of the acetoxymethoxy compound (0.01 mol) in 70 ml of anhydrous 1,2-dichloroethane, and 2.67 g (0.012 mol) of trimethylsilyl trifluoromethanesulfonate are added at -30 0 C and the reaction mixture is stirred at -30 0 C for 2 hours. HPLC analysis of the crude product, carried out as in gives an isomer ratio of 7-isomer/9-isomer of 90:6. Chromatographic purification over silica gel using ethyl acetate/methanol 20:1 yields 2.15 g (53.8% of theory) of a white powder of melting point 72 74 0

C.

The following were prepared in this manner: 5.1. 2-Acetamido-6-chloro-7-[1,3-bis(ethoxy)-2-propoxymethyl]purine of melting point 76 78°C 5.2. 2-Acetamido-6-chloro-7-[1,3-bis(propoxy)-2-propoxymethyl]purine of melting point 74°C 5.3. 2-Acetamido-6-chloro-7-(2-isopropoxyethoxymethyl)purine of melting point 116 118°C 5.4. 2-Acetamido-6-chloro-7-(l-benzyloxy-3-isopropoxy- 2-propoxymethyl)purine as a viscous oil ('H-NMR (270 MHz, d6-DMSO), ppm: 10.70 1H), 8.86 1H), 7.40 7.15 5H), 5.85 2H), 4.38 (s, 21), 3.84 1H), 3.50 3.25 5H), 2.17 (s, 3H), 0.87 6H)), 2-Acetamido-6-chloro-7-[l,3-bis(methoxy)-2-propoxymethyl]purine of melting point 83 84"C 5.6. 2-Acetamido-6-chloro-7-[1,3-bis(prop-2-en-l-oxy)- 33 2-propoxymethyl]purine of melting point 79°C 5.7. 2-Acetamido-6-chloro-7-[1,3-bis(cyclopentyloxy)- 2-propoxymethyl]purine as a viscous oil; 1 H-NMR (60 MHz, d6-DMSO), ppm: 10.73 1H), 8.83 1H), 5.83 2H), 3.75 3H), 3.27 4H), 2.18 3H), 1.42 broad, 16H).

5.8. 2-Acetamido-6-chloro-7-(2-benzyloxy-3-isopropoxyl-propoxymethyl)purine as a viscous oil; 1 H-NMR (60 MHz, d6-DMSO) ppm: 10.77 1H), 8.92 1H), 7.32 5H), 5.82 2H), 4.53 2H), 3.67 3.20 6H), 2.2 3H), 0.93 6H).

5.9. 2-Acetamido-6-chloro-7-[1,3-bis(pivaloyloxy)- 2-propoxymethyl]purine as a glassy foam; 1H-NMR (210 MHz, d6-DMSO), ppm: 10.72 1H), 8.88 1H), 5.79 2H), 5.04 1H), 4.23 1H), 4.05 1H), 3.63 2H), 2.18 3H), 1.05 (s, 9H), 1.01 9H), 5.10. 2-Acetamido-6-chloro-7- (-benzyloxy-3-pivaloyloxy- -2-propoxymethyl)purine as a viscous oil; IH-NMR (270 MHz, d6-DMSO), ppm: 10.70 1H), 8.89 1H), 7.35 7.15 5H), 5.85 2H), 4.40 (s, 2H), 4.15-3.94 3H), 3.49 2H), 2.18 3H), 0.97 9H).

Process according to 6.1. Compound of the formula I in which R, thio, R 2 thioacetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 3.8 g (0.01 mol) of the compound from Example 2. are stirred at 80 85°C under argon for 3 hours with 34 4.4 g (0.011 mol) of 2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in 150 ml of dry toluene. After completion of the reaction, the mixture is allowed to cool, the precipitate is filtered off with suction, the residue is washed with toluene and the filtrate is evaporated. A yellow syrup remains which is purified by chromatography on silica gel using ethyl acetate/methanol 20:1. In this way, 2 g (48.6 of theory) of 2-thioacetyl-7-(1,3-bis(isopropoxy)-2-propoxymethyl)thioguanine are obtained.

The yellowish powder decomposes at 220 0

C.

6.2. Compound of the formula I in which R, thio, R 2 amino, R 3 isopropoxymethyl, R 4 isopropoxy and

R

5 hydrogen: 1.6 g (0.00472 mol) of 7-(1,3-bis(isopropoxy)- 2-propoxymethyl)guanine are heated under reflux for 6 hours with 1.01 g (0.0025 mol) of Lawesson's reagent in a mixture of 50 ml of dry toluene and 10 ml of dry pyridine under argon. The crude product of the reaction is purified by column chromatography on silica gel using a mixture of dichloromethane/ methanol 5:1. 1.2 g (71.6% of theory) of a weakly yellow powder of melting point 232 236 0 C are obtained.

IH-NMR (60 MHz, d6-DMSO), ppm: 12.05 1H), 8.37 1H), 6.55 2H), 6.10 2H), 3.93 3.22 (mp 7H), 0.97 12H).

The compound 6.2. can also be prepared by heating 0.413 g (0.001 mol) of the compound of Example 6.1.

to reflux with 4 ml of 40% strength aqueous methylamine solution and 4 ml of methanol for 3 hours.

Yield: 0.25 g (70.4% of theory).

6.3. Compound of the formula I in which R, methoxy, microtiter plates. After 3 hours, the cultures were infected with different viruses. Vero cells were infected 35

R

2 acetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 1.4 g (0.0035 mol) of the compound from Example are dissolved in 14 ml of methanol with 13 mg (0.2 mmol) of potassium cyanide and the mixture is stirred at room temperature for 24 hours. It is then diluted with 20 ml of methanol and treated for minutes in each case with Serdolit Blue (R) (Serva) (OH form) and Amberlyst 15 (Fluka) (H+ form), the ion exchanger is filtered off and the filtrate is evaporated. The remaining syrup crystallizes on addition of diisopropyl ether. 1.05 g (75.8% of theory) of 2-acetamido-6-methoxy-7-(1,3bis(isopropoxy)-2-propoxymethyl)purine of melting point 67 68*C are obtained.

'H-NMR (60 MHz, d6-DMSO), ppm: 10.73 1H), 8.87 1H), 5.83 2H), 3.80 3.15 10H), 2.17 3H), 0.88 12H).

6.4.1. Compounds of the formula I in which R, amino, R, acetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R. hydrogen and 6.4.2. R, amino, R 2 amino, R 3 isopropoxymethyl,

R

4 isopropoxy and R 5 hydrogen: 6.4.1. 10 g (0.025 mol) of the compound from Example 2.

are treated with about 150 ml of liquid ammonia in 100 ml of methanol and the mixture is heated at 80 0 C in an autoclave at a pressure of 5 bar for 20 hours. The reaction mixture is then completely evaporated and purified by column chromatography (silica gel, dichloromethane- /methanol 0.26 g of theory) of 2-acetamido-6-amino-7-[1,3-bis(isopropoxy)- 2-propoxymethyl3purine of melting point 136 137°C is obtained as a first fraction.

-1 1- MEMOd 36 1 H-NMR (60 MHz, d6-DMSO), ppm: 9.72 1H), 8.30 1H), 6.73 2H), 5.73 2H), 3.83 3.20 7H), 2.20 3H), 0.97 12H).

6.4.2. The second fraction yields 4.6 g (54.4% of theory) of 2,6-diamino-7-[1,3-bis(isopropoxy)- 2-propoxymethyl]purine of melting point 228 229"C.

'H-NMR (60 MHz, d6-DMSO), ppm: 8.10 1H), 6.52 2H), 5.85 2H), 5.67 2H), 3.83 3.22 7H): 1.00 12H).

6.5.1. Compounds of the formula I in which Ri methylamino, R 2 acetamido, R 3 isopropoxymethyl,

R

4 isopropoxy and R, hydrogen and 6.5.2. R, methylamino, R 2 amino, R 3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 6.5.1. 1.4 g (3.5 mmol) of the compound from Example 2 are heated under reflux with 7 ml of 40% strength aqueous methylamine solution and 14 ml of methanol for 2 hours. The reaction solution is then completely evaporated and the residue is separated by column chromatography on silica gel using a mixture of dichloromethane/methanol 10:1.

The first fraction is composed of 0.45 g (32.6% of theory) of 2-acetamido-6-methylamino-7-[1,3bis (isopropoxy) -2-propoxymethyl ]purine of meltir, point 159°C.

1H-NMR (60 MHz, d6-DMSO), ppm: 9.75 1H), 8.28 1H), 6.67 1H), 5.75 2H), 3.77 3.22 7H), 3.00 3H), 2.27 3H), 0.97 (d, 12H).

6.5.2. The second fraction is composed of 0.45 g (36.5% of theory) of 2-amino-6-methylamino-7-[1,3rl. r.i I -g b I 37 bis (isopropoky) -2-propoxymethyl ]purine of melting point 103 104"C.

1 H-NMR (270 MHz, dG-DMSO), ppm: 7.99 1H), 6.29 1H), 5.65 2H), 5.63 2H), 3.65 (m, 1H), 3.45 2H), 3.36 4H), 2.92 3H), 1.00 12H).

If a larger excess of methylamine solution is used and the reaction time is lengthened, the deblocked product 6.4.2. is isolated exclusively in 92% yield.

6.6. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 isopropoxymethyl, R 4 isopropoxy and R, hydrogen: 16 g (0.04 mol) of the compound from Example are exhaustively hydrogenolyzed with hydrogen at room temperature in a duck-shaped shaking vessel using 3.5 g of palladium on carbon and 11.06 ml (0.08 mol) of triethylamine in 350 ml of methanol. After completion of hydrogen absorption, the catalyst is filtered off with suction and the methanolic phase is evaporated. The residue is stirred in ethyl acetate, the precipitate of triethylamine hydrochloride is separated off and the ethyl acetate solution is completely concentrated. The crystalline residue is purified by column chromatography on silica gel using ethyl acetate/methanol 9:1 as the eluent. 14 g (95.9% of theory) of 2-acetamido- 7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine of melting point 94 96 0 C are obtained.

'H-NMR (270 MHz, d6-DMSO), ppm: 10.43 1H), 9.02 1H), 8.71 1H), 5.79 2H), 3.70 1H), 3.41 2H), 3.32 4H), 2.19 (s, 3H), 0.93 12H).

L ,1 i Y_ .L _i i -nLI -r L- 1~C I ~-II ~I 38 6.7. Compound of formula I in which R 1 hydrogen,

R

2 amino, R 3 isopropoxymethyl, R 4 isopropoxy and R 5 hydrogen: 0.178 g (0.5 mmol) of the compound of Example 6.2. are treated with 1.0 g of Raney nickel washed with absolute ethanol in 20 ml of absolute ethanol and the mixture is heated to reflux for hours. The reaction mixture is then cooled, the Raney nickel is filtered off with suction and the ethanolic solution is completely concentrated. The residue is purified by column chromatography on silica gel using ethyl acetate- /methanol 20:1 as the eluent. 0.1 g (61.7% of theory) of 2-amino-7-[l,3-bis(isoprcpoxy)- 2-propoxymethyl]purine is obtained as white flakes of melting point 153 154 0

C.

1H-NMR (270 MHz, d6-DMSO), ppm: 8.65 1H), 8.38 1H), 6.22 2H), 5.67 2H), 3.65 (m, 1H), 3.42 2H), 3.32 4H), 1.00 12H).

The compound of Example 6.7. can also be prepared from the compound of Example 6.6. by reaction with aqueous methylamine solution in methanol.

1.1 g of the compound of Example 6.6. yields 0.8 g (82.2% of theory) of the compound of Example 6.7.

6.8. Compound of the formula I in which Ri hydrogen,

R

2 acetamido, R 3 hydrogen, R 4 isopropoxy and hydrogen: The compound of Example 5.3. is subjected to hydrogenolysis as in Example 6.6. and yields 2-acetamido-7-(2-isopropoxyethoxymethyl)purine of melting point 152 0 C in 95.6% yield.

6.9. Compound of the formula I in which Ri hydrogen,

I~

i 1I~I111 39

R

2 acetamido, R 3 benzyloxymethyl, R 4 isopropoxy and R 5 hydrogen: 4.47 g (0.01 mol) of the compound of Example 5.4.

are subjected to hydrogenolysis as in Example 6.6. and yield 3 g (72.6% of theory) of 2-acetamido-7-( -benzyloxy-3-isopropoxy-2-propoxymethyl)purine as an oil.

IH-NMR (270 MHz, d6-DMSO), ppm: 10.43 1H), 9.03 1H), 8.72 1H), 7.36 7.15 5.82 2H), 4.39 2H), 3.83 1H), 3.50 3.25 5H), 2.18 3H), 0.90 6H).

6.10. Compound of the formula I in which R, hydrogen, R, amino, R 3 hydroxymethyl, R4 isopropoxy and R 5 hydrogen: 1.6 g (4.95 mmol) of the compound of Example 8.3.

are heated under reflux with 50 ml of 40% aqueous methylamine solution in 50 ml of methanol for 1 hour. After distilling off the solvent an oil remains which is treated with acetone and crystallizes after some time. 0.7 g (50.3% of theory) of 2-amino-7-(l-hydroxy-3-isopropoxy-2-propoxymethyl)purine of melting point 125 130 0 C are obtained.

1 H-NMR (270 MHz, d6-DMSO), ppm: 8.66 1H), 8.37 1H), 6.23 2H), 5.67 2H), 4.70 1H), 3.55 1H), 3.36 3.20 5H), 0.95 6H).

6.11. Compound of the formula I in which R, hydrogen,

R

2 amino, R 3 hydrogen, R 4 isopropoxy and

R

5 hydrogen: 2.2 g of the compound of Example 6.8. are treated as in Example 6.10. and yield 1.4 g (74.3% of 40 th.,ry) of 2-amino-7-(2-isopropoxy-2-ethoxymethyl)purine of melting point 158 0

C.

6.12. Compound of the formula I in which R, hydrogen,

R

2 amino, R 3 hydroxymethyl, R 4 hydroxyl and

R

5 hydrogen: 1.6 g (0.0057 mol) of the compound of Example 8.2. are heated to reflux for 2 hours with 10 ml of methanol, 10 ml of 40% strength aqueous methylamine solution and 5 ml of water. Workingup yields 1 g (73.4% of theory) of 2-amino- 7-(1,3-dihydroxy-propoxymethyl)purine of melting point 176 177C.

'H-NMR (270 MHz, d6-DMSO), ppm: 8.68 1H), 8.38 1H), 6.23 2H), 5.69 2H), 4.62 2H), 3.38 6.13.1. Compound of the formula I in which R, hydroxyl, R, hydroxyl, R 3 isopropoxymethyl, R 4 isopropoxy and R. hydrogen and 6.13.2. Compound of the formula I in which R 1 amino,

R

2 hydroxyl, R 3 isopropoxymethyl, R 4 isopropoxy and R, hydrogen.

6.13.1. 1.4 g (0.0041 mol) of the compound of Example 6.4.2. are dissolved in a mixture of 45 ml of tetrahydrofuran and 30 ml of water. 1.8 g (0.027 mol) of sodium nitrite and 24 ml of glacial acetic acid are added, the mixture is stirred at for 90 minutes, a further 1.8 g of sodium nitrite and 9 ml of glacial acetic acid are added, the reaction mixture is completely evaporated, and the residue is treated with a little water and neutralized with concentrated ammonia.

An oil precipitates which becomes solid after L. .L L_ III 41 some time. The precipitate is filtered off, recrystallized from isopropanol and 0.3 g (21.3% of theory) of 7-[1,3-bis(isopropoxy)-2-propoxymethyl]xanthine of melting point 200 201 0 C is obtained.

1 H-NMR (270 MHz, d6-DMSO), ppm: 11.60 1H), 10.89 1H), 8.13 1H), 5.63 2H), 3.83 1H), 3.46 2H), 3.30 4H), 1.01 (m, 12H).

6.13.2. The aqueous mother liquors are evaporated, taken up with dichloromethane and a little water and extracted three times by shaking with 100 ml of dichloromethane. The organic phase is dried (sodium sulfate) and evaporated. The syrup thus obtained is purified by chromatography (silica gel, dichloromethane/methanol After recrystallization from water, 60 mg of theory) of 6-amino-2-hydroxy-7-[1,3-bis(isopropoxy)- 2-propoxymethyl]purine (7-[1,3-bis(isopropoxy)-2-propoxymethyl]isoguanine) of melting point 213 0 C are obtained.

'H-NMR (270 MHz, d6-DMSO), ppm: 11.15 1H), 8.02 1H), 6.88 2H), 5.64 2H), 3.70 1H), 3.47 2H), 3.38 4H), 1.01 (d, 12H).

6.14. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 methoxymethyl, R 4 methoxy and R5 hydrogen: 1.6 g (4.7 mmol) of the compound of Example are subjected to hydrogenolysis as in Example 6.6. and after chromatography on silica gel (ethyl acetate/methanol 5:1) yield 1.25 g (86% of theory) of 2-acetamido..7-[1,3-bis(methoxy)-2propoxymethyl]purine of melting point 42 101 102 0

C.

8.15. Compound of the formula I in which R, hydrogen, R2 acetamido, R 3 ethoxymethyl, R 4 ethoxy and

R

5 hydrogen: 3.7 g (0.01 mol) of the compound of Example 5.1.

are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification on silica gel (ethyl acetate/methanol 9:1) yield 2.9 g (86% of theory) of 2-acetamido-7-[1,3-bis- (ethoxy)-2-propoxymethyl]purine of melting point 117 118 0

C.

6.16. Compound of the formula I in which Ri hydrogen, R, amino, R. prop-2-en-l-oxymethyl, R 4 prop- 2-enoxy and R, hydrogen: 4.35 g (11 mmol, of compound of Example 5.6. are heated to reflux in 60 ml of water with 3.84 g of zinc dust. 1.7 ml of concentrated ammonia are then added dropwise over a period of 2 hours. The cooled suspension is treated with 50 ml of methanol and filtered off with suction; and the residue is washed with methanol. The combined filtrates are concentrated and chromatographed on silica gel using ethyl acetate/methanol 9:1.

2.9 g (82.5% of theory) of 2-amino-7-[1,3-bis- (prop-2-en-l-oxy)-2-propoxymethyl]purine of melting point 140 143"C are obtained.

6.17. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 cyclopentyloxymethyl, R 4 cyclopentyloxy and R 5 hydrogen: 1.1 g (2.44 mmol) of the compound of Example 5.7.

are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification (silica gel, ethyl acetate/methanol 9l1) yield 43 0.8 g (78.6% of theory) of 2-acetamido-7-[1,3bis(cyclopentyloxy)-2-propoxymethyl]purine of melting point 98 0

C.

6.18. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 hydrogen, R 4 benzyloxy and

R

5 isopropoxymethyl: g (16.8 mmol) of the compound of Example 5.8.

are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification on silica gel (ethyl acetate/methanol 9:1) yield 6.3 g (90.6% of theory) of 2-acetamido-7-(2-benzyloxy-3-isopropoxy-l-propoxymethyl)purine of melting point 116 117 0

C.

6.19. Compound of the formula I in which R 1 hydrogen,

R

2 acetamido, R 3 benzyloxymethyl, R 4 pivaloyloxy and R 5 hydrogen: 20.5 g (41.9 mmol) of the compound of Example 5.10. are subjected to hydrogenolysis as in Example 6.6. and after chromatography on silica gel (ethyl acetate/methanol 9:1) yield 17 g (89.2% of theory) of 2-acetamido-7-(l-benzyloxy- 3-pivaloyloxy-2-propoxymethyl)purine of melting point 76 77 0

C.

1 H-NMR (270 MHz, d6-DMSO), 6 ppm: 10.45 1H), 9.05 1H), 8.77 1H), 7.35 7.18 5.83 2H), 4.40 2H), 4.13 1H), 3.99 2H), 3.49 2H), 2.19 3H), 0.98 (s, 9H).

6.20. Compound of the formula I in which Ri hydrogen,

R

2 amino, R 3 -lethoxymethyl, R 4 methoxy and

R

5 hydrogen: 0.77 g (2.25 mmol) of the compound of Example i 44 6.14. is treated with methylamine solution as in Example 6.10. and yields 0.54 g (89.9% of theory) of 2-amino-7-[l,3-bis(methoxy)-2-propoxymethyl]purine of melting point 148"C.

6.21. Compound of the formula I in which R, hydrogen,

R

2 amino, R 3 ethoxymethyl, R 4 ethoxy and

R

5 hydrogen: 1.35 g (4 mmol) of the compound of Example 6.15.

are treated with methylamine solution as in Example 6.10. and yield 0.8 g (67.8% of theory) of 2-amino-7-[1,3-bis(ethoxy)-2-propoxymethyl]purine of melting point 151"C.

6.22. Compound of the formula I in which R I hydrogen,

R

2 amino, R 3 cyclopentyloxymethyl, R 4 cyclopentyloxy and R 5 hydrogen: g (1.2 mmol) of the compound of Example 6.17.

is treated with methylamine solution as in Example 6.10. and yields 0.3 g (66.7% of theory) of 2-amino-7-[1,3-bis(cyclopentyloxy)-2-propoxymethyl]purine of melting point 158*C.

6.23. Compound of the formula I in which R, hydrogen,

R

2 amino, R 3 hydrogen, R 4 hydroxyl and R. hydroxymethyl: 1.4 g (5 mmol) of the compound of Example are treated with methylamine solution as in Example 6.10. and yield 0.45 g (37.7% of theory) of 2-amino-7-(2,3-dihydroxy-l-propoxymethyl)purine of melting point 130 133°C; IH-NMR (270 MHz, ds-DMSO), ppm: 8.67 1H), 8.40 1H), 6.25 2H), 5.60 2H), 4.75 (d, 1H), 4.50 1H), 3.60-3.25 45 6.24. Compound of the formula I in which R, hydrogen, R2 amino, R 3 benzyloxymethyl, R 4 hydroxyl and R 5 hydrogen: 0.66 g (1.45 mmol) of the compound of Example 6.19. is treated with methylamine solution as in Example 6.10. and yields 0.25 g (52.4% of theory) of 2-amino-7- l-benzyloxy-3-hydroxy-2-propoxymethyl)purine of melting point 122"C; 1H-NMR (270 MHz, d 6 DMSO), 6 ppm: 8.68 1H), 8.39 1H), 7.36-7.18 5H), 6.25 2H), 5.71 2H), 4.73 1H), 4.38 2H), 3.68 1H), 3.50-3.31 4H).

6.25. Compound of the formula I in which R, hydrogen,

R

2 acetamido, benzyloxymethyl, R 4 hydroxyl and R 5 hydrogen: g (1.1 mmol) of the compound of Example 6.19.

is dissolved in 10 ml of methanol, and the solution is treated with 10 ml of concentrated aqueous ammonia and stirred at room temperature for 24 hours. Working-up yields 0.25 g (61.3% of theory) of 2-acetamido-7-(l-benzyloxy-3-hydroxy- 2-propoxymethyl)purine of melting point 149°C; IH-NMR (60 MHz, do-DMSO), 6 ppm: 10.47 1H), 9.10 1H), 8.78 1H), 7.30 5H), 5.87 2H), 4.73 1H), 4.40 2H), 3.80-3.30 5H), 2.17 3H).

6.26 Compound of the formula I in which R I hydrogen,

R

2 acetamido, R 3 acetoxymethyl, R 4 acetoxy and R 5 hydrogen: 0.24 g (1 mmol) of the compound of Example 6.12.

is treated with 10 ml of acetic anhydride and mg of N,N-dimethylam,nopyridine and the 46 mixture is stirred at room temperature for 18 hours. After neutralization of the reaction mixture and chromatographic purification of the crude product on silica gel using ethyl acetate/methanol 9:1, 0.2 g (61.9% of theory) of 2-acetamido-7-[1,3-bis(acetoxy)-2-propoxymethyl]purine of melting point 141 0 C is obtained.

1 H-NMR (270 MHz, d 6 -DMSO), 6 ppm: 10.46 1H), 9.04 1H), 8.77 1H), 5.82 2H), 4.16- 4.09 2H), 4.05-3.95 3H), 2.19 1H), 1.70 6H).

Combination of the processes according to 1) 4) with the process according to 7.1. Compound of the formula I in which R I isopropoxy, R 2 e amino, R 3 isopropoxymethyl, R 4 isopropoxy and R, hydrogen: 2 g (0.005 mol) of the compound of Example 5 are dissolved in 25 ml of anhydrous isopropanol, the solution is treated with a solution of 0.345 g (0.015 mol) of sodium in anhydrous isopropanol and the mixture is heated to reflux for 2 hours.

The cooled suspension is treated with ice-water and neutralized with 2 N acetic acid. The precipitate is filtered off with suction, washed with water and dried. 1.5 g (78.6% of theory) of 2-amino-6-isopropoxy-7-[1,3-bis(isopropoxy)- 2-propoxymethyl]purine of melting point 85 87*C are obtained.

'H-NMR (60 MHz, d6-DMSO), ppmt 8.22 1H), 6.08 2H), 5.62 2H), 5.50 1H), 3.87 3.17 7H), 1.35 6H), 0.97 12H).

7.2. Compound of the formula I in which R w methoxy, R2 amino, RS m isopropoxymethyl, R, isopropoxy i r; 47 and Rs hydrogen: 2 g (0.005 mol) of the compound of Example 5. are dissolved in 20 ml of methanol and the solution is added to a solution of sodium ethanolate in methanol (0.35 g of sodium and 20 ml of methanol). The mixture is heated under reflux for 2 hours. Precipitated sodium chloride is filtered off with suction, and the methanolic solution is completely concentrated. The residue is dissolved in a little water and the solution is neutralized with acetic acid. The precipitated product is filtered off with suction, washed with water and dried. 1.5 g (84.9% of theory) of 2-amino-6methoxy7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine of melting point 111 0 C are obtained.

Processes according to 1) 4): 8.1. Compound of the formula I in which Ri hydroxyl,

R

2 acetamido, R 3 hydroxymethyl, R 4 hydroxyl and R 5 hydrogen: 3.81 g (0.01 mol) of the compound of Example 2 are dissolved in 150 ml of anhydrous dichloromethane and the mixture is cooled to -60°C with stirring in an argon atmosphere. 60 ml (0.06 mol) of a 1 molar solution of boron trichloride in n-hexane or dichloromethane are then slowly added, the temperature of the reaction mixture is slowly allowed to rise to -400C to -20'C, and the mixture is stirred at this temperature for 3 hours and then at -10 0 C for a further hour. The mixture is cooled again to -600C, 60 ml of methanol and 60 ml of dichloromethane are slowly added dropwise and a solution is obtained which is treated with 37 ml of triethylamine. The solution is subsequently additionally stirred at room temperature for 30 minutes before the I i _i i _L -ILI _ii -i_ 48 reaction mixture is completely evaporated.

Chromatography on silica gel using a mixture of dichloromethane/methanol 3:1 yields 1.32 g (44.4% of theory) of 2-acetyl-7-(1,3-dihydroxy-2-propoxymethyl)guanine of melting point 155 158°C (decomposition).

1 H-NMR (270 MHz, d6-DMSO), ppm: 12.15 1H), 11.61 1H), 8.37 1H), 5.77 2H), 4.61 2H), 3.62 1H), 3.35 4H), 2.17 (s, 3H).

8.2. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 hydroxymethyl, R 4 hydroxyl and R s hydrogen: According to the same method, 3.65 g (0.01 mol) of the compound of Example 6.6. were reacted with 0.05 mol of boron trichloride and after crystallization from methanol yielded 2.2 g (78.3% of theory) of 2-acetamido-7-(1,3-dihydroxy-2-propoxymethyl)purine of melting point 214 215*C.

'H-NMR (270 MHz, d6-DMSO), ppm: 10.43 1H), 9.07 1H), 8.72 1H), 5.81 2H), 4.65 2H), 3.55 3.28 5H), 2.20 3H).

8.3. Compound of the formula I in which R, hydrogen,

R

2 acetamido, R 3 hydroxymethyl, R 4 isopropoxy and R 5 hydrogen: 3 g of the compound of Example 6.9. are heated under reflux with 4 g of ammonium formate and 1 g of palladium/carbon for 8 hours in 75 ml of methanol. The reaction mixture is filtered, concentrated, treated with acetone and stirred until it crystallizes. 0.9 g (57.4% of theory) of 2-acetamido-7- (l-hydroxy-3-isopropoxy-2-propoxymethyl)purine of melting point 170*C is obtained.

49 'H-NMR (270 MHz, d6-DMSO), ppm: 10.43 1H), 9.04 1H), 8.72 1H), 5.80 2H), 4.73 1H), 3.60 1H), 3.46 3.20 5H), 2.17 3H), 0.90 6H).

8.4. Compound of the formula I in which R, hydrogen, R, ace.amido, R 3 hydrogen, R 4 hydroxyl and

R

5 hydrogen: 2.93 g (0.01 mol) of the compound from Example 6.8. are treated at -60 0 C with boron trichloride for 6 hours as in Example 8.1. After chromatography on silica gel using dichloromethane/methanol 5:1, 2.2 g (87.6% of theory) of 2-acetamido-7- 2-hydroxyethoxymethyl purine of melting point 194*C are obtained.

8.5. Compound of the formula I in which R, hydrogen, R, acetamido, R 3 hydrogen, R 4 hydroxyl and R, hydroxymethyl: 4.13 g (10 mmol) of the compound of Example 6.18.

are treated with boron trichloride as described in Example 8.1. and after chromatographic purification on silica gel (dichloromethane/methanol 3:1) yield 2.8 g (99.6% of theory) of 2-acetamido-7- (2,3-dj.hydroxy-l-propoxymethyl )purine of melting point 167 168 0

C.

so Table 4 Example

R

1 2. OH NHC(O)CH 3

CH

2 00H(0H 3 2 OCH(C11 3 2

H

3.1.

Cl NHC(O)CH 3

CH

2 0CH(CH 3 2

OCH(CH

3 2 Hi 51. Cl NHC(O)CH 3

CH

2

OCH

2

CH

3

OCH

2

CH

3 5.2. Cl NHC(O)CH1 3

CH

2

OCH

2

CH

3

OCH

2

CH

3

H

5.2. Cl NHC(O)CH 3 H20C22 OC(CH) 2 H H 5.52 Cl NHC(O)CH 3

HH

2

OCH

3

OCH

3

H

5.6. cl NHC(O)CHi 3

CH

2

OCH

2 C6HC OCH 2

CHCH

2

H

515 Cl NHC(O)CH 3

CH

2 OCOCCH) OC(OCCH) H Cl NHC(0)CH 3

CH

2 0CH2CH=C OC(0C(CH2) H 6.1. SH NHC(S)CH 3

CH

2 O-cH(cH 3 2 t O-cH(cH 3 2 t H 6.2. ci NCH)H CH 2 COC H 3 )3 OCHO)(CH 3 )3 H 6.3. OCX NHC(O)CH 3

CH

2

OCH(%CH

3 2

OCH(CH

3 2

H

51 Continuation of Table 4; formula I Example R 1 R R 3

R

4

R

6.4.1. NH 2 NHC(0)CH 3

CH

2 0CH(CH 3 2

OCH(CH

3 2

H

6.4.2. NH 2

NH

2

CH

2 0CH(CH 3 2

OCH(CH

3 2

H

6.5.1. NHCH 3

NHC(O)CH

3

CH

2 0CH(CH 3 2

OCH(CH

3 2

H

2. NHCH 3

NH

2

CH

2 0CH(CH 3 2

OCH(CH

3 2

H

6.6. H NHC(0)CH 3

CH

2 0CH(CH 3 2

OCH(CH

3 2

H

6.7. H NH 2

CH

2

OCH(CH

3 2

OCH(CH

3 2

H

6.8. H NHC(0)CH 3 H OCH(CH 3 2

H

6.9. H NHC(O)CH 3

CH

2 00H 2

C

6

H

5

OCH(CH

3

H

6.10. H NH 2

CH

2 0H OCH(CH 3 2

H

6.11. H NH 2 H OCH(CH 3 2

H

6.12. H NH 2

CH

2 0H OH H 6.13.1. OH OH CH 2

OCH(CH

3 2

OCH(CH

3 2

H

6.13.2. NH 2 OH CH 2

OCH(CH

3 2

OCH(CH

3 2

H

6.14. H NHC(O)CH 3

CH

2

OCH

3

OCH

3

H

6.15. H NHC(O)CH 3

CH

2

OC

2

H

5 0C 2

H

5

H

-52 Continuation of Table 4; formula I Examiple R, 6.16. X C"H 2 OCH1 2

CH=CH

2

OCH

2

CH=CH

2

H

6.17. H NFiC(O)CHT 3

CH

2 O-cyclopentyl 0-cyclopenty. H 6.18. 1H NEC(O)CH 3 H OCH 2 C6H 5

CH

2 0CHi(CH 3 2 6.19. H EC C1 3

CH

2 0CH 2

C

6

H

5

OC(O)C(CH

3 3

H

6.20. H NH 2

CH

2 OCH3 OCH 3

H

CH OC 2

H

5 OC H 5

H

H H- CIL: 0cyclopentyl O-cyclopenty. H H1 F OF CH OH

CHOC

2 Ci OH2 HO()H CH OCH C 6

FH

5 OH H 2 CHOHC 3 2

C(H)

OH HO

Claims

1. A compound of the formula I R3 R4 CC(I in which R, is hydrogen, halogen, azide, hydroxyl, C 1 -C 6 -alkoxy, benzyloxy, phenoxy, mercapto, Cl-C 6 -alkylthio, benzylthio, phenylthio, amino, C 1-C 6 -alkyl amino, benzyl amino, phenylamino, C 2 -C 1 2 -dial kyl amino, dibenzylamino, cyclic dialkylamino, diphenylamino, Cl-C-acylamino C 2 -C 1 6 -diacyl amino, (N-alkyl-

2-pyrrolidinylidene) amino or C 2 -C 10 -di alkyl amino methylideneainino, R 2 is hydrogen, halogen, azide, hydroxyl, mercapto, amino, C lkyl amino, C 2 -C 2 -dia lkyl amino, benzylaxnino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenylanino, Cl-C-acylamino and thioacylamino, C 2 -Cl.-diacyl amino or di (thioacyl) amino, R 3 is hydrogen,A C-C 6 -alky, optionally gubstituted by 0s. ar- esQN. halogen or by a hydroxyl, amino, thio, Cl-C 6 -alkcxy, C-C-alkylthio t C-C-alkyl amino, benzyloxy, benzylamino, benzylthio, C 2 -C 1 2 -dialkylamino, di- benzylamino, diphenylamino, Cl-C-acyloxy, CI-C- acyl amino, CI-C 16 -diacyl amino or C 2 -C-acylthio group or a radical Re, where Re is -P(O)(0R 6 )(OR7), 0-(ICaly)-P (OORS) (R7 OI )s C-4akl P(0 R6 R7-NH-(C I-C4 -alkyl) -P (OR 6 -N (CI-C 8 -alkyl) -C 1 -C 4 -alkyl-P (OR 6 (OR,),I -54 (Cl-C-alkyl -P (C,-C-alkyl) (ORB),I (Cl-C,-alkyl) -P (Cl-C 6 -alky1) (OR 6 -NH- (Cl-C-alkyl) -P (C,-C-alkyl) (OR 6 ),I -N Cl-C-alkyl) -C,-C-alkyl-P (C-C 6 -alkyl) (OR 6 in which R. and R7 are independently of one another hydrogen or a Cl-C-alkyl radical or amnmonium, triethyl ammonium or an alkali metal or alkaline earth metal ion, R 4 is hydrogen, Cl-C 6 -alkyl,Ahydroxyl, mercapto, amino, halogen, azide, C,-C 6 -alkoxy, Cl-C 6 -alkylthio, Cl-C-alkylamino, C 2 -C 1 2 dialkyl amino, benzyloxy, benzylthio, benzylainino, dibenzylainino, phenylamino, diphenylamino, phenoxy, phenylthio, CI-C 6 -acyloxy, C-C 8 -acyJlthio, Cl-C-acylamino, C 1 -diacyl amino or C-C 4 -alkyl (O0) (ORB) (OR7) o r -O-(C 1 -C 4 -alkyl)-P(C 1 -C 6 -alkyl) (OR 6 where the radicals R. and R 7 are as defined above, and is hydrogen, C 1 -C 6 -alkyl, optionally substituted by a hydroxyl, I. tIM amino, CI-C 6 -alkoxy, C 1 -Cs-alkylthio, CI-C 6 -alkyl amino, C 2 -C 12 -dialkyl amino, C 1 -CB-acyloxy, C,-Cs-acylthio, Cl-C 6 -acylamino C2-C 1 6 -di acyl amino I benzyloxy, benzylthio, benzylanino, dibenzylanino, phenoxy, phenylthio, phenylamino, diphenylamino group or a radical R8, where Re is -P(O)(ORO)(OR7), -O-(C 1 -C 4 -alkyl)-P(O)(0R 6 )(OR7), (C 1 -C 4 -alkyl) -P (OR 6 (OR 7 ),I -NH- (CI-C 4 -alkyl) -P (0RB)(OR7) -N CI-C-alkyl) -CI-C 4 -alkyl-P (OR 6 (OR,),I -P(C,-Co-alkyl) (0RO),I (CI-C 4 -alkyl) -P (C 1 -C 6 -alkyl) (OR 6 ),I (CI-C 4 -alkyl) -P (C 1 -Cs-alkyl) (0RO),I -NH- (Cl-C 4 -alkyl) -P (C 1 -C 6 -alkyl) (OR 6 ),I N(C 1 -C 6 -alkyl)-C 1 -C 4 -alkyl-P(C 1 -C 6 -alkyl) (OR 6 in which R6 and R 7 are independently of one another i~r__l hydrogen or a C,-Cs-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable salts and obvious chemical equivalents, with the exception of compounds in which, at the sarie time: R, is hydroxyl and R 2 is amino or acetamido; or R, is chlorine or methoxy, R 2 is amino, R 3 is benzyloxymethyl, R 4 is benzyloxy and R 5 is hydrogen; or R 1 is chlorine, R 2 is amino, R 3 is methylthiomethyloxymethyl, R 4 Is benzyloxy and R 5 is hydrogen; or R, is chlorine, R 2 is amino, Ra is hydrogen, R 4 is methylthiomethyloxy and R 5 is benzyloxymethyl; or R 1 is chlorine, R 2 is amino, R 3 is benzyloxymethyl, R 4 is benzyloxy and Rg is methyl; or R, is methoxy, R 2 is amino, R 3 is hydroxymethyl, R 4 is hydroxyl and R 5 is hydrogen; or R, is chlorine or amino, R 2 is hydrogen, R 3 is hydroxymethyl or benzyloxymethyl, R 4 is hydroxyl or benzyloxy and R 5 is hydrogen; or R 1 is amino, R 2 is mercapto, R 3 is benzyloxymethyl, R 4 is benzyloxy and R 5 is hydrogen; or R, is benzyloxy, R 2 is chlorine, R 3 is benzyloxymethyl, P 4 Is benzyloxy and R 5 Is hydrogen; or R, is chlorine, R 2 is amino, R 3 is acetoxymethyl, R 4 is acetoxy and Rg is hydrogen; or R 1 is benzyloxy, R 2 is chlorine, R 3 is hydrogen, R4 is benzyloxy and R 5 Is benzyloxymethyl; or R, and R, are chlorine, R 3 is hydrogen or benzyloxymethyl, R 4 is benzyloxy and R s Is hydrogen; or R 1 is amino, R 2 is mercapto, R 3 and R 5 are hydrogen and R 4 is acetoxy; or R 1 is hydroxyl or chlorine, R 2 is 4-n-butylanilino, R3 and Rs are hydrogen and R4 Is hydroxyl or acetoxy; or R 1 is hydrogen, R 2 is amino, R3 and Rs are hydrogen and R 4 is hydroxyl or acetoxy; or 55a R, is iodine, R 2 is chlorine, R 3 and are hydrogen and R 4 is hydroxyl; or RI, R 2 and R 5 are hydrogen and R 4 is acetoxy; 56 'J"AP~n R 2. A compound of the formula I as claimed in claim 1, in which R, is hydrogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms, amino, CI-C 6 -alkylamino or C 2 -Cs-di (alkyl) amino, or Cl-C-alkylthio, R 2 is hydrogen, halogen, hydroxyl, amino, C 1 -C 6 -alkylamino, C.-C 6 -di alkyl amino or C I-Ce-acyl amino, R 3 is hydrogen, Cl-C 6 -alkyl, optionally substituted by a hydroxyll amino or CI-C 6 -alkoxy group or halogen or a Cl-C-acyloxy, C 1 -C8-acylamino or CI-C 6 -alkyl amino group or a group Raj where Ra is -O-(Cl-C 4 -alkyl)-P(O)(OR 6 ),OR7)I -P(O)(0R 6 )0 7 or -P(C 1 -C 4 -alkyl)(O)(0R 6 in which R 6 and R 7 are independently of one another It, drogen or a CI-C 6 -alkyl radical or an alkali metal or alkaline earth metal ion, R 4 is hydrogen, hydroxyl, amino, mercapto, CI-C 6 -alkoxy, CI-C8-acyloxy, CI-C 6 -alkyl amino or a (C 1 -C 4 -alkyl) P (ORO) (OR 7 or (CI-C 3 -alkyl) -P (CI-C6-alkyl) (OR 6 radical having the meanings R 6 and R 7 as described above and R 5 is hydrogen or C 1 -C 4 -alkyl, optionally substituted by hydroxyl, Cl-Co-acyloxy, benzyloxyj C 1 -Cs-alkoxy, amino.. Cl-C 6 -alkylamino or a radical where R 8 is -P (OR 6 or -P (C 1 -C4-alkyl) (0)(OR 6 in which R6 and R7 are def ined as described above.

3. A compound of the formula I as claimed in claims 1 or 2, in which R, is hydrogen, hydroxyl, chlorine, mercapto, benzyloxy, Cl-C-alkoxy, amino, C 2 -C 3 -alkylamina or C2-C-dialkylamino, 57 R 2 is hydrogen, hydroxyl, amino or Cj-C 8 acyl amino, R 3 is hydrogen, Cl-C 3 -alkyl, optionally substituted by a hydroxyl, C,-C.-acyloxy or Cj-C.,-alkoxy group or a 0 K 0-CH 2 P-OR 6 OR 7 or -P (ORB)(OR7) group where R. and R 7 have the above meanings, R 4 is hydrogen, hydroxyl or a Cl-Cs-acyloxy or 0 CI-C 6 -alkoxy group or -C 2 P0R and OR 7 R 5 is hydrogen or Cl-C 4 -alkyl, optionally substituted by hydroxyl, CI-C.-acyloxy or Cl-Cs-alkoxy or -P (0RB) (R 7 where R 6 and R 7 have the above- mentioned meanings.

4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which R, is hydrogen, hydroxyl, chlorine, C 1 -C 4 -alkoxy, amino, C I-C 3 alkyl amino or C 2 -C 8 -dialkyl amino, R 2 is hydrogen, hydroxyl, amino or Cl-C3-acyl amino, R 3 is CI-C 3 -alkyl, optionally substituted by hydroxyl or by CI-C-acyloxy or by CI-C 8 -alkoxy or by -P(O)(0R6)(OR7), where R6 and R, have the above- mentioned meanings, R 4 is hydroxyl or Cl-Cs-acyloxy or C 1 -C 6 -alkoxy and R 5 is hydrogen. A compound of the formula I as claimed in one or more of claims 1 to 4, in which R, is hydrogen, chlorine or amino, R 2 is amrino or C I-C3-acyl amino, YLL-- R 3 is Ci-Cs-alkyl, optionally substituted by hydroxyl or by Ci-Cs-acyloxy or by C1-Cs-alkoxy or by -P(O)(OR 6 )(OR 7 where R 6 and R 7 have the abovementioned meanings, R 4 is hydroxyl or C1-Cs-acyloxy or C1-Cs-alkoxy and Rs is hydrogen.

6. A compound of the formula I as claimed in one or more of claims 1 to 5, in which R 1 Is hydrogen, R 2 is amino, R 3 is C1-C 3 -alkyl, optionally substituted by hydroxyl or by C 1 -C 4 -acyloxy or by Cl-C 4 -acyloxy or by C 1 -C4-alkoxy, R 4 is hydroxyl or C 1 -C 4 -acyloxy or C 1 -C 4 -alkoxy and Rs is hydrogen.

7. A compound of the formula I as claimed In one or more of claims 1 to 6, in which R 1 Is hydrogen, R 2 is amino, R 3 Is hydroxymethyl, R 4 is hydroxyl and Rs is hydrogen.

8. A preparation for the preparation of a compound of the formula I as claimed In one or more of claims 1 to 7, which comprises a) if in the compound of the formula I R 4 is hydroxyl, amino, aminoalkyl or mercapto, replacing a protecting group At in a compound of the formula H Rl 3 IRS I I I Ri CH-O-CH-H-Al U IZ I C- N/ by a hydroxyl, amino, aikylamino or mercapto group, or b) If In the compound of the formula I R3a Is hydroxyalkyl, aminoalkyl, alkylaminoalkyl or mercaptoalkyl, replacing a protecting group A 2 In a compound of the formula III H alkyl-A 2 F 1 CH-O-CH-CH-Rs I I 1 (111) by a hydroxyl, amino, alkylamino or mercapto group, c) if In the compound of the formula I Rl 5 Is hydroxyalkyl, aminoalkyl, monoalk)-laminoalkyl or mercaptoalkyl, replacing a protecting group A 3 In a compound of the formula IV H Rl 3 aikyl-A 3 I3 1 1 I F 1 CH-O--CH-CH (IV) I I I N N\ Hl 4 II/C R2 NN N by a hydroxyl, amino, aikylamino or mercapto group, or d) If in the compound of the formula I F13 Is hydroxyalkyl, aminoalkyl, monoalkylamlnoalkyl or thioalkyl and/or R1 4 is hydroxyl, amino, alkylamino or mercapto and/or Ps 5 Is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyi I I or mercaptoalkyl, replacing a protecting group A 4 and/or As and/or A 6 In a compound of the formula V H alkyl-A 4 I I Ri CH-O-CH-CH-As (V) I I C Nalkyl-A 6 R C C by a hydroxyl, amino, alkylamino or mercapto group, or e) converting a compound at the formula VI H RS R 4 SCH-O-CH-CH-R 5 (VI N CI I CN C N In which Y and Z are precursors of the groups Rj and R 2 Into a compound of the formula I in which R 1 and R 2 have the meanings described above, or f) reacting a compound of the formula VII I 1 N Cr N I Ii C (ViI) Ll with a compound of the formula VIII R 3 R 4 II (Vill) L2 CH2C 0 H (vII) I HS i clil- g) removing a blocking group from a compound of the formula I In which one or both radicals R 1 and R 2 are blocked, and if the product of the reaction is a base of the formula I, optionally converting it into an acid addition product of this base of the formula I, or if the product of the reaction is a salt of a base of the formula I, optionally converting it into its base or into another salt of this base. 9, A method of prophylaxis or treatment of viral diseases comprising administering to a patient requiring such treatment, an effective amount of a compound of the formula I as claimed in any one of claims 1 to 7 or their physiologically tolerable salts or obvious chemical equivalents, A pharmaceutical containing at least one compound of the formula I as claimed in one or more of claims 1 to 7 In adjunct with pharmaceutically acceptable carriers and exclpients.

11. A method of preparation of pharmaceuticals for the treatment of virus diseases comprising admixing in a pharmacologically effective ratio purine derivatives of the formula I as claimed in any one of claims 1 to 7 with pharmaceutically acceptable carriers and exciplents, and bringing said admixture into suitable administration form. DATED this 1st day of October, 1993. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA WA K3 MS WA. ax bV) AU?3I5 441 W0O