CA2038589A1 - Substituted purines, processes for their preparation and their use as antiviral agents - Google Patents

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

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Publication number
CA2038589A1
CA2038589A1 CA002038589A CA2038589A CA2038589A1 CA 2038589 A1 CA2038589 A1 CA 2038589A1 CA 002038589 A CA002038589 A CA 002038589A CA 2038589 A CA2038589 A CA 2038589A CA 2038589 A1 CA2038589 A1 CA 2038589A1
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alkyl
hydrogen
amino
hydroxyl
compound
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Gerhard Jahne
Manfred Rosner
Irvin Winkler
Matthias Helsberg
Thomas Scholl
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Abstract of the disclosure:

Substituted purines, processes for their preparation and their use as antiviral agents Compounds of the formula I

Description

r~

- HOECHST AKTIENGESELLSCHAFT ~OE 90/F 093 Dr.WN/PP

De~cription Substituted purines, processes for their preparation and their use as antiviral agents The pre~ent invention relates to derivative~ 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 purine~ ~uch 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-substi~uted 2-hydro~yethoxymethyl radical or 1,3-dihydro~y-2-propoxymethyl radical or 1~ 2,3-dihydroxy-1-propox~methyl radical in the 7-position.

The invention further relates to the phyQiologically tolerable ~alts of said compounds.

While the antiviral activity and the prepara~ion of purine nucleosides which carry an acyclic radical in the 9-position are already l~ng-known (~ee, for example, DE-OS 2,539,963 or R.g. Ogilvie et al., Can.JOChem. 62, 241 (1~84) or C.g. Chu and S.J. Cutler, J. ~eterocyclic Chem. 23, 289 (1986)), to date nothing i~ known about a specific synthesis of a~yclic purines substituted in the 2S 7-position or their antiviral activity.

Only J. R~ellberg et al., J. Heterocyclic Chem. 23, 625 (1986) and J. ~. 8essler et al., Nucleo ide~ + ~ucleo-tides 8, 431 (1989) de~crlbe a more or le~s selective method for the preparation of carboacyclic guanines and 2-aminopurines substituted in the 7~po~ition. However, the compounds prepared in this way were not lnve~tigated for their antiviral activity or were inactive in in vitro 2 ~

investigations.

In individu l cases, the acyclic purine derivatives substituted in the 7-po~ition were ~eparated from the desired acyclic purine deriva~ives substituted in the 9-position and investigated for their antiviral activity in vitxo (R. ~. Ogilvie et al.~ Can. J. Chem. 62, 2702 (1984), R. ~. Ogilvie et al.~ Can. J. Ch~m. ~2, 241 (1984)) and found to be inactive.

It has now surprisingly been found that certain 7-~ub-stituted purines and ~heir physiologically tolerablesalts have antiviral prop~rties agsins~ various DNA
~iruses, ~NA viruses and retroviruses.

The invention accordingly relates to compounds of the formula I

R3 ~R~
Rl CH2 _ O- CH I~H ~5 N ~ C ~ ~ ~ (I) in which Rl is hydrogen, halo~en, azide, hydroxyl, Cl-C6-alkoxy, benzyloxy, phenoxy, m~rcapto, Cl-C5-alkylthio, benzylthio, phenylthio, amino, Cl C6-alkyl~mino, benzylamino, phenylæmino, C2-Cl2-dialkylamino, dibenæylamino, cyclic dialkylamino, diphenyl~mino, C1-C8-acylamino, C2-C16-diacylamino, (N-alkyl-2-pyrrolidinylidene)amino or C2-C1O-dial~ylamino-methylideneamino, R2 is hydrogen, halogen, azide, hydroxyl, mercapto, ~5 amino, Cl-C6-alkylamino, C2-C12-dialkylamino, benzylamino/ dibenzylamino, cyclic dialkylamino, ~2 ~ 8 ~

phenyl~nino, diphenylamino, C1-C3-acylamino and thioacylamino, C2-Cl6-diacylamino or di(thioacyl)-amino, R3 is hydrogen, C~C6-alkyl, optionally substituted by halogen or ~y a hydroxyl, amino, thio, C1~C6-alkoxy, C1 C6-alkylthio, Cl~C6-alkylamino, benzylo~y, benzylamino, b~nzylthio, C2-C12-dialkylamino, di-benzylamino, diphenylamino, C1-Ca-acyloxy, C1-C~-acylamino, C2-C1~-diacylamino or C1-C~-acylthio group or a radical R6, where R6 is -P~O~OR~)(OR7), -o-~Cl-C4-alky~)-P(~)(oRB)(~R7)~
-S ~cl~C4-alkyl)-P(o~(oR6)( NH (cl-c4-alkyl)-P(~)(OR6)(oR7)~
-N(Cl c6-alkyl)-C,-C4-alkYl-P(O)(OR8)(0R7)~
-P(cl-c6-alkyl~(o)(oR6~, -o-(Cl-C4-alk~l)-P(Cl-C6-a~ )(O)(OR6)~
-S-(Cl-(:~4-alk~l)-P(Cl-C6-alkyl)(O)(OR6), -NH-(Cl-C4-alkyl)-P(Cl-C6-~lkyl)(O)(OR6), -N(Cl-C6-alkyl)-Cl-C~-alkyl-P(Cl~C~-alkyl)(O)(OR6) in which R6 and R7 are independently of one another hydrogen or a Cl-C6-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R4 is hydrogen, Cl-C6-~lkyl, hydroxyl, mercapto, amino, 2~ halogen, azide, Cl-C6-alkoxy, Cl-C6 alkylthio, Cl-C6-alkylamino, C2-Cl2-dialkylamino, benzyloxy, benzylthio, benzylamino, dibenzylaminol phenylamino, diphenylamino, phenoxy, phenylthio, Cl-C8-acylo~y, Cl-C6-acylthio, Cl-C8-acylamino, C2-Cl6-diacyl~ino or -O-~Cl-C4-alkyl)-P~O)(OR6~(0R7) or -O-(Cl-C4-alkyl)-p(O)(~R6)(OR7) or -O-(C1-C4-alXyl)-P(C1-C6-alkyl)(O)(OR~), where the radicals R6 and ~7 are as defined above, and R5 is hydrogen, Cl-C6-alkyl, optionally ~ubstituted by a hydroxyl, thio, amino, C1-C6-B1kOXY, 2~3~

C1C6-a~ thio, c~-c6 alkylamino~ C2-C12-dialkylamino, C~_CB_aCY10XY, C~_Ca_aCY1thiO~ Cl-CB-acylamino, C2-C~6~diacylamino, benzyloxy, ben~ylthio, benzyl~nino, dibenzylamino, phenoxy, phenylthio, phenylamino or diphenylamino group or a radical R
where R8 is _p(~)(OR6)(~R7)~
-O-(Cl-~4-alkyl)P(O)(OR~)(OR~, -S-(C~ C4-alkyl)-P(O)(OR~)(OR7), -NH-(cl-c4-alkyl)-p(o)(oR6~(oR7)~
-N ( C1_C~_a1kY1~ -C~ C4 alkyl-P(O)(OR6)(OR7), -P(cl-c6-;~ ) () (OR6) ~
-O-(C~-C4-alkyl)-P(Cl-C~;-alkyl)(O)~OR6), -S- ( Cl-C4-alkyl ) -P ( Cl-C6-~llkyl ) ( O ) ( OR6 ), -NH-(Cl-C~-alkyl) P(C~-C6-alkyl~(O)(OR6), N(C~-C6-alkyl)-Cl-C4 alkyl-P(C1-C6-alkyl~(O)(OR~), in which R5 and R~ are independently of one another hydro~en or a Cl-C6-alkyl radical or ammonium, triethyla~monium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable ~alts and obvious chemical equivalents, with the proviso that, at the s2me time, Rl is not hydroxyl and R2 is not amino or R1 is not hydroxyl, R2 i6 not acetamido, R3 is not benzyloxymethyl, R4 i6 not benzyloxy and R5 i~ not hydro-gen or Rl is not chlorine or methoxy, R2 i~ not amino, R3 ~ not benzyloxymethyl, R4 i~ not benzyloxy and R5 is not hydrogen or Rl i~ not hydroxyl, R2 is not acetamido, R3 i8 not acetoxymethyl, R4 i8 not acetoxy and R5 i.s not hydrogen or Rl is not methoxy, R2 is not amino, R3 ~. not hydroxy-methyl, R4 i~ not hydroxyl and Rs i~ not hydrog9n or Rl is not chlorine or amino, Rz i~ not hydrosen/ R3 i~ not hydroxymethyl or benzyloxymethyl, R4 i~ not hydroxyl or ~enzyloxy and Rs i~ not hydrogen or R1 ie not amino, R2 is not mercapto, R3 i8 not benzyloxy-methyl, R4 is not benzyloxy and Rs is not h~drogen or ; ~

~ ~ ~3 ~ ~ ~ 9 Rl is not benzyloxy, R2 iS not chlorine, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or R1 is not chlorine, R2 iS not amino, R~ i5 not aceto~y-methyl, R4 is not acetoxy and R5 is not hydrogen or Rl i5 not benzyloxy, R2 i8 not chlorine, ~3 i8 not hydrogen, R4 i8 not ben~yloxy and R5 i~ not ben~ylo~y-methyl or Rl and R2 are not chlorine, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 iS not hydro~en or Rl is not amino, R2 is not mercapto, R3 and R5 are not hydrogen and R4 is not acetoxy or R, is not hydrogen, R2 is ~ot amino, R3 and R5 are not hydrogen and R4 is not hydroxyl or acetoxy or R1 and R2 are not chlorine, R3 and R5 are not hydrogen and R4 is not benzyloxy or R1 is not iodine, R2 is not chlorine, R3 and R5 are not hydrogen and R4 is not hydroxyl.

Preferred compounds of the formula I are those in which Rl is hydrogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms~ amino, C1-C6-alkylamino or C2-C6-di(alkyl~amino, or Cl~-C6-alkylthio, R2 is hydrogen, halogen, hydroxyl, amino, C1-C6-alkylamino, Cz-C6-di~alkyl)amino or C1-C6~acylamino, R3 i~ hydrogen, Cl-C6-alkyl, optionally ~ubstituted by a hydroxyl, amino or Cl-C6-alkoxy group or halogen or a Cl-C~ acyloxy, Cl-C8-a~ylamino or Cl C6-alkylamino group or a group R~, where R8 is -O-(C1-C~-alkyl)-P(O)(OR6)(OR7), -~(O)(ORs)tOR7) or -P(Cl-C4-alkyl)(O)~OR6), in which R6 and R~ are independen~ly of one another hydrogen or a Cl~C6-alkyl radical or an alXali metal or alXaline earth metal ion, ~3~

~ R4 i~ hydrogen, hydroxyl, amino, mercapto, C1-C6-alkoxy~
C~-C8-acyloxy, C1~C6-alkylamino or an O-(C,-C4 alkyl)-P(O~(OR6)(OR7) or -O-(C1-C~-alkyl)~P(C1~C~-alkyl)(O)(OR6)radicalhaving the meanings R6 and R7 a~ described above and R5 i~ hydrogen or C1-C4-alkyl, optionally sub~tituted by hydroxyl, Cl C8-acylo~y, benzyloxy, C1-C6-alkoxy, amino, C1-C6-alkylamino or a radical R8, where R8 i6 -P(O)(OR6)(OR7~ or -P(Cl-c4-alkyl)(o)~oR6)~ in which Rs and R7 are d~fined as de~cribed above.

Particularly preferred compound~ of the formula I are those in which Rl is hydrogen, hyd~oxyl, chlorine, mercapto, ben~yloxy, Cl-C6-alkoxy, Emino, Cl-C3-alkylamino or C2-C6-dialkylamino, R2 i~ hydro~en, hydroxyl, ami.no or Cl-C8-acylEmino, R3 is hydrogen, Cl-C3-alkyl, optionally substituted by a hydroxyl, Cl-C8-acylo~y or Cl-C6-alkoxy group or a 2- ~- OR6-or P~O)(OR6)(OR7) group, where R6 and R7 have the above meanings, R4 i~ hydrogen, hydroxyl or Cl-C8-acyloxy sr Cl-C6alkoxy or CH2-P-OR6 and ~R7 R5 is hydrogen or C1-C4-alkyl, optionally ~ubstituted by hydroxyl, Cl-C8-acyloxy or Cl-C6-alkoxy or -P(O)(OR6)(OR7), where R6 and R7 have the above-mentioned meanings.

Very particularly preferred compounds of the formula I

are those in which Rl is hydrogen, hydroxyl, chlorine, Cl-C4-alkoxy, amino, Cl-C3~alkylamino or C2-C6-dialkylamino, R2 is hydrogen, hydroxyl, amino or Cl-C3-acylamino, R3 is Cl-C3-alXyl, optionally substituted by hydroxyl or by C1-C8~acyloxy or by Cl-C6-alkoxy or by -P(O)~OR6)(0R~), where R6 and R7 ha~e the above-mentioned meanings, R4 is hydroxyl ox Cl-Ca acyloxy or Cl-C~ alkoxy a~d R5 is hydrogen.

Compounds of the formula I furthermore have particular significance, in which Rl is hydrogen, chlorine or amino, R2 is amino or Cl-C3-acylamino, 5 R3 is C1-C3-alkyl, optionally substituted by hydroxyl or by C1-Cs-acyloxy or by C1-C5-alkoxy or by -P(O)(OR8)(OR7), where R6 and R7 have the above-mentioned meanings, R4 is hydxoxyl or Cl-C5 acylo~y or C1-Cs-alkoxy and 0 R5 is hydrogen;

and compounds of the formula I have very particular signific~nce, in which R1 is hydrogen, R2 is amino, 5 R3 is C1-C3-alkyl, optionally substituted by hydroxyl or by C1-C4-acyloxy or by Cl-C4-alkoxy, R4 is hydroxyl or Cl-C4-acyloxy or Cl-C4-aIkoxy and R5 iB hydrogen, in particular the compound of the formula I in which R~ is hydrogen, Rz is amino, R3 is hydro~ymethyl, R4 is hydroxyl and Rs is hydrogen.

Said alkyl groups as substituents of the aboveme~tioned formula I can be branched, u~branched or cyclic. Examples of alkyl groups are the methyl, ethyl, propyl, isopropyl, bu~yl 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, pipPridino, morpholino, ~methylpiperazino or 1,2,4 triazolo group.

The preferred halogen substituent is chlorine~ Particu-larly suitable alkali metal or alkaline earth metal substituents are sodium and calcium.

The compounds of these inventions are all ~ubstituted acyclic purine nucleosidesj ~hich carry the acyclic substituent in the 7-position of the purine ring system.

Salts o~ the compounds according to the invention par-ticularly suitable for therapeutical purposes are saIts of physiologically tolerable organic and inorganic acids such as acetic acid, lactic acid, malic acid, p-toluene-sulfonic acidl methane6ulfonic acid, isethionic acid, hydrochloric acid or sulfuric acid.

Obvious chemical equival~nts of the compounds according to the invention are in particular derivative~ thereof which can be converted into the compounds according to the invention without problem, for example under phy~io logical conditions~

Of the compounds of the formula I according to the invention 2-amino-7-(lg3-dihydroxy-2 propoxymethyl)purine = compound of th~ fonmula I in which Rl = H, R2 = NH2~

9 2~$e3~5~
- R3 = CH2-OH, R~ = 3H and Rs = H tExample 6.12.), 2-amino-7 (l-hydroxy 3-i~opropoxy-2-propox~methyl)purine = compound of the formula I in which R, = h~drogent R2 =
amino, R3 = hydroxymethyl, R4 = i~vpropoxy ~nd R5 =
hydrogen (Example 6.10.
and 2-amino-7-(1,3-bisti~opxopoxy)-2-propoxymethyl)purine =
compound of the formula I in which Rl = ~ R~ = NR2, R3 a CH2-O-CH(CH3~ 2 ~ R4 - O-CH(CH3)2 and R5 = ~ ~xample 6.7.) are particularly preferred, in particular because of their particularly hi~h antiviral activity asainst herpes viruses.

Other compounds of the formula I where R~ = hydrogen, R2 = amino and an acyclic side chain whose h.ydroxyl function or hydroxyl functions is/are e~terified with Cl-C6-alkyl radicals or esterified with Cl-C6-acyl radicals show particularly high antiviral activity.

The invention furthermore r~lates to the use of said cvmpounds as antiviral agents, the compound~ classif~ed above as excluded not being excluded. The compound~
accordin~ to the inv~ntion are particularly active against herpe~ simplex viruses type 1 and type 2, cyto-megaloviruses, varicella zostex viruses, Epstein Barr viruses and human herpes viruses ~ (HEV6).

~he present invention furthermore relates to proces~e for the preparation of substituted purine~ of the formula I or a physiologically ~olerable salt thereof, which comprise 1) if in the compound of the formula I R4 is hydroxyl, amino, alkylamino or mercapto, replacing a protact-ing group (blocking group~ Al in a compound of the formula II

2~3~9 ~3 ~5 Rl ~--O~Ag N~ ~ ~C ( I
~ C~ jC '~.. N~

by a hydroxyl, amino, alkylamislo or merc:apto group, 2 ) if in the compound of the formula I R3 is hydroxya lkyl, aminoalkyl, alk~rlaminoalkyl or thioalkyl, replacing a protecting group Aa in a compound of the 5formula III

R~ o ~ 5 N ~ \t: ~ ~ C
.4 by a hydroxyl, amino, alkylamino s:r mercapto group, 3 ) if in the compound of the formula I Rs i~ hydro~y-alkyl, aminoalkyl, morloalkylaminoal3cyl ox thioalkyl, rep~acing a protecting group A3 in a compolmd of the 10:fonnula IV
R3 ~lkyl- ~3 O~ R4 ~C~ ~N~ (~Y) R2 ~N ~ N

by a hydroxyl, amino, alkylamino or mercapto group, 4 ) if in the compound of the formula I R3 i5 hydro~-alkyl, aminoalkyl, monoalkylaminoalkyl ox thioallcyl and/or R4 i5 hydroxyl, ~ninol alkylamino or mercapto and/or Rs is hydxoxyalkyl, aminoalkyl, - monoalkylaminoalkyl or thioalkyl, replacing a protec~ing group A4 and/or A5 and/or ~5 in a compound of the formul V

~;C ~ ~N ~ Y1~6 N e ~ ~v3 R~ ~aD ~a by a hydroxyl, ~mino, allcylamino or mercPpto group, 5 ) converting a compound of the fo:rmul2 VI

~3 ~l4 Y C~2~ 5 ~N~
R 6 ~VI ) Z f ~ ~ C ~N~

in which Y and Z are precursors of the grollps Rl and R2 into a compound of the formula I in which Rl and R2 have tha meanings described above, 6 ) reacting a compound of the fonnula VII
' 3i~.
1~
S~ S
~ ~ ~ ~ ~ N /

with a coml?ound of the formula VIII

~3 ~4 L2--CH2--0- CH~ C~ (VII2) R!i in which Lz is a leaving group and ~ hydrogen or 2~3~

-- a leaving group, 7~ removing a blocking group from a compound of the formula I in which one or both radicals Rl and R2 are blocked, and if the product o~ the reaction i8 a base of the formula I, optionally converting it into an acid addition product of khi~ base of the formula I, or if the product of the reaction is a ~al$ of a base of the foxmula I, optionally con~erting it into its base or into another sal~ of this ba~e.

In the cases of processes 1) - 4), hydroxyl, mercapto, amino and mono ubstituted amino $unctions of the acyclic side chain in the 7 po~ition of the purine ~y~tem, if present, are modified at the end by a blocki~g group D
and, if appropriate, a further blocking group E, where D
can be identic~l to or different from E.

~hese blocking groups can be ester~ - for example acyloxy groups - and/or benzyloxy groups - and/or Cl-C6-alkyloxy groups - for example isopropo~y groups.

In the first case, the acyloxy group can be aliphatic -for example acetoxy or pivaloyloxy - or aromatic - for ex~mple benzoyloxy.
Both types of acyl groups can be removed, for e~ample, by mild basic hydrolysi~; in ~eneral warming with agueou~ or alcoholic methylamine i~ adequate in order to achieve removal of the blocking group.

In the ~econd case, the benzylo~y blocking group can be removed by hydrogenolysis, either catalytically or by means of hydrog2n and Raney nickel or pallad~u~/carbon or by means of ammonium formate and palladium/carbon or 39 by means of a transfer hydrogenoly~is with palladium hydroxide and cyclohexene or cyclohexadiene or chomically by reaction with boron halides - for example boron trichloride - at low temperatures - for example at -70 degrees Celsius - or by means of sodium in liquid 3S ammonia, the liquid ammonia being used as solvent.

2~3~

- In the ca~e of catalytic hydrogenolysis, th~ preferred solvent is an alkanol; however, a series of inert solvents can also be u ~d i the substrate i8 at least partially soluble therein. Examples of the~e are benzene, toluene, tetrahydrofuran or dio~ane.
For chemical reaction by mean~ of boron trichloride 9 in which a ~olution of boron trichloride in n-hexane or in dichloromethane or alternatively gaseous boron trichloride is used, dichlorom2thane i~ the preferred solvent.

In the third case, deblocking of the Cl~C6-alkyloxy groups can be achieved if boron rihalides - for example boron trichloride ~ are reacted with the substrate at tempera-tures which are not quite so low - for example at -60C
to 0C, preferably at ~40C to -20C. The preferred solvent for this is dichloromethane and the boron trichloride can be employed in gaseous iorm, as a solution in n-hexane or as a solution in dichlorome~hane.

The conversion of a compound of $he formula VI into a compound of the formula I can be achieved in a ~ery different manner by process 5). For example, one of the two radicals R1 or R2 or both the radicals Rl and R2 can be converted into a halogen by halogenation, into a hydroxyl group by hydrolysis, into a Cl-C6=~alko~y group by conversion with a C1-C~-alkanolate, into a mercap~o group by sulfurization, into a Cl-C8-alkylthio group by reaction with a Cl-C6-alkylthiolate, into an amino group by ammonolysis ~ into sn amino group by deblocking a Cl-Ca-acylamino, Cl-C~-thioacylamino, benzylamino or Cl-C6-alkylamino group, into a Cl-C~ alkylamino group or C2-Cl2-dialkylamino group by aminolysis, or into hydrogen by hydro~enolysis or desulfurization or formation of the azide.

All these processes are known and can be found, for example, in: Heterocyclic Compound~ - Fused Pyrimidines Part II, Purines, editor: D~J. Brown, published by ~:~3~

Wiley-Interscience, 1971.

In process 6), the leaving group L2 f a compound of the formula VIII is either a reactive radical of an inorganic acid and can thus be a~ halogen, preferably chlorin~, or b) a Cl~C6-alkyl~hio or Cl-C6-alXylsulfin~l or Cl-C6-alkylsulfonyl group, preferably the ~ethylthio or the methyl~ulfinyl or the methylsulfo~yl group, or it is a reac~ive radical of an organic ac1d and can thu be c) Cl-C8-acyloxy or benæoyloxy, preferably aceto~y.

In proces~ 6a), the leaving group L1 in a compound of the formula VII is hydrogen or trialkylsilyl, preferably trLmethyl~ilyl.

In process 6b), the leaving group L1 in a compound of the formula VII is a Cl-C8-acylo~ group, preferably the acetoxy group, or a trialkyl ilyl group, preferably the trLmethyl~ilyl yroup.

In process 6c), the leaving g:roup Ll in a compound of the formula VII is a C1-C8-acyloxy group or altern2ti~ely preferably a trialkylsilyl group, in particular the trLmethylsilyl group.

The preferred proce6s according to 6a) compri~es the condensation of a purine with the desired ~ub~titution in the 2- and 6 position with a C1-C8-acyl- or benzyl- or C1-C6-alkyl-blocked 1-(halomethoxy)ethanol, for example 1-(chlorome~hoxy)-2-aceto~yethane or 1-(chloromethoxy)-2-benzyloxyethan~ or 1-(chloromethoxy)-2-isopropoxyethane, or an acyl- andtor arylal~yl- and/or alkyl-blocked 2-(halomethoxy)-1~3-propanediol, ~or example 2-(chloromethoxy)-1,3-bi~(acetoxy)propane or 2-(chloromethoxy)-1,3-~is(benzylo~y)propane or ~3~
- ~5 ~
- 2-(chloromethoxy) l/3-bis(isopropoxy)pxopane, or l (halomethoxy)-2,3-propanediol blocked by a Cl-C~-acyl andJor benzyl an~/or Cl-C6-alkyl, for example 1-(chloromethoxy)-2,3-bis(acetoxy~propane or l~(chloromethoxy)-2,3-bis(benzyloxy)propane or l-(chloromethoxy)-2,3-bi~ opropoxy)propan~
in a ~trongly polar solvent such as dimethylformamide, dimethylacetamidel ~-methylpyrrolid-2-one, te~r~methyl-urea or ~imethyl sulfo~ide/ in the pre3ence of a base, such as triethylamine, ~-ethylmorpholine or of an alkali metal carbona~e, such as, for examplep potas~ium carbonate, at room temperature for 1 - 72 hour~, if L1 in a compound of the formula VII is hydrogen, or in aprotic solvents such as benzene, toluene, xylene, 1,2-dichloroethane, chlorob~nzene, 1,2-dimethoxyethane, dioxane or acetonitrile, in the pre~ence of a base ~uch as triethyl~mine or N-ethylmorpholine, at a reaction temperature of 0 to 150C, preferably at room temperature, for 1 - 7~ hours, if Ll in a compound of the formula VII is trimethyl~ilyl.

It is known that alkylthioalkyl ethers, in particular methylthiomethyl ethers such a~, for example, comp~unds of the fonmula VIII where Lz = methylthio, can be reacted with oxygen nucleophiles and Lewis acids such ~s mercury~II) chloride (E.J. Corey, ~.G. Bock, ~etrahedron Letters 197S, 3269 or R. Yamada, ~. Rato, H. Nag2se, Y. Hirata, ~etrahedron Letters 1976, 65) or ~lkyl-sulfinylalkyl ethers, in particular methyl~ul~inylmethyl ether6 ~uch as, for example, compound~ of the formula VIII where Lz = methylsulfinyl, can be reacted with carbon nucleophiles and Lewi~ acids ~uch a~ zinc iodide (J.A.
Schwindeman, P.D. Magnus, Tetrahedron ~ettex~ 1981, 4925).

The preferred process according to 6bj comprises the condensation of a ~urine with the desired ~ubstitution in the 2- and 6-position with a Cl C8-acyl- or benzyl- or Cl-C6-al~yl-blocked l-(alkyl~hioalkoxy)ethanol, for example l-(methylthiometho~y) -2-acetoxyethane or 1-(methylthiomethoxy)-2-benzyloxyethane or l-(methylthiometho~y)-2-isopropoxyethane or 2-(alkylthioalkoxy3- 1, 3-propanediolorwithaCl-Ca-acyl-and/or benzyl- and/or C,-C6-alkyl-blocked, for example 2-(methylthiomethoxy)-1,3-bis(acetoxy)propane or 2-tmethylthiomethoxy)-1,3 bis(benzyloxy)propane or 2-(methylthiometho~y)-1,3-bis(isopropoxy)propane,orwith a Cl-Ca-acyl- and/or benzyl- and/or C,-C6-alkyl- blocked 1-(alkylthioalkoxy)-2,3propanediol, for example l-(methylthiomethoxy)-2,3-bi6(acetoxy)propane or 1-(methylthiomethoxy)-2,3-bis(benzyloxy)propanP or l-(methylthiomethoxy~2,3-bis(i~opropoxy3propane, where in each case instead o~ the alkyl~hioalkoxy group the alkylsulfinylalkoxy or alkylsulfonylalkoxy group can advantageously also be employed, in a strongly polar solv~nt or solvent mixture such as dLmethylformamide, dimethylacetamide, N-methylpyrrolid-2-one, tetramethylurea and/or dimethyl ~ulfoxide, in the presence of a protonic acid or Lewi~ acid, such ~s iron trichloride, boron trifluoride, ~allium trichloride, aluminum trichloride, titanium tetrachloride, but pxefer-ably tin tetrachloride, or iodine or trialkylsilyl trifluoromethanesulfonate, preferably trimethylsilyl trifluoromethanesulfonate, at a temperature of -40C to +lOO~C, preferably between -20C and ~80C, for ~eYeral hours, if Ll in a compound of the formula VII is C1_CD_aCY1, pre~erably acetyl, or in a le~s polar solvent or solvent mixture ~uch as dichloro~ethane or 1,2-dichloroethane in the pre~ence of a Lewis acid such asiron~III) chloride, boron trifluoride, gallium trichlo-ride, aluminum trichloride, titanium tetrachloride or tin tetrachloride or of a trialkylsilyl trifluoromethane-sulfonate, preferably trimethylsilyl trifluorom~thane-sulfonate, at a temperature of -40C to ~lOODC, preferably between -30C and l20CI for 0.5 to 8 hours, preferably for 1 to 4 hourQ, if Ll in a compound of the formula VII is trial~ylsilyl, preferably trimethylsilyl or in a polar aprotic solvent ~uch as acetonitrile in the ~3~

presence of a Lewis acid such as iron (III) chloridP, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride, ~ut preferably tin tetrachloride, at a temperature of -40C ~o + 100C, pre-ferably between -30C and +20~C, for 0.5 to 8 hour~, perferably for 1 to 4 hours, if ~1 in a compound of the formula VII is trial~ylsilyl, preferably tri~thylsilyl.

The preferred process according to 6c) compri~es the condensation of a purine having the desired sub~titution in the 2- and 6-position, preferably an expediently modified 2-amino-6-chloropurine, in particular per-tri~
methylsilylated 2-acetamido-6~chloropurine, with a Cl-C~-acyl- or benzyl- or C~-C6-alkyl- blocked 1-(C1-C8-acyloxymethoxy)ethanol, for example l-acetoxy-methoxy-2-acetoxyethane or 1-acetoxymethoxy-2-benzyloxy-ethane or l-acetoxymethoxy-2-isopropoxyethan~, or with a Cl-C8-acyl- and/or benzyl- and/or Cl-C6-alkyl-blocked 2-~C~-C8-acyloxymethoxy)-1,3-propan2diol, for example 2-acetoxymethoxy-1,3-bis(acetoxy)propane or 2-acetoxy-methoxy-1,3-bis(benzyloxy)propane or 2-acetoxy-methoxy-1,3-bis(isopropoxy)propane, or with a C~-C8-acyl- and/or benzyl- and/or Cl-C6-al~yl-blocked l-(C1-C8-acyloxymethoxy)-2,3-propanediol, for example 1-acetoxymethoxy-2,3-bis~acetoxy)propane or 1 acetoxymethoxy-2,3-bis(benzyloxy)propane or 1-acetoxy-methoxy-2,3-bis(isopropoxy)propane, in an aprotic solvent such a~ benzene, toluene, xylene, acetonitrile, dichloro-methane or 1,2-dichloroethane or mixtures thereof, in the presence of an acld, preferably a Lewi~ acid such as aluminum trichloride, boron trifluoride, lron trichlo-ride, gallium trichloride, tin tetrachloride or titanium tetrachloride or in the presence of iodine or preferably trialkylsilyl trifluoromethanesulfonate, particularly trimethylsilyl trifluoromethanesulfonate, the amount~ of the~e reagents being 0.1 to 10, preferably 0.8 to 7 equivalents, relative to the amount of the acetoxymethoxy ~$~

compound employed in each case, at tempexa~ures between -70C and +80C, preferably between -40C and ~30C, for 2 to 24 hours, preferably for 2 to 6 hours, i Ll in a compound of the formula VII
is trialkylsilyl, par~icularly trimethylsilyl.

This process yields in high regio&ele~tivity, as a rule ~>9sl, preferably the 7-isomer of the respectiv~ acyclic purine derivative.

If product mixtures are formed by prQce~se6 6a) - 6c), these are separated into the pure components, if neces-sary after conversion into anothar purine dexi~ative, ~y chromatography or by fractional crystallization.

Compounds of the formula VIII where L2 = halogen can be prepared by reacting an expediently modified and protec-ted alkanol, for example l-acetoxyethanol or 1,3-bis-(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol or 1-benzyloxyethanol or 1,3-bis(benzylo~y)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 paraformaldehyde and a gaseous hydrogenhalide, for ex2mple hydxogen chl~ride, in sn inert solvent, for example dichloromethane, at room temperature or below.

The preparation of halomethyl ethers i~ a generally utilizable reaction; a detail~ description can be found, for example, in: Houben-Weyl, ~ethoden der organi~chen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, S~uttgart, 1965, volume VI/3, pp. 125 ~t ~eq.

Compounds of the formula VIII where L2 = methylthio can be prepared by reacting an expendiently modified and prot~cted alkanol, for ex~mple l-acetoxyethanol or 1,3-bis(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol or l-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2,3-bis(benzyloxy)propanol or 1 isopropoxyethanol or - 19 - 2~
ll3~bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)-propanol with dLmethyl sulfoxide, Cl-C8-acid anhydride and Cl-C8 carbo~ylic acid in a temperature range between 0C
and +40C, pr~ferably at room tempexature, for several days, as a rule 2 to 4 days.

A detailed description of the preparation of methyl-thiomethyl ethers of prLmary, secondary and tertiary alcohols can be found in P.M. Pojer and S.J. Angyal, ~ust. J. Chem~, 31, 1031 (1978~.

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

Compounds of the formula VIII where L2 = Cl-C~-acyloxy can be prepared either from a compound of the formula VIII
where L2 = halogen, which i~ accessible as described above, by reaction with an alkali metal carboxylate, preferably sodium or potas~i~n acetate, in acetone or dimethylfoxmamide, or by converting an expediently modified and protected alkanol into the alkoxyalkyl ether, preferably the methox~methyl ether, which is then in turn converted into the Cl-C8-acyloxy compound, preferably l:he acetoxy compound, by reaction with a C1-C8-carboxylic acid anhydride, preferably acetic an-hydride, under protonic or Lewi~ acid cataly.is, preferably boron trifluoride etherate ca~alysis (for both processes see:
Houben-Weyl, Methoden der organi~chen 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 L2 =
Cl-C8-acyloxy are particularly 8imply and effectively prepared by combining an expediPntly modified and protected alkanol, for example l-aceto~yethanol or 1,3-bis(acetoxy)propan-2-ol or ~,3-bis(acetoxy)propanol '~3~81~
20 ~
or 1 benzyloxyethanol or 1,3-bis~benzyloxy)propan-2-ol or 2,3-bis(benzyloxy)propanol or l-i~opropoxyethanol or 1,3~bis(isopropoxy)propan-2-ol or 2,3-bis~isopropoxy)-propanol with a carboxylic acid, preferably ace~ic aci~, and the anhydride pertaining to it, preferably acetic anhydride, in dimethyl sulfo~ide, preferably about 60 ml of acid, about 50 ml of anhydride and about 1~0 ml of dimethyl sulfoxide being used per 0.1 mol of alkanol, below room temperature, preferably at 0C, and stirring for several h~urs, preferably 4 to 6 hour~, at elevated temperature, preferably at 40 to 100 degr~es CQlsiu6.

In proces6 7), the ~ubs~ituents R1 and R2 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-trLmeth~ylsilylated purine and a compound of the formula VIII a~; in process 6).

These blocking group~ are labile and can be removed by solvolysis with water, with a~leous or alcoholic ammonia or ~ith aqueous hydro~en carbonate solution or by al-coholysis.

A further process com~ines processe~ 1) or 2~ or 3) or 4) with process 5); in thi~ caseJ deblockin~ can be achieved by solvolysis at the same time a6 the replacement of a group leaving the purine system, or e~ample halogen, such as, for exampl~, by reaction with liquid ammonia. In this ca6e, in addition to the deblocking of the side chain, if this was protected by a C,-C8-acyloxy group (see processes 1) ~ 4)), the leaving group in the purine system is at the same time replaced by the amino group.
In addition here, a Cl-Ca-acyl blocked group in the purine sy~tem c~n be deblocked.

The compounds of the formula I according to the invention can have one or more chiral centers in the acyclic ~ide chain. The compounds are as a rule racema~0s; preparation or i~olation of the pure enantiomers is po~sible. The invention therefore relates both to the pure enantiomers and ~o mixtur ~ ~hereof, uch as, for example/ the respective racemate.

The present invention in addition relates to pharmaceut-icals containin~ at least one compound ac ording to the invention.

The pharmaceuticals accordin~ to the invention can be administered enterally (orally) parenterally (intravenously), and rectally or locally ~topically).
They can be administered in the form of ~olutions, powders ~tablets, cap ules including microcapsules~, ointments tcreams or gel) or suppositories. Suitable lS auxiliaries for formulations of this type are the phax-maceutically customary liquid or solid fillers and extenders, solvents, emul~ifiers, lubricants, flavor correc~ants, colorants and/or buffer substances.
0.1 - 10, preferably 0.2 - 8 mg/kg of body weight, are administered as an expedient dlosage. The compounds are expediently administered in dos,age units which contain at least the effective daily amount of the compounds accord~
ing to the invention, for example 30 - 300, preferably 50 - 250 mg.

The compounds according to the invention can also be administered in combination wi~h other anti~iral agenks and immunostimulants ~ such as interferons.

In vitro testB and results:

The antiviral activity of the compounds according to the invention was tested in in Yitro te5ts. To do ~his, the compounds sccording to the in~ention 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 - 22 ~
with various human pathogenic herpes viru~es, HeLa cells were infected with vaccinia virus and ~DBR cells with vesicular j~omatitis virus. 48 72 hours after infec-tion, the result of treatment was determinsd microscop-ically by the cytopathic effect and photometrically(Finter, N.B., in "Interferon~" (N.B. Finter et a~
North Holland Publi6hing Co., ~m~terdam tl966), by neutral red ab~orption (color test according to Finter~.
The minimum concentration at which about half the cells show no cy~opathogenic effect is con~idered as the minimum inhibitory concentration (~IC). The res~lt~ are summarized in Table 1.

- ~3 Table 1 Substance T~D (~/ml) from ~IC (~J~) Example XSV-1 ~SV-2 Vaccinia VSV
7-tl,3-di-hydroxy-2- ~400 >400 >400 ~00 isopropoxy >400 ~400 >400 >400 methyl~yuanine >400 >400 ~400 ~400 6.7 >~00 >400 ~90 ~400 >400 ~400 ~400 >400 6.10. >~00 ~00 ~400 >400 133.3 133.3 44.~ ~400 6.12. 1.65 1.65 4.94 >400 Standard:
9-(1,3-di- ~400 ~400 ~400 >133.3 hydroxy-2- 4.94 1.65 >400 133.3 isopropo~y-methyl)guanine HSV-1 = Herpes sLmplex virus 1 HSV 2 = Herpe simplex virus 2 MIC - Minimum inhibitory concentration TMD = ~olerated maximum dose VSV = Vesicular stomatitis virus - 24 ~ $~
In vivo tests and results-NMRI mice, specifically pathogen-free, with a weight of about 15 g were infected intraperitoneally ~ith herpe6 sLmplex virus 1 and then treated intraperitoneally or orally with the compound according to the invention (see Table 2 or Table 3). Treatment was carried out for the first tLme 3 hours after inection and wa~ continued twice daily for 4 days. The re~ul~ of trea~ment was determined by the course of the di~ease and the ~urvival rate compared to untreated infection control~. The latter received physiological ~aline ~olution instead of the compound according to the invention. The observation period was two week~O

2~3~

Table 2: Antiviral action again~t HSV 1 in ~MRI mice 9n intraperitoneal administration ~xample Dosage Mean ~urvival Surviving/
(~mol/kg) time (days) total ~
9 x 10 7.0 0.0 4 / 5 6.7. 3~ - 5 / 5 10~ - 5 / 5 ~ x 1~ 1~.0 + 1.~ 3 / 5 6.10. 30 - 5 / 5 9 x 10 - 5 / 5 6.12. 30 - 5 / 5 10~ ~ 5 / 5 7-(1,3-di-9 x 10 10.0 + 1.4 3 / 5 hydroxy-2- 30 10.0 i O.0 4 / 5 isopropoxy-100 9.3 + 2.1 2 / 5 methyl)guanine Control 0 8.3 + 2.8 1 / 5 ~3~

Table 3., ~tiviral action agains~ HSV-l in N~I
mice on oral ~dmini~ration Example Dosage Mean survival Surviving/
(~mol/kg) time ~days) total 9x 10 - 5 / 5 6.7. 3~ - 5 / S

9~c 101~.0 + 0.0 ~ / 5 6 . 10 . 30 - 5 ~ 5 9x 108.3 + 1.5 ~ / 5 6 . 12 . 30 - 5 / 5 100 - ~ / 5 7-(1,3-di- 9x 10 6.5 2.1 3 / 5 hydroxy-2- 30 8 . 5 O . 7 3 / 5 isopropoxy- 100 9 . O + 1. 4 3 / 5 methyl ) guanine Control 0 7 . 7 + 1. 5 2 / 5 , ' ~ ~ s,~

B~a~ple~0 Process according to 6b)s 1. Compound of the formula VIII in which L2 = me~hyl-thio, R3 = isopropoxymethyl, R4 G isopropoxy ~nd R5 - hydrogen:

303 ml of anhydrous dimethyl sulfoxide ~re slowly added dropwise with 6tirring and cooling to about 30~C to a mixture of 180 ml of glacial acetic acid and 150 ml of acetic anhydride. After the addition is complete, the mixtur2 is su~seguently ~tirred for 30 min. 52.8 g (O03 mol) of 2,3-bi (isopropoxy)-propan-2-ol tprepared by reaction of sodium iso-propylate with 2,3-epo~propyl isopropyl ether in isopropanol) are then added dropwi~e at about 25C.
The reaction mixture is allowed ~o ~tand at room temperature for 4 days with periodic stirring. The reaction mixtuxe is then ~3tirred into about 1 1 of ice-water and extracted ~everal times by shaking with diethyl ether or hex,ane. The organic pha~e is washed several times with water, dxied over sodium sulfate and evaporated. The oily re~idue is fractionated in vacuo.

~he 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 preC~ure of 2 n~n Hg.

2. Comp~und of the formula I in which Rl = hydroxyl, Rz = scetamido, R3 = isopropoxymethyl, R4 = i~opro-po~ and R5 = hydrogen:

5.7 g tO.0218 mol) of the methylthiomethyl ether from Example 1 are combined with 4.9 g of anhydrous dimethyl ~ulfoxide and 4 . 9 g ( O . 0209 mol ) of 2N, 9N~
diacetylguanine (prepared from guanine and acetic anhydride in N-methylpyrrolid-2-one) in 20 ml of ~3~9 - ~8 -anhydrous dLmethylformamide. The mixture is cooled to ~O~C and 5.5 g (0.0209 mol) cf tin tetrachloride are added dropwise to the suspension with ~tirring.
After addition i~ complete, the reaction mixture is ~tirred at 80C for 5 hours. It is then allowed to cool, ~.he reaction mixture i~ treated with dichloro-methane and ice-water, extracted ~ vQral times with dichlorometh~ne, and the co~bined organic pha~e~ are fir~t sh~ken with water, then with a~ueous sodium h~drogen carbonate ~olution and finally with ~atur-ated sodium chloride solution. ~he or~anic pha~e is dried over sodium ~ulfate, filtered ~nd evaporated.
HPLC analysis (RP 18 (~iChro~pher (R) 100 RP 18, 5 ~m, 125-4), wat~r/mekhansl 1:1 ~ 0.1% of trifluoroacetic acid, ammonium acetate) ~hows a ratio of 7-isomer/9-i60mer 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 i~ carr~ed out by means of column chromatography on nsutral alumina uRing a mixture of ethyl acetate~methanol 9:1 and yields 3.5 g (44% of theory) ~f 2N~acetyl-7-[1,3-bi~-(isopropoxy)-2-propoxymethyl]guanine of melting point 162 - 163C.

lH-NMR (60 MHz, d6-D~SO), ppm: 11.93 ( 8 , broad, 2H), 8.35 (s, 1~), 5.73 (s~ 2H), 3.83 (m, l~), 3.55 -3.17 (m, 6H), 2.20 (s, 3H), 0.93 (d, 12H~.

3.1. Compound of the fonmula I in which Rl - chlorinef R2 = ~cetamido, R3 = i~opropoxymethyl, R4 isopropoxy and R5 = hydrogen:

6.9 g (0.033 mol) of 2-acetamido-6-chloropurine (for preparation ~ee under Sa.) are heated to reflux under argon for 3 hours with 28 ml of hexamethyl-disilazane (HMDS) and 0.2 g of ammonium sulfate in 28 ml of dry xylene. The ~olvent and exce~s ~MDS are then distilled off, the residue i~ dissolved in 85 ml of dry 1,2-dichloroethane and the solution is ~3~

- .29 ~
added at -30C to a solution of ~.3 g (0.024 mol) of the methylthiomethyl ather from Example 1 in 85 ml of dxy 1,2-dichloroethane. 5 ml (0.026 mol) of trimethyl~ilyl tri1uoromethanesulonate are then added and the mixture i8 stirred at 30~C for 2 hours.

The reaction product i8 poured into 150 ml of ice-water and filtered, and the re~idue i8 washed with 1/2-dichloroethane. The aqueous phase i~ extracted by shaking with 1,2-dichloroethane; the combined organic phases are extracted by shaking with water, then with dilute sodium hydroge~ carbonate solution, dried over ~odium 6ulfate and concentra ed. HPLC
analysis (RP lB (LiChrospher 100 ~P 18, 125 x 4)l 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 u~ing 3.B equivalents of tin tetrachloride gives 73~ of the 7-isomer and 23~ sf the 9-isomer (HPLC analysis of the crude product as in the preceding exampl~).

Process according to 6c):

4.1. Compound of the formula VIII in which ~2 = ~cetoxy, R3 = isopropoxymethyl, R4 = isopropoxy and R5 =
hydrogen:

200 ml of anhydrous dLmethyl ~ulfo~ide are added dropwise with ætirring to a mixture of 120 ml of glacial acetic acid and 100 ml of acetic anhydride in ~uch a way that the temperature of the mixture does not rise above 35C. 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. A~ter ~3~

- 30 -~
completion of the addition, ~he mixture i6 hea~ed at 90 lOOnC for 7 hours. The cooled reaction mixture is poured into water and ex~rac~ed with diathyl ether several ~Lme~ ~y shaking. ~he organic phase i~
then ~ashed with water and sub~equently with agueous hydrogen carbonate ~olution, dried over ~odium sulfate and evaporated~ A pale yellow oil remain~, which is ~ubjected to fractional di~tillation. A
forerun o boiling point 46 - 47C at a pressure of 15 ~m Hg is composed of thiometh~lmethyl acetate.
The reaction product, 2~ace~oxymetho~y-1,3-bis-(isopropoxy)propane~ boils a~ 87 - 92C at a pressure of 1 mm Hg. The yield is 27.3 g (55% of theory).

lH~~nMR (60 MHz, CDCl3), ppm: 5.43 ( , 2~I), 4.0 - 3.33 (m, 7H), 2.12 (~, 3H), 1.33 (d, 12H).

The following were prepared in thi6 m~nner:

4.2. 2-acetoxymethoxy-1,3-bi~(methoxy)propane 4.3. 2-acetoxymethoxy-1,3-bis(ethoxy~propane 4.4. ~-acetoxymethoxy-1,3-bis(propoxy)propane 4.5. 2~acetoxymethoxy 1,3-bi~(benzyloxy)propane 4.6. 2-acetoxymetho~y-1,3-bis(cyclopentyloxy) propane 4.7. 2-acetoxymetho~y-1~3-bi~(prop-2-en-1-o~y) propane 4.8. 2-acetoxymethoxy-1-benzyloxy-3-(isopropoxy) pxopane 4.9. ~-acetoxymetho~y~l-isopropoxy-ethane 4.10. 1-acetoxymethoxy-2-benzylo~y-3-isopropoxy-propane 4.11. 2-acetoxymethoxy-1-benzylo~y-3-pivaloyloxy-propane 4.12. 2 acetoxymethoxy 1,3-bis(pivaloyloxy~propane 5. Compound of tha fonmula I in which Rl = chlorinP, R2 a acetamido, R3 = isopropoxymethyl, R4 ~ iBopropoxy and R5 = hydrogen:
5a. 3.17 g (O.015 mol) of 2-acetamido-6-rhloropurine (prepared according to E.N. Acton and R.H. Iwamoto in W.W. Zorbach and ~.S. Tipson (editors) Synthetic Procedures in Nucleic Acid Chemistry, Volume 1, Inter~cience Publi~hers, John Wiley ~ Son~, New York, 1968, pp. 25 et ~eq.) are heated under reflux in an inert gas atmosphexe for 3-4 hours with 11.3 ml of hexamethyldisilazane and 100 mg of ammonium sulfate in 13 ml of . nhydrou~ xylene and thus converted into the bis-trimethylsilyl compound.
After the reaction i~ complete, ~he ~olvent and excess hexamethyldisila~ane are evaporated in ~acuo.
The residue is dissolved in 10 ml of anhydrous acetonitrile and added dropwise with _tirring to a solution of 2.8 g (9.01 mol) of 2-aceto~y~ethoxy-1,3-bis(isopropoxy)propane in ~0 ml of anhydrous acetonitrile. 13 g (0.05 mol) of tin tetrachloride are then added slowly at -20~C and undex an inert yas atmosphere and the mi.xture is stirred at 20C
for 3 hour~. The reaction mixture i~ ~tirred into a mixture of ice-water ~md dichloromethane and filtered. The aqueous phase is extracted ~everal times with dichloromethane and the combined organic phases are then washed twice with sodium chloride solution, dried over sodium ~ulfate, and filtered and Pvaporated. A pale ~yrup xemains who~e HPLC
analysis (RP 18 (Nucleosil 5 Cl8~ (R), water/-acetonitrile 3:1 ~ O.1~ TEA) give~ a eontent of 86~
of the 7-isomer and 4% of the 9-i~omer. Chromato-graphic purification on ~ilic~ gel using ethyl acetate/methanol 20sl ~ives 1.8 g (45~ of theory) of 2-acetamido~6-chloro~7-[1,3-bis~i~opropoxy)-2 propoxyme~hyl]purine of mel~ing point 73-75C.

lH-NMR (270 MHz, d6-DMS0), ppm: 10.68 ~s, lH), 8.84 (s, lH), 5.81 (s, 2H), 3.71 (m, lH), 3.46 - 3.24 (m, 6H), 2-18 (8, 3H), 0.90 (m, 12H).

- 5b. Reaction procedure as in 5a., with the difference tha~ the ~ilylated 2-acetamido 6-chloropurine (0.015 mol~ di~solved in 10 ml of anhydrous 1,2~dichloroethane is added dropwi~e to a solution o~ the acetoxymetho~y compound (O.01 mol) in 70 ml of anhydrous I,2-dichloroethane, and 2.67 g (0.012 mol) of trimethylsilyl trifluorom~thane-sulfonate are added at -30~C and the reaction mix~ure is stirred at -30C for 2 hour~. XP~C
analysis of ~he crude p~oduct, carried ou~ as in Sa., gives an isomer ratio of 7-i~omer/9-i~omer of 90:6. Chromatographic purification over ~ilica gel using ethyl acetate/methanol 20:1 yields 2.15 g (53.8~ of theory) of a white powder of melting point 7~ - 74C.

T~e following w~re pr~pared in thi~ ~3nner-5.1. 2-A~etamido-6-chloro-7-[1,3-bis(ethoxy)-2-propoxy-methyl]purine of melting point 76 - 78C

5.2. 2-Acetamido-6-chloro-7-C1,3-bis(propoxy)-2-propoxy me~hyl]purine of melting point 74C

5.3. 2-Acetamido-6-chloro-7-(2-i~opropoxyethoxymethyl)-purlne of melting point 116 - 118C

5.4. 2-Acetamido-6-chloro-7 (1-benzyloxy-3-isopropoxy-2-propoxymethyl)purine a a viscous oil (1~_NMR t270 NHz, d6-D~S03, ppm: 10.70 (B, lH~, 8.86 (s, lH), 7.40 - 7.15 (m, 5H), 5.85 (m, 2H), 4.38 (s, 2H), 3.84 (m, lH), 3.50 - 3.25 (m, 5H), 2.17 ( 3H), 0.~7 (m, 6H)), 5.5. 2-Acetamido-6-chloro-7-[1,3-bis(methoxy)-2-propoxy-methyl]purine of melting point 83 - 84C

5.6. 2-Acetamido-6-chloro-7-~1,3-bi~(prop-2-~n-1-oxy)-;~ ~ 3 ~

2-propo~ymethyl~purine of melting point 79C
5.7. 2-Acetamido-6-chloro-7 ll,3-bislcyclopentyloxy) 2-propoxymethyl]purine aæ a YiSCoU8 oil;

1H-NMR (60 NHz, d6-DMSO), ppm: 10.73 (B~ lH), 8.83 (s, lH~, 5.83 (s, 2H), 3.7S ~m, 3H), 3.27 (m~ 4H), 2.18 (~/ 3H), 1.42 (6, broad, 16H).

5.8. 2-Acetamido-6-chloro-7-~2-benzyloxy-3 isopropoxy~
l~propoxymethyl)purine as a viscous oil;

l~_NMR (60 ~Hz, d6-DMS0) ppm: 10~77 (~, lH), ~.92 (s, lH), 7.32 (s, 5H), 5.82 (s, 2~), 4-53 (s, 2~), 3.67 - 3.20 (m, 6H), 2~2 (s, 3H), 0.93 ~dt 6~).

.9. 2-Acetamido-6-chloro-7-[1,3-bis(pivaloyloxy)-2-propoxymethyl~purine as a glassy foam;

l~_NMR (210 MHz, d6-DMS0), ppm: 10.72 (s, lH), 8.88 (s, lH), 5~79 (s, 2H), 5.04 (m, lH), 4.23 (m, lH), 4.05 (m, lH), 3.63 (d, 21I), 2.18 ~s, 3H), 1.05 (s, 9H), l.01 (~, 9H), 5.10. 2-Acetamido-6-chloro-7-(1-benzyloxy-3-pivaloyloxy-2-propoxymethyl)purine a~ a vi cous oil;

lH-N~R (270 ~Hz, d6-DNSO), ppm: 10.70 ~6, lH~, 8.89 (s, lH), 7.35 - 7.15 (m, ~H), 5.85 ( ~ 2H), 4.40 (s, 2H), ~.15-3.94 (m, 3H), 3.49 (m, 2H), 2.18 ~8, 3H), 0.97 (s, 9H~.

Proce~s according to 5)-6.1. Compound of the fo~mula I in which R1 = thio, R2 =
thioacetamido, R3 - isopropoxymethyl, R4 = isopropoxy and R5 - hydrogen:

3.8 g (0.01 mol) of the ~ompound from Example 2. are stirred at 80 - 85C under argon for 3 hours with , - 34 - 2~3$~
4,4 g (0~011 mol) of 2,~-bis(4-methoxyphenyl)-1,3 dithia-2,4-dipho~phetane-2,4 di ulfide (Law~s~on's reagent) in 150ml of ~ toluene.After completion of the reaction, the mixture i allowed to cool, the precipitate is filtered off with suction, the residue is wa~hed with toluene ~nd the filtrate isevaporated.Ayellow~y~pr~mainswhich is purifisd by chroma~ography on silica gel u~ing ethyl acet~e/methanol 20.1. In thi~ way, 2 (48.6 % of theory) of 2 thioacetyl-7-(1,3-bis(iso-propoxy)~2-propoxymethyl)thioguanine are obtained.
Ths yellowish powder decomposs~ at 220C.

6.2. Compound of the fonmula I in which R~ = thio, R2 =
amino, R3 = i~opropoxymethyl, R4 - i~opropoxy and Rs = 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 ~awesson's reagent in a mixture of !50 ml of dry toluene and 10 ml of dry pyridine unde:r argon. The crude product of the reaction is purified by column chromatography on silica gel using a mi~ture of dichloromethane/
methanol 5:1. 1.2 g (71.6~ of theory) of a weakly yellow powder of m~lting point 232 - 236~ are obtained.

H-NMR (60 NHz, d6-DM50), ppm: 12.05 ~ lH), 8.37 (s, 1~), 6.55 (~, 2H), 6.10 (s, 2H), 3.93 - 3.22 ~m, 7H), 0.97 ~d, 12H).

~he compound 6.2. can al~o be prepared by heating 0.413 g (0.001 mol) of th~ compound of ~x2mple 6.1.
to reflux with 4 ml of 40% strength aqueou~ methyl-amine solution and 4 ml of methanol for 3 hours.
Yield: 0.~5 g (70.4% of theory).

6.3. Compound of the formula I in which R~ = methoxy, R2 = acetamido, R3 = isopropo~ymethyl, R4 = i~o-propoxy and R5 = hydrogen:

1.4 g (Q.0035 mol~ of the compound from ~xample 5.
are di solved in 14 ml of methanol with 13 mg (O.2 mmol~ of potassium cyanide and the mixture is stirred at room temperature ~or 24 hours. It i6 then diluted with 20 ml of m~thanol and trsated for 5 minutes in each case with S~rdolit Blue (R) (Serva) (OH form) and Amberlyst 15 (R) ~Fluka) (H~
form~, the ion exchanger is fil~ered off and the filtrate is evaporated. ~he remaining ~yrup cry8-talli~es on addition of diisopropyl ether. 1.05 g (75O8% of theory) of 2-acetamido-6Dmethoxy-7-(1,3-bis~isopropoxy)-2-propoxymethyl)purine of melting point 67 - 63C are obtained.

~_NMR (60 MHz, d6-D~SO), ppm: 10.73 (s, lH), 8.87 (s~ lH), 5.83 (s, 2H), 3.80 - 3.15 (m, 10H), 2.17 (8, 3H), 0.88 (d, 12H).

6.4.1. Compounds of the formu:La I in which Rl = amino, R2 G acetamido, R3 = isopropoxymethyl, R4 isopropoxy and Rs ~ hydrogen and 6.4.2. Rl = amino, R2 = amino, R3 = isopropoxymethyl, R4 = isopxopoxy and R5 = hydrogen:

6.4.1. 10 g (0~025 mol) o~ the compound from Example 2.
are treated with about 150 ml of liquid amMonia in 100 ml of meth~nol and the mix~ure i8 heated at 80~C in an autoclave at a pre~sure of 5 bar for 20 hours. The reaction mixture i~ then completely evaporated and purified by column chromatography (silica ~el, dichloromethane-/methanol 9:1). 0.26 g t2.7% of theo~y~ of ~-acetamido-6-amino-7-~1,3-bis(isopropoxy)-2-propvxymethyl]purine of melting point 136 - 137C is obtain~d as a first fraction.

2~3~8~

H-N~R (60 N~z, d6~D~S0), ppm: 9.72 (c, lH), 8.30 (~, lH), 6.73 (8, 2H), 5.73 (~l 2H), 3.~3 - 3.2 (m, 7H), 2.20 (s, 3~), 0.97 (d, 12H)o 6.4.2. The ~econd fraetion yields 4.6 g (54.4% of theory) of 2,6-diamino-7-~1,3-bis(i~opropoxy)-2-propoxym~thyl]purine of m~l~ing point 228 - 2~9C.

H-NMR (60 ~Hz, d6-DM50), ppm: 8.10 (s, lH3, 6.52 (s, 2~), 5.85 (8, 2H), 5.67 (s, 2H), 3.83 - 3.22 (m, 7H), l.00 (d, 12H~.

6.5.1. Compound~ of the formula I in which Rl = methyl-amino, R2 = acetamido, R3 = isopropoxymethyl, R~ = isopropoxy and R5 = hydrogen and 6.5.2. R~ = methylamino, R2 -- amino, R3 = i30propo~y~
methyl, R4 = isopropoxy and Rs = 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 agueous methylamine solution and 14 ml of methanol for 2 hours. The reaction 801ution i8 then completely evaporated and the residue is separated by column chromatography on 8ilica gel using a mixture of dichloromethane/methanol 10:1.
The first fraction i~ composed o~ 0.45 g (32.6%
of theory) of 2-acetamido-6-methylamino-7-~1,3-bis(isopropoxy)-2~propox~nnethyl]purineofmelting point 159C.

H-NNR (60 MH~, d6-DMS0), ppms 9.75 (s, lH), 8.28 (s, lH), 6.67 (q, lH), 5.75 ~8, 2H)l 3.77 - 3.22 (m, 7~), 3.00 (d, 3~), 2.27 ts, 3H), 0.97 (d, 12H).

6.5.2. The second fraction i8 composed o 0.45 g (36.5%
of theory) of 2-amino-6 methylamino-7-~1,3 2~33~9 - bis(isvpropoxy)-2-propoxymethyl]purineofmelting point 103 - 104~C.

H-NMR (270 MHz, d6-DNSO), ppms 7.99 ~ ), 6.29 (q, lH), 5.65 (s, 2H), 5.63 (3, 2~), 3.65 (m, lH), 3.45 (ml 2~), 3.36 (m, 4H~, 2.92 (d, 3H~, 1.00 tq, 12H3.

If a larger excess of methylami~e solution i~
u~ed and the reaction time i8 lengthened/ the d~blocked product 6.4.2. i8 isolated exclu~ively in g2% yield.

6.6. Compound of the formula I in which Rl = hydrogen, R2 = acetamido, R3 = isopropoxymethyl, R4 =
isopropoxy and R5 = hyd:rogen:

16 g (O.04 mol) of the compound from Example S
are exhau~ti~ely hydrogenolyzed with hydrogen at room temperature in a duck-shaped shaking ~es~el using 3.5 g of palladium on carbon (10~) and 11.06 ml (0.08 mol) o~ triethylamine in 350 ml of methanol. After completion of hydrogen absorp-tion, the catalyst i6 filtered off with suction ;~ and the methanolic pha~e i6 evaporated. The residue is stirred in ethyl acetate, the precipitate of tri~thylamine hydxochlori~e is separated off and the ethyl acetste ~olution i~
completely concentrated. The cry~t~lline residue is purified by column chromatography on ~ilica gel using ethyl acetate/methanol 9:1 as the eluent. 14 g (95.9% o theory) 5f 2~ace~amido-7-[1,3-bi~(isopxopoxy~ propoxymethyl]purine of meltiny point 94 - 96C are obtained.

H-NMR (270 MHz, d6-DM50), ppm: 10.43 (s, lH), 9.02 (s, lH), 8.71 l8, lH), 5.79 (8, 2~), 3.70 (m, lH), 3.41 (m, 2H), 3.32 (m, 4~), 2.19 (8, 3H), 0.93 (m, 12H~.

2~3~9 -- 38 ~
. 7 . Compouald of formula I in which Rl = hydrogen, R2 = amino, R3 = isopropoxymethyl, R4 = i~opropoxy and R5 = hydrogen:

û.178 g (0.5 mmol) of the compound of ~3xample 6 . 2 . are treated with 1. 0 ~ of Raney nickel washed with absolute ethanol in 20 ml o absolute ethanol and the ~ixture is heated to reflux for 1 . 5 hours . The reactiosl mla~ture is then cooled, the Raney niclcel i~ filtered off with ~uction and tha ethanolic ~olution i8 completely concen-trated. The residue i8 purified by column chroma-tography on 6ilica gel using ethyl acet~te-~metharlol 2 0: 1 as the eluent . O . 1 g ( 61. 7 ~6 of thec>xy) of 2-amino-7- [ 1, 3 bis ~ isopropoa~y) -2-propoxymethyl ]purir~e is obtained as white flakes of melting point 153 - 154C.

NMR (270 MHz, d6-DMS0), ppm: 8.65 (s, lH), 8.38 ( s ~ lH) ~ 6 . 22 ( 8 ~ 2H) r 5 . 67 ( E; ~ 2H), 3 . 65 (m, lH), 3 . 42 (m, 2H~, 3 . 32 (m, 4EI), 1. 00 (m, 12H) .

The compound of Example 6.7. can al80 be prepared from the compound of Example 6 ~ 6 . by reac~ion with aqueous methylamine solu~ion in methanc)l.
1.1 g of the compound: of 13xample 6 . 6 . yields 0 . 8 ~ ( 82 . 296 of theory) of the compound of Example 6 . 7 .

6.8. Compound of th~ formula I in which Rl = hydrogen, R2 = ~cetamido , R3 = hydrogel, R4 = iBopropoxy and Rs ~ hydr~gen:

The co~pound of Example 5 . 3 . i~ sub~ected to hydrogenolysis as in Example 606. and yields 2-acetEmido-7-(2-isopropoxyethoxymethyl)purine of melking point 152C in 95.6% yield.

6.9. Compound of the formula I in which Rl = hydrogen, ' 2~3~8~

R2 = acetamido, R3 - benzylo~ymethyl, R4 = iso-propoxy and R5 = hydrog~nO

4.47 g ~0.01 mol) of the compound of ~xample 5.4.
are ~ubjected to hydrogenolysis as in Example 6.6. and yield 3 g (72.6% of theory) of 2-acet-amido-7-(1 b~nzyloxy-3-iaopropoxy-2-propoxy-methyl)purine a~ an oil.

H-NNR (270 NNz, d6-DMS0~, ppm. 10.43 (~, lH), 9.03 (3~ lH), 8.72 (5, 1~), 7.36 - 7.15 (~, 5H), 5-~ t~ 2~3; 4.39 (3~ 2H), 3.83 (8, lH), 3.50 -3.25 (mJ 5H), 2.18 (8, 3H)~ 0.90 (m, 6H~.

6.10. Compound of the formula I in which R1 - hydrogen, Rz = amino, R3 = hydro.xymethyl, R4 = isopropoxy and R3 = 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 ~olu~ion i.n ~0 ml of methanol for 1 hour. After distill.in~ off th~ solYent an oil remains which is treat~ed with acetone and ~rys-talli~es after some time. 0.7 g (50.3~ of theory) of 2 ~mino-7~ h~dro~y-3-isopropoxy-2-propoxy-methyl)purine of melting point 125 - 130-C are obtained.

l~_NMR (270 ~Mz, d6-DNSO)t ppm: 8.66 ~8, lH), R.37 (~, lH), 6.23 (~, 2H), 5.67 tm, 2H), 4.70 (t, lH), 3.55 (m, lH), 3.36 - 3.20 (m, S~), 0.95 (m~ 6H)-6.11. Compound of the formula I in which Rl = hydrogen, Rz = amino, R3 = hydrogen, R4 = i~opropoxy and R~ = hydrogen:

2.2 g of the compound of Example 6.8. ar~ treated a~ in Example 6.10. and yield 1.4 g (74.3% of ~3~8~

theory) of 2 amino-7-(2-i.sopropoxy-2-ethoxy-methyl)purine of melting point 158C.

6.12. Compound of the ~onmula I in which Rl = hydrogen, R2 = amino, R3 = hydrox~methyl, R4 = hydroxyl and R5 = hydrogens 1o6 ~ ~O.0057 mol) of the compound of Example 8.2. are heated to reflux for 2 hour~ with 10 ml of methanol, 10 ml of 40~ tr~ngth aqueous methylamine solution and 5 ml of water. Working-up yields 1 g t73.4% Of theory) of 2-amino-7~(1,3-dihydroxy propoxymethyl)purine of melting point 176 - 177C.

H-NMR (27G.~Hz, d6-DMSO), ppm. 8.fi8 (~, ~H), 8.38 ~s, lH), 6.23 ~s, 2H), 5.69 (s, 2H), 4.62 (~ 2H)/ 3.38 (ml ~H).

6.13.1. Compound of the ~ormula I in which Rl - hydro~yl, R2 = hydroxyl, R3 = isop:ropoxymethyl, R4 = isopro-poxy and R5 = hydrogen and 6.13.2. Compound of the formula I in which R1 = amino, R2 = hydroxyl, R3 = isopropo~ymethyl, R4 isopropoxy and R5 = hydrogen.

6.13.1. 1.4 g (0.0041 mol) o~ the compound of ~xample 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 i8 stirred at 50C for 90 minutes, a further 1.8 g ~f sodium nitri~e and 9 ml of ~lacial acetic acid are added, the reaction mixture is completely evapor-atedl and the residue is treated with a ~ittle water and neutralized with concentrated ammonia.
An oil precipitates which becomes solid after 2~3~8~1 some time. The precipitate is filtered off, recrystallized from i~opropanol and 0.3 g (21.3%
of theo~y) of 7-tl,3-bi~(isopropoxy)-~-propoxy-methyl]xanthine of melti~ point 200 - 2Q1C i~
obtained.

H-NMR (270 N~z, d6-D~O), ppm: 11.60 (8, lH), 10.89 (~, lH), 8.13 (~, lH), 5.63 (8, 2H), 3.83 (m, 1~), 3.46 ~m, 2H), 3.30 ~m, 4H~, 1.01 ~m~
12H).

6.13.2. The a~ueou~ mother liquors are evaporated, taken up with dichloromethane and a little wa~er and extracted three times by haking with 100 ml of dichloromethane. The organic phase i~ dried (sodium sulfate) and evaporated. The ~yrup thus obtained is purified by chromatography (silica gel, dichloromethanefmethanol 9:1). After recry-stallization from water, 60 mg (4.3% of theory) of 6-amino-2-hydroxy-7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine (7-[1,3 ~is~i~opro-poxy)-2-propoxymethyl].i~oguanine) of melting p~int 213C are obtaini~d.

H-NMR (270 MHz, d6-DMSO), ppm: ll.lS (s, lH), : 8.02 (s, lH), 6.88 (s, 2H), 5.64 ~s, 2H~, 3.70 (m, 1~), 3.47 (m, 2H), 3.38 (ml 4H), 1.01 (d, 12H).

6.14. Compound of the foxmula I in which Rl = hydrogen, R2 = acetamido/ R3 = methoxymethyl, R~ = methoxy and R5 = hydrogen:

1.6 g (4.7 mmol) of the compound o~ ~xample 5.5.
are ~ub~ected to hydrogenolysis a~ 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-t1,3-biR(methoxy)-2-propoxymethyl~purine of melting poin~

2~3~
- ~2 102C.

.15. Compound of the formula I in which Rl = hydrogen, R2 - acetamido, R3 = ethoxymethyl, R4 = ethoxy and R5 c hydrogen:

3.7 g (O.01 mol) of the c~mpound of Exa~ple 5.1.
are subjected to hydrogenoly~is as in Example 6.6. and after chrom~tographic purification on silica gel (ethyl acetate/methanol 9sl) yield 2.9 g (86~ of theory) of 2-acetamido-7-~1,3-bi3-~ethoxy)-2-propox~methyl]purîne of melting point 117 l18C.

6.16. Compound of the formula I in which R1 = hy~rogen, R2 = ~mino, R3 = prop-2-en-1-oxymethyl, R4 = prop-2enoxy and R5 = 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 ~inc dust. 1.7 ml of concentrated ammonia are then added dropwise over a period of 2 hours. The cooled suspen~ion i8 treated with 50 ml of methanol and filtered off wi~h suction, and ~he ~:~ residue is wa~hed with methanol. ~he co~bined : filtrates are concentrated and ~hromatographed on sili~a gel using ethyl acet~te/methanol 9:1.
2.9 g (82.6% of theory) of 2-amino-7-l1,3-bis~
(prop-2 en-1-oxy)-2-propoxymethyl]purine of melting point 140 - 143C are obtained.

6.17. Compound of the formula I în which Rl = hydrogen, R2 = acetamido, R3 = cyclopentyloxymethyl, R4 =
cyclopentyloxy and R3 = hydrogen:

1.1 g (2.44 mmol) of the compound of Example 5.7.
are sub~ected to hydrogenolysis as in Exa~ple 6.6. and aft~r chromatographic purification (silica gel, ethyl acetate/methanol 9sl) yield ~ 43 -0.8 g (78.6% of theory) of ~-acet~mido-7-~1,3-bis(cyclopentyloxy)-2 pxopoxymethyl]purine of melting point 9BC.

6.18. Compound of the formula T in which R1 - hydrogen, R2 = acetamido, R3 = hydrDgen, R4 = benzyloxy and R5 - i~opropoxymethyl:

7.5 g ~16.8 mmol) of the compound of Example 5.8.
are ~ub~ected to hydrog~nolysi6 as in ~xample 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-ben-æyloxy-3-i opropoxy-l-propoxymethyl)purine of melting point 116 - 117C.

6.19. Compound of the formula I in which Rl = hydrogen, R2 = acetamido, R3 = benzyloxymethyl, R4 = piva-loyloxy and R5 = hydrogen:

20.5 g (41.9 mmol) of the compound of Example 5.10. are ~ub~ected t;o hydrogenolysis a~ in Example 6.6. and after chromatography on silica gel (ethyl acetate/me~thanol 9:1) yield 17 g (~9.2~ of theory) of 2-acetamido-7 (1-benzyloxy-3-pivaloyloxy-2-propoxymethyl~purine o~ melting point 76 - 77C.

H-NNR (270 ~Hz, d6-DNSO), ~ pp~: 10.45 (8, 1~), ~5 9.05 (~, lH), 8.77 ~s, 1~), 7.35 - 7.18 ~m, SH), 5.83 (~, ~H), 4.40 (2, 2~), 4.13 (m, lH), 3.99 (m, 2H), 3.49 (m, 2H~, 2.19 (~, 3H), 0.98 (8, 9H).

6.20. Compound of the formula I in which Rl = hydrogen, R2 - amino, R3 = methoxymethyl, R4 = metho~y and R5 = hydrogen:

0.77 g ~2.25 mmol~ of the compound of Exampl~

44 2~3~
6.14. is tr~a~ed wiih methylamine solution a~ in Example 6.10. and yields 0.54 g (89.9~ of theory) of 2-amino-7-[1,3-bis(methoxy~-2-propo~ymethyl]-purine of melting point 148C.

6.21. Compound of the formula I in which Rl - hydrogen, Rz = amino, R3 = ethox~methyl, R~ = ethoxy and R5 - hydrogen:

1.35 g (4 mmol) of the compound of Examplæ 6.15.
are treated with methylamine ~olution a~ in Example 6.10. and yi~ld 0o8 ~ (S7.~% of theory) of 2-amino-7~[1,3-bis(ethoxy~-2-propox~methyl~-purine of melting point 151C.

6.22. Compound of the formula I in which Rl = hydrogen, R2 = amino, R3 = cyclope~tyloxymethyl, R4 cyclopentyloxy and R5 = hydrogen:

0.5 g (1.2 mmol) of the compound of ~xample 6.17.
is treated with methylamine solution as in Example 6.10. and yielcls 0.3 g (66.7% of theory) of 2-amino-7-[1,3-bis(cyclopentyloxy) 2-propoxy-methyl]purine of melting point 158C.

6.23. ~ompound of the formula I in which Rl = hydrogen, R2 = amino, R3 = hydrogen, R4 = hydroxyl and R5 =
hydroxymethyl:

1. 4 g ( 5 mm51 ) of the compound of Example 8.5.
are treated with methyl~mine ~olution ~s in Example 6.10. and yield 0.45 g (37.7~ of theory~
of 2-amino-7-(2~3-dihydroxy-1-propoxymethyl)-purine of melting point 130 - 133C;

lH-NMR (270 ~Hz, d6 D~SO), ppm: 8.67 (8, lH), 8.40 (s, lH), 6.25 (s, 2H), 5.60 (~/ 2H), 4.75 (d, lH), 4.50 (d~ lH), 3.60-3.25 ~m, SH).

~3~
_ 4~ -6.24. Compound of the formula I in which Rl = hydrogen, R2 = amino, R3 = benzyloxymethyl, Rb c hydroxyl and Rs = hydrogen:

0.66 g ~1.45 mmol) of the compound of ~ample 6.19. iB treated ~ith methylamine ~olut~on as in ~xample 6.10. and yields 0.25 g ~5~.4% ~f theory~
of 2-amino-7~ ben~yloxy-3-hydrQxy-2-prepoxy-methyl)purine of m~lting point 122DC;

1H-N~R ~270 MXz, d6 - DMSO~, ~ ppm: 8.68 (8, lH), 8.39 ~sl lH), 7.36-7.18 (m, 5~), 6.25 (5~ 2H), 5.71 (s, 2H), 4.73 (t, lH), 4.38 (s, 2~), 3.68 (m, lH), 3.50 3.31 (m, 4H).

6.25~ Compound of the formula I in which Rl = hydrogen, R2 = acetamido, R3 = benzyloxymethyl, R4 = hydrox-yl and R5 = hydrogen:

0.5 g (1.1 mmol) of the compound of Example 6.19.
i~ dissolved in 10 ml of methanol, and the solution is treated with 10 ml of concen~rated aqueou~ ammonia and stirred at room temperature : 20 for 24 hours. Working-up yields 0.25 g (61.3~ oftheory) of 2-acetamido~7~ benzyloxy-3-hydroxy-; 2-propoxymethyl)purine of melting point 149C;

H-NMR (60 MH~, d6-DNSO3, ~ ppm: 10.47 (8, 1~), 9 . 10 ( B, lH3, 8.78 (s, lH~, 7.30 (m, 5H), 5.87 (B, 2H)~ 4.73 (t, lH), 4.40 (8, 2H) t 3.80-3.30 (m~ 5H), 2,17 ~s, 3H).

6.26 C~mpound of the formula I in ~hich Rl a hy~rogen, R2 = acetamido~ R3 = acetoxymethyl, R4 ~ acetoxy and R5 = hydrogen:

0.24 g ~1 mmol) of the compound of Example 6.12.
i8 treated with 10 ml of ~cetic anhydride and 30 mg of N,N-dimethylaminopyridine and the 2~8~
~ 4~ -mixture is ~tirxed at room temperature for 18 hours. After n~utralization o the reaction mixture and chromatographic purification of the crude product on 6ilica gel u~ing ethyl acetate/-methanol 9:1, 0.2 g ~61.9~ of ~heory) of 2-acetamido-7-~1,3-bis~acetoxy)-2~pxopo~ymethyl]-purine of melting point 141C is obtained.

H-NMR (270 ~Hz, d6-DNSO), ~ pp~: 1~.46 (8, lH), 9.04 (~, lH), 8.77 (8, lH), 5.82 ~s, 2H~, 4.16-4.09 (m, ~), 4.05-3.95 (m, 3H), 2.19 ( 5 t lH), 1.70 ~8/ 6~).

Combination of the proces~es according to 1) - 4) with the process according to 5): -7.1. Compound of the formula I in which R1 = isopro-poxy, R2 = amino, R3 ~ i~opropo~ymethyl, R4 =
isopropoxy and R5 = hydrogen:

~ g (O.005 mol) of the compound of Example 5 are dissolved in 25 ml of a:nhydrous i~opropanol, the 601ution is treated with a solution of 0.345 g ~0.015 mol~ of sodium in a~hydrous i~opropanol and the mixture is heated to reflux for 2 hours.
The cooled 8U . pe~sion i6 treated with ic~-water and neutralized with 2 N acetic acid. The precipitate i6 filtered off with suction, washed with water and dried. 1.5 g (78.6~ of theory) of 2-amino 6-isopropoxy-7- [ 1 / 3-bi (i~opropoxy)~
2-propo~ymethyl]purine of melting point 85 - 87C
are obtained.

1H~NMR (60 ~z, d6-DNSO), ppmO 8.22 (8, lH~, 6.08 (~ 2H), 5.62 ts/ 2H), 5.50 lm, lH)~ 3.87 - 3.17 t~, 7H)~ 1-35 (d, 6H), 0.97 td, 12H).

7.2. Compound of the formula I in which Rl = methoxy, R2 = amino, R3 = i~opropoxymethyl, R4 = isopropo~y 2~3~

and R5 = hydrogen~

2 g (0.005 mol) of the compound of Ex~mple 5. are dissolved in 20 ml of methanol and the 301ution is added to a solution of sodium ethanolate in methanol (O.35 g o~ ~odium and 20 ml of meth~nol). The mixture i~ heated under reflu~ fox 2 hour~. Precipitated ~odium chloridP i6 filtered off with suction, and the ~ethanolic solu~ion is completely conoentrated. The resldue iB dis~olved in a little water ~nd the ~olution i~ 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-6~
methoxy7-[1,3-bis(i~opropo~y)-2-propoxymethyl]-purine of melting point lll~C are obtained.

Pxocesses according to 1) - 4):

8.1. Compound of the formula I in which Rl = hydroxyl;
R2 = acetamido, R3 = hyclroxymethyl, R4 = hydroxyl and R5 = hydrogen:

3.81 g ~0.01 mol) of t:he compound of Example 2 are dissolved in 150 ml of anhydrous dichloro-methane and the mixture i~ cooled to -60C with stirring in an ar~on atmosphere. 60 ml (0.06 mol) of a 1 mol8r ~olution of boron trichloride in n-hexane or dichlorQmethsne are then slowly added, the temperature of the reaction mixture i8 slowly allowed to risQ to -40C to -20C, and the mixture is ~tirred at thi6 tempera~ure ~or 3 hours and then at 10C for a further hour. The mixture i8 coolad again to -6a DC ~ 60 ml of methanol and 60 ml of dichl~romethane are 810wly added dropwise and a ~olution is obtained which is treated with 37 ml of triethylamine. The solution i5 ~ubsequently addi~ionally ~tirred at room temperature ~or 30 minute~ before the , ~ ,, reactîon mixture i~ comple~ely eYaporated.
Chromatography on ~ilica gel using a mixture of dichloromethane/methanol 3:1 yields 1.32 g (44~4 of theory~ sf 2-acetyl-7-(1,3-dihydroxy~2-pro~
pox~methyl)guanine of melting point 155 - 158~C
(decompoæition).

H-NMR (270 NHz, d6-DNS0), ppm: 12.15 (6, lH)~
11.61 (~, lH), 8.37 (B, 1~), 5-77 t~ 2~)~ 4-61 (t, 2H), 3.62 (m, lH), 3.35 (m, 4~, 2.17 (s, 3H)~

8.~. Compound of the for~ula I in which Rl = hydrogen, R2 = acetamido, R3 = hydroxymethyl, R4 = hydroxyl and R5 = hydrogen:

According ~o the same method, 3065 g ~0.01 mol) of the compound of Example 6.6. were reac~ed with O.05 mol of boron trichloride and after cry tal-lization from methanol yielded 2.2 g (~8.3% of theory) of 2-acetamido-7-(1,3-dihydroxy~2-pro-poxymethyl)purine of me;lting point 214 - 215~C.

lH-NMR (270 MHz, d6-DMS0), ppm: 10.43 (~, lH), 9.07 (~, lH), 8.72 (~, lH), 5.81 (s, 2H), 4.65 (t, 2H3, 3.55 - 3.28 (m, 5H), 2.20 (8, 3H).

8.3. Compound of the formula I in which Rl = hydrogen, : R2 = acetamido, R3 = hydro~ymethyl, R4 = isopro-poxy and R5 = hydrogen:

3 g of the compound of Examp~e 6.9. are heated under reflux with 4 g of ammonium formate and 1 g of palladium/carbon (10%) for 8 hour~ in 75 ml of me~hanol. The reaction mixture i~ filtered, concentrated, treatPd with acetone and ~tirred until it crys~allizes. 0.9 g (57.44 of theory) of 2-acetamido--7-(l-hydroxy~3-i opxopoxy-~-propoxy-methyl)purine of melting point 170C is obtained.

.. . . . .

~3~

H-NMR (270 M~z, d6-DMSO~, ppm: 10.43 (~, lH), 9.04 (s, lH), 8.72 (~, lH), 5.80 (m, 2~), 4.73 (t~ lH), 3.60 ~m, lH), 3.46 - 3.20 (m, 5H), 2.17 (~, 3H), 0.90 (m, 6H).

8.4. Compound of the formula I in which Rl = hydrogen, R2 = acetamido, R3 - hydrogen~ R4 = hydroxyl and R5 = hydrogen:

2.93 g (0.01 mol) of the compound from ~xample 6.8. are treated at -60C with boron trichloride for 6 hours as in Ex~mple 8.1. After chromato-graphy on silica gel using dichloromethane/-methanol 5:1, 2.2 g (87.6~ of theory) of ~-acetzmido-7 (2-hydroxyethoxymethyl~purine of melting point 194C are obtained.

15 8.5. Compound of the formula I in which R~ - hydrogen, R2 = acetamido, R3 = hydrogen, R4 = hydroxyl and R~ = hydro~ymethyl:

4.13 ~ (10 mmol) of the compound of Example 6.18.
are treated with boron trichloride as descri~ed : 20 in Example 8.1. and after chromatographic purifi-ca~ion on ~ilica gel (dichlorome~hane/methanol 3:1) yield 2.3 g (99.6% of theory) of 2-acet-amido-7-(2,3-dihydroxy-1-propo~ymethyl)purine of melting point 167 - 168C.

, `

- 50 ~ 8 ~ ~ ~
Tabla 4 Example Rl R2 ~3 ~4 R5 2. OHNHC(O)CH3i:H20CH(cH3)2OC~(~H3)2 ______ ___ _ ___ _ _______ _________ ~_; ____ __ 3 .1.
5.ClNHC(O)CH3 CH2OC~cH3~2 OCH~H3)2 __ ___ _____ ______ _ ___ ______ ______ _ _ 5.1. Cl NHC(O3CH3 CH~OCH2CH3 ~ H2~H3 H
___ ____ _ ________ _____ _ ____,____________ ___ 5.2. Cl NHC(O)CH3 CEi2O(cH2)2c~3 o(~I2)2CH3 _ _ _ _ _ _ _ _ _ _ _ _ ~ _ _ _ ~ _ _ _ _ _ _ 5 . 3 . Cl NHC(O)CH3 OCH(~H3~2 H
_____ ___ _ _ _ ___ ____ _ __ _ _ 5 . 4 . Cl NHC ( O ) ~H3 CH20CH2C6H5 QCH ( ~H3 ) 2 H
_ _ _ _ .. _ _ _ _ _ _ _ _ _ _ ,. _ _ _ _ 5. 5 Cl NHC(O)CH3CH2OCH3 OCH3 H
__ ..... ._ _ _ __ __ _ _ __ 5 . 6. Cl NHC(O)CH3 CH~OCH~CH=CH2 ocH2cH ~H2 H
____ _ _ _ _ _ ___..... .._ _ _ ____ _ ___ 5,7 Cl NHC(O)CH3 CH20-cyclopentyl O-cyclop~rltyl H
____~_ _ ________ __ _ _ __ _ _ _ ___ _ 5 . 8 C 1 NHC ( ) ~;3 il OCH2c6H6 CH2 OCH ( CH3 ) 2 ___ _ _ _____ __ _______ _ _ _ _ ___ __ _____ 5.9 Cl (O)CH3 C}I2Oc(O)~(c~3)3 oc(33c(eH3)3 H
___ _ _ _____ __ ______________--__________ ___________ ____ 5 .10 I::l NIIC(O)CH3 C~;j!OC~I2t 6~5 oc(o)t:tC:~33)3 ~3 __ ._ _.. ,~.. , __-- _--_------_--_--_--___--_--____________________ 6.1. SH NHC(S)CH3 CH2OCH(CH3)~ OCH~CH3~2 H
___ _ ___ _____--___. _--___-- ___--________ __~ ______ __ __ 6.2. SH NH2 CH2C)c~(CH3)2 OCX~t H3)2 H
__ _ ___ _ ________ ___ _____ ___________ _________ _ 6.3. OCH3 NHC(O)~H3 C:H2OCH(~3)2 OCH(CH3)2 __ ___ _ __ __ _____ ____ ____ __ __ - ",~, 2 ~

Continu,~tion of Table 4; ~ormula I

E~ample Rl R2 R3 R4 R5 6 . ~ . 1 . NH2 NHC ( O ) ~ H3 CH2 O~ 3 ) 2 OCH ( CH3 ) 2 H
_______________________________ ______________________~________ 6 . 4 . 2 . NH2 ~H2 CH20~ H3 ) 2 O~H ( I: H3 ~ 2 H
_____________ _________________________________________________ 6 . 5 . 1 . I~HCH3 NH~ ( O ) C~3 ~HZocH ( C~3 ) 2 OCH ( CH3 ) 2 H
_____________ _________________________________________________ 6 . 5 . 2 . NHCH3 NH2 CH;~OCH ( CH3 ~ 2 OCH ( CH3 ~ 2 }I
_______ ______________________________.. _____________________,__ ~ . 6 . H NHC ( O ) CH3 CH;~ OCH ( ~H3 ) 2 OCH ( CH3 ) 2 H
__ _ ____ ___________________________________________ __.. __ 6 . 7 . H NH2 CH20~H ~ CH3 ) .2 OCH ~ C~3 ) 2 H
__ ____ ___________________________ _________________________ 6 . 8 . H N~IC~O)CH3 H OCH(CH3)2 H
___ __ _______________________________________________________ 6 . 9 . H NHC ( O ) CH3 CH20C H2C6H5 OCH ( CH3 ) 2 H
__ ___ _ ___ _______ ________________________________________ 6.10. H NH2, CH20H Ol:~(CH3~2 H
__ __________________________________________________________ 6 . 11 . ~I NH2 H OCH ( eH3 ) 2 H
__ __~__ _____________________________________________________ 6.12. H NH2 CH20H O~I H
_______________________~._______________________________________ 6 . 13 . 1 . OH OH CH20CH ( CH3 ) 2 OC:H ( CH3 ) 2 H
__________________________ ___________~_,______,_______________ 6 . 13 . 2 . NH2 t)H CH;~OCH ~ CH3 ) 2 OCH ( CH3 ) 2 H
_____________________________________________~_________________ .
6 . 14 . H ~IHC ( O ) CH3 C:H20CH3 OCH3 H

_______________________________________________________________ 6.15. H NH~:(O)CH3 cH2oe2H5 C2H5 H
_______ _______________________~____O__________~.. ______________ 2~3~

~ontinuation of Table 4; formula I

Example Rl R2 ~3 ~4 R5 6.16. H N~2 CH20C~2C~=cH2 OCH2CH=CH2 H
____ _______ ____________ ___________________ _________________ 6.17. H h~C(O)CH3 CH2O-cyclopentyl O-cyclopentyl H
________________________________ ____________________________ 6.18. H MHC(O)CH3 H OcH2c6H5 C~2OC~(CH3)2 2 ____________________________________,,_________________________ 6.19. H NHC(O)CH3 CH20CH2C6H5 oC(O)C(CH3)3 H
_______ _ ______________________________ ______ __________ 6.20. H NH2 CH20CH3 OCH3 _ _ _ _ _ _ _ _ ~:
6.21. X h~2 CH23C~H5 C2H5 H
___ ______ __ ____~______ ___ ________ ___________________ 6.22. ~ h~2 CH20-cyclopentyl O-cyclopentyl H
_____ _ __ _______ __________._______________ __________ 6.23. .- h-~2 X OH CH20H
___ _ _________ _____ _____ ___ ___________ __ ____ 6.~. r. hH2 CH20C~2c6H5 OH
__ _ ____ _ ________ ____ _____ ___ _ ________ 6 . 25 . Y. NHC(O)C~3 CX20C~2c6H5 OH H
~ _ 5 ,5 H ~r:C(O)cH3 C~2OC(O)CH3 OC(0)CH3 ___ _ ___ ____ ______ _ ____ _____ __ ._ ~__ _______ 1 _ CH(CH3)~_NH2___ ~__ CH20CH(CX~)2 OCH(CH3)2 H
7.2. OC.-3 NH2 C~2ocH(cH3)2 oCH(CH3)2 H
______ __ __________________ ___________~._____ ___________ 8.'. OH NHC(O)C-~3 CX2H OH H
___ ____ _ _ ___ __________ ______ ___ 8.2. r. NHC(O)C~3 C~2H OH H
__ _______ _ _____ _ ____ __ __ ________ a.3. r. NHC(O)C~3 C~20C~(C~3)2 ~ ~
_________ __ __ _ ___ _ _ _ _ ____ ___ ~ 8.~. H NXC(O)C.i3 H OH H
__ __ ____ _ ___________ __ 8.5. L h~C(O)C~3 H 0H CH2~' .. ______ _ _ _____ __ __ _ _______

Claims (15)

1. A compound of the formula I

(I) in which R1 is hydrogen, halogen, azide, hydroxyl, C1-C5-alkoxy, benzyloxy, phenoxy, mercapto, C1-C5-alkylthio, benzylthio, phenylthio, amino, C1-C6-alkylamino, benzylamino, phenylamino, C2-C12-dialkylamino, dibenzylamino, cyclic dialkylamino, diphenylamino, C1-C8-acylamino, C2-C18-diacylamino, (N-alkyl-
2-pyrrolidinylidene)amino or C2-C10-dialkylamino-methylideneamino, R2 is hydrogen, halogen, azide, hydroxyl, mercapto, amino, C1-C6-alkylamino, C2-C12-dialkylamino, benzylamino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenylamino, C1-C8-acylamino and thioacylamino, C2-C16-diacylamino or di(thioacyl)-amino, R3 is hydrogen, C1-C6-alkyl, optionally substituted by halogen or by a hydroxyl, amino, thio, C1-C6-alkoxy, C1-C6-alkylthio, C1-C5-alkylamino, benzyloxy, benzylamino, benzylthio, C2-C12-dialkylamino, di-benzylamino, diphenylamino, C1-C8-acyloxy, C1-C8-acylamino, C1-C16-diacylamino or C2-C8-acylthio group or a radical R6, whare R8 is -P(O) (OR6)(OR7), -O-(C1-C4-alkyl)-P(O)(OR8)(OR7), -S-(C1-C4-alkyl)--P(O)(OR5)(OR7), -NH-(C1-C4-alkyl)-P(O)(OR6)(OR7), -N(C1-C6-alkyl)-C1-C4-alkyl-P(O)(OR6)(OR7), -P(C1-C6-alkyl)(O)(OR5), -O-(C1-C4-aalkyl)-P(C1-C6-alkyl)(O)(OR5), -S-(C1-C4-alkyl)-P(C1-C8-alkyl)(O)(OR6), -NH-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -N(C1-C6-alkyl)-C1-C4-alkyl-P(C1-C6-alkyl)(O)(OR6) in which R6 and R7 are independently of one another hydrogen or a C1-C6-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R4 is hydrogen, C1-C6-alkyl, hydroxyl, mercapto, amino, halogen, azide, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylamino, C2-C12-dialkylamino, benzyloxy, benzylthio, benzylzmino, dibenzylamino, phenylamino, diphenylamino, phenoxy, phenylthio, C1-C8-acyloxy, C1-C8-acylthio, C1-C8-acylamino, C2-C16-diacylamino or - O - (C1 - C4 - a l k y l ) - P ( O ) ( O R6) ( O R7) o r -O-(Cl-C4-alkyl)-P(Cl-C6-alkyl)~O)(OR6), where the radical R6 and R7 are as defined above, and R5 is hydrogen, C1-C6 alkyl, optionally substituted by a hydroxyl, thio, amino, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylamino, C2-C12-dialkylamino, C1-C8-acyloxy, C1-C8-acylthio, C1-C8-acylamino, C2-C16-diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino, diphenylamino group or a radical R8, where R8 is -P(O)(OR6)(OR7), -O-(C1-C4-alkyl)-P(O)(OR6)(OR7), -S-(C1-C4-alkyl)-P(O)(OR6)(OR7), -NH-(C1-C4-alkyl)-P(P)(OR6)(OR7), -N(C1-C6-alkyl)-C1-C4-alkyl-P(O)(OR6)(OR7), -P(C2-C6-alkyl)(O)(OR6), -O-(C1-C4-alkyl)-P(C1-C5-alkyl)(O)(OR6), -S-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -NH-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), N(C1-C6-alkyl)-C1-C4-alkyl-P(C1-C6-alkyl)(O)(OR5), in which R6 and R7 are independently of one another hydrogen or a C1-C6-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, R1 is not hydroxyl and R2 is not amino or R1 is not hydroxyl, R2 is not acetamido, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydro-gen or R1 is not chlorine or methoxy, R2 is not amino, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or R1 is not hydroxyl, R2 is not acetamido, R3 is not acetoxymethyl, R4 is not acetoxy and R5 is not hydrogen or R1 is not methoxy, R2 is not amino, R3 is not hydroxy-methyl, R4 is not hydroxyl and R5 is not hydrogen or R1 is not chlorine or amino, R2 is not hydrogen, R3 is not hydroxymethyl or benzyloxymethyl, R4 is not hydroxyl or benzyloxy and R5 is not hydrogen or R1 is not amino, R2 is not mercapto, R3 is not benzyloxy-mathyl, R4 is not benzyloxy and R5 is not hydrogen or R1 is not benzyloxy, R2 is not chlorine, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or R1 is not chlorine, R2 is not amino, R3 is not acetoxy-methyl, R4 is not acetoxy and R5 is not hydrogen or R1 is not benzyloxy, R2 is not chlorine, R3 is not hydrogen, R4 is not benzyloxy and R5 is not benzyloxy-methyl or R1 and R2 are not chlorine, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or R1 is not amino, R2 is not mercapto, R3 and R5 are not hydrogen and R4 is not acetoxy or R1 is not hydrogen, R2 is not amino, R3 and R5 are not hydrogen and R4 is not hydroxyl or acetoxy or R1 and R2 are not chlorine, R3 and R5 are not hydrogen and R4 is not benzyloxy or R1 is not iodine, R2 is not chlorine, R3 and R5 are not hydrogen and R4 is not hydroxyl.

2. A compound of the formula I as claimed in claim 1, in which R1 is hydrogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms, amino, C1-C6-alkylamino or C2-C8-di(alkyl)amino, or C1-C6-alkylthio, R2 is hydrogen, halogen, hydroxyl, amino, C1-C6-alkylamino, C2-C5-di(alkyl)amino or C1-C8-acylamino, R3 is hydrogen, C1-C6-alkyl, optionally substituted by a hydroxyl, amino or C1-C6-alkoxy group or halogen or a C1-C8-acyloxy, C1-C8-acylamino or C1-C6-alkylamino group or a group R8, where R8 is -O-(C1-C4-alkyl)-P(O)(OR6)(OR7), -P(O)(OR6)(OR7) or -P(C1-C4-alkyl)(O)(OR6), in which R6 and R7 are independently of one another hydrogen or C1-C6-alkyl radical or an alkali metal or alkaline earth metal ion, R4 is hydrogen, hydroxyl, amino, mercapto, C1-C4-alkoxy, C1-C8-acyloxy, C1-C61alkylamino or a -O-(C1-C4-alkyl)-P(O)(OR6)(OR7) or -O-(C1-C3-alkyl)-P(C1-C6-alkyl)(O)(OR6)radical having the meanings R6 and R7 as described above and R5 is hydrogen or C1-C4-alkyl, optionally substituted by hydroxyl, C1-C8-acyloxy, benzyloxy, C1-C8-alkoxy, amino, C1-C6-alkylamino or a radical R8, where R8 is -P(O)(OR6)(OR7) or -P(C1-C4-alkyl)(O)(OR6), in which R6 and R7 are defined as described above.
3. A compound of the formula I as claimed in claims 1 or 2, in which R1 is hydxogen, hydroxyl, chlorine, mercapto, benzyloxy, C1-C6-alkoxy, amino, C1-C3-alkylamino or C2-C6-dialkylamino, R2 is hydrogen, hydroxyl, amino or C1-C8-acylamino, R3 is hydrogen, Cl-C3-alkyl, optionally substituted by a hydroxyl, C1-C8-acyloxy or C1-C8-alkoxy group or a or -P(O)(OR6)(OR7) group, where R6 and R7 have the above meanings, R4 is hydrogen, hydroxyl or a C1-C8-acyloxy or C1-C8 alkoxy group or and R5 is hydrogen or C1-C4-alkyl, optionally substituted by hydroxyl, C1-C8-acyloxy or C1-C8-alkoxy or -PPO)(OR6)(OR7), where R6 and R7 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 R1 is hydrogen, hydroxyl, chlorine, C1-C4-alkoxy, amino, C1-C3-alkylamino or C2-C8-dialkylamino, R2 is hyrdrogen, hydroxyl, amino or C1-C3-acylamino, R3 is C1-C3-alkyl, optionally substitutad by hydroxyl or by C1-C8-acyloxy or by C1-C6-alkoxy or by -P(O)(OR6)(OR7), where R6 and R7 have the above-mentioned meanings, R4 is hydroxyl or C1-C8-acyloxy or C1-C6-alkoxy and R5 is hydrogen.
5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which R1 is hydrogen, chloxine or amino, R2 is amino or C1-C3-acylamino, R3 is C1-C3-alkyl, optionally substituted by hydroxyl or by C1-C5-acyloxy or by C1-C5-alkoxy or by -P(O)(OR6)(OR7), where R6 and R7 have the above-mentioned meanings, R4 is hydroxyl or C1-C5-acyloxy or C1-C5-alkoxy and R5 is hydrogen.
6. A compound of the formula I as claimed in one or more of claims 1 to 5, in which R1 is hydrogen, R2 is amino, R3 is C1-C3-alkyl, optionally substituted by hydroxyl or by C1-C4-acyloxy or by C1-C4-alkoxy, R4 is hydroxyl or C1-C4-acyloxy or C1-C4-alkoxy and R5 is hydxogen.
7. A compound of the formula I as claimed in one or more of claims 1 to 6, in which R1 is hydrogen, R2 is amino, R3 is hydroxymethyl, R4 is hydroxyl and R5 is hydrogen.
8. A compound of the formula I

(I) in which R1 is hydrogen, halogen, azide, hydroxyl, C1-C6-alkoxy, benzyloxy, phenoxy, mercapto, C1-C6-alkylthio, benzylthio, phenylthio, amino, C1-C6-alkylamino, benzylamino, phenylamino, C2-C12-dialkylamino, dibenzylamino, cyclic dialkylamino, diphenylamino, C1-C8-acylamino, C2-C16-diacylamino, (N-alkyl-2-pyrrolidinylidene)amino or C2-C10-dialkylamino-methylideneamino, R2 is hydrogen, halogen, azide, hydroxyl, mercapto, amino, C1-C8-alkylamino, C2-C12-dialkylamino, benzylamino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenylamino, C1-C8-acylamino and thioacylamino, C2-C16-diacylamino or di(thioacyl)-amino, R3 is hydrogen, C1-C6-alkyl, optionally substituted by halogen or by a hydroxyl, amino, thio, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkylamino, benzyloxy, benzylamino, benzylthio, C2-C12-dialkylamino, di-benzylamino, diphenylamino, C1-C6-acyloxy, C1-C8-acylamino, C1-C16-diacylamino or C2-C8-acylthio group or a radical R8, where R8 is -P(O)(OR6)(OR7), -O-(C1-C4-alkyl)-P(O)(OR6)(OR7), -S-(C1-C4-alkyl)--P(O)(OR6)(OR7), -NH-(C1-C4-alkyl)-P(O)(OR6)(OR7), -N(C1-C6-alkyl)-C1-C4-alkyl-P(O)(OR6)(OR7), -P(C1-C6-alkyl)(O)(OR6), -O-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -S-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -NH-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -N(C1-C6-alkyl)-C1-C4-alkyl-P(C1-C6-alkyl)(O)(OR6) in which R6 and R7 are independently of one another hydrogen or a C1-C6-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R4 is hydrogen, C1-C6-alkyl, hydroxyl, mercapto, amino, halogen, azide, C1-C6-alkoxy, C1-C8-alkylthio, C1-C6-alkylamino, C2-C12-dialkylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenylamino, diphenylamino, phenoxy, phenylthio, C2-C16-acyloxy, C1-C8-acylthio, C1-C8-acylamino, C2-C16-diacylamino or - O - ( C1 - C4- a l k y l ) - P ( O ) ( O R6) ( O R7) o r -O-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), where the radicals R6 and R7 are as defined above, and R5 is hydxogen, C1-C4-alkyl, optionally substituted by a hydroxyl, thio, amino, C1-C3-alkoxy, C1-C6-alkylthio,C1-C6-alkylamino,C2-C12-dialkylamino, C1-C8-acyloxy, C1-C5-acylthio, C1-C8-acylamino, C2-C16-diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino, diphenylamino group or a radical R8, where R8 is -P(O)(OR6)(OR7), -O-(C1-C4-alkyl)-P(O)(OR6)(OR7), -S-(C1-C4-alkyl)-P(O)(OR6)(OR7), -NH-(C1-C4-alkyl)-P(O)(OR6)(OR7), -N(C1-C6-alkyl)-C1-C4-alkyl-P(O)(OR6)(OR7), -P(C1-C6-alkyl)(O)(OR6), -O-(C1-C4-alkyl)-P(C1-C6-alkyl)(O)(OR6), -S-(C1-C4-alkyl)-P(C1-C6-alkyl3(O)(OR6), -NH-(C1-C4-alkyl)-P(C1-C5-alkyl)(O)(OR6), N(C1-C6-alkyl)-C1-C4-alkyl-P(C1-C6-alkyl)(O)(OR6), in which R6 and R7 are independently of one another hydrogen or a C1-C6-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable salts and obvious chemical equivalents for the prophylaxis or treatment of virus diseases.
9. A process 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 R4 is hydroxyl, amino, aminoalkyl or mercapto, replacing a protect-ing group A1 in a compound of the formula II

(II) by a hydroxyl, amino, alkylamino or mercapto group, or b) if in the compound of the formula I R3 is hydroxy-alkyl, aminoalkyl, alkylaminoalkyl or mercaptoalkyl, replacing a protecting group A2 in a compound of the formula III

(III) by a hydroxyl, amino, alkylamino or mercapto group, c) if in the compound of the formula I R5 is hydroxy-alkyl, aminoalkyl, monoalkylaminoalkyl or mercapto-alkyl, replacing a protecting group A3 in a compound of the formula IV

(IV) by a hydroxyl, amino, alkylamino or mercapto group, or d) if in the compound of the formula I R3 is hydroxy-alkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl and/or R4 is hydroxyl, amino, alkylamino or mercapto and/or R5 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or mercaptoalkyl, replacing a protecting group A4 and/or A5 and/or A6 in a compound of the formula V
(V) by a hydroxyl, amino, alkylamino or mercapto group or e) converting a compound of the formula VI

(VI) in which Y and Z are precursors of the groups R1 and R2 into a compound of the formula I in which R1 and R2 have the meanings described above, or f) reacting a compound of the formula VII

(VII) with a compound of the formula VIII

(VIII) in which L2 is a leaving group and L1 is hydrogen or a leaving group, g) removing a blocking group from a compound of the formula I in which one or both radicals R1 and R2 are blocked, and is 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.
10. The use of purine derivatives substituted in the 7-position for the treatment of virus diseases.
11. A pharmaceutical containing at least one compound of the formula I as claimed in one or more of claims 1 to 4.
12. The use of purine derivatives substituted in the 7-position for the production of pharmaceuticals for the treatment of virus diseases.
13. The use of purine derivatives of the formula I as claimed in one or more of claims 1 to 8 for the produc-tion of pharmaceuticals for the treatment of virus diseases.
14. A process for the production of pharmaceutically as claimed in claim 11, which comprises bringing at least one compound of the formula I as claimed in claims 1 to 7 into a suitable administration form, if appropriate with suitable auxiliaries and/or excipients.
15. The compound as claimed in claim 1 and substantially as described herein.
CA002038589A 1990-03-20 1991-03-19 Substituted purines, processes for their preparation and their use as antiviral agents Abandoned CA2038589A1 (en)

Applications Claiming Priority (2)

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DE4008858A DE4008858A1 (en) 1990-03-20 1990-03-20 New substd. purine antiviral cpds.
DEP4008858.8 1990-03-20

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DE4210221A1 (en) * 1992-03-28 1993-09-30 Hoechst Ag Carboxylic acid esters of 2-amino-7- (1,3-dihydroxy-2-propoxymethyl) purine, their preparation and their use
DE59310344D1 (en) * 1992-09-24 2003-07-24 Hoechst Ag N1-Substituted 1H-1,2,3-triazolo [4,5-d] pyrimidines, processes for their preparation and their use as antivirals
DE4311801A1 (en) * 1993-04-09 1994-10-13 Hoechst Ag New carboxylic acid esters of 2-amino-7- (1,3-dihydroxy-2-propoxymethyl) purine, their preparation and their use
DE19536164A1 (en) * 1995-09-28 1997-04-03 Boehringer Ingelheim Kg Improved Process for the Production of 9 - [(2-Hydroxyethoxy) methyl] guanine (Acyclovir)
US5891881A (en) * 1997-11-21 1999-04-06 Clarion Pharmaceuticals Inc. Aminoheterocycle-substituted glycerols
FR2793794B1 (en) * 1999-05-21 2001-07-27 Hoechst Marion Roussel Inc NOVEL PURINE DERIVATIVES, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NEW USE
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4

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GB1523865A (en) * 1974-09-02 1978-09-06 Wellcome Found Purine compunds and salts thereof
US4816447A (en) * 1981-08-26 1989-03-28 Merck & Co., Inc. Anti-viral guanine compounds
DE3627024A1 (en) * 1985-09-24 1987-04-02 Hoechst Ag 2-AMINOPURINS SUBSTITUTED IN 6 AND 9 POSITIONS, THEIR USE, MEDICINAL PRODUCTS CONTAINING THESE PURINES AND METHOD FOR THE PRODUCTION OF THE PURINS
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CS70891A2 (en) 1991-11-12
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EP0452680B1 (en) 1996-11-06
DE4008858A1 (en) 1991-09-26
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KR910016751A (en) 1991-11-05
NO911081D0 (en) 1991-03-19
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JPH04217984A (en) 1992-08-07
AU7351491A (en) 1991-09-26
PT97080A (en) 1991-11-29
DE59108319D1 (en) 1996-12-12
IE910908A1 (en) 1991-09-25
GR3021591T3 (en) 1997-02-28

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