IE910908A1 - Substituted purines, processes for their preparation and¹their use as antiviral agents - Google Patents

Substituted purines, processes for their preparation and¹their use as antiviral agents

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IE910908A1
IE910908A1 IE090891A IE90891A IE910908A1 IE 910908 A1 IE910908 A1 IE 910908A1 IE 090891 A IE090891 A IE 090891A IE 90891 A IE90891 A IE 90891A IE 910908 A1 IE910908 A1 IE 910908A1
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alkyl
hydrogen
amino
hydroxyl
compound
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IE090891A
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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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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

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

Description

Substituted purines, processes for their preparation and their use as antiviral agents The present invention relates to derivatives of purine, which carry an alkoxymethyl radical in the 7-position, to processes for the preparation of these compounds and to their use as antiviral agents.
The invention in particular relates to purines such as adenine, guanine, 6-chloro-2-aminopurine, 2-aminopurine, 6- isopropoxy-2-aminopurine, 2,6-diaminopurine, purine and thioguanine which carry an unsubstituted or acyl- and/or alkyl- and/or benzyl-substituted 2-hydroxyethoxymethyl radical or 1,3-dihydroxy-2-propoxymethyl radical or 2,3-dihydroxy-1-propoxymethyl radical in the 7-position.
The invention further relates to the physiologically tolerable salts of said compounds.
While the antiviral activity and the preparation of purine nucleosides which carry an acyclic radical in the 9-position are already long-known (see, for example, DE-OS 2,539,963 or K.K. Ogilvie et al., Can.J.Chem. 62, 241 (1984) or C.K. Chu and S.J. Cutler, J. Heterocyclic Chem. 2_3, 289 (1986)), to date nothing is known about a specific synthesis of acyclic purines substituted in the 7- position or their antiviral activity.
Only J. Kjellberg et al., J. Heterocyclic Chem. 23, 625 (1986) and J. L. Sessler et al., Nucleosides + Nucleotides 8, 431 (1989) describe a more or less selective method for the preparation of carboacyclic guanines and 2-aminopurines substituted in the 7-position. However, the compounds prepared in this way were not investigated for their antiviral activity or were inactive in in vitro IE 91908 investigations.
In individual cases, the acyclic purine derivatives substituted in the 7-position were separated from the desired acyclic purine derivatives substituted in the 9-position and investigated for their antiviral activity in vitro (Κ. K. Ogilvie et al., Can. J. Chem. £2, 2702 (1984), Κ. K. Ogilvie et al., Can. J. Chem. 62., 241 (1984)) and found to be inactive.
It has now surprisingly been found that certain 7-substituted purines and their physiologically tolerable salts have antiviral properties against various DNA viruses, RNA viruses and retroviruses.
The invention accordingly relates to compounds of the formula I in which Rx is hydrogen, halogen, azide, hydroxyl, Cx-C6-alkoxy, benzyloxy, phenoxy, mercapto, Ci-Cg-alkylthio, benzylthio, phenylthio, amino, Cx-Ce-alkylamino, benzylamino, phenylamino, C2-C 12-di alkyl amino, dibenzylamino, cyclic dialkylamino, diphenylamino, Ci-Ce-acylamino, C2-C16-diacylamino, (N-alkyl2-pyrrolidinylidene)amino or C2-C10-dialkylaminomethylideneamino, R2 is hydrogen, halogen, azide, hydroxyl, mercapto, amino, Cx-Ce-alkylamino, C2-C12-dialkylamino, benzylamino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenyl amino, Cx-C8-acylamino and thioacylamino, C2-C16-diacylamino or di(thioacyl)amino, IE 91908 R3 is hydrogen, Cx-C6-alkyl, optionally substituted by 5 halogen or by a hydroxyl, amino, thio, Cj-Cg-alkoxy, C1-C6-alkylthio, Cj-Cg-alkylamino, benzyloxy, benzylamino, benzyl thio, C2-C12-dialkylamino, dibenzylamino, diphenylamino, Cx-C8-acyloxy, Ci-Ce-acylamino, C2-C16-diacylamino or Cx-C8-acylthio group or a radical R8, where R8 is -P(O) (ORg) (OR7), -O-(Cx-C4-alkyl)-P(O) (ORJ (OR7), -S-(C1-C4-alkyl)-P(O) (OR6) (OR7), -NH- (Ci-C.-alkyl) -P (0) (OR6) (OR7), -NiCi-Ce-alkyl)-C1-C4-alkyl-P(O) (OR6) (OR7), -P(Cx-C6-alkyl) (0) (0R6), -0- ((Υ-C.,-alkyl) -P (Cx-C6-alkyl) (0) (ORg), -S-iCx-C.-alkylJ-PiCx-Cg-alkyl) (0) (OR6), -NH- (C1-C4-alkyl) -P (Cx-C6-alkyl) (0) (OR6), -NiCx-Cg-alkylJ-Cx-C.-alkyl-PiCx-Cg-alkyl) (Ο) (OR6) in which R6 and R7 are independently of one another hydrogen or a ϋχ-Cg-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R4 is hydrogen, Cx-C6-alkyl, hydroxyl, mercapto, amino, halogen, azide, Cx-C6-alkoxy, Cx-C6-alkylthio, Cx-Cg-alkylamino, C2-Ci2-dialkylamino, benzyloxy, benzyl thio, benzylamino, dibenzylamino, phenylamino, diphenylamino, phenoxy, phenyl thio, Cj-Cg-acyloxy, Ci-C8-acylthio, Cx-C8-acylamino, C2-Cx6-diacylamino or -O-(Cx-C4-alkyl)-P(O) (ORg) (0R7) or -0-(Cx-C4-alkyl) P(O) (0R6) (0R7) or -O-(Cx-C4-alkyl)P(Cx-Cg-alkyl) (0) (ORg), where the radicals Rg and R7 are as defined above, and Rs is hydrogen, Cx-C6-alkyl, optionally substituted by a hydroxyl, thio, amino, Cx-C6-alkoxy, IE 91908 ---- . > - 4 Cx-Cg-alkylthio, Cx-C6-alkylamino, C2-C12-dialkylamino, Cx-Ca-acyloxy, Cx-C8-acylthio, Cx-C8-acylamino, C2-Cx6-diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino or diphenylamino group or a radical R8, where Re is -P(O)(OR6)(OR7), -O-(C1-C4-alkyl)P(O) (ORg) (0R7), -S-(Cx-C4-alkyl)-P(O) (ORg) (0R7) , -NH-(Cx-C4-alkyl)-P(O) (ORg) (0R7), -N(Cx-C6-alkyl)-Ci-C4-alkyl-P(O) (ORg) (OR7), -P(Cx-Cg-alkyl) (0) (ORg), -O-(Cx-C4-alkyl)-P(Cx-C6-alkyl) (0) (ORg), -S-(Cx-C4-alkyl)-P(Ci-Cg-alkyl) (0) (0R6), -NH- (Cx-C4-alkyl) -P (Cx-C6-alkyl) (0) (OR6), N (Cx-Cg-alkyl) -Cx-C4-alkyl-P (Cx-C6-alkyl) (0) (0R6), in which Rg and R7 are independently of one another hydrogen or a Οχ-Cg-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, Rx is not hydroxyl and R2 is not amino or Rx is not hydroxyl, R2 is not acetamido, R3 is not benzyloxymethyl, R4 is not benzyloxy and Rs is not hydrogen or Rx is not chlorine or methoxy t R2 is not amino, Ra is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or 30 Rx is not hydroxyl, R2 is not acetamido, R3 is not acetoxymethyl, R4 is not acetoxy and R5 is not hydrogen or Rx is not methoxy, R2 is not amino, R3 is not hydroxymethyl , R4 is not hydroxyl and R5 is not hydrogen or Rx 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 Rx is not amino, R2 is not mercapto, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or IE 91908 Rx is not benzyloxy, R2 is not chlorine, R3 is not benzyloxymethyl, RA is not benzyloxy and R5 is not hydrogen or Rx is not chlorine, R2 is not amino, R3 is not acetoxy5 methyl, R4 is not acetoxy and R5 is not hydrogen or Rx is not benzyloxy, R2 is not chlorine, R3 is not hydrogen, R4 is not benzyloxy and R5 is not benzyloxymethyl or Rx and R2 are not chlorine, R3 is not benzyloxymethyl, R4 is not benzyloxy and R5 is not hydrogen or Rx is not amino, R2 is not mercapto, R3 and Rs are not hydrogen and R4 is not acetoxy or Rx is not hydrogen, R2 is not amino, R3 and Rs are not hydrogen and R4 is not hydroxyl or acetoxy or Rx and R2 are not chlorine, R3 and R5 are not hydrogen and R4 is not benzyloxy or Rx 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 Rx is hydrogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms, amino, Cx-C6-alkylamino or C2-C6-di(alkyl)amino, or Cx-C6-alkylthio, R2 is hydrogen, halogen, hydroxyl, amino, Cx-C6-alkylamino, C2-C6-di( alkyl) amino or Cx-C6-acylamino, R3 is hydrogen, Cx-C6-alkyl, optionally substituted by a hydroxyl, amino or Cx-C6-alkoxy group or halogen or a Cx-CB-acyloxy, Cx-C8-acylamino or Cx-C6-alkylamino group or a group Re, where Re is -O-(Cx-C4-alkyl)-P(O)(OR6)(OR7), -P(0) (ORe) (0R7) or -P(Cx-C4-alkyl) (0) (OR6), in which R6 and R7 are independently of one another hydrogen or a Cx-C6-alkyl radical or an alkali metal or alkaline earth metal ion, IE 91908 - 6 ·* R4 is hydrogen, hydroxyl, amino, mercapto, Ci-Cg-alkoxy, Cx-Ce-acyloxy, Cj-Cg-alky lamino or an -0- (Cx-C4-alkyl) -P (0) (ORB) (0R7) or -O-CCi-C^-alkylJ-PiCi-Cg-alkyl) (0) (ORg) radical having 5 the meanings Rg and R7 as described above and R5 is hydrogen or Cx-C^-alkyl, optionally substituted by hydroxyl, Cj-Ce-acyloxy, benzyloxy, Ci-Cg-alkoxy, amino, Cx-Cg-alkylamino or a radical Re, where R8 is -P(O) (OR6) (0R7) or -PCCi-C^-alkyl) (0) (ORe), in which R6 and R7 are defined as described above.
Particularly preferred compounds of the formula I are those in which Rx is hydrogen, hydroxyl, chlorine, mercapto, 15 benzyloxy, Ci-Cg-alkoxy, amino, Ci-Cs-alkylamino or C2-C6-dialkylamino, R2 is hydrogen, hydroxyl, amino or Cx-Cg-acylamino, R3 is hydrogen, Ci-Ca-alkyl, optionally substituted by a hydroxyl, Ci-Cg-acyloxy or Cx-C6-alkoxy group or a • O· CH^-ORg« or7 or -P(0) (0R6) (0R7) group, where Rg and R7 have the above meanings, R4 is hydrogen, hydroxyl or Cx-CB-acyloxy or II Cx-Cg-alkoxy or and 0R7 R5 is hydrogen or Cj-C^-alkyl, optionally substituted by 25 hydroxyl, Cj-Cg-acyloxy or Cx-Cg-alkoxy or -P (0) ( ORb ) (0R7), where R6 and R7 have the abovementioned meanings.
Very particularly preferred compounds of the formula I - 7 IE 91908 are those in which Rx is hydrogen, hydroxyl, chlorine, Cj-C^-alkoxy, amino, C1-C3-alkylamino or C2-C6-dialkylamino, R2 is hydrogen, hydroxyl, amino or Cx-Ca-acylamino, R3 is Cx-C3-alkyl, optionally substituted by hydroxyl or by Cj-Ce-acyloxy or by Cj-Cg-alkoxy or by -P(0) (OR6) (0R7), where R6 and R7 have the abovementioned meanings, Ra is hydroxyl or Cj-Cg-acyloxy or Ci-Cg-alkoxy and R5 is hydrogen.
Compounds of the formula I furthermore have particular significance, in which R3 is hydrogen, chlorine or amino, R2 is amino or Cj-Ca-acylamino, R3 is Ci-Cs-alkyl, optionally substituted by hydroxyl or by Ci-Cs-acyloxy or by Cx-Cs-alkoxy or by -P(O) (ORg) (0R7), where Rg and R7 have the abovementioned meanings, R4 is hydroxyl or Cj-Cs-acyloxy or Cj-Cs-alkoxy and R5 is hydrogen; and compounds of the formula I have very particular significance, in which Rx is hydrogen, R2 is amino, R3 is Ci-Ca-alkyl, optionally substituted by hydroxyl or by Cj-C^-acyloxy or by Ci-C^-alkoxy, R4 is hydroxyl or Cj-C^-acyloxy or Cj-C^-alkoxy and R5 is hydrogen, in particular the compound of the formula I in which Rx is hydrogen, R2 is amino, IE 91908 - 8 R3 is hydroxymethyl, RA is hydroxyl and R5 is hydrogen.
Said alkyl groups as substituents of the abovementioned formula I can be branched, unbranched or cyclic. Examples of alkyl groups are the methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. Examples of alkoxy groups are the methoxy, ethoxy, propoxy, isopropoxy, butoxy or cyclopentyloxy group.
Examples of cyclic dialkylamino groups are the pyrrolidino, piperidino, morpholino, N-methylpiperazino or 1,2,4-triazolo group.
The preferred halogen substituent is chlorine. Particularly suitable alkali metal or alkaline earth metal substituents are sodium and calcium.
The compounds of these inventions are all substituted acyclic purine nucleosides, which carry the acyclic substituent in the 7-position of the purine ring system.
Salts of the compounds according to the invention par20 ticularly suitable for therapeutical purposes are salts of physiologically tolerable organic and inorganic acids such as acetic acid, lactic acid, malic acid, p-toluenesulfonic acid, methanesulfonic acid, isethionic acid, hydrochloric acid or sulfuric acid.
Obvious chemical equivalents of the compounds according to the invention are in particular derivatives thereof which can be converted into the compounds according to the invention without problem, for example under physiological conditions.
Of the compounds of the formula I according to the invention 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine = compound of the formula I in which Rx = H, R2 = NH2, IE 91908 - 9 R3 = CH2-0H, R4 = OH and R5 = H (Example 6.12.), 2-amino-7-(1-hydroxy-3-isopropoxy-2-propoxymethyl)purine = compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = hydroxymethyl, R4 = isopropoxy and R5 = hydrogen (Example 6.10.) and 2-amino-7-(1,3-bis(isopropoxy)-2-propoxymethyl)purine = compound of the formula I in which Rx = H, R2 = NH2, R3 = CH2-O-CH(CH3)2, R4 = O-CH(CH3)2 and R5 = H (Example 6.7.) are particularly preferred, in particular because of their particularly high antiviral activity against herpes viruses.
Other compounds of the formula I where R3 = hydrogen, R2 = amino and an acyclic side chain whose hydroxyl function or hydroxyl functions is/are esterified with Cx-Cg-alkyl radicals or esterified with Cj-Ce-acyl radicals show particularly high antiviral activity.
The invention furthermore relates to the use of said compounds as antiviral agents, the compounds classified above as excluded not being excluded. The compounds according to the invention are particularly active against herpes simplex viruses type 1 and type 2, cytomegaloviruses, varicella zoster viruses, Epstein Barr viruses and human herpes viruses 6 (HHV6).
The present invention furthermore relates to processes for the preparation of substituted purines of the formula I or a physiologically tolerable salt thereof, which comprise 1) if in the compound of the formula I R4 is hydroxyl, amino, alkylamino or mercapto, replacing a protecting group (blocking group) A2 in a compound of the formula II (II) IE 91908 B f3 »5 R. CH 0—CH—CH—Αχ ι · I c by a hydroxyl, amino, alkylamino or mercapto group, 2) if in the compound of the formula I R3 is hydroxyalkyl , aminoalkyl, alkylaminoalkyl or thioalkyl, replacing a protecting group A2 in a compound of the formula III tH—pi—Rs (HI) by a hydroxyl, amino, alkylamino or mercapto group, 3) if in the compound of the formula I R5 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl, replacing a protecting group A3 in a compound of the formula IV A3 by a hydroxyl, amino, alkylamino or mercapto group, 4) if in the compound of the formula I R3 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl and/or R4 is hydroxyl, amino, alkylamino or mercapto and/or R5 is hydroxyalkyl, aminoalkyl, - 11 monoalkylaminoalkyl or thioalkyl, replacing a protecting group Aa and/or and/or Ag in a compound of the formula V IE 91908 H alkyl-A* tx 0— CH— CH—As i ilkyl10 I II (V) ) 6) by a hydroxyl, amino, alkylamino or mercapto group, converting a compound of the formula VI Y N C > II /% N CHr " N ?3 ^4 .0— CH—CH—Ri (VI) in which Y and Z are precursors of the groups Rx and R2 into a compound of the formula I in which Rx and R2 have the meanings described above, reacting a compound of the formula VII fl c (VII) with a compound of the formula VIII l2--ch2--o--ch--ch (VIII) in which L2 is a leaving group and Lx is hydrogen or IE 91908 a leaving group, 7) removing a blocking group from a compound of the formula I in which one or both radicals Rx and R2 are blocked, and if the product of the reaction is a base of the formula I, optionally converting it into an acid addition product of this base of the formula I, or if the product of the reaction is a salt of a base of the formula I, optionally converting it into its base or into another salt of this base.
In the cases of processes 1) - 4), hydroxyl, mercapto, amino and monosubstituted amino functions of the acyclic side chain in the 7-position of the purine system, if present, are modified at the end by a blocking group D and, if appropriate, a further blocking group E, where D can be identical to or different from E.
These blocking groups can be esters - for example acyloxy groups - and/or benzyloxy groups - and/or C1-C6-alkyloxy groups - for example isopropoxy groups.
In the first case, the acyloxy group can be aliphatic 20 for example acetoxy or pivaloyloxy - or aromatic - for example benzoyloxy.
Both types of acyl groups can be removed, for example, by mild basic hydrolysis; in general warming with aqueous or alcoholic methylamine is adequate in order to achieve removal of the blocking group.
In the second case, the benzyloxy blocking group can be removed by hydrogenolysis, either catalytically or by means of hydrogen and Raney nickel or palladium/carbon or by means of ammonium formate and palladium/carbon or by means of a transfer hydrogenolysis with palladium hydroxide and cyclohexene or cyclohexadiene or chemically by reaction with boron halides - for example boron trichloride - at low temperatures - for example at -70 degrees Celsius - or by means of sodium in liquid ammonia, the liquid ammonia being used as solvent.
IE 91908 ~- 13 In the case of catalytic hydrogenolysis, the preferred solvent is an alkanol; however, a series of inert solvents can also be used if the substrate is at least partially soluble therein. Examples of these are benzene, toluene, tetrahydrofuran or dioxane.
For chemical reaction by means of boron trichloride, in which a solution of boron trichloride in n-hexane or in dichloromethane or alternatively gaseous boron trichloride is used, dichloromethane is the preferred solvent.
In the third case, deblocking of the Cx-Ce-alkyloxy groups can be achieved if boron trihalides - for example boron trichloride - are reacted with the substrate at temperatures which are not quite so low - for example at -60°C to 0°C, preferably at -40°C to -20°C. The preferred solvent for this is dichloromethane and the boron trichloride can be employed in gaseous form, as a solution in n-hexane or as a solution in dichloromethane.
The conversion of a compound of the formula VI into a compound of the formula I can be achieved in a very different manner by process 5). For example, one of the two radicals Rx or R2 or both the radicals Rj and R2 can be converted into a halogen by halogenation, into a hydroxyl group by hydrolysis, into a Cx-C6-alkoxy group by conversion with a Cx-C6-alkanolate, into a mercapto group by sulfurization, into a Cx-C6-alkylthio group by reaction with a Cj-Ce-alkyl thiolate, into an amino group by ammonolysis, into an amino group by deblocking a Cx-C8acylamino, Cx-C8-thioacylamino, benzylamino or Cx-Ce-alkylamino group, into a Cx-C6-alkylamino group or C2-C12-dialkylamino group by aminolysis, or into hydrogen by hydrogenolysis or desulfurization or formation of the azide.
All these processes are known and can be found, for example, in: Heterocyclic Compounds - Fused Pyrimidines Part II, Purines, editor: D.J. Brown, published by 91908 Wiley-Interscience, 1971.
In process 6), the leaving group L2 of a compound of the formula VIII is either a reactive radical of an inorganic acid and can thus be a) halogen, preferably chlorine, or b) a Cj-Cg-alkylthio or Cj-Cg-alkylsulfinyl or Cx-Cg-alkylsulfonyl group, preferably the methylthio or the methylsulfinyl or the methylsulfonyl group, or it is a reactive radical of an organic acid and can thus be c) Cx-Cg-acyloxy or benzoyloxy, preferably acetoxy.
In process 6a), the leaving group Lx in a compound of the formula VII is hydrogen or trialkylsilyl, preferably trimethylsilyl.
In process 6b), the leaving group Lx in a compound of the formula VII is a Cx-Cg-acyloxy group, preferably the acetoxy group, or a trialkylsilyl group, preferably the trimethylsilyl group.
In process 6c), the leaving group Lx in a compound of the formula VII is a Cv-Cg-acyloxy group or alternatively preferably a trialkylsilyl group, in particular the trimethylsilyl group.
The preferred process according to 6a) comprises the condensation of a purine with the desired substitution in the 2- and 6-position with a Cx-Cg-acyl- or benzyl- or Ci-Cg-alkyl-blocked l-(halomethoxy)ethanol, for example 1-(chloromethoxy)-2-acetoxyethane or 1-(chloromethoxy)-2-benzyloxyethane or 1- (chloromethoxy)-2-isopropoxyethane, or an acyl- and/or arylalkyl- and/or alkyl-blocked 2- (halomethoxy)-1,3-propanediol, for example 2-(chloromethoxy)-1,3-bis (acetoxy)propane or 2-(chloromethoxy)-1,3-bis(benzyloxy)propane or IE 91908 - 15 2-(chloromethoxy)-l,3-bis(isopropoxy)propane, or l-(halomethoxy)-2,3-propanediol blocked by a Ci-Cg-acyl and/or benzyl and/or Ci-Cg-alkyl, for example 1-(chloromethoxy)-2, 3-bis(acetoxy)propane or l-(chloromethoxy)-2,3-bis(benzyloxy)propane or 1-(chloromethoxy)-2,3-bis(isopropoxy)propane, in a strongly polar solvent such as dimethylformamide, dimethylacetamide, N-methylpyrrolid-2-one, tetramethylurea or dimethyl sulfoxide, in the presence of a base, such as triethylamine, N-ethylmorpholine or of an alkali metal carbonate, such as, for example, potassium carbonate, at room temperature for 1-72 hours, if Lx in a compound of the formula VII is hydrogen, or in aprotic solvents such as benzene, toluene, xylene, 1,2-dichloroethane, chlorobenzene, 1,2-dimethoxyethane, dioxane or acetonitrile, in the presence of a base such as triethylamine or N-ethylmorpholine, at a reaction temperature of 0 to 150°C, preferably at room temperature, for 1-72 hours, if Lx in a compound of the formula VII is trimethylsilyl.
It is known that alkylthioalkyl ethers, in particular methylthiomethyl ethers such as, for example, compounds of the formula VIII where L2 = methylthio, can be reacted with oxygen nucleophiles and Lewis acids such as mercury(II) chloride (E.J. Corey, M.G. Bock, Tetrahedron Letters 1975, 3269 or K. Yamada, K. Kato, H. Nagase, Y. Hirata, Tetrahedron Letters 1976, 65) or alkylsulfinylalkyl ethers, in particular methylsulfinylmethyl ethers such as, for example, compounds of the formula VIII where Lz = methylsulfinyl, can be reacted with carbon nucleophiles and Lewis acids such as zinc iodide (J.A. Schwindeman, P.D. Magnus, Tetrahedron Letters 1981, 4925).
The preferred process according to 6b) comprises the condensation of a purine with the desired substitution in the 2- and 6-position with a Cj-Cg-acyl- or benzyl- or Ci-Cg-alkyl-blocked 1-(alkylthioalkoxy)ethanol, for IE 91908 example 1-(methylthiomethoxy)-2-acetoxyethane or 1-(methylthiomethoxy)-2-benzyloxyethane or 1- (methylthiomethoxy)-2-isopropoxyethane or 2- (alkylthioalkoxy)- 1,3-propanediol or with a Cj-C8-acyl5 and/or benzyl- and/or Cx-Cg-alkyl-blocked, for example 2-(methylthiomethoxy)-1,3-bis(acetoxy)propane or 2-(methylthiomethoxy)-1,3-bis(benzyloxy)propane or 2-(methylthiomethoxy)-l,3-bis(isopropoxy)propane, orwith a Cj-Cg-acyl- and/or benzyl- and/or Ci-Cg-alkyl- blocked 1-(alkylthioalkoxy)-2,3propanediol, tor example 1-(methylthiomethoxy)-2,3-bis(acetoxy)propane or 1-(methylthiomethoxy)-2,3-bis(benzyloxy)propane or 1- (methylthiomethoxy)2,3-bis(isopropoxy)propane, where in each case instead of the alkylthioalkoxy group the alkylsulfinylalkoxy or alkylsulfonylalkoxy group can advantageously also be employed, in a strongly polar solvent or solvent mixture such as dimethylformamide, dimethylacet amide, N-methylpyrrolid2- one, tetramethylurea and/or dimethyl sulfoxide, in the presence of a protonic acid or Lewis acid, such as iron trichloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride, but preferably tin tetrachloride, or iodine or trialkylsilyl trifluoromethanesulfonate, preferably trimethylsilyl trifluoromethanesulfonate, at a temperature of -40°C to +100°C, preferably between -20°C and +80°C, for several hours, if Lx in a compound of the formula VII is Ci-Cg-acyl, preferably acetyl, or in a less polar solvent or solvent mixture such as dichloromethane or 1,230 dichloroethane in the presence of a Lewis acid such as iron(III) chloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride or tin tetrachloride or of a trialkylsilyl trifluoromethanesulfonate, preferably trimethylsilyl trifluoromethane35 sulfonate, at a temperature of -40 °C to +100 °C, preferably between -30°C and +20C, for 0.5 to 8 hours, preferably for 1 to 4 hours, if Lx in a compound of the formula VII is trialkylsilyl, preferably trimethylsilyl or in a polar aprotic solvent such as acetonitrile in the IE 91908 presence of a Lewis acid such as iron (III) chloride, boron trifluoride, gallium trichloride, aluminum trichloride, titanium tetrachloride, but preferably tin tetrachloride, at a temperature of -40eC to + 100°C, pre5 ferably between -30°C and +20°C, for 0.5 to 8 hours, perferably for 1 to 4 hours, if Lx in a compound of the formula VII is trialkylsilyl, preferably trimethylsilyl.
The preferred process according to 6c) comprises the condensation of a purine having the desired substitution in the 2- and 6-position, preferably an expediently modified 2-amino-6-chloropurine, in particular per-trimethylsilylated 2-acetamido-6-chloropurine, with a Cx-Ce-acyl- or benzyl- or Cx-C6-alkyl- blocked 1- (Cx-C8-acyloxymethoxy)ethanol, for example 1-acetoxy15 methoxy-2-acetoxyethane or l-acetoxymethoxy-2-benzyloxyethane or l-acetoxymethoxy-2-isopropoxyethane, or with a Cx-C8-acyl- and/or benzyl- and/or Cx-C6-alkyl-blocked 2- (Cx-C8-acyloxymethoxy )-1,3-propanediol, for example 2-acetoxymethoxy-1,3-bis(acetoxy)propane or 2-acetoxy20 methoxy-1,3-bis(benzyloxy)propane or 2-acetoxymethoxy-1,3-bis (isopropoxy)propane, or with a Cx-C8-acyl- and/or benzyl- and/or Cx-C6-alkylblocked l-(Ci-C8-acyloxymethoxy)-2,3-propanediol, for example l-acetoxymethoxy-2,3-bis(acetoxy)propane or l-acetoxymethoxy-2,3-bis(benzyloxy)propane or l-acetoxymethoxy-2, 3-bis (isopropoxy )propane, in an aprotic solvent such as benzene, toluene, xylene, acetonitrile, dichloromethane or 1,2-dichloroethane or mixtures thereof, in the presence of an acid, preferably a Lewis acid such as aluminum trichloride, boron trifluoride, iron trichloride, gallium trichloride, tin tetrachloride or titanium tetrachloride or in the presence of iodine or preferably trialkylsilyl trifluoromethanesulfonate, particularly trimethylsilyl trifluoromethanesulfonate, the amounts of these reagents being 0.1 to 10, preferably 0.8 to 7 equivalents, relative to the amount of the acetoxymethoxy IE 91908 compound employed in each case, at temperatures between -70’C and +80’C, preferably between -40’C and +30 °C, for 2 to 24 hours, preferably for 2 to 6 hours, if Lx in a compound of the formula VII is trialkylsilyl, particularly trimethylsilyl.
This process yields in high regioselectivity, as a rule »9:1, preferably the 7-isomer of the respective acyclic purine derivative.
If product mixtures are formed by processes 6a) - 6c), these are separated into the pure components, if necessary after conversion into another purine derivative, by chromatography or by fractional crystallization.
Compounds of the formula VIII where L2 = halogen can be prepared by reacting an expediently modified and protec15 ted alkanol, for example 1-acetoxyethanol or 1,3-bis(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2.3- bis(benzyloxy)propanol or 1-isopropoxyethanol or 1.3- bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)20 propanol with paraformaldehyde and a gaseous hydrogen halide, for example hydrogen chloride, in an inert solvent, for example dichloromethane, at room temperature or below.
The preparation of halomethyl ethers is a generally utilizable reaction; a detailed description can be found, for example, in: Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg Thieme Verlag, Stuttgart, 1965, volume VI/3, pp. 125 et seq.
Compounds of the formula VIII where L2 = methylthio can be prepared by reacting an expendiently modified and protected alkanol, for example 1-acetoxyethanol or 1.3- bis(acetoxy)propan-2-ol or 2,3-bis(acetoxy)propanol or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2.3- bis(benzyloxy)propanol or 1-isopropoxyethanol or IE 91908 l,3-bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)propanol with dimethyl sulfoxide, Cx-C8-acid anhydride and Ci-Cg-carboxylic acid in a temperature range between 0eC and +40°C, preferably at room temperature, for several days, as a rule 2 to 4 days.
A detailed description of the preparation of methylthiomethyl ethers of primary, secondary and tertiary alcohols can be found in P.M. Pojer and S.J. Angyal, Aust. J. Chem., 31, 1031 (1978).
The corresponding methylsulfinylmethyl compounds and methylsulfonylmethyl compounds can be obtained in a simple manner by oxidation by means of peracids, for example m-chloroperbenzoic acid or peracetic acid.
Compounds of the formula VIII where L2 = Cx-C8-acyloxy can be prepared either from a compound of the formula VIII where L2 = halogen, which is accessible as described above, by reaction with an alkali metal carboxylate, preferably sodium or potassium acetate, in acetone or dimethylformamide, or by converting an expediently modified and protected alkanol into the alkoxyalkyl ether, preferably the methoxymethyl ether, which is then in turn converted into the Cx-C8-acyloxy compound, preferably the acetoxy compound, by reaction with a Cx-C8-carboxylic acid anhydride, preferably acetic an25 hydride, under protonic or Lewis acid catalysis, preferably boron trifluoride etherate catalysis (for both processes see: Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg Thieme Ver lag, Stuttgart, 1965, volume VI/3, pp. 286 et seq).
However, the compounds of the formula VIII where L2 = Ci-C8-acyloxy are particularly simply and effectively prepared by combining an expediently modified and protected alkanol, for example I-acetoxyethanol or l,3-bis(acetoxy)propan-2-ol or 2,3-bis(acetoxyJpropanol IE 91908 - 20 or 1-benzyloxyethanol or 1,3-bis(benzyloxy)propan-2-ol or 2.3- bis(benzyloxyJpropanol or 1-isopropoxyethanol or 1.3- bis(isopropoxy)propan-2-ol or 2,3-bis(isopropoxy)propanol with a carboxylic acid, preferably acetic acid, and the anhydride pertaining to it, preferably acetic anhydride, in dimethyl sulfoxide, preferably about 60 ml of acid, about 50 ml of anhydride and about 100 ml of dimethyl sulfoxide being used per 0.1 mol of alkanol, below room temperature, preferably at 0’C, and stirring for several hours, preferably 4 to 6 hours, at elevated temperature, preferably at 40 to 100 degrees Celsius.
In process 7), the substituents Rx 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-trimethylsilylated purine and a compound of the formula VIII as in process 6).
These blocking groups are labile and can be removed by solvolysis with water, with aqueous or alcoholic ammonia or with aqueous hydrogen carbonate solution or by alcoholysis .
A further process combines processes 1) or 2) or 3) or 4) with process 5); in this case, deblocking can be achieved by solvolysis at the same time as the replacement of a group leaving the purine system, for example halogen, such as, for example, by reaction with liquid ammonia. In this case, in addition to the deblocking of the side chain, if this was protected by a Cx-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 Cx-C8-acyl-blocked group in the purine system can be deblocked.
The compounds of the formula I according to the invention can have one or more chiral centers in the acyclic side IE 91908 chain. The compounds are as a rule racemates; preparation or isolation of the pure enantiomers is possible. The invention therefore relates both to the pure enantiomers and to mixtures thereof, such as, for example, the respective racemate.
The present invention in addition relates to pharmaceuticals containing at least one compound according to the invention.
The pharmaceuticals according to the invention can be administered enterally (orally) parenterally (intravenously), and rectally or locally (topically). They can be administered in the form of solutions, powders (tablets, capsules including microcapsules), ointments (creams or gel) or suppositories. Suitable auxiliaries for formulations of this type are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavor correctants, colorants and/or buffer substances. 0.1 - 10, preferably 0.2-8 mg/kg of body weight, are administered as an expedient dosage. The compounds are expediently administered in dosage units which contain at least the effective daily amount of the compounds according to the invention, for example 30 - 300, preferably - 250 mg.
The compounds according to the invention can also be administered in combination with other antiviral agents and immunostimulants, such as interferons.
In vitro tests and results: The antiviral activity of the compounds according to the invention was tested in in vitro tests. To do this, the compounds according to the invention were added in various dilutions to cell cultures of Vero cells in microtiter plates. After 3 hours, the cultures were infected with different viruses. Vero cells were infected IE 91908 - __ > - 22 with various human pathogenic herpes viruses, HeLa cells were infected with vaccinia virus and MDBK cells with vesicular stomatitis virus. 48 - 72 hours after infection, the result of treatment was determined microscop5 ically by the cytopathic effect and photometrically (Finter, N.B., in Interferons (N.B. Finter et al.), North Holland Publishing Co., Amsterdam (1966), by neutral red absorption (color test according to Finter). The minimum concentration at which about half the cells show no cytopathogenic effect is considered as the minimum inhibitory concentration (MIC). The results are summarized in Table 1.
IE 91908 Table 1 Substance TMD (Mg/ml) from MIC (Mg/ml) Example HSV-1 HSV-2 Vaccinia VSV 7-(l,3-di- hydroxy-2isopropoxymethyl) guanine >400 >400 >400 >400 >400 >400 >400 >400 10 >400 >400 >400 >400 6.7 >400 >400 >400 >400 >400 >400 >400 >400 6.10. >400 >400 >400 >400 133.3 133.3 44.4 >400 15 6.12. 1.65 1.65 4.94 >400 Standard: 9-(l,3-di- >400 >400 >400 >133 hydroxy-2- isopropoxy- 4.94 1.65 >400 133 20 methyl) guanine HSV-1 = Herpes simplex virus 1 HSV-2 = Herpes simplex virus 2 MIC = Minimum inhibitory concentration TMD = Tolerated maximum dose VSV = Vesicular stomatitis virus IE 91908 - 24 10 In vivo tests and results: NMRI mice, specifically pathogen-free, with a weight of about 15 g were infected intraperitoneally with herpes simplex virus 1 and then treated intraperitoneally or 5 orally with the compound according to the invention (see Table 2 or Table 3). Treatment was carried out for the first time 3 hours after infection and was continued twice daily for 4 days. The result of treatment was determined by the course of the disease and the survival rate compared to untreated infection controls. The latter received physiological saline solution instead of the compound according to the invention. The observation period was two weeks.
IE 91908 NMRI mice on Table 2: Antiviral action against HSV-1 in intraperitoneal administration Example Dosage Mean survival (pmol/kg) time (days) 5 -Surviving/ total 6.7. 9 x 10 30 100 7.0 ± 0.0 9 x 10 10.0 ± 1.4 6.10. 30 - 100 - 9 x 10 - 6.12. 30 - 100 - 7-(l,3-di- 9 x 10 10.0 ± 1.4 hydroxy-2- 30 10.0 ± 0.0 isopropoxymethyl) guanine 100 9.3 ± 2.1 Control 0 8.3 + 2.8 4/5 /5 /5 3/5 /5 /5 /5 /5 /5 3/5 4/5 2/5 1/5 IE 91908 Table 3 Antiviral action against HSV-1 in NMRI mice on oral administration Example Dosage Mean survival Surviving/ (pmol/kg) time (days) total 6.7. 9 x 10 30 100 6.10. 9 x 10 30 100 6.12. 9 x 10 30 100 7-(1,3-dihydr oxy- 2isopropoxymethyl) guanine 9 x 10 30 100 Control 0 /5 /5 /5 .0 ±0.0 4/5 /5 5/5 8.3 + 1.5 2/5 /5 5/5 6.5 ± 2.1 ’ 3/5 8.5 ±0.7 3/5 9.0 ±1.4 3/5 7.7 ±1.5 2/5 - 27 IE 91908 Examples: Process according to 6b): 1. Compound of the formula VIII in which L2 = methylthio, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogens 300 ml of anhydrous dimethyl sulfoxide are slowly added dropwise with stirring 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 mixture is subsequently stirred for 30 min. 52.8 g (0.3 mol) of 2,3-bis(isopropoxy)propan-2-ol (prepared by reaction of sodium isopropylate with 2,3-epoxypropyl isopropyl ether in isopropanol) are then added dropwise at about 25°C. The reaction mixture is allowed to stand at room temperature for 4 days with periodic stirring. The reaction mixture is then stirred into about 1 1 of ice-water and extracted several times by shaking with diethyl ether or hexane. The organic phase is washed several times with water, dried over sodium sulfate and evaporated. The oily residue is fractionated in vacuo.
The yield is 53.5 g (75.5% of theory) of 1,3-bis(isopropoxy)-2-methylthiomethoxypropane. Colorless oil of boiling point 68-74 °C at a pressure of 2 mm Hg. 2. Compound of the formula I in which Rx = hydroxyl, R2 = acetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogens .7 g (0.0218 mol) of the methylthiomethyl ether from Example 1 are combined with 4.9 g of anhydrous dimethyl sulfoxide and 4.9 g (0.0209 mol) of 2N,9Ndiacetylguanine (prepared from guanine and acetic anhydride in N-methylpyrrolid-2-one) in 20 ml of IE 91θ08 anhydrous dimethylformamide. The mixture is cooled to -20°C and 5.5 g (0.0209 mol) of tin tetrachloride are added dropwise to the suspension with stirring. After addition is complete, the reaction mixture is stirred at 80°C for 5 hours. It is then allowed to cool, the reaction mixture is treated with dichloromethane and ice-water, extracted several times with dichloromethane, and the combined organic phases are first shaken with water, then with agueous sodium hydrogen carbonate solution and finally with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. HPLC analysis (RP 18 (LiChrospher (R) 100 RP 18, 5 μτα, 125-4), water/methanol lsl + 0.1% of trifluoroacetic acid, ammonium acetate) shows a ratio of 7-isomer/9-isomer of 47.5:47.7. The crude yield is 7.5 g (94.4% of theory) of a pale oil. The isolation of the 7-isomer is carried out by means of column chromatography on neutral alumina using a mixture of ethyl acetate/methanol 9:1 and yields 3.5 g (44% of theory) of 2N-acetyl-7-[l,3-bis(isopropoxy)-2-propoxymethyl]guanine of melting point 162 - 163°C.
XH-NMR (60 MHz, d6-DMSO), ppm: 11.93 (s, broad, 2H), 8.35 (s, IH), 5.73 (s, 2H), 3.83 (m, IH), 3.55 3.17 (m, 6H), 2.20 (s, 3H), 0.93 (d, 12H). 3.1. Compound of the formula I in which Rx = chlorine, r2 = acetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: 6.9 g (0.033 mol) of 2-acetamido-6-chloropurine (for preparation see under 5a.) are heated to reflux under argon for 3 hours with 28 ml of hexamethyldisilazane (HMDS) and 0.2 g of ammonium sulfate in 28 ml of dry xylene. The solvent and excess HMDS are then distilled off, the residue is dissolved in ml of dry 1,2-dichloroethane and the solution is IE 91908 - 29 added at -30°C to a solution of 6.3 g (0.024 mol) of the methyl thiomethyl ether from Example 1 in 85 ml of dry 1,2-dichloroethane. 5 ml (0.026 mol) of trimethylsilyl trifluoromethanesulfonate are then added and the mixture is stirred at -30 eC for 2 hours.
The reaction product is poured into 150 ml of icewater and filtered, and the residue is washed with 1.2- dichloroethane. The aqueous phase is extracted by shaking with 1,2-dichloroethane; the combined organic phases are extracted by shaking with water, then with dilute sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated. HPLC analysis (RP 18 (LiChrospher 100 RP 18, 125 x 4), water/acetonitrile 3:1 + 0.1% TEA) shows the presence of 73% of 2-acetamido-6-chloro-7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine in addition to 2% of the corresponding 9-isomer. 3.2. The analogous conversion in acetonitrile and using 3.8 equivalents of tin tetrachloride gives 73% of the 7-isomer and 23% of the 9-isomer (HPLC analysis of the crude product as in the preceding example).
Process according to 6c): 4.1. Compound of the formula VIII in which L2 - acetoxy, R3 = isopropoxymethyl, R4 - isopropoxy and R5 = hydrogen: 200 ml of anhydrous dimethyl sulfoxide are added dropwise with stirring to a mixture of 120 ml of glacial acetic acid and 100 ml of acetic anhydride in such a way that the temperature of the mixture does not rise above 35°C. The mixture is stirred for a further 30 minutes before 35.2 g (0.2 mol) of 1.3- bis(isopropoxy)propan-2-ol (prepared as described above) are added dropwise. After IE 91908 . - 30 completion of the addition, the mixture is heated at 90 - 100eC for 7 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether several times by shaking. The organic phase is then washed with water and subsequently with aqueous hydrogen carbonate solution, dried over sodium sulfate and evaporated. A pale yellow oil remains, which is subjected to fractional distillation. A forerun of boiling point 46 - 47°C at a pressure of 15 mm Hg is composed of thiomethyImethyl acetate. The reaction product, 2-acetoxymethoxy-l,3-bis(isopropoxy)propane, boils at 87 - 92eC at a pressure of 1 mm Hg. The yield is 27.3 g (55% of theory). hl-NMR (60 MHz, CDC13), ppm: 5.43 (s, 2H), 4.0 - 3.33 (m, 7H), 2.12 (s, 3H), 1.33 (d, 12H).
The following were prepared in this manner: 4.2. 2-acetoxymethoxy-l,3-bis(methoxy)propane 4.3. 2-acetoxymethoxy-l,3-bis(ethoxy)propane 4.4. 2-acetoxymethoxy-l,3-bis(propoxy)propane 4.5. 2-acetoxymethoxy-l,3-bis(benzyloxy)propane 4.6. 2-acetoxymethoxy-l,3-bis(cyclopentyloxy) propane 4.7. 2-acetoxymethoxy-l,3-bis(prop-2-en-1-oxy) propane 4.8. 2-acetoxymethoxy-l-benzyloxy-3-(isopropoxy) propane 4.9. 2-acetoxymethoxy-l-isopropoxy-ethane 4.10. l-acetoxymethoxy-2-benzyloxy-3-isopropoxypropane 4.11. 2-acetoxymethoxy-l-benzyloxy-3-pivaloyloxypropane 4.12. 2-acetoxymethoxy-l,3-bis(pivaloyloxy)propane Compound of the formula I in which Rx = chlorine, R2 = acetamido, R3 = isopropoxymethyl, R4 = IE 91908 - 31 isopropoxy and R5 = hydrogen: 5a. 3.17 g (0.015 mol) of 2-acetamido-6-chloropurine (prepared according to E.M. Acton and R.H. Iwamoto in W.W. Zorbach and R.S. Tipson (editors) Synthetic Procedures in Nucleic Acid Chemistry, Volume 1, Interscience Publishers, John Wiley & Sons, New York, 1968, pp. 25 et seq.) are heated under reflux in an inert gas atmosphere for 3-4 hours with 11.3 ml of hexamethyldisilazane and 100 mg of ammonium sulfate in 13 ml of anhydrous xylene and thus converted into the bis-trimethylsilyl compound. After the reaction is complete, the solvent and excess hexamethyldisilazane are evaporated in vacuo. The residue is dissolved in 10 ml of anhydrous acetonitrile and added dropwise with stirring to a solution of 2.8 g (0.01 mol) of 2-acetoxymethoxy1,3-bis(isopropoxy)propane in 70 ml of anhydrous acetonitrile. 13 g (0.05 mol) of tin tetrachloride are then added slowly at -20°C and under an inert gas atmosphere and the mixture is stirred at -20°C for 3 hours. The reaction mixture is stirred into a mixture of ice-water and dichloromethane and filtered. The aqueous phase is extracted several times with dichloromethane and the combined organic phases are then washed twice with sodium chloride solution, dried over sodium sulfate, and filtered and evaporated. A pale syrup remains whose HPLC analysis (RP 18 (Nucleosil 5 C18) (R), water/acetonitrile 3:1 + 0.1% TEA) gives a content of 86% of the 7-isomer and 4% of the 9-isomer. Chromatographic purification on silica gel using ethyl acetate/methanol 20:1 gives 1.8 g (45% of theory) of 2-acetamido-6-chloro-7-[1,3-bis(isopropoxy)-2propoxymethyl]purine of melting point 73-75’C.
XH-NMR (270 MHz, d6-DMSO), ppm: 10.68 (s, IH), 8.84 (s, IH), 5.81 (s, 2H), 3.71 (m, IH), 3.46 - 3.24 (m, 6H), 2.18 (s, 3H), 0.90 (m, 12H).
IE 91908 - 32 5b. Reaction procedure as in 5a., with the difference that the silylated 2-acetamido-6-chloropurine (0.015 mol) dissolved in 10 ml of anhydrous 1,2-dichloroethane is added dropwise to a solution of the acetoxymethoxy compound (0.01 mol) in 70 ml of anhydrous 1,2-dichloroethane, and 2.67 g (0.012 mol) of trimethylsilyl trifluoromethanesulfonate are added at -30 eC and the reaction mixture is stirred at -30 °C for 2 hours. HPLC analysis of the crude product, carried out as in 5a., gives an isomer ratio of 7-isomer/9-isomer of 90:6. Chromatographic purification over silica gel using ethyl acetate/methanol 20:1 yields 2.15 g (53.8% of theory) of a white powder of melting point 72 - 74°C.
The following were prepared in this manner: .1. 2-Acetamido-6-chloro-7- [ 1,3-bis (ethoxy) -2-propoxymethyl ] purine of melting point 76 - 78°C .2. 2-Acetamido-6-chloro-7-[1,3-bis(propoxy)-2-propoxymethyl ] pur ine of melting point 74°C .3. 2-Acetamido-6-chloro-7- (2-isopropoxyethoxymethyl) purine of melting point 116 - 118*C .4. 2-Acetamido-6-chloro-7-(l-benzyloxy-3-isopropoxy2-propoxymethyl)purine as a viscous oil (’H-NMR (270 MHz, d6-DMSO), ppm: 10.70 (s, 1H), 8.86 (s, 1H), 7.40 - 7.15 (m, 5H), 5.85 (m, 2H), 4.38 (s, 2H), 3.84 (m, 1H), 3.50 - 3.25 (m, 5H), 2.17 (s, 3H), 0.87 (m, 6H)), .5. 2-Acetamido-6-chloro-7-[1,3-bis(methoxy)-2-propoxymethyl]purine of melting point 83 - 84eC .6. 2-Acetamido-6-chloro-7-[1,3-bis(prop-2-en-l-oxy)IE 91908 -' - 33 2-propoxymethyl]purine of melting point 79°C .7. 2-Acetamido-6-chloro-7-[1,3-bis(cyclopentyloxy)2-propoxymethyl]purine as a viscous oil; XH-NMR (60 MHz, d6-DMSO), ppm: 10.73 (s, IH), 8.83 (s, IH), 5.83 (s, 2H), 3.75 (m, 3H), 3.27 (m, 4H), 2.18 (s, 3H), 1.42 (s, broad, 16H). .8. 2-Acetamido-6-chloro-7-(2-benzyloxy-3-isopropoxy1- propoxymethyl)purine as a viscous oil; XH-NMR (60 MHz, d6-DMSO) ppm: 10.77 (s, IH), 8.92 (s, IH), 7.32 (s, 5H), 5.82 (s, 2H), 4.53 (s, 2H), 3.67 - 3.20 (m, 6H), 2.2 (s, 3H), 0.93 (d, 6H). .9. 2-Acetamido-6-chloro-7-[1,3-bis(pivaloyloxy)2- propoxymethyl]purine as a glassy foam; ^-NMR (210 MHz, d6-DMSO), ppm: 10.72 (s, IH), 8.88 (s, IH), 5.79 (s, 2H), 5.04 (m, IH), 4.23 (m, IH), 4.05 (m, IH), 3.63 (d, 2H), 2.18 (s, 3H), 1.05 (s, 9H), 1.01 (s, 9H), .10. 2-Acetamido-6-chloro-7-(l-benzyloxy-3-pivaloyloxy-2-propoxymethyl)purine as a viscous oil; hl-NMR (270 MHz, d6-DMSO), ppm: 10.70 (s, IH), 8.89 (s, IH), 7.35 - 7.15 (m, 5H), 5.85 (s, 2H), 4.40 (s, 2H), 4.15-3.94 (m, 3H), 3.49 (m, 2H), 2.18 (s, 3H), 0.97 (s, 9H).
Process according to 5): 6.1. Compound of the formula I in which Rx = thio, R2 = thioacetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: 3.8 g (0.01 mol) of the compound from Example 2. are stirred at 80 - 85 °C under argon for 3 hours with l,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) in 150 ml of dry toluene. After completion of the reaction, the mixture is allowed to cool, the precipitate is filtered off with suction, the residue is washed with toluene and the filtrate is evaporated. A yellow syrup remains which is purified by chromatography on silica gel using ethyl acetate/methanol 20:1. In this way, 2 g (48.6 % of theory) of 2-thioacetyl-7-(1,3-bis(isopropoxy )-2 -propoxymethyl) thioguanine are obtained. The yellowish powder decomposes at 220°C. 6.2. Compound of the formula I in which Rx = thio, R2 = amino, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: 1.6 g (0.00472 mol) of 7-(1,3-bis(isopropoxy)2-propoxymethyl)guanine are heated under reflux for 6 hours with 1.01 g (0.0025 mol) of Lawesson's reagent in a mixture of 50 ml of dry toluene and ml of dry pyridine under argon. The crude product of the reaction is purified by column chromatography on silica gel using a mixture of dichloromethane/ methanol 5:1. 1.2 g (71.6% of theory) of a weakly yellow powder of melting point 232 - 236°C are obtained. 1H-NMR (60 MHz, d6-DMSO), ppm: 12.05 (s, 1H), 8.37 (s, 1H), 6.55 (s, 2H), 6.10 (s, 2H), 3.93 - 3.22 (m, 7H), 0.97 (d, 12H).
The compound 6.2. can also be prepared by heating 0.413 g (0.001 mol) of the compound of Example 6.1. to reflux with 4 ml of 40% strength aqueous methylamine solution and 4 ml of methanol for 3 hours. Yield: 0.25 g (70.4% of theory). 6.3. Compound of the formula I in which Rx = methoxy, IE 91908 R2 = acetamido, R3 = isopropoxymethyl, R4 - isopropoxy and R5 = hydrogen: 1.4 g (0.0035 mol) of the compound from Example 5. are dissolved in 14 ml of methanol with 13 mg (0.2 mmol) of potassium cyanide and the mixture is stirred at room temperature for 24 hours. It is then diluted with 20 ml of methanol and treated for 5 minutes in each case with Serdolit Blue (R) (Serva) (OH form) and Amberlyst 15 (R) (Fluka) (H+ form), the ion exchanger is filtered off and the filtrate is evaporated. The remaining syrup crystallizes on addition of diisopropyl ether. 1.05 g (75.8% of theory) of 2-acetamido-6-methoxy-7-(1,3bis(isopropoxy)-2-propoxymethyl)purine of melting point 67 - 68°C are obtained.
Y-NMR (60 MHz, d6-DMSO), ppm: 10.73 (s, IH), 8.87 (s, IH), 5.83 (s, 2H), 3.80 - 3.15 (m, 10H), 2.17 (s, 3H), 0.88 (d, 12H). 6.4.1. Compounds of the formula I in which Rx = amino, R2 = acetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen and 6.4.2. Rx = amino, R2 = amino, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: 6.4.1. 10 g (0.025 mol) of the compound from Example 2. are treated with about 150 ml of liquid ammonia in 100 ml of methanol and the mixture is heated at 80°C in an autoclave at a pressure of 5 bar for 20 hours. The reaction mixture is then completely evaporated and purified by column chromatography (silica gel, dichloromethane/methanol 9:1). 0.26 g (2.7% of theory) of 2-acetamido-6-amino-7-[1,3-bis (isopropoxy)2-propoxymethyl]purine of melting point 136 - 137°C is obtained as a first fraction. 6.
IE 91908 6. 6. 6. - 36 hi-NMR (60 MHz, d6-DMSO), ppm: 9.72 (s, 1H), 8.30 (s, 1H), 6.73 (s, 2H), 5.73 (s, 2H), 3.83 - 3.20 (m, 7H), 2.20 (s, 3H), 0.97 (d, 12H). .2. The second fraction yields 4.6 g (54.4% of theory) of 2,6-diamino-7-[1,3-bis(isopropoxy)2-propoxymethyl]purine of melting point 228 - 229eC.
XH-NMR (60 MHz, d6-DMSO), ppm: 8.10 (s, 1H), 6.52 (s, 2H), 5.85 (s, 2H), 5.67 (s, 2H), 3.83 - 3.22 (m, 7H), 1.00 (d, 12H). . 1. Compounds of the formula I in which Rx - methylamino, R2 = acetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen and .2. Ri = methylamino, R2 = amino, R3 - isopropoxymethyl, R4 = isopropoxy and Rs = hydrogen: .1. 1.4 g (3.5 mmol) of the compound from Example 2 are heated under reflux with 7 ml of 40% strength aqueous methylamine solution and 14 ml of methanol for 2 hours. The reaction solution is then completely evaporated and the residue is separated by column chromatography on silica gel using a mixture of dichloromethane/methanol 10:1. The first fraction is composed of 0.45 g (32.6% of theory) of 2-acetamido-6-methylamino-7-[l,3bis (isopropoxy) -2-propoxymethyl ]purine of melting point 159eC.
^-NMR (60 MHz, d6-DMSO), ppm: 9.75 (s, 1H), 8.28 (s, 1H), 6.67 (q, 1H), 5.75 (s, 2H), 3.77 - 3.22 (m, 7H), 3.00 (d, 3H), 2.27 (s', 3H), 0.97 (d, 12H) . .2. The second fraction is composed of 0.45 g (36.5% of theory) of 2-amino-6-methylamino-7-[l,36.
IE 91908 - 37 bis (isopropoxy) -2-propoxymethyl ]purine of melting point 103 - 104eC.
^-NMR (270 MHz, d6-DMSO), ppm: 7.99 (s, 1H), 6.29 (q, 1H), 5.65 (s, 2H), 5.63 (s, 2H), 3.65 (m, 1H), 3.45 (m, 2H), 3.36 (m, 4H), 2.92 (d, 3H), I. 00 (q, 12H).
If a larger excess of methylamine solution is used and the reaction time is lengthened, the deblocked product 6.4.2. is isolated exclusively in 92% yield. 6.6. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: g (0.04 mol) of the compound from Example 5 15 are exhaustively hydrogenolyzed with hydrogen at room temperature in a duck-shaped shaking vessel using 3.5 g of palladium on carbon (10%) and II. 06 ml (0.08 mol) of triethylamine in 350 ml of methanol. After completion of hydrogen absorp20 tion, the catalyst is filtered off with suction and the methanolic phase is evaporated. The residue is stirred in ethyl acetate, the precipitate of triethylamine hydrochloride is separated off and the ethyl acetate solution is completely concentrated. The crystalline residue is purified by column chromatography on silica gel using ethyl acetate/methanol 9:1 as the eluent. 14 g (95.9% of theory) of 2-acetamido7-[1,3-bis(isopropoxy)-2-propoxymethyl]purine of melting point 94 - 96°C are obtained.
XH-NMR (270 MHz, d6-DMSO), ppm: 10.43 (s, 1H) , 9.02 (s, 1H), 8.71 (s, 1H), 5.79 (s, 2H), 3.70 (m, 1H), 3.41 (m, 2H), 3.32 (m, 4H), 2.19 (s, 3H), 0.93 (m, 12H).
IE 91908 - 38 6.7. Compound of formula I in which Rx = hydrogen, R2 = amino, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen: 0.178 g (0.5 mmol) of the compound of Example 5 6.2. are treated with 1.0 g of Raney nickel washed with absolute ethanol in 20 ml of absolute ethanol and the mixture is heated to reflux for 1.5 hours. The reaction mixture is then cooled, the Raney nickel is filtered off with suction and the ethanolic solution is completely concentrated. The residue is purified by column chromatography on silica gel using ethyl acetate/methanol 20:1 as the eluent. 0.1 g (61.7% of theory) of 2-amino-7-[1,3-bis(isopropoxy)15 2-propoxymethyl]purine is obtained as white flakes of melting point 153 - 154°C. 1H-NMR (270 MHz, d6-DMSO) , ppm: 8.65 (s, IH) , 8.38 (s, IH), 6.22 (s, 2H), 5.67 (s, 2H), 3.65 (m, IH), 3.42 (m, 2H), 3.32 (m, 4H), 1.00 (m, 12H).
The compound of Example 6.7. can also be prepared from the compound of Example 6.6. by reaction with aqueous methylamine solution in methanol. 1.1 g of the compound of Example 6.6. yields 0.8 g (82.2% of theory) of the compound of Example 6.7. 6.8. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 - hydrogen, R4 = isopropoxy and Rs = hydrogen: The compound of Example 5.3. is subjected to 30 hydrogenolysis as in Example 6.6. and yields 2-acetamido-7-(2-isopropoxyethoxymethyl)purine of melting point 152°C in 95.6% yield. 6.9. Compound of the formula I in which Rx = hydrogen, •Ε 91908 R2 = acetamido, R3 = benzyloxymethyl, R4 = isopropoxy and R5 = hydrogen: 4.47 g (0.01 mol) of the compound of Example 5.4. are subjected to hydrogenolysis as in Example 6.6. and yield 3 g (72.6% of theory) of 2-acetamido-7- (l-benzyloxy-3-isopropoxy-2-propoxymethyl)purine as an oil.
^-NMR (270 MHz, d6-DMSO), ppm: 10.43 (s, IH), 9.03 (s, IH), 8.72 (s, IH), 7.36 - 7.15 (m, 5H), .82 (m, 2H), 4.39 (s, 2H), 3.83 (s, IH), 3.50 3.25 (m, 5H), 2.18 (s, 3H), 0.90 (m, 6H). 6.10. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = hydroxymethyl, R4 = isopropoxy and R5 = hydrogen: 1.6 g (4.95 mmol) of the compound of Example 8.3. are heated under reflux with 50 ml of 40% agueous methylamine solution in 50 ml of methanol for 1 hour. After distilling off the solvent an oil remains which is treated with acetone and crys20 tallizes after some time. 0.7 g (50.3% of theory) of 2-amino-7-(l-hydroxy-3-isopropoxy-2-propoxymethyl)purine of melting point 125 - 130 °C are obtained.
^-NMR (270 MHz, d6-DMSO), ppm: 8.66 (s, IH), 8.37 (s, IH), 6.23 (s, 2H), 5.67 (m, 2H), 4.70 (t, IH), 3.55 (m, IH), 3.36 - 3.20 (m, 5H), 0.95 (m, 6H). 6.11. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = hydrogen, R4 = isopropoxy and R5 = hydrogen: 2.2 g of the compound of Example 6.8. are treated as in Example 6.10. and yield 1.4 g (74.3% of IE 91908 - 40 theory) of 2-amino-7-(2-isopropoxy-2-ethoxymethyl)purine of melting point 158°C. 6.12. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = hydroxymethyl, R4 = hydroxyl and R5 = hydrogen: 1.6 g (0.0057 mol) of the compound of Example 8.2. are heated to reflux for 2 hours with 10 ml of methanol, 10 ml of 40% strength aqueous methylamine solution and 5 ml of water. Working10 up yields 1 g (73.4% of theory) of 2-amino7-(1,3-dihydroxy-propoxymethyl)purine of melting point 176 - 177eC.
^-NMR (270 MHz, d6-DMS0), ppm: 8.68 (s, 1H), 8.38 (s, 1H), 6.23 (s, 2H), 5.69 (s, 2H), 4.62 (t, 2H), 3.38 (m, 5H). 6.13.1. Compound of the formula I in which Rx = hydroxyl, R2 = hydroxyl, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen and 6.13.2. Compound of the formula I in which Rx = amino, R2 = hydroxyl, R3 = isopropoxymethyl, R4 = isopropoxy and R5 = hydrogen. 6.13.1. 1.4 g (0.0041 mol) of the compound of Example 6.4.2. are dissolved in a mixture of 45 ml of tetrahydrofuran and 30 ml of water. 1.8 g (0.027 mol) of sodium nitrite and 24 ml of glacial acetic acid are added, the mixture is stirred at 50°C for 90 minutes, a further 1.8 g of sodium nitrite and 9 ml of glacial acetic acid are added, the reaction mixture is completely evaporated, and the residue is treated with a little water and neutralized with concentrated ammonia. An oil precipitates which becomes solid after •Ε 91908 some time. The precipitate is filtered off, recrystallized from isopropanol and 0.3 g (21.3% of theory) of 7-[1,3-bis(isopropoxy)-2-propoxymethyl]xanthine of melting point 200 - 201’C is obtained.
XH-NMR (270 MHz, d6-DMSO), ppm: 11.60 (s, IH), 10.89 (s, IH), 8.13 (s, IH), 5.63 (s, 2H), 3.83 (m, IH), 3.46 (m, 2H), 3.30 (m, 4H), 1.01 (m, 12H) . 6.13.2. The aqueous mother liquors are evaporated, taken up with dichloromethane and a little water and extracted three times by shaking with 100 ml of dichloromethane. The organic phase is dried (sodium sulfate) and evaporated. The syrup thus obtained is purified by chromatography (silica gel, dichloromethane/methanol 9:1). After recrystallization from water, 60 mg (4.3% of theory) of 6-amino-2-hydroxy-7-[1,3-bis(isopropoxy)2-propoxymethyl]purine (7-[1,3-bis(isopropoxy) -2 -propoxymethyl] isoguanine) of melting point 213°C are obtained.
XH-NMR (270 MHz, d6-DMSO) , ppm: 11.15 (s, IH), 8.02 (s, IH), 6.88 (s, 2H), 5.64 (s, 2H), 3.70 (m, IH), 3.47 (m, 2H), 3.38 (m, 4H), 1.01 (d, 12H). 6.14. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = methoxymethyl, R4 = methoxy and R5 = hydrogen: 1.6 g (4.7 mmol) of the compound of Example 5.5. 30 are subjected to hydrogenolysis as in Example 6.6. and after chromatography on silica gel (ethyl acetate/methanol 5:1) yield 1.25 g (86% of theory) of 2-acetamido-7-[l,3-bis(methoxy)-2propoxymethyl]purine of melting point - 42 IE 91908 101 - 102°C. .15. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = ethoxymethyl, R4 = ethoxy and R5 = hydrogen: 3.7 g (0.01 mol) of the compound of Example 5.1. are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification on silica gel (ethyl acetate/methanol 9:1) yield 2.9 g (86% of theory) of 2-acetamido-7-[l,3-bis(ethoxy)-2-propoxymethyl]purine of melting point 117 - 118eC. .16. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = prop-2-en-l-oxymethyl, R4 = prop2-enoxy 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 zinc dust. 1.7 ml of concentrated ammonia are then added dropwise over a period of 2 hours. The cooled suspension is treated with 50 ml of methanol and filtered off with suction; and the residue is washed with methanol. The combined filtrates are concentrated and chromatographed on silica gel using ethyl acetate/methanol 9:1. 2.9 g (82.6% of theory) of 2-amino-7-[1,3-bis(prop-2-en-l-oxy)-2-propoxymethyl]purine of melting point 140 - 143"C are obtained. 6.17. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = cyclopentyloxymethyl, R4 = cyclopentyloxy and R5 = hydrogen: 1.1 g (2.44 mmol) of the compound of Example 5.7. are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification (silica gel, ethyl acetate/methanol 9:1) yield if 9190® 0.8 g (78.6% of theory) of 2-acetamido-7-[l, 3bis(eyelopentyloxy)-2-propoxymethylJpurine of melting point 98°C. 6.18. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = hydrogen, R4 = benzyloxy and R5 = isopropoxymethylϊ 7.5 g (16.8 mmol) of the compound of Example 5.8. are subjected to hydrogenolysis as in Example 6.6. and after chromatographic purification on silica gel (ethyl acetate/methanol 9:1) yield 6.3 g (90.6% of theory) of 2-acetamido-7-(2-benzyloxy-3-isopropoxy-l-propoxymethyl)purine of melting point 116 - 117°C. 6.19. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = benzyloxymethyl, R4 = pivaloyloxy and R5 = hydrogen: .5 g (41.9 mmol) of the compound of Example .10. are subjected to hydrogenolysis as in Example 6.6. and after chromatography on silica gel (ethyl acetate/methanol 9:1) yield 17 g (89.2% of theory) of 2-acetamido-7-(1-benzyloxy3-pivaloyloxy-2-propoxymethyl)purine of melting point 76 - 77’C.
XH-NMR (270 MHz, d6-DMSO), S ppm: 10.45 (s, 1H), 9.05 (s, 1H), 8.77 (s, 1H), 7.35 - 7.18 (m, 5H), .83 (s, 2H), 4.40 (2, 2H), 4.13 (m, 1H), 3.99 (m, 2H), 3.49 (m, 2H), 2.19 (s, 3H), 0.98 (s, 9H) . 6.20. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = methoxymethyl, R4 = methoxy and R5 = hydrogen: 0.77 g (2.25 mmol) of the compound of Example IE 91908 6.21. 6.22. 6.23. - 44 6.14. is treated with methylamine solution as in Example 6.10. and yields 0.54 g (89.9% of theory) of 2-amino-7-[1,3-bis(methoxy)-2-propoxymethyl]purine of melting point 148C.
Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = ethoxymethyl, R« = ethoxy and Rs = hydrogen: 1.35 g (4 mmol) of the compound of Example 6.15. are treated with methylamine solution as in Example 6.10. and yield 0.8 g (67.8% of theory) of 2-amino-7-[l,3-bis(ethoxy)-2-propoxymethyl]purine of melting point 151°C.
Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = cyclopentyloxymethyl, R4 = cyclopentyloxy and R5 = hydrogen: 0.5 g (1.2 mmol) of the compound of Example 6.17. is treated with methylamine solution as in Example 6.10. and yields 0.3 g (66.7% of theory) of 2-amino-7-[1,3-bis(cyclopentyloxy)-2-propoxymethyl] purine of melting point 158eC.
Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = hydrogen, R<, = hydroxyl and R5 = hydroxymethyl: 1.4 g (5 mmol) of the compound of Example 8.5. are treated with methylamine solution as in Example 6.10. and yield 0.45 g (37.7% of theory) of 2-amino-7-(2,3-dihydroxy-1-propoxymethyl)purine of melting point 130 - 133°C; 1H-NMR (270 MHz, d6-DMSO) , ppm: 8.67 (s, 1H) , 8.40 (s, 1H), 6.25 (s, 2H), 5.60 (s, 2H), 4.75 (d, 1H), 4.50 (d, 1H), 3.60-3.25 (m, 5H).
IE 91908 - 45 6.24. Compound of the formula I in which Rx = hydrogen, R2 = amino, R3 = benzyloxymethyl, R4 = hydroxyl and R5 = hydrogen: 0.66 g (1.45 mmol) of the compound of Example 5 6.19. is treated with methylamine solution as in Example 6.10. and yields 0.25 g (52.4% of theory) of 2-amino-7-(l-benzyloxy-3-hydroxy-2-propoxymethyl)purine of melting point 122C; ^-NMR (270 MHz, d6 - DMSO), δ ppm: 8.68 (S, 1H), 10 8.39 (s, 1H), 7.36-7.18 (m, 5H), 6.25 (s, 2H), .71 (s, 2H), 4.73 (t, 1H), 4.38 (s, 2H), 3.68 (m, 1H), 3.50-3.31 (m, 4H). 6.25. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = benzyloxymethyl, R4 = hydrox15 yl and Rg = hydrogen: 0.5 g (1.1 mmol) of the compound of Example 6.19. is dissolved in 10 ml of methanol, and the solution is treated with 10 ml of concentrated aqueous ammonia and stirred at room temperature for 24 hours. Working-up yields 0.25 g (61.3% of theory) of 2-acetamido-7-(l-benzyloxy-3-hydroxy2-propoxymethyl)purine of melting point 149*C; hi-NMR (60 MHz, d6-DMSO), δ ppm: 10.47 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 7.30 (m, 5H), 5.87 (s, 2H), 4.73 (t, 1H), 4.40 (s, 2H), 3.80-3.30 (m, 5H), 2.17 (s, 3H). 6.26 Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = acetoxymethyl, R4 = acetoxy and Rg = hydrogen: 0.24 g (1 mmol) of the compound of Example 6.12. is treated with 10 ml of acetic anhydride and 30 mg of Ν,Ν-dimethyl aminopyridine and the IE 91908 - 46 mixture is stirred at room temperature for 18 hours. After neutralization of the reaction mixture and chromatographic purification of the crude product on silica gel using ethyl acetate/5 methanol 9:1, 0.2 g (61.9% of theory) of 2-acetamido-7-[ 1,3-bis (acetoxy) -2-propoxymethyl ] purine of melting point 141*C is obtained.
^-NMR (270 MHz, d6-DMSO), δ ppm: 10.46 (S, IH), 9.04 (s, IH), 8.77 (s, IH), 5.82 (s, 2H), 4.1610 4.09 (m, 2H), 4.05-3.95 (m, 3H), 2.19 (s, IH), 1.70 (s, 6H).
Combination of the processes according to 1) - 4) with the process according to 5): 7.1. Compound of the formula I in which Rx = isopro15 poxy, R2 = amino, R3 = isopropoxymethyl, R4 isopropoxy and R5 = hydrogen: g (0.005 mol) of the compound of Example 5 are dissolved in 25 ml of anhydrous isopropanol, the solution is treated with a solution of 0.345 g (0.015 mol) of sodium in anhydrous isopropanol and the mixture is heated to reflux for 2 hours. The cooled suspension is treated with ice-water and neutralized with 2 N acetic acid. The precipitate is filtered off with suction, washed with water and dried. 1.5 g (78.6% of theory) of 2-amino-6-isopropoxy-7- [ 1,3-bis (isopropoxy)2-propoxymethyl]purine of melting point 85 - 87°C are obtained.
^-NMR (60 MHz, d6-DMSO), ppm: 8.22 (s, IH), 6.08 (s, 2H), 5.62 (s, 2H), 5.50 (m, IH), 3.87 - 3.17 (m, 7H), 1.35 (d, 6H), 0.97 (d, 12H). 7.2. Compound of the formula I in which Rx - methoxy, R2 = amino, R3 = isopropoxymethyl, R4 = isopropoxy IE 91908 κ-----4 - 47 and R5 = hydrogen: g (0.005 mol) of the compound of Example 5. are dissolved in 20 ml of methanol and the solution is added to a solution of sodium ethanolate in methanol (0.35 g of sodium and 20 ml of methanol). The mixture is heated under reflux for 2 hours. Precipitated sodium chloride is filtered off with suction, and the methanolic solution is completely concentrated. The residue is dissolved in a little water and the solution is neutralized with acetic acid. The precipitated product is filtered off with suction, washed with water and dried. 1.5 g (84.9% of theory) of 2-amino-6me thoxy 7- [ 1,3-bis (isopropoxy) -2-propoxymethyl]15 purine of melting point 111 °C are obtained.
Processes according to 1) - 4): 8.1. Compound of the formula I in which Rx = hydroxyl, R2 = acetamido, R3 = hydroxymethyl, R4 = hydroxyl and Rs = hydrogen: 3.81 g (0.01 mol) of the compound of Example 2 are dissolved in 150 ml of anhydrous dichloromethane and the mixture is cooled to -60 °C with stirring in an argon atmosphere. 60 ml (0.06 mol) of a 1 molar solution of boron trichloride in n-hexane or dichloromethane are then slowly added, the temperature of the reaction mixture is slowly allowed to rise to -40’C to -20°C, and the mixture is stirred at this temperature for 3 hours and then at -10°C for a further hour. The mixture is cooled again to -60 °C, 60 ml of methanol and 60 ml of dichloromethane are slowly added dropwise and a solution is obtained which is treated with 37 ml of triethylamine. The solution is subsequently additionally stirred at room temperature for 30 minutes before the IE 91908 reaction mixture is completely evaporated. Chromatography on silica gel using a mixture of dichloromethane/methanol 3:1 yields 1.32 g (44.4% of theory) of 2-acetyl-7-(l,3-dihydroxy-2-pro5 poxymethyl)guanine of melting point 155 - 158 °C (decomposition).
XH-NMR (270 MHz, d6-DMSO), ppm: 12.15 (s, IH), 11.61 (s, IH), 8.37 (s, IH), 5.77 (s, 2H), 4.61 (t, 2H), 3.62 (m, IH), 3.35 (m, 4H), 2.17 (s, 3H) . 8.2. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = hydroxymethyl, R4 = hydroxyl and R5 = hydrogen: According to the same method, 3.65 g (0.01 mol) 15 of the compound of Example 6.6. were reacted with 0.05 mol of boron trichloride and after crystallization from methanol yielded 2.2 g (78.3% of theory) of 2-acetamido-7-(1,3-dihydroxy-2-propoxymethyl )purine of melting point 214 - 215’C.
XH-NMR (270 MHz, d6-DMSO), ppm: 10.43 (s, IH) , 9.07 (s, IH), 8.72 (s, IH), 5.81 (s, 2H), 4.65 (t, 2H), 3.55 - 3.28 (m, 5H), 2.20 (s, 3H). 8.3. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = hydroxymethyl, R4 = isopro25 poxy and R5 = hydrogen: g of the compound of Example 6.9. are heated under reflux with 4 g of ammonium formate and 1 g of palladium/carbon (10%) for 8 hours in 75 ml of methanol. The reaction mixture is filtered, concentrated, treated with acetone and stirred until it crystallizes. 0.9 g (57.4% of theory) of 2-acetamido-7- (1-hydroxy-3-isopropoxy-2 -propoxymethyl) purine of melting point 170eC is obtained.
IE 91908 - 49 XH-NMR (270 MHz, d6-DMSO), ppm: 10.43 (s, IH), 9.04 (s, IH), 8.72 (s, IH), 5.80 (m, 2H), 4.73 (t, IH), 3.60 (m, IH), 3.46 - 3.20 (m, 5H), 2.17 (s, 3H), 0.90 (m, 6H). 8.4. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = hydrogen, R4 = hydroxyl and Rs = hydrogen: 2.93 g (0.01 mol) of the compound from Example 6.8. are treated at -60 °C with boron trichloride for 6 hours as in Example 8.1. After chromatography on silica gel using dichloromethane/methanol 5:1, 2.2 g (87.6% of theory) of 2-acetamido-7-(2-hydroxyethoxymethyl)purine of melting point 194°C are obtained. 8.5. Compound of the formula I in which Rx = hydrogen, R2 = acetamido, R3 = hydrogen, R4 - hydroxyl and R5 = hydroxymethyl: 4.13 g (10 mmol) of the compound of Example 6.18. are treated with boron trichloride as described in Example 8.1. and after chromatographic purification on silica gel (dichloromethane/methanol 3:1) yield 2.8 g (99.6% of theory) of 2-acetamido-7-(2,3-dihydroxy-1-propoxymethyl)purine of melting point 167 - 168°C.
Table 4 IE 91908 Example *1 *2R3 r4R5 2. OH NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 3.1. 5. Cl NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 5.1. Cl NHC(O)CH3 ch2och2ch3 och2ch3 H 5.2. Cl NHC(O)CH3 CH2O(CH2)2CH3 O(CH2)2CH3 H 5.3. Cl NHC(O)CH3 H OCH(CH3)2 H 5.4. Cl NHC(O)CH3 ch2och2c6h5 OCH(CH3)2 H 5.5 Cl NHC(O)CH3 ch2och3 och3 H 5.6. Cl NHC(O)CH3 ch2och2ch=ch2 OCH2CH=CH2 H 5.7 Cl NHC(O)CH3 CH2O-cyclopentyl 0-cyclopentyl H 5.8 Cl NHC(O)CH3 H OCH2C6H6 CH2OCH(CH3)2 5.9 Cl NHC(O)CH3 CH2OC(O)C(CH3)3 OC(O)C(CH3)3 H 5.10 Cl NHC(O)CH3 ch2och2c6h5 OC(O)C{CH3)3 H 6.1. SH NHC(S)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 6.2. SH nh2 CH2OCH(CH3)2 OCH(CH3)2 H 6.3. och3 NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H IE 91908 Ζ-~~- - 51 > Continuation of Table 4; fonnula I ExampleR1R2R3R4RS 6.4.1. nh2 NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 6.4.2. nh2 nh2 CH2OCH(CH3)2 OCH(CH3)2 H 6.5.1. nhch3 NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 6.5.2. nhch3 nh2 CH2OCH(CH3)2 OCH(CH3)2 H 6.6. H NHC(O)CH3 CH2OCH(CH3)2 OCH(CH3)2 H 6.7. H nh2 CH2OCH(CH3)2 OCH(CH3)2 H 6.8. H NHC(0)CH3 H OCH(CH3)2 H 6.9. H NHC(O)CH3 ch2och2c6h5 OCH(CH3)2 H 6.10. H nh2, ch2oh OCH(CH3)2 H 6.11. H nh2 H OCH(CH3)2 H 6.12. H nh2 ch2oh OH H 6.13.1. OH OH CH20CH(CH3)2 OCH(CH3)2 H 6.13.2. nh2 OH CH2OCH(CH3)2 OCH(CH3)2 H 6.14. H NHC(O)CH3 ch2och3 och3 H 6.15. H NHC(O)CH3 ch2oc2h5 oc2h5 H IE 91908 - 52 Continuation of Table 4; formula I ExampleR1R2R3R4R5 6.16. H nh2 ch2och2ch=ch2 och2ch=ch2 H 6.17. H NHC(O)CH3 CH2O-cyclopentyl 0-cyclopentyl H 6.18. H NKC{O)CH3 H och2c6h5 CH2OCH(CH3)2 6.19. H NHC(O)CH3 ch2och2c6h5 OC(O)C(CH3)3 H 6.20. nh2 ch2och3 och3 H 6.21. H nh2 ch2oc2k5 oc2h5 H 6.22. nk2 CK20-cyclopentyl 0-cyclopentyl H 6.2 3 . H nh2 H OH ch2oh c . 24 . K nh2 ch2och2c6h5 OH H 6.25. u NHC(O)CH3 ch2och2c6h5 OH H 5.26. H NKC(0)CK3 CK2OC(O)CH3 OC(O)CH3 H 7.1 OCH (CH-,) CH70CH(CH^) -, OCH(CH3)2 H 7.2 . oc?:3 nh2 CH2OCH(CK3)2 OCH{CH3)2 H 8.1. OK NHC(O)CH3 ck2oh OH H 8.2 . K NHC(O)CH3 ch2ok OH H 8.3 . K NKC(O)CK3 CH2OCK(CH3)2 OH H 8.4. u NHC(O)CH3 K OH H 8.5 . Η NKC(O)CH3 H OH ch2ok

Claims (18)

1. Patent claims:
1. A compound of the formula I IE 91908 CH 2 -0—CH—CH—Rg (I) in which r 2 r 2 is hydrogen, halogen, azide, hydroxyl, Cx-C 6 -alkoxy, benzyloxy, phenoxy, mercapto, Cx-C 6 -alkylthio, benzylthio, phenylthio, amino, Cx-C 6 -alkylamino, benzylamino, phenylamino, C 2 -C 12 -dialkylamino, dibenzylamino, cyclic dialkylamino, diphenylamino, Ci-Cg-acylamino, C 2 -C 16 -diacylamino, (N-alkyl2-pyrrol idinyl idene) amino or C 2 -C 10 -dialkylaminomethylideneamino, is hydrogen, halogen, azide, hydroxyl, mercapto, amino, Cx-C 6 -alkylamino, C 2 -C 12 -dialkylamino, benzylamino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenylamino, Cx-C 8 -acylamino and thioacylamino, C 2 -C X6 -diacylamino or di (thioacyl)amino, is hydrogen, Cx-C 6 -alkyl, optionally substituted by halogen or by a hydroxyl, amino, thio, C x -C 6 -alkoxy, Ci-Cg-alkylthio, Cj-Cg-alkylamino, benzyloxy, benzylamino, benzylthio, C 2 -C 12 -dialkylamino, dibenzylamino, diphenylamino, Cx-C e -acyloxy, Cx-Ce-acylamino, Cx-C 16 -diacylamino or C 2 -C 8 -acylthio group or a radical R 8 , where R e is -P(0) (0R 6 ) (0R 7 ), -O-(Cx-C 4 -alkyl)-P(O) (0R 6 ) (0R 7 ), -S-(Cx-C 4 -alkyl)-P(O)(OR 6 )(OR 7 ), -NH-(Cx-C 4 -alkyl)-P(O) (0R 6 ) (0R 7 ) , -N(Cx-C 6 -alkyl)-Cx-C 4 -alkyl-P(O) (0R 6 ) (0R 7 ) IE 91908 -P(C X -C 6 -alkyl) (0)(OR 6 ), -O-(C x -C 4 -alkyl)-P(C x -C 6 -alkyl) (0) (0R 6 ), -S-(C x -C 4 -alkyl)-P(C x -C 6 -alkyl) (0) (ORg), -NH-(C x -C 4 -alkyl)-P(C x -C 6 -alkyl) (0) (0R 6 ), -N(C x -C 6 -alkyl)-C 1 -C 4 -alkyl-P(C 1 -C 6 -alkyl) (0) (ORe) in which Rg and R 7 are independently of one another hydrogen or a C x -C 6 -alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R 4 is hydrogen, C x -C 6 -alkyl, hydroxyl, mercapto, amino, halogen, azide, C x -C 6 -alkoxy, C x -C 6 -alkylthio, C 1 -C 6 -alkylamino, C 2 -C 12 -dialkylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenylamino, diphenylamino, phenoxy, phenylthio, C x -C 8 -acyloxy, C x -C e -acylthio, C x -C 8 -acylamino, C 2 -C x6 -diacylamino or -0-(C x -C 4 -alkyl)-P(0) ( 0R 6 ) ( 0R 7 ) or -O-(C x -C 4 -alkyl)-P(C x -C 6 -alkyl) (0) (ORg), where the radicals R e and R 7 are as defined above, and R 5 is hydrogen, C x -C 6 -alkyl, optionally substituted by a hydroxyl, thio, amino, C x -C 6 -alkoxy, Cj-Cg-alkylthio, C x -C 6 -alkylamino, C 2 -C X2 -dialkylamino, C x -C 8 -acyloxy, C x -C 6 -acylthio, C x -C 8 -acylamino, C 2 -C x6 -diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino, diphenylamino group or a radical R e , where R 8 is -P(0) (ORg) (0R 7 ) , -0-(C x -C 4 -alkyl)-P(0) (ORg) (0R 7 ) , -S-(C x -C 4 -alkyl)-P(O) (0R 6 ) (0R 7 ), -NH- (C x -C 4 -alkyl) -P (0) (0R 6 ) (0R 7 ), -N(C x -C 6 -alkyl)-C x -C 4 -alkyl-P(O) (0R 6 ) (0R 7 ), -P(C x -C 6 -alkyl) (0) (ORg), -0- (C x -C 4 -alkyl) -P (C x -C 6 -alkyl) (0) (0R 6 ), -S-(C x -C 4 -alkyl)-P(C x -C 6 -alkyl) (0) (ORg), -NH- (C x -C 4 -alkyl) -P (C x -C 6 -alkyl) (0) (0R 6 ), N(C x -C 6 -alkyl)-C x -C 4 -alkyl-P(C x -Cg-alkyl) (0) (0R 6 ), in which R 6 and R 7 are independently of one another 91908 hydrogen or a Cx-C 6 -alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable salts and obvious chemical equivalents, with the proviso that, at the same time, Rx is not hydroxyl and R 2 is not amino or R x is not hydroxyl, R 2 is not acetamido, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R s is not hydrogen or R x is not chlorine or methoxy, R z is not amino, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R 5 is not hydrogen or Rx is not hydroxyl, R 2 is not acetamido, R 3 is not acetoxymethyl, R 4 is not acetoxy and R 5 is not hydrogen or Rx is not methoxy, R 2 is not amino, R 3 is not hydroxymethyl, R 4 is not hydroxyl and R s is not hydrogen or Rx is not chlorine or amino, R 2 is not hydrogen, R 3 is not hydroxymethyl or benzyloxymethyl, R 4 is not hydroxyl or benzyloxy and R 5 is not hydrogen or Rx is not amino, R 2 is not mercapto, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R 5 is not hydrogen or Rx is not benzyloxy, R 2 is not chlorine, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R 5 is not hydrogen or Rx is not chlorine, R 2 is not amino, R 3 is not acetoxymethyl, R 4 is not acetoxy and R s is not hydrogen or R x is not benzyloxy, R 2 is not chlorine, R 3 is not hydrogen, R 4 is not benzyloxy and R 5 is not benzyloxymethyl or Rx and R 2 are not chlorine, R 3 is not benzyloxymethyl, R 4 is not benzyloxy and R 5 is not hydrogen or R x is not amino, R 2 is not mercapto, R 3 and R s are not hydrogen and R 4 is not acetoxy or Rx is not hydrogen, R 2 is not amino, R 3 and R 5 are not hydrogen and R 4 is not hydroxyl or acetoxy or Rx and R 2 are not chlorine, R 3 and R 5 are not hydrogen and R 4 is not benzyloxy or R x is not iodine, R 2 is not chlorine, R 3 and R 5 are not hydrogen and R 4 is not hydroxyl.
2. A compound of the formula I as claimed in claim 1, in which R x is hydrogen, halogen, hydroxyl, benzyloxy, alkoxy having 1-6 carbon atoms, amino, Cx-C 6 -alkylamino or C 2 -C e -di (alkyl) amino, or Cx-C 8 -alkylthio, R 2 is hydrogen, halogen, hydroxyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -di(alkyl) amino or Ci-Ce-acylamino, R 3 is hydrogen, Cx-C 8 -alkyl, optionally substituted by a hydroxyl, amino or C^-Cg-alkoxy group or halogen or a Ci-Cg-acyloxy, Cx-C 8 -acylamino or Cx-C 6 -alkylamino group or a group R 8 , where R 8 is -O-(Cx-C 4 -alkyl)-P(O)(OR 8 )(OR 7 ), -P(0) (ORJ (0R 7 ) or -P(Cx-C 4 -alkyl) (0) (0R 6 ), in which R 8 and R 7 are independently of one another hydrogen or a Cx-C 8 -alkyl radical or an alkali metal or alkaline earth metal ion, R 4 is hydrogen, hydroxyl, amino, mercapto, Ci-C 6 -alkoxy, Ci-Cj-acyloxy, Cx-C 8 -alkylamino or a -0- (Cx-C 4 -alkyl) -P (0) (0R 8 ) (0R 7 ) or -0- (Cx-C 3 -alkyl) -P (Cx-C 8 -alkyl )(0)( 0R 6 ) radical having the meanings R 6 and R 7 as described above and R 5 is hydrogen or Cx-C 4 -alkyl, optionally substituted by hydroxyl, Cx-C 8 -acyloxy, benzyloxy, Ci-C 8 -alkoxy, amino, Cx-C 8 -alkylamino or a radical R e , where R e is -P(0) (0R 6 ) (0R 7 ) or -P(Cx-C 4 -alkyl) (0) (ORe), in which R 8 and R 7 are defined as described above.
3. A compound of the formula I as claimed in claims 1 or 2, in which R x is hydrogen, hydroxyl, chlorine, mercapto, benzyloxy, Ci-C 8 -alkoxy, amino, Cx-C 3 -alkylamino or C 2 -C 8 -dialkylamino, IE 91908 Λ R 2 is hydrogen, hydroxyl, amino or Cx-C e -acylamino, R 3 is hydrogen, Cx-C 3 -alkyl, optionally substituted by a hydroxyl, Ci-C 8 -acyloxy or Cx-C 6 -alkoxy group or a -o-ch 2 -p-or 6 or 7 or -P(0) (ORg) (0R 7 ) group, where Rg and R 7 have the above meanings, R 4 is hydrogen, hydroxyl or a Ci-C 8 -acyloxy or O N Cx-Cg-alkoxy group or -CH 2 -p-ORg and OR ? R 5 is hydrogen or Cx-C 4 -alkyl, optionally substituted by hydroxyl, Cx-C 8 -acyloxy or Cx-C 6 -alkoxy or -P(0) (ORg) (0R 7 ), where R 6 and R 7 have the abovementioned meanings.
4. A compound of the formula I as claimed in one or more of claims 1 to 3, in which Rx is hydrogen, hydroxyl, chlorine, Ci-C A -alkoxy, amino, Cx-C 3 -alkylamino or C 2 -C 6 -dialkylamino, R 2 is hydrogen, hydroxyl, amino or Cx-C 3 -acylamino, R 3 is Cx-C 3 -alkyl, optionally substituted by hydroxyl or by Ci-C e -acyloxy or by Cx-C 6 -alkoxy or by -P(0) (ORg) (0R 7 ), where R 6 and R 7 have the abovementioned meanings, R 4 is hydroxyl or Cj-Cg-acyloxy or Cx-C 6 -alkoxy and R 5 is hydrogen.
5. A compound of the formula I as claimed in one or more of claims 1 to 4, in which Rx is hydrogen, chlorine or amino, R 2 is amino or Cx-C 3 -acylamino, IE 91908 58 R 3 is Ci-C 3 -alkyl, optionally substituted by hydroxyl or by Ci-C 5 -acyloxy or by Ci-C 5 -alkoxy or by -P(0) (OR 6 ) (0R 7 ), where R 6 and R 7 have the abovementioned meanings, R 4 is hydroxyl or Ci-C 5 -acyloxy or Ci-C 5 -alkoxy and R 5 is hydrogen.
6. A compound of the formula I as claimed in one or more of claims 1 to 5, in which R x is hydrogen, R 2 is amino, R 3 is Cx-C 3 -alkyl, optionally substituted by hydroxyl or by Cx-C 4 -acyloxy or by Cx-C 4 -alkoxy, R 4 is hydroxyl or Ci-C 4 -acyloxy or Cx-C 4 -alkoxy and R 5 is hydrogen.
7. A compound of the formula I as claimed in one or more of claims 1 to 6, in which Ri is hydrogen, R 2 is amino, R 3 is hydroxymethyl, R 4 is hydroxyl and R 5 is hydrogen.
8. A compound of the formula I CH, O— CH— CH—Re I (I) in which Rx is hydrogen, halogen, azide, hydroxyl, Ci-C 6 -alkoxy, benzyloxy, phenoxy, mercapto, Ci-C 6 -alkylthio, benzylthio, phenylthio, amino, Ci-C 6 -alkylamino, benzylamino, phenylamino, C 2 -Ci 2 -dialkylamino, IE 91908 - 59 dibenzylamino, cyclic dialkylamino, diphenylamino, Ci-Cg-acylamino, C 2 -C 16 -diacylamino, (N-alkyl2-pyrrol idinyl idene) amino or C 2 -C 10 -dialkylaminomethylideneamino, R 2 is hydrogen, halogen, azide, hydroxyl, mercapto, amino, Cx-C 6 -alkylamino, C 2 -C 12 -dialkylamino, benzylamino, dibenzylamino, cyclic dialkylamino, phenylamino, diphenylamino, Cx-C 8 -acylamino and thioacyl amino, C 2 -C 16 -diacylamino or di (thioacyl)amino, R 3 is hydrogen, Ci-C 6 -alkyl, optionally substituted by halogen or by a hydroxyl, amino, thio, C x -C 6 -alkoxy, Cj-C 6 -alkylthio, Cx-C 6 -alkylamino, benzyloxy, benzylamino, benzylthio, C 2 -C 12 -dialkylamino, dibenzylamino, diphenylamino, Cj-Cg-acyloxy, Ci-Cg-acylamino, Cx-Ci 6 -diacylamino or C 2 -C 8 -acylthio group or a radical R 8 , where R 8 is -P(0) (OR 6 ) (0R 7 ), -0- (Cx-Cz.-alkyl) -P (0) (ORg) (0R 7 ), -S- (Cx-C A -alkyl) -P(O)(OR 6 )(OR 7 ), -NH- (C 1 -C A -alkyl) -P (0) (ORg) (0R 7 ), -N(Cx-Cg-alkyl)-Cx-C A -alkyl-P(O) (ORg) (0R 7 ), ^(Cx-Cg-alkyl) (0)(0R 6 ), -0- (Cx-C 4 -alkyl) -P (Ci-C 6 -alkyl) (0) (0R 6 ), -S- (Cx-C 4 -alkyl) -P (Cx-Cg-alkyl) (0) (0R 6 ) , -NH- (Cx-C 4 -alkyl) -P (Cx-Cg-alkyl) (0) (0R 6 ), -N(Cx-C 6 -alkyl)-Ci-C A -alkyl-P(Cx-Cg-alkyl) (0) (0R 6 ) in which Rg and R 7 are independently of one another hydrogen or a Cx-Cg-alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, R a is hydrogen, Cx-Cg-alkyl, hydroxyl, mercapto, amino, halogen, azide, Ci-C 6 -alkoxy, Cx-C 6 -alkylthio, Cx-Cg-alkylamino, C 2 -Cx 2 -dialkylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenylamino, diphenylamino, phenoxy, phenylthio, Cx-C 8 -acyloxy, Ci-C 8 -acylthio, Cx-C 6 -acylamino, C 2 -C 16 -diacylamino or IE 91908 -OHCx-CralkylJ-PtOJtORJiOR,) or -0- (Cx-C^-alkyl) -P (Cx-C 6 -alkyl )(0)( ORg), where the radicals Rg and R 7 are as defined above, and R s is hydrogen, Cx-C 4 -alkyl, optionally substituted by a hydroxyl, thio, amino, Cx-Cg-alkoxy, Cx-Cg-alkylthio, Cj-C 6 -alkylamino, C 2 -C 12 -dialkylamino, Cx-Cg-acyloxy, Cx-C e -acylthio, Cy-Cg-acylamino, C 2 -C 16 -diacylamino, benzyloxy, benzylthio, benzylamino, dibenzylamino, phenoxy, phenylthio, phenylamino, diphenylamino group or a radical R e , where R 8 is -P(0) (0R 6 ) (0R 7 ), -0- (Cx-C.-alkyl) -P (0) (0R 6 ) (OR 7 ), -S- (Cx-C.-alkyl) -P (0) (ORg) (0R 7 ), -NH- (Cx-C.-alkyl) -P (0) (0R 6 ) (0R 7 ), -N(Ci-C 6 -alkyl)-Cx-C 4 -alkyl-P(O) (ORg) (0R 7 ), -P(C 1 -Cg-alkyl)(O)(OR 6 ), -0- (C x -C 4 -alkyl) -P (Cx-C 6 -alkyl) (0) (0R 6 ), -S-(C 1 -C A -alkyl)-P(C 1 -C 6 -alkyl) (0) (ORg), -NH-(Ci-C 4 -alkyl)-P(Ci-C 6 -alkyl) (0) (0R 6 ), NiCx-Cg-alkylJ-Cx-C^-alkyl-PiCx-Cg-alkyl) (0) (ORg), in which R 6 and R 7 are independently of one another hydrogen or a Cx-C 6 -alkyl radical or ammonium, triethylammonium or an alkali metal or alkaline earth metal ion, and their physiologically tolerable salts and obvious chemical equivalents 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 R 4 is hydroxyl, amino, aminoalkyl or mercapto, replacing a protecting group A x in a compound of the formula II - 61 0—CH—CH—A, IE 91908 V CH— > CD by a hydroxyl, amino, alkylamino or mercapto group, or b) if in the compound of the formula I R 3 is hydroxyalkyl , aminoalkyl, alkylaminoalkyl or mercaptoalkyl, replacing a protecting group A 2 in a compound of the formula III alkyl-A 3 tn—CH— Rc ι s *4 (XXI) by a hydroxyl, amino, alkylamino or mercapto group, c) if in the compound of the formula I R 5 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or mercaptoalkyl, replacing a protecting group A 3 in a compound of the formula IV H ι CH· *3 alkyl—A 3 0—CH—CH ι (IV) by a hydroxyl, amino, alkylamino or mercapto group, or IE 91908 d) if in the compound of the formula I R 3 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or thioalkyl and/or R 4 is hydroxyl, amino, alkylamino or mercapto and/or R 5 is hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl or mercaptoalkyl, replacing a protecting group A 4 and/or A 5 and/or Ag in a compound of the formula V H I CH I N alkyl—A4 -O—CH—CH—Ai alkyl—A 6 (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 R x and R 2 into a compound of the formula I in which R x and R 2 have the meanings described above, or f) reacting a compound of the formula VII (VII) with a compound of the formula VIII IE 91908 63 Rg R4 l 2 --ch 2 --o--4h--ch (VIII) R S in which L 2 is a leaving group and L x is hydrogen or a leaving group, g) removing a blocking group from a compound of the formula I in which one or both radicals R x and R 2 are blocked, and if the product of the reaction is a base of the formula I, optionally converting it into an acid addition product of this base of the formula I, or if the product of the reaction is a salt of a base of the formula I, optionally converting it into its base or into another salt of this base.
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 production of pharmaceuticals for the treatment of virus diseases.
14. A process for the production of pharmaceuticals 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. IE 91908
15. A compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
16. A process for the preparation of a compound as claimed in claim 1, substantially as hereinbefore described and exemplified.
17. A compound as claimed in claim 1, whenever prepared by a process claimed in claim 9 or 16.
18. A pharmaceutical as claimed in claim 11, substantially as hereinbefore described.
IE090891A 1990-03-20 1991-03-19 Substituted purines, processes for their preparation and¹their use as antiviral agents IE910908A1 (en)

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

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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
EP0589335B1 (en) * 1992-09-24 2003-06-18 Hoechst Aktiengesellschaft N1-Substituted- (1H)-1,2,3-Triazolo (4,5-d) pyrimidines, process for their preparation and their use as antiviral means
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
AP160A (en) * 1987-08-15 1991-11-18 The Wellcome Foundation Ltd Therapeutic acyclic nucleosides.

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FI911310A0 (en) 1991-03-18
FI911310A (en) 1991-09-21
ATE144984T1 (en) 1996-11-15
NO911081D0 (en) 1991-03-19
EP0452680B1 (en) 1996-11-06
HU910928D0 (en) 1991-10-28
GR3021591T3 (en) 1997-02-28
DK0452680T3 (en) 1997-04-07
NO911081L (en) 1991-09-23
KR910016751A (en) 1991-11-05
DE59108319D1 (en) 1996-12-12
ES2093651T3 (en) 1997-01-01
PT97080A (en) 1991-11-29
CA2038589A1 (en) 1991-09-21
CS70891A2 (en) 1991-11-12
EP0452680A1 (en) 1991-10-23
DE4008858A1 (en) 1991-09-26
JPH04217984A (en) 1992-08-07
IL97586A0 (en) 1992-06-21
JP3146423B2 (en) 2001-03-19
HUT57764A (en) 1991-12-30
AU644414B2 (en) 1993-12-09
ZA912015B (en) 1991-12-24
CN1054982A (en) 1991-10-02

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