[go: up one dir, main page]

WO1990009999A1 - Seco-nucleoside derivatives and drugs containing them - Google Patents

Seco-nucleoside derivatives and drugs containing them Download PDF

Info

Publication number
WO1990009999A1
WO1990009999A1 PCT/EP1990/000299 EP9000299W WO9009999A1 WO 1990009999 A1 WO1990009999 A1 WO 1990009999A1 EP 9000299 W EP9000299 W EP 9000299W WO 9009999 A1 WO9009999 A1 WO 9009999A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compounds
alkyl
thymine
general formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1990/000299
Other languages
German (de)
French (fr)
Inventor
Alfred Mertens
Harald Zilch
Bernhard Koenig
Edith Koch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Mannheim GmbH filed Critical Boehringer Mannheim GmbH
Publication of WO1990009999A1 publication Critical patent/WO1990009999A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the invention relates to seconucleoside derivatives, processes for the preparation of these compounds and medicaments containing them.
  • the present invention relates to seco-nucleoside or nucleotide derivatives of the general formula I
  • R denotes hydrogen, an aliphatic acyl group with 1-20 C atoms or a monophosphate, diphosphate or triphosphate group,
  • R 1 is a C 1 -C 7 alkyl, halo C 1 -C 7 alkyl, trifluoromethyl, C 2 -C 7 alkenyl, C 3 -C 7 alkanedienyl, C 2 -C 7 - Alkynyl, cyano, formyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, aminocarbonyl, azido, C 3 -C 7 cycloalkyl, C 3 -C 7 Is cycloalkenyl or aryl group or a saturated, unsaturated or aromatic heterocycle, and
  • R 2 is a thymine, uracil, cytosine, adenine, hypoxanthine or guanine group, where a) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl, cycloalkyl or phenyl group and R 2 is an uracil or thymine group, and b) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl group and R 2 is an adenine, guanine or hypoxanthine group, their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids and bases, and processes for their preparation and medicaments containing these compounds.
  • the invention also relates to the optically active forms and racemic mixtures of these compounds.
  • the stereoisomeric compounds can be prepared from the racemic mixtures by methods known per se using diastereomeric salts. For example, tartaric acid, malic acid or camphoric acid can be used for the resolution.
  • EP-A-0,046,307 describes uracil and thymine derivatives in which R can be a hydrogen atom or an acyl group and R 1 can be an alkyl, cycloalkyl or phenyl group. These compounds have an anti-tumor effect as a drug. Such compounds are not covered by disclaimer a) from the definition given above with respect to formula I.
  • R 2 can mean an adenine, guanine or hypoxanthine group. These compounds have an antiviral effect. You are disclaimer b) of the above definition regarding.
  • Formula I does not include.
  • Chem.Pharm.Bull. 33, 1703 (1985) describes the synthesis of pyrimidine acyclonucleosides in which R 1 represents a methyl group and R 2 represents the uracil or thymine group.
  • seco-nucleosides such as acycloadenosine can be used as an inhibitor of adenosine deaminase (J.Med.Chem. 14, 367, 1971), acycloguanosine is active against herpes simplex (Lancet 243, 1979) and acyclonucleosides of pyrimidine have an inhibitory effect Have an effect on the enzyme uridine phosphorylase.
  • J.Med.Chem. 32, 73, 1989 describes acyclic nucleosides which have only a weak effect in HIV-infected cells.
  • the object of the present invention is to provide new compounds which are more effective than the known compounds.
  • the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the
  • Varicella zoster virus or Epstein-Barr virus or RNA viruses such as Toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 or -2, caused. They are therefore particularly suitable for the production of antiviral drugs.
  • PDL generalized lymphadenopathy
  • ARC AIDS-related complex
  • RNA viruses at the level of virus-specific DNA or RNA transcription.
  • the substances can influence the multiplication of retroviruses especially by inhibiting the enzyme reverse transcriptase (cf. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 or Nature 325, 773 1987).
  • reverse transcriptase cf. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 or Nature 325, 773 1987.
  • AIDS 3'-azido-3'-deoxythymidine
  • 3'-azido-3'-deoxythymidine (DE-A-3,608,606) is currently approved for the treatment of AIDS in AIDS patients.
  • toxic side effects of 3'-azido-3'-deoxythymidine on the bone marrow require blood transfusions in about 50% of the patients treated.
  • the compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacological
  • the aliphatic acyl radical in the definition of the substituent R in the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-20, preferably 1-10 or 1-6 carbon atoms.
  • acetyl, propionyl, isopropionyl and tert-butyryl radical is particularly preferred.
  • alkyl, haloalkyl, alkylcarbonyl and alkoxycarbonyl radicals occurring in the definition of the substituent R 1 of the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-7, preferably 1-4 carbon atoms.
  • the methyl, ethyl, propyl, isopropyl, trifluoromethyl, methyloxycarbonyl, ethyloxycarbonyl and halomethyl radical is particularly preferred, where halogen means fluorine, chlorine, bromine and iodine.
  • alkenyl, alkanedienyl and alkynyl radicals occurring in the definition of the substituent R 1 of the general formula I can be straight-chain or branched and contain 2-7, preferably 2-4, carbon atoms.
  • the vinyl, propenyl, 2-methylpropenyl, butadienyl, ethynyl and propynyl radical is particularly preferred.
  • the cycloalkyl and cycloalkenyl radicals occurring in the definition of the substituent R 1 of the general formula I can contain 3-7, preferably 3-6 carbon atoms.
  • the cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical is particularly preferred.
  • the aryl and hetaryl radicals occurring in the definition of the substituent R 1 of the general formula I are preferably phenyl, heterocyclic five-membered rings with 1-4 heteroatoms and heterocyclic six-membered rings with 1-2 heteroatoms, the heteroatoms of the aforementioned five- and six-membered rings being identical or different can mean oxygen, sulfur and nitrogen.
  • pyridyl pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl radical, as well as their di and tetrahydro derivatives.
  • the group R 1 is in particular a C 1 -C 4 alkyl group, for example methyl or ethyl group; a halogen-C 1 - C 4 -alkyl-, for example the chloroethyl group; a
  • Cycloalkyl for example cyclopentyl or cyclohexyl group; a phenyl, furyl, pyridyl or triazolyl group, it being possible for the heterocyclic radical to be bonded via the 1-, 2-, 3- or 4-position, such as, for example, 2-furyl, 3-furyl, 2-pyridyl , 4-triazolyl or 4-pyridyl.
  • R 2 is preferably the thymine group.
  • the group R preferably denotes a hydrogen atom, a C 1 -C 4 -alkylcarbonyl group, for example the acetyl group, or the mono- or triphosphate group.
  • Possible salts of the compounds of the general formula I are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups.
  • alkali salts are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups.
  • ammonium salts are understood to be salts which contain the ammonium ion, which can be substituted up to four times by alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals.
  • the substituents can be the same or different.
  • the compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable acids.
  • suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • the compounds of general formula I are new compounds. They can be prepared analogously to known, related compounds (cf. Chem. Pharm.Bull. 33, 1703, 1985). It has proven particularly expedient to prepare the compounds of the general formula I by using a compound of the general formula II
  • R 1 has the meaning given
  • R 3 is hydrogen or an easily removable oxygen protective group, such as, for example, the trityl, acetyl, benzoyl, benzyl or trialkylsilyl group
  • X is a leaving group, such as chlorine, bromine or iodine , Tosylate, mesylate or acetate, with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases, and after splitting off any protective groups, compounds of the general formula I
  • R 1 and R 2 have the meaning given and R 3 is hydrogen
  • R 1 and R 2 have the meaning given and R 3 is hydrogen
  • compounds of the general formula I in which R 1 and R 2 have the meaning given and R 3 is hydrogen, in a known manner into the mono -, Di- or triphosphates or the corresponding acyl derivatives
  • reaction of the compounds of the general formula II is advantageously carried out using silyl-protected thymine, uracil, cytosine, adenine, hypoxanthine or guanine in an aprotic solvent, such as, for example, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, dichloromethane or chloroform at temperatures between 0 ° C.
  • an aprotic solvent such as, for example, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, dichloromethane or chloroform
  • the Reaction mixture advantageously catalytic amounts of a Lewis acid, such as aluminum trichloride, zinc bromide, zinc iodide, boron trifluoride, titanium tetrachloride or tin tetrachloride, or molar amounts of trimethylsilyl chloride, bromide or iodide can be added.
  • a Lewis acid such as aluminum trichloride, zinc bromide, zinc iodide, boron trifluoride, titanium tetrachloride or tin tetrachloride, or molar amounts of trimethylsilyl chloride, bromide or iodide can be added.
  • organic or inorganic acids e.g. Hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or by acidic ion exchange, e.g. Amberlite IR-120 or Amberlist 15.
  • organic or inorganic acids e.g. Hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or by acidic ion exchange, e.g. Amberlite IR-120 or Amberlist 15.
  • the silyl-protected bases R 2 can according to known
  • Processes are obtained, such as reaction of the respective base R 2 with hexamethyl disilazane.
  • reaction of compounds of general formula III with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases is advantageously carried out in a protic or aprotic solvent at temperatures between -25 ° C and 150 ° C, preferably between 25 ° C and 75 ° C carried out, whereby conditions of phase transfer catalysis can be used in particular, in which the above-mentioned bases are converted into a corresponding anion, for example by 50 percent.
  • aqueous sodium hydroxide solution and the anion formed in this way are hydrophobized by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine, and are transported into the organic phase in which it reacts with the reactive compound of the formula III.
  • the phosphate groups are introduced in a known manner in compounds of the general formula I in which R is hydrogen.
  • the monophosphates are obtained, for example, by phosphorylating compounds of the formula I where R is hydrogen with phosphorus oxychloride in trimethyl phosphate.
  • the triethylammonium salts obtained in this way can be converted into other salts by salting in a known manner.
  • the di- or triphosphates are obtained by known methods, preferably from the monophosphates by reaction with o-phosphates or pyrophosphates. Their various salts can also be prepared by known methods.
  • Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, Talc, highly disperse silicas, high-molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high-molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, flavorings and sweeteners
  • the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active ingredient content of 0.5-1000 mg being administered with each application.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the active substance content of the retarded tablets can be 2-2000 mg.
  • the active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5-4000 mg per day usually being sufficient.
  • the mixture was stirred in an ice bath for a further 15 minutes and then added dropwise to a solution of 0.5 mmol bis-tributylammonium pyrophosphate, 2 ml DMF, 2 ml pyridine and 0.2 ml tributylamine while cooling with ice. After 5 minutes, 2 ml of a 0.2 molar aqueous triethylammonium hydrogen carbonate solution were added to stop the reactions, the mixture was diluted with water after 30 minutes, applied to a Sephadex DEAE column and with a 0.1-0.5 molar linear gradient eluted from triethylammonium bicarbonate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention concerns novel seco-nucleoside derivatives of general formula (I), where R is hydrogen, an aliphatic acyl group with 1 to 20 atoms or a monophosphate, diphosphate or triphosphate group, R1 is a C¿1? to C7 alkyl, halogen C1 to C7 alkyl, trifluormethyl, C2 to C7 alkenyl, C3 to C7 alkandienyl, C2 to C7 alkinyl, cyano, formyl, C1 to C7 alkyl carbonyl, C1 to C7 alkoxycarbonyl, aminocarbonyl, azido, C3 to C7 cycloalkenyl or aryl group or a saturated, unsaturated or aromatic heterocycle, and R?2¿ is a thymine, uracil, cytosine, adenine, hypoxanthine or guanine group, whereby a) R cannot be a hydrogen atom or an acyl group if R1 is an alkyl, cycloalkyl or phenyl group and R2 is a uracil or thymine group, and b) R cannot be a hydrogen atom or an acyl group if R1 is an alkyl group and R2 is an adenine, guanine or hypoxanthine group. The invention also concerns their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids and bases, as well as processes for manufacturing them and drugs containing these ccompounds.

Description

Seco-Nucleosid-Derivate und diese enthaltende Arzneimittel Seco-nucleoside derivatives and medicinal products containing them

Die Erfindung betrifft Seco-Nucleosid-Derivate, Verfahren zur Herstellung dieser Verbindungen sowie diese enthaltende Arzneimittel. The invention relates to seconucleoside derivatives, processes for the preparation of these compounds and medicaments containing them.

Gegenstand der vorliegenden Erfindung sind Seco-Nucleosid- bzw. Nucleotid-Derivate der allgemeinen Formel I The present invention relates to seco-nucleoside or nucleotide derivatives of the general formula I

Figure imgf000003_0001
in der
Figure imgf000003_0001
in the

R Wasserstoff, eine aliphatische Acylgruppe mit 1-20 C- Atomen oder eine Monophosphat-, Diphosphat- oder Trip-hosphatgruppe bedeutet, R denotes hydrogen, an aliphatic acyl group with 1-20 C atoms or a monophosphate, diphosphate or triphosphate group,

R1 eine C1-C7-Alkyl-, Halogen-C1-C7-alkyl-, Trifluormethyl-, C2-C7-Alkenyl-, C3-C7-Alkandienyl-, C2-C7- Alkinyl-, Cyano-, Formyl-, C1-C7-Alkyl-carbonyl-, C1-C7-Alkoxycarbonyl-, Aminocarbonyl-, Azido-, C3-C7- Cycloalkyl-, C3-C7-Cycloalkenyl- oder Arylgruppe oder ein gesättigter, ungesättigter oder aromatischer Heterocyclus ist, und R 1 is a C 1 -C 7 alkyl, halo C 1 -C 7 alkyl, trifluoromethyl, C 2 -C 7 alkenyl, C 3 -C 7 alkanedienyl, C 2 -C 7 - Alkynyl, cyano, formyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, aminocarbonyl, azido, C 3 -C 7 cycloalkyl, C 3 -C 7 Is cycloalkenyl or aryl group or a saturated, unsaturated or aromatic heterocycle, and

R2 eine Thymin-, Uracil-, Cytosin-, Adenin-, Hypoxanthin- oder Guaningruppe bedeutet, wobei a) R kein Wasserstoffatom oder eine Acylgruppe sein kann, wenn R1 eine Alkyl-, Cycloalkyl- oder Phenylgruppe und R2 eine Uracil- oder Thymingruppe darstellen, und b) R kein Wasserstoffatom oder eine Acylgruppe sein kann, wenn R1 eine Alkylgruppe und R2 eine Adenin-, Guanin- oder Hypoxanthingruppe ist, deren Tautomere, optisch aktive Formen oder physiologisch verträgliche Salze anorganischer und organischer Säuren und Basen, sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltene Arzneimittel. R 2 is a thymine, uracil, cytosine, adenine, hypoxanthine or guanine group, where a) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl, cycloalkyl or phenyl group and R 2 is an uracil or thymine group, and b) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl group and R 2 is an adenine, guanine or hypoxanthine group, their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids and bases, and processes for their preparation and medicaments containing these compounds.

Da die Verbindungen der allgemeinen Formel I an der Verknüpfungsstelle von R1 und R2 ein asymmetrisches Kohlenstoffatom enthalten, sind auch Gegenstand der Erfindung die optisch aktiven Formen und racemischen Gemische dieser Verbindungen. Die stereoisomeren Verbindungen können aus den racemischen Gemischen nach an sich bekannten Methoden über diastereomere Salze hergestellt werden. Zur Racematspaltung können z.B. Weinsäure, Apfelsäure oder Camphersäure verwendet werden. Since the compounds of the general formula I contain an asymmetric carbon atom at the point of attachment of R 1 and R 2 , the invention also relates to the optically active forms and racemic mixtures of these compounds. The stereoisomeric compounds can be prepared from the racemic mixtures by methods known per se using diastereomeric salts. For example, tartaric acid, malic acid or camphoric acid can be used for the resolution.

Ähnliche Verbindungen sind aus dem Stand der Technik bereits bekannt. Similar compounds are already known from the prior art.

EP-A-0,046,307 beschreibt Uracil- und Thymin-Derivate, in denen R ein Wasserstoffatom oder eine Acylgruppe und R1 eine Alkyl-, Cycloalkyl- oder Phenylgruppe sein können. Diese Verbindungen weisen eine antitumorale Wirkung als Arzneimittel auf. Derartige Verbindungen werden durch Disclaimer a) von der oben angegebenen Definition bzgl. Formel I nicht umfaßt. EP-A-0,046,307 describes uracil and thymine derivatives in which R can be a hydrogen atom or an acyl group and R 1 can be an alkyl, cycloalkyl or phenyl group. These compounds have an anti-tumor effect as a drug. Such compounds are not covered by disclaimer a) from the definition given above with respect to formula I.

In US-A-4,199,574 sind Verbindungen beschrieben, in denen R ein Wasserstoffatom oder eine Acylgruppe, R1 eine US Pat. No. 4,199,574 describes compounds in which R is a hydrogen atom or an acyl group, R 1 is a

Alkylgruppe darstellt und R2 eine Adenin-, Guanin- oder Hypoxanthingruppe bedeuten kann. Diese Verbindungen besitzen eine antivirale Wirkung. Sie werden durch Disclaimer b) von der oben angegebenen Definition bzgl. Represents alkyl group and R 2 can mean an adenine, guanine or hypoxanthine group. These compounds have an antiviral effect. You are disclaimer b) of the above definition regarding.

Formel I nicht umfaßt. Chem.Pharm.Bull. 33, 1703 (1985) beschreibt die Synthese von Pyrimidin-Acyclonucleosiden, in denen R1 eine Methylgruppe und R2 die Uracil- oder Thymingruppe darstellt. Formula I does not include. Chem.Pharm.Bull. 33, 1703 (1985) describes the synthesis of pyrimidine acyclonucleosides in which R 1 represents a methyl group and R 2 represents the uracil or thymine group.

Diese Verbindungen werden durch den Disclaimer a) von der oben angegebenen Definition bzgl. Formel I nicht umfaßt. These compounds are not covered by disclaimer a) from the definition given above with respect to formula I.

Weiterhin ist beschrieben, daß Seco-Nucleoside wie Acycloadenosin als Inhibitor der Adenosin-Deaminase einsetzbar ist (J.Med.Chem. 14, 367, 1971), Acycloguanosin wirksam ist gegen Herpes Simplex (Lancet 243, 1979) und Acyclonucleoside des Pyrimidins einen inhibitorischen Effekt auf das Enzym Uridinphosphorylase besitzen. In J.Med.Chem. 32. 73, 1989 werden acyclische Nucleoside beschrieben, die in Hiv-infizierten Zellen nur eine schwache Wirkung zeigen. Furthermore, it is described that seco-nucleosides such as acycloadenosine can be used as an inhibitor of adenosine deaminase (J.Med.Chem. 14, 367, 1971), acycloguanosine is active against herpes simplex (Lancet 243, 1979) and acyclonucleosides of pyrimidine have an inhibitory effect Have an effect on the enzyme uridine phosphorylase. In J.Med.Chem. 32, 73, 1989 describes acyclic nucleosides which have only a weak effect in HIV-infected cells.

Die vorliegende Erfindung hat sich zur Aufgabe gestellt, neue Verbindungen zur Verfügung zu stellen, die gegenüber den bekannten Verbindungen eine höhere Wirksamkeit aufweisen. The object of the present invention is to provide new compounds which are more effective than the known compounds.

Die Verbindungen der vorliegenden Erfindung besitzen wertvolle pharmakologische Eigenschaften auf. Insbesondere eignen sie sich zur Therapie und Prophylaxe von Infektionen, die durch DNA-Viren wie z.B. das Herpes-Simplex- Virus, das Zytomegalie-Virus, Papilloma-Viren, das The compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the

Varicella-Zoster-Virus oder Epstein-Barr-Virus oder RNA- Viren wie Toga-Viren oder insbesondere Retroviren wie die Onko-Viren HTLV-I und II, sowie die Lentiviren Visna und Humanes-Immunschwäche-Virus HIV-1 oder -2, verursacht werden. Sie eignen sich deshalb insbesondere zur Herstellung von antiviralen Arzneimitteln.  Varicella zoster virus or Epstein-Barr virus or RNA viruses such as Toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 or -2, caused. They are therefore particularly suitable for the production of antiviral drugs.

Besonders geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifestationen der retroviralen HIV-Infektion beim Menschen, wie der anhaltenden, generalisierten Lymphadenopathie (PGL), dem fortgeschrittenen Stadium des AIDS-verwandten Komplex (ARC = AIDS related complex) und dem klinischen Vollbild von AIDS . Überraschenderweise wurde nun gefunden, daß Verbindungen der allgemeinen Formel I die Vermehrung von DNA- bzw. The compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC = AIDS-related complex) and the clinical full picture of AIDS. Surprisingly, it has now been found that compounds of the general formula I increase the DNA or

RNA-Viren auf der Stufe der virusspezifischen DNA- bzw. RNA-Transkription hemmen. Die Substanzen können speziell über die Inhibierung des Enzyms Reverse Transkriptase die Vermehrung von Retroviren beeinflussen (vgl. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 bzw. Nature 325, 773 1987). Von besonderem therapeutischem Interesse ist die Hemmwirkung auf das HIV-Virus, dem Verursacher der Immunschwäche-Erkrankung AIDS. Zur Behandlung von AIDS ist heute nur 3'-Azido-3'-desoxythymidin (DE-A-3,608,606) bei AIDS Patienten zugelassen. Jedoch machen toxische Nebenwirkungen des 3'-Azido-3'-desoxythymidins auf das Knochenmark bei etwa 50% der behandelten Patienten Bluttransfusionen erforderlich. Die Verbindungen der allgemeinen Formel I besitzten diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakologisch relevanten Dosen cytotoxisch zu sein. Inhibit RNA viruses at the level of virus-specific DNA or RNA transcription. The substances can influence the multiplication of retroviruses especially by inhibiting the enzyme reverse transcriptase (cf. Proc.Natl. Acad.Sci. USA 81, 1911, 1986 or Nature 325, 773 1987). Of particular therapeutic interest is the inhibitory effect on the HIV virus, the cause of the immune deficiency disease AIDS. Only 3'-azido-3'-deoxythymidine (DE-A-3,608,606) is currently approved for the treatment of AIDS in AIDS patients. However, toxic side effects of 3'-azido-3'-deoxythymidine on the bone marrow require blood transfusions in about 50% of the patients treated. The compounds of the general formula I do not have these disadvantages. They have an antiviral effect without being cytotoxic in pharmacologically relevant doses.

Der aliphatische Acylrest in der Definition des Substituenten R in der allgemeinen Formel I kann gesättigt oder ungesättigt, geradkettig oder verzweigt sein und 1-20, vorzugsweise 1-10 oder 1-6 Kohlenstoffatome enthalten. The aliphatic acyl radical in the definition of the substituent R in the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-20, preferably 1-10 or 1-6 carbon atoms.

Besonders bevorzugt ist der Acetyl-, Propionyl-, Isopropionyl- und tert.-Butyrylrest. The acetyl, propionyl, isopropionyl and tert-butyryl radical is particularly preferred.

Die in der Definition des Substituenten R1 der allgemeinen Formel I vorkommenden Alkyl-, Halogenalkyl-, Alkylcarbonyl- und Alkoxycarbonylreste können gesättigt oder ungesättigt, geradkettig oder verzweigt sein und 1-7, vorzugsweise 1-4 Kohlenstoffatome enthalten. Besonders bevorzugt ist der Methyl-, Ethyl-, Propyl-, Isopropyl-, Trifluormethyl-, Methyloxycarbonyl-, Ethyloxycarbonyl- und Halogenmethylrest, wobei unter Halogen Fluor, Chlor, Brom und Iod zu verstehen ist. Die in der Definition des Substituenten R1 der allgemeinen Formel I vorkommenden Alkenyl-, Alkandienyl- und Alkinylreste können geradkettig oder verzweigt sein und 2-7, vorzugsweise 2-4 Kohlenstoffatome enthalten. Besonders bevorzugt ist der Vinyl-, Propenyl-, 2-Methylpropenyl-, Butadienyl-, Ethinyl- und Propinylrest. The alkyl, haloalkyl, alkylcarbonyl and alkoxycarbonyl radicals occurring in the definition of the substituent R 1 of the general formula I can be saturated or unsaturated, straight-chain or branched and contain 1-7, preferably 1-4 carbon atoms. The methyl, ethyl, propyl, isopropyl, trifluoromethyl, methyloxycarbonyl, ethyloxycarbonyl and halomethyl radical is particularly preferred, where halogen means fluorine, chlorine, bromine and iodine. The alkenyl, alkanedienyl and alkynyl radicals occurring in the definition of the substituent R 1 of the general formula I can be straight-chain or branched and contain 2-7, preferably 2-4, carbon atoms. The vinyl, propenyl, 2-methylpropenyl, butadienyl, ethynyl and propynyl radical is particularly preferred.

Die in der Definition des Substituenten R1 der allgemeinen Formel I vorkommenden Cycloalkyl- und Cycloalkenylreste können 3-7, vorzugsweise 3-6 Kohlenstoffatome enthalten. Besonders bevorzugt ist der Cyclopropyl-, Cyclopentyl-, Cyclohexyl-, Cyclopentenyl- und Cyclohexenylrest. The cycloalkyl and cycloalkenyl radicals occurring in the definition of the substituent R 1 of the general formula I can contain 3-7, preferably 3-6 carbon atoms. The cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical is particularly preferred.

Die in der Definition des Substituenten R1 der allgemeinen Formel I vorkommenden Aryl- und Hetarylreste sind vorzugsweise Phenyl, heterocyclische Fünfringe mit 1-4 Heteroatomen und heterocyclische Sechsringe mit 1-2 Heteroatomen, wobei die Heteroatome der vorgenannten Fünf- und Sechsringe gleich oder verschieden sein können und Sauerstoff, Schwefel und Stickstoff bedeuten können. Besonders bevorzugt ist der Pyridyl-, Pyridazinyl-, Pyrimidinyl-, Pyrazinyl-, Furyl-, Thienyl-, Pyrrolyl-, Imidazolyl-, Pyrazolyl-, Oxazolyl-, Thiazolyl-, Oxadiazolyl-, Thiadiazolyl-, Triazolyl- und Tetrazolylrest, sowie deren di- und tetrahydro-Derivate. The aryl and hetaryl radicals occurring in the definition of the substituent R 1 of the general formula I are preferably phenyl, heterocyclic five-membered rings with 1-4 heteroatoms and heterocyclic six-membered rings with 1-2 heteroatoms, the heteroatoms of the aforementioned five- and six-membered rings being identical or different can mean oxygen, sulfur and nitrogen. Particularly preferred is the pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl radical, as well as their di and tetrahydro derivatives.

Die Gruppe R1 ist insbesondere eine C1-C4-Alkylgruppe, beispielsweise Methyl- oder Ethylgruppe; eine Halogen-C1- C4-alkyl-, beispielsweise die Chlorethylgruppe; eine The group R 1 is in particular a C 1 -C 4 alkyl group, for example methyl or ethyl group; a halogen-C 1 - C 4 -alkyl-, for example the chloroethyl group; a

Cycloalkyl-, beispielsweise Cyclopentyl- oder Cyclohexylgruppe; eine Phenyl-, Furyl-, Pyridyl- oder Triazolylgruppe, wobei die Bindung der heterocyclischen Rest über 1-, 2-, 3- oder 4-Stellung erfolgen kann, wie z.B. 2- Furyl-, 3-Furyl-, 2-Pyridyl-, 4-Triazolyl- oder 4-Pyridyl. R2 bedeutet vorzugsweise die Thymingruppe. Cycloalkyl, for example cyclopentyl or cyclohexyl group; a phenyl, furyl, pyridyl or triazolyl group, it being possible for the heterocyclic radical to be bonded via the 1-, 2-, 3- or 4-position, such as, for example, 2-furyl, 3-furyl, 2-pyridyl , 4-triazolyl or 4-pyridyl. R 2 is preferably the thymine group.

Die Gruppe R bedeutet vorzugsweise ein Wasserstoffatom, eine C1-C4-Alkylcarbonyigruppe, beispielsweise die Acetylgruppe, oder die Mono- oder Triphosphatgruppe. The group R preferably denotes a hydrogen atom, a C 1 -C 4 -alkylcarbonyl group, for example the acetyl group, or the mono- or triphosphate group.

Als mögliche Salze der Verbindungen der allgemeinen Formel I kommen vor allem Alkali-, Erdalkali- und Ammoniumsalze der Phosphatgruppen in Frage. Als Alkalisalze sind Possible salts of the compounds of the general formula I are, in particular, alkali metal, alkaline earth metal and ammonium salts of the phosphate groups. As alkali salts are

Lithium-, Natrium- und Kaliumsalze bevorzugt. Als Erdalkalisalze kommen insbesondere Magnesium- und Calciumsalze in Frage. Unter Ammoniumsalzen werden erfindungsgemäß Salze verstanden, die das Ammoniumion enthalten, das bis zu vierfach durch Alkylreste mit 1-4 Kohlenstoffatomen und/oder Aralkylreste, bevorzugt Benzylreste, substituiert sein kann. Die Substituenten können hierbei gleich oder verschieden sein. Lithium, sodium and potassium salts preferred. Magnesium and calcium salts are particularly suitable as alkaline earth metal salts. According to the invention, ammonium salts are understood to be salts which contain the ammonium ion, which can be substituted up to four times by alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals. The substituents can be the same or different.

Die Verbindungen der allgemeinen Formel I können basische Gruppen, insbesondere Äminogruppen enthalten, die mit geeigneten Säuren in Säureadditionssalze übergeführt werden können. Als Säuren kommen hierfür beispielsweise in Betracht: Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Milchsäure, Maleinsäure oder Methansulfonsäure. The compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable acids. Examples of suitable acids for this purpose are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

Die Verbindungen der allgemeinen Formel I sind neue Verbindungen. Sie können in Analogie zu bekannten, verwandten Verbindungen hergestellt werden (vgl. Chem.Pharm.Bull. 33, 1703, 1985). Als besonders zweckmäßig hat sich zur Herstellung der Verbindungen der allgemeinen Formel I ein Verf.ihren erwiesen, bei dem man eine Verbindung der allgemeinen Formel II The compounds of general formula I are new compounds. They can be prepared analogously to known, related compounds (cf. Chem. Pharm.Bull. 33, 1703, 1985). It has proven particularly expedient to prepare the compounds of the general formula I by using a compound of the general formula II

Figure imgf000008_0001
oder der allgemeinen Formel III
Figure imgf000008_0001
or the general formula III

Figure imgf000009_0001
in denen R1 die angegebene Bedeutung hat, R3 Wasserstoff oder eine leicht abspaltbare Sauerstoffschutzgruppe, wie z.B. die Trityl-, Acetyl-, Benzoyl-, Benzyl- oder Trialkylsilylgruppe bedeutet, und X für eine Abgangsgruppe, wie z.B. Chlor-, Brom, Iod, Tosylat, Mesylat oder Acetat steht, mit Thymin, Uracil, Cytosin, Adenin, Hypoxanthin, Guanin oder einem silylgeschützten Derivat dieser Basen umsetzt, und nach Abspaltung gegebenenfalls vorhandener Schutzgruppen Verbindungen der allgemeinen Formel I
Figure imgf000009_0001
in which R 1 has the meaning given, R 3 is hydrogen or an easily removable oxygen protective group, such as, for example, the trityl, acetyl, benzoyl, benzyl or trialkylsilyl group, and X is a leaving group, such as chlorine, bromine or iodine , Tosylate, mesylate or acetate, with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases, and after splitting off any protective groups, compounds of the general formula I

Figure imgf000009_0002
in der R1 und R2 die angegebene Bedeutung haben und R3 Wasserstoff bedeutet, erhält und gewunschtenfalls anschließend Verbindungen der allgemeinen Formel I, in der R1 und R2 die angegebene Bedeutung haben und R3 Wasserstoff bedeutet, in bekannter Weise in die Mono-, Di- oder Triphosphate oder die entsprechenden Acylderivate
Figure imgf000009_0002
in which R 1 and R 2 have the meaning given and R 3 is hydrogen, and if desired subsequently obtains compounds of the general formula I in which R 1 and R 2 have the meaning given and R 3 is hydrogen, in a known manner into the mono -, Di- or triphosphates or the corresponding acyl derivatives

überführt, und gewunschtenfalls erhaltene freie Basen bzw. Säuren in die entsprechenden Salze oder erhaltene Salze in die entsprechenden Basen bzw. Säuren umwandelt. transferred and, if desired, free bases or acids obtained converted into the corresponding salts or salts obtained into the corresponding bases or acids.

Die Umsetzung der Verbindungen der allgemeinen Formel II wird zweckmäßigerweise mit silylgeschütztem Thymin, Uracil, Cytosin, Adenin, Hypoxanthin oder Guanin in einem aprotischen Lösungsmittel, wie z.B. Diethylether, Tetrahydrofuran, Toluol, Dimethylformamid, Dichlormethan oder Chloroform bei Temperaturen zwischen 0°C und 200°C, vorzugsweise zwischen 25°C und 100°C durchgeführt, wobei der Reaktionsmischung vorteilhafterweise katalytische Mengen einer Lewissäure, wie z.B. Aluminiumtrichlorid, Zinkbromid, Zinkiodid, Bortrifluorid, Titantetrachlorid oder Zinntetrachlorid, oder molare Mengen Trimethylsilylchlorid, -bromid oder -iodid zugesetzt werden. Bei der The reaction of the compounds of the general formula II is advantageously carried out using silyl-protected thymine, uracil, cytosine, adenine, hypoxanthine or guanine in an aprotic solvent, such as, for example, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, dichloromethane or chloroform at temperatures between 0 ° C. and 200 ° C, preferably between 25 ° C and 100 ° C, the Reaction mixture advantageously catalytic amounts of a Lewis acid, such as aluminum trichloride, zinc bromide, zinc iodide, boron trifluoride, titanium tetrachloride or tin tetrachloride, or molar amounts of trimethylsilyl chloride, bromide or iodide can be added. In the

wässrigen Aufarbeitung werden die Silylschutzgruppen der Basen bereits abgespalten. aqueous work-up, the silyl protective groups of the bases are already split off.

Verbindungen der Formel II sind aus EP-A-0,046,307 bekannt oder können analog zu dem dort beschriebenen Verfahren hergestellt werden. Insbesondere eignet sich hierzu die Herstellung durch Kondensation eines Aldehyds der Formel R1-CHO mit Ethylenglykol in saurem Medium, wie Compounds of the formula II are known from EP-A-0,046,307 or can be prepared analogously to the process described there. Production by condensation of an aldehyde of the formula R 1 -CHO with ethylene glycol in an acidic medium, such as

beispielsweise in Gegenstand von organischen oder anorganischen Säuren, z.B. Salzsäure, p-Toluolsulfonsäure, Methansulfonsäure, oder durch saure Ionenaustausch, wie z.B. Amberlite IR-120 oder Amberlist 15. e.g. in the subject of organic or inorganic acids, e.g. Hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, or by acidic ion exchange, e.g. Amberlite IR-120 or Amberlist 15.

Die silylgeschützten Basen R2 können nach bekannten The silyl-protected bases R 2 can according to known

Verfahren erhalten werden, wie beispielsweise Umsetzung der jeweiligen Base R2 mit Hexamethyl-disilazan. Processes are obtained, such as reaction of the respective base R 2 with hexamethyl disilazane.

Die Umsetzung von Verbindungen der allgemeinen Formel III mit Thymin, Uracil, Cytosin, Adenin, Hypoxanthin, Guanin oder einem silylgeschütztem Derivat dieser Basen wird zweckmäßigerweise in einem protischen oder aprotischen Lösungsmittel bei Temperaturen zwischen -25°C und 150°C, vorzugsweise zwischen 25°C und 75°C durchgeführt, wobei besonders auch Bedingungen der Phasentransferkatalyse angewendet werden können, bei der die oben genannten Basen in ein entsprechendes Anion überführt werden, beispielsweise durch 50proz. wässrige Natronlauge und das so entstandene Anion durch einen Phasentransferkatalysator, beispielsweise Tris[2-(2-methoxyethoxy)ethyl]amin, hydrophobiert und in die organische Phase transportiert wird, in der es mit der reaktiven Verbindung der Formel III abreagiert. Die Phosphatgruppen werden in Verbindungen der allgemeinen Formel I, in denen R Wasserstoff bedeutet, in bekannter Weise eingeführt. Die Monophosphate erhält man beispielsweise, indem man Verbindungen der Formel I mit R gleich Wasserstoff mit Phosphoroxychlorid in Trimethylphosphat phosphoryliert. Die auf diesem Wege erhaltenen Triethylammoniumsalze können in bekannter Weise in andere Salze durch Umsalzen überführt werden. Die Di- bzw. Triphosphate werden nach bekannten Methoden, vorzugsweise aus den Monophosphaten durch Umsetzung mit o-Phosphaten bzw. Pyrophosphaten erhalten. Ihre verschiedenen Salze können ebenfalls nach bekannten Methoden hergestellt werden. The reaction of compounds of general formula III with thymine, uracil, cytosine, adenine, hypoxanthine, guanine or a silyl-protected derivative of these bases is advantageously carried out in a protic or aprotic solvent at temperatures between -25 ° C and 150 ° C, preferably between 25 ° C and 75 ° C carried out, whereby conditions of phase transfer catalysis can be used in particular, in which the above-mentioned bases are converted into a corresponding anion, for example by 50 percent. aqueous sodium hydroxide solution and the anion formed in this way are hydrophobized by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine, and are transported into the organic phase in which it reacts with the reactive compound of the formula III. The phosphate groups are introduced in a known manner in compounds of the general formula I in which R is hydrogen. The monophosphates are obtained, for example, by phosphorylating compounds of the formula I where R is hydrogen with phosphorus oxychloride in trimethyl phosphate. The triethylammonium salts obtained in this way can be converted into other salts by salting in a known manner. The di- or triphosphates are obtained by known methods, preferably from the monophosphates by reaction with o-phosphates or pyrophosphates. Their various salts can also be prepared by known methods.

Verbindungen der Formel I, in der R eine Acylgruppe bedeutet, erhält man durch Umsetzung von Verbindungen, in denen R ein Wasserstoffatom darstellt, mit entsprechend geeigneter Acylierungsmitteln, wie z.B. Säureanhydride oder Halogeniden. Compounds of the formula I in which R represents an acyl group are obtained by reacting compounds in which R represents a hydrogen atom with correspondingly suitable acylating agents, such as e.g. Acid anhydrides or halides.

Zur Herstellung von Arzneimitteln werden die Substanzen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder öl, wie z. B. Olivenöl, suspendiert oder gelöst. Die erfindungsgemäßen neuen Substanzen der allgemeinen Formel I und ihre Salze können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Zusätze, wie Stabilisierungsmittel, Lösungsvermittler oder Puffer enthält. Derartige Zusätze sind z.B. Tartrat- und Citratpuffer, Ethanol, Komplexbildner (wie Ethylendiamintetraessigsäure und deren nichttoxische Salze) und hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung. Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, hochmolekulare Fettsäuren (wie Stearinsäure), Gelantine, Agar-Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette und feste hochmolekulare Polymere (wie Polyethylenglykole). Für orale Applikation geeignete Zubereitungen können gewunschtenfalls Geschmacks- und Süßstoffe For the manufacture of medicaments, the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as, for. B. olive oil, suspended or dissolved. The new substances of general formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers. Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, Talc, highly disperse silicas, high-molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high-molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, flavorings and sweeteners

enthalten. contain.

Die erfindungsgemäßen Verbindungen werden üblicherweise in Mengen von 0.1-100 mg, vorzugsweise 0.2-80 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tagesdosis auf 2-5 Applikationen zu verteilen, wobei bei jeder Applikation 1-2 Tabletten mit einem Wirkstoffgehalt von 0.5-1000 mg verabreicht werden. Die Tabletten können auch retardiert sein, wodurch sich die Anzahl der Applikationen pro Tag auf 1-3 vermindert. Der Wirkstoffgehalt der retardierten Tabletten kann 2-2000 mg betragen. Der Wirkstoff kann auch durch Injektion ein- bis achtmal pro Tag bzw. durch Dauerinfusion gegeben werden, wobei Mengen von 5-4000 mg pro Tag normalerweise ausreichen. The compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 tablets with an active ingredient content of 0.5-1000 mg being administered with each application. The tablets can also be delayed, which reduces the number of applications per day to 1-3. The active substance content of the retarded tablets can be 2-2000 mg. The active ingredient can also be given by injection one to eight times a day or by continuous infusion, with amounts of 5-4000 mg per day usually being sufficient.

Neben den in den Beispielen genannten Verbindungen kommen im Sinne der vorliegenden Erfindung auch die nachfolgenden Substanzen in Frage: In addition to the compounds mentioned in the examples, the following substances are also suitable for the purposes of the present invention:

1. 1-[1-(2-Hydroxyethoxy)phenylmethyl]cytosin 1. 1- [1- (2-Hydroxyethoxy) phenylmethyl] cytosine

2. 1-[1-(2-Hydroxyethoxy)phenylmethyl]adenin 2. 1- [1- (2-Hydroxyethoxy) phenylmethyl] adenine

3. 1-[1-(2-Hydroxyethoxy)phenylmethyl]guanin 3. 1- [1- (2-Hydroxyethoxy) phenylmethyl] guanine

4. 1-[1-(2-Hydroxyethoxy)-2-propen-1-yl]thymin 4. 1- [1- (2-Hydroxyethoxy) -2-propen-1-yl] thymine

5. 1-[1-(2-Hydroxyethoxy)-2-methyl-2-propen-1-yl]thymin 6. 1-[1-(2-Hydroxyethoxy)-2-buten-1-yl]thymin 5. 1- [1- (2-Hydroxyethoxy) -2-methyl-2-propen-1-yl] thymine 6. 1- [1- (2-Hydroxyethoxy) -2-buten-1-yl] thymine

7. 1-[1-(2-Hydroxyethoxy)-2-propin-1-yl]thymin 7. 1- [1- (2-Hydroxyethoxy) -2-propin-1-yl] thymine

8. 1-[1-(2-Hydroxyethoxy)cyanomethyl]thymin 8. 1- [1- (2-Hydroxyethoxy) cyanomethyl] thymine

9. 1-[1-(2-Hydroxyethoxy)-2,2,2,-trifluorethan-1- yl]thymin 9. 1- [1- (2-Hydroxyethoxy) -2,2,2, -trifluoroethan-1-yl] thymine

10. 1-[1-(2-Hydroxyethoxy)ethan-1-yl]thymin 10. 1- [1- (2-Hydroxyethoxy) ethan-1-yl] thymine

11. 1-[1-(2-Hydroxyethoxy)-2-chlorethan-1-yl]thymin 11. 1- [1- (2-Hydroxyethoxy) -2-chloroethan-1-yl] thymine

12. 1-[1-(2-Hydroxyethoxy)-3-chlorpropan-1-yl]thymin 12. 1- [1- (2-Hydroxyethoxy) -3-chloropropan-1-yl] thymine

13. 1-[1-(2-Hydroxyethoxy)methoxycarbonylmethyl]thymin 13. 1- [1- (2-Hydroxyethoxy) methoxycarbonylmethyl] thymine

14. 1-[1-(2-Hydroxyethoxy)methylcarbonylmethyl]thymin 14. 1- [1- (2-Hydroxyethoxy) methylcarbonylmethyl] thymine

15. 1-[1-(2-Hydroxyethoxy)formylmethyl]thymin 15. 1- [1- (2-Hydroxyethoxy) formylmethyl] thymine

16. 1-[1-(2-Hydroxyethoxy)azidomethyl]thymin 16. 1- [1- (2-Hydroxyethoxy) azidomethyl] thymine

17. 1-[1-(2-Hydroxyethoxy)cyclopenten-1-ylmethyl]thymin 18. 1-[1-(2-Hydroxyethoxy)cyclopenten-1-ylmethyl]cytosin 17. 1- [1- (2-Hydroxyethoxy) cyclopenten-1-ylmethyl] thymine 18. 1- [1- (2-Hydroxyethoxy) cyclopenten-1-ylmethyl] cytosine

19. 1-[1-(2-Hydroxyethoxy)-2-furylmethyl]adenin 19. 1- [1- (2-Hydroxyethoxy) -2-furylmethyl] adenine

20. 1-[1-(2-Hydroxyethoxy)-3-furylmethyl]uracil 20. 1- [1- (2-Hydroxyethoxy) -3-furylmethyl] uracil

21. 1-[1-(2-Hydroxyethoxy)-2-furylmethyl]guanin 21. 1- [1- (2-Hydroxyethoxy) -2-furylmethyl] guanine

22. 1-[1-(2-Hydroxyethoxy)-1,2,3-triazol-4(5)- ylmethyl]adenin 22. 1- [1- (2-Hydroxyethoxy) -1,2,3-triazol-4 (5) ylmethyl] adenine

23. 1-[1-(2-Hydroxyethoxy)-1,2,3-triazol-4(5)- ylmethyl]guanin 24. 1-[1-(2-Hydroxyethoxy)cyclohexylmethyl]uracil 23. 1- [1- (2-Hydroxyethoxy) -1,2,3-triazol-4 (5) - ylmethyl] guanine 24. 1- [1- (2-Hydroxyethoxy) cyclohexylmethyl] uracil

25. 1-[1-(2-Hydroxyethoxy)cyclohexylmethyl]cytosin 25. 1- [1- (2-Hydroxyethoxy) cyclohexylmethyl] cytosine

26. 1-[1-(2-Hydroxyethoxy)cyclohexen-1-ylmethyl]guanin 26. 1- [1- (2-Hydroxyethoxy) cyclohexen-1-ylmethyl] guanine

27. 1-[1-(2-Hydroxyethoxy)cyclohexen-1-ylmethy1]adenin 27. 1- [1- (2-Hydroxyethoxy) cyclohexen-1-ylmethy1] adenine

28. 1-[1-(2-Hydroxyethoxy)cyclohexan-1,4-dien-1- ylmethyl]uracil 28. 1- [1- (2-Hydroxyethoxy) cyclohexane-1,4-dien-1-ylmethyl] uracil

29. 1-[1-(2-Hydroxyethoxy)cyclohexan-1,4-dien-1- ylmethyl]thymin 29. 1- [1- (2-Hydroxyethoxy) cyclohexane-1,4-dien-1-ylmethyl] thymine

30. 1-[1-(2-Hydroxyethoxy)-2-pyridylmethyl]cytosin 30. 1- [1- (2-Hydroxyethoxy) -2-pyridylmethyl] cytosine

31. 1-[1-(2-Hydroxyethoxy)-2-pyridylmethyl]adenin 31. 1- [1- (2-Hydroxyethoxy) -2-pyridylmethyl] adenine

32. 1-[1-(2-Hydroxyethoxy)-3-pyridylmethyl]guanin 32. 1- [1- (2-Hydroxyethoxy) -3-pyridylmethyl] guanine

33. 1-[1-(2-Hydroxyethoxy)-4-pyridylmethyl]uracil 33. 1- [1- (2-Hydroxyethoxy) -4-pyridylmethyl] uracil

34. 1-[1-(2-Hydroxyethoxy)-4-pyridylmethyl]thymin Beispiel 1 34. 1- [1- (2-Hydroxyethoxy) -4-pyridylmethyl] thymine example 1

1-[1-(2-Hydroxyethoxy)phenylmethyl]thymin 1- [1- (2-Hydroxyethoxy) phenylmethyl] thymine

13 g (87 mmol) 2-Phenyl-1,3-dioxolan, 25.8 g (95 mmol) Bistrimethylsilylthymin und 200 ml absolutes Dichlormethan wurden vorgelegt und 1.1 ml (8.7 mmol) Zinn(IV) Chlorid bei 20°C zugetropft. Nach 2 Tagen wurde der Ansatz in 24 g Natriumhydrogenkarbonat, gelöst in 100 ml Methanol/Wasser 1:1 eingerührt, über Celite abgesaugt, eingedampft und durch Säulenchromatographie an Kieselgel (Laufmittel: 13 g (87 mmol) of 2-phenyl-1,3-dioxolane, 25.8 g (95 mmol) of bistrimethylsilylthymine and 200 ml of absolute dichloromethane were initially introduced and 1.1 ml (8.7 mmol) of tin (IV) chloride were added dropwise at 20 ° C. After 2 days, the mixture was stirred in 24 g of sodium bicarbonate, dissolved in 100 ml of methanol / water 1: 1, suction filtered through Celite, evaporated and by column chromatography on silica gel (mobile solvent:

Dichlormethan/Methanol, 99:1) gereinigt. Man erhält 15.1 g (62.8 %) der Titelverbindung vom Schmp. 137-40°C aus Dichloromethane / methanol, 99: 1). 15.1 g (62.8%) of the title compound are obtained with a melting point of 137-40 ° C.

Essigester. Ethyl acetate.

Beispiel 2 Example 2

Analog Beispiel 1 erhält man die folgenden The following are obtained analogously to Example 1

Endverbindungen: a) 1-[1-(2-Hydroxyethoxy) cyclopentylmethyl]thymin End compounds: a) 1- [1- (2-hydroxyethoxy) cyclopentylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Essigester/Methanol 99:1) in 65 % Ausbeute mit Schmp. 159-62°C aus Essigester. b) 1-[1-(2-Hydroxyethoxy)cyclohexylmethyl]thymin  Ethyl acetate / methanol 99: 1) in 65% yield with mp. 159-62 ° C from ethyl acetate. b) 1- [1- (2-Hydroxyethoxy) cyclohexylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Essigester/Methanol 99:1) in 73 % Ausbeute mit Schmp. 129-31°C aus Essigester. c) 1-[1-(2-Hydroxyethoxy)-2-furylmethyl]thymin  Ethyl acetate / methanol 99: 1) in 73% yield with mp. 129-31 ° C from ethyl acetate. c) 1- [1- (2-Hydroxyethoxy) -2-furylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol 98.5:1.5) in 48 % Ausbeute mit Schmp. 120-22°C aus Essigester. d) 1-[1-(2-Hydroxyethoxy)-3-furylmethyl]thymin Dichloromethane / methanol 98.5: 1.5) in 48% yield with mp 120-22 ° C from ethyl acetate. d) 1- [1- (2-Hydroxyethoxy) -3-furylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol 99:1) in 68 % Ausbeute mit Schmp. 141-46°C aus Essigester. e) 1-[1-(2-Hydroxyethoxy)-3-pyridylmethyl]thymin  Dichloromethane / methanol 99: 1) in 68% yield with mp. 141-46 ° C from ethyl acetate. e) 1- [1- (2-Hydroxyethoxy) -3-pyridylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol 97.5:2.5) in 51 % Ausbeute mit Schmp. 163-68°C aus Essigester. f) 1-[1-(2-Hydroxyethoxy)-2-pyridylmethyl]thymin  Dichloromethane / methanol 97.5: 2.5) in 51% yield with mp. 163-68 ° C from ethyl acetate. f) 1- [1- (2-Hydroxyethoxy) -2-pyridylmethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol 97.5:2.5) in 48 % Ausbeute mit Schmp. 166-69°C aus Essigester. g) 1-[1-(2-Hydroxyethoxy)ethyl]thymin  Dichloromethane / methanol 97.5: 2.5) in 48% yield with mp. 166-69 ° C from ethyl acetate. g) 1- [1- (2-Hydroxyethoxy) ethyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol, 95:5) in 58 % Ausbeute mit Schmp. 151-53°C. h) 1-[1-(2-Hydroxyethoxy)propyl]thymin  Dichloromethane / methanol, 95: 5) in 58% yield with mp. 151-53 ° C. h) 1- [1- (2-Hydroxyethoxy) propyl] thymine

nach Säulenchromatographie (Laufmittel:  after column chromatography (eluent:

Dichlormethan/Methanol, 95:5) in 63 % Ausbeute mit Schmp. 88-93°C.  Dichloromethane / methanol, 95: 5) in 63% yield with mp. 88-93 ° C.

Beispiel 3 Example 3

1-[1-(2-Hydroxyethoxy)-1,2,3-triazol-4(5)-ylmethyl]thymin a) 5 g (39 mmol) Propiolaldehyddiethylacetal wurden mit 5.7 g (43 mmol) Benzylazid in 10 ml Ethanol 40 Stunden im Autoklaven auf 90°C erhitzt. Nach Abdestillieren des Ethanols wurde der ölige Rückstand durch Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Heptan 1:2) gereinigt. Nach Eindampfen der gewünschten Fraktionen erhält man 8.8 g eines Gemisches von 1-Benzyl-1,2,3-triazol-4-aldehyddiethylacetal und 1-Benzyl-1,2,3-triazol-5-aldehyddiethylacetal als öl. b) 4.4 g (16.8 mmol) des unter a) erhaltenen Gemisches wurden in 100 ml Toluol mit 10 ml Ethylenglykol und 0.2 g p-Toluolsulfonsäure 7 Stunden am Rückfluß gekocht. Nach Abkühlen wurde die organische Phase mit Natriumhydrogenkarbonat-Lösung und Wasser 1- [1- (2-Hydroxyethoxy) -1,2,3-triazol-4 (5) -ylmethyl] thymine a) 5 g (39 mmol) of propiolaldehyde diethylacetal were mixed with 5.7 g (43 mmol) of benzyl azide in 10 ml of ethanol 40 Heated to 90 ° C in an autoclave. After the ethanol had been distilled off, the oily residue was purified by column chromatography on silica gel (mobile phase: ethyl acetate / heptane 1: 2). After evaporation of the desired fractions, 8.8 g of a mixture of 1-benzyl-1,2,3-triazole-4-aldehyde diethylacetal and 1-benzyl-1,2,3-triazole-5-aldehyde diethylacetal are obtained as an oil. b) 4.4 g (16.8 mmol) of the mixture obtained under a) were boiled under reflux in 100 ml of toluene with 10 ml of ethylene glycol and 0.2 g of p-toluenesulfonic acid. After cooling, the organic phase with sodium hydrogen carbonate solution and water

ausgeschüttelt, die organische Phase getrocknet, eingeengt und der Rückstand im Vakuum destilliert. Man erhält 3 g eines Gemisches von 1-Benzyl-4-(1,3- dioxolan-2-yl)-1,2,3-triazol und 1-Benzyl-5-(1,3- dioxolan-2-yl)-1,2,3-triazol als öl. c) Analog Beispiel 1 erhält man aus 0.5 g (2.16 mmol) des unter b) erhaltenen Gemisches und 0.64 g (2.38 mmol) Bistrimethylsilylthymin nach Säulenchromatographie an Kieselgel (Laufmittel: Essigester/Methanol 98:2) 0.2 g eines Gemisches von 1-[1-(2-Hydroxyethoxy)-1-(1-benzyl-1,2,3-triazol-4-yl)methyl]thymin und 1-[1-(2-Hydroxyethoxy)-1-(1-benzyl-1,2,3-triazol- 5-yl)methyl]thymin als amorphen Rückstand. d) 0.2 g (0.5 mmol) des unter c) erhaltenen Gemisches wurden in Ethanol bei 25°C und 100 bar unter Zusatz von 0.02 g 5proz. Palladium auf Kohle hydriert. Nach 5 Stunden wurde abgekühlt und nach Abtrennen des Katalysators wurde zur Trockne eingedampft. Der Rückstand wurde über Kieselgel (Laufmittel: Essigester/ Methanol 98:2) gereinigt. Nach Eindampfen der gewünschten Fraktionen erhält man 0.1 g (74.9 %) der Titelverbindung vom Schmp. 154-57°C aus Essigester. Beispiel 4 extracted, the organic phase dried, concentrated and the residue distilled in vacuo. 3 g of a mixture of 1-benzyl-4- (1,3-dioxolan-2-yl) -1,2,3-triazole and 1-benzyl-5- (1,3-dioxolan-2-yl) are obtained. -1,2,3-triazole as an oil. c) Analogously to Example 1, from 0.5 g (2.16 mmol) of the mixture obtained under b) and 0.64 g (2.38 mmol) of bistrimethylsilylthymine after column chromatography on silica gel (mobile phase: ethyl acetate / methanol 98: 2) 0.2 g of a mixture of 1- [ 1- (2-Hydroxyethoxy) -1- (1-benzyl-1,2,3-triazol-4-yl) methyl] thymine and 1- [1- (2-Hydroxyethoxy) -1- (1-benzyl-1 , 2,3-triazol-5-yl) methyl] thymine as an amorphous residue. d) 0.2 g (0.5 mmol) of the mixture obtained under c) were in ethanol at 25 ° C and 100 bar with the addition of 0.02 g of 5%. Palladium hydrogenated on carbon. After 5 hours, the mixture was cooled and, after the catalyst had been separated off, the mixture was evaporated to dryness. The residue was purified on silica gel (mobile solvent: ethyl acetate / methanol 98: 2). After the desired fractions have been evaporated, 0.1 g (74.9%) of the title compound, mp. 154-57 ° C., is obtained from ethyl acetate. Example 4

1-[1-(2-Acetyloxyethoxy)-2-chlorethyl]thymin a) 6.0 ml (81.3 mmol) Acetylbromid werden unter Eiskühlung vorgelegt und langsam 7.6 ml 2-Chlormethyl- 1,3-dioxolan zugetropft. Nach Stehen über Nacht wurde im Hochvakuum destilliert. Man erhält 11.3 g 1-(2- Acetyloxyethoxy)-1-brom-2-chlorethan vom Sdp. 88- 100°C/0.2 mm. b) 7.9 g (32.0 mmol) der unter a) erhaltenen Verbindung, 13.0 g (48.0 mmol) Bistrimethylsilylthymin und 50 ml Dichlormethan werden bei 0°C zusammengegeben und 2 Stunden bei 25°C weitergerührt. Nach Abdampfen des Lösungsmittels wird der Rückstand nochmals in 200 ml Dichlormethan gelöst, eine Stunde mit 50 ml Wasser gerührt, abgesaugt, die organische Phase getrocknet und eingedampft. Das farblose öl wurde anschließend aus Essigester kristallisiert. Man erhält 4.8 g (51.6 %) der Titelverbindung vom Schmp. 102-104°C. 1- [1- (2-Acetyloxyethoxy) -2-chloroethyl] thymine a) 6.0 ml (81.3 mmol) of acetyl bromide are introduced with ice cooling and 7.6 ml of 2-chloromethyl-1,3-dioxolane are slowly added dropwise. After standing overnight, the mixture was distilled under high vacuum. 11.3 g of 1- (2-acetyloxyethoxy) -1-bromo-2-chloroethane of bp 88-100 ° C./0.2 mm are obtained. b) 7.9 g (32.0 mmol) of the compound obtained under a), 13.0 g (48.0 mmol) of bistrimethylsilylthymine and 50 ml of dichloromethane are combined at 0 ° C. and stirring is continued at 25 ° C. for 2 hours. After the solvent has been evaporated off, the residue is redissolved in 200 ml of dichloromethane, stirred for one hour with 50 ml of water, filtered off with suction, the organic phase is dried and evaporated. The colorless oil was then crystallized from ethyl acetate. 4.8 g (51.6%) of the title compound of mp 102-104 ° C. are obtained.

Beispiel 5 Example 5

1-[1-(2-Hydroxyethoxy)phenylmethyl]thymin-triphosphat x 3 mol NEt3 1- [1- (2-Hydroxyethoxy) phenylmethyl] thymine triphosphate x 3 mol NEt 3

(0,2mmol) 1-[1-(2-Hydroxyethoxy)phenylmethyl]thymin (Bsp. 1) wurden in absol. Toluol suspendiert und bei etwas erhöhter Raumtemperatur im Hochvakuum zur Trockne gebracht (2x 1 ml). Der Rückstand wurde in 2 ml Phosphorsäuretrimethylester bei 25°C gelöst, im Eisbad gekühlt, 85 mg (0,4mmol) Proton Sponge (1,8-Bis-dimethylamino-naphtalin) zugegeben, 0,027 ml (0,15 mmol) Phosphoroxychlorid zugetropft und nach 15 Minuten 0,04 ml absol. DMF zugesetzt. Der Ansatz wurde weitere 15 Minuten im Eisbad gerührt und dann in eine Lösung von 0,5 mmol Bis-Tributylammonium-Pyrophosphat, 2 ml DMF, 2 ml Pyridin und 0,2 ml Tributylamin unter Eiskühlung eingetropft. Nach 5 Minuten wurden zum Abstoppen der Reaktionen 2 ml einer 0,2 molaren, wässrigen Triethylammonium-Hydrogenkarbonat-Lösung zugesetzt, der Ansatz nach 30 Minuten mit Wasser verdünnt, auf eine Sephadex DEAE-Säule aufgetragen und mit einem 0,1-0,5 molaren, linearen Gradienten von Triethylammonium-Hydrogencarbonat eluiert. Die gewünschten Fraktionen wurden vereinigt und man erhielt nach zweimaliger Lyophilisierung 42 mg der Titelverbindung als Tris-Triethylammoniumsalz.31 P-NMR (D2O/H2O+Ethylenamintetraessigsäure): δ =-7.76 (d, P-α), -8.07 (d, P-τ), -20.03 (t, P-ß). (0.2mmol) 1- [1- (2-hydroxyethoxy) phenylmethyl] thymine (Ex. 1) were in absolute. Suspended toluene and brought to dryness in a high vacuum at room temperature (2x 1 ml). The residue was dissolved in 2 ml of trimethyl phosphoric acid at 25 ° C., cooled in an ice bath, 85 mg (0.4 mmol) of Proton Sponge (1,8-bis-dimethylamino-naphthalene) were added, 0.027 ml (0.15 mmol) of phosphorus oxychloride were added dropwise and after 15 minutes 0.04 ml absolute. DMF added. The mixture was stirred in an ice bath for a further 15 minutes and then added dropwise to a solution of 0.5 mmol bis-tributylammonium pyrophosphate, 2 ml DMF, 2 ml pyridine and 0.2 ml tributylamine while cooling with ice. After 5 minutes, 2 ml of a 0.2 molar aqueous triethylammonium hydrogen carbonate solution were added to stop the reactions, the mixture was diluted with water after 30 minutes, applied to a Sephadex DEAE column and with a 0.1-0.5 molar linear gradient eluted from triethylammonium bicarbonate. The desired fractions were combined and, after lyophilization twice, 42 mg of the title compound were obtained as the tris-triethylammonium salt. 31 P-NMR (D 2 O / H 2 O + ethylene amine tetraacetic acid): δ = -7.76 (d, P-α), -8.07 (d, P- τ ), -20.03 (t, P-ß).

Beispiel 6 Example 6

Analog zu Beispiel 5 erhält man die folgenden The following are obtained analogously to Example 5

Endverbindungen: a) 1-[1-(2-Hydroxyethoxy)cyclopentylmethyl]thymintriphosphat x 3 mol NEt3 End compounds: a) 1- [1- (2-hydroxyethoxy) cyclopentylmethyl] thymine triphosphate x 3 mol NEt 3

31P-NMR: 6= -7.78 (d, P-α), -8.18 (d, P-τ), -20.18 (t, P -ß). 31 P NMR: 6 = -7.78 (d, P-α), -8.18 (d, P- τ ), -20.18 (t, P -ß).

b) 1-[1-(2-Hydroxyethoxy)-3-furylmethyl]thymintriphosphat x 3 mol NEt3 b) 1- [1- (2-Hydroxyethoxy) -3-furylmethyl] thymine triphosphate x 3 mol NEt 3

31P-NMR:δ=-7.82 (d, P-α), -8.13 (d, P-τ), -20.09 (t, P -ß). c) 1-[1-(2-Hydroxyethoxy)-2-furylmethyl]thymintriphosphat x 3 mol NEt3 31 P NMR: δ = -7.82 (d, P-α), -8.13 (d, P- τ ), -20.09 (t, P -ß). c) 1- [1- (2-Hydroxyethoxy) -2-furylmethyl] thymine triphosphate x 3 mol NEt 3

31P-NMR:6=-7.84 (d, P-α), -8.17 (d, P-τ) , -20.40 (t, P -ß). d) 1-[1-(2-Hydroxyethoxy)ethyl]thymin-triphosphat x 3 mol NEt3 31 P NMR: 6 = -7.84 (d, P-α), -8.17 (d, P- τ ), -20.40 (t, P -ß). d) 1- [1- (2-hydroxyethoxy) ethyl] thymine triphosphate x 3 mol NEt 3

31P-NMR: ô=-7.71 (d, P-α), -8.01 (d, P-τ), -20.18 (t, P -ß). e) 1-[1-(2-Hydroxyethoxy)propyl]thymin-triphosphat x 3 mol NEt3 31 P NMR: ô = -7.71 (d, P-α), -8.01 (d, P- τ ), -20.18 (t, P -ß). e) 1- [1- (2-Hydroxyethoxy) propyl] thymine triphosphate x 3 mol NEt3

31P-NMR:δ=-8.81 (d, P-α), -9.16 (d, P-τ) , -21.20 (t, P -ß). 31 P NMR: δ = -8.81 (d, P-α), -9.16 (d, P- τ ), -21.20 (t, P -ß).

Claims

Patentansprüche Claims 1. Verbindungen der allgemeinen Formel I 1. Compounds of the general formula I
Figure imgf000021_0001
in der
Figure imgf000021_0001
in the R Wasserstoff, eine aliphatische Acylgruppe mit 1-20 C-Atomen oder eine Monophosphat-, Diphosphat- oder Triphosphatgruppe bedeutet, R denotes hydrogen, an aliphatic acyl group with 1-20 C atoms or a monophosphate, diphosphate or triphosphate group, R1 eine C1-C7-Alkyl-, Halogen-C1-C7-alkyl-, Trifluormethyl-, C2-C7-Alkenyl-, C3-C7-Alkandienyl-, C2-C7- Alkinyl-, Cyano-, Formyl-, C1-C7-Alkyl-carbonyl-, C1-C7-Alkoxycarbonyl-, Aminocarbonyl-, Azido-, C3- C7-Cycloalkyl-, C3-C7-Cycloalkenyl- oder Arylgruppe oder ein gesättigter, ungesättigter oder R 1 is a C 1 -C 7 alkyl, halo C 1 -C 7 alkyl, trifluoromethyl, C 2 -C 7 alkenyl, C 3 -C 7 alkanedienyl, C 2 -C 7 - Alkynyl, cyano, formyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl, aminocarbonyl, azido, C 3 - C 7 cycloalkyl, C 3 -C 7 - Cycloalkenyl or aryl group or a saturated, unsaturated or aromatischer Heterocyclus ist, und  aromatic heterocycle, and R2 eine Thymin-, Uracil-, Cytosin-, Adenin-, Hypoxanthin- oder Guaningruppe bedeutet, wobei a) R kein Wasserstoffatom oder eine Acylgruppe sein kann, wenn R1 eine Alkyl-, Cycloalkyl- oder Phenylgruppe und R2 eine Uracil- oder Thymingruppe darstellen, und b) R kein Wasserstoffatom oder eine Acylgruppe sein kann, wenn RI eine Alkylgruppe und R2 eine Adenin-, Guanin- oder Hypoxanthingruppe ist, deren Tautomere, optisch aktive Formen oder R 2 is a thymine, uracil, cytosine, adenine, hypoxanthine or guanine group, where a) R cannot be a hydrogen atom or an acyl group if R 1 is an alkyl, cycloalkyl or phenyl group and R 2 is an uracil or thymine group, and b) R cannot be a hydrogen atom or an acyl group if RI is an alkyl group and R 2 is an adenine, guanine or hypoxanthine group, their tautomers, optically active forms or physiologisch verträgliche Salze. physiologically acceptable salts. 2. Verbindungen der Formel I gemäfe Anspruch 1, in der R1 eine C1-C4-Alkyl-, Halogen-C1-C4-alkyl-, C5-C6-Cycloalkyl- oder Phenylgruppe bedeutet. 2. Compounds of formula I according to claim 1, in which R 1 is a C 1 -C 4 alkyl, halogen-C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl or phenyl group. 3. Verbindungen der Formel I gemäß Anspruch 1, in der R1 einen gesättigten, ungesättigten oder aromatischen heterocyclischen Rest bedeutet, der die Pyridyl-, 3. Compounds of formula I according to claim 1, in which R 1 is a saturated, unsaturated or aromatic heterocyclic radical which is the pyridyl, Pyridazinyl-, Pyrimidinyl-, Pyrazinyl-, Furyl-,  Pyridazinyl, pyrimidinyl, pyrazinyl, furyl, Thienyl-, Pyrolyl-, Imidazolyl-, Pyrazolyl-, Oxazolyl-, Thiazolyl-, Oxadiazolyl-, Thiadiazolyl-, Triazolyl- und Tetrazolylgruppe sein kann.  Can be thienyl, pyrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups. 4. Verbindungen der Formel I gemäß Anspruch 1, 2 oder 3 der R1 eine Methyl-, Ethyl-, 2-Chlorethyl-, Cyclopentyl-, Cyclohexyl-, Phenyl-, 2-Furyl-, 3-Furyl-, 2- Pyridyl-, 3-Pyridyl-, 4-Pyridyl- oder 4-Triazolylgruppe bedeutet. 4. Compounds of formula I according to claim 1, 2 or 3 of R 1 is methyl, ethyl, 2-chloroethyl, cyclopentyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-pyridyl -, 3-pyridyl, 4-pyridyl or 4-triazolyl group. 5. Verbindungen gemäß einem der Ansprüche 1-4, dadurch 5. Compounds according to any one of claims 1-4, characterized gekennzeichnet, daß R2 eine Thymingruppe bedeutet. characterized in that R 2 represents a thymine group. 6. Verbindungen gemäß einem der Ansprüche 1-5, dadurch 6. Compounds according to any one of claims 1-5, characterized gekennzeichnet, daß R ein Wasserstoffatom, eine Acetylgruppe oder eine Mono- oder Triphosphatgruppe darstellt.  characterized in that R represents a hydrogen atom, an acetyl group or a mono- or triphosphate group. 7. Verfahren zur Herstellung von Verbindungen gemäß einem der Ansprüche 1-6, dadurch gekennzeichnet, daß man in an sich bekannter Weise Verbindungen der allgemeinen Formel II 7. A process for the preparation of compounds according to any one of claims 1-6, characterized in that compounds of the general formula II
Figure imgf000022_0001
in der R1 die oben angegebenen Bedeutungen besitzt, oder Verbindungen der allgemeinen Formel III
Figure imgf000022_0001
in which R 1 has the meanings given above, or compounds of the general formula III 11
Figure imgf000023_0001
Figure imgf000023_0001
 in der R1 die oben angegebenen Bedeutungen hat und R3 Wasserstoff oder eine leicht abspaltbare Sauerstoffschutzgruppe darstellt, und X für eine Abgangsgruppe bedeutet, mit Thymin, Uracil, Cytosin, Adenin, in which R 1 has the meanings given above and R 3 represents hydrogen or an easily removable oxygen protective group, and X denotes a leaving group, with thymine, uracil, cytosine, adenine, Hypoxanthin, Guanin oder deren silylgeschützten  Hypoxanthine, guanine or their silyl-protected Derivaten umsetzt, und nach Abspaltung gegebenenfalls vorhandener Schutzgruppen Verbindungen der allgemeinen Formel I erhält, in der R1 und R2 die oben angegebenen Bedeutungen haben und R3 Wasserstoff bedeutet, und gewunschtenfalls anschließend Verbindungen der allgemeinen Formel I, in der R3 Wasserstoff bedeutet, in bekannter Weise in die Mono-, Di- oder Triphosphate oder die entsprechenden Acylderivate überführt, und gewunschtenfalls erhaltene freie Basen bzw. Säuren in die entsprechenden Salze oder erhaltene Salze in die entsprechenden Basen bzw. Säuren umwandelt. Converts derivatives, and after splitting off any protective groups present, compounds of the general formula I are obtained in which R 1 and R 2 have the meanings given above and R 3 is hydrogen, and if desired subsequently compounds of the general formula I in which R 3 is hydrogen, converted in a known manner into the mono-, di- or triphosphates or the corresponding acyl derivatives, and, if desired, converted free bases or acids into the corresponding salts or converted salts into the corresponding bases or acids. 8. Arzneimittel enthaltend mindestens eine Verbindung der Formel I gemäß einem der Ansprüche 1-6, sowie geeignete pharmazeutische Träger- oder Hilfsstoffe. 8. Medicament containing at least one compound of formula I according to any one of claims 1-6, and suitable pharmaceutical carriers or excipients. 9. Verwendung von Arzneimittel gemäß Anspruch 8 zur 9. Use of medicament according to claim 8 for Behandlung von viralen Infektionen.  Treatment of viral infections. 10. Verfahren zur Herstellung von Arzneimitteln, dadurch gekennzeichnet, daß man Verbindungen gemäß den 10. A process for the preparation of medicaments, characterized in that compounds according to the Ansprüchen 1-6 zusammen mit pharmakologischen Hilfsoder Trägerstoffen zu pharmazeutischen  Claims 1-6 together with pharmacological auxiliaries or carriers to pharmaceutical Darreichungsformen verarbeitet.  Dosage forms processed.
PCT/EP1990/000299 1989-02-24 1990-02-22 Seco-nucleoside derivatives and drugs containing them Ceased WO1990009999A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3905725.9 1989-02-24
DE3905725A DE3905725A1 (en) 1989-02-24 1989-02-24 SECO-NUCLEOSIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AN ANTIVIRAL AGENT

Publications (1)

Publication Number Publication Date
WO1990009999A1 true WO1990009999A1 (en) 1990-09-07

Family

ID=6374830

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/000299 Ceased WO1990009999A1 (en) 1989-02-24 1990-02-22 Seco-nucleoside derivatives and drugs containing them

Country Status (2)

Country Link
DE (1) DE3905725A1 (en)
WO (1) WO1990009999A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046307A1 (en) * 1980-08-19 1982-02-24 Chugai Seiyaku Kabushiki Kaisha Novel uracil derivatives, process for preparing the same and a pharmaceutical composition containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046307A1 (en) * 1980-08-19 1982-02-24 Chugai Seiyaku Kabushiki Kaisha Novel uracil derivatives, process for preparing the same and a pharmaceutical composition containing the same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Journal of Medicinal Chemistry, Band 32, 1989, American Chemical Society, (Washington, US), P. SCHEINER et al.: "Acyclic Analogues of 3'-Azido-3'-Deoxythymidine as Potential Antiviral Agents. Nucleoside Synthesis by Michael Addition", seiten 73-76 *

Also Published As

Publication number Publication date
DE3905725A1 (en) 1990-09-06

Similar Documents

Publication Publication Date Title
DE69806919T2 (en) ANTIVIRAL PYRIMIDINE NUCLEOSIDE ANALOGS
DE68926137T2 (en) Pyrimidine nucleosides
EP0545966B1 (en) New phospholipid derivatives of nucleosides, their preparation and their use as antiviral drugs
DE60005502T2 (en) 4'-C-ETHYNYL-PURINE-NUCLEOSIDES
DE69034119T2 (en) Substituted-1,3-oxathiolanes with antiviral activity
EP0484333B1 (en) Nucleoside derivatives and their use as medicaments
DE69425574T2 (en) L-2 ', 3'-DIDEOXY NUCLEOSIDE ANALOGS AS ANTI-HEPATITIS B- (HBV) AND ANTI-HIV ACTIVE SUBSTANCES
DE69232845T2 (en) 1,3-oxathiolane nucleoside analog compounds
AT390000B (en) USE OF 3'-AZIDO-3'-DESOXYTHYMIDINE OR A PHARMACEUTICAL ACCEPTABLE DERIVATIVES THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS
DE3687397T2 (en) 2-FLUORARABINOFURANOSYLPURINE NUCLEOSIDES.
EP0316704B1 (en) Fluorocytidine derivatives, their preparation and medical preparations containing them
DE69330274T2 (en) ENANTIOMERICALLY PURE BETA-D-DIOXOLAN NUCLEOSIDES
DE69021242T2 (en) Antiviral compounds.
DE69407419T2 (en) 2 'OR 3' -DEOXY- AND 2 '-DIDEOXY-BETA-L-PENTAFURANONUCLEOSIDES, METHODS FOR THE PRODUCTION AND USE IN THERAPY, IN PARTICULAR AS ANTIVIRAL ACTIVE SUBSTANCES
WO1993016091A1 (en) New liponucleotides, their preparation and their use as antiviral medicaments
DE69109482T2 (en) PYRIMIDINE NUCLEOSIDE DERIVATIVE.
WO1993016092A1 (en) New lipophosphonic acid-nucleoside conjugates and their use as antiviral medicaments
DE3739366A1 (en) DESAZA-PURIN-NUCLEOSIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN NUCLEIC ACID SEQUENCING AND AS AN ANTIVIRAL AGENT
DE2508312A1 (en) NEW PROCESS FOR THE PRODUCTION OF NUCLEOSIDES
CH676712A5 (en)
DD255351A5 (en) PROCESS FOR THE PREPARATION OF CARBOCYCLIC PURE NUCLEOSIDES
DE68918215T2 (en) 2'-halomethylidene, 2'-ethenylidene and 2'-ethynyl adenosine derivatives.
WO1996032403A2 (en) Novel cytosine and cytidine derivatives
DE68923913T2 (en) Neplanocin derivatives.
DE69719511T2 (en) ANTIVIRAL 2,4-PYRIMIDINDION DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE

WR Later publication of a revised version of an international search report