DE2909709A1 - Nucleotide derivs. of purine, pyrimidine or (dihydro)pyridone base - having antiviral activity against resistant herpes virus strains - Google Patents

Nucleotide derivs. of purine, pyrimidine or (dihydro)pyridone base - having antiviral activity against resistant herpes virus strains

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Publication number
DE2909709A1
DE2909709A1 DE19792909709 DE2909709A DE2909709A1 DE 2909709 A1 DE2909709 A1 DE 2909709A1 DE 19792909709 DE19792909709 DE 19792909709 DE 2909709 A DE2909709 A DE 2909709A DE 2909709 A1 DE2909709 A1 DE 2909709A1
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pyrimidine
base
opt
atoms
substd
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German (de)
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Kailash Kumar Dr Gauri
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Priority to EP80101241A priority patent/EP0015584A3/en
Priority to JP3147480A priority patent/JPS55127397A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings
    • 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 System
    • 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
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/048—Pyridine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Nucleotides of formulae (I) and (II), including cyclophosphate esters with the 3-OH gp. of the pentofuranosyl gp. in the case of (I) are new ("Base" is the residue of a purine, pyrimidine, pyridone-2 or 3,6-dihydropyridone-2-base in which (a) the pyrimidine or pyridone-2 is opt. 4-substd. by amino; (b) the pyridone-2 is opt. 5-halo substd.; and (c) the pyrimidine is opt. 5-substd. by halogen, 2-6C alkyl, 2-6C alkenyl, 2-6C haloalkyl or 2-6C haloalkenyl; opt. 6-substd. by Cl; and if 5-substd. by 2-6C alkyl, opt. also 3-substd. by 1-4C alkyl; R' is halogen, H or OH; R is opt. branched 2-6C alkylene opt. interrupted in the chain by an ether gp.). (I) and (II) have antiviral activity, and induce and promote cell growth. They are active against herpes virus infections, including resistant herpes simplex strains. They can be used locally, orally or parenterally.

Description

Verfahren zur Herstellung von Nucleotidderivaten, neue Nucleotidderivate und daraus hergestellte Arzneimittel Die Erfindung betrifft ein Verfahren zur Herstellung von Nucleotidderivaten, die sich von natürlichen und synthetischen Nucleosiden ableiten aber auch Phosphorsäureester solcher Verbindungen darstellen, bei denen die Veresterung an einem Hydroxyalkylrest - anstelle des Zuckerrestes - erfolgt ist, sowie neue Nucleotidderivate und daraus hergestellte Arzneimittel.Process for the preparation of nucleotide derivatives, novel nucleotide derivatives and medicines made therefrom The invention relates to a Process for the preparation of nucleotide derivatives different from natural and synthetic Derive nucleosides but also represent phosphoric acid esters of such compounds, in which the esterification on a hydroxyalkyl residue - instead of the sugar residue - has taken place, as well as new nucleotide derivatives and medicinal products made from them.

Das erfindungsgemäße Verfahren kann zur Herstellung von bekannten Nucleosidderivaten, aber auch zur Herstellung von Phosphorsäureestern neuer Hydroxyverbindungen dienen, die überraschend vorteilhafte pharmakologische Eigenschaften besitzen.The inventive method can be used for the production of known Nucleoside derivatives, but also for the production of phosphoric acid esters of new hydroxy compounds serve that have surprisingly advantageous pharmacological properties.

Das erfindungsgemäRe Verfahren betrifft die Herstellung von Verbindungen der allgemeinen Formel I: worin der Rest "Base" für einen monocyclischen oder bicyclisch kondensierten heterocyclischen Rest mit 5 bis 10 Ringatomen, von denen bis zu 5 Atome Stickstoffatome sein können und der 1 bis 2 H2N-, HO-, HO-CH2- und/oder Cl-C6-Alkylsubstituenten und/oder 1 bis 2 O=Atome tragen kann, einen Pyrimidin- oder Purinrest, der die vorbezeichneten Substituenten tragen kann, steht; R für eine gerade oder verzweigte Alkylenkette mit 2 bis 6 C-Ato men, die gegebenenfalls ein Ather-Sauerstoffatom in der Kette enthalten kann, für einen Desoxyribosyl-, Ribosyl- oder Arabinosylrest steht; es ist dadurch gekennzeichnet, daß man eine Verbindung der allge meinen Formel II: Base - R - OH (11) worin "Base" und R die obengenannten Bedeutungen haben, mit Phosphoroxychlorid in einem geeigneten Lösungsmittel phosphoryliert und das dabei erhaltene Phosphat der Formel I durch Ausfällung mit Ather, Petroläther oder einem Gemisch dieser Lösungsmittel aus dem Reaktionsgemisch abtrennt.The process according to the invention relates to the preparation of compounds of the general formula I: wherein the radical "base" stands for a monocyclic or bicyclically fused heterocyclic radical with 5 to 10 ring atoms, of which up to 5 atoms can be nitrogen atoms and the 1 to 2 H2N-, HO-, HO-CH2- and / or Cl-C6 -Alkyl substituents and / or 1 to 2 O = atoms can carry a pyrimidine or purine radical which can carry the aforementioned substituents; R represents a straight or branched alkylene chain with 2 to 6 C atoms, which may optionally contain an ether-oxygen atom in the chain, represents a deoxyribosyl, ribosyl or arabinosyl radical; it is characterized in that a compound of the general formula II: base - R - OH (11) in which "base" and R have the meanings given above, is phosphorylated with phosphorus oxychloride in a suitable solvent and the phosphate of the formula I obtained is through Separation of precipitation with ether, petroleum ether or a mixture of these solvents from the reaction mixture.

Vorteilhafte Lösungsmittel bei der Phosphorylierung sind Trimethyl- bzw. Triäthylphosphat, wobei man aber auch von einer Lösung des nicht phosphorylierten Ausgangsproduktes der Formel II in einem niedrigen Alkohol mit 1 bis 4 Kohlenstoffatomen ausgehen kann und dieser Lösung ein Gemisch von Phosphoroxychlorid und Triäthyl- bzw. Trimethylphosphat zusetzt, das soviel Phosphoroxychlorid enthält, daß einerseits der in die Reaktion eingebrachte Lösungsmittel-Alkohol verestert wird und andererseits das in die Reaktion eingesetzte Ausgangsprodukt der Formel II verestert wird. Es wurde gefunden, daß für die Phosphorylierung der Purinverbindungen ein etwa stöchiometrisc-her Anteil Phosphoroxychlorid ausreichend ist, während bei den Pyrimidinverbindungen ein Oberschuß an Phosphoroxychlorid erforderlich ist.Advantageous solvents in phosphorylation are trimethyl or triethyl phosphate, but also from a solution of the non-phosphorylated Starting product of the formula II in a lower alcohol with 1 to 4 carbon atoms can go out and this solution is a mixture of phosphorus oxychloride and triethyl or trimethyl phosphate is added, which contains so much phosphorus oxychloride that on the one hand the solvent alcohol introduced into the reaction is esterified and on the other hand the starting product of the formula II used in the reaction is esterified. It it was found that for the phosphorylation of the purine compounds an approximately stoichiometric The proportion of phosphorus oxychloride is sufficient, while with the pyrimidine compounds an excess of phosphorus oxychloride is required.

Geeignete Purinbasen sind z.B. Purin, Adenin, Guanin, Hypoxanthin und Xanthin, Beispiele für geeignete Pyrimidinbasen sind Pyrimidin, Cytosin, Uracil, Thymin, 5-Methylcytosin, 5-Hydroxymethylcytosin und Pseudouridin. Die obigen Zuckerreste R können in der «- oder ß-Form vorliegen.Suitable purine bases are, for example, purine, adenine, guanine, hypoxanthine and xanthine, examples of suitable pyrimidine bases are pyrimidine, cytosine, uracil, Thymine, 5-methylcytosine, 5-hydroxymethylcytosine and pseudouridine. The above sugar residues R can be in the «- or ß-form.

Gegenstand der vorliegenden Erfindung sind auch neue Uracilderivate der allaemeinen Formel III: worin R1 einen verzweigten oder geradkettigen Niedrigalkylrest mit 2 bis 6 C-Atomen darstellt; und der allgemeinen Formel IV: worin R2 und R3 für gleiche oder verschiedene Niedrigalkylreste mit 1 bis 4 C-Atomen stehen, X ein Wasserstoff- oder Chloratom bedeutet; und R die oben im Zusammenhang mit der Formel 1 definierten Bedeutungen besitzt.The present invention also relates to new uracil derivatives of the general formula III: wherein R1 is a branched or straight-chain lower alkyl radical having 2 to 6 carbon atoms; and the general formula IV: in which R2 and R3 are identical or different lower alkyl radicals having 1 to 4 carbon atoms, X is a hydrogen or chlorine atom; and R has the meanings defined above in connection with formula 1.

Die Verbindungen der Formel III sind «-5-Niedrigalkyl,2'-deoxyuridin-5'-monophosphate, die entsprechenden ß-Formen können in analoger Weise hergestellt werden. Bevorzugt sind 5 Athyl- bZw.The compounds of formula III are «-5-lower alkyl, 2'-deoxyuridine-5'-monophosphate, the corresponding β-forms can be produced in an analogous manner. Preferred are 5 ethyl or

5-Propyl-2'-deoxyuridin-5'-monophosphat in der i- und/oder ß-For.5-propyl-2'-deoxyuridine-5'-monophosphate in the i- and / or ß-form.

Die neuen erfindungsgemäßen Verbindungen haben überraschßnde pharmakologische Eigenschaften, sie wirken insbesondere virostatisch und sie haben eine das Zellwachstum induzierende und fördernde Wirkung.The new compounds of the invention have surprising pharmacological properties Properties, they are particularly virostatic and they have a cell growth inducing and promoting effect.

Die folgenden Beispiele dienen zur weiteren Erläuterung der Erfindung.The following examples serve to further illustrate the invention.

B e i s n i e 1 1 α-5-Äthyl-2'-deoxyuridin-5'-monophosphat o6-5-Xthyl-2'-deoxyuridin (d-ADU) 25,6 g (0,1 Mol) wird mit 5 ml ethanol angefeuchtet und bei ca. OOC mit einem Gemisch aus 120 ml POCl3 und 100 ml Triäthylphosphat versetzt. Nach etwa l-stündigem Rühren bei Zimmertemperatur erhält man eine klare Lösung. Bei der DC (Dünnschichtchromatographie)-Kontrolle zeigt sich, daß die Phosphorylierung insgesamt nach etwa 2 Stunden fast abgeschlossen ist. Zur Beendigung der Reaktion wird die klare Lösung mit 200 ml Ather verdünnt und anschließend solange mit Petroläther unter Rühren versetzt bis keine weitere Trübung mehr auftritt. Nach Abkühlung auf -200C wird der klare Uberstand abdekantiert und der flocke Rückstand mehrmals mit Ather/Petroläther-Gemisch 1:1 gründlich nachgewaschen. Zur Entfernunq der Lösungsmittelreste empfiehlt es sich, den Rückstand einige Zeit an ein Ulpumpenvakuum anzuschließen. Danach wird der Rückstand in Natriumbicarbonat-Lösung aufgenommen und anschließend schonend im Vakuum bis zur Trockne eingedampft. For example 1 1 α-5-ethyl-2'-deoxyuridine-5'-monophosphate O6-5-Xthyl-2'-deoxyuridine (d-ADU) 25.6 g (0.1 mol) is moistened with 5 ml of ethanol and at about OOC with a mixture of 120 ml of POCl3 and 100 ml of triethyl phosphate. After stirring for about 1 hour at room temperature, a clear solution is obtained. The TLC (thin layer chromatography) control shows that the phosphorylation is almost complete after about 2 hours. To stop the reaction the clear solution is diluted with 200 ml of ether and then as long as petroleum ether added with stirring until no further turbidity occurs. After cooling down -200C the clear supernatant is decanted and the flaky residue with several times Thoroughly rewashed the ether / petroleum ether mixture 1: 1. To remove the solvent residues it is advisable to connect the residue to a pump vacuum for some time. Thereafter the residue is taken up in sodium bicarbonate solution and then gently evaporated to dryness in a vacuum.

Das farblose Produkt besteht bis zu 70 % aus dem *-5-Athyl-2'-deoxyuridin-5'-monophosphat; es enthält als Verunreinigung neben dem Ausgangsprodukt i-ADU noch etwaso(-DU-31,5'-diphosphat Für pharmazeutische und pharmakologische Zwecke ist das Reaktionsprodukt genügend rein.The colorless product consists of up to 70% of the * -5-ethyl-2'-deoxyuridine-5'-monophosphate; In addition to the starting product i-ADU, it also contains some o (-DU-31,5'-diphosphate The reaction product is sufficient for pharmaceutical and pharmacological purposes pure.

Beispiel 2 ß-D-Arabinofuranosyladenin-5'-monophosphat 2,6 g ß-D-Arabinofuranosyladenin (ca. 0,01 Mol) werden bei ca. Example 2 β-D-arabinofuranosyladenine 5'-monophosphate 2.6 g β-D-arabinofuranosyladenine (approx. 0.01 mol) are approx.

0°C mit einem Gemisch aus 2 ml POC13 und 20 ml Triäthylphosphat ' versetzt und bei ca. +10°C solange gerührt bis das Ausgangsprodukt fast vollständig umgesetzt ist (ca. 45 Min. ermittelt durch DC-Kontrolle). Die klare Lösung wird dann solange mit Ather verdünnt bis keine weitere Trübung mehr auftritt Nach kurzem Stehen im Kühlschrank wird das Lösungsmittel abdekantiert, der Niederschlaq mehrmals mit Äther gewaschen, in möglichst wenig Ethanol gelöst und nochmals mit Ether gefällt Nach Abkühlung auf -20°C wird der Oberstand abdekantiert. Der erhaltene Rückstand (ca. 2,5 q) besteht zu über 90 % aus dem gewünschten t3-D-Arabinofuranosyladenin-5'-monophosphat.0 ° C with a mixture of 2 ml POC13 and 20 ml triethyl phosphate ' added and stirred at approx. + 10 ° C until the starting product is almost complete is implemented (approx. 45 min. determined by TLC control). The clear solution will then diluted with ether until no further turbidity occurs. After a short time Standing in the refrigerator, the solvent is decanted off and the precipitate several times washed with ether, dissolved in as little ethanol as possible and precipitated again with ether After cooling to -20 ° C, the supernatant is decanted off. The residue obtained (approx. 2.5 q) consists of more than 90% of the desired t3-D-arabinofuranosyladenine-5'-monophosphate.

Auf die gleiche Weise läßt sich ausgehend von der «-Verbindung das α-D-Arabinofuranosyladenin-5'-monophosphat herstellen.In the same way, starting from the «connection, the Prepare α-D-arabinofuranosyladenine 5'-monophosphate.

Beispiel 3 3§5-Diäthyluracil-1-propyl-3'-phosphat 3,5-Diäthyl-9-(3'-hydroxypropyl)-uracil (2,2 g, ca. 0,01 Mol) wird bei ca. 0°C mit einem Gemisch von 2 ml POC13 und 20 ml Triäthyl phosphat versetzt und nach dem Verfahren von Beispiel 2 aufgearbeitet. Anstelle von äther wird Petroläther verwendet. Example 3 3§5-Diethyluracil-1-propyl-3'-phosphate 3,5-Diethyl-9- (3'-hydroxypropyl) -uracil (2.2 g, approx. 0.01 mol) is added at approx. 0 ° C with a mixture of 2 ml of POC13 and 20 ml Triethyl phosphate added and worked up according to the procedure of Example 2. Instead of ether, petroleum ether is used.

Die Ausbeute an gewünschtem Phosphatderivat beträgt 80 % (ermittelt durch DC). Die Ausbeute an Rohprodukt beträgt 1,8.The yield of the desired phosphate derivative is 80% (determined by DC). The yield of the crude product is 1.8.

Auf die gleiche Weise läßt sich auch das 3-Methyl-5-propyl-Ç-chlor-uracil-i-(2'-oxabutyl-4'-phosphat) der Formel aus dem entsprechenden 3-Methyl-5-propyl-6-chloruracil-1-(2'-oxabutan-4'-ol) herstellen.In the same way, 3-methyl-5-propyl-Ç-chloro-uracil-i- (2'-oxabutyl-4'-phosphate) of the formula from the corresponding 3-methyl-5-propyl-6-chloruracil-1- (2'-oxabutan-4'-ol).

Dem «-ADU-Monophosphat kommt eine ungewöhnliche Eigenschaft zu, die vom Fachmann nicht vorhersehbar war. Es ist nämlich in der Lage, die Vermehrung von Herpes-Simplex-Viren zu hemmen. In Gewebekulturen von Hühnerembryofibroblasten hemmt «-ADU-MP in einer Konzentration von 10 pg/ml deutlich die Virusvermehrung Unter qleicher Bedingung ist α-ÄDU selbst ohne Wirkung.The «-ADU monophosphate has an unusual property that could not have been foreseen by the specialist. Namely, it is capable of reproduction to inhibit herpes simplex viruses. In tissue cultures of chicken embryo fibroblasts inhibits «-ADU-MP in a concentration of 10 pg / ml clearly the Virus multiplication Under the same conditions, α-ADU itself has no effect.

Das erfindungsgemäß hergestellte t-ADU-Monophosphat besitzt den überraschenden Vorteil, daß es virostatisch wirkt, ohne in die DNS eingebaut zu werden. Es stellt somit keine genetische Gefahr dar.The t-ADU monophosphate produced according to the invention has the surprising The advantage is that it has a virostatic effect without being incorporated into the DNA. It puts therefore do not pose a genetic risk.

Claims (3)

P a t e n t a n s p r ü c h e Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I: worin Base" für einen monocyclischen oder bicyclisch kondensierten heterocyclischen Rest mit 5 bis 10 Ringatomen, von denen bis zu 5 Atome Stickstoffatome sein können und der 1 bis 2 H2N-, HO-, HO-CH2- und/oder C1-C6-AlkYlsubsti; tuenten und/oder 1 bis 2 O=Atome tragen kann, einen Pyrimidin- oder Purinrest, der die vorbezeichneten Substituenten traqen kann, steht, und R für eine gerade oder verzweigte Alkylenkette mit 2 bis 6 6 C-Atomen, die gegebenenfalls ein Äther-Sauerstoffatom in der der Kette enthalten kann, oder für einen Desoxyribosyl-, Ribosyl- oder Arabinosylrest steht, dadurch gekennzeichnet, daß man eine Verbindung der allgemeinen Formel II: Base - R - OH (11) worin Base und R die obengenannten Bedeutungen haben, mit Phosphoroxychlorid in einem geeigneten Lösungsmittel phosphoryliert und das dabei erhaltene Phosphat der Formel 1 durch Ausfällung mit äther, Petroläther oder einem Gemisch dieser Lösungsmittel aus dem Reaktionsgemisch abtrennt.P atent claims process for the preparation of compounds of the general formula I: wherein base "represents a monocyclic or bicyclic condensed heterocyclic radical with 5 to 10 ring atoms, of which up to 5 atoms can be nitrogen atoms and of 1 to 2 H2N, HO, HO-CH2- and / or C1-C6-AlkYlsubsti; tuenten and / or 1 to 2 O = atoms can carry a pyrimidine or purine residue, which can carry the aforementioned substituents, and R is a straight or branched alkylene chain with 2 to 6 6 carbon atoms, which may optionally be an ether Oxygen atom in which the chain can contain, or represents a deoxyribosyl, ribosyl or arabinosyl radical, characterized in that a compound of the general formula II: Base - R - OH (11) in which base and R have the meanings given above, with Phosphorylated phosphorus oxychloride in a suitable solvent and the resulting phosphate of formula 1 is separated from the reaction mixture by precipitation with ether, petroleum ether or a mixture of these solvents. 2. Uracilverbindungen der allgemeinen Formel III: worin R1 einen verzweigten oder geradkettigen Nledrigalkylrest mit 2 bis 6 C-Atomen darstellt; sowie der allgemeinen Formel IV: worin R2 und R3 für gleiche oder verschiedene Niedrigalkylreste mit 7 bis 4 C-Atomen stehen, X ein Wasserstoff- oder Chloratom bedeutet; und R die in Anx spruch 1 genannten Bedeutungen hat.2. Uracil compounds of the general formula III: wherein R1 is a branched or straight-chain lower alkyl radical having 2 to 6 carbon atoms; as well as the general formula IV: in which R2 and R3 are identical or different lower alkyl radicals having 7 to 4 carbon atoms, X is a hydrogen or chlorine atom; and R has the meanings given in claim 1 Anx. 3. Arzneimittel enthaltend mindestens eine Verbindung gemäß Anspruch 2 in einem üblichen pharmazeutisch verträglichen Träger und/oder Formul ierungsmittel3. Medicaments containing at least one compound according to claim 2 in a customary pharmaceutically acceptable carrier and / or formulation agent
DE19792909709 1979-03-12 1979-03-12 Nucleotide derivs. of purine, pyrimidine or (dihydro)pyridone base - having antiviral activity against resistant herpes virus strains Withdrawn DE2909709A1 (en)

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DE19792909709 DE2909709A1 (en) 1979-03-12 1979-03-12 Nucleotide derivs. of purine, pyrimidine or (dihydro)pyridone base - having antiviral activity against resistant herpes virus strains
EP80101241A EP0015584A3 (en) 1979-03-12 1980-03-11 Nucleotides, methods for their preparation and medicaments
JP3147480A JPS55127397A (en) 1979-03-12 1980-03-12 Novel nucleotide*its manufacture and drug

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CS264222B1 (en) * 1986-07-18 1989-06-13 Holy Antonin N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them

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