DE3010399A1 - Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. - Google Patents
Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs.Info
- Publication number
- DE3010399A1 DE3010399A1 DE19803010399 DE3010399A DE3010399A1 DE 3010399 A1 DE3010399 A1 DE 3010399A1 DE 19803010399 DE19803010399 DE 19803010399 DE 3010399 A DE3010399 A DE 3010399A DE 3010399 A1 DE3010399 A1 DE 3010399A1
- Authority
- DE
- Germany
- Prior art keywords
- haloalkyl
- derivs
- pyrimidine nucleoside
- group
- cytostatic
- 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.)
- Withdrawn
Links
Classifications
-
- 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
Abstract
Description
Verwenduno von 5-Haloalkyl-pyrimidinnukleosi-Use of 5-haloalkyl-pyrimidine nucleosi-
den als Virostatika und Cytostatika 5-Haloalkyldesoxyuridine, z.B. 5-Trifluormethyl desoxyuridin und 5-Bromvinyldesoxyuridin stellen virostatische insbesondere bei Herpes-Viren wirksame Substanzen dar. Deren Anwendung ist jedoch mit Nachteilen behaftet, denn die Herpes-Viren entwickeln häufig Resistenzen gegenüber diesen Substanzen. Auch die an sich bekannte cytostatische Wirksamkeit von Trifluorthymidin ist mit Nachteilen verbunden, die sich aus dem ungünstigen pharmokokinetischen Verhalten dieser Substanz ableiten.as antivirals and cytostatics 5-haloalkyldeoxyuridines, e.g., 5-trifluoromethyl deoxyuridine and 5-bromovinyl deoxyuridine are virostatic in particular in the case of herpes viruses are effective substances. However, their application is fraught with disadvantages, because the herpes viruses often develop resistance to it these substances. Also the known cytostatic effectiveness of trifluorothymidine is associated with disadvantages arising from the unfavorable pharmocokinetic behavior derive from this substance.
Oberraschenderweise wurde nun gefunden, daß die erfindungsgemäßen 5-Haloalkyl-pyrimidinnukleoside gegenüber den bekannten Substanzen wesentliche Vorteile aufweisen, da sie einerseits gegenüber resistenten Herpes-Viren wirksam sind und andererseits ein günstigeres pharmakokinetisches Verhalten aufweisen.Surprisingly, it has now been found that the invention 5-Haloalkyl-pyrimidine nucleosides have significant advantages over the known substances have, since they are effective on the one hand against resistant herpes viruses and on the other hand have a more favorable pharmacokinetic behavior.
Die Erfindung betrifft somit 5-Haloalkylpyrimidinnukleoside der allgemeinen Formel I: worin: R = einen Haloalkylrest mit 1-6 C-Atomen; x = H oder OH; wobei R1 = C1-C6-Alkyl, gerade oder verzweigt, beispielsweise Methyl, Athyl, Propyl, Butyl, Isobutyl, Pentyl oder Hexyl, insbesondere äthyl, Isopropyl oder Isobutyl bedeutet; wobei R2 = -NH2, -COOH, n = 1 - 4, wobei n = 1-4 wobei Hal r F oder Cl, worin n = 1 bis 4 ist und A für ein Pyrimidinnukleosid der Formel: steht, in der R und X die oben genannten Bedeutungen haben, bedeuten, wobei die y-Reste statt mit der '-OH-Gruppe gewünschtenfalls mit der OH-Gruppe in 3'-Siellung verestert sein können, bei der Bekämpfung von malignen und viralen Erkrankungen.The invention thus relates to 5-haloalkylpyrimidine nucleosides of the general formula I: wherein: R = a haloalkyl radical with 1-6 carbon atoms; x = H or OH; where R1 = C1-C6-alkyl, straight or branched, for example methyl, ethyl, propyl, butyl, isobutyl, pentyl or hexyl, in particular ethyl, isopropyl or isobutyl; where R2 = -NH2, -COOH, n = 1 - 4, where n = 1-4 where Hal r F or Cl, where n = 1 to 4 and A is a pyrimidine nucleoside of the formula: in which R and X have the meanings given above, where the y radicals instead of the '-OH group, if desired, can be esterified with the OH group in 3'-Siellung, in the fight against malignant and viral Diseases.
Beispiele für geeignete Reste R sind der Trifluormethyl-, Bromvinyl-, Chlorvinyl-, tlodvinyl-, (einschließlich Struktur- und stereoisomere Halovinylreste), Trifluoräthyl-, Trifluorpropyl-, Trifluorbutyl-, Trifluorpentyl -, Trifluorhexyl-, Fluorpropenyl-, Fluorbutenyl-, Fluorpentenyl-, Fluorhexenyl-, Chlor- oder Brompropenyl-, Chlor- oder Brombutenyl-, Chlor- oder Brompentenyl-, Chlor- oder Bromhexenylrest. Die vorbezeichneten Haloalkylreste können geradkettig oder verzweigt sein.Examples of suitable radicals R are trifluoromethyl, bromovinyl, Chlorovinyl, tlodvinyl, (including structural and stereoisomeric halovinyl residues), Trifluoroethyl, trifluoropropyl, trifluorobutyl, trifluoropentyl, trifluorohexyl, Fluoropropenyl, fluorobutenyl, fluoropentenyl, fluorohexenyl, chloro or bromopropenyl, Chlorine or bromobutenyl, chlorine or bromopentenyl, chlorine or bromhexenyl radical. The abovementioned haloalkyl radicals can be straight-chain or branched.
Die erfindungsgemäß verwendeten Verbindungen können ausgehend von einem Nukleosid der allgemeinen Formel II: worin R die oben genannten Bedeutungen besitzt und R3 für H oder eine UblicheSchutzgruppe, insbesondere für den Acetyl- oder den Propionylrest steht, hergestellt werden, indem man die oben bezeichnete Verbindung der Formel II mit einem funktionellen Carbonylderivat, das sich von einem der oben definierten Reste der Formel Y ableitet, ins besondere einem Halogencarbonylderivat der Formel Y-C1, in einem basischen Milieu zwischen etwa -10 und +100°C umsetzt.The compounds used according to the invention can, starting from a nucleoside of the general formula II: in which R has the meanings given above and R3 represents H or a customary protective group, in particular the acetyl or propionyl radical, can be prepared by combining the above-identified compound of the formula II with a functional carbonyl derivative which is derived from one of the radicals defined above of the formula Y, in particular a halogenocarbonyl derivative of the formula Y-C1, in a basic medium between about -10 and + 100 ° C.
Vorzugsweise arbeitet man bei einer Temperatur zwischen etwa 0°C und Raumtemperatur.Preferably one works at a temperature between about 0 ° C and Room temperature.
Die Nukleoside der allgemeinen Formel II sind entweder bekannt oder können in an sich bekannter Weise hergestellt werden.The nucleosides of the general formula II are either known or can be prepared in a manner known per se.
Als funktionelles Carbonylderivat kann auch ein üblicher leicht, umesterbarer Ester verwendet werden.The functional carbonyl derivative can also be a conventional, easily transesterified Esters can be used.
Die erfindungsgemäßen Arzneimittel sind dadurch gekennzeichnet, daß sie mindestens eine Verbindung der allgemeinen Formel I in einem üblichen pharmazeutischen Träger, sowie gegebenenfalls anderer Zusätze enthalten.The medicaments according to the invention are characterized in that they at least one compound of the general formula I in a conventional pharmaceutical Contain carrier, as well as possibly other additives.
Die Anwendung der erfindungsgemäßen Substanzen kann oral oder parenteral in Verbindung mit einem üblichen, pharmazeutisch verträglichen Verdünnungsmittel oder Träger erfolgen.The substances according to the invention can be used orally or parenterally in conjunction with a conventional, pharmaceutically acceptable diluent or carrier.
Ausführungsbeispiel 5-Trifluormethyl-2'-desoxyuridin-5'-0-pivaloat Eine Lösung von 5-Trifluormethyl-2'-desoxyuridin (29,6 g; 0,1 Mol) in 150 ml trockenem Pyridin wird unter Rühren und Kühlen im Eisbad zu einer Lösung von 12 g (0,1 Mol) Pivaloylchlorid in 80 ml Pyridin langsam zugetropft. Man rührt die Reaktionslösung bei Zimmertemperatur etwa 4 Stunden lang, engt dann das Gemisch im Vakuum ein, nimmt den Rückstand in Methylenchlorid auf und extrahiert die Lösung zuerst mit 1 %-iger Schwefelsäure und anschließend mit 5 %-iger wäßriger Natriumbicarbonatlösung. Die Methylenchloridlösung wird über Natriumsulfat getrocknet und anschließend eingeengt. Der Rückstand wird an einer Kieselgelsäule unter Verwendung von Chloroform/Methanol (98/2) gereinigt. Man sammelt die dünnschichthomogenen Fraktionen, engt ein und erhält das gewünschte Produkt in reiner Form, Ausbeute 12,5 n; Fp. = 15700.Exemplary embodiment 5-trifluoromethyl-2'-deoxyuridine-5'-0-pivaloate A solution of 5-trifluoromethyl-2'-deoxyuridine (29.6 g; 0.1 mol) in 150 ml of dry Pyridine is stirred and cooled in an ice bath to a solution of 12 g (0.1 mol) Pivaloyl chloride in 80 ml of pyridine was slowly added dropwise. The reaction solution is stirred at room temperature for about 4 hours, then the mixture is concentrated in vacuo, takes the residue in methylene chloride and the solution extracted first with 1% Sulfuric acid and then with 5% aqueous sodium bicarbonate solution. the Methylene chloride solution is dried over sodium sulfate and then concentrated. The residue is precipitated on a silica gel column using chloroform / methanol (98/2) cleaned. The thin-layer homogeneous fractions are collected, concentrated and receives the desired product in pure form, yield 12.5 n; M.p. = 15700.
Auf gleiche Weise lassen sich die anderen erfindungsgemäß verwendeten Produkte herstellen.The others used in the present invention can be used in the same way Manufacture products.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19803010399 DE3010399A1 (en) | 1980-03-18 | 1980-03-18 | Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19803010399 DE3010399A1 (en) | 1980-03-18 | 1980-03-18 | Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. |
Publications (1)
Publication Number | Publication Date |
---|---|
DE3010399A1 true DE3010399A1 (en) | 1981-09-24 |
Family
ID=6097575
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19803010399 Withdrawn DE3010399A1 (en) | 1980-03-18 | 1980-03-18 | Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE3010399A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0056265A2 (en) * | 1981-01-09 | 1982-07-21 | Dr. Thilo & Co. GmbH | Pyrimidinenucleosides esterified in position 5' having antiviral activity, method for their preparation and medicinal compositions containing them |
EP0080305A1 (en) * | 1981-11-19 | 1983-06-01 | Beecham Group Plc | Antiviral 2'-deoxyuridines, their preparation and use |
EP0082668A1 (en) * | 1981-12-18 | 1983-06-29 | Beecham Group Plc | 5-(2-Halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in treating viral infections |
EP0095292A1 (en) * | 1982-05-22 | 1983-11-30 | Beecham Group Plc | 5-(2-halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in treating viral infections" |
EP0095294A1 (en) * | 1982-05-22 | 1983-11-30 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
EP0097039A1 (en) * | 1982-06-16 | 1983-12-28 | Beecham Group Plc | 5-(E-2-halovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in treating viral infections |
FR2531962A1 (en) * | 1982-08-17 | 1984-02-24 | Sandoz Sa | NOVEL DERIVATIVES OF DESOXYURIDINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
EP0104857A1 (en) * | 1982-09-28 | 1984-04-04 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
EP0604409A1 (en) * | 1990-01-11 | 1994-07-06 | Isis Pharmaceuticals, Inc. | Compositions and methods for detecting and modulating rna activity and gene expression |
US5587469A (en) * | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides containing N-2 substituted purines |
US6262241B1 (en) * | 1990-08-13 | 2001-07-17 | Isis Pharmaceuticals, Inc. | Compound for detecting and modulating RNA activity and gene expression |
-
1980
- 1980-03-18 DE DE19803010399 patent/DE3010399A1/en not_active Withdrawn
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0056265A2 (en) * | 1981-01-09 | 1982-07-21 | Dr. Thilo & Co. GmbH | Pyrimidinenucleosides esterified in position 5' having antiviral activity, method for their preparation and medicinal compositions containing them |
EP0056265A3 (en) * | 1981-01-09 | 1982-09-01 | Dr. Thilo & Co. Gmbh | Pyrimidinenucleosides esterified in position 5' having antiviral activity and medicinal compositions containing them |
EP0080305A1 (en) * | 1981-11-19 | 1983-06-01 | Beecham Group Plc | Antiviral 2'-deoxyuridines, their preparation and use |
EP0082668A1 (en) * | 1981-12-18 | 1983-06-29 | Beecham Group Plc | 5-(2-Halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in treating viral infections |
EP0095292A1 (en) * | 1982-05-22 | 1983-11-30 | Beecham Group Plc | 5-(2-halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in treating viral infections" |
EP0095294A1 (en) * | 1982-05-22 | 1983-11-30 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
EP0097039A1 (en) * | 1982-06-16 | 1983-12-28 | Beecham Group Plc | 5-(E-2-halovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use in treating viral infections |
FR2531962A1 (en) * | 1982-08-17 | 1984-02-24 | Sandoz Sa | NOVEL DERIVATIVES OF DESOXYURIDINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
WO1984000759A1 (en) * | 1982-08-17 | 1984-03-01 | Sandoz Ag | Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals |
EP0104857A1 (en) * | 1982-09-28 | 1984-04-04 | Beecham Group Plc | Deoxyuridine compounds, methods for preparing them and their use in medicine |
EP0604409A1 (en) * | 1990-01-11 | 1994-07-06 | Isis Pharmaceuticals, Inc. | Compositions and methods for detecting and modulating rna activity and gene expression |
EP0604409A4 (en) * | 1990-01-11 | 1996-06-12 | Isis Pharmaceuticals Inc | Compositions and methods for detecting and modulating rna activity and gene expression. |
US5587469A (en) * | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides containing N-2 substituted purines |
US5808027A (en) * | 1990-01-11 | 1998-09-15 | Isis Pharmaceuticals, Inc. | N-2 substituted purines in oligonucleotides |
US6166199A (en) * | 1990-01-11 | 2000-12-26 | Isis Pharmaceuticals, Inc | N-2 substituted purines |
US6262241B1 (en) * | 1990-08-13 | 2001-07-17 | Isis Pharmaceuticals, Inc. | Compound for detecting and modulating RNA activity and gene expression |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AT390000B (en) | USE OF 3'-AZIDO-3'-DESOXYTHYMIDINE OR A PHARMACEUTICAL ACCEPTABLE DERIVATIVES THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS | |
EP0538194B1 (en) | Bicyclic nucleosides, oligonucleotides, their method of preparation and intermediates therein | |
EP0056265B1 (en) | Pyrimidinenucleosides esterified in position 5' having antiviral activity, method for their preparation and medicinal compositions containing them | |
CH628897A5 (en) | Method for producing new substituted purines. | |
DE60101223T2 (en) | ANTIVIRAL PYRIMIDINE NUCLEOSIDE DERIVATIVES | |
DE4207363A1 (en) | ANTIVIRAL NUCLEOSIDE ANALOGS, THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE | |
DD297650A5 (en) | METHOD FOR PRODUCING FLUOR-SUBSTITUTED PURIN NUCLEOSIDES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
EP0316704A2 (en) | Fluorocytidine derivatives, their preparation and medical preparations containing them | |
EP0545966A1 (en) | New phospholipid derivatives of nucleosides, their preparation and their use as antiviral drugs. | |
EP0003229A1 (en) | Method for the preparation of nucleosides | |
DE3010399A1 (en) | Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. | |
CH676712A5 (en) | ||
EP0355031A2 (en) | Substituted pyrimidine nucleosides, process for their preparation and pharmaceutical compounds containing them | |
DE3390162T1 (en) | Deoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals | |
DE60204859T2 (en) | Process for the preparation of 2'-halo-beta-L-arabino-furanosylnucleosides | |
WO1996025421A1 (en) | Specific lipid conjugates of nucleoside diphosphates and their use as drugs | |
EP0015584A2 (en) | Nucleotides, methods for their preparation and medicaments | |
WO2009129798A2 (en) | Diphosphate and triphosphate prodrugs, in particular nucleoside diphosphate and triphosphate prodrugs | |
EP1224198B1 (en) | Nucleoside derivatives with photolabile protecting groups | |
DD251984A5 (en) | PROCESS FOR THE PREPARATION OF 3'-AZIDONUCLEOSIDES AND PHARMACEUTICALLY CONFIDENT DERIVATIVES THEREOF | |
EP0507188A1 (en) | Substituted 2',3'-dideoxy-5-trifluoromethyluridines, method of their preparation and their use in medicaments | |
DE3010397A1 (en) | USE OF 5-ALKYL-PYRIMIDINE NUCLEOSIDES AS A CYTOSTATIKA | |
JP2665527B2 (en) | 2'-deoxy-2'-methylidenepyrimidine nucleotide compounds | |
DE2807588A1 (en) | Antiviral 2'-deoxy-ribofuranoside nucleoside derivs. - prepd. by esterifying 2'-deoxy-uridine derivs. with 1-adamantane-carboxylic acid | |
DE1695297C3 (en) | 5-Fluoro-1- (2-tetrahydrofuryl) -uracil and its alkali metal salts, processes for their preparation and agents containing them |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
8141 | Disposal/no request for examination |