WO1984000759A1 - Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals - Google Patents

Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals Download PDF

Info

Publication number
WO1984000759A1
WO1984000759A1 PCT/EP1983/000219 EP8300219W WO8400759A1 WO 1984000759 A1 WO1984000759 A1 WO 1984000759A1 EP 8300219 W EP8300219 W EP 8300219W WO 8400759 A1 WO8400759 A1 WO 8400759A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acid addition
addition salt
formula
free form
Prior art date
Application number
PCT/EP1983/000219
Other languages
English (en)
French (fr)
Inventor
Herfried Griengl
Erich Wanek
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Priority to AT904183A priority Critical patent/ATA904183A/de
Publication of WO1984000759A1 publication Critical patent/WO1984000759A1/de

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • Desoxyuridine derivatives processes for their preparation and their use as pharmaceuticals
  • the present invention concerns desoxyuridine derivatives, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals in particular as viricides in particular against herpes viruses.
  • R 1 and R 2 represent independently hydrogen or tower alkyl
  • R 3 represents halogen, CHF 2 or CF 3 ,
  • R 4 represents hydrogen, hydroxy or fluorine
  • X represents oxygen or imino, and n is 0 or 1, whereby the sugar radical is ⁇ - or ß-glycosically bound to the pyrimidine ring; in free form or acid addition salt form.
  • the compounds of the invention can be prepared according to the invention a) by reacting a compound of formula II
  • R 3 group whereby in the formulas Ia, II and III, R 1 , R 2 , R 3 ,
  • R 4 , X and n are as defined above, R 5 represents halogen or acyloxy,
  • R 3 ' represents hydroxy in free or protected form and any hydroxy group present in the sugar radical may be protected; and when requi red removing any protecting group from the compound thus obtained; and recovering the compound thus obtained in free form or in aci d additi on sal t form.
  • Process a) can be carried out for example by converti ng a compound of formula II in conventional manner into i ts trimethylsilyl derivative and reacting this with a compound of formula III whose hydroxy groups are protected in a sol vent eg a halogenated hydrocarbon or acetoni trile.
  • a compound of formula Ia in unprotected or protected form can be dissolved in a solvent inert under the reaction conditions eg a Tower alkyl carboxylic acid amide such as di methylformamide.
  • R 3 'to halogen can be carried out either with free or with protected OH-groups in the sugar moiety.
  • R 3 represents halogen
  • the reaction can be carried out using a conventional halogenation method eg employing carbon tetrachloride or bromosuccinimide.
  • R 3 represents CHF 2 or CF 3
  • the reaction can be carried out using conventional fluorination methods eg from a compound of formula Ia after oxidation to an aldehyde with a dialkylsulfurtrifluoride or after oxidation to a carboxylic acid, with a sulfur tetrafluoride.
  • protecting groups are those conventionally employed in reactions of this nature such as p-toluyl, benzyl, p-nitrobenzoyl, trimethylsilyl. These can be introduced and removed using conventional procedures.
  • Salt forms can be prepared in conventional manner from free forms and vice versa.
  • the compounds of formula I and Ia can be in ⁇ - or ⁇ -configuration with respect to bonding of the sugar radical.
  • the compound of formula I is shown in ß-form.
  • the pyrimidine radical in the compounds of formula I and Ia can exist in tautorneric forms such as
  • the invention is intended to cover all tautorneric forms of the compounds.
  • the compounds of formula I and Ia can also exist in the form of optical isomers or mixtures which isomers can be separated in conven tional manner.
  • the invention is intended to cover isomer! c forms and mixtures thereof, whereby the compounds are present in the latter form unless otherwise mentioned.
  • Lower alkyl groups contain 1 to 4 preferably 1 or 2 carbon atoras.
  • the starting materials of formula Ia are also new and form part of the invention. They can be prepared by reacting a compound of formula II a
  • R 1 , R 2 , R 3 '.X and n are as defined above analogously to process a) with a compound of formula III
  • the compounds of formula II, Ila and III are either known or can be prepared analogously to known methods eg as illustrated hereinafter in the examples.
  • End products and intermediates can be isolated and purified in conventional manner.
  • the compounds of formula I exhibit chemotherapeutic, in particular anti-viral agents as indicated in particular by their effect against Herpes viruses which can be demonstrated in vitro and in vivo, for example by the reduction of cytopathogenic effects (CPE) of various viruses eg Herpes simplex I and II in vitro from concentration of approx. 0.003 ug / ml to approx. 300 ⁇ g / ml and in vivo in tests carried out in mice and guinea pig using systemic, topical and encephalitis-infection models (of. HE Renis et al. J. Med. Chem. 16 (7) 754 [1973]).
  • CPE cytopathogenic effects
  • the compounds are therefore useful as chemo therapeutics in particular as agents for combating herpes diseases and infections.
  • a suitable daily dosage is from about 200 to 1200 mg suitably given in divided doses two to four times a day containing about 50 to 600 mg of the compounds or in retard form.
  • Compounds can be employed in free form or, when the compound is sufficiently basic, also in the form of a chemotherapeutically acceptable acid addition salt thereof, especially when X is imino, which forms have the same Order of activity as the free forms.
  • Suitable salt forms include hydrochloride, hydrogen fumarate and naphthalene-1,5-disulfonate.
  • Compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and administered in such forms as tablets or capsules or parenterally. Such compositions also form part of the invention.
  • the invention therefore also concerns a method of combating herpes diseases or infections comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof and such compounds for use as chemotherapeutic agents, in particular as anti-viral agents especially against herpes viruses.
  • R 1 , R 2 a) H b) tower alkyl preferably methyl or ethyl
  • R 4 a) H, OH, F b) H, OH, especially H and combinations of these.
  • Examples of particular compound groups are thus those of formula I a) wherein R 1 and R 2 represent hydrogen, R 3 represents halogen, R 4 represents hydrogen, hydroxy or fluorine, X represents oxygen or imino and n is 1; b) wherein R 1 and R 2 are as defined above, R 3 represents halogen, X represents oxygen, R 4 represents hydrogen, hydroxy or fluorine and n is 1.
  • a particularly preferred individual compound is 1- (2-deoxy- ⁇ -D-erythro-pentofuranosyl) -5- (2-chloroethyl) - (1H, 3H) -pyrimidine-2,4-dione in free form or acid addition salt shape.
  • Example 1 1- (2-deoxy- ⁇ -D-erythro-pentofuranosyl) -5 (2-chloroethyl) -
  • Example 8 1- ( ⁇ -D-arabinofuranosyl) -5- (2-bromoethyl) - (1H, 3H) - pyrimidine-2,4-dione
  • Example 10 4-amino-5- (2-chloroethyl) -1- (2-deoxy- ⁇ -D-erythropento furanosyl) -1H-pyrimidine-2-one 3.12 g of a 4-amino-5- (2- hydroxyethyl) -1H-pyrimidine-2-one are silated analogously to Example 6 and reacted with 7.76 g of 2-deoxy-3,5-di-Op-toluoyl-D-erythro-pentofuranosyl-chloride.
  • the required starting materials may be prepared for example as follows:
  • the methanol ic residue of the hydrogenation is neutral ised with ion exchanger Merck II (strongly basic), filtered over active carbon, concentrated and the crystalline residue recrystallized from water.
  • the title product is obtained as colorless needles mp212-15 °.
  • KH-1 ' ⁇ , KH-1' ß proton on C-1 of deoxyribose moiety, the bondi ng properties of whi ch al low assi gnment of anomers.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Description

Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals
The present invention concerns desoxyuridine derivatives, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals in particular as viricides in particular against Herpes viruses.
More particularly the invention concerns compounds of formula I
Figure imgf000003_0001
wherein
R1 and R2 represent independently hydrogen or Tower alkyl,
R3 represents halogen, CHF2 or CF3,
R4 represents hydrogen, hydroxy or fluorine,
X represents oxygen or imino, and n is 0 or 1, whereby the sugar radical is α- or ß-glycosically bound to the pyrimidine ring; in free form or acid addition salt form.
The compounds of the invention can be prepared according to the invention a) by reacting a compound of formula II
Figure imgf000004_0001
with a compound of formula III
or
Figure imgf000004_0002
b) by replacing the group R3' in the hydroxalkyl side chain of a compound of formula Ia
Figure imgf000004_0003
by an R3 group whereby in the formulae Ia, I I and III , R1 , R2 , R3,
R4, X and n are as defined above , R5 represents halogen or acyloxy ,
R3' represents hydroxy in free or protected form and any hydroxy group present in the sugar radical may be protected; and when requi red removing any protecting group from the compound thus obtained; and recovering the compound thus obtained in free form or in aci d additi on sal t form.
Process a) can be carried out for example by converti ng a compound of formula I I in conventional manner into i ts trimethylsi lyl derivative and reacting this with a compound of formula III whose hydroxy groups are protected in a sol vent e. g. a halogenated hydrocarbon or acetoni trile. According to process b) a compound of formula Ia in unprotected or protected form can be dissolved in a solvent inert under the reaction conditions e.g. a Tower alkyl carboxylic acid amide such as di methylformamide.
The conversion of R3' to halogen can be carried out either with free or with protected OH-groups in the sugar moiety.
When R3 represents halogen the reaction can be carried out using a conventional halogenation method e.g. employing carbon tetrachloride or bromosuccinimide. When R3 represents CHF2 or CF3 the reaction can be carried out using conventional fluorination methods e.g. from a compound of formula Ia after oxidation to an aldehyde with a dialkylsulfurtrifluoride or after oxidation to a carboxylic acid, with a sulphur tetrafluoride.
Examples of protecting groups are those conventionally employed in reactions of this nature such as p-toluyl, benzyl , p-nitrobenzoyl , trimethylsilyl. These can be introduced and removed using conventional procedures.
Salt forms can be prepared in conventional manner from free forms and vice versa. As stated above, the compounds of formula I and Ia can be in α- or β-configuration with respect to bonding of the sugar radical. Merely for convenience the compound of formula I is shown in ß-form.
The pyrimidine radical in the compounds of formula I and Ia can exist in tautorneric forms such as
Figure imgf000005_0001
The invention is intended to cover all tautorneric forms of the compounds.
The compounds of formula I and Ia can also exist in the form of optical isomers or mixtures which isomers can be separated in conven tional manner. The invention i.s intended to cover isomer! c forms and mixtures thereof, whereby the compounds are present in the latter form unless otherwise mentioned.
Lower alkyl groups contain 1 to 4 preferably 1 or 2 carbon atoras.
The starting materials of formula Ia are also new and form part of the invention. They can be prepared by reacting a compound of formula II a
Figure imgf000006_0001
wherein R1 , R2, R3'.X and n are as defined above analogously to process a) with a compound of formula III The compounds of formula II, Ila and III are either known or can be prepared analogously to known methods e.g. as illustrated hereinafter in the examples.
End products and intermediates can be isolated and purified in conventional manner. The compounds of formula I exhibit chemotherapeutic, in particular anti-viral agents as indicated in particular by their effect against Herpes viruses which can be demonstrated in vitro and in vivo, for example by the reduction of cytopathogenic effects (CPE) of various viruses e.g. Herpes simplex I and II in vitro from concentration of ca. 0.003 ug/ml to ca. 300μg/ml and in vivo in tests carried out in mice and guinea pig using systemic, topical and encephalitis-infection models(of. H.E. Renis et al. J. Med. Chem. 16(7) 754 [1973]). The compounds are therefore useful as chemo therapeutics in particular as agents for combating Herpes diseases and infections. For this use a suitable daily dosage is from about 200 to 1200 mg suitably given in divided doses two to four times a day containing about 50 to 600 mg of the compounds or in retard form.
Compounds can be employed in free form or, when the compound is sufficiently basic, also in the form of a chemotherapeutically acceptable acid addition salt thereof, especially when X is imino, which forms have the same Order of activity as the free forms. Suitable salt forms include hydrochloride, hydrogen fumarate and naphthalene-1 ,5-disulfonate. Compounds may be admixed with conventional chemotherapeutically acceptable diluents and carriers, and administered in such forms as tablets or capsules or parenterally. Such compositions also form part of the invention.
The invention therefore also concerns a method of combating herpes diseases or infections comprising administering to a subject in need of such treatment an effective amount of a compound of formula I or a chemotherapeutically acceptable acid addition salt thereof and such compounds for use as chemotherapeutic agents, in particular as anti-viral agents especially against herpes viruses.
Examples of particular substituent meanings are R1, R2 = a) H b) Tower alkyl preferably methyl or ethyl
R3 = a) halogen b) chlorine, bromine, iodine X = oxygen n = 1 R4 = a) H, OH, F b) H, OH, especially H and combinations of these.
Examples of particular compound groups are thus those of formula I a) wherein R1 and R2 represent hydrogen, R3 represents halogen, R4 represents hydrogen, hydroxy or fluorine, X represents oxygen or imino and n is 1; b) wherein R1 and R2 are as defined above, R3 represents halogen, X represents oxygen, R4 represents hydrogen, hydroxy or fluorine and n is 1.
A particularly preferred individual compound is 1-(2-desoxy-ß-D-erythro-pentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione in free form or acid addition salt form.
The following examples illustrate the invention whereby temperatures are given in degrees centi grade. Example 1 : 1-(2-desoxy-β-D-erythro-pentofuranosyl)-5 (2-chloroethyl)-
(1H,3H)-pyrimidine-2,4-dione (Process b):
200 mg of 1-(2-desoxy-ß-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione and 400 mg of triphenylphosphine are dissolved in 20 ml of abs. dimethylformamide reacted with 0.2 ml of carbon tetrachloride and 0.2 ml of abs. pyridine and left Standing for 1 hour at room temperature. The solvent is then removed in vacuum with addition of 1-butanol, chromatographed on a silica gel column (chloroform/methanol = 9/1) to obtain the title compound as colourless crystals m.p. 166-67° (from abs. methanol).
Example 2: 1-(2-desoxy-α-D-erythrg-pentofuranosyl)-5-(2-chloroethyl)- (1H,3H)-pyrimidine-2,4-digne (Process b):
1.5 g of 1-(2-desoxy)-3,5-di-O-p-toluyl-α-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl )-(1H,3H)-pyrimidine-2,4-dione are dissolved in 20 ml of abs. dimethylformamide, reacted with 2.3 g of triphenylphosphine, 1 ml of abs. carbon tetrachloride and 0.5 ml of abs. pyridine and maintained for 10 minutes at 70°. The solvent is then removed at 0.1 bar and the remaining syrup chromatographed on silica-gel ( toluene/ethylace täte = 2/1). 0.5 g of 1-(2-desoxy-3,5-di-O-p-toluyl-α-D-efythro-pentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione are obtained as colourless crystals (m.p. 142-144°). To remove the p-toluyl groups the compound is dissolved in 10 ml of abs. ethanol and reacted with 1.5 ml of 1N-sodium ethanolate solution in ethanol, left for 15 minutes at room temperature and reacted with 1.5 ml of 1N acetic acid. The solvent is removed in vacuum and the remaining syrup treated with diethylether/water. Chromatography of the aqueous phase on silica-gel (chloroform/methane = 9/1) yields the title compound as colourless crystals m.p. 140-142° (ethanol/chloroform). Example 3: 1-(2-desgxy-β-D-erythro-pentofuranosyl)-5-(2-bromoethyl- (1H,3H)-pyrimidine-2,4-dione (Process b):
1.14 g of 1-(2-desoxy-ß-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione are dissolved in 30 ml of abs. dimethylformamide, reacted with 2.3 g of triphenylphosphine and 1.2 g of N-bromosuccinimide and kept for 90 minutes at room temperature. The solvent is removed in vacuum and evaporation repeated following addition of n-butanol. A yellow syrup is obtained which, after crystallisation from ethanol/chloroform, yields the title compound as colourless crystals m.p. 161-163º.
Example 4: 1-(2-desgxγ-α-D-erythrg-pentofuranosyl)-5-(2-bromoethyl)- (1H,3H)-pyrimidine-2,4-digne (Prgcess b) :
380 mg of 1-(2-desoxy-α-D-erythro-pentofuranosyl)-5-(2-hydroxy-ethyl )-(1H,3H)-pyrimidine-2,4-dione are reacted analogously to Example 3 to yield the title product m.p. 131-133° (ethanol/chloroform),
Example 5: 1-(2-desoxy-β-D-erythro-pentofuranosyl)-5-(2-iodoethyl)- (1H,3H)-pyrimidine-2,4-dione (Prgcess b) :
550 mg of 1-(2-desoxy-ß-Drerythro-pentofuranosyl)-5-(2-hydroxyethyl )-(1H,3H)-pyrimidine-2,4-dione and 1.1 g of triphenylphosphine are dissolved in 25 ml of abs. dimethylformamide, reacted with
550 mg of N-bromosuccinimide and 3.3 g of tetrabutylammonium iodide and kept for 90 minutes at room temperature. The solvent is then removed,after addition of n-butanol, in vacuum and the residue chromatographed on silica-gel (chloroform/methanol = 9/1) to obtain the title compound m.p. 160-161º Example 6: 1-(2-desoxy-β-D-erythro-pentofuranosyl)-5-(2-chloroethyl)- (1H, 3H)-pyrimidine-2,4-dione (Process a):
480 mg of 5-(2-chloroethyl)-uracil are suspended in hexamethyl disalazane, reacted with 0.3 ml of trimethylchlorosilane and refluxed for 3 hours. Volatile matter is then removed in vacuum and evaporation repeated twice after addition of abs. xylene. The remaining syrup is dissolved in 30 ml of abs. Chloroform and reacted at room temperature with 1.2 g of 3,5-di-O-p-toluyl-2-desoxy-D- erythro-pentofuranosyl-chloride and then with 0.5 ml of trifluoromethanesulfonic acid trimethylsilylester. The mixture is kept for 30 minutes at room temperature and then shaken with 1.5 ml of cold saturated aqueous KHCO3. Concentration of the organic phase in vacuum yields a syrup which is chromatographed on silica-gel (toluene/ethyl acetate = 4/1) to yield 1-(2-desoxy-3,5-di-O-p-toluyl-ß-D-erythro-pentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione (m.p. 167-169°). Removal of the p-toluyl groups is carried out analogously to Example 2 to yield 1-(2-desoxy-ß-D-erythropentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione as colourless crystals m.p. 165-166° (from water). Example 7: 1-(β-D-arabinofuranosyl)-5-(2-chlooroethyl)-(1H,3H)- pyrimidine-2,4-dione (Process b):
400 mg of 1-(ß-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione are dissolved in 10 ml of abs. dimethylformamide, reacted with 0.7 g of triphenylphosphine, 0.3 ml of carbon tetrachloride and 0.3 ml of pyridine and kept for 1.5 hours at room temperature. Following addition of 1-butanol the mixture is evaporated to dryness on a Rotavapor and the syrupy residue chromatographed on silica-gel (chloroform/methanol = 8/1). Concentration of the appropriate fractions gives the title compound as colourless crystals m.p. 182-183° (from ethanol). Example 8: 1-(β-D-arabinofuranosyl)-5-(2-bromoethyl)-(1H,3H)- pyrimidine-2,4-dione
320 mg of 1-(ß-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione are dissolved in 5 ml of abs. dimethylformamide, reacted with 650 mg of triphenylphosphine and 300 mg of N-bromosuccinimide and kept a room temperature for 1.5 hours. Following addition of 5 ml of 1-butanol the mixture is concentrated to dryness on a Rotavapor and the syrupy residue chromatographed on silica-gel (chloroform/methanol = 6/1). Concentration of the fractions yields the title compound as colourless crystals m.p. 166-167° (from acetone/chloroform).
Example 9: 1-(2-desoxy-2-fluoro-β-D-arabinofuranosyl)-5-(2-chloro ethyl)-(1H,3H)-pyrimidine-2,4-dione
200 mg of 1-(2-desoxy-2-fluoro-ß-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione are dissolved in 5 ml of abs. dimethylformamide and reacted with 300 mg of triphenylphosphine and 0.3 ml of a 1:1 mixture of abs. pyridine and carbon tetrachloride. The mixture is stirred for 4 hours at room temperature, 10 ml 1-butanol added and the mixture concentrated to dryness on an oil pump. The residue is chromatographed on silica-gel (chloroform/methanol = 9/1). Concentration of the fractions yields the title compound as a highly hygroscopic colourless powder.
Example 10: 4-amino-5-(2-chloroethyl)-1-(2-desoxy-β-D-erythropento furanosyl)-1H-pyrimidine-2-one 3.12 g of a 4-amino-5-(2-hydroxyethyl)-1H-pyrimidine-2-one are silated analogously to Example 6 and reacted with 7.76 g of 2-desoxy-3,5-di-O-p-toluoyl-D-erythro-pentofuranosyl-chloride. After shaking with 100 ml of saturated aqueous KHCO3 the chloroform is removed in vacuum and the residue chromatographed on silica-gel (chloroform/methanol = 9/1) to yield 4-amino-1-(2-desoxy-3,5-di-O-p-toluoyl-D-erythro-pentofuranosyl)- 5-(2-hydroxyethyl)-1H-pyrimidine-2-one. 1.4 g of this anomeric mixture are stirred in 20 ml of dimethylformamide with 1.4 g of triphenylphosphine, 0.6 ml of abs. carbon tetrachloride and 0.6 ml of abs. pyridine for 2 hours at room temperature. After addition of 10 ml of 1-butanol the solvents are removed in vacuum and the residue mixed with 20 ml of methanol and 5 ml of 1N methanolic sodium methanolate. On completion of reaction the mixture is neutralised with 1N acetic acid and evaporated in vacuum. Treatment of the residue with 30 ml of ethylacetate and 10 ml of methanol yields the title compound as colourless crystals m.p. 174° (from water).
The required starting materials may be prepared for example as follows:
A) 1-(2-desoxy-ß-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione (for examples 1, 3, 5): 10.5 g of 5-(2-hydroxyethyl)-uracil are suspended in 60 ml of hexamethyldisilazane, reacted with 3 ml of trimethylchlorosilane and refluxed for 2 hours. All volatile material is removed in vacuum and evaporation repeated twice after addition of abs. xylene. The remaining syrup is dissolved in 400 ml of abs. chloroform and reacted at room temperature with 26.2 g of 3,5-di-O-p-toluyl-2-desoxy-D-erythro-pentofuranosyl-chloride and then with 0.5 ml of trifluoromethane sulfonic acid trimethylsilylester. The mixture is kept at room temperature for 1 hour and shaken with 100 ml saturated aqueous KHCO3. Concentration of the organic phase in vacuum yields a yellow syrup which is crystallised to give 5-(2-hydroxyethyl )-3',5'-di-O-p-toluyl-ß-D-2'-desoxyuridine (m.p. 176-178°). Removal of the p-toluyl groups is carried out analogously to Example 2 to yield, after crystallisation from ethanol in a refrigerator, 1-(2-desoxy-ß-D.erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione as colourless crystals, m.p. 160-161°. B) 1-(2-desoxy-3,5-di-O-p-toluyl-α-Derythro-pentofuranosyl)-5-(2-hydroxyethyl-(1H,3H)-pyrimidine-2,4-dione (for Example 2):
Using 5-(2-hydroxyethyl)-uracil and 3,5-di-0-p-toluyl-2-desoxy-D-ribofuranosylchloride and proceeding analogously to A) there is obtained following fractional crystallisation from ethanol the title compound.
C) 1-(2-desoxy-α-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione (for Example 4):
Obtained after removal of tolyl groups analogously to Example 2 and chromatographed on silica-gel (chloroform/methanol = 3/1). Colourless oil.
D) 5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione (for example 6):
0.5 g of 5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione are dissolved in 20 ml of abs. dimethylformamide and 2.5 g of triphenylphosphine, 30 ml of carbon tetrachloride and 1 ml pyridine added. The solution is kept for 1.5 hours at 80°, concentrated and the oily residue taken up in chloroform/methanol (9/1) to yield the title compound as colourless crystals, m.p. 260-262° (from ethylacetate).
E) 1-(ß-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione (for examples 7 and 8)
5 g of 2,3,5-tri-O-benzyl-l-O-p-nitrobenzoyl-D-arabinose are dissolved in 80 ml of abs. dichloromethane, which had been saturated 1 hour previously at 0° with HCl. Stirring is carried out for 2 hours at 0° with passage of further HCl and the precipitated p-nitrobenzoic acid removed. The filtrate is concentrated to dryness and the oily residue left for a further 2 hours on a Rotavapor at 0.0013 bar. The residue is dissolved in abs. dichloromethane, reacted with a syrup containing hexamethylsilazane-free silated 5-(2-hydroxyethyl )-uracil [prepared from 2.93 g of 5-(2-hydroxyethyl )-uracil (analogously to A)] and shaken in the presence of 10 g molecular sieve (4 A°), for 2 days at room temperature. After filtration and washing of the molecular sieve the filtrate is shaken with cold saturated aqueous KHCO3, the aqueous phase washed once with dichloromethane and the combined organic phases concentrated on a Rotavapor to give a partially crystalline syrup. 1 g of PdCl2 is suspended in 150 ml of methanol and hydrogenated on a PARR-apparatus to Pd (H2, room temperature at 4 atmospheres, ca. 30 minutes). To this is added the above syrup dissolved in 100 ml of methanol and the mixture hydrogenated over night at 4 atmospheres with H2. A white crystalline precipitate is formed in the hydrogenation vessel , further product is in solution. The precipitate and the Pd are filtered off the product dissolved in water and filtered off from the Pd, the filtrate concentrated on a Rotavapor and the residue recrystallised from water. The methanol ic residue of the hydrogenation is neutral ised with ion-exchanger Merck II (strongly basic), filtered over active carbon, concentrated and the crystalline residue recrystallised from water. The title product is obtained as colourless needles m.p.212-15°.
F) 1-(2-desoxy-2-fluoro-ß-D-arbinofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine-2,4-dione (for example 9):
3.1 g of 5-(2-acetoxyethyl)-uracil are silated analogously to A) and after working-up reacted with 4 g of 3-O-acetyl-5-O-benzoyl-2-desoxy-2-fluoro-D-arabinofuranosylbromide in abs. dichloromethane. After 14 days the mixture is worked up by addition of a few ml of methanol, filtration, and column separati-on (chloroform/methanol =9/1). After removal af the protecting groups (of. Example 2) the title compound is obtained as colourless crystals, m.p. 177-178°. NMR-Spectra
KH = imprecisely assi gned proton in desoxyri bose moiety
KH-1 'α, KH-1 ' ß = proton on C-1 of desoxyribose moiety , the bondi ng properties of whi ch al low assi gnment of anomers .
NMR-Apparatus : Bruker WH-90 , 90 MHz.
Example Spectrum 2.10 (t, 2H, KH); 2.67 (t, 2H, CH2CH2CI, J = 7 Hz); 3.4-3.9 (m, 5H, CH2CH2Cl, KH); 4.1-4.4 (m, 1H, KH); 5.03 (t, 1H, J = 5.1 Hz, 5'-OH); 5.24 (d, 1H, J = 4.3 Hz, 3'-OH); 6.17 (t, 1H, J = 6.7 Hz, KH-1'ß); 7.83 (s, 1H, H-6); 11.4 (br, 1H, NH).
1.8-2.7 (m, 2H, KH); 2.66 (t, 2H, J = 7 Hz, CH2CH2Cl); 3.43 (d, 2H, KH); 3.69 (t, 2H, J = 7 Hz, CH2CH2Cl); 4.1-4.3 (m, 2H, KH); 4.82 (t, 1H, J = 5.7 Hz, 5'-OH); 5.30 (d, 1H, J =
3.1 Hz, 3'-OH); 6.10 (dubl.d, 1H, J = 7.4 Hz, KH-1'α); 7.85 (3, 1H, H-6); 10.9 (br, 1H, NH).
2.14 (t, 2H, KH); 2.79 (t, 2H, J = 7.9 Hz, CH2CH2Br); 3.5-4.0 (m, 5H, CH2CH2Br, KH); 4.29 (d, 1H, KH); 4.76 (br, 2H, 3'-OH,5'-OH); 6.20 (t, 1H, J = 6.7 Hz, KH-1'ß); 7.85 (s, 1H, H-6); 11,4 (s, 1H, NH).
1.7-2.5 (m, 2H, KH); 2.71 (t, 2H, J = 7 Hz, CH2CH2Br); 3.3- 3.5 (m, 2H, KH); 3.53 (t, 2H, J = 7 Hz, CH2CH2Br); 4.0-4.3 (m, 2H, KH); 4.80 (t, 1H, J -= 5.1 Hz, 5'-OH); 5.27 (d, 1H, J = 3.2 Hz, 3'-OH); 6.07 (dubl.d, 1H, J = 7.5 Hz, KH-1'α); 7.82 (3, 1H, H-6); 11.32 (s, 1H, NH).
2.06 (t, 2H, KH)-. 2.72 (t, 2H, J = 7 Hz, CH2CH2J); 3.4-3.9 (m, 5H, CH2CH2J, KH); 4.21 (br, 1H, KH); 4.99 (t, 1H, J =2.5 Hz. 5 '-OH); 5.20 (d, 1H, J = 4 Hz, 3'-OH); 6.13 (t, 1H, J = 6.5 Hz, KH-1'ß); 7.77 (s, 1H, H-6); 11.35 (s, 1H, NH). 2.66 (t, 2H, J = 7.2 Hz, CH2CH2Cl); 3.5-3.8 (m, 5H, CH2C! and KH); 3.85-4.1 (m, 2H, KH); 5.0 (t, 1H, J = 5.4 Hz, 5'-OH); 5.36 and 5.45 (je ld, J = 5 Hz, 2H, 3'-OH and 5'-OH); 6.02 (d, 1H, J = 5.4 Hz, KH-1'β); 7.67 (a, 1H, H-6); 11.32 (s, 1H, NH).
2.75 (t, 2H, J = 7.4 Hz, CH2CH2Br); 3.4-3.8 (m, 5H, CH2Br and KH); 3.85-4.1 (m, 2H, KH); 4.2-5.7 (br, 3H, 2'-OH,3'-OH, 5'-OH); 6.01 (d, 1H, J = 4.5 Hz, KH-1'ß); 7.66 (s, 1H, H-6); 11.32 (s, 1H, NH).
2.7 (t, 2H, J = 7 Hz, CH2CH2Cl); 3.5-4.25 (m, 7H, CH2Cl and KH); 4.25 (dt, 1H, H-3', JH-3'_F = 20,45 Hz, JH-H = 4 Hz); 5.05 (dt, 1H, H-2', JH-2,-F = 52.2 Hz, JH-H = 4 Hz); 6.1 (dd, 1H, H-1, JH-l'-F =15.3 Hz, JH-H = 4.1 Hz); 7.7 (s, 1H, H-6); 11.55 (s, 1H, NH).
2.0 (m, 2H, KH); 2.8 (t, 2H, J = 7 Hz, CH2CH2Cl); 3.5-3.9 (m, 5H, CH2Cl and KH); 4.2 (br s, 1H, KH); 5.0-5.2 (br s, 2H, 2 OH); 6.2 (t, 1H, J = 7 Hz, KH-1'ß); 7.3 (s, 2H, NH2); 7.8 (s, 1H, H-6).
2.1 (t, 2H, KH); 2.3 (t, 2H, CH2CH2OH); 3.3-3.7 (m, 4H, CH2CH2OH, KH); 3.7-3.85 (m, 1H, KH); 4.1-4.4 (m, 1H, KH); 4.54 (t, 1H, J = 5 Hz, CH2CH2OH); 5.00 (t, 1H, J = 5 Hz, 5--OH); 5.23 (d, 1H, J = 4.3 Hz, 3'-OH); 6.16 (t, 1H, J = 7 Hz, KH-1'ß); 7.68 (s, 1H, H-6); 11-11.5 (br, 1H, NH).
2.1-2.4 (m, 10H, toluyl-CH3, CH2CH2OH, KH); 3.32 (t, 2H, J = 8 Hz, CH2CH2OH); 4.3-4.7 (m, 3H, KH, CH2CH2OH); 5.02 (m, 1H, KH); 5.56 (d, 1H, KH); 6.23 (dubl.d, 1H, J = 5.5 Hz, KH-1'α); 7.28-7.40 (m, 4H, toluyl); 7.66 (s, 1H, H-6); 7.78-7.98 (m, 4H, toluyl); 11.32 (a, 1H, NH). 1.7-2.5 (m, 2H, KH); 2.31 (t, 2H, J = 7 Hz, CH2CH2OH); 3.3 (m, 2H, KH); 4.1 (m, 2H, KH); 4.5 (br s, 1H, OH); 4.8 (br d, 1H, OH); 5,27 (br t, 1H, OH); 6.08 (dd, 1H, KH-1'α); 7.71 (a, 1H, H-6); 11.0 (br a, 1H, NH).
2.71 (t, 2H, J = 8 Hz, CH2CH2CI); 3.70 (t, 2H, J = 8 Hz, CH2Cl); 7.16 (d, 1H, J = 7 Hz, H-6); 10.16 and 10.34 (2 br s, each 1H, 2NH) .
2.36 (t, J = 6.3 Hz, 2H, CH2CH2OH); 3.4-3.8 (m, 5H, CH2CH2OH, KH); 3.85-4.1 (m, 2H, KH); 4.46 (t, J = 5.4 Hz, 1H, CH2CH2OH); 5.00 (t, 3 = 5.4 Hz, 1H, 5' -OH); 5.37 and 5.45 (2d, J = 5 Hz, 2H, 2'-OH, 3'-OH); 6.01 (d, J = 4.5 Hz, 1H, KH-1'ß); 7.54 (s, 1H, H-6); 11.95 (s, 1H, NH).
2.34 (t, 2H, J = 7 Hz, CH2CH2OH); 3.3-4.0 (m, 5H, CH2OH, KH); 4.25 (br dt, 1H, JH-3'-F = 22.5 Hz, H-3'); 4.57 (t, 1H, CH2OH); 5.05 (dt, 1H, JH_2'-F = 51.1 Hz, JH_H = 4 Hz, H-2'); 5.1 (m, 1H, 5'-OH); 5.86 (d, 1H, JH-H = 4 Hz, 3'-OH); 6.1 (dd, 1H, JH- l'- F = 16.4 Hz, JH-H = 4.1 Hz, H-1'); 7.57 (s, 1H, H-6); 11.41 (s, 1H, NH).

Claims

We Claim :
1. Compounds of formula I
Figure imgf000019_0001
wherein
R1 and R2 represent independently hydrogen or lower alkyl, R3 represents halogen, CHF2 or CF3,
R4 represents hydrogen, hydroxy or fluorine, X represents oxygen or imino, and n is 0 or 1 , whereby the sugar radical is α- or ß-glycosically bound to the pyrimidine ring; in free form or acid addition salt form.
2. A compound according to Claim 1 a) wherein R1 and R2 represent hydrogen, R3 represents halogen, R4 represents hydrogen, hydroxy or fluorine, X represents oxygen or imino and n is 1, in free form or acid addition salt form.
3. A compound according to Claim 1 wherein R1 and R2 are as defined in Claim 1, R3 represents halogen, X represents oxygen, R represents hydrogen, hydroxy or fluorine and n is 1, in free form or acid addition salt form.
4. 1-(2-desoxy-ß-D-erythro-pentofuranosyl)-5-(2-chloroethyl)-(1H, 3H)-pyrimidine—2,4-dione.
5. A chemotherapeutical composition comprising a compound according to Claim 1, in free form or chemotherapeutically acceptable acid addition salt form together with a chemotherapeutically acceptable diluent or carrier.
6. A method of combating herpes diseases or infections which comprises administering to a subject in need of such treatment an effective amount of a compound according to Claim 1 in free form or in chemotherapeutically acceptable acid addition salt form.
7. A compound according to Claim 1, in free form or in chemotherapeutically acceptable acid addition salt form for use as a pharmaceutical .
8. A process for preparing a compound of formula I according to Claim 1 in free form or in acid addition salt form
a) by reacting a compound of formula II
Figure imgf000020_0001
with a compound of formula III
or
Figure imgf000020_0002
b) by replacing the group R3' in the hydroxalkyl side chain of a compound of formula Ia
Figure imgf000021_0002
by an R3 group whereby in the formulae Ia, II and III, R1 , R2, R3,
R4, X and n are as defined in Claim 1, R5 represents halogen or acyloxy, R3' represents hydroxy and any hydroxy group present in the sugar radical may be protected; and when required removing any protecting group from the compound thus obtained; and recovering the compound thus obtained in free form or in acid addition salt form.
9. A compound of formula Ia
Figure imgf000021_0001
wherein R1 , R2, R4, X and n are as defined in Claim 1 , and whereby the sugar radical is α- or ß-glycosidally bound to the pyrimidine ring.
PCT/EP1983/000219 1982-08-17 1983-08-12 Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals WO1984000759A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT904183A ATA904183A (de) 1982-08-17 1983-08-12 Verfahren zur herstellung von neuen desoxyuridinderivaten

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH492282 1982-08-17

Publications (1)

Publication Number Publication Date
WO1984000759A1 true WO1984000759A1 (en) 1984-03-01

Family

ID=4284858

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1983/000219 WO1984000759A1 (en) 1982-08-17 1983-08-12 Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals

Country Status (16)

Country Link
JP (1) JPS5953499A (de)
AU (1) AU1800483A (de)
BE (1) BE897516A (de)
DE (1) DE3390162T1 (de)
DK (1) DK372283A (de)
ES (1) ES8604943A1 (de)
FI (1) FI832884A (de)
FR (1) FR2531962B1 (de)
GB (1) GB2125401B (de)
IL (1) IL69497A0 (de)
IT (1) IT1169765B (de)
NL (1) NL8302859A (de)
PT (1) PT77209B (de)
SE (1) SE8304408L (de)
WO (1) WO1984000759A1 (de)
ZA (1) ZA836072B (de)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0211354A2 (de) * 1985-07-29 1987-02-25 Merrell Dow Pharmaceuticals Inc. Nukleoside und ihre Verwendung als antineoplastische Wirkstoffe
WO1988004662A1 (en) * 1986-12-19 1988-06-30 Astra Läkemedel Aktiebolag Use of nucleosides for the manufacture of medicament for treatment of diseases caused by retrovirus or hepatitis b virus
EP0291230A2 (de) * 1987-05-11 1988-11-17 Merck & Co. Inc. 1-(2-(Hydroxymethyl)-cycloalkylmethyl)-5-substituierte Uracile
US5215971A (en) * 1986-12-19 1993-06-01 Medivir Ab Antiviral pharmaceutical composition comprising 5-substituted pyrimidine nucleosides
US5409906A (en) * 1987-04-16 1995-04-25 Medivir Ab α nucleoside compounds and a method for treating HBV using said compounds
WO1998045309A1 (en) * 1997-04-04 1998-10-15 Astra Pharmaceuticals Ltd. Novel phosphate compounds and their use as medicaments
EP1425022A1 (de) * 2001-08-24 2004-06-09 Koronis Pharmaceuticals, Inc. Mutagene nucleosid-analoga zur behandlung von viruserkrankungen

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4526988A (en) * 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
US5401838A (en) * 1992-06-22 1995-03-28 Eli Lilly And Company Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
MX9303708A (es) * 1992-06-22 1994-05-31 Lilly Co Eli Proceso de glucosilacion anionica estereoselectiva para preparar 2'-desoxifluoro-beta nucleosidos.
US5821357A (en) * 1992-06-22 1998-10-13 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoropurine and triazole nucleosides
US5426183A (en) * 1992-06-22 1995-06-20 Eli Lilly And Company Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5594124A (en) * 1992-06-22 1997-01-14 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-Deoxy-2',2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides and intermediates thereof
US5606048A (en) * 1992-06-22 1997-02-25 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5371210A (en) * 1992-06-22 1994-12-06 Eli Lilly And Company Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5424416A (en) * 1993-08-25 1995-06-13 Eli Lilly And Company Process for preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-hydroxy protected-1-alkyl and aryl sulfonates and their use in preparation of 2',2'-difluoro-2'-deoxy nucleosides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2915254A1 (de) * 1978-04-24 1979-11-15 Stichting Rega V Z W Neue chemische verbindungen, verfahren zu deren herstellung und deren verwendung als arzneimittel mit antiviraler wirkung
DE3002197A1 (de) * 1980-01-22 1981-07-23 Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen 5-alkylsubstituierte pyrimidin-nukleoside, verfahren zu deren herstellung und daraus hergestellte virostatische und cytostatische mittel
DE3010399A1 (de) * 1980-03-18 1981-09-24 Kailash Kumar Dr. 2359 Lentföhrden Gauri Verwendung von 5-haloalkyl-pyrimidin-nukleosiden als virostatika und cytostatika

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3709874A (en) * 1970-03-19 1973-01-09 Syntex Corp 1-beta-d-arabinofuranosyl cytosine derivatives and methods of preparing
GB2060604B (en) * 1979-10-03 1983-11-23 Univ Birmingham And Stichting E15-(2-halogenovinyl)-2'-deoxycytidines
HU183567B (en) * 1981-09-07 1984-05-28 Mta Koezponti Kemiai Kutato In Process for preparing /e/-5-/2-bromo-vinyl/-uridine and derivatives thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2915254A1 (de) * 1978-04-24 1979-11-15 Stichting Rega V Z W Neue chemische verbindungen, verfahren zu deren herstellung und deren verwendung als arzneimittel mit antiviraler wirkung
DE3002197A1 (de) * 1980-01-22 1981-07-23 Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen 5-alkylsubstituierte pyrimidin-nukleoside, verfahren zu deren herstellung und daraus hergestellte virostatische und cytostatische mittel
DE3010399A1 (de) * 1980-03-18 1981-09-24 Kailash Kumar Dr. 2359 Lentföhrden Gauri Verwendung von 5-haloalkyl-pyrimidin-nukleosiden als virostatika und cytostatika

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
BIOCHEMISTRY, vol. 21, 20 juillet 1982, Am. Chemical Society, pages 3698-3703; E. LIVNEH et al.: "Light-induced free-radical reactions of purines and pyrimidines in deoxyribonucleic acid. Effect of structure and base sequence on reactivity" *
CHEMICAL ABSTRACTS, vol. 74, no. 19, 10 mai 1971, page 540, no. 100336k, Columbus, Ohio, US; V.S. GUPTA et al.: "Synthesis and properties of 5-hydroxymethyl-2'-deoxyuridine and its alpha-anomer" & CAN. J. CHEM. 1971, 49(5), 719-24 *
CHEMICAL ABSTRACTS, vol. 86, no. 15, 11 avril 1977, page 546, no. 106946d, Columbus, Ohio, US; S. YA. MEL'NIK et al.: "Transformation of 5-(polyfluoroalkyl)- and 5-(polyfluoroalkoxymethyl)uridines" & BIOORG. KHIM. 1976, 2(11), 1520-5 *
CHEMICAL ABSTRACTS, vol. 90, no. 23, 4 june 1979, page 696, no. 187266q, Columbus, Ohio, US; S.YA. MEL'NIK et al.: "Synthesis and study of 5-(polyfluoroalkyl)- and 5-(polyfluoroalkoxymethyl)-2'-deoxypyrimidine nucleosides" & BIOORG. KHIM. 1979, 5(1), 41-6 *
CHEMICAL ABSTRACTS, vol. 92, no. 25, 23 june 1980, page 31, no. 208903d, Columbus, Ohio, US; T.A. BEKTEMIROV et al.: "Study of the antiviral activity of anomeric 5-substituted 2'-deoxyuridines"& VOPR. VIRUSOL. 1979, (6), 603-6 *
CHEMICAL ABSTRACTS, vol. 97, no. 23, 6 décembre 1982, page 608, no. 198501h, Columbus, Ohio, US; S.Y. MEL'NIK et al.: "Synthesis of thymidine analogs with branched substitutions at the 5 position of the pyrimidine ring" & BIOORG. KHIM. 1982, 8(8), 1102-7 *
EIGHTH SYMPOSIUM ON NUCLEIC ACIDS CHEMISTRY, held in Sapporo, 21-23 août 1980, Nucleic Acids Symposium Series no. 8, Information Retrieval Ltd., 1980 (londres, GB), pages S39-S42; S. SHINJI et al.: "Synthesis and antiherpesviral activity of 5-C-substituted uracil nucleosides" *
J. CARBOHYDRATES-NUCLEOSIDES-NUCLEOTIDES, vol. 5, no. 3, 1978, pages 187-224; MARCEL DEKKER, INC.; E. DE CLERCQ et al.: "Nucleoside analogs with selective antiviral activity" *
THE VTH SYMPOSIUM ON THE CHEMISTRY OF NUCLEIC ACID COMPONENTS held at Bechyne Castle Czechoslovakia, 6-11 septembre 1981, Nucleic Acids Symposium Series no. 9, pages 53-55, Information Retrieval Ltd., 1981 (londres, GB); S.YA. MELNIK et al.: "Synthesis and investigation *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0211354A2 (de) * 1985-07-29 1987-02-25 Merrell Dow Pharmaceuticals Inc. Nukleoside und ihre Verwendung als antineoplastische Wirkstoffe
EP0211354A3 (de) * 1985-07-29 1988-02-10 Merrell Dow Pharmaceuticals Inc. Nukleoside und ihre Verwendung als antineoplastische Wirkstoffe
WO1988004662A1 (en) * 1986-12-19 1988-06-30 Astra Läkemedel Aktiebolag Use of nucleosides for the manufacture of medicament for treatment of diseases caused by retrovirus or hepatitis b virus
US5215971A (en) * 1986-12-19 1993-06-01 Medivir Ab Antiviral pharmaceutical composition comprising 5-substituted pyrimidine nucleosides
US5409906A (en) * 1987-04-16 1995-04-25 Medivir Ab α nucleoside compounds and a method for treating HBV using said compounds
EP0291230A2 (de) * 1987-05-11 1988-11-17 Merck & Co. Inc. 1-(2-(Hydroxymethyl)-cycloalkylmethyl)-5-substituierte Uracile
EP0291230A3 (de) * 1987-05-11 1990-06-13 Merck & Co. Inc. 1-(2-(Hydroxymethyl)-cycloalkylmethyl)-5-substituierte Uracile
WO1998045309A1 (en) * 1997-04-04 1998-10-15 Astra Pharmaceuticals Ltd. Novel phosphate compounds and their use as medicaments
EP1425022A1 (de) * 2001-08-24 2004-06-09 Koronis Pharmaceuticals, Inc. Mutagene nucleosid-analoga zur behandlung von viruserkrankungen
EP1425022A4 (de) * 2001-08-24 2009-04-29 Koronis Pharmaceuticals Inc Mutagene nucleosid-analoga zur behandlung von viruserkrankungen

Also Published As

Publication number Publication date
NL8302859A (nl) 1984-03-16
GB2125401A (en) 1984-03-07
IT1169765B (it) 1987-06-03
ES8604943A1 (es) 1986-02-16
GB2125401B (en) 1985-10-16
PT77209A (en) 1983-09-01
SE8304408L (sv) 1984-02-18
ES524997A0 (es) 1986-02-16
BE897516A (fr) 1984-02-13
ZA836072B (en) 1985-03-27
FI832884A (fi) 1984-02-18
DE3390162T1 (de) 1985-02-21
SE8304408D0 (sv) 1983-08-15
IT8322565A0 (it) 1983-08-16
AU1800483A (en) 1984-02-23
DK372283D0 (da) 1983-08-15
FR2531962A1 (fr) 1984-02-24
GB8321880D0 (en) 1983-09-14
FR2531962B1 (fr) 1986-11-14
DK372283A (da) 1984-02-18
IL69497A0 (en) 1983-11-30
JPS5953499A (ja) 1984-03-28
PT77209B (en) 1986-03-18
FI832884A0 (fi) 1983-08-10

Similar Documents

Publication Publication Date Title
EP0269574B1 (de) Adenosin-Derivate und pharmazeutische Zusammenstellungen, welche diese als aktiven Bestandteil enthalten
US5607922A (en) 1,5-anhydrohexitol nucleoside analogues
Verheyden et al. Halo sugar nucleosides. I. Iodination of the primary hydroxyl groups of nucleosides with methyltriphenoxyphosphonium iodide
CA2105112C (en) A process for anomerizing nucleosides
WO1984000759A1 (en) Desoxyuridine derivatives, processes for their preparation and their use as pharmaceuticals
US4762823A (en) Nucleosides of 5-monofluoromethyluracil and 5-difluoromethyluracil
US5218106A (en) 2',3'-dideoxy-2'-fluoronucleosides
HU203363B (en) Process for producing 2',3'-dideoxy-2',2'-difluoronucleosides and pharmaceutical compositions comprising same as active ingredient
US4177348A (en) Carbocyclic analogs of cytosine nucleosides
Robins et al. Nucleic Acid Related Compounds. LXXXI. Efficient General Synthesis of Purine (Amino, Azido, and Triflate)-Sugar Nucleosides
US5498819A (en) Griseolic acid derivatives, their preparation and their use
US8586729B2 (en) Synthesis of decitabine
US3721664A (en) Preparation of 5-cytosine nucleosides
IL25712A (en) 5',5'-dinucleoside phosphate
US4182859A (en) Process for the preparation of 2'-deoxyribofuranosyl nucleosides
EP0061283A1 (de) Antivirale Verbindungen, ihre Herstellung und Anwendung
JPS6133038B2 (de)
EP0491793B1 (de) 2'-deoxy-4'-thioribonucleoside als antivirale und antikrebsmittel
Chu et al. Nucleosides. 107. Synthesis of 5-(. beta.-D-arabinofuranosyl) isocytosine and related C-nucleosides
EP0072977A1 (de) Verfahren zur Herstellung von 2-beta-D-Ribofuranosylthiazol-4-Carboxamide
US6518254B1 (en) Ribonucleoside-TRIBOSE
US4730001A (en) Carbocyclic analogues of amino and azido thymidines
IL25768A (en) Derivatives of 1-beta-d-arabino-furanosylcytosine 2'-and 3'-phosphates and process for producing same
Watanabe et al. Nucleosides. XXXI. 3'-Amino-3'-deoxyhexopyranosyl Nucleosides. IV. Nucleoside Conversions in the 3'-Aminohexose Series1
Falco et al. Nucleosides. XLVIII. Synthesis of 1-(5-deoxy-. beta.-D-arabinosyl) cytosine and related compounds

Legal Events

Date Code Title Description
AK Designated states

Designated state(s): AT CH DE

ENP Entry into the national phase

Ref document number: 1983 9041

Country of ref document: AT

Date of ref document: 19840301

Kind code of ref document: A

RET De translation (de og part 6b)

Ref document number: 3390162

Country of ref document: DE

Date of ref document: 19850221

WWE Wipo information: entry into national phase

Ref document number: 3390162

Country of ref document: DE