GB2125401A - Desoxyuridine derivatives and their use as pharmaceuticals - Google Patents
Desoxyuridine derivatives and their use as pharmaceuticals Download PDFInfo
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- GB2125401A GB2125401A GB08321880A GB8321880A GB2125401A GB 2125401 A GB2125401 A GB 2125401A GB 08321880 A GB08321880 A GB 08321880A GB 8321880 A GB8321880 A GB 8321880A GB 2125401 A GB2125401 A GB 2125401A
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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
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- 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
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- 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
Abstract
Desoxyuridine derivatives such as 1-(2-desoxy- beta -D-erythropentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4-dione which derivatives are useful as chemotherapeutical agents particularly in combatting Herpes diseases and infections.
Description
SPECIFICATION
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
wherein R, 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 O or 1, whereby the sugar radical is a or ,5-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
with a compound of formula III
or
b) by replacing the group R3, in the hydroxyalkyl side chain of a compound of formula la
by an R3 group whereby in the formulae la, II and Ill, Ra, Rz, R3, R4, X and n are as defined above, 115 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 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.
Process a) can be carried out for example by converting a compound of formula II in conventional manner into its trimethylsilyl derivative and reacting this with a compound of formula Ill whose hydroxy groups are protected in a solvent e.g. a halogenated hydrocarbon or acetonitrile.
According to process b) a compound of formula la in unprotected or protected form can be dissolved in a solvent inert under the reaction conditions e.g. a lower alkyl carboxylic acid amide such as dimethylformamide.
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 la 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 la can be in a- or jB-configuration with respect to bonding of the sugar radical. Merely for convenience the compound of formula I is shown in form.
The pyrimidine radical in the compounds of formula I and la can exist in tautomeric forms such as
The invention is intended to cover all tautomeric forms of the compounds.
The compounds of formula I and la can also exist in the form of optical isomers or mixtures which isomers can be separated in conventional manner. The invention is intended to cover isomeric 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 atoms.
The starting materials of formula la are also new and form part of the invention. They can be prepared by reacting a compound of formula Ila
wherein Rr, R > , R3', X and n are as defined above analogously to process a) with a compound of formula
The compounds of formula 11, 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 yg/ml to ca. 300 ,ug/ml and in vivo in tests carried out in mice and guinea pig using systemic, topical and encephalitis-infection models (cf. H. E. Renis et al. J. Med.
Chem. 16 (7) 754 [1973]). The compounds are therefore useful as chemotherapeutics in particular as agents for combating Herpes diseases and infections.
For this use a suitable daily dosage is from about 200 to 1 200 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, hydrogenfumarate and naphthalene- 1 ,5-disu Ifonate.
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 R" R2=a) H
b) lower 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 R, and R2 represent hydrogen, R3 represents halogen, R4 represents hydrogen, hydroxy
or fluorine, X represents oxygen or imino and n is 1;
b) wherein Ra and R2 are as defined above, R3 represents halogen, X represents oxygen, R4 represents hydrogen, hydroxy or fluorine and n is 1.
A particular preferred individual compound is 1-(2-desoxy-ss-D-erythro-pentofuranosyl)-5-(2chloroethyl)-(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 centigrade.
Example 1:1 -(2-desoxy-ss-D-erythro-pentofuranosyl )-5-(2-chloroethyl)-( 1 H, 3H)-pyrimidine-2,4dione (Process b):
200 mg of 1-(2-desoxy-ss-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1H,3H)-pyrimidine2,4-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.
16667 (from abs. methanol).
Example 2: 1-(2-desoxy-α-D-erythro-pentofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine-2,4- dione (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 700.The solvent is then removed at 0.1 bar and the remaining syrup chromatographed on silica-gel (toluene/ethylacetate=2/1). 0.5 g of 1 -(2-desoxy-3,5-di-O-p-toluyl-a-D-erythro-pentofuran- osyl)-5-(2-chloroethyl)-( 1 H, 3H)-pyrimidine-2,4-dione are obtained as colourless crystals (m.p. 142- 1440). To remove the p-toluyl groups the compound is dissolved in 10 ml of abs. ethanol and reacted with 1.5 ml of 1 N-sodium ethanolate solution in ethanol, left for 15 minutes at room temperature and reacted with 1.5 ml of 1 N 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. 140142c (ethanol/chloroform).
Example 3: 1-(2-desoxy-ss-D-erythro-pentofuranosyl)-5-(2-bromoethyl-(1H,3H)-pyrimidine-2,4dione (Process b): 1.14 9 of 1 -(2-desoxy-,B-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1 H, 3H)-pyrimidine-2,4dione 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.
161-163 C.
Example 4: -(2-desoxy-a-D-erythro-pentofuranosyl)-5-(2-bromoethyl)-( 1 H, 3H)-pyrimidine-2,4- dione (Process b):
380 mg of 1-(2-desoxy-α-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(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--D-erythrn-pentofuranosyl)-5-(2-iodoethyl)-( 1 H, 3H)-pyrimidine-2,4- dione (Process b):
550 mg of 1-(2-desoxy-ss-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1 H, 3H)-pyrimidine2,4-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.
160161 .
Example 6: 1 -(2-desoxy-p-D-erythro-pentofuranosyl )-5-(2-chloroethyl)-( 1 H, 3H)-pyri midine-2,4- dione (Process a):
480 mg of 5-(2-chloroethyi)-uracil are suspended in hexamethyldisalazane, reacted with 0.3 ml
of trimethylchlorosilane and refluxed for 3 hours. Volatile matter is then removed in vacuum and eliaporation 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 chromato
graphed on silica-gel (toluene/ethyl acetate=4/1) to yield 1-(2-desoxy-3,5-di-0-p-toluyl-,B-D-erythro- pentofuranosyl)-5-(2-chloroethyl)-(1 H, 3H)-pyrimidine-2,4-dione (m.p. 1 67-1 690). Removal of the p
toluyl groups is carried out analogously to Example 2 to yield 1 -(2-desoxy-P-D-eryth ropento- furanosyl)-5-(2-chloroethyl)-(1 H. 3H)-pyrimidine-2,4-dione as colourless crystals m.p. 165-166
(from water).
Example 7: 1-(ss-D-arabinofuranosyl)-5-(2-chloroethyl)-(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 -(ss-D-arabinofuranosyl)-5-(2-bromoethyl)-(1 H, 3H)-pynmidine-2,4dione 320 mg of 1-(/3-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1 H, 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 at 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 chromato
graphed 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-ss-D-arabinofuranosyl)-5-(2-chloroethyl)-(1H,3H)-pyrimidine .2,4-dione
200 mg of 1-(2-desoxy-2-fluoro-ss-D-arabinofuranosyl)-5-(2-hydroxyethyl)-(1 H, 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: Samino-5-(2-chloroethyl)-1 -(2-desoxy-P-D-erythropentof uranosyl )-1 H-pyri midine
2-one
3.12 g of a 4-amino-5-(2-hydroxyethyl)-1 H-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)-1 H-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 soivents are removed in vacuum and the residue mixed with 20 ml of
methanol and 5 ml of 1 N methanolic sodium methanolate. On completion of reaction the mixture is neutralised with 1 N 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. 1 740 (from water).
The required starting materials may be prepared for example as follows:
A) 1 -(2-desoxy-,B-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-(1 H, 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-0-p-toluyl-2-desoxy-Derythro-pentofuranosyl-chloride and then with 0.5 ml of trifluoromethanesulfonic acid trimethylsilyl; ester.The mixture is kept at room temperature for 1 hour and shaken with 100 ml saturated aqueous KHC03. 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-,B-D-2'-desoxyuridine (m.p. 1 76-1 780). Removal of the ptoluyl groups is carried out analogously to Example 2 to yield, after crystallisation from ethanol in a refrigerator, 1 -(2-desoxy-,B-D-erythro-pentofu ranosyl )-5-(2-hydroxyethyl)-( 1 H, 3 H)-pyri m idine-2,4- dione as colourless crystals, m.p. 1 60-161 .
B) 1 -(2-desoxy-3,5-di-O-p-toluyl-a-D-erythro-pentofuranosyl )-5-(2-hydroxyethyl-( 1 H, 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-a-D-erythro-pentofuranosyl)-5-(2-hydroxyethyl)-( 1 H, 3H)-pyrimidine-2,4-dione (for example 4):
Obtained after removal of tolyl groups analogously to Example 2 and chromatographed on silicagel (chloroform/methanol=3/1). Colourless oil.
D) 5-(2-chloroethyl)-(1 H, 3H)-pyrimidine-2,4-dione (for example 6):
0.5 g of 5-(2-hydroxyethyl)-(1 H, 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 800, concentrated and the oily residue taken up in chloroform/methanol (9/1) to yield the title compound as colourless crystals, m.p. 260--2620 (from ethylacetate).
E) 1-(p-D-arabinofuranosyl)-l5-(2-hydrnxyethyl)-(1 H, 3H)-pynmidine-2,4-dione (for examples 7 and 8)
5 g of 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinose are dissolved in 80 ml of abs. dichloromethane, which had been saturated 1 hour previously at 0 with HCI. Stirring is carried out for 2 hours at 0 with passage of further HCI 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 hexamethylsilazanefree 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 AO), 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 PdCIz 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 methanolic residue of the hydrogenation is neutralised with ionexchanger 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-24luorn--D-arabinofuranosyI)-5-(2-hydrnxyethyl)-( 1 H, 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-benzoy-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 separation (chloroform/methanol=9/1). After removal of the protecting groups (cf. Example 2) the title compound is obtained as colourless crystals, m.p. 177-1 780.
NMR-spectra
KH=imprecisely assigned proton in desoxyribose moiety KH-1 'a, KH-1 ',8=proton on C-I of desoxyribose moiety, the bonding properties of which allow assignment of anomers.
NMR-Apparatus: BrukerWH-90, MHz.
Example Spectrum
1 2.10 (t, 2H, KH); 2.67 (t, 2H, CH2CH2Cl, , J=7 Hz); 3.4-3.9 (m, 5H, CH2CH2CI, KH); 4.1-4.4 (m, 1 H, KH); 5.03 (t, 1 H, J=5.1 Hz, 5'-OH); 5.24 (d, 1 H, J=4.3 Hz, 3'-
OH); 6.17 (t, 1H, J=6.7 Hz, KH-1'ss); 7.83 (s, 1 H, H-6); 11.4 (br. 1 H, NH).
2 1.8-2.7 (m, 2H, KH); 2.66 (t, 2H, J=7 Hz, CH2CH2CI); 3.43 (d, 2H, KH); 3.69 (t,
2H, J=7 Hz, CH3CH2Cl); 4.1-4.3 (m, 2H, KH); 4.82 (t, 1H, J=5.7 Hz, 5'-OH);
5.30 (d, 1 H, J=3.1 Hz, 3'-OH); 6.10 (dubl.d, 1 H, J=7.4 Hz, KH-1'α); 7.85 (s,
1 H, H-6); 10.9 (br, 1H, NH).
3 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, 1 H, J=6.7 Hz, KH
1'ss); 7.85 (s, 1H, H-6); 11,4 (s, 1H, NH).
4 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, 1 H, J=5.1 Hz, 5'-OH);
5.27 (d, 1 H, J=3.2 Hz, 3'-OH); 6.07 (dubl. d, 1H, J=7.5 Hz, KH-1'α); 7.82 (s,
1 H, H-6); 11.32 (s, 1 H, NH).
5 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, 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).
7 2.66 (t, 2H, J=7.2 Hz, CH2CH2CI); 3.5-3.8 (m, 5H, CH2CI and KH); 3.85-4.1 (m,
2H, KH); 5.0 (t, 1 H, J=5.4 Hz, 5'-OH); 5.36 and 5.45 (je 1 d, J=5 Hz, 2H, 3'-OH
and 5'-OH); 6.02 (d, 1H, J=5.4 Hz, KH-1'ss); 7.67 (s, 1 H, H-6); 11.32 (s, 1 H,
NH).
8 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, 1 H, H-6); 11.32 (s, 1 H, NH).
9 2.7 (t, 2H, J=7 Hz, CH2CH2CI); 3.5-4.25 (m, 7H, CH2CI and KH); 4.25 (dt, 1H, H
3',JH-3'-F="=;$% 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-a'-F=15.3 Hz, JH-H=4.1 Hz); 7.7 (s, 1H, H-6); 11.55 (s,
1 H, NH).
10 2.0 (m, 2H, KH); 2.8 (t, 2H, J=7 Hz, CH2CH2CI); 3.5-3.9 (m, 5H, CH2CI and KH);
4.2 (br s, 1 H, KH); 5.0-5.2 (br s, 2H, 2 OH); 6.2 (t, 1 H, J=7 Hz, KH-1'ss); 7.3 (s,
2H, NH,), 7.8 (s, 1 H, H-6).
A 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, 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).
B 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, 1 H, KH); 5.56 (d, 1 H, 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, t.oluyl); 11.32 (s, 1 H, NH).
C 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, 1 H, OH); 4.8 (br d, 1 H, OH); 5.27 (br t, 1 H, OH); 6.08 (dd, 1 H, KH
1'a); 7.71(s, 1H, H-6); 11.0 (brs, 1H, NH).
D 2.71 (t, 2H, J=8 Hz, CH2CH2CI); 3.70 (t, 2H, J=8 Hz, CH2CI); 7.16 (d, 1 H;J=7 Hz,
H-6); 10.16 and 10.34 (2 br s, each 1 H, 2NH).
E 2.36 (t, J=6.3 Hz, 2H, CH2CH2OH); 3.4-3.8 (m, 5H, CH2CH20H, KH); 3.85-4.1 (m,
2H, KH); 4.46 (t, J=5.4 Hz, 1 H, CH2CH2OH); 5.00 (t, J=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).
F 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-1'-F=16.4 Hz, JH-H=4.1 Hz, H-1'); 7.57 (s, 1H, H-6); 11.4 (s, 1H, NH).
Claims (9)
1. Compounds of formula I
wherein
R, 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 O or 1, whereby the sugar radical is a- or p-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 R, and R2 are as defined in Claim 1,113 represents halogen, X represents oxygen, R4 represents hydrogen, hydroxy or fluorine and n is 1, in free form or acid addition salt form.
4. 1 -(2-desoxy-p-D-erythro-pentofuranosyl)-5-(2-chloroethyl)-(1 H, 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
with a compound of formula III
or
b) by replacing the group R3' in the hydroxyalkyl side chain of a compound of formula la
by an R3 group whereby in the formulae la, II and III, R1, R2, 113. 114. 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 la
wherein R1, R2. R4, X and n are as defined in Claim 1, and whereby the sugar radical is a- or glycosically bound to the pyrimidine ring.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH492282 | 1982-08-17 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8321880D0 GB8321880D0 (en) | 1983-09-14 |
| GB2125401A true GB2125401A (en) | 1984-03-07 |
| GB2125401B GB2125401B (en) | 1985-10-16 |
Family
ID=4284858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08321880A Expired GB2125401B (en) | 1982-08-17 | 1983-08-15 | Desoxyuridine derivatives and their use as pharmaceuticals |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPS5953499A (en) |
| AU (1) | AU1800483A (en) |
| BE (1) | BE897516A (en) |
| DE (1) | DE3390162T1 (en) |
| DK (1) | DK372283A (en) |
| ES (1) | ES8604943A1 (en) |
| FI (1) | FI832884A (en) |
| FR (1) | FR2531962B1 (en) |
| GB (1) | GB2125401B (en) |
| IL (1) | IL69497A0 (en) |
| IT (1) | IT1169765B (en) |
| NL (1) | NL8302859A (en) |
| PT (1) | PT77209B (en) |
| SE (1) | SE8304408L (en) |
| WO (1) | WO1984000759A1 (en) |
| ZA (1) | ZA836072B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4808614A (en) * | 1983-03-10 | 1989-02-28 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
| 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 |
| 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 |
| 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 |
| 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 |
| US5744597A (en) * | 1992-06-22 | 1998-04-28 | Eli Lilly And Company | Stereoselective anion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
| 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 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1295998C (en) * | 1985-07-29 | 1992-02-18 | Sai P. Sunkara | Nucleosides and their use as antineoplastic agents |
| SE8605503D0 (en) * | 1986-12-19 | 1986-12-19 | Astra Laekemedel Ab | NOVEL MEDICINAL USE |
| US5215971A (en) * | 1986-12-19 | 1993-06-01 | Medivir Ab | Antiviral pharmaceutical composition comprising 5-substituted pyrimidine nucleosides |
| US5215970A (en) * | 1987-04-16 | 1993-06-01 | Medivir Ab | Nucleosides and nucleotide analogues, pharmaceutical composition and processes for the preparation of the compounds |
| US4863927A (en) * | 1987-05-11 | 1989-09-05 | Merck & Co., Inc. | 1-(2-hydroxymethyl)cycloalkylmethyl)-5-substituted uracils |
| SE9701219D0 (en) * | 1997-04-04 | 1997-04-04 | Astra Pharma Prod | New compounds |
| EP1425022A4 (en) * | 2001-08-24 | 2009-04-29 | Koronis Pharmaceuticals Inc | Mutagenic nucleoside analogs for the treatment of viral disease |
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| GB1335493A (en) * | 1970-03-19 | 1973-10-31 | Syntex Corp | 1a-beta-d arabinofuranosyl cytosine derivatives and process for making same |
| GB2060604A (en) * | 1979-10-03 | 1981-05-07 | Univ Birmingham And Stichting | E15-(2-halogenovinyl)-2'-deoxycytidines |
| GB1601020A (en) * | 1978-04-24 | 1981-10-21 | Stichting Grega Vzw | 2'-deoxy-5 (2-halogenovinyl)-uridines |
| GB2106107A (en) * | 1981-09-07 | 1983-04-07 | Egyt Gyogyszervegyeszeti Gyar | (e)-5-(2-bromovinyl)-uridine, its derivatives and a process for the preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3002197A1 (en) * | 1980-01-22 | 1981-07-23 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-Alkyl- and 5-alkenyl-uracil and -cytidine nucleoside derivs. - prepd. e.g. by reaction of 5'-chloro-5'-deoxy cpds. with ammonia |
| DE3010399A1 (en) * | 1980-03-18 | 1981-09-24 | Kailash Kumar Dr. 2359 Lentföhrden Gauri | Cytostatic and antiviral pyrimidine nucleoside derivs. - which are 5-haloalkyl-pyrimidine nucleoside 5'-ester derivs. |
-
1983
- 1983-08-10 FI FI832884A patent/FI832884A/en not_active Application Discontinuation
- 1983-08-10 FR FR8313242A patent/FR2531962B1/en not_active Expired
- 1983-08-11 BE BE0/108521A patent/BE897516A/en not_active IP Right Cessation
- 1983-08-12 DE DE19833390162 patent/DE3390162T1/en not_active Withdrawn
- 1983-08-12 WO PCT/EP1983/000219 patent/WO1984000759A1/en active Application Filing
- 1983-08-15 SE SE8304408A patent/SE8304408L/en not_active Application Discontinuation
- 1983-08-15 IL IL69497A patent/IL69497A0/en unknown
- 1983-08-15 GB GB08321880A patent/GB2125401B/en not_active Expired
- 1983-08-15 AU AU18004/83A patent/AU1800483A/en not_active Abandoned
- 1983-08-15 DK DK372283A patent/DK372283A/en not_active Application Discontinuation
- 1983-08-15 NL NL8302859A patent/NL8302859A/en not_active Application Discontinuation
- 1983-08-16 JP JP58150111A patent/JPS5953499A/en active Pending
- 1983-08-16 IT IT22565/83A patent/IT1169765B/en active
- 1983-08-16 PT PT77209A patent/PT77209B/en unknown
- 1983-08-17 ZA ZA836072A patent/ZA836072B/en unknown
- 1983-08-17 ES ES524997A patent/ES8604943A1/en not_active Expired
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1335493A (en) * | 1970-03-19 | 1973-10-31 | Syntex Corp | 1a-beta-d arabinofuranosyl cytosine derivatives and process for making same |
| GB1601020A (en) * | 1978-04-24 | 1981-10-21 | Stichting Grega Vzw | 2'-deoxy-5 (2-halogenovinyl)-uridines |
| GB2060604A (en) * | 1979-10-03 | 1981-05-07 | Univ Birmingham And Stichting | E15-(2-halogenovinyl)-2'-deoxycytidines |
| GB2106107A (en) * | 1981-09-07 | 1983-04-07 | Egyt Gyogyszervegyeszeti Gyar | (e)-5-(2-bromovinyl)-uridine, its derivatives and a process for the preparation thereof |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4808614A (en) * | 1983-03-10 | 1989-02-28 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
| US5015743A (en) * | 1983-03-10 | 1991-05-14 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
| US5118820A (en) * | 1983-03-10 | 1992-06-02 | Eli Lilly And Company | Difluro antivirals and intermediate therefor |
| 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 |
| 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 |
| 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 |
| US5648473A (en) * | 1992-06-22 | 1997-07-15 | Eli Lilly And Company | 2'-deoxy-2', 2'-difluoropyrimidine nucleosides and 2'-deoxy-2'-fluoropyrimidine nucleosides and intermediates |
| US5744597A (en) * | 1992-06-22 | 1998-04-28 | Eli Lilly And Company | Stereoselective anion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides |
| 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| SE8304408L (en) | 1984-02-18 |
| IT8322565A0 (en) | 1983-08-16 |
| PT77209A (en) | 1983-09-01 |
| FI832884A0 (en) | 1983-08-10 |
| AU1800483A (en) | 1984-02-23 |
| DK372283A (en) | 1984-02-18 |
| SE8304408D0 (en) | 1983-08-15 |
| PT77209B (en) | 1986-03-18 |
| FR2531962B1 (en) | 1986-11-14 |
| FR2531962A1 (en) | 1984-02-24 |
| IT1169765B (en) | 1987-06-03 |
| WO1984000759A1 (en) | 1984-03-01 |
| JPS5953499A (en) | 1984-03-28 |
| ES8604943A1 (en) | 1986-02-16 |
| FI832884A (en) | 1984-02-18 |
| ES524997A0 (en) | 1986-02-16 |
| DK372283D0 (en) | 1983-08-15 |
| BE897516A (en) | 1984-02-13 |
| DE3390162T1 (en) | 1985-02-21 |
| ZA836072B (en) | 1985-03-27 |
| GB2125401B (en) | 1985-10-16 |
| IL69497A0 (en) | 1983-11-30 |
| NL8302859A (en) | 1984-03-16 |
| GB8321880D0 (en) | 1983-09-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |