DE3045375A1 - 5-Substd. pyrimidine nucleoside derivs. - useful as antiviral agents - Google Patents

Abstract

Pyrimidine nucleosides of formula (I) are new. In (I), R1 is CH2OR' or 1-3C alkyl; R2 is H or hydroxy; R3 is halo, pref. chloro or hydroxy; R4 is hydroxy, OR", NHY, -Q-P(O)(OR)2 or pivaloyl; R' is allyl, CH2.CH:CH Halo, methyl, or ethyl; R" is -CONHX; X is 2-4C alkyl or cyclohexyl; Y is 2-haloethylcarbonyl or 2-haloethylthiocarbonyl; Q is oxygen, direct bond, COCH2 or CO; Each R is H, Na or NH4. They are made e.g. by reacting 5-hydroxymethyluridine with allyl alcohol, silylation, reacting with a dideoxyribofuranosyl chloride and deprotecting. (I) have antiviral activity.

Description

New substituted pyrimidine nucleosides with antiviral

Effect, process for their production and the form of food made from them.

Examples: Example 1 2 ', 3'-Dideoxy-5-ethyl-3'-chloruridine 66: 274.70 Mp: 195 ° C (Z) 1. 3'-chloro-5'- 0-trityl-2; 3'-dideoxy-5-ethyluridine 2.58 g (5.17 mmol) of the pyridine nucleoside protected in the 5'-position by a triphenylmethane group (yield 82%) , 8%, melting point: 182-185 ° C.) are dissolved in a mixture of 30 ml of absolute dichloromethane and 5 ml of absolute pyridine. The solution of 1.0 ml (13.0 mmol) of thionyl chloride is then added dropwise to the clear yellow solution of the nucleoside at room temperature over the course of 15 minutes. After a further 15 minutes, the batch is rotated in under reduced pressure and the residue is taken up in ethanol. The solution thus obtained is poured into a mixture of 200 ml of ice water and 60 ml of dichloromethane and the phases are separated in a separating funnel.

After drying, the organic phase is filtered over sodium sulfate and concentrated to dryness in vacuo. Remaining pyridine is by two abrotiren removed with ethanol.

The crude yield obtained is 2.4 g (93.8%) of a brown-beige, powdery Substance. Purification by isopropanol gives 1.6 g (62.5 ', - o') of a pale beige Substance which sintafts at 1200C.

2. 2 ', 3'-dideoxy-5-ethane-3'-chlorudine 7.0 g (13.5 # mmol) of 3'-chlorine - 5'- 0 - trityl - 2,3'- dideoxy-- 5-ethyluridine and 200 ml of 80% acetic acid are refluxed for 10 minutes and after cooling to 600 ml of ice water poured. After standing for one hour in the refrigerator, the precipitated triphenlycarbinol becomes Aspirated through a layer of kieselguhr. The clear filtrate is on a rotary evaporator concentrated in vacuo to a syrup consistency. The yellow syrup is made with 50 ml of 96% Shaken ethanol and left to stand overnight.

The yellow color changes into the ethanol. The white residue is filtered off and dried.

Yield: 2.2 g (59.1%) melting point: 195 ° C. (Z) TLC: chloroform / isopropanol 9/1 rf: 0.5 (UV 254 nm) ice pie 1 2: 5 '- 0 - pivaloyl - 1 - ß - D - arabinofuranosyl - 5 - ethyluracil Starting from 5 - ethyluridine (melting point: 184-186 C), which is obtained by reacting silylated 5 - ethyluracil with 1 - bromo - 2,3,5 - tri - o - benzoyl - a, ß - ribofuranoside and subsequent unblocking of the hydroxyl groups , is accessible, is obtained in a known manner: 2,2'-anhydro-1-β-d-ribofuranosyl-5-ethyluridine (yield: 53%, melting point: 204-205 ° C., TLC: CHCl3 / EtOH: 10 / 1: v / v) (rf: 0.1) from which 1-ß-D-arabinofuranosyl-5-ethyluracil (yield: 49.7%, melting point: 188-189 ° C., TLC CHCl3 / Isopropanol: 7/3). (rf: 0.85) 3 By reacting this compound with pivalic acid chloride in a base, preferably pyridine, 5'-pivaloyl-1-ß-D-arabinofuranosyl-5-ethyluracil is obtained (yield: 78.4%, mp. : 256-258 OC, TLC CHCl3 / EtOH: 10/1: v / v) rf: 0.45 (UV 254 nm) Example 3 5-Ethyl-5'0- E (-ethylamino -) - carbamoyl-2 ' -dt60xyuridine MW: 327.33 M.p .: 223.5-224 oC By reacting the corresponding pyrimidine-ilucleoside with ethyl isocyanate in acetonitrile / triethylamine, a strong precipitate is obtained after four hours at 80-120 °, which is filtered off with suction and dried.

Crude yield: 3.0 g (91.6%) mp .: sintered at approx. 19008 and melts at 208-2720C The crude product is purified on a 35 x 2.5 cm long column (silica gel 0.05-0.2mm; 70-325 mesh ASTM from Merck).

A mixture of 10 parts of chloroform is used as the eluent and one part of 96% ethanol.

2.5 g (76.5%) of a colorless, chromatographically precipitated product as the pure product pure, substance.

M.p .: 223.5-224 ° C TLC: chloroform / ethanol 10/1 v / v B. e i s »i e 1 4: 1 - (- 2 '-deoxy-ß-D-ribofuranosyl -) - 5-allyloxymethyluracil Stufel: 2,4-Bistrimethylsilyloxy-5-allyloxymethyluracil A mixture of 7.28 g (0.04 moles) 5-allyloxymethyluracil (yield: 89.4, s, m.p .: 206-207 OC, rf = 0.5 in EtOAc), 30 ml of hexamethyldisilazane and three spatula tips (NH4) 2S04 are added after the 5-Allyloxymethyluracils for 13 hours at an oil bath temperature of 140 to 150 ° C held. Then the excess hexamethyldisilazane (14 ml) in a water pump vacuum distilled off. The slightly red-brown, viscous distillation residue becomes without any further Purification used for the next stage.

Step 2: 1- [2'-Deoxy-3 ', 5'-di-O - (- p -chlorobenzoyl) -a, β, D-ribofuranosyl -] - 5-allyloxymethyluracil 15.06 g (0.035 moles) of 2-deoxy-3 ', 5'-di-O - (- p -chlorobenzoyl -) - α, β-D -ribofuranosyl chloride (Mp .: 120 ° C) dissolved in 480 ml of absolute dichloromethane are added to the distillation residue (theoretical 13.06 g = 0.04 moles) and 15 minutes with exclusion of moisture touched. 9.0 ml of a standard SnCl4 solution are now added dropwise over a period of approx. 20 minutes (1 mmol SnCl4 / ml) = 0.009 mol) and stir for a further four hours with exclusion of moisture.

The batch is then thoroughly hydrolyzed using 25 ml of water Stirring for ten minutes and sucks the precipitate over a layer of kieselguhr. the Phases are separated in a separating funnel. The organic phase is shaken with 140 ml NaHCO3 solution

and with 50 ml of water and dried over sodium sulfate. The dichloromethane is removed on a rotary evaporator in vacuo at a bath temperature of approx. 30 ° C and the syrupy residue in hot: toluene added. The solution is placed in the refrigerator overnight. According to thin-layer chromatography Investigation, the ß-anomer is obtained as a beige powder.

Yield: 9.3 g (40.4% based on the total yield) (based on 80.8 s on ß-anomer yield) m.p .: 166-169 oC (crude) recrystallization from 96% ethanol gives a product with a melting point of 169-171 ° C. in pure chromatography.

Dc: chloroform / ether 8/2 v / v rf: 0.45 Level 3: 1 - (- 2'-Deoxy-β-D-ribofuranosyl -) - 5-allyloxymethyluracil 5.75 g (0.01 moles) of the protected nucleoside are mixed with 50 ml of absolute Methanol and 1.8 ml of a 30% sodium methylate solution (Riedel de Häen) and stir 20 hours at room temperature and with exclusion of moisture. From the minor insoluble The residue is filtered off and on a rotary evaporator in vacuo at a bath temperature concentrated from approx. 30 ° C to a volume of approx. 5 l.

The syrupy solution is mixed with 30 ml of water and extracted resulting p-chlorobenzoic acid methyl ester by shaking out three times with Je 20 ml dichloromethane.

The yellow-brown aqueous phase is clarified with activated charcoal (Darco G60) and concentrated to dryness on a rotary evaporator. A residue is obtained glassy pale yellow substance with rf 0.75 (chloroform / isopropanol 7/3 v / v) and a Fp .: 140-150 OC (bubbly foaming). The yield is 2.4 g (80.5%);

Claims (4)

P atent claims 1. Substituted pyrimidine nucleosides of the general formula 1: where R¹ = -CH2-OR 'where R' = -CH2-CH = CH2, t 'halogen -CH2 «LCH = Cx Halogen corresponding to F, Cl, Br, I, preferably a bromine atom = -CH3 = -CH2-CH3 = an alkyl group with 1 to 3 carbon atoms, R2 = a hydrogen atom, a hydroryl group, R3 = a halogen atom, preferably a chlorine atom, a hydroxyl group , R4 = a hydroxyl group, = -O-R "where R" = X = an alkyl group with 2 to 4 carbon atoms or a cyclohexyl group, where Y a = O, S Hal = F, Cl, Br, I preferably a chlorine atom where R each: -H, -Na, -NH4 mean. 2. A method for the preparation of the compounds according to claim 1, characterized characterized in that c) when R¹ is an allyloxymethyl group, starting from the well-known 5-hydroxymethyluracil, silylated by reaction with allyl alcohol by means of Hexcmethylcisilazon and subsequent reaction with the corresponding deoxyribofuranosyl chloride in dichloromethane, followed by deblocking of the hydroxyl groups. b) if a chlorine atom stands for R³1 starting from the corresponding Pyrimidine nucleosides, the hydroxyl groups in 5 'position by reaction with Triphenylchloromethane in a basic solvent protected the hydroxyl group in the 3'-position by means of thionyl chloride in a solvent mixture from pyridine and dichloromethane, chlorinated and then removal of the protective group. c) when R4 is -O-R, starting from the corresponding pyrimidine - Nucleosides, by reaction with alkyl or cycloalkyl isocyanates or the corresponding Isothiocyanates in a mixture of acetonitrile and triethalamine. c) when R4 is -RH-Y-, by reaction of the corresponding 5'-aminopyrimidine - Nucleosides with haloalkyl isocyanates, preferably chloroalkyl isocyanates in a solvent mixture as already described under c, which under claim 1 contained compounds. In the case of the compounds characterized under claim 1, it can be the α and the 0 configuration, as well as their mixture. 3. The method according to claim 2, characterized in that caß man ols Solvent an ease, such as. -. Pyridine, triethylamine or dimethylformamide, or a mixture of one of these bases with acetonitrile or a horoo hydrocarbon, preferably dichloromethane is used. 4. Medicament containing at least one compound according to claim 1, or a combination of these compounds, in a pharmaceutically acceptable one Carrier or diluent, optionally in conjunction with a compatible one Pharmaceutical formulants. The invention relates to the objects characterized by the claims. It is known that nucleosides can be used in medicine and have antiviral activity (W. H. Prusoff and D. C. Ward, Nucleoside Analogs with Antiviral Activity, Biochem. Pharmac. 25, 1233 61976). J. Descamps and E. DeClercq, J. Med. Chem. 22, 6, 647 (1979). E. DeClerq et al, Antimic. Agents and Chemother. 13, 3, 545 (1978). N. K. Ayisi et al; Antimic. Agents and Chemother. 17, 4, 558 (1980). Examples are 5-ethyl-2'-deoxyuridine (K. K. Gauri, G. Malorny and W. Schiff, Chemotherapy 14, 129 (1969) and the 5-iodine-2'- deoxyuridine (H. E. Kaufman, E. L. Martola and C. Dohlman, Arch. Ophthalmol. 68, 235 (1962) mentioned, both of which have an effect against viruses.