• 专利附录
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    • 专利摘要:
    The present invention relates to certain 5-substituted pyrimidine nucleosides and pharmaceutically acceptable derivatives thereof of formula (I) <CHEM> wherein X represents a vinylene or ethynylene group; R<1> represents an oxo or imino group; R2 represents hydrogen, a C1-2 alkyl or a C3-4 branched or cycloalkyl group e.g. isopropyl or cyclopropyl; R<3> represents a hydrogen atom or an acyl e.g. C1-4 alkanoyl or benzoyl group optionally substituted for example by one or more halogen, alkyl, hydroxy or alkoxy substituents; and R<4> represents a hydrogen atom or a hydroxy group; providing that (a) when X is ethynyl R<2>, R<3> and R<4> each represents a hydrogen atom, R<1> does not represent an oxo group, and (b) when X represents a vinylene group and R<2> represents hydrogen, R<3> represents an acyl group; or a pharmaceutically acceptable derivative thereof, in the treatment and prophylaxis of varicella zoster virus, cytomegalovirus and Epstein Barr virus infections. Also provided are pharmaceutical formulations and process for the preparation of the compounds according to the invention.
    公开号:SU1731064A3
    申请号:SU874355176
    申请日:1987-12-14
    公开日:1992-04-30
    发明作者:Джордж Рахим Саад；Джейн Мартин Пьюрифой Дороти
    申请人:Дзе Велкам Фаундейшн, Лимитед (Фирма)；
    IPC主号:
    专利说明:

    Derivatives of 5-fluorouracil or derivatives of 2-deoxy-5-fluorouridine are known to have antitumor activity.
    Closest to the proposed compounds is 2-deoxy-5-ethynyl uridine, which has an in vitro antiviral activity against vaccinia and herpes simplex (HSV). However, nothing is known about its use for treating a person.
    The purpose of the invention is to obtain new pyrimidine nucleosides with a wider spectrum of antiviral activity and lower toxicity.
    The goal is achieved by the method of obtaining new pyrimidine nucleosides of the general formula I, which consists in the fact that the compound of the general formula
    ABOUT
    NgU
    0A,
    wherein Mg and Mg are each a hydroxy protecting group, and R / ja is hydrogen or a hydroxy protecting group;
    Z - halogen, subjected to interaction with the compound of the General formula
    HC CR2, (Hi)
    where Ra is as indicated
    using bis (triphenylphosphine) palladium chloride and copper iodide as a catalyst in the presence of an organic base at 50 ° C.
    PRI me R 1,
    a) 02,2 -anhydrouridine. 10 g (0.04 mol) of uridine is dissolved in 20 ml of warm dry dimethylformamide and 11.4 g (0.06 mol) of diphenyl carbonate and 0.2 g of sodium bicarbonate are added to the prepared solution. The solution is stirred at 150 ° C until carbon dioxide evolution ceases (about 30 minutes). After cooling, the solution is poured into 200 ml of ether with vigorous stirring. The precipitate thus formed is filtered off, washed with ether and recrystallized from methanol. The result is 7.2 g (80%) of the title compound as white.
    crystalline substance with so pl. 235-240 ° C.
    b) arabinofuranosyl) uracil 7.0 g (0.03 mol) of the product obtained in a), is dissolved in 585 ml of a mixture of ethanol and water, taken in a 1: 1 ratio, and 41 ml of III are added to the resulting solution sodium hydroxide. After stirring at room temperature for 2 hours, the solution is acidified to pH 4-5, Dowex ion exchange resin 50 (H) is added in portions to it, the resin is filtered and washed with 100 ml of a mixture of ethanol and water (1: 1). The filtrate is evaporated to dryness and the residue is recrystallized from ethanol. The result is 5.51 g (75%) of the title compound as a white crystalline substance with mp. 220-223 ° C.
    c) 1- ((-0-arabinofuranosyl-5-iodine) uracil.
    A mixture of 3.0 g (12.3 mmol) of the product obtained in stage b), 3.0 g (22.8 mmol) of iodine, 15 ml of chloroform and 30 ml of 0.1 M nitric acid is boiled in reverse. cooler with vigorous stirring for 2 hours. After cooling, the precipitated crystalline precipitate is separated by filtration and washed thoroughly with ether to remove excess iodine, and then recrystallized from water. The result is 2.55 g (56%) of the desired compound as a white crystalline substance with mp. (with decomposition of 191-193 ° C). PRI me R 2.1 - (/ 3-0-arabinofuranosyl) - 5-propynylcytosine.
    a) 5-iodo-1- (2,3,3-tri-0-acetyl- / J-D-apa-binofuranosyl) uracil.
    To a solution of 1 g (2.7 mmol) of 1 - ((-0-grabinofuranosyl) -5-ioduracil) in 10 ml of dry pyridine was added 1.04 g (11 mmol) of acetic anhydride. After stirring for 3 hours at room temperature, the solvent is distilled off, and the residue is evaporated several times together with CHaCte. The residue obtained is triturated with ethanol, the precipitate is filtered off and
    dried. The result is 1.25 g (93%) of the title compound with m.p. 175-179 ° C.
    b) 5-propinyl-1- (2,3,5-tri-0-acetyl-p-0-arabinofuranosyl) uracil.
    1.16 g (2.3 mmol) of the product obtained in stage a), 35 mg of copper iodide (), and 35 mg of bis (triphenylphosphine) palladium (II) chloride in 95 ml are stirred in a dry N2 atmosphere for 15 minutes. dry triethylamine, propine gas is passed through the mixture for 15 minutes and stirred for 1 hour in an atmosphere of Na at 50 ° C,
    after which the solution is filtered and the filtrate is evaporated to dryness. The residue is dissolved in 30 ml of CH2CI2, washed twice with 2% aqueous solution of ethylene diaminetetraacetic acid disodium salt in 25 ml portions and 50 ml of water.
    The organic fraction was dried (No. 2804) and evaporated. The result is 0.65 g of crude product, which is used in the next stage of the synthesis.
    d) -0-arabinofuranosyl) 5-propynylcytosine.
    The crude product obtained in stage b), the NH3 and NaO (3: 2: 1) is left to stand overnight at room temperature. Then the solution is evaporated to dryness, and a yellow colored oily liquid is obtained, which is triturated with ethanol. The result is 0.22 g of pure product with so pl. 241-243 C (with decomposition).
    Calculated,%: C49.05; H 5.586; N 14.30.
    C12H15N305:
    Found,%: C 49.28; H 5.32; N 13.95.
    EXAMPLE 3 2-Deoxy-5- {3-methylbut-1-ynyl) uridine.
    Iodoxuridine (5.31 g. 15 mmol), 50 ml of pyridine, 4.35 ml, (5.08 g, 33 mmol) of p-toluoyl chloride are stirred overnight at room temperature in a closed flask. The pyridine is then removed under vacuum at 50 ° C. The white solid residue is boiled with 100 ml of ethanol and then cooled. The white solid is filtered off, washed with 50 ml of ethyl alcohol, 50 ml of methyl alcohol, 100 ml of ether and dried in an oven at 80 ° C.
    100 ml of dry double-distilled triethylamine are deoxygenated by passing nitrogen for 10 minutes. While maintaining the atmosphere of nitrogen, 1.475 g (2.5 mmol) of di-p-toluoylidoxuridine, 40 mg of palladium bistriphenyl phosphine chloride, 11.40 mg of monovalent copper iodide and 1.54 ml (1.025 g, 12.5 mmol) of methyl -1-butine. The mixture is stirred for 3 hours at 50 ° C. The solid suspension is filtered and washed with a small amount of triethylamine. The solid compound is placed in methylene chloride (200 ml), washed with 2 x 75 ml EDTA, 100 ml of water, dried over magnesium sulfate, evaporated and a white solid is obtained. The white solid is dissolved in 25 ml of hot methylene chloride, diluted with ethanol to 50 ml, and incubated overnight at 5 ° C. White crystals are filtered off, washed with ethyl alcohol, ethyl ether and dried in a vacuum on a substrate at 70 ° C. 272 mg (0.5 mmol) of the product and 7.5 ml of a 0.2 M solution of sodium methylate (freshly prepared from metallic sodium and methyl alcohol) are stirred for 2.5 hours at room temperature. The solution is neutralized, adding Dowex (H) resin in portions. The resin is quickly filtered off and washed thoroughly with methyl alcohol. The filtrate is evaporated to dryness and the residue is treated with a mixture of 20 ml of water and 20 ml of ether. The aqueous layer is further washed with 20 ml of ether. The aqueous layer is evaporated to half the volume in a Buchi apparatus and then freeze dried to give a white solid. The white solid was chromatographically purified on silica gel, eluting with 7% MeOH in CHaCla. The fractions containing the desired compound are evaporated and a sticky solid is obtained, which is triturated with ether, filtered off and dried under vacuum at 70 ° C, mp. 180-181 ° C.
    Calculated,%: C 56.10; H 6.25; N 9.35.
    Found,%: C (56.24; H 5.97; N 9.31.
    Example 4. 2-Deoxy-5-cycloprolylethynyl uridine.
    The procedure of Example 3 is used, replacing 3,3-dimethyl-1-butyn with cycloproperylethin. Mp. 187-188 ° C.
    Calculated,%: C 57.53; H 5.52; N 9.59.
    Found %: C 57.75; H 5.53; N 9.52
    EXAMPLE 5.1- (8-0-arabinofuranopil) - 5- {3,3-bimethylbut-1-ynil) uracil.
    From a suspension (1.45 g, 2 mmol) of 5-iodo-1 -2, 3, 5 -tri-O-4-toluloyl-α-D-arabinofuranosyl) uracil in 80 ml of dry double-distilled triethylamine are removed oxygen , skip nitrogen for 20 min. While maintaining the nitrogen atmosphere, 30 mg of bis (triphenylphosphine) palladium chloride, 11.30 mg of monovalent copper iodide, 2 ml of 3,3-dimethyl-1-butine are added. The mixture was stirred in an oil bath for 4 hours under reflux at 50 ° C. The dark suspension is cooled, evaporated to a dry residue, which is dissolved in methylene chloride, washed with a 2% EDTA solution, 2 x 50 ml, 50 ml of water, then dried over magnesium sulfate, evaporated and a pale yellow solid is obtained. The solid compound is recrystallized from 20-30 ml of ethanol. The white crystals are filtered, washed with ethanol, and sulfuric ether and dried under vacuum at 70 ° C. This product (0.68 g, 1 mmol) and 20 ml (4 mmol) of 0.2M sodium methylate in methanol (freshly prepared from metallic sodium and methanol) are stirred for 3 hours at room temperature. The solution is neutralized by adding Dowex (H) resin in portions. The resin is quickly filtered and thoroughly mixed.
    methanol. The filtrate is distilled and the residue is treated with a mixture of 20 ml of water and 20 ml of ether. The aqueous layer is additionally washed with 20 ml of ether, evaporated to half the volume in a Buchi apparatus, lyophilized, and a white solid is obtained. The solid is purified chromatographically on silica gel, eluting with methylene chloride: methanol (9: 1), mp. 209-208 ° C.
    Calculated,%: C 55.55; H 6.22; N 8.64. Found,%: C 55.27; H 6.39; N 8.38. PRI me R 13. N / J-D-arabinofuranose l) -5 (-but-1 -and n and l) in rac and l.
    Use the method of example 5, replacing the Z. D-dimethyl-1-butin on 1-butin, so pl. 195-197 ° C.
    Calculated: C52JOMH 5.44; N.9,46. Found,%: C 52.34; H 5.33; N 9.35. Example14. -D-arabinofuranosyl) -5 (-3-methylbut-1-ynyl) uracil.
    The procedure of Example 5 is used, replacing 3,3-dimethyl-1-butyn with Z-methyl-1-butin, m.p. 204-205 ° C.
    Calculated,%: C 54.19; H 5.85; N 9.03. Found,%; C 53.83; H 5.91; N 8.71. , 1 p and mep 15, 1 - {/ 3-0-arabinofuranosyl) -5- (cyclopropylethynyl) uracil.
    The procedure of Example 5 is used, replacing 3,3-dimethyl-1-butyn with cyclopropylethin, m.p. 193-195 ° C.
    Calculated,%: C, 52.99; H 5.40; N 8.83. Found,%: C 52.85; H 5.05; N 8.64. Tests for toxicity and antiviral activity.
    Human cytomegalovirus (HCMV) was detected in monolayers of MRCs (human lung embryonic cells) or Detroit 532 (the foreskin of human fibroblast) in cellular trays.
    The activity of the compounds was determined in experiments to reduce the number of blood plates in which the monolayer of cells was infected with HCMV suspension, after which a layer of nutrient agarose was applied in the form of a gel in order to prevent the spread of the virus through the culture. Solutions of the test compound of various known molar concentrations were applied on top of the nutrient agarose. For each concentration, the number of blood plates was determined, expressed as a percentage of the number of plates in the control experiment, and a corresponding concentration dependence curve was constructed. From this curve, the concentration (ICso) was found, at which 50% inhibition was observed.
    Herpes Virus Generalizing Virus (VZV) was determined in MRC5 cells in a similar way with the difference that over the monolayer cells were not applied
    agarose layer.
    During the experiment, virus-producing cells (P3HR-1) were exposed to the drug for 14 days, after which the number of copies of the EBV genome in
    cell, for which EBV-specific hybridization with -RNA-DNA was performed. Epstein-Varr virus was detected by the methods of Nomoyama and Pagano. The resulting ICso value is
    the concentration required to inhibit by 50% the number of EBV genomes in a cell.
    Cell toxicity was determined in experiments on cell growth inhibition. Subconfluent cultures of Vero cells grown in 96-cell Mlcrotiter vessels were exposed to preparations with different content of active substance, and daily viability was determined
    cells on replicative cultures by uptake of tetrazolium dye (MTT). The concentration at which the 50% inhibition of cell viability occurred after 96 hours was taken as CCIDso.
    The results are shown in the table.
    As can be seen from the above data, the newly obtained compounds have activity in relation to VZV and significantly
    lower toxicity than the well-known structural analogue of 2-deoxy-5-ethynyl uridine, which is ineffective in human chemotherapy, due to its unacceptably high level of toxicity (CCIDso, μM: 0.3-3).
    权利要求:
    Claims (1)
    [1]
    The invention The method of obtaining pyrimidine nucleosides of the general formula
    45
    where R is an oxo or imino group;
    R2 is a C1-2 alkyl, branched alkyl or cyclopropyl radical;
    R4 is a hydrogen or hydroxy group, provided that if Ri is an oxo group, and R4 is hydrogen or a hydroxy group, then R2 can not be methyl, ethyl or isobutyl, characterized in that the compound of general formula II:
    where each of M2 and M3 is a hydroxy protecting group;
    R4a is hydrogen or a hydroxy-protecting group;
    Z is halogen
    subjected to interaction with the compound of General formula III
    HC5CR2,
    where R2 has the indicated values using bis (triphenylphosphine) palladium chloride and copper iodide as a catalyst in the presence of an organic base at 50 ° C.
    Note tested.
     means that the indicated concentration is the highest of
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB868629892A|GB8629892D0|1986-12-15|1986-12-15|Antiviral compounds|LV920338A| LV5273A3|1986-12-15|1992-12-18|Satisfaction with the production of pirimidine nucleosides|
    LTRP271A| LT2064B|1986-12-15|1992-12-30|THE PRICE OF PYRIMIDIN NUCLEOSID RECEPTION|
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