• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The invention relates to (E)-5-(2-bromovinyl)-uridine and its derivatives of general formula VI, <IMAGE> VI wherein R1 stands for a hydrogen atom, C1-8 alkanoyl group, benzoyl group or a benzoyl group substituted in para position either with a C1-4 alkyl group or a halogen atom, and a process for preparing them by brominating 2',3',5'-tri-O-acyl-5-ethyl-uridine of general formula IV, <IMAGE> IV wherein R is identical with R1, except where R1 stands for a hydrogen atom, dehydrohalogenating the resulting dibromo compound of general formula V <IMAGE> V and optionally deacylating it. The resulting compounds of general formula VI are exhibiting significant potency against Herpes simplex virus species and are of remarkably low acute toxicity.
    公开号:SU1240363A3
    申请号:SU823491621
    申请日:1982-09-07
    公开日:1986-06-23
    发明作者:Саболч Анна；Етвеш Ласло；Шаги Янош；Семзе Аттила；Переди Мариа；Хорват Иштван；Коцка Иштван；Ретати Чилла；Иван Пал；Фритцше Илдико；Надь Янош
    申请人:Эдът Дъедъсерведъесети Дъяр (Инопредприятие)；
    IPC主号:
    专利说明:

    "SA- CH-SNtrG
    where R has the indicated values, directly or after separation and dissolving in an alcohol with 1-4 carbon atoms, is deacylated with an alkali metal alcohol with 1-4 carbon atoms.
    The invention relates to chemistry; nucleosides, namely, to the method of semi-. The new compound EO-S-SZ-bromovinyl) uridine is formulated.
    snvg;
    BUT HE
    The aim of the invention is to develop a process for the production of a ribonucleoside of formula 1, possessing anti-herpes activity and a lower toxicity than the structural analogue-. -2-deoxynucleoside E3-5- (2-bromo-vinyl) uracil.
    NOTE 1. 2, 3, 5 -tri-0-benzosh1-EZ-5- (2-bromovinyl) uridine (IVjR-benzoyl).
    56.0 g (0.095 mol) 2, 3
    five
    - Three O-benzosh1-5-ethyluridine with weak heating is dissolved in 400 ppm of anhydrous dichloromethane. Heating is stopped. In a stream of nitrogen and under UV irradiation for 20-25 minutes, 34.15 g (11 ml) of bromine is added to the solution. After the addition of bromine is completed, the source of UV radiation is turned off and the reaction mixture is heated for 30-40 min under reflux. Then the solvent and hydrogen bromide formed are removed in vacuo. The remaining pale yellow syrup is diluted with 20 ml of anhydrous dichloromethane and recharged again. The residue is then dissolved in 200 ml of anhydrous acetate, the solution at constant
    0
    five
    0
    five
    0
    40
    five
    After stirring, 15 ml of lio added are added drops of triethylamine, the resulting triethylamine hydro- / bromide is filtered off and the filter is washed with 2 x 20 ml of ethyl acetate. The filtrate is combined with the washings and evaporated under vacuum. 63.0 g of stiff foam are obtained as a residue from injection. 100% yield. After rubbing with ethyl alcohol, white crystals are obtained, melting at 160-170 s. The product, if desired, can be deactivated directly.
    . 2, 3, 5 -tri-0-benzosh1-5-etsh1-uridine, used as starting material, can be obtained as follows:
    a) 2,4-bis- (0-trimethylsilyl) -5-g-ethylsuracil. ..
    To 40 g (0.285 mol) of pre-dried, under vacuum at 150 ° C, ethyl succinic surfactant is 80, ml; (0.5 mol) 1,1,1,3,3, 3-hexamethyldiilazane.
    The reaction mixture was refluxed for 24 hours in the absence of moisture. The resulting clear solution is evaporated at atmospheric pressure. A dry syrup is obtained as an ohstat from a rotary anion, which is distilled under discharging., Yield 78.95 g (97%). TGkip. T34 C (1733 Pa).
    c) 1-0-acetyl-2,3,5-tri-0-benzosh1-β-D-ribose.
    60 g (0.4 mol) of D-ribsy are dissolved in 1280 ml of absolute methanol. 34 ml was added to the solution; 11.2% methanolic hydrochloric acid solution. The reaction mixture was neighing for 24 hours at 20 ° C under conditions that prevent ingress of moisture. The mixture is then neutralized with 120 ml of pyridine and vacuum in at 30-40 ° C.
    The residue is treated with another 120 ml of pyridine and again evaporated. The slightly yellow viscous syrup 5 obtained is dissolved in a mixture of 304 ml of pyridine
    crystals that have been separated are separated by decantation of water. The crystals are stirred with 500 ml of water, the liquid is decanted again, then again mixed with 200 ml of 50-80% methanol and then filtered. The crude product is transfer of 320 ml of chloroform. The mixture during cooling is crystallized from l of methanol4, and treated with ice is treated with 233.8 ml. 128.5 g (60%) of the product is obtained, and the distilled beisochloride is melted and melted at 131 C. then left overnight in chlorodilne-10 c) 2,3,5 -trigO benzoyl-5-etyp. ke.Na next day the mixture is poured on uridine
    ice and thus decompose in excess of 48.1 g (0.095 mol) of 1-0-acetyl benzoyl chloride. Then, -2,3,5-tri-0-benzoyl-d-ribO: the seeds are grown. The aqueous phase is extracted with steeped in 1690 ml of dichloromethia. Grow 2x160 ml of chloroform, chloroform f the thief with stirring is treated. Extracts are combined. Washed with 200 ml of 33.7 g (mol) 2,4-bis- (0-trime- water, dried over anhydrous sulfylsily l) -5-ethyluracil and 14 ml of sodium chloroformate and heated at 30 - Tg of tin (IV) in 110 ml of dichloromethane in a vacuum. 100 ml is added. The reaction mixture is stirred for 2-3 hours of luol and again evaporated. After removal, 20 and then kept at 24 hours at. A mixture of traces of solvent is obtained. Then the mixture is shaken with 2300 ml of a red oil. It is dissolved in a standard aqueous solution of bicarbonate, a mixture of 96 ml of glacial acetic acid potassium. The organic layer is separated, you are 224 ml of acetic anhydride, dried, and evaporated under a solution with vigorous stirring and 25 times. Belm crystalline residue is cooled with ice slowly (during recrystallization from 250 ml of this
    2-3 hours) are treated with 32 ml. 95-97% sulfuric acid and then left in the refrigerator overnight. The next day, the mixture is drunk on ice, and from vynola. Yield 53.5 g (95%). T. pl. 155
    156 C.
    The products obtained in examples 2 to 5, are presented in table. 1. „
    / -.
    Example
    I
    Product
    2,3,5 -tri-0-acetyl-fE -5- (2-bromo-vinyl) ypidine
    2, 3, 5 -pri-0- (p xl6benzoyl) (2-bromovinyl) -uridine
    2,3,5 -tri-0-octanpyl-E-5- (2-bpbmvinyl) uridine
    2,3,5 -tri-0- (p-methylbenzoyl) -5-, (2-bromovinyl) uridine
    The starting materials for Examples 2-5 were prepared in the manner described in Example 1. .
    Example 6: E3-5- (2-bromovinyl) uridine (1)
    , To 65.5 g (0.11 Yol) 2, 3, 5 -. -Benzoyl-E3-5- (2-bromo-vinyl) -ridine, the crude product of Example 1) was added 250 mp 0.5 n. sodium methylate and 250 ml of absolute methanol. The reaction mixture is stirred
    nola. Yield 53.5 g (95%). T. pl. 155
    156 C.
    The products obtained in examples 2 to 5, are presented in table. 1. „
    . . . Table 1
    / -.
    Indicators
    M.p. 145.5 ° C
    M.p. 187-188 seconds
    T. 98-1. (133.3 Pa)
    Bp 209 С
    at -. If the precipitate is removed, it is filtered, the pH of the clear solution is set to 5-6. Using a Domex 50H ion exchange resin. the resin is then separated by filtration and; .- washed with 2x100 ml of methanol. The filtrate and the washings are combined and then evaporated under vacuum. The residue is treated with ethanol and benzene. After that, rubbing up the residue with ether will get 33 hours of r-uncleaned product which is crossed from water and then from ethanol. Yield 28 g (71.7%). T. pl / 165-167 C.
     PRI me R 7. Confirmation of -. development of 5- (1,2-dibromoethyl) .- 2, 3, 5 - three O (p-chloro benzoyl) uridine. as an intermediate product in the process. : booking 2, 3, / 5-three-0- (-chlorine
    benzryl) -5-ethyluride.
    2,3, 5-tripi-0 - () - chlorobenzoyl) - -5-ethylurelIdIn is reserved as described in example 1, after the end of the reaction the solvent is evaporated, the remaining syrup-like product is added
    {l
    anhydrous methyl alcohol, the reaction mixture is held for 10-15 minutes at room temperature, the methanol is evaporated in vacuo at room temperature. The residue is chromatographed on a column filled with silica gel 60. (particle size 70-350 microns, column diameter 2 cm, loading height 50 cm, eluent chloroform}.
    The residue obtained after evaporation of chloroform was subjected to NMR studies. The NMR spectrum was taken on a Varian X -100-VFT spectrophotometer, frequency 100, 1 MHz, deuterochloroform was used as a standard, tetramethylsilane was used as an internal standard.
    The results of NMR spectrometry are given in Table. 2.;
    Table 2
    The data obtained unambiguously confirm that 5- (1-methoxy--2-bromo), 3, 5 -tri-0- (p-chloro-55 benzoyl) uridine are formed by reaction with methanol. This compound can only be formed if the so-called bromine atom is in the ethyl
    five

    1st radical of 5- (1,2-dibromoethyl) -2, 3, 5 -tri-0- (p-chlorobenzyl) uridine, formed during bromination, replaced; when treated with methanol on; methoxyl group.
    The presented data unequivocally proves that the synthesized derivative of 5- (1,2-dibromo-ethyl) ypidine is formed by synthesizing the derivatives of Z-ztiluridine under the conditions of example 1.
    The activated activity of the compound of formula T is evaluated as follows; First, the concentration of the substance in the tissue culture fluid that does not cause cell damage, which can be seen or measured, is determined. This concentration is designated CT. The compound is highly specific, i. E. It is suitable for treatment, if it is in a concentration of Mpd or even less. It inhibits the multiplication of viruses in tissue. . .
    The potency of the compound of general formula 1 against viruses is shown in Tables 1 and 2.
    The action of analogues nukleozida. . virus multiplication in cell cultures at concentrations is given in table 1.
    Table 3
    ++++
    ABOUT
    The inhibitory effect of the compound of formula 1 on the reproduction of viruses is given in Table 2.
    . T a b l and c a 4

    2.77 2.5. 2.5 3.0
    3.23i 3.33 3.25 3.0.
    , Continuation of table 4
    For the experiment with Herpes Simp Tech-25 Tour1 in the Heha-cell culture for CU -5- (2-bromo-twin) -uridine, the ratio between the therapeutic and the harmful dose of the drug was obtained: 10 63, from a value showing 50% action on. control.
    Intravenously
    Intraperitoneal
     Toxicity Study i.V. limited due to
     solubility in the water of the compound. Aqueous suspensions of compounds prepared with polyoxyethylene; Rbitol-L-monoleate (Tween 80): and carboxymethylcellulose.
     (2-bromovinyl) uridine is different. Slight toxicity for; Tissue (2-bromovinyl) -uridine was also confirmed by mouse acute toxicity tests (LD-).
    Acute toxicity on the skin (solvent: water containing 20% dimeti - formamide 24 h is given in tab. B.
    T a b l and c a 6
    0/5
    4/5
    9 . . 124036310 Drugs, cooked tablets, etc., can be used
    In a known manner with (2-against diseases caused by Neg-bromovinyl) -uridine as ree 5imp6ex type 1, not only. lobiologicheskogo active agents, tykalno, but also a sstaticheskichesky solutions for injections, ointments ,.
    权利要求:
    Claims (1)
    [1]
    METHOD OF OBTAINING [e] -5- (2-BROMVINIL) URIDINE formula
    Sn 2 Sn 3
    where k is an alkanoyl group with 1-8. carbon atoms, a benzoyl group unsubstituted or substituted in the para position by halogen or alkyl radical with 1-4 carbon atoms, is reacted with elemental bromine under the action of UV and emission in a halogenated hydrocarbon, for example, in dichloromethane, followed by boiling the reaction mass by distilling off the solvent, and formed dibromo derivatives of the general formula
    WITH
    with
    about
    t ^ mon- 2
    Vg Vg
    but
    BUT HE
    ΌΗ0Η
    This is due to the fact that 2, 3 *, 2 5 ^ -tri-0-acyl-5-ethyluridine.
    general formula
    where K has the indicated meanings, is treated with a lower tertiary alkylamine, for example, triethipamine, and 'ethyl acetate, after which the resulting 2 3 *, 5 * -tri-0-acyl- (X] -5- (2-bromovinyl Uridine of the general formula
    1240363
    -СН »СН2рГ
    ΗΝ ·
    Ο ^ -ι
    where K has the indicated values, directly or after separation and dissolution in alcohol with 1-4 carbon atoms, are deacylated with alkali metal alcoholate with 1-4 carbon atoms.
    *,' :· ' 'four. . . /
    ' one
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