• 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 heterocyclic substances, in particular, the preparation of isoxazole derivatives of the total f-ly 1: AO (CH 2 ) 7 -C = CH-C (CH 3 ) = NO, where the A group of the f-files is P or W: -C = CH-CH-CK-S (P) -C = CH-S-CHK-CH 2 (III) with K-C = N- (CH 2 ) 2 -O, which have antiviral activity that can be used in medicine. The goal is to create more active substances of the specified class. Synthesis is carried out by cyclization of compounds f-ly 1U or Y: HO- (CH 2 ) 2 -NH-C (O) -X 1 -O- (CH 2 ) 7 -C = CH-C (CH 3 ) = NO (1U ) HO- (CH 2 ) 2 -NH-C (O) -X 2 -O- (CH 2 ) 7 -C = CH-C (CH 3 ) = NO (V), where X 1 is @ and X 2 - @, using a dehydration agent and thionyl chloride in an inert solvent. The novel compounds, when antivirals are active, are superior in comparison with the known lipophilic properties, which allow BLUT-HIRNSCHRANKE to overcome. 2 tab.
    公开号:SU1493106A3
    申请号:SU864027501
    申请日:1986-05-16
    公开日:1989-07-07
    发明作者:Биндер Дитер；Ровенски Франц
    申请人:Хеми Линц, Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new isoxazole derivatives of the general formula
    NZS
    TL- (CH2) 7-0-A V
    where A is a group of general formula
    RI

    or
    ABOUT
    tya)
    S o
    where R, is hydrogen, possessing antiviral activity.
    The purpose of the invention is the creation of new compounds of the isoxazole series, which have an improved antiviral activity.
    Example 1 (4,5-dihydro-2-oxazolyl) -2-thienyl} -oxyheptyl j-3-methylisoxazole.
    0.60 g (1.64 mmol) of N- (2-oxyethyl) amide (3-methyl-5-isoxazo-, lil) heptyloxy} -2-thiophenecarboxylic acid amide is added with 2.5 ml of thionyl chloride. The mixture is stirred for 15 minutes at which time the excess amount is removed in Vacuum.
    CO 00
    oh oh

    s
    Thionyl chloride. The residue is distributed between a saturated solution of sodium hydrogencarbonate and ethyl acetate. Sa is then extracted twice more with ethyl acetate. The combined organic solutions are dried over sodium sulfate with the addition of activated carbon, and then evaporated.
    The crude product (0.52 g of a yellowish colored crystalline substance) is purified by chromatography on a column (1:35, silica gel 60, grain size 0.040-0.063; eluting agent; ethyl ester of acetic acid and petroleum ether 3: one).
    Yield: 0.29 g of a colorless crystalline substance (50.7% of the theoretically calculated value). M.p. 69-70 ° C (from diisopropyl ether).
    The starting material is prepared in the manner described below.
     H-NMR: (CDCl) cG, ppm: 7.27; 7.22; 6.18; 6.13 (AB; 2H; Th-Hj and Th-H); 5.79 (s; 1H ;; I sox - H); 4.05 (t; J 6.6 Hz; 2H; -OCH, -); 4.50-3.92 (,; 4H; -0-CH-CHj-N-); 2.70 (t, J 6.6 Hz; 2H; I - - GU-); 2.25 (s; 3H; CH p; 1.85-1.12 (in; lOH; - (CH) -).
    5- (7-chlorheptyl) -3-methylisoxazole
    21.0 g (0.216 mol) of 3,5-dimethyl-isoxazole is dissolved in 200 ml of absolute tetrahydrofuran, the solution is cooled to, and then at this temperature, 160 ml of n-butyl lithium solution is added to the solution within 40 minutes 1.35 M solution in n-hexane, 0.216 mol). Then the mixture is additionally stirred for 15 min at -75 ° C.
    Immediately after this, the reaction mixture is added dropwise to a solution of 53.5 g (0.217 mol) of 1-iodine
    6-chlorohexane in 150 ml of absolute tetrahydrofuran so that the temperature does not rise above
    -60 ° C. After completing the addition

    the reaction mixture is further stirred for 15 minutes at −60 ° C, and then the temperature of the mixture is allowed to rise to room temperature.
    The reaction mixture is partitioned between methylene chloride and 0.2 and.
    ABOUT
    15
    20
    25
    thirty
    -j
    40
    45
    0
    five
    with a solution of hydrochloric acid, the aqueous phase is extracted three times with methylene chloride, the combined organic phases are dried over sodium sulfate and evaporated.
    The crude product (about 45 g) is distilled in portions in a tube with ball expansion (air bath temperature, 0.2 mbar).
    Yield 26.9%, a yellowish oily substance.
     H-NMR (CDCl1) f, ppm: 5.81 (s; 1H; I SOX - H); 3.51 (t, 6 Hz; 2H; -CH-jCl); 2.68 (t, J 6.6 Hz;
    - SOX
    -); 2.23 (s; 3H; I
    5 ox
    ); 1.85 - 1.15 (m; 10H; - (CH) -).
    Methyl 5-G7- (3-methyl-5- -isoxazolyl) -heptyloxy} -2-thiopheicarboxylic ester.
    9.3 g (43.1 mmol) of 5- (7-chlorheptyl) -3-methylisoxazole and 7.12 g (47.4 mmol) of sodium iodide are heated for 24 hours in 60 ml of absolute acetone at the boiling point of the reaction mixture. mixture with reflux. Immediately after this, the reaction mixture is cooled, the precipitated porous sodium is filtered off, washed with a small amount of acetone, after which the filtrate is mixed with 7.16 g (45.3 mmol) of 5-hydroxy-2-thiophenecarboxylic acid methyl ester and 13.1 g (94.8 mmol) potassium carbonate. The mixture is heated under reflux at its boiling point for 2 hours, cooled and then evaporated. The residue is partitioned between water and diethyl ether, after which the aqueous phase is extracted twice with diethyl ether. The combined organic solutions are washed with a small amount of a saturated sodium hydrosulfite solution, dried over sulfuric acid, with sodium when activated carbon is added, but: 5. then evaporated. .
    The crude product (11.9 g 82 of the theoretically calculated value) is recrystallized from diisopropyl ether).
    Yield 5.2 g of a crystalline substance colored in light, pink color (35.5% of the theoretically calculated value). T. pl. 55-5b C (from diisopropyl ether).
    H - NMR (CDClI) (G, ppm: 7.54; 7.49; 6.18; 6.13 (AB; 2H; Th-Hj and Th-H); 5.79 (s; 1H: I sox H 4);
    4.04 (t, J 6.6 Hz; 2H; -OCHj-); 3.88 (s; 3H; -OCH3-); 2.67 (t, J 6.6 Hz; 2H; Ijox -); 2.25 (s; 3H; ISOA - CH.-); 1.88-1.12 (s; 10H; - (CHj), -).
    (3-Methyl-5-isoxazolyl) -Pheptyloxy -2-thiophenecarboxylic acid.
    0.98 g (2.90 mmol) of 5-G7- (3-methyl-5-isoxazolyl) -heptyloxy -2-thiophenecarboxylic acid methyl ester is heated in 8 ml of ethanol and 4 ml of water under reflux to the boiling point of the mixture, After that, 0.18 g (3.19 mmol) of potassium hydroxide dissolved in 6 ml of water and A ml of ethyl alcohol are added dropwise to the solution obtained during 10 minutes. Directly after this, the reaction mixture is additionally stirred for 2.5 hours under reflux at its boiling point.
    After cooling, most of the mixture is distilled off, the residue is partitioned between water and diethyl ether, and the aqueous phase is then acidified by the addition of 2N. hydrochloric acid to pH 1.5. Then 80 ml of the latter are used, the combined organic solutions are dried over sodium sulfate with the addition of activated carbon and dried.
    Yield 0.90 g of a colorless crystalline substance (95.8% of the theoretically calculated value). T.SH1. 96-9T with (from diisopropyl ether).
    H-NMR (CDCl1) il, ppm: 10.5 (S.Breit; 1H; -OH); 7.64; 7.59; 6.26 6.21: (AB; 2H; Th — N g and Th — H); 5.80 (s; H; I zoh 4.09 (t, J 6.6 Hz; 2H; -OCHj-); 2.69 (t, J 6.6 Hz; 2H; I); 2.26 ( s; 3H; Isox - CH3); 1.95 - 1.30 (ha; YUN; - (CH) 5-).
    N- (2-Hydroxyethyl) amide-5- 7- (3-methyl-5-isocSazolyl) heptyloxy -2-thiophenic carboxylic acid.
    To 0.81 g (2.51 mmol) of (3-methyl-5-isoxazolyl) -heptyloxy-2-thiophencarboxylic acid, 2 ml of thionyl chloride are slowly added dropwise with stirring and cooling, resulting in a clear solution. Then the reaction mixture was further stirred for 30 minutes at room temperature, and the non-intermediate was then distilled under vacuum in an excess amount of thionyl chloride. The residue is dissolved in 6 ml of absolute methylene chloride, after which, at 15 ° C, a solution of 0.34 g (5.51 mmol) of ethanolamine in 5 ml of absolute methylene chloride is added dropwise to the prepared solution. The reaction mixture is further stirred for 1 hour at room temperature, somewhat evaporated, and then partitioned between water and ethyl acetate. The aqueous phase is again extracted with a small amount of ethyl acetate, the combined organic solutions are washed with water, dried over
    0 Sodium sulphate when activated carbon is added and evaporated.
    Yield 0.81 g of a yellowish crystalline substance (88.2% of the theoretically calculated value). T. pl. 107-110 ° C (from acetonitrile).
    GN-NMR (CDClj) / ppm: 7.25; 7.20; 6.17; 6.13- (AB, 2H, Th-H), 6.73 (t.breit, 1H, N-H), 5.80 (s,
    30 1H, ISPX-H), 4.04 (t,, 6 H, 2H, Th-OCH, -); 3.78 (t,, 9 Hz; 2H;); 3.57 (t,, 1 Hz; 2H, -N-CH -); 2.69 (t,, 6 Hz; 2H; Igox-CH -), 2.25 (s, 3H, ISQ-CHP.
    5 I 1.85-1.12 (m, 10H, - (CH2) 5-).
     Example 2. (4,5-Dihydro-2-oxazolyl) -2-thienyl J-hydroxyheptyl J-3-methylisoxazole.
    0.60 g (1.64 mmol) N- (2-oxyethyl)
    The 40 (3-methyl-5-isoxazolyl) -heptyloxy -2-thiophenecarboxylic acid amide is dissolved in 30 ml of chloroform, after which the prepared solution is mixed at 0 ° C with 0.3 g
    45 (2.54 mmol) of thionyl chloride. Immediately thereafter, the reaction mixture is stirred for 60 minutes at, as a result of which a dry residue is obtained. The residue is distributed between the whole (sodium hydrogen carbonate solution and ethyl acetate). Extraction is carried out twice with ethyl acetate, and the combined organic solutions are dried over sodium sulfate by the addition of activated carbon and evaporated. Purification of the crude product with: help column chromatography was carried out by analogy with that described in Example 1.
    Yield 0.24 g of a colorless crystalline substance (42% of the theoretical value 1) of the theoretically calculated value. T.im. 68-70 ° C (from dinzopropyl ether).
    Example 3. (4,5-Dihydro-2-oxazolyl) -4-thien-1-hydroxy-3-methylisoxazole.
    2.06 g (5.62 mmol) of K- (2-hydroxyeth-1) amide-4-C7- (3-methyl-5-isoxazolyl) - heptyloxy J-2-thiophenecarboxylic acid at 0 ° C are introduced into 5 ml of chloride thionyl. The mixture is stirred for 10 minutes at 0 ° C, after which an excess amount of thionyl chloride is removed in a vacuum without heating. The residue is partitioned between saturated sodium carbonate 20 solution and acetic acid ethyl ester. Extraction is carried out twice with ethyl acetate and the combined organic solutions are dried over sodium sulfate 25 with the addition of activated carbon and evaporated. The crude oily substance is purified by chromatography on a column (1:40, silica gel 60, grain size of the DZ from 0.040 to 0.063; eluting agents: ethyl acetate and petroleum ether in a ratio of 3: 1).
    The yield of 0.52 g of a crystalline substance colored in yellowish color, - (26.5% of the theoretically calculated value). T. pl. 67-68 ° C (from di - and zopropyl ether).
    The starting material is prepared as described below. 4Q
    H-NMR (CDClI) d, ppm: 7.22 (d, 7 Hz; 1H, Th-Hz), 6.37 (d, 7 Hz; 1H, Th-H), 5.80 (s, 1H, I SQX - -H,), 4.50-3.92 (, 4H, -0-CH, -), 3.93 (t ,, 6 Hz; 2H, 45), 2.70 (t, , 6 Hz: 2H, ISQX CH-2-), 2.25 (s, 3H, Isox-CHP, 1.85-1.20 (m, 10H, - (CH) -).
    Methyl 4-hydroxy-2-thiofesh aronic acid .50
    50.0 g (0.347 mol) of 4-hydroxy-2-thiophene carbonic acid and 58.3 g (0.694 mol) of sodium carbonate are heated under nitrogen in 900 ml of absolute 2-butanone to the boiling point, and then to the prepared mixture 43.7 g (0.347 mol) of dimethyl sulfate are added dropwise over 20 minutes. Then the reaction mixture is additionally heated for 2.5 hours under reflux at boiling point. Immediately after this, the reaction mixture is evaporated in vacuo, the residue is distributed between saturated sodium carbonate solution and diethyl ether, the aqueous phase is extracted five more times with diethyl ether, each time using 80 ml of the latter. The combined organic solutions are dried over sodium sulfate with the addition of activated carbon, filtered and evaporated.
    Yield 49.6 The yellowish-colored Tbtfi color of the crystalline substance (90% of the theoretically calculated value). T. pl. 84-85 ° C (from a mixture of diisopropyl ether and petroleum ether).
    GN-NMR (CDCl,) tf, ppm: 7.22 (d, 7 Hz; W, Th-Hz), 6.64 (d, J 1.7 Hz, 1H, Th-H4), 6.70 (s, 1H, -OH), 3.88 (s, 3H, -OCHj).
    5- (7-iodoheptyl) -3-methylisoxazole.
    16.66 g (77.23 mmol) of 5- (7-chloroheptyl) -3-methylisoxazole and 12.75 g (85.06 mmol) of sodium iodide are heated under reflux in 110 ml of anhydrous acetone at the boiling point of the mixture.
    According to -H-NMR spectroscopy, after 7 hours the degree of transference is approximately 85%, and after 22 hours - approximately 89%. After 27 hours, the reaction mixture was evaporated and the residue was partitioned between dichloromethane and water (with the addition of a few milliliters-shitts of 2N hydrochloric acid). The aqueous phase is extracted several times with dichloromethane, with a total of 250 ml of the latter being used, and the organic phase is dried over sodium sulfate and evaporated.
    Yield 22.95 g of brown colored liquid (96.7%) of the theoretically calculated value.
    H-NMR: (CBC1) cG, ppm: 5.81 (s, 1H, Isox-H4), 3.18 (t, 6 Hz; 2H, -CH), 2.69 (t, 6 Hz) ; 2H, -CH, -), 2.55 (s, 3H, Ijox-CHj), 1.85-1.25 (ra, 10H, - (CHg) 5-).
    Methyl 4-t7- (3-methyl-5- -isoxazolyl) -heptyloxy} -2-thiophenecarboxylic ester.
    6, (40.60 mmls) of 4-hydroxy-2-thiophenecarboxylic acid methyl ester and 11.88 g (38.67 mmol) of 5- (7-iodoheptonl) -3-methylisoxazole are heated from 5.34 for 8 hours g (40.60 mmol) of potassium carbonate in 130 ml of anhydrous acetone at reflux temperature. The reaction mixture was incubated overnight, and then evaporated. The residue is distributed between 2N. With a solution of sodium hydroxide and diethyl ether, the aqueous phase is extracted several times with diethyl ether, with a total of 150 ml of the latter being used. The organic phase is dried over sodium sulfate with the addition of activated carbon and evaporated.
    Yield 12.56 g of a yellow colored crystalline substance (95.3% of the theoretically calculated value), m.p. 58-60 C.
    H-NMR (CDCl) tf, ppm: 7.41 (d: 7 Hz; 1H, Th-Ne), 6.50 (d, 7 Ng; 1H, Th-H), 5.80 (s, 1H; ISOX-H) 3.94 (t, 6 Hz; 2H,), 3.87 (s, 3H, -OCHj), 2.70 (t, 6 Hz; 2H, l5o, (), 2 , 26 (s, 3H, I5o - CHj), 1.88-1.25 (m, 10H, - (CH,) 5-).
    4-7- (3-Mityl-5-isoxazolyl) - heptyloxy 3-2-thiophenecarboxylic acid.
    11.34 g (33.61 mmol) of 4-G7- (3-methyl-5-isoxazolyl) -heptyloxyJ-thiophencarboxylic acid methyl ester is heated under reflux in 95 ml of ethanol and 45 ml of water at boiling point, after To this, 2.18 g (38.9 mmol) of potassium hydroxide dissolved in 70 ml of water and 46 ml of ethyl alcohol are added dropwise to the prepared solution. After heating for 3 hours at reflux temperature, the reaction mixture is cooled, evaporated, the residue is partitioned between water and diethyl ether, and the aqueous phase after acidification with 2N. hydrochloric acid is extracted several times with diethyl ether. The combined organic solutions are dried over sodium sulfate with the addition of activated carbon and evaporated.
    Yield 9.28 g of a yellow colored crystalline substance (85.6% of the theoretically calculated value). T. pl. 1 10-1 13 ° C.
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    The crude product, which can be directly applied in the subsequent step, W1I can be recrystallized from diisopropyl ether, with the result that a colorless crystalline substance is formed.
    IH-NMR (SG) C1Z), PPT: .10.8 (S.breit, 1H, -OH), 7.48 (d, 7 Hz; 1H, Th-Hj), 6.58 (d, 7 Hz; 1H, Th-H), 5.80 (s, 1H, ISOX-H), 3.94 (t, 2 Hz; 2H, -OCH, -), 2.70 (t, 6 Hz; 2H;, -), 2.26 (s, 3H,), 1.95-1.30 (m, 10H, - (CH,) 5-)
    N- (2-hydroxyethyl) -amide-4- 7- (3-methyl-5-isoxazolyl) heptyloxy -2-thiophenic carboxylic acid.
    Approximately 15 ml of thionyl chloride was added to 5.3 g (16.44 mmol) of 4-17- (3-methyl-5-isoxazolyl) -heptyloxyJ-2-thiophencarboxylic acid, followed by reaction. the mixture is stirred at room temperature for 20 minutes. The residue obtained after filtration using vacuum of a water jet pump is dissolved in 40 ml of anhydrous dichloromethane, and then a solution of 2.2 g (36.09 mmol) of ethanolamine in 40 ml of anhydrous dichloromethane is added dropwise to the prepared solution while cooling. . The reaction mixture is stirred for 2 hours at room temperature, then evaporated, the residue is distributed between water and dichloromethane, and a small amount of 2N is added to improve phase separation. hydrochloric acid solution. The organic phase obtained after separation of the phases is dried over sodium sulfate upon the addition of activated carbon and evaporated.
    Yield 5.74 g of the brown colored crystalline substance (95.6% of the theoretically calculated value). M.p. 56-57 ° C (the crude product, without reducing the yield, directly be used to prepare the compound of the present formula.
    IH-NMR (CDClI), J, ppm: 7.41 (d, 7 Hz; 1H, Th-Hj), 6.50 (d; J 1.7 Hz; .1H, Th-H), 6, 78 (t.breit, 1H, NH), 5.80 (s, 1H,), 4.04 (t, 6 Hz; 2H, -OCH, -), 3.78 (t, Hz; 2H, - CH -OH), 3.57 (t,, 1 Hz; 2H, -N-CHj-), 2.69 (t, 6.6 Hz; 2H, ISOX-CH, -), 2.25 (e, 3H,
    Isox-CHj), 1.85 - 1.12 (m, 10H, - (CHj) -).
    Example 4. (4,5-Dihydro-2 oxazole) -2-tnenyl oxyheptyl} - -3-methnlxoxazole.
    Example 1 is repeated except that the addition of thionyl chloride and the subsequent 15 minutes of stirring are carried out at a temperature specified in the table. The following yields are obtained (4,5-dihydro-2-oxazolyl) -2-thienyl-oxyheptyl) -3-methyl-isoxazole,% of theory: -20 ° C 38.2; -15 ° C 34.6} -10 ° C 41.4; -5 with 48.3 50.7; 4.5 ° C 47.5; 35.8. - Example 5. 5-17- 2- (4,5-Di-hydro-2-oxazolyl) -4-thienyl oxyheptyl-3-methylisoxazole.
    2.06 g (5.62 mmol) of the amide H- (2-hydroxyethyl) (3-methyl-5-isoxazolyl) -heptyloxy -2-thiophenecarboxylic acid is introduced into 10 ml of phosphorus oxychloride and stirred for another 10 minutes. Thereafter, it is carefully evaporated under vacuum, and the residue is dispersed between 50 ml of saturated sodium bicarbonate solution and 80 ml of ethyl acetate. The aqueous phase is extracted twice more, each time with 40 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on a column, the desired product being eluted as the first (silica gel 60, solvent: ethyl acetate and petroleum ether 1: 1).
    Output 0.43 g (21.9% of theory), so pl. 66-68 ° C (diisopropyl ether)
    The compounds of the present general formula have an anti-infection effect and have a pronounced ability to neutralize the action of viruses. These valuable pharmacological properties can be determined in vitro and in vivo using standard methods. At the same time, the proposed compounds of the general formula show, in particular, an excellent effect against various TYPES of foodborne viruses, Picorna viruses and rhinoviruses, and therefore can be used in medicine for the treatment and prevention of viral diseases.
    The following test method is used to investigate the ability to neutralize the effect of viruses.
    a
    five
    0
    five
    0
    five
    0
    five
    0
    five
    A series of serially diluted three solutions of the substance to be examined in an MEA (minimal essential medium) is prepared on flat bottom microtitre plates. Equal volumes of diluted viruses in MES and cell suspensions in MES are mixed with 15% FCS (boLtales Kalber - blood serum). At the same time, the concentration of cells is chosen so that after 1-2 days a continuous cell cover is formed. The dilution of the virus is regulated so that, without the addition of an inhibitor, a full cytopathoheptic effect occurs after 3-4 days.
    Cells (cell control), cells with a virus (virus control), and cells with a substance in various concentrations (control of toxicity) were used as control samples. As the minimum toxicity of concentration (MTC), the concentration of the substance is determined, at which an even lower cell density was observed than in
    cell control experience. I
    The substance used in the test is dissolved in dimethyl sulfoxide, diluted in MEA and carefully suspended using ultrasound.
    The proposed compounds are examined for their ability to neutralize the action of various representatives of viruses, namely rhinoviruses of type B1-B55, echoviruses of type B-9, and polyoviruses of type 2, and in these cases the minimum inhibitory concentration (MIC in µg / ml ).
    Determination of antiviral properties.
    The following compounds are tested to determine the anti-viral properties: (4,5-dihydro-2-oxazolyl) -2-thienyl} -oxyheptyl-3-met1 Schizoxaz) L (compound A), (4,5-dihydro-2 α-oxazolyl) -4-thienyl-oxyheptyl j-3-methylisoxazole (compound B) and (4,5-dihydro-2-oxazolyl) phenoxy} -hep-, tylJ-3-methylisoxazole (compound C) (analog). The values of the minimum inhibition concentration (MKT) and the minimum toxic concentration (LC) are determined, the data are given in Table. one.
    Table 1
    As can be seen from the table. 1, the substances of examples 1 and 2 in all of the viral strains tested are significantly superior to known substance C. Substance B (in example 3) is superior to substance C in eight viral strains (Phino types 3, 16, 37, 55, 81, 82 and 88, as well as Pdio type 2); in the three strains (Phino types 26, 32, and 48), the effect is the same and in one viral strain (Echo type B9), compound C exceeds compound B. The results obtained to this extent. Since the values of MTK for all three compounds are the same, Table 2 differs from Table. 1 are only absolute values of quantities, but the relative values remain the same.
    Compound B has a better spectrum of action than Compound C. Cell toxicity is the same for all three compounds.
    Determination of therapeutic index, t
    According to the table. .1 the therapeutic index is calculated as the ratio of the toxic concentration of a substance through the concentration of action. Table 2 for each viral strain is given in Table 2, Table 2
    In comparison with the known ones, which have the ability to neutralize the effect of viruses, the proposed compounds have improved lipophilic properties that allow Blut-Hirnschranke to be overcome.
    The compounds of the present general formula may be used as a medicine, for example in the form of pharmaceutical preparations. Such pharmaceutical preparations can be obtained by mixing the proposed compound with suitable for internal or parenteral use, pharmaceutical, organic or inorganic inert auxiliary substances and / or carrier substances, which can be used, for example, from a pharmaceutical point of view. from the point of view of solvent, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable
    oils, polyalkylene glycols, petroleum jelly and
    etc., after which the mixture is processed into solid dosage forms, for example, into tablets, dragees, suppositories, capsules, etc .; in semi-solid dosage forms, for example, in an ointment, or in liquid dosage forms, for example, in solutions, suspensions or emulsions. In some cases, the preparations obtained are sterilized, and they may also contain such excipients as a preservative, a stabilizer, an emulsifier (to change the osmotic pressure), and the like.
    The pharmaceutical preparations of the compounds of the invention may also contain other therapeutically valuable substances, for which, for example, other biologically active substances can be used.


    where R is hydrogen
    Va, having anti-infection action or ability to neutralize the effect of viruses.
    Thus, the proposed compounds have improved antiviral activity.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing isoxazol derivatives of the general formula
     ) 7-0-A
    v
    where A is a group of general formula
    R, K v-- or Y
    оS About
    distinguish
    R
    u and with the fact that the compound formula
    (CH2) 7-0-B
    m
    where B is a group of general formula
    XV C-NH-CH2-OH S
    thirty
    or
    Y ct n-shn he
    oh oh
    35
    40
    where R, - is as defined, cyclized by treating with an excess of a dehydration reagent, such as thionyl chloride, in an inert solvent.
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    Buscemi et al.2002|A generalized synthesis of 3-amino-5-aryl-, 3-amino-5-polyfluorophenyl-, and 3-amino-5-alkyl-1, 2, 4-oxadiazoles through ring-degenerate rearrangements
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    US4143047A|1979-03-06|2-sulfinyl and 2-sulfonyl oxazoles
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    同族专利:
    公开号 | 公开日
    DD258812A1|1988-08-03|
    JPH0680059B2|1994-10-12|
    UA5548A1|1994-12-28|
    NO861923L|1986-11-18|
    JPS61268680A|1986-11-28|
    KR930006776B1|1993-07-23|
    CA1271481A|1990-07-10|
    AU588315B2|1989-09-14|
    EP0211157A1|1987-02-25|
    AU5750886A|1986-11-20|
    HUT43594A|1987-11-30|
    NO164352B|1990-06-18|
    HU197003B|1989-02-28|
    ZA863652B|1987-01-28|
    FI861934A|1986-11-18|
    DK228086D0|1986-05-16|
    FI83782C|1991-08-26|
    ES8801805A1|1987-07-16|
    ES555030A0|1987-07-16|
    FI861934A0|1986-05-09|
    NO164352C|1990-09-26|
    DK167679B1|1993-12-06|
    US4812472A|1989-03-14|
    DE3676378D1|1991-02-07|
    SG43191G|1991-08-23|
    NZ216125A|1988-10-28|
    EP0211157B1|1991-01-02|
    AT59647T|1991-01-15|
    KR860009011A|1986-12-19|
    DK228086A|1986-11-18|
    FI83782B|1991-05-15|
    CS254349B2|1988-01-15|
    引用文献:
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    US2714082A|1955-07-26|New oxazoline derivatives |
    US4451476A|1982-12-13|1984-05-29|Sterling Drug Inc.|Isoxazoles as antiviral agents|
    NZ209209A|1983-08-29|1988-02-12|Sterling Drug Inc|Substituted phenyl-aliphatic isoxazole derivatives and pharmaceutical compositions|US4861791A|1983-08-29|1989-08-29|Sterling Drug Inc.|Dihydro-oxazolyl substituted-phenyl-aliphatic lower alkyl and their use as antiviral agents|
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    US5070090A|1989-05-15|1991-12-03|Janssen Pharmaceutica N.V.|Antipicorpaviral herterocyclic-substituted morpholinyl alkylphenol ethers|
    GB8911158D0|1989-05-16|1989-07-05|Janssen Pharmaceutica Nv|Antiviral pyridazinamines|
    AU1303099A|1997-11-07|1999-05-31|American Cyanamid Company|Herbicidal furanyl- and thienyloxyazines|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    AT149385|1985-05-17|LV931248A| LV5506A3|1985-05-17|1993-11-17|Saturation of isoxazole derivatives|
    MD94-0141A| MD89C2|1985-05-17|1994-04-14|Process for obtaining the isoxasol derivative|
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