• 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:
    Known and novel compounds of formula (I), wherein R, and R<2> represent <CHEM> substituents selected from halogen atoms and nitro, cyano, trifluoromethyl, lower alkyl, lower alkoxyl, amino and hydroxyl groups are active against viruses, especially rhinoviruses. Methods for producing the compounds are described, as are pharmaceutical formulations and methods for administering the compounds to cure or prevent rhinoviral infections.
    公开号:SU986296A3
    申请号:SU802912758
    申请日:1980-04-25
    公开日:1982-12-30
    发明作者:Фредерик Батчелор Джон；Джон Бауер Денис；Фрэнсиз Ходсон Гарольд；Вильям Тальбот Селвэй Джон；Альберт Блейкер Янг Дэвид
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    .-methoxyphenyl) -propan-1-ol, m.p. lU. The whole product is boiled under reflux with 100 ml of acetic acid for 2 hours, the solution is evaporated, and the astatok is chromatographed on aluminum gel, eluted with toluene, and 8.0 g of 4-methoxy flavanane are obtained, m.p. 82-83 ° C. Example 8. Synthesis of 2, k-dimethyl flavan. 8.20 g of 2-OXY-2, α-dimethylhalbolone are suspended in 150 ml of ethyl alcohol and 2.50 g of sodium borohydride are added in separate portions. The mixture was stirred for half an hour, and the resulting solution was incubated for 8 hours. The solvent was evaporated, the residue was dissolved in chloroform and washed with water. By evaporation of the chloroform, a crude intermediate carbinol is obtained, which is refluxed together with 100 ml of acetic acid for 2 hours. By evaporation, an oily residue is obtained, which is chromatographed on an aluminum gel using toluene as an eluting solvent. After evaporation of the solvent, the main fraction was distilled off in vacuo, resulting in it, 80 g of 2, k-dimethylflavane, b.p. 135-1 5 C at 0.8 mm RT. Art. (107 Pa). Examples Compounds are obtained in a manner analogous to that described in the examples (see Table 1. Example 4). In viv tests Pharmaceutical grade olive oil is dissolved in 4,6-dichloro van in a quantity of 3 mg / ml and 1 mg / ml, 0.1 ml aliquots of these solutions are administered orally to mice, cause retroorbital bleeding for half an hour, an hour after a dose, hourly (7 hours) and clearly after 2 hours. Plasma is removed from the taken blood and tested for antiviral activity in according to the plaque inhibition procedure. After 2 hours, the total number of feces is collected from each mouse. liquefied and softened with a minimum amount of absolute alcohol, and this liquid is tested for antiviral activity in accordance with the platelet suppression procedure. The bile vesicles are removed from the mice and each is extracted with 10 µl of absolute alcohol. Each extract is also subjected to a plaque suppression test .6 Antiviral activity was observed on plasma samples for 2 hours after administration on gallbladder and feces extracts. By calibration against a standard plasma concentration curve, one hour later, it was determined that e 2-C μM for mice that receive a low dose, and U μN for mice that receive a large dose (doses, respectively, equal to 30 mg / kg and 10 mg / kg body weight). PRI me R 6. Introduction through the nose .. In vitro modeling. Petri dishes are prepared in the same way as in platelet suppression experiments, and the confluent layer of cells is covered with a layer of agarose gel. 1 µg of 5-dichloroflavane is dissolved in ethanol and applied to the lid of the petri dishes. After evaporation of this alcohol, the remaining compound spreads over the inner surface of the caps. Covers are placed on Petri dishes. The acceptable compound penetrates the agarose layer, causing complete suppression of the formation of plaque. The following compositions are prepared according to methods known in the pharmaceutical industry. Example 57: Prepare a composition for inhalation using the following components, g: k, 6-DichloroflavO, About Isopropyl myristate 10 Tween 80 0.5 Span 800.5 Methyl para-hydroxybenzene acid Up to 100 ml P Formulation 58, Preparing suspension for use as nasal drops using the following components, g: k, 6-Dichloroflavane 0.6 Keltrol 0.1, Sodium chloride 0.5 Sodium lauryl sulfate, 1 Methyl-para-hydroxybenzoic acid 0.1 Water Up to 100 ml. PRI me R 59. Capsules 1 A, 6-Dichloroflavane, g 6 Dried milk sugar, g 300 Each gelatin capsule (size 0) is filled with 500 mg tava per 10 mg of active ingredient per capsule. EXAMPLE 60 Capsules 2, 4, 6-Dichloroflavane, g 6 Dried milk sugar, g 208 Cornstarch, g 20.8 Polyvinylpyrrolidine, g 5.2 Each gelatin capsule (size 1) is filled with tOO mg of the formulation at the rate of 10 mg of the active component per capsule. EXAMPLE 1. Tablets with 4, 6-dichloroflavane. A wet granulation method was used to prepare a composition for tablets containing a mixture of V, 6-dichloroflavan (10 mg of milk sugar (90 mg), corn starch (10 mg) and magnesium stearate (1 mg). Examples 62-112. Following the procedure of example 60 , tablets are prepared, each of which contains one of the flavan derivatives of the examples. EXAMPLE 113. Oil solutions of 4,6-dichloroflavane., 6-dichloroflavane, g 1; Pharmaceutical olive oil, g 1 For oral administration the compound is dissolved in olive oil. EXAMPLE 114. Experimental flavan derivatives are tested to reduce platelets according to the method described above and their definitions are given to the Rhinovirus sirotype 1B (see Table 3). The compounds of formula (1) were found to have low toxicity and are 1-D (at dosage over 500 mg / kg The activity can be established in experiments on the suppression of plaques and measured in experiments to reduce them. Both methods of analysis will include the formation of a culture monolayer of cells in a Petri dish followed by their infection with a virus suspension and then applying nutrient agarose to the culture in the form of a gel . This gel does not allow the virus to spread through the culture, and as a result, areas of localized destruction of cells or plaques are formed. In a plaque suppression test, a filter paper disc that holds 0.01 ml of impregnation with a compound solution is placed on top of an agarose gel. The compound can then diffuse throughout the gel, so that its highest concentration will be around the disk and itself low at the edge of the petri dish. Compound efficacy can be detected in the plaque formation inhibition zone. Activity is measured by the plaque reduction method. Compounds of formula (1) of known polarity are introduced into nutrient agarose, used as an upper layer. Plaque suppression is proportional to the concentration of the compound. The number of plaques is expressed as a percentage of the control number and plotted on the dose-response curve. From this curve, a 50% effective dose (ED5o) can be found. The pharmaceutical compositions can be administered parenterally, perralally or inside the nose, or used in the form of suppositories, inhalations, ointments, creams, aerosols, powder, or nasal drops. etc when the composition is used for the treatment of rhinovirus infections. In the case of such infections, the compositions are administered orally or parenterally in dosage amounts calculated for free flavan, from about 0.125 μg to 125 mg per kg, preferably 0.25 μg to 125 mg / kg and most preferably 8-30 μg / kg of the mammalian body. . These compositions are administered several times a day in an amount of 10 µg - 100 mg, preferably 0.1-10 mg per single dose. For oral administration, fine powders or granules may contain a diluent, dispersant and / or surfactant and may be present in a liquid, water, syrup, capsules or tablets in a dry state, or non-aqueous solutions, or suspensions, in which may include a suspending agent; in tablets, which may include binders and lubricants; or in suspension in water or in syrup. Where desired or necessary, flavoring, preserving, slurrying, emulsifying, or thickening agents may be added. Tablets, capsules and granules are preferred, and they may be coated.
    The compositions are administered as a solution of a compound of formula (I} in a suitable oily medium.
    Compositions can also be administered through the nose in the form of inhalation formulations, aerosols or jets, or by inhalation of vapors that contain a compound of formula (I).
    When administered parenterally or when used in aerosol form, the sprays and drops of the compound {I) may be present in the aqueous solution in a concentration of from about 0.1 to 10%, more preferably from 0.1 to U, / most preferably 0.2% (weight / volume). Solutions can contain (antioxidants, buffers, etc.).
    Table 1
    2,4-Dimethyl-2-ok.
    sikhalkon122-123
    eleven
    Example
    Compound
    Z-Chlorflavin
    3 -Methoxyflavane
     - Fluoroflavin
    C-Brom-6-chloroflavane 6-Fluoroflav
    6-Bromflavan
    6-Bromo-4 -methyl flavan
    6-Bromo-4-chloroflavin
    2-Methyloxyflavane
    3. Trifluoromethylflavane.
    6-Methoxyflavan
    i, 8-dichlorflavane
    k-oksiflavan
    2-Oxyflavan
    6-Chlorflavin
    6-Methylflavan Z-Methylflavan
    4 - (N, N-dimethylamino) flavan
    4-Aminoflavan
    4-Isopropylflavin
    6-Chloro-4 - Isopropylflavin
    6-Ethyl flavan
    4,5,7-trioxyflavane
    8-Chlorflavin
    6,8-Dichloroflavin
     4-Chloro-6-ethyl flavan
    98629612
    Continued tabl, 2
    Melting point, ° C
    Bp 120-125 ° С 0.07 mmND (9.3 Pa)
    53-55
    66-67
    05Н07
    66-68
    58-59 78-81 80-81 64-65 85-86
    Bp 137-142 s / 0.06 mm Nd (8 Pa)
    97-98
    M.p. 130-1354 / 0.45mm Nd (60 Pa)
    71-72
    So. 138-148 ° С / 0.5 mm Nd (67 Pa)
    Bp P4-120 ° C / 0.1 mMd (13 Pa)
    77-78
    85-87
    46-47
    17-119
    T. Kip. 130-140 ° С / 0.15 mmNd (20 Pa)
    12-215
    Bp 155-1bO ° C / 0,08mmNd (10.7 Pa)
    74-76 61-63
    n
    Flavan ED50 Derivatives
    V, 6-Dichlor
    V-MethylV-Metoxy-6-chloro
    - Chloro-7-methyl1 - Fluoro-BpoM3, - Dichloroflavin
    , 7-dichloro-chloro, 4-dichloro
    k -Methoxy
     Methyl-7-chloro
    2-Chloro-6-Methyl-Chlor-2-Methoxy
    3-Trifluoromethylli-Matil-6-hlrr
    6-Methoxy2-Methyl
    3, Dichloro-6-meth
     -SpOM-6-chloro
    4-Chloro 4, 6-Dimethyl 2, 6-Dichlor 4-Amino.
    .4-Oxy4-Acetoxy7-Chloro4-Methoxy-6-methyl
    3-Methoxy4-M, M-dimethylamine 3-Methyl2-Oxy
    eleven
    986246
    Table 3
    Concentration, µm
    权利要求:
    Claims (3)
    [1]
    Claim
    1. A method of obtaining derivatives of flavan of the formula (1) where R 1 R 2
    I5 halogen, cyano, lower alkyl, lower alkoxy or hydroxy, halogen, cyano, lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, amino or di (lower alkyl) amino, integer 0.1 or 2;
    or a salt thereof, except the following flavan and flavan derivatives: 6-aminoflavan, 5 _ oksiflavan, oksiflavan-6, 7-oksiflavan, 4-oksiflavan, metoksiflavan-5, 6-metoksiflavan, metoksiflavan ~ 7, 8-metoksiflavan 4 -metok -siflavan, 6-methylflavan, 8-methylflavan-4 · -n-butoxy-6-hydroxyflavan, 4 * -t-butoxy-6-hydroxyflavan, 6-tert-butoxy-4'-methoxyflavane, 5 - n ~ butyl- 7 _ oxyflavan, 6-n-b. Butyl-7oxyflavan, 6-tert.-butyl-8-methylfLavan, 6-tert.-butyl-4 1 -methoxyflavan, 5,7 “-dioxiflavan, 6,4'-dioxiflavan , 7,4-dioxiflavan, 3 '· 4'-dioxiflavan, 5,7 “dimethoxyflavan, 6,4 * -dimethoxyflavan, 7,8-dimet oxyflavan, 7,4-dimethoxyflavane, 8,4-dimethoxyflavane, 3,4-dimethoxyflavane, 5.7 - Dimethylflavan, 6.8-dimethylflavan, 5 ~ ethyl ~ 7 _ oxyflavan, 6-ethyl-7 _ oxyflavan, b- hydroxy-4 * -isopropoxyflavan, 5 - hydroxy-y-methoxyflavan ^ b-hydroxy-7-methoxyflavan, b-hydroxy-4'-methoxyflavan, 7 “-oxy-5“ methoxyflavan, 7 ~ hydroxy-4-methoxyflavan, 4 '-oxy-6-methoxyflavan, 4'-hydroxy-7-methoxyflavan, 7 “hydroxy-5 ~ methylflavan, 7oxy-6-methylflavan, 7 ~ hydroxy-8-methylflavan, 7-hydroxy-4' methylflavan, 4 ' -izobutrksi-6-metoksiflavan, 4'-isopropoxy-6-metoksiflavan, 8-isopropyl-5 _ metilfla.van, 4'-methoxy-6-metilflavan, 4-methoxy-7- etilflavan, 5.7 ~ Dihydroxy-4 -meVNIIPI Order 10194/79
    986296 16 toxiflavan, 5,4'-dioxi-7-methoxyflavan, 6,3'-dimethoxy-4 * ethoxyflavane, 6,3 * -dimethoxy-4'-oxifLavan, 7,4'-dimethoxy-5 “oxyflavan, 6 ^ 4 '-dimethoxy-8-methylphloroan,' 3 *, 4 * -dimethoxy-6-methylflavan, '6,8-dimethyl-. -4-methoxyphpavan, 4'-hydroxy-7-methoxy-8-methylflavan, 5,7,4 * -trioxiflavan, 6,3 ', 4'-trioxyflavan, 7,8,4 * -trioxiflavan, 7,3 1 4'-trioxyflavan, 5,7,4 * -trimethoxyphpavan, .6,7, 4 -trimethoxyflavan, 7,8,3 * -trimethoxyflavan, 7,3 ', 4 utrimethoxyflavan, 5,7 - dioxi-3', 4-dimethoxy flavan, 3 ', 4'-dioxi-5,7 _ dimethoxy flavan, 4', 6 '-dioxo-5,7 “dimethoxy flavan, 4 * methoxy-5,7, 3'-trioxy flavan, 5.7,3' , 4'-tetraoxyflavan, 5,7,3, 4'-tetramethoxyflavane, 7,8,3 *, 4 * -tetramethoxyphpavan, characterized in that the compound of formula 11 '35
    Kp g ', where R 4 , R 2 , η and p Have the indicated meanings, they are reduced with an alkali metal hydride in an organic solvent, followed by cyclization in the presence of an acid catalyst, and the desired product is isolated in free form and / or a compound of formula (I) where R 4 and / or R 2 is an oxy group, converted to a salt by the action of an inorganic or organic base.
    [2]
    2. The method according to π. 1, with the fact that the ethanol is used as a solvent,
    [3]
    3. The method of pop. 1, characterized in that acetic acid is used as the acid catalyst.
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    同族专利:
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    法律状态:
    优先权:
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