• 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 caustic derivatives and, in particular, to the preparation of compounds of the general formula 3-OH, 4-OH, 5-X-CeH2-C (0) -NRiR2, where the NRifa-p-benzoylpridinium group or with RI is H Ra is benzyl, lower hydroxyalkyl, adamantyl; X - N02 or CN, which inhibited against the catechin-0-methyltransferase enzyme of a specific action, which can be used in medicine and biology. The purpose of the invention is the creation of new more active substances of the specified class. The synthesis is carried out by treatment with the corresponding amine of a hydroxyl protected benzoic acid halide followed by hydrolysis to remove the hydroxyl protecting groups. The new compounds practically do not block the biosynthesis of vital catechins, provide the transfer of the methyl group from 5-adenosyl-Methionine (known substances penetrate the blood – brain barrier and block the catechinins biosynthesis), to a small extent penetrate the blood – brain barrier. 1 tab. (/ with
    公开号:SU1729291A3
    申请号:SU894613317
    申请日:1989-01-23
    公开日:1992-04-23
    发明作者:Йоханнес Бякстрем Рейе；Эверт Хейнола Калеви；Юхани Хонканен Эркки；Калеви Кааккола Сеппо；Юхани Кайрисало Пекка；Инге-Бритт.Линден Ивонне；Топиас Мяннисте Пекка；Арне Олави Ниссинен Пентти Похто Эркки；Кюлликки Пиппури Аино；Йохан Пюстюнен Ярмо
    申请人:Орион-Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to new catechin derivatives of the general formula
    BUT
    It is known to use for inhibition of COMT 3,4-dianuroxy-2-methylphenone of the formula UQ
    rtrt-x-CHj
    0 ShSh3
    VI
    to yu
    ND
    Che

    CJ
    where NRiR2 is a p-benzoylpiperidinium group or, with RI - H R2 - benzyl, exhibiting inhibitory activity against the enzyme catechin-0-methyltransferase (COMT) of a specific action.
    However, its activity is not very high.
    The aim of the invention is to develop a method for producing new catechin derivatives having a higher activity than the known,
    Example. M- (1-Adamantyl) -3,4-diacetoxy-5-nitrobenzamide.
    A solution containing 0.85 g of 3,4-diacetoxy-5-nitrobenzoic acid and 0.32 ml of thionyl chloride and a catalytic amount of M, M-dimethylformamide in 10 ml of toluene is heated for 1 hour at 80 ° C. The solvent is evaporated in vacuo, the residue is dissolved in 5 ml of dichloromethane and added to a mixture containing 0.56 g of 1-aminoadamantane hydrochloric acid and 0.94 ml of triethylamine in 10 ml of dichloromethane, stirred for 15 minutes at 0 ° C, and then 15 min at 20 ° C, water is added to the reaction mixture and the dichloromethane phase is separated. The solvent is distilled off in vacuo to give 1.2 g (100%) of a yellow viscous oil.
    PRI me R 2, L- (1-Adamantyl) -3,4-dioxy-5-nitrobenzamide.
    A solution containing 2 g of the product obtained in Example 1 and a catalytic amount of sulfuric acid in 10 ml of methanol is refluxed for 3 hours. 20 ml of water are added and cooled, 0.85 g is crystallized (89.5%). %) of the target product, so pl. 207-208 ° C.
    Calculated,%: C, 61.43; H 6.07; N 8.43.
    Found,%: C 61.39; H 6.31; N 8.61.
    PRI me R 3. 4-Cyclohexylcarbonyl-1- (3,4-diacetoxy-5-nitrobenzoyl) -piperid in.
    Work according to the procedure of Example 1, using 0.58 g of cyclohexylcarbonylpiperidine and 0.38 ml of 2,6-lutidine instead of hydrochloric acid 1-aminoadamantane and triethylamine, respectively. Yield 1.2 g (87%), a viscous yellow oil.
    EXAMPLE 4 4-Cyclohexylcarbonyl-1- (3,4-dioxy-5-nitrobenzene) -piperidine.
    Work according to the method of example 2, using 1.2 g of the product obtained in example 3. Yield 0.5 g (50%), so pl. 155-165 ° C.
    Calculated,%: C 60.62; H 6.43; N 7.44.
    Found,%: C 60.48; H 6.31; N 7.54.
    PRI me R 5. M-Benzyl-3,4-diacetoxy-5-nitrobenzamide.
    0.75 g of 3,4-diacetoxy-5-nitrobenzoic acid is converted to the corresponding acid chloride as described in Example 1. It is dissolved in 5 ml of dichloromethane and added to a solution containing 0.27 ml of benzylamine and 0.5 ml 2,6-lutidine in 7 ml of dichloromethane. Yield 0.95 g (96%), viscous oil.
    PRI me R 6. M-Benzyl-3,4-dioxy-5-nitrobenzamide.
    Work according to the method of example 2, using 0.95 g of the product obtained in example 5. Yield 0.5 g (60%), so pl. 185-189 ° C.
    Calculated,%: C 58.74; H 3.52; N 9.79.
    Found,%: C 58.94; H 3.59; N 9.59.
    Example. M- (1-Adamantyl) -3,4-diacetoxy-5-cyanobenzamide.
    0.6 g of 3,4-diacetoxy-5-cyanoobenzoic acid is converted into the corresponding acid chloride and then worked according to the procedure of Example 1. The yield is 0.75 g (88%), a viscous oil.
    Example M- (1-Adamantyl) -3,4-diox-0 Si-5-cyanobenzamide.
    0.75 g of the obtained product is deacetylated by the method of Example 2. The yield is 0.5 g (89%), so pl. 253-255 ° C.
    Calculated,%: C 69.21; H 6.45; N 8.97. 5 Found,%: C 69.50; H 6.61; N 9.01.
    PRI me R 9. M- (3-hydroxypropyl) -3,4-dioxy-5-nitrobenzamide.
    The process is carried out analogously to examples 1 and 2, using 3,4-diacetoxy-5-nitrobenzoic acid and 3-aminopropan-1-ol. Yield 85%, mp. 160-163 ° C.
    Calculated,%: C 46.88; H 4.72; N 10.93.
    Found,%: C, 03.03; H 4.92; N 11.10.
    The effectiveness of COMT inhibition with 5 using the obtained compounds.
    COMT catalyzes the transfer of a methyl group from 3-adenosyl-β-methionine to a series of catechin-type compounds.
    Determination of the activity of COMT in vitro. 0In vitro activity for COMT was determined for enzyme preparations isolated from the brain and liver of Han: WIST rats weighing about 100 g. Rats were killed by carbon dioxide, and tissues were removed and stored at -80 ° C until the enzymatic determination activity.
    The enzyme preparation was prepared by homogenizing tissues in 10 mM phosphate buffer, pH 7.4 (1:10 g / ml), which 0 contains 0.5 mM dithiothreitol. The homogenate is centrifuged at 15000xG for 20 minutes. The supernatant is re-centrifuged for 60 min at HOOOOHC. All procedures were performed at + 4 ° C. The supernatant from the last centrifugation (UOOXC) is used to determine the soluble COMT enzyme.
    Definition of IR. performed by measuring 0 COMT activity for several drug concentrations in the reaction mixture, which contains the enzyme preparation, 0.4 mM dioxybenzoic acid (substrate), 5 mM magnesium chloride, 0.2 mM 5 5-adenosyl-β-methionine and COMT inhibitor in 0.1 M phosphate buffer, pH 7.4. An inhibitor of COMT was not added to the control. The mixture is incubated for 30 minutes at 37 ° C, after which the reaction is stopped with perchloric acid and removed by centrifugation
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining derivatives of catechin of the General formula. where NR1R2 is a p-benzoylpiperidinium group or, when Ri is H R2, benzyl, lower hydroxy-alkyl, adamantyl;
    X is N02, CN, characterized in that the compound of the general formula * RQ - wherein R is lower alkanoyl;
    X is cyano, nitro,
    Y-Hal is reacted with a compound of the general formula wherein Ri and R2 have the indicated meanings, followed by deprotection of the 0-protection by hydrolysis.
    Connection example Sop-inhibition in brain tissue ICbo / nm 2 19 4 20 6 18 8 92 9 10 I-0521 6000
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    法律状态:
    2010-07-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20061128 |
    优先权:
    申请号 | 申请日 | 专利标题
    FI864875A|FI864875A0|1986-11-28|1986-11-28|NYA FARMAKOLOGISKT AKTIVA FOERENINGAR, DESSA INNEHAOLLANDE KOMPOSITIONER SAMT FOERFARANDE OCH MELLANPRODUKTER FOER ANVAENDNING VID FRAMSTAELLNING AV DESSA.|
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