• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    A compound of the formula wherein R1 is a hydrogen atom or a lower alkyl group which may be substituted with hydroxy, lower alkyl or di-lower alkylamino; R2 is a hydrogen atom, an amino group or a lower alkylamino group; and R3 is a lower alkyl group, and a nontoxic salt thereof, and a process for preparing the same are disclosed. The compound and the salts thereof exhibit antiallergic effects by the two different mechanisms and are expected to be useful as drugs for treating allergic diseases such as asthma, pollen allergy, atopic dermatitis and the like.
    公开号:SU1419517A3
    申请号:SU864027536
    申请日:1986-05-22
    公开日:1988-08-23
    发明作者:Мори Такаси；Охи Нобухиро；Охсуги Есиюки；Ямасита Ясухиро
    申请人:Чугай Сейяку Кабусики Кайся (Фирма)；
    IPC主号:
    专利说明:

    t14195
    The invention relates to the field of the preparation of pyridine derivatives, in particular, to pyridine tricarboxylic acid derivatives of the general formula
    COOR,, R,
    RjHNOC N CONHR;
    where Rj is hydrogen or C, -C-alkyl, not necessarily replaced by an oxy group or a kylamino group;
    R is hydrogen, amino or
    With, -C-alkylamino; R, - C, kil,
    or their acid addition salts, (anti-allergic anti-allergic effect.
    The aim of the invention is to create, on the basis of known methods, a method of producing new compounds with valuable pharmacological properties.
    Example 1. To a mixture of triethylpyridine-2,4, 6-tricarboxylate with 140 tetrahydrofuran, 1 1 g of a 40% aqueous solution of methylamine was slowly added and then the mixture was stirred overnight. After adding acetic acid (9 g), the reaction mixture was evaporated under reduced pressure, water was added to the residue, and then extraction was performed with chloroform. The organic layer is separated and charred to dryness, which is purified by silica gel column chromatography. The product is recrystallized from a mixture of chloroform and hexane to obtain 8.9 g of ethyl 2,6-bis (N-methylcarbamoyl) 11-yridine-4-carboxylate. M.p. 183-18А ° С.
    NMR spectrum (CDCl 3): 8.86 (2H, singlet); 8.40 (2H, duRlt); 4.42 (2P, quartet); 2.98 (6I doublet); 1.40 (3N, triplet).
    Example 2. Methanol (20 ml) was added to 4.5 g of ethyl 2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylate prepared in Example 1, and a solution of 0.9 was added to the mixture. g of sodium hydroxide in 20 ml of water, with stirring. The mixture is heated to 50-60 ° C and, after addition of 250 ml of water, a small amount of the undissolved compounds is removed by filtration.
    0
    five
    0
    five
    0 s o
    172
    The pH of the diluent is added to 1 with dilute chlorohydric acid and the filtrate is adjusted to pH 5 and, after heating to 90-100 ° C, an additional amount of diluted hydrochloric acid is added to the filtrate, lowering the pH to 2-3. The mixture is cooled, the solid is collected by filtration, washed with water to obtain 3.5 g of 2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylic acid. T.SH1. 300 ° C.
    NMR spectrum (DMSO-dg) S: 9.34 (2H, doublet); 8.57 (2I, singlet), 2.97 (6H, .doublet).
    Example 3. 2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylic acid (1 g) is mixed with methanol (50 ml) and thionyl chloride (2 ml) is added to the mixture. After addition of the thionyl chloride, the mixture was stirred at room temperature overnight. The mixture is then evaporated under reduced pressure, water is added to the residue, and extraction is carried out with chloroform. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and added to dryness. The remaining crystals recrystallized from toluene to obtain 0.4 g of methyl 2,6-bis (N-methylcarbamoyl (pyridine-4-carboxylate, mp. 202–203 ° C).
    NMR spectrum (CBCI3) 5: 8.81 (2H, singlet); 8.18 (2H, doublet); 3.93 (SA, singlet); 2.98 (6H, doublet).
    Examples 4-7. According to a procedure similar to that described in Example 1, the compounds listed in Table 1 are obtained.
    Table 1
    COOR f
    HjCHNOC- N CONHCHj
    4n-propyl 180-181 chloroform /
    hexane
    5Nzopropyl 183-184 Toluene
    314195
    Example 8. 2,6-bis (L-methyl-narbamoyl) pyridine-4-carboxylic acid (2.3 g) obtained in Example 2 is mixed with 50 ml of tetrahydrofuran and 3.1 g of ethylene glycol. After addition of dicyclohexylcarbodiimide (2.5 g), the mixture was stirred at room temperature overnight. The mixture is then evaporated, the residue is purified by column chromatography on silica gel, recrystallized from dimethylformamide / benzene to obtain 0.3 g of 2-hydroxyethyl-2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylate. M.p. 214-215 C.
    NMR spectrum (DMSO-db): 9.32 (2H, doublet); 8.48 (2H, singlet); 4.98 (1H, triplet); 4.37 (2H, multiplet) 3.77 (2H, multiplet); 2.90 (6H, doublet).
    Example 9. As the starting compound, triethylpyridine-2,4,6-tricarboxylate was used, which was reacted with ethylamine and then with an aqueous solution of sodium hydroxide as in Examples 1 and 2, and 2,6-bis ( N-ethylcarbamoyl) pyridine-4-carboxylic acid. Approximately 39%. M.p. 278-280 s (after recrystallization from tetrahydrofuran / benzene).
    Example 10. To a solution of 7.5. triethyl-3-aminopyridine-2,4,6-tricarboxylate in 100 ml of tetrahydrofuran and 100 ml of ethanol for three days a 40% aqueous solution of methylamine was added at room temperature once a day in a total of 30 After 4 days from the start of the reaction, acetic acid (25 g) was added to the reaction mixture, and then evaporation was carried out under reduced pressure. Water was added to the residue and extraction was performed with chloroform. The organic layer is dried over sodium sulfate and evaporated.
    0
    5 0 5
    thirty
    5 do

    50
    55
    174
    dry to a dry residue. The residue is purified by column chromatography on: silica gel, recrystallized from toluene, and 3.5 g of ethyl 3-amino-2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylate are obtained. M.p. 185-186 c.
    I TR spectrum (CDC1,) 5: 7.8-9.2 (5H); 4.34 (2H, quartet); 2.92 (6H, double doublet); 1.33 (ZN, triplet).
    Example 11. Triethyl-3-chloro; Pyridine-2,4,6-tricarboxylate is reacted with methylamine, as in Example 10, and ethyl 3-methyl-amino-2,6-bis (E-methylcarbamoyl) pyridine-4 -carboxylate is obtained. Yield 51%. T.g.l. 169-170 C (after recrystallization from toluene).
    NMR spectrum (CDC1,) S: 9.59 (2H, doublet); 8.60 (2H, doublet); 8.1-8.5 (2H); 4.32 (2H, quartet); 2.7-3.1 (9H, multiplet); 1.33 (ZN, triplet).
    Example 12. Dimethylaminoethyl chloride (1.2 g) was added to a mixture of 2,6-bis (N-methylcarbamoyl) pyridine-4-carboxylic acid (2.37 g) and isopropyl alcohol (30 ml), after boiling under reflux with stirring for 2 days. After cooling the mixture, the resulting crystals are isolated by filtration and recrystallization from methanol / benzo | sol get 0.5 g of 2-di-methylaminoethyl-2,6-bis (L-methylcarbamoyl) pyridine-4-carboxylate hydrochloride. M.p. 240-242 ° C (with decomposition).
    NMR spectrum (DMSO-dg): 9.66 (2H, doublet); 8.64 (2H, singlet); 4.78 (2H, multiplet); 3.60 (2H, multiplet); 2.90 (12H).
    Pharmacological testing.
    Experience 1. Inhibitory effect on passive skin anaphylaxis (PKA).
    Rat antiserum against egg albumin was prepared according to the method of I. Mota (Immunology, 1964, 7, 681-699) and diluted 400-fold. Diluted antiserum (0.1 ml) was injected into the dorsal skin of rats (line 8D / ICL, males,, 9 weeks old) for passive immunization.
    After 48-72 hours, the compound obtained by the proposed method, suspended in a 1% aqueous solution of gum arabic, was orally administered to each rat. 5 min after administration to each rat by intravenous injection
    514
    1 ml of a mixture containing equal volumes of a 0.5% solution of egg albumin in saline solution and a 0.5% solution of evansonon blue in saline solution is introduced into the tail. After 30 minutes, each rat was decapitated and the leaked dye was quantified by the method of Katayama et al. (Microbiol. Iramunol, 1978, 22, 89-101).
    The percent inhibition is calculated by comparing the amount of evanescent blue that was observed in the test groups with the amount assigned to the control group, in which a water solution of gum arabic, not containing the test compound, was injected into the test animals.
    The results are presented in table 2.
    table 2
    176
    From the next day after immunization with DNP-KLH, each of the mice was orally administered the test compound suspended in a 1% aqueous solution of gum arabic using a gastric catheter. The control mice were administered only gum arabic solution.
    Short-haired samples are taken from each mouse and the amount of IgE measured in them according to the Test for 48 hr-PKA test in rats (Iburnal of the Immunological method, 1977, 14, 381-390) in the same way as described in the experiment
    1. The amount of IgE is expressed in units of the maximum dilution of serum, at which the development of a skin reaction is observed on an area with a diameter of 5 mm and more.
    The results are presented in table 3.
    Note. Inhibition efficiencies of 30–50, 51–70, 71–90, and 91% and above are indicated respectively, ++, +++, and ++++.
    Experience 2. The effect of inhibiting the production of IgE antibodies.
    SIL / I mice (females, 8 weeks old) were irradiated with X-rays at a dose of 400 R and parallel to the intraperitoneal injection were injected a mixture of 1 µg Keycell Hemocyanin YpfeG (KLH) and 4 mg of gel-like aluminum hydroxide. After 1 week, the mice were intraperitoneally injected with a mixture of 1 µg KLH, which binds the dinitrophenyl group (DNP-KLH), with gel aluminum hydroxide.
    Table 3
    Note. Efficacy and inhibition of 25-50, 50-75 and 75% and Bbmie are respectively ++, ++ and
    formula of invention
    1. A process for the preparation of pyridine tricarboxylic acid derivatives of general formula
    COOR
    55
    RjHNOC
    BUT:
    CONHR
    where R is hydrogen or C, - (; 4-alkyl, optionally substituted

     14195
    oKcurpyinini i, Cj - (; -ldkoxygrug111 (1Y or di-C, -Cz-alknolimino group; RJ - hydrogen, amino group or
    C-Cz-alkylamino; RJ - C, -C-alkyl,
    their acid-additive co -, characterized in that the compound of the general form is
    (Ii)
    Pjooc
    C O OB;
    where R is like R, except that it is not hydrogen;
    Rlj, as Rj or halogen, is reacted with an alkyl amine of the general formula, where R} has the indicated meaning, to form a compound of the general formula
    17
    (la)
    PiNOC H
    CONRj H
    five
    0
    five
    where R |, R ,, R have the indicated meanings,
    and the desired product is hydrolyzed or hydrolyzed to form a compound of the general formula (I), where R is H, and, if necessary, the compound is esterified with subsequent hydrolysis of the target product in free form or in the form of an acid addition salt.
    2, the method according to claim 1, wherein the compound of the general formula (II) is reacted with an alkylamine in an inert organic solvent at 0-50 ° C.
    3. Method according to Claims 1 and 2, characterized in that the lower alkylaiin of the formula RjNHj is used in an amount of 2-20 mol / mol of the compound of the general formula (II).
    权利要求:
    Claims (3)
    [1]
    The method of obtaining derivatives of pyridine tricarboxylic acids of the General formula
    R 3 HN0C
    C00R,
    C0NHR 3 where R ( is hydrogen or C ( -C 4 -alkyl, optionally substituted or R 3 is their hydroxy, C ( -C, alkoxy or di-C, C 4 -alkylamino group;
    hydrogen, amino group or
    Sc-C 4 alkylamino group;
    C, -C4-alkyl, acid-addition compounds distinguishing the compound of the general form with the form where Rj,
    BjOOC
    COORj (II)
    C 0 OB ', where what like R ( except it is not hydrogen;
    as R 2 or halogen, R <'it R 1 is reacted with an alkylamine of the general formula R 3 NH 2> wherein R 5 is as defined, to form a compound of the general formula
    HjNOC Η (la)
    R ,, R 3 have the indicated meanings, and the target product is isolated or hydrolyzed to obtain a compound of general formula (I), where
    R - H, and, if necessary, the compound formed as a result of hydrolysis is esterified with subsequent isolation of the target product in free form or in the form of an acid addition salt.
    [2]
    2. The method according to claim 1, characterized in that the interaction of the compounds of General formula (II) with an alkylamine is carried out in an inert organic solvent at 0-50 ° C
    [3]
    3. The method according to claims 1 and 2, characterized in that the lower alkylamine of the formula R NH 2 is used in an amount of 2-20 mol / mol of the compound of general formula (II).
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    法律状态:
    优先权:
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