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    • 专利摘要:
    <CHEM> wherein R and R<3> independently represent hydrogen or alkyl; R<1> represents hydrogen, alkyl, benzyl or benzoyl; R<2> represents hydrogen or alkyl; or R<1> and R<2> taken together with the adjacent nitrogen atom form a saturated heterocyclic ring containing from 5 to 7 ring atoms and optionally including a further heteroatom selected from oxygen and nitrogen; Z is O, S or CH2; X is S or O; n is 2 or 3 when Z is O or S and n is 1, 2 or 3 when Z is CH2; R<5> is H or CH3; m is 1, 2 or 3; A is (C1-C5)alkylene or (CH2)qX(CH2)p wherein q and p are individually 0, 1, 2 or 3 and the sum of q plus p is 0-4, and B is H, CH3, cycloalkyl, a heteroaryl group optionally substituted with one or two alkyl, alkoxy, halo, hydroxy or amino groups; naphtyl, (1,3-benzodioxolyl), 2,3-dihydro-1,4-benzodioxinyl, phenyl optionally substituted with one or two alkyl, alkoxy, halo, OH, benzyloxy, CF3, alkyl-O-alkylene, phenoxy or di[alkyl]aminoalkylene groups; and their pharmaceutically-acceptable salts are effective anti-ulcer agents.
    公开号:SU1195906A3
    申请号:SU823526201
    申请日:1982-12-24
    公开日:1985-11-30
    发明作者:Пол Пиоч Ричард
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    one
    This invention relates to a process for the preparation of new pyrimidine derivatives or their pharmaceutically acceptable salts, biologically active compounds that can be used in medicine.
    The purpose of the invention is a process for the preparation of novel pyrimidine derivatives or their pharmaceutically acceptable salts, which are Nd receptor antagonists that exhibit higher anti-ulcer activity.
    Example 1. (2-Dimethylaminoetom 1-4-thiazolylmethylthio) -ethylZ amino-5- (3-pyridyl) methyl-4-pyrimidone
    The reaction mixture obtained from 1.24 g of 2-nitroamino-5- (3-pyridyl) methyl-4-pyrimidone, 1.14 g of 2- (2-dimethylaminomethyl 1-4-thiazolylmethylthio) ethylamine and 6 ml of anhydrous zanol is boiled under nitrogen at reflux for a day, after which the volatile components of the reaction mixture are removed by evaporation in vacuum, leaving an oily substance in the residue. Water is added to the residue and the aqueous layer is extracted with ethyl acetate and ethyl acetate, the organic extracts are combined, dried and evaporated to dryness, leaving the desired (2-dimethylaminomethyl-4-thiazolylmethylthio) ethyl-amino-5- (3-pyridyl) as residue. Mets1-4-pyrimidone, which is crystallized by treatment with diethyl zfir. By recrystallization of the obtained product from ethanol-ethyl ether mixture, pure (2-diethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5 (3-pyridine 1) methyl-4-pyrimidone is obtained, yield 0.68 g, mp. 122-123 0.
    Calculated,%: C 54.78; H 5.81; N 20.17.
    Found,%: C 54.94; H 5.65; N 19.91.
    Example 2. (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl} amino-5- (5- (1,3-benzodioxolyl) metsh-1-4-pyrimidone.
    1.09 g of 2- (2-dimethylaminomethyl-4thiazolylmethylthio) ethylamine and 1.40 g of 2-nitroamino-5-5- (1,3-benzodioxol) j methyl 4-pyrimidone as in Example 1 are dissolved in 6 ml of anhydrous ethanol and the solution is refluxed for days. The volatile components of the reaction mixture were removed by evaporation. Received by
    959062
    the residue is extracted with ethyl acetate, the ethyl acetate extract is washed in a separating funnel with water, organ. The cation layer is dried and ethyl acetate. evaporated. The oil residue is triturated with cyclohexane, the crystalline product is filtered off. Recrystallization of the obtained product from ethyl acetate gives 0.38 g of the desired 0 (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethshIJmino-5- | 5- (1,3-benzo-Dioxolyl) methyl-4-pyrimidone, having so pl. 110-11 1C.
    Calculated,%: C 54.88; H 5.48; 15N15.24.
    Found,%: C 54.68; H 5.22;
    N 14.95.
    EXAMPLE 3 (2-Dimethylaminomethyl-4-thiazolylmethyl-Thio) -ethyl-20-amino-5- (6-methyl-3-pyridyl) methyl-4-pyrimidone.
    0.75 g of 2- (2-dimethylaminomethyl-4thiazolylmethylthio) ethylamine and 0.78 g of 2-nitroamino-5- (6-methyl-3-pyridyl)
    5 methyl-4-pyrimidone as in Example 1 is dissolved in 5 ml of anhydrous ethanol and the resulting solution is refluxed for a day. Next, the solvent is evaporated and the residue is extracted with ethyl acetate. The ethyl acetate extract is washed in a separatory funnel with water, dried and evaporated. Crystalline residue is obtained.
    with (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl} amino-5- (6-methylZ-pyridyl) -methyl-4-pyrimidone, which, after recrystallization from ethyl acetate-diethyl ether, has a mp of 154-155 ° s The yield of the target Product 0,56 g
    Calculated,%: C 55.79; H 6.09;
    N 19.52. Found,%: C 56.02; H 6.06;
    5, 19.50.
    PRI me R 4. (2-Dimesh1-aminomethyl-4-thiazolylmethylthio) ethyl-amino-5- (6-methoxy-3-pyridyl) methyl-4-pyrimidone;
    0 1.29 grams of 2- (2-dimethylaminomethyl-4-thiazolylmethylthio) ethylamine and 1.54 g of 2-nitroamino-5- (6-methoxy3-pyridylmethyl) -4-pyrimidone as in Example 1 are dissolved
    5 in 50 ml of absolute ethanol and the resulting solution is heated at boiling point for a week. The solvent was evaporated. The residue was purified by gradient elution chromatography on silica gel using ethanol / ammonium hydroxide as the eluent of the solvent system. Fractions of the eluate containing the desired pyrimidone are combined and evaporated to dry. The residue is recrystallized from ethyl acetate, resulting in a total of (2-dimethylaminomethyl-4-thia zolylmethylthio) -ethyl-amino-5- (6-methoxy-3-pyridyl) methyl-4-pyrimidone, m.p. 137-138C. Calculated,%: C 53.79; H 5.87; N 18.82. . Found,%: C 53.53; H 6.01; N 18.72. PRI me R 5. (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (5,6-dimethyl-3-pyridyl) methyl-4-pyrimidone. 1.29 g of 2- (2-dimethylaminomethyl4-thiazolylmethylthio) ethylamine and 1.29 g of 2-nitroamino-5- (5,6-dimethyl-3-pyridyl) methyl-4-pyrimidone analogously, Example 1 was dissolved in 2, 5 g of anhydrous ethanol and the resulting mixture was boiled for 51 h. The solvent was distilled off and the residue obtained from the residue was purified by high pressure liquid gradient elution chromatography on a column of silica gel, using ethanol - ethyl acetate - ammonium hydroxide as the eluent of the solvent system. The fractions of the eluate containing the desired 2-, 2- (2-dimethylaminomethyl-4-thiaz-olylmethylthio) -ethyl amino 5- (5,6-dimethyl-3-pyridyl) methyl-4-pyrimidone are combined and evaporated to removing all solvents present in these combined fractions. An excess of an ethanolic solution of hydrogen chloride is added to the residue. Ethanol is evaporated to give (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl 3-amino-5- (5,6-dimethyl-3-pyridate 1) methyl 4-pyrimidone trihydrochloride (mp) after about 207-210 ° C (after double recrystallization from a solvent mixture ethanol - ethyl acetate). Output 1.13 g. Calculated,%: C 45.54; H 5.64; N 5.17. Found,%: C 45.29; H 5.39; N 5.21. 064 EXAMPLE 6. (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethylJ amino-5- (2-methoxy-4-pyridyl) methyl-4-pyrimidone. As in Example 1, the reaction mixture is prepared, starting from 1.62 g of 2- (2-dimethylaminomethyl-4-thiazolylmethylthio) ethylamine and 1.94 g of 2-nitroamino-5- (2-methoxy-4-pyridyl) methyl-4-pyrimidone in 30 ml of absolute ethanol. The reaction mixture is stirred and boiled for 42 hours. The volatile components of the reaction mixture are distilled off and the substance obtained in the residue is purified by high pressure liquid gradient elution chromatography using a silica gel column and the solvent system ethanol / ammonium hydroxide as eluent. Fractions of the eluate containing the desired 2- (2- (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethylZamino-5- (2-methoxy-4-pyridyl-4-pyrimidone) are combined and evaporated to remove the solvents. Recrystallization of the residue obtained. (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl 2-amino-5- (2-methoxy-4-pyridyl) methyl-4-pyrimidone with m.p. 79-80c is calculated from a mixture of cyclohexane-diethyl ether with a melting point of 79-80 s. Calculated: C 53.79 ; H 5.87; N 18.82. Found.%: C 53.53; H 5.71; N 18.64. Example 7. (2-Dimethylamino-methyl-1-4-thiazolylmethylthio) -eth-11-amino-5- (3- pyridyl) methyl-6-methyl-4-pyrimidone. A mixture of 1.16 g of 2-2-dimethyl - aminomethyl-4-thiazolylmethylthio1-ethylamino, 1.31 g of 2-nitroamino-5-TZpyridyl) methyl-6-methyl-4-pyrimidone and 25 ml of anhydrous ethanol are boiled for 5 days, the solvent is distilled off. The residue obtained is purified t using high pressure liquid chromatography elution chromatography on a column of silica gel and using an ethanol – ethyl acetate – ammonium hydroxide solvent system as eluent. Fractions of the eluate containing the desired (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl-3-amino-5- (3-pyridyl) ethyl-6-methyl-4-pyrimidone are combined, the solvent is distilled off. 1.1 g of crystalline product are obtained which, after recrystallization from a mixture of ethanol and diethyl ether, has a mp. 130-131 ° C. The yield of the desired 2-C 2- (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (3-pyridyl) metsh-6-methyl-4-pyrimidone is 1.03 g. Calculated,%: C 55, 79; H 6.09; N 19.52. Found,%: S. 55.73; H 5.98; N 19.31. Example 2-C2- (2-Dimethylaminomethyl-4-thiazolylmethyl-thio) -ethyl-3-amino-5- (2-pyridyl) methyl-7A-pyrimidone Analogously to Example 1 of 1.62 g of 2- (2-dimethylaminomethyl-4-thiazole-1-methyl-1-thio) ethylamine, 1, 73 g of 2-nitroamino-5- (2-pyridyl) methyl-4-pyrimidone and 20 ml of ethanol are prepared and the solution is boiled for 21 h. The solvent is distilled off in vacuo and the residue obtained is purified by the method of a liquid gradient elution chromatography on silica gel column using ethanol-ethyl acetate ammonium hydroxide system as eluent. Fractions of the eluate containing the desired 2-C2- (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl3 amino-5- (2-pyridyl) methyl-4-pyrimidone as determined by thin layer chromatography are combined and the solvent is distilled off in vacuo . The resulting crystalline substance was dissolved in ethanol, and a small excess of 5 N aqueous hydrochloric acid was added to the solution. The reaction mixture is evaporated to dryness and the resulting crystalline residue is recrystallized from a mixture of methanol and ethanol to obtain 1.2 g of the desired trihydrochloride (2-dimethyl aminomethyl-4-thiazolylmethylthio) ethyl ethyl-5- (2-pyridyl) methyl-4-pyrimido 205- 207 0. on c. Calculated,%: C 43.39; H 5.17; N 15.98. Found.%: C 43.11; H 5.21; N 16.01. PRI me R 9. (2-Dimethylaminomethyl-4-thiazolsh1methylthio) -ethyl amino-5- (4-pyridyl) methyl-4-pyrimidone. 2-Nitroamino 5- (4-pyridyl) methyl-4-pyrimidone is reacted with 2- (2-dimethylaminomethyl4-thiazolylmethylthio) ethylamine; methyl 4-pyrimidone in the form of trihydrochloride, having after recrystallization from a mixture of meth NOL - ethanol m.p. 200-202 ° C. Calculated,%: C 43.39; H 5.17; N 15.98. Found,%: C 43.37; H 5.33; N 15.71. Example 10. (2-Dimethylaminomethyl-4-thiazolpmethylthio) -ethylZamino-5-C2- (3-pyridyl) -ethylJ-4pyrimidone. A mixture of 1.29 g of 2- (2-dimethylaminomethyl-4-thiazolylmethylthio) ethylamine and 1.37 g of 2-methylthio-5-2- (3-pyridyl) ethyl 4-pyrimidone in 25 ml of anhydrous pyridine is boiled 4 days The solvent is distilled off in vacuo. The residue is dissolved in ethanol and the solution is again evaporated. The residue obtained is purified by high pressure liquid chromatography on a column of silica gel, using a gradient elution method with an ethyl acetate – ethanol – ammonium hydroxide solvent system as the eluent. Fractions of the eluate. containing the desired product according to thin layer chromatography, the combined eluant is again chromatographed on silica gel using preparative thin layer chromatography using 3% ammonia in ethanol as the eluent (mobile phase). The resulting (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino5- 2- (3-pyridyl) -ethylJ4-pyri and schdone is converted to the corresponding trihydrochloride (tris-hydrochloric acid salt) according to a known procedure. After recrystallization from a mixture of solvents, ethanol - ethyl acetate - diethyl ether, the target trihydrochloride (2dimethylaminomethyl-4-thiazolylmethylthio) ethyl ethyl-5- 2- (3-pyridyl) ethyl-4-pyrimidone has so pl. 226-228 C. Exit 1.0-g. Calculated,%: C 44.49; H 5.41; N 15.56. Found,%: C 44.24; H 5.29; N 15.34. Using the examples described, the following compounds are prepared. Example 11. (2-H-Pyropropidinomethyl-4-thiazolylmethylthio) -ethyl 7
    amino-5- (6-methyl-3-pyridyl) methyl-4-pyrimidone, starting from .2-2-pyrrolidinomethyl-4-thiazolylmethylthio) ethylamine and 2-methylthio-5-П2- (6-methyl-3-11Iridyl) methyl 3 4-pyrimidone. The yield of the target product 38% of theoretically possible, so pl. 159-160,5 p.
    Example 12. 2-C2- (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino- (2-methyl-4-pyridyl) methyl-4-pyrimidone-trihydrochloride, based on 2- (2-dimethylaminomethyl-4-thiazoylmethylthio a) these.pamine and 2-metsh1Tio-5 2- (2-methyl-4-pyridyl) -methyl-4-pyrimidone. The yield of the target product is 18% of the theoretically possible, tpl, 191-193s.
    Example 13. (2-Dimesh1-aminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (2-thiazolyl) methyl-4 pyrimidone, starting from 2- (2-dimesh1aminomethyl-4-thiazolylmetsthio) ethylamine and 2-nitroamino-5- ( 2-thiazolyl) methyl 4-pyrimidone. The product yield 53% of theoretically possible, so pl. 115-11b C.
    Example 14, (2-dimethylaminomethyl-4-thiazolylImethylthio) ethanol; amino-5- (2-furyl) methyl-4-pyrimidone dihydrochloride, starting from 2- (2dmethylaminomethyl-4-thiazolylmethylamine-ethylamino-isomethylaminomethylaminomethylaminomethylaminoethylamine, and starting with 2- (2dnmethylaminomethyl-4-thiazolylmethylaminoethylthylamine); 5- (2furyl) metsh1-4-pyrimidone. The yield of the target product 33% of theoretically possible, so pl. -156-8 S.
    . Example 15. 2-C2- (2-Methylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (6-metsh-3-pyridate) methyl 4-pyrimidone, starting from 2- (2-methylaminomethyl-4-thiazolylmethylthio) ethylamine and 2-MetSh1thio-5- (6-methyl-3-pyridyl) -methyl-4-pyrimidone. The yield of the target product is 15%. M.p. 192-4 ° C.
    Example 16. (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (imidazol-4-yl) methyl-4-pyrimidone.
    A solution of 2- (dimethylaminomethyl-4thiazolylmethylthio) ethylamine (2.3 g) and 2-nitroamino-5-Ql- (4,4-dimethoxy-benzhydryl) imidazol-4-ylmethyl-4-pyrimidone (4.62 g in 11 ml of ethanol) t under reflux for 22 hours. Ethanol is distilled off, the residue is chromatographed by high pressure liquid chromatography. The appropriate eluate fractions are combined and after evaporation
    59068
    solvent is obtained as a residue
    1.6 g target (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl1amf
    but-5- | 1- (4,4-dimethoxybenzhydryl) 5 imidazol-4-ylmethyl-4-pyrimidone as a glassy product.
    A solution consisting of about 1.6 g of the obtained compound, 3 ml of anisole and 30 ml of trifluoroacetic acid to the acid is refluxed for 3 hours. After the indicated time has elapsed, thin layer chromatography shows the absence of the initial substance in the reaction mixture. . Thereafter, the volatile components of the reaction mixture are distilled off in vacuo, and to the residue at B is added a 5 N solution of hydrogen chloride in ethanol. The solution is again evaporated to dryness, water is added to the residue and the resulting solution is extracted in a separatory funnel with diethyl ether. The acidic aqueous solution is made alkaline with potassium carbonate, and the 25 basic solution obtained is evaporated to dryness, isopropanol is added to the residue and the mixture is again evaporated. The substance obtained in the residue is extracted several times with fresh
    30 portions of hot isopropanol. After cooling, the combined extracts are filtered, the filtrate is evaporated in vacuo, and a glass-shaped product is obtained in the residue, which represents the desired (2-dimersiline-1-4-thiazolshmethylthio) ethyl} amino-5 (imidazol-4-yl) methyl-4-pyrimidone. The crude product is cleaned by high performance liquid x-romatography.
    0 high pressure, an amorphous solid is obtained, which has been identified according to mass spectroscopy: m / e 406, P + 1.
    Example 17. 2 - {; 2- (2-Dimethyl5 aminomethyl-4-thiazolylmethylthio) ethyl ethyl-5- (5-methyl-3-pyridyl) methyl-4 pyrimidone trihydrochloride, hydrate. The specified connection receive in the form of a hydrate (3,5-N20), based on
    0 2- (2-dimesh1aminomethyl-4-t azolsh1metsh1tio) et1shamina and 2-methylthio-5 (5-methyl-3-pyridi-t) methyl-4-pyrimidone. The yield of the target product is 6% of theoretically possible, so pl. 80 ° C
    5 (foaming), 220-240 ° C (decomposition).
    Example 18 2-2- (2-Dimethylaminomethyl-4-thiazolylmethyl-Thio) -ethyl 3
    9
    amino-5- (2-methoxy-3-pyridyl) methyl 4-pyrimidone, the anal is obtained in an enormous manner, starting from 2- (2-dimethylaminomethyl-4-thiazolylmethylthio) ethylamine and 2-nitroamino-5- 2- (2-methoxy- 3pyrimidyl) methylj-4-pyrimidone. The yield of the target product, which is a glassy substance that does not have a clear melting point, was 44% of the theoretical value.
    Biological tests have shown that the compounds of the present invention are potential IL receptor antagonists and, therefore, potential anti-ulcer agents.
    The detected and estimated blocking activity of the proposed compounds with respect to H-receptors is carried out as follows.
    On the 24th experiment start, estrone was administered to female white rats. The rats are then sacrificed, their corneal formations of the uterus are removed and suspended at ambient temperature in isolated organ bathes containing Dejalon’s solution. After reaching equilibrium (after equilibration), the strips of the uterus are subjected to a 50-mmol aqueous solution of potassium chloride, which causes prolonged contraction (muscle contraction). When the uterus is contracted in this way, histamine causes uterine relaxation (relaxation), which is dependent on the dose used and associated with H. receptor mediation. On each sample of tissue, a control and calibration curve is plotted for the degree of relaxation of the contracted uterine tissue (reaction or response) as a function of the histamine dose. After constructing such calibration dose – response curves, the histamine was thoroughly washed and each of the test subjects was added; antagonists (compounds of the present invention) at a concentration of 10 mol (10 MO) for a period of 30 minutes. Then, the uterine tissue strips are contracted (transferred to the contraction state - contraction) by exposure to an aqueous solution of potassium chloride in the presence of the antagonist under study and constructed.
    95906-10
    the second dose curve is the response depending on the added amount (dosage) of histamine. In the presence of a competitive antagonist curve
    5 Dependence of the degree of relaxation of the contracted tissue (response) on the histamine dose shifts parallel to the right with no depression maximum relative to the control
    10 (calibration curve). For each concentration of antagonist, a dosage ratio (TO) is calculated by dividing ED (ED), histamine in the presence of a competitive antagonist.
    5 per control ED value for histamine. From the obtained values of the dosage ratio, the dissociation constant (Kg) of the antagonist is calculated, using the following equation
    20 K antagonist / (DO-1).
    Cimetidine is used as an internal standard.
    The results of these in vitro tests carried out in accordance with the described method on a number of arbitrarily selected proposed compounds are presented in Table. one.
    Table 1
    | -bg, KB
    Compounds
    (2-Dimethylaminomethyl-sh-4-thiazolylmethylthio) -ethyl amino-5- (3-pyridyl) methyl-4-pyrimidone 8.96
    (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl} amino-5-5 (1,3-benzodioxolyl)
    methyl 4-pyrimidon8,36
    2- 2- (2-Dimethylaminomethyl-4-thiaz olylmethylthio) -ethylJ-amino-5 (6-methyl-3-pyridyl) methyl-4-pyrimidone 7.95
    (2-Dimethyl-amino-methyl-4-thiazolyl-methyl-thio) -ethyl-amino-5- (4-pyridyl) methyl-4-pyrimidone 7.89
    (2-Dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5 (2-pyridyl) methyl-47, 76
    pyrimidone 6.14
    Cimetidine 11 From table. 1 shows that the tested representatives of the compounds of formula 1 are 10-100 times more active than cimetids. To carry out the second series of in vitvo bioassays, the isolated mucous membrane of the stomach of a hen hog is used to evaluate the blocking activity of the proposed compounds in relation to the HR-receptor. . To do this, the stomach muscles of the bullish bulls (Raiia Catesbeiana) separate the mucous membrane of the stomach and place it between a pair of Ussing chambers made from an acrylic plastic of lucite. . The chambers are filled with a dried Ringer's solution and the secretion of acid is released (stimulated) by the addition of histamine and the serous side of the gastric mucosa at a concentration (final). The amount of acid released (acid output) is automatically otitrovshta to pH 4.5. After establishing a stable response to the concentration of histamine, the antagonist under investigation (compound of the present invention) is added to the serous chamber and the maximum inhibition of acid secretion is recorded at each concentration of H, antagonist . The data obtained are used to plot the dependence of the antago dose — the answer from which the EDD value of the investigational drug is calculated. The results obtained when testing the proposed compounds using the described methods are presented in table. 2, where R is a substituent in position 6 of the pyrimidine ring. Table 2 pg t 1 g —SgN gt nn; STS (H 3-Pyridyl1,15x10 H 6-Methyl-3-pyridyl 1.35x10 0b Continued table 2 I - 1 I II - Ttt h 6-Methoxy-3-pyridyl 1,26x10 H 6-Oxy-3-pyridyl 2.52x10 H 5- (1,3-Benzodioxalil) 1.11x10 1.96x10 H 4-Pyridyl 1.63x10 H. 2-Pyridyl H 5,6-Dimethyl-3-Pyridyl 2, 35x10 2.00x10 CH, 3- Pyridyl H 2-methoxy-4-pyridyl 3, 00x10 H 2-Oxy-4-pyridyl 6.03 x 10 Table 2 shows that the compounds obtained by the proposed method have comparable activity. In vivo tests of the compounds of the present invention are carried out in order to evaluate the antisecretory the effects of these medicinal agents on acid secretion are carried out when used and dogs with gastric fistula, dogs with vagal-innervated gastric fistula, and dogs with a vaginal denervated Heidentein pocket (Heiden-thain pouch). Stable (stable) gastric secretion in experimental animals is induced by intravenous infusion (intravenous administration) of histamine. the study was administered either intravenously - by infusion 30 minutes (after histamine), or orally 75 minutes before collecting the gastric juice from the fistula. As a result of this gray bio-digestion, It was found that (2-dimethylaminomethyl-4-thiazolylmethylthio) -ethyl amino-5- (3-pyridyl) methyl-4-pyrimidone exceeded cimetidine 11 times when administered intravenously and exceeded cimetidine 14 times when administered orally. Accordingly, the 6-methyl-3-pyridyl analog of this compound, i.e. (2-dimesh1-aminomethyl-4-thiazolylmethylthio) -ethylZamino-5- (6-methyl-313 pyridyl) methyl-4-pyrimidone, cimetidine is more active than 14.4 times when administered intravenously. According to these and other tests, the proposed compounds are more active than cimetidine, in particular when administered orally. These compounds also have a significantly longer effect than cimetidine, since the restoration of gastric secretion after administration of an effective dose of (2-dimethylaminomethyl-4thiazolylmethylthio) ethyl} amino-5- (3pyridyl) methyl-4-pyrimidone occurs after 3-4 hours in total only by 25%, while after the same period after administration of cimetidine, acid secretion is restored by about 50%. 06 In addition, compared with cimetidine, the proposed compounds also have an inhibitory effect on histamine H receptors and, in a severe way, can affect those physiological states that arise as a result of stimulation of the H and H aggregate of histamine receptors. The compounds of general formula 1 obtained by the proposed method exhibit a higher biological activity than cimetidine at comparable toxicity values: DMD-o for cimetidine in mice after intravenous administration of 150 mg / kg for compounds of general formula 1 obtained by the proposed method 115 -205 mg / kg.
    权利要求:
    Claims (3)
    [1]
    The method of obtaining pyrimidine derivatives of General formula
    (= η-ΩΗ 2 -δ-№2) 2 -ΝΗ - ( 3γΝ Μ
    Ηι
    %
    DB
    where K, K 1 - hydrogen, methyl;
    - hydrogen;
    K ^ and - together
    - Ν-2-M-pyrrolidinomethyl;
    13
    B - 2 (3 or 4) -pyridyl;
    [2]
    2 (6) -methoxy-4 (3) -pyridyl; 2-methoxy-3-pyridyl; 5,6-dimethyl-3-pyridyl; 6-methyl-3-pyridyl; 1,3-benzodioxoline;
    [3]
    5-methyl-3-pyridyl,
    or their pharmaceutically acceptable salts by reacting the amine of the general formula
    ^ pCNgg-B-CCH ^ H
    γΝ
    SNG-Ν ^
    Kg
    n 2
    with pyrimidine derivatives of the general formula
    where 0 is nitroamino, methylthio, followed by allocation of the target product in free form or in the form of their pharmaceutically acceptable salts.
    51) „, 1195906
    2
    eleven
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    同族专利:
    公开号 | 公开日
    EP0083186B1|1988-05-11|
    DK574782A|1983-06-29|
    GB2111995B|1985-07-24|
    FI824407A0|1982-12-21|
    GR78415B|1984-09-27|
    IL67496A|1986-11-30|
    CA1206151A|1986-06-17|
    ZA829247B|1984-07-25|
    PH19797A|1986-07-02|
    AT34173T|1988-05-15|
    PT76004B|1985-12-03|
    HU192951B|1987-08-28|
    DE3278473D1|1988-06-16|
    KR840002831A|1984-07-21|
    NZ202797A|1985-08-30|
    AU9153982A|1983-07-07|
    CS235976B2|1985-05-15|
    GB2111995A|1983-07-13|
    PL239796A1|1984-05-21|
    AU558153B2|1987-01-22|
    ES8403895A1|1984-04-01|
    JPS58118585A|1983-07-14|
    PT76004A|1983-01-01|
    KR860000106B1|1986-02-19|
    ES518592A0|1984-04-01|
    EP0083186A3|1984-05-23|
    EP0083186A2|1983-07-06|
    IE823031L|1983-06-28|
    DD203720A5|1983-11-02|
    FI824407L|1983-06-29|
    IE54313B1|1989-08-16|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US33478481A| true| 1981-12-28|1981-12-28|
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