• 专利附录
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    • 专利摘要:
    Compounds having the formula (I) <CHEM> and their pharmaceutically acceptable salts, wherein one or two of A1, A2, A3, and A4 is N, and the remaining A1, A2, A3, and A4 are CH, provided that if A4 is N, then one of A1, A2, and A3 is also N, and provided that one of A1, A2, and A3 may be CX where X is halo; and each of R1, R2, and R3 is independently hydrogen, C1-C4 alkyl, C1-C4, alkoxy, allyloxy, benzyloxy, (C1-C4 alkyl) thio, (C1-C4 alkyl) sulfinyl, (C1-C4 alkyl)sulfonyl, hydroxy, halo, cyano, nitro, amino, mono- or di-(C1-C4alkyl)amino, trifluoromethyl, or Z-Q-substituted C1-C4 alkoxy, wherein Q is oxygen, sulfur, sulfinyl, sulfonyl, or a bond, and Z is C1-C4 alkyl, phenyl or phenyl substituted with halo, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro, amino, C1-C4 alkylthio, C1-C4 alkylsulfinyl, or C1-C4 alkylsulfonyl are ionotropic agents or intermediates thereto.
    公开号:SU1255052A3
    申请号:SU833679907
    申请日:1983-12-26
    公开日:1986-08-30
    发明作者:Альфред Шпитцер Вейн
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the production of new compounds that can be used in medicine.
    The goal of iso-absorption is the synthesis of new compounds with valuable properties.
    Example 1 OC-Brom-2,4-dimethoxyacetophenone.
    53 g of aluminum chloride are added in portions to 55.2 ml (400 mol) of 1,3-dimethoxybenzene and 34.5 ml (400 mmol) of bromoacetyl bromide using an ice bath VI maintaining the temperature around 0 ° C. After completing the addition of aluminum chloride ice the bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was carefully added to ice water and the resulting mixture was extracted with 1500 ml of ethyl acetate. The organic phase is washed with 500 ml of 1N hydrochloric acid. The organic phase is reduced, dried and evaporated in vacuo. The residue is crystallized from diethyl ether, resulting in 54.1 g of the expected product in the form of white crystals.
    Example 2. l-Bromo-2-methoxy-4-methylmercaptoacetophenone.
    A. Preparation of 2 hydroxy-4-benzyloxy-acetophenone. I
    50 g of 2,4-dioxyacetophenone are dissolved in 250 ml of dimethylformamide and the resulting solution is cooled to 0 ° C. with an ice bath. After adding 15 g of a 50% oil dispersion of sodium hydride, 40 ml of benzyl chloride is added dropwise and the reaction mixture is allowed to warm to room temperature. After stirring overnight, the reaction mixture was added to 700 ml of ethyl acetate. The organic phase is washed with 1000 ml of 1N hydrochloric acid and twice in 1000 ml of saturated sodium chloride solution. The organic layer is dried and the solvent is removed in vacuo. The oily residue is treated with 100 ml of methanol and 50 ml of hexane ,. The desired 2-hydroxy-4-benzyloxy-acetophenone (36.7 g) is isolated by filtration.
    B. Preparation of 2-methoxy-4-benzsh1 hydroxyacetophenone.
    70 g of 2-hydroxy-4-benzyloxy-acetophenone are dissolved in 300 ml of dimethylformamide and the resulting solution is cooled to an ice-bath. After adding g to 50% ma
    54 ml of methyl iodide are added to the reaction mixture in a mixture of sodium hydride. Then the reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is added to 500 ml of ethyl acetate and washed three times with 500 ml of saturated sodium chloride solution. The organic phase is dried and the solvent is removed in vacuo. Hexane is added and, after filtration, 52 g of crystalline 2-methoxy-4-benzyloxy-acetophenone are obtained.
    5 C. Preparation of 2-methoxy-4-oxyacetophenone.
    20 g of 5% palladium on carbon are added to a solution of 94.6 g of 2-methoxy-4-benzyloxy-acetophenone in 785 ml
    0 tetrahydrofuran. The resulting mixture is hydrogenated at 45-50 ° C for 5 hours at 60 psi, and by this time 95% of the theoretical absorption of hydrogen occurs. Catalyst
    5 was removed by filtration and the solvent was removed in vacuo. 52 g of 2-methoxy-: 4-oxyacetophenone is isolated as a solid. The resulting product is used in a further stage.
    0 without further purification.
    D. Preparation of 2-methoxy-4- (dimethylthiocarbamoyloxy) acetophenone.
    To a suspension of 7.5 g of a 50% oil dispersion of sodium hydride in 75 ml
    dimethylformamide 26.5 g added
    2-methoxy-4-oxyacetophenone, while the reaction mixture is cooled with an ice bath. After the addition of 23.2 g of dimethylthiocarbamoyl chloride, the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into 50 ml of ethyl acetate and washed with 300 ml of a saturated solution of sodium chloride. The aqueous layer is extracted with 300 ml of ethyl acetate and the combined ethyl acetate solutions are washed three times with 500 ml portions of a saturated solution of sodium chloride. Organic layer
     and the solvent is evaporated in vacuo. The remaining oil is thoroughly triturated with hexane. The hexane is decanted and a small volume of diethyl ether is added, which causes crystallization. After filtration, 15j4 g of 2-methoxy-4- (dimethylthiocarbamoyloxy) acetophenone from the ester mixture, plus an additional 3.5 g, are isolated.
    3
    Crystallized from decanted hexane.
    E. Preparation of 2-methoxy-D-dimethylcarbamoyl mercapto) acetophenone.
    10 g of 2-methoxy-4- (dimethylthiocarbamoyloxy-acetophenone is placed in two flasks with a capacity of 100 ml under nitrogen and heated to 235-240 ° C. on an oil bath for 1 hour. The residues obtained are combined and purified on a chromatographic column with silica gel, eluting with 50% ethyl acetate / hexane. The product obtained is collected and crystallized from a minimum volume of ether to yield 8.3 g of 2-methoxy-4- (dimethylcarbamoylmercapto) acetophenone.
    F. Preparation of 2-methoxy-D-mercap of toacetophenone.
    A solution of 1.8 g of 2-methoxy-4- (dimethylcarbamoyl mercapto) acetophenone in 20 ml of methanol and 7.2 ml of 5N sodium hydroxide is allowed to reflux for 2 hours. Then the reaction mixture is taken up in 200 ml of ethyl acetate . After washing with 200 ml of 1N. hydrochloric acid, the organic phase is dried and. evaporated in vacuo. The residue is crystallized after removal of the solvent to obtain 1.1 g of 2-methoxy-4-mercapto-aceto}) enone.
    Calculated: C 59.32; H 5.53; S 17.59.
    C, F, 0, S
    Found: C, 59.70; H 5.55; S 17.41.
    G. Preparation of 2-methoxy-4-methyl-mercapto-acetophenone.
    3 g of 2-methoxy-4-mercaptoacetophenone are dissolved in 30 ml of methanol. 3 g of potassium hydroxide is added, after which 3 mp methyl iodide is added. The reaction mixture was stirred at room temperature for 30 minutes,. then it is added into 200 ml of ethyl acetate, washed with 200 ml of saturated sodium chloride solution, dried and evaporated in vacuo. The remaining oil is dissolved in a small volume of ether and hexane is added until cloudy. Crystallization occurs, resulting in 2.3 g of 2-methoxy-4-methyl mercaptoacetophenone.
    Calculated: C 61.20; H 6.16; S 16.34.
    C, OH, go5
    Found: C, 61.45; H 5.91-,
    S 16.63.
    550524
    N. Preparation of od-bromo-2-methoxy-4-methylmercaptoacetophenone
    A solution of 1.6 ml of diisopropylamine in 30 ml of dry tetrahydrofuran is cooled to -20 ° C under a nitrogen atmosphere. 7 ml of a 1.6 M n-butyl lithium solution is slowly added to the solution. The light solution is stirred for 20 minutes while maintaining the temperature.
    ten
    from -5 to. Then the temperature
    reduce to and add a solution of 2 g of 2-methoxy-4-methylmercaptoacetophenone in 10 ml of dry tetrahydrofuran. After stirring the 15 solution at -78 ° C for 30 minutes, 2 mp chlorotrimethylsilane was added. The solution is brought to room temperature and stirred for 90 minutes. The solvent is removed in vacuo and 200 ml of diethyl ether are added to the residue. The solution is filtered and the resulting filtrate is evaporated in vacuo to yield 2.3 g of solid product, which is dissolved in 35 ml of dry 5 tetrahydrofuran under nitrogen atmosphere. The resulting solution is cooled to O C and 1.8 g of N bromosuccinimide is added. After stirring for 45 minutes at 0 ° C, 200 ml of methylene chloride was added to the solution. The resulting solution was washed with cold sodium bicarbonate solution. The organic layer is separated, dried over magnesium sulphate and evaporated in vacuo. The resulting residue is crystallized from diethyl ether, whereby 1.05 gob-bromo-2-methoxy-4-methylmercaptoacetophenone, M 274.276, is obtained. The spectrum of proton magnetic resonance corresponds to the assumed structure.
    Example 3. oi-Bromo-2-methoxy- -4-metshlsulfinylacetophenone.
    A solution of 1.5 g of i-bromo-2-methoxy-5-4-methyl mercapto acetophenone in 75 ml of methylene chloride is cooled to 0 C, after which one equivalent (760 mg) of 85% meta-chloroperbenzoic acid is added. After stirring 0 at 0 ° C for 1 h, add
    200 ml of methylene chloride, the organic solution is washed with M sodium bicarbonate solution. The organic layer is dried over magnesium sulphate and the 5 solvent is removed in vacuo. The oily residue can be used in subsequent reactions without further purification. After crystallisation,
    From the ether, a purified desired product is obtained,, 292.
    Calculated: C, 41.25; H 3.8), S P, P1u Vg 27, D4. S „N„ Vg50z
    Found: C 40.76; H 3.82; S 10.40; Br 28.58.
    Example 4. about-Brom-2-methoxy-4-metnpsulfonusch1 acetophenone,
    A. Preparation of 3-Fluorophenyl Acetate 19.5 ml of pyridine are added to a solution of 20 ml of 3-fluorophenol in 200 ml of dry methylene chloride. The resulting solution was cooled to O C and 17.5 ml of acetyl chloride was added dropwise with stirring. After the addition is complete, the reaction mixture is stirred for 1 hour at 0 ° C. Then another 200 ml of methylene chloride are added and the organic solution is extracted one pas with 300 ml of 1N hydrochloric acid. The organic solution is dried over magnesium sulphate and evaporated in vacuo to yield 34.3 g of 3-fluorophenyl acetate as an oil, which is used in the next step without further purification.
    B. Preparation of 2-hydroxy-4-fluoroacetophenone.
    In a flask with 34.2 g of 3-fluorophenylacetate, which is cooled to 0 ° C, 40 g of aluminum chloride are added in portions. The flask is allowed to warm to room temperature, then it is transferred to an oil bath and heated to 160-180 ° C for 2 hours. The reactor is cooled to 0 ° C and carefully added ice, and then 150 ml of concentrated hydrochloric acid and 250 ml ethyl acetate. The resulting mixture is stirred until a clear solution is obtained, the layers are separated, the ethyl acetate is removed in vacuo. The residue is subjected to steam distillation. The resulting distillate is acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is dried and the solid portion is removed in vacuo to give 28 g of 2-hydroxy-4-fluoroacetophenone as an oil, which crystallizes upon cooling.
    C. Preparation of 2-methoxy-4-fluoroacetophenone.
    To a solution of 13.9 g of 2-hydroxy-4-fluoro-acetophenone and 75 ml of dry dimethylformamide was added 30 mp of methyl iodide. The solution is cooled to and carefully added 4.1 g of a 50% sodium dispersion oil dispersion. After stirring for 2 hours at 0 ° C, the reaction mixture is extracted with ethyl acetate. The organic extract is washed three times with 200 ml portions of 1N hydrochloric acid. The ethyl acetate solution is then dried and evaporated in vacuo. As a result of this reaction and the subsequent identical reaction, 28 g of 2-methoxy-4-α-fluoroacetophenone are obtained in the form of an oil, which is used in the next step without further purification.
    D. Preparation of 2-methoxy-4-methyl-mercapto-acetophenone,
    . A suspension of 17 g of potassium hydroxide in 100 ml of dry dimethylformamide in a nitrogen atmosphere is cooled to C with an ice bath. 26 ml of methanethiol are added to this suspension. The reaction mixture is stirred until all the potassium hydroxide is dissolved. At this time, 33.1 g of 2-methoxy-4-fluoroacetophenone was added, the reaction mixture was stirred at 0 ° C for 2 hours and poured into 400 ml of ethyl acetate, and the resulting solution was washed three times with 300 ml of 1N hydrochloric acid. Then organic
    the phase is dried and evaporated in vacuo to an oil. As a result of crystallization from a 50% mixture of ether / hexane, 21.3 g of the desired 2-methoxy-4-methyl mercapto acetophenone is obtained,
    E. Preparation of 2-methoxy-4-methylsulfonylacetophenol,
    To a solution of 3f92 g of 2-methoxy-4- -methyl mercapto-acetone in 200 ml of methylene chloride was added 4 g of meta-chloroperbenzoic acid. Thin layer chromatography indicates the formation of an intermediate sulfoxide derivative 10 minutes later another 4 g of meta-chloroperbenzoic acid is added. After stirring for 1 hour, the reaction mixture was washed with 500 ml of saturated sodium bicarbonate solution. Organic
    the phase is isolated and dried over magnesium sulphate. The organic solution is then vacuum filtered to obtain 3.61 g of 2-methoxy-4-methylsulfonyl acetphenone.
    F. Preparation of oi-bromo-2-methoxy-4-methylsulfonylacetophenone.
    To a suspension of 3.6 g of 2-methoxy-4- -methylsulfonylacetophenone and 100 ml
    7
    Acetic acid was added in sufficient amount of methylene chloride to form a solution. While stirring at room temperature, 0.91 MP of bromine is added. The reaction mixture is stirred until the bromine disappears, is poured into 300 ml of ethyl acetate and twice in portions of 300 ml of sodium chloride solution. The organic layer is then washed with 300 m of saturated sodium bicarbonate solution. The organic phase is dried and the solvent is removed under vacuum. The resulting oil crystallizes upon the addition of diethyl ether, to give 4.05 g of the desired o (α-bromo-2-methoxy-4-methylsulfonylacetophenone).
    Calculated: C 39.10; H 3.61; S 10.44; Вг 26, ОЬ
    С, ОН „Вг504
    Found: C 38.92; H 3.51; S 10.28; Br 26.30.
    EXAMPLE 5 2- (2,4-Dimethoxy-phenyl) imidazo (1,2-a) pyrimidine.
    A solution of 1.9 g (20 mmol) of 2-aminopyrimidine and 5.2 gs6-bromo-2,4-dimethoxy-acetophenone in 40 ml of dimethylformamide is stirred at room temperature for about 60 hours. React the mixture into approximately 300 ml of ethyl acetate. The organic solution is washed with a complete solution of sodium bicarbonate, and then twice a portion of 300 mp with a saturated solution of sodium chloride. The organic phase is dried, the solvent is removed in vacuo. The residue obtained is crystallized from hot ethanol to obtain 2 g of the intended product, M 255.
    Calculated: C, 65.87; H 5.13; N 16.46
    C ,, 1I ,, N, 02
    Found: C, 65.59; H 5.08;
    N 16.30.

    Example 6: 2- (2,4-Dimethoxyphenyl) imidazo (1,2-a) pyridine hydrobromide.
    A solution of 5.7 g of 2-aminopyrikidin and 15.6 c6-bromo-2,4-dimethoxy acetate-phenone in 30 ml of dimethylformamide is stirred at room temperature for 4 hours. The resulting precipitate is collected by filtration and washed with ethyl acetate to obtain 10 g of the desired product,.





    eight
    Calculated: C 50.02; H 4.20; N 17.50.
    C ,,, 0, .HBr
    Found: C 49.82, H 4.07 j 5 N 12.30.
    Example 7. 2- (2,4-Dimethoxy-phenyl) imidazo (1,2-a) pyrazine.
    As in Example 1, 1.9 g of 2-aminopyrazine and 5.2 goi-bromo-2,4-dimeth- 0 hydroxy-acetophenone are reacted in 40 ml of dimethylformamide. The product obtained is purified on a chromatographic column with silica gel, eluting with 10% methanol. in ethyl acetate to give 330 mg of the title product, M 255.
    Calculated: C, 65.87; H 5.13; N 16.46.
    C, 4H ,, N, 02
    20 Found: C 63.39, H 5.66} N 15.46.
    Example 7. 6- (2,4-Dimethoxy-phenyl) -imidazo (1,2-b) (1,2,4) triazine.
    As in the example, 1.9 g of 3-amino-1, 2,4-triazine and 2.7 roi-bromo-2,4-dimethoxy-acetophenone are heated for 2 hours at 60 ° C in 30 ml of dimethylformamide. The reaction mixture was added to 300 MP of ethyl acetate. And washed with 300 ml of a saturated solution of sodium bicarbonate, and then twice with 300 MP of a saturated solution of sodium chloride. The organic layer is evaporated to dryness and the residue is purified on a chromatographic column 5 with silica gel, eluting with ethyl acetate to obtain 200 mg of the desired product,.
    Calculated: C 60.93; H 4.72; N 21.86.
    WITH,,,,
    Found: C 60.57, H 4.52; N 21.56,
    PRI me R 9. 2- (2,4-dimethoxy-phenyl) imidazo (1,2-c) pyrimidine.
    A. Preparation of 4-amino-6-chloropyridine,.
    The specified product is obtained by a known method.
    B. Preparation of 2- (2,4-dimethoxyphenyl) -6-chloro-imidazo (1,2-c) pyrimidine hydrobromide.
    As in Example 2, 2.6 g (20 mmol) of 4-amino-6-chloropyrimidine and 5.1 got-6poM-2,4-dimethoxy-acetophenone are stirred in 10 ml of dimethylformamide for 3 days at room temperature. The precipitate obtained is filtered and washed with ethyl acetate to give 7.37 g of the expected product,.
    Calculated: C 45.37; H 3.54; N 11.34; C 9.57, Br .21.56.
    C ,, H ,, 0. NVG
    Found C 45.08; H Z.ZTs N 11,14; All 9.35 Вг 21,32.
    C. Preparation of 2- (2,4-dimethoxyphenyl) imidazo (1,2-c) pyrimidine.
    Approximately 7.3 g of 2- (2,4-dimethoxyphenyl) -6-chloro-imidazo (1,2-c) pyrimidine hydrobromide is converted into the free base, suspended in ethyl acetate, added with 20 ml of propylene oxide and shaken to obtain solution. The ethyl acetate solution is washed with water, dried and the solid is isolated in vacuo to give the free amine.
    A solution of 3 g of 2- (2,4-dimethoxyphenyl) -6-chloro-imidazo (1,2-c) -pyrimidine (free base) in ethyl acetate is treated with 1 g of 5% palladium on carbon and hydrogenation is carried out until hydrogen absorption takes place, 2 g of triztilamine is added and hydrogenation is continued. When absorption of hydrogen ceases, the catalyst is removed by filtration and the ethyl acetate solution is treated with 300 m of a saturated sodium chloride solution. The organic solution is evaporated in vacuo, and the resulting residue is crystallized from ethyl acetate / ether to obtain 1.2 g of the intended product. .
    Calculated: C, 65.87; H, 5.13; N 16.46
    C ,, H ,, N, 02
    Found: C, 64.75; H 4.91; N 15.61.
    Example 10. 2- (2-Methoxy-4- -methylsulphinyl) imidazo (1,2-a) pyrimidine hydrobromide.
    Analogously to Example 2, 294 mg of 2-am dopirimidine and 900 mg of A-bromo-2-met-hydroxy-4-methylsulfinyl acetophenone solution o-t in 5 ml of dimethylformamide and stirred overnight at room temperature. The precipitate formed is collected by filtration and washed with hexane to obtain approximately 300 mg of the desired product,. ,
    Calculated from 45.66; H 3.83; N 11.41; S 8.69; Br 21.70,
    C ,, H ,,,. HBr
    Found C 45.39; H 3.86; N 11.67; S 8.49; Br 21.51,
    Example 7, 2- (2-Methoxy-4- -methylsulfonylphenyl) imidazo (1,2-ai pyrimidine hydrobromide.
    Analogously to Example 2, 1.26 g of 2-aminopyrimidine and 4.05 th; -bromo-2- methoxy-4-methylsulfonylacetophenone in 10 ml of dimethylformamide are stirred at room temperature for 6 hours. After filtering the reaction mixture and washing with ethyl acetate, 2 , 32 g of the desired product. By stirring the filtrate for an additional 16 hours, an additional 1.4 g of product is obtained.
    Calculated: C 43.76; H 3.67; N 10.94; S 8.34; Br 20.79.
    C ,, H, N, Oy NVB
    Found C 43.92; H 3.54; N 11.08, - S 8.27 Bg 20.68.
    Example P. 2- (2-Methoxy-4- -methylsulfonylphenyl) imidazo (, 2-a) pyrazine.
    In analogy to Example 5 (B), 3.88 g of 2-amino-3-chloropyrazine and 9.21-bromo-2-methoxy-4-methylsulfonyl acetophenone are reacted to obtain 4.8 g of intermediate 8-chloro-2- (2 -methoxy-4-methylsulfonylphenyl) imidazo (1,2-a) pyrazine hydrobromide. Hydrobromide salt (3.6 g) is hydrogenated in 195 ml of dimethylformamide and 2.7 g of triethylamine in the presence of 1 g of 5% palladium on barium sulfate. After filtration, the solution is poured into 700 ml of ethyl acetate, washed four times with a solution of sodium chloride, and the solvent is concentrated in vacuo. After the volume has decreased, crystallization occurs, and 540 mg of the desired product is isolated by filtration.
    Calculated: C 55.43; H 4.32; , N 13.85; S 10.57.
    C ,, H ,, N, 0,
    Found: C 53.91, H 4.01; N 13.52; S 9.91.
    Example 12. 2- (2-Methoxy-4- -methylsulfonylphenyl) imidazo (1,2-a) pyrimidine.
    As in Example 1, 2.0 g of 2-aminopyrimidine and about 4.9 gob-bromo-2-methoxy-4-methylsulfinyl acetophenone are reacted in dimethylformamide. The solvent is evaporated in vacuo, and the residue is chromatographed on a column with highly elution with 20% methanol in ethyl acetate). The appropriate fraction is combined and evaporated to give 1.3 g of the desired product containing about 2% of residual silica gel.
    C 58.52; H 4.56-,
    N
    N
    Calculated: 14.62; S 11.16.
    C ,, H ,, N,
    Found: C 57.35, - And 4.35; 13.71; S 10.61.
    As the active ingredient, any pharmaceutical compounds according to the invention may be used.
    The inventive compounds and their pharmaceutically acceptable salts have been found to possess beneficial pharmaceutical properties, including positive inotropy and vasodilation. Experienced pharmaco dynamic properties of the proposed compounds in the following test systems.
    Positive inotropic activity in isolated papillary cats cat.
    Cats of either sex are anesthetized with methofan (.1,1-difluoro-2,2-dichloroethyl methyl ether, - Piffman-Moore), their hearts are immediately removed and papillary excisions are dissected and suspended in cuvettes for individual organs. At one end of the muscle, a platinum hook is attached to the electrode mounted at the bottom of the cuvette, and the silk thread is attached to the tendon and the isometric sensor. Statham. A Krebs-Hensefeit solution (purged with a mixture of 95% oxygen - 5% CO) is in the cuvette of the following millimolar composition: NaCf 118; KCf 4,5i CaCfj 2,5; KE.PO l, i MgS04 1,2} NaHCO, 25, glucose 11,
    Ha, each pulse is supplied with an initial tension of 1.5 g, Right angle pulses with a duration of 5.0 ms, three times the threshold voltage, are fed through a hook electrode, and the second electrode located near the upper end of the finger registers 12 contractions per minute, which are recorded on a GraSS polygraph. After equilibrating the muscles for 60 minutes, the recorder amplifier is set so that
    feather about clone on 10 mm. The drug is administered in normal saline in an amount such that
    bring the final drug to 10 or
    concentration - 1 O mole,
    The increase in contractility is given in the table as millimeters of pen deviation compared with the base value. In each experiment, the maximum reduction was measured. The test results are shown in Table 1 and are expressed as a percentage of the control (the control is 100% y. Each value is an average of 2-8 min.
    Experiments on anesthetized dogs.
    A yard of any sex weighing 7–14 kg was anesthetized using sodium phenobarbital (30 mg / kg intravenously) and additional doses were administered as necessary. A positive pressure pump was used to vet the lung of dogs through an endotracheal tube (18 base / min / kg-sucr), and the heating pad kept the body temperature between 37-38 ° С,
    The blood pressure in the femoral artery was measured using a polyethylene catheter filled with a heparin solution (16 U / ml) and attached to a Statham pressure transducer. A tensometric arc, sewn into the right ventricle of the heart, measured heart contractions. The pressure on the strain gauge was set to 50 and the recorder's gain (Bacman’s dinograph) was set so that the 50 g corresponded to a pen deflection of 10 mm. Heart rate was measured as pen deviations or stress grams. The drug was administered after a 30- to 45-minute equilibrium period intravenously (2.5 ml in normal saline). In the control experiment, a quick intravenous injection of 50 ml of 5% dextran and mechanical aortic compression showed that measurements of contractility do not depend on changes in pre and post loads. The heart rate was measured with a cardiotachometer, which was controlled by a pulse of blood pressure and recorded on a polygraph. Maximum effect
    I)
    nx doses presented as prod2-phenyl-imidazo (4,5-b) pyridines
    2- (3,4-Dimethoxyphenyl) -imidazo- (4,5-b) pyridine
    2- (2-Methoxy-4-methylsulfonylphenyl) -imide- 30- (4,5-b) pyridine 120
    Picose reactions are presented at the indicated concentrations of the drug.
    em 100%) in the table. 2. Table 1
    Comparative compounds
    101
    112
    103
    116
    129
    table 2
    15
    The effect on contractility with the dose of the drug, mg / kg
    ziizzizzin
    nt nt nt
    160 247 352 AI5
    Values are peak responses to intravenous drug administration.
    "
    Not tested ,.
    Compound 8 is characterized by the following actions.
    with appropriate doses:
    Dose, mg / kg Deviation,%
    0,01115
    0.02135
    0.05205
    0.125 260
    0.25300
    1255052 b
    Continued tabl, 2
    权利要求:
    Claims (2)
    [1]
    The method of obtaining substituted imidazopyrimidines, -pyrazines or triazines of the general formula Ϊ
    de one or two of A ( , A g , A,
    and A 4 * "
    A 2 , A 5 and A 4 - CH
    M, and the rest of A, provided that, if A 4 - Ν, then one of A ,, A g and A e is also Ν, and provided that one of A, A 2 and A 5 can be CX
    where X is halogen;
    K, is hydrogen;
    K 2 - methoxy;
    K 3 ~ methoxy, methylsulfinip or methylsulfonyl, or their pharmaceutically acceptable salts, characterized in that the amine of formula II
    0 Αγ
    where a 4 , a 2 , a ^ and a 4 have the indicated meanings,
    subjected to interaction with "b-haloketone formula III
    0 Κι
    X-CHP-S - ^ * ^ 2
    Where is K 4 -K have the indicated meanings
    X is halogen, or a compound of the formula I is hydrogenated, where one of A,
    A 2 and A 3 - CX, with the selection of the target product in free form or in the form of a pharmaceutically acceptable salt,
    5Ts., 1255052 AZ
    one
    1255052
    [2]
    2
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    同族专利:
    公开号 | 公开日
    AT26719T|1987-05-15|
    AU2288383A|1984-07-05|
    FI834773A|1984-06-28|
    DD210689A5|1984-06-20|
    DK595483A|1984-06-28|
    CS997783A2|1985-06-13|
    NZ206622A|1986-03-14|
    CA1262460A|1989-10-24|
    EP0113236B1|1987-04-22|
    GB2132203A|1984-07-04|
    ES528275A0|1985-08-01|
    ES8506712A1|1985-08-01|
    EP0113236A1|1984-07-11|
    GB2132203B|1986-04-09|
    GR81509B|1984-12-11|
    DK595483D0|1983-12-23|
    FI834773A0|1983-12-23|
    GB8334096D0|1984-02-01|
    PT77844B|1986-05-08|
    RO87859A|1985-12-30|
    ZA839398B|1985-08-28|
    PL245275A1|1985-03-26|
    RO87859B|1985-12-31|
    PT77844A|1984-01-01|
    IL70495D0|1984-03-30|
    KR840007003A|1984-12-04|
    DE3371081D1|1987-05-27|
    JPS59130886A|1984-07-27|
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    RU2608611C2|2009-11-05|2017-01-23|Юниверсити Оф Нотр Дам Дю Лак|Imidazo[1,2-a]pyridine compounds, synthesis thereof and methods of using same|DE1026321B|1955-05-26|1958-03-20|Ind Chimica Profarmaco S R L|Process for the preparation of - imidazole-1, 2, 4-triazines|
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    FR2510576B1|1981-07-29|1983-12-23|Synthelabo|MC1673A1|1984-06-27|1986-06-03|Wellcome Found|ARYLIC DERIVATIVES OF IMIDAZOLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE FOR THE PREPARATION OF DRUGS|
    DE3446812A1|1984-12-21|1986-06-26|Dr. Karl Thomae Gmbh, 7950 Biberach|NEW IMIDAZO DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    DE3446778A1|1984-12-21|1986-07-03|Dr. Karl Thomae Gmbh, 7950 Biberach|NEW IMIDAZO DERIVATIVES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US45356582A| true| 1982-12-27|1982-12-27|
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