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    • 专利摘要:

    公开号:SU1395143A3
    申请号:SU853936405
    申请日:1985-08-15
    公开日:1988-05-07
    发明作者:Затцингер Герхард；Гартенштейн Иоганнес；Маннхардт Карл；Клейншрот Юрген；Оссвальд Гартмут；Вейнгеймер Гюнтер；Фричи Эдгар
    申请人:Гедеке Аг,Западный Берлин (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining new 1,6-naphthyridine derivatives of the general formula
    OBg-Bi
    where R, is unsubstituted phenyl or phenyl substituted by halogen, nitro, cyano, difluoromethoxy, difluoromethylthio, methylene dioxy or trifluoromethyl, or unsubstituted thienyl-2; RJ is lower alkyl or benzyl; R, is hydrogen, lower alkyl or
    lower alkoxycarbonyl; lower alkyl; R is a carboxyl group or benzyloxycarbonyl, Direct or branched lower alkoxycarbonyl, which can be substituted by a lower alkylthio group, a lower-alkylamino group, a benzyl-lower-alkylamino group, or a piperidino group, in the form of racemates or enantiomers, or their acidic or piperidino group, in the form of racemates or enantiomers; with calcium-antagonistic activity.
    The purpose of the invention is to develop, on the basis of known methods, a method for the preparation of new compounds possessing valuable pharmacological activity with low toxicity.
    Example 1. Methyl ester (+) - 4- (2-fluorophenyl) -1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylic acid.
    1.1 g (37 mmol) of sodium hydride (80% in paraffin oil) are suspended in 70 ml of dry dimethylformamide and stirring At room temperature, a solution of 10 g (32 mmol) of methyl esfra (+ ) -4- (2-fluorophenyl) -1,4,5,6-tetrahydro-2-methyl-5-oxo--1,6-naphthyridine-3-carboxylic acid in 100 ml of dimethylformamide. After cessation of gas evolution, it is additionally stirred for 30 minutes at room temperature. Then, 5.9 g (33 mmol) of iso-propyl dihydride in 30 ml of dimethylformamide is added, stirred for 20 hours at

    at room temperature, the solvent is removed in vacuo and the oily residue is stirred with 100 ml of water. The resulting light brown crystalline mass is sucked off, rinsed with water and dried.
    The crude product is purified by crystallization from a mixture of 400 ml of ethyl acetate and 50 ml of methanol. At the same time, the 0-alkylation product in a highly concentrated form remains in the mother liquor, which is chromatographed on silica gel using dichloromethane and methanol in a ratio of 9: 1. At the same time, the remaining raw materials are completely separated. Further chromatography on silica gel using toluene and ethyl acetate in a ratio of 3: 1 yields pure methyl ester (+) - 4- (2-fluorophenyl) -1,4-dihydro-5-isoproxy -2-methyl -1, 6-naphthyridine-3-carboxylic acid (R. 0.3), after crystallization from a mixture of n-hexane and diisopropyl ether, the crystals of Art. square 164-165 seconds
    Methyl ester (+) - -4- (2-fluorophenyl) -1,4,5,6-tetrahydro-2-meFil-5-oxo-1,6-naphthyridine-3-, - carboxylic acid is obtained as follows.
    To a suspension of 3.8 g (130 mmol) of sodium hydride (80% in paraffin oil) in 60 ml of dry dimethylfrommayd, a solution of 31.5 g (120 mmol) of dimethyl ether 4 (2- p porfe-, nyl) -1,4-dihydro-2,6-dimethylpyridine-3, 5, dicarboxylic acid in 260 ml of dimethylformamide. While reducing the degree of gas separation, the mixture is stirred for another 10 minutes at room temperature, and then 10.0 g (120 mmol) of S-triazine in 260 ml of dimethylformamide is added dropwise. The reaction mixture is heated to 110 ° C for 16 hours and, after cooling, concentrated in vacuo. The dark residue is mixed with 600 ppm of acetone, filtered and the filtrate is concentrated under vacuum. The product is boiled together with 300 ml of methanol formed after cooling. The crystals are filtered and recrystallized from methanol.
    Methyl ester (j -) - 4- (2-fluorophenyl) -1, 4,5,6-tetrahydro-2-methyl-5-oxo-1.6-naphthyridine-3-carboxylic acid is obtained in the form of slightly beige crystals with t. pl. 315-3Id C (decomposition),
    Example 2. Ethyl ester (+) -, 4-dihydro-5-isopropoxy -2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid (1) ...
    12.5 g (33 mmol) of ethyl ester of () -, 4,5,6-tetragide-po-2-methyl-5-oxy-4- (2-triftopermethyl-phenyl) -1, 6-naphthyridine-3 -carboxylic acid is added in portions at room temperature to a suspension of 1.3 g (43 mmol) of sodium hydride (80% in oil) in 200 ml of dry dimethyl form amide. After the evolution of hydrogen is stopped, the mixture is stirred for 15 minutes at room temperature, then 7.2 g (43 mmol) of isopropyl iodide is added and stirred for 3 days at room temperature. It is evaporated in a vacuum, the residue is mixed with 500 ml of water and subjected to ultrasonic treatment for 30 minutes The precipitated crystals are filtered and dried at,
    The crude product is dissolved in an insignificant amount of ethnacetate and subjected to chromatography on silica gel using toluene and ethyl acetate in a ratio of 3: 1. The fractions with K / 0.4 are evaporated under vacuum and the residue is mixed with n-hexane dB crystallization. The resulting product is filtered and recrystallized from 60 ml of n-hexane. Colorless materials are obtained: ists with a melting point of 102-103 ° C.
    Ethyl ester (j;) -1,4,5,6-tetrahydro-2-methyl-5-oxo-4- (2-trifluoromethyphene 1) -1, b-naphthyridine- Z-Carbondvoic acids are obtained in the following manner.
    6.0 g (0.2 mmol) of sodium hydride (80% in oil) are suspended in 100 ml of dry dimethylformamide at room temperature, a solution of 79.2 g (0.2- mol of 1,4-dig1adr6-2,6-dimethyl-, 4- (2-trifluoromethylphenyl) pyridine-3.5-carboxylic acid diethyl ester in 400 ml of dimethylformamide. After graduation
    0
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    434
    hydrogen evolution is stirred for another 10 minutes at room temperature, then 16.2 g, (0.2 mol) of S-triazine in 300 ml of dimethylformamide are added dropwise, and the mixture is stirred for 16 hours at 110 C. After cooling the reaction solution is concentrated under vacuum, the residue is stirred with 1.5 l-acetone, the undissolved compound is removed by filtration, the acetone solution is evaporated under vacuum and the residue is subjected to chromatography on silica gel using dichloromethane and methanol in a ratio of 9: 1, The fraction with an Rf value of 0.45 is mixed with 200 ml of chloroform and undissolved light beige crystals are removed by filtration. It is further purified by recrystallization from ethanol. Colorless crystals are obtained with m, pl, 261 ° C,
    The 1,4-dihydro-2,6-dimethyl-4- (2-trifluoro-methylphenyl) -pyridine-3,5-carboxylic acid diethyl ester used as the starting material was prepared as follows.
    50 g (0.29-mol) of 2-trifluoromethylbenzaldehyde, 76 g (0.58 mol) of ethyl acetate-acetic acid and 30 ml of concentrated ammonia are dissolved in 200 ml of ethanol and heated to boiling for 16 After precipitation after cooling, the product is filtered and additionally washed with cold ethanol. Light yellow crystals are obtained with mp, 42-143 ° C,
    Similarly, Examples 1 and 2 receive the following compounds:
    (+) - 4- (2- -bro (enip) -1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridium-3-carboxylic acid methyl ester (2, t, pl 201-202 ° C from simple diisopropyl ether) a;
    (+) -, 4- -dihydro-5-isopropion-2-methyl-4- (2-nitrophenyl) -1,6-naphthyridine-3-carboxylic acid methyl ester (3), mp,
    170 C. of simple diisopropyl
    ether and methanol;
     (+) -, 4- -dihydro-5-isopropoxy-2-methyl-4-phenyl-1, methyl 6-naphthyridine-3-carboxylic KHCJjOTbi (4) methyl ester, m.p. 32-133 with iZ n-hexane;
    methyl ester (+) - 4- - (3-chloro-2-fluorophenyl) -1,4-digo-5-isopropoxy-2-methyl-1, 6-n.1ftiri
    din-3-carboxylic acid (5), so pl. 166-167 ° C from n-gelsana;
    (+) - 1,4- -dihydro-5-isopropoxy-2-methyl-D- (3-nitrophenyl) -1,6-naphthyridine-3-carboxylic acid methyl ester (6), mp . 174-175 ° C from n-hexane;
    (+) -, 4- -dihydro-5-isopropoxy-2-methyl-4g methyl (4-trifluoromethylphenyl) -1j6-naphtyridine-3-carboxylic acid methyl ester (7), t, pl. 199-200 C from npocToi o diisopropyl ether;
    (+) - 4- (2- -chlorop-6-fluorophenyl) -l, 4-dihydro-5-p1-zo-propoxy-2-methyl-1, 6-gnaphthyridine-3-carboxylic acid methyl ester (8) t. pl. 194 is from diisopropyl ether;
    (+) -, 4- -dihydro-2-methyl-5-propoxy-4- (2-trifluoromethylphenyl) -, 6-naphthyridine-3-carboxylic acid methyl ester (9), t, pl. 151-152 ° C from n-hexane and diisopropyl ether;
    (+) - 4- (2- -bromophenyl) -5-ethoxy-1,4-dihydro-2- -methyl-1,6-naphthyridine-3-carboxylic acid methyl ester (10), so pl. 203-204 ° C from toluene and ethyl acetate;
    (+) - 5-butoxy-1,4-dihydro-2-methyl-4- (2-trifluoromethylphenyl) -, 6-naphthyridine-3-carboxylic acid ethyl ester (II), t. pl. 107-109 ° C from n-hexane;
    2-methoxyethyl ester (+) -, 4-dihydro-5-isopropoxy-2-methyl-4- (3-nitrophenyl) -1,6-naphthyridine-3-carboxylic acid (12), mp 174-175 C from diisopropyl ether;
    isopropyl ester (j;) -. -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid (13), t. Pl. 111-112 ° C from n-hexane;
    (+) - 1,4-β-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethyl) -1,6-naphthyridine-3-carboxylic acid isobutyl ester (14), mp. 115 116 C from n-hexane;
    ethyl ester (+) - 4- - (2,3-dichlorophenyl) -1,4-dihydro-5- -isopropyxy-2-methyl-1,6-naphthyridine-3-carboxylic acid (1 5), t pl. 272-273 with from diisopropyl ether;
    ethyl ester hydrochloride (+) - 5-sec-butoxy-1,4-dihyd5
    Q
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    40
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    50
    55
    ro-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carbonic acid (16), so pl. 148-150 ° C from diisopropyl ether and ethyl acetate; ;
    () -1,4-β-dihydro-5-isobutoski-2-methyl-4- - (2-trifluoromethylphenyl) -1, 6-caftyridine-3-carboxylic acid ethyl ester (17), m.p. 118-119 ° C of gasoline;
    (+) - -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid tert-butyl ester (18), mp. :. from n-hexane and diisopropyl ether;
    (+) -2-ethyl--1, 4-dihydro-5-isopropoxy-8-methyl-4-phenyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (19), m.p. 176-177 ° C from n-hexane and diisopropyl ether;
    2- (N-6eH-zyl-K-methylamino) ethyl ester (+) - 1,4-dihydro-5-isopropoxy-2-methyl-4- (3-nitrophenyl) -1,6-naphthyridine dihydrochloride salt - -3-carboxylic acid (20), t. Pl. 148-150 ° C from ethyl acetate and acetonitrile;
    2-dimethyl-aminoethyl ester of (-t -) -, 4-dihydro-5-isopropoxy-2-methyl-4- (3-nitrophenyl) -, 6-naphthyridine-3-carboxylic acid dihydrochloride (21 ) t. pl. 148-150 ° C from diisopropyl ether;
    2-methylthioethyl ether (+) - -1,4-dihydro-5-isopropoxy-2-methyl-4- (3-nitrophenyl) -1,6-naphthyridine-3-carboxylic acid (22), mp. . 154-155 ° C from di-dischropyl ether and ethyl acetate;
    2- (N-6eH-zyl-N-methylamino) ethyl ester (+) -, 4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) naphthyridine-3-carboxylic acid dihydrochloride (23), t. Pl. 163-165 ° C (decomposition) of acetonitrile;
    (+) -, 4- -dihydro-5-from opropyl-2-methyl-4- - (2-trifluoromethylphenyl) -1,6-naphthyridine-3.8 dicarboxylic acid diethyl ester (24), t. square 140-141 ° C from n-hexane;
    (+) -, 4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyrIdine-3-carboxylic acid ethyl ester hydrochloride (25), m.p. 137 С from ethylace - t-ta:
    71
    () -, 4-di-hydro-5-isopropoxy-A- (2-methoxyphenyl) -2-methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (26), so pl. . 145-146 C from n-hexane and diisopropyl ether;
    ethyl ester (+) 1,4-dihydro-5-isopropoxy-2-methyl-4- (2-thienyl) -1,6-naphthyridine-3-carboxylic acid (27), t. pl. 110-111 ° C of n-hexane;
    (+) - 4- (2- -cyanophenyl) -1,4-dihydro-5-i-ipropane ethyl si-2-methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (28), t., pl. 182-183 ° C from n-hexane and diisopropyl ether;
    (+) - 5-Benzyloxy-1,4-dihydro-2-methyl-4- (2-tri fluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid ethyl ester (29), mp. . 142-143 ° C from n-hexane and di-isopropyl ether;
    (+) -2-ethyl--1,4-dihydro-5-isopropoxy-8-methyl-4 - (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid ethyl ester (30) j t. mp 112-113 ° C from n-hexane;
    (+) - 1,4-β-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid benzyl ester (31), m.p. 126-127 ° C from n-hexane;
    (+) -, 4-. Dihydro-5-iso-propoxy-2-methyl-4- (2-trifluoromethylphenyl) -1, 6-naphthyridine-3-carboxylic acid (2) complex 2-dimethylamine ester (32) t. pl. 104-105 ° C from n-hexane;
    3 + dimethylaminopropyl ester (+) -, 4-dihydro-5-iso-propoxy-2-methyl-4- (3-nitrophenyl) -1,6-naphthyridine-3-carboxylic acid (33), mp. . 134-136 ° C from n-hexane and simple diisopropyl ether;
    (+) - 4- (2-di fluoromethoxyphenyl) -, 4-dihydro-5- -isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (34), m.p. 145-147 ° C from hexane and diisopropyl ether;
    (+) -, 4-dihydro-5-isopropoxy--2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid (35) complex 2-dibenzylaminoethyl ester (35), mp . 132-133 ° C in the form of sesquiphosphate) of isopropanol;
    ethyl ester (+) -, 4-dihydro-5-isopropoxy-2-methyl-4- (2-me
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    Tylphenyl) -, 6-naphthyridine-3-carboxylic acid (36), so pl. 122-124 ° C from n-hexane and diisopropyl ether;
    2-dimethylaminoethyl ester (+) -, 4-dihydro-5-isopropoxy-2-methyl-4- (3-trophenyl) -1,6-naphthyridine-3-carboxylic acid (37), mp. 91-93 ° C from n-hexane and diisoprolyl ether.
    Example 3. Methyl (+) -, 4-diHydro-5-methoxy-2-methyl-4-phenyl-1,6-naphthyridine-3-carboxylic acid methyl ester.
    5 g (17 mmol) of methyl ester (+ -1,4,5,6-tetrahydro-2-methyl-5-oxo-4-phenyl-1,6-naphthyridine-3-carboxylic acid and 5 g (34 mmol) of trimethyloxonium tetrafluoroborate in 200 ml of 1,2-dichloroethane is stirred for 1.5 hours at room temperature. Injected with 50 ml of water, the organic phase is separated and evaporated. By recrystallizing the residue from isopropanol, the desired compound tetrafluoroborate is obtained. It is stirred with a saturated solution of potassium hydrogencarbonate and ether, the ether solution is separated, dried over sodium sulfate and ivayut Crystallization of the free base of 50 cm esi ml of n-hexane and diisopropyl ether in a ratio of 2:. 1 to give colorless crystals with m.p. 210-212 ° C...
    Use as starting material methyl (+) -, 4,5,6-tetrahydro-2-methyl-5-oxo-4-phenyl-1,6-naphthyridine-3-carboxylic acid methyl ester was prepared as in Example 1 using 1,4-dihydro-2,6-dimethyl-4-phenylpyridin-3 dimethyl ester, 5-dicarboxylic acid.
    The following compounds are prepared analogously:
    (+) - 4- (2- -chlorophenyl) -, 4-dihydro-5-methoxy-2- -methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (38), so pl. 173-174 ° C from n-hexane and diisopropyl ether;
    (n) -1,4-di-hydro-5-methoxy-2-methyl-4- (3-nitrophenyl) -, 6-naphthyridine-3-carboxylic acid ethyl ester (39), so pl. 184-186 ° C from diisopropyl ether and ethanol;
    () -4- (2- -fluorophenyl) -, 4-dihydro-5-methoxy--2-methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (40), t. pl. from n-hexane; ,
    (+) - 1,4-dihydro-5-methoxy-2-metsh-1-4- (2-trifluoromethylphenyl) -, 6-naphthyridine-3-carboxylic acid complex ethyl ester (41) t. pl. 118-120 ° C from n-hexane;
    (+) - 4- (3- -chloro-2-fluorophenyl) -1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carvonic acid methyl ester (42 ) t. pl. 214-21b C from diiopropyl ether and methanol;
    (+) - 4- - (2-bromophenyl) -1,4-dihydro-5-methoxy-2-methyl-1,6-naphthyridine-3-carboxylic acid methyl ester, (43), so pl. 204-205 С out. simple diisopropyl ether and methanol.
    Example 4. (+) -, 4-Dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -, 6-naphthyridine-3-carboxylic acid.
    3.0 g (6.2 mmol) of benzyl ester (+) -, 4-dihydr | 0-5- -isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-naphthyridine -3-carboxylic acid is hydrogenated with 1.5 g of 10% palladium on active carbon at normal pressure and room temperature. After 30 minutes, the absorption of hydrogen ends. The catalyst is filtered, the solvent is distilled off under vacuum, and the colorless crystalline residue is recrystallized from a mixture of diisopropyl ether and ethyl acetate. (+) - -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphensh1) -1,6-naphthyridine-3-carboxylic acid is obtained in the form of colorless crystals with m.p. 164- (decomposition).
    The benzyl ester (+) - g1,4-dihydro-5-isopropoxy-2r-methyl-4- (2-trifteropropylethylenfenyl) -l, 6-naphthyridine-3-carboxylic acid pbluch- analogously to Example 1 using 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -pyridine-3,5-Dicyrbonic acid dibenzyl ester dibenzyl ester. The following compounds are similar to Examples I and 2. :

    ten
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    35
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    (2-amino-ethyl) ester (; +) - li 4 -dihydro-5-yzopropoxy-2g-methyl-4- - (2-trifluoromethylphenyl) -1,6-naphthyridine-3-carboxylic acid (44), m.p. 166-167 ° C from diisopropyl ether and ethyl acetate;
    (+) - 4- - (2-difluoromethylthiophenyl) -1,4-dihydro-5-isopropoxy-2-methyl-, 6-naphthyridine-3-carboxylic acid ethyl ester (45), t., pl . 124-125 ° C from n-hexane and di-isopropyl ether;
    (+) - 1,4-di-hydro-5 isopropoxy-2-methyl-4- (2,3- -methylenedioxyphenyl) -1,6-naphthyridine-3-carboxylic acid ethyl ester (46), t. square 156-158 ° C from diethopropyl ether and ethyl acetate;
    (2-piperidinoethyl) ester (+) - 1,4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6-and-3-carboxylic acid (47) t. pl. 118-120 ° C from y-hexane;
    (+) - 4- (2- -chlorophenyl) -, 4-dihydro-5-isopro-C-2-mets-1-1,6-naphthyridine-3-carboxylic acid ethyl ester (48), m.p. 135-136 With of hexane;
    ethyl ester (+) - 1,4-di-hydro-5-isopropoxy-2-methyl-4-phenyl--1,6-naphthyridine-3-karboonovoy acid (49), so pl. 136-137 0 from n-hexane;
    dihydrochloride complex f3- (H-beisch1-H-methylamino) prop1-ester, (+) -I, 4-dihydro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1,6- naphthyridine-3-carbonic acid (50), so pl. 143-144 ° C from dioxanine acetonitrile; .
    (4RS) -1,4-dihydro-5-isopropoxy-2-methyl-4- (2-triphypermophenylphenyl) -l, 6-naphthyridine-3-carboxylic acid (5) t-complex (K) -2-butyl ester (5), t pl. from hexane; ..
    dihydrochloride of f2- (N-6eH-zyl-M-methylamino) ethyl-ester (4RS) -5- (K-sec-butoxy-1,4-dihydro-2-methyl-4- (2-trifluoromethylphenyl) complex ) -1,6-naphthyridine-3-carboxylic acid (52), mp 149-152 with acetonitrile;
    complex (2-dmethylaminoethyl) yfir- (+) -, 4-dihydro-5-methoxy-2-metsh-1- -4- (2-trifluoromethylphenyl) 1,6-naphtn-edin-3-carboxylic acid (.53), m.p. 137-138 ° C from ethyl acetate;
    ethyl ester (+) - 4- (2- -cyanophenyl) -, 4 Dihydro-5-isopropoxy-2-metsh1-1, 6 -nafyrhyrid n-3-carb-J5
    1113951
    oic acid (54), so pl. 182-183 ° C from n-hexane and diisopropyl ether; ;
    ethyl ester (+) - 4- (ditormethoxyphenyl) -, 4-dihydro-5-isoropoxy.-2-methyl-, 6-naphthyridine-3-carboxylic acid (55), so pl. 145- 47 with from n-hexane and diisopropyl ether; 10
    (+) - 4- (2-difluoromethylthiophenyl) -1,4-dihydro-5-isopropoxy-2-methyl-1,6-naphthyridine-3-carboxylic acid ethyl ester (56), t. tin. 124-125 ° C from n-hexane and di-isopropyl ester;
    (+) - 1,4-dihydro-5-methoxy-2-methyl-4- - (2-trifluoromethylphene1) -1,6-naphthyridine-3-carboxylic acid (2-dimethylpaminoethyl) ester (57), m.p. jn 137-138 ° C from ethyl acetate;
    dihydrochloride complex (2-N-6eH-zil-N-methylamino) ethyl ester (4RS) -5- (K8) second-butoxy -1,4-dig hydro-2-methyl-4- (2-trifluoromethylphenol-5 nyl) -1,6-aaftiridine-3-carboxylic acid (58), so pl. 149-152 with acetonitrile}
    the dihydrochloride complex 3- (K-benzyl-N-methylamino) propyl ester (j;) -, -1,4-digiroDro-5-isopropoxy-2-methyl-4- (2-trifluoromethylphenyl) -1, 6-naphthyridine-3-carboxylic acid (59), so pl. 143-144 ° C from dioxane and acetonitrile;
    dihydrochloride complex 2- (N-6eH- 35 zil-N-methylamino) ethyl-ether (RS) -5- (K8) -isopropoxyZ-1,4-dihydro-2-methyl-4- (2-chloro- 3-trifluoromethyl-phenyl) -1,6-naphthyridine-3-carboxylic acid (60), t. square 165 s (decomposition) of isopropanol;
    2- (N-6eH-zyl-N-methylamino) ethyl ester (4RS) -5- (K8) -isobutoxy D-1,4-dihydro-2- -methyl-4- (2-trifluoromethylphenyl) - 1,6-naphthyridine-3-carbsnova acid (61), so pl. 148-150 ° C from acetonitrile.
    The improvement in the pharmacological activity of the compounds of general formula (I) 50 in comparison with diltiazem is illustrated by the following comparative experiment.
    The isolated smooth muscles of rabbits (vascular rings, main arteries, right coronary arteries, arteries hidden, average diameter 0.5–1.0 mm) are clamped in a bath.
    43
    12
    five
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    five

    five
    isothermal contractions can be measured. Contraction is caused by potassium depolarization in Tyrode solution, Such a method. is a known standard model for testing substances capable of blocking open potassium calcium depolarization of calcium channels.
    The table shows the concentrations of the compounds under study, at which 50% of the contraction of the vascular rings S caused by depolarization of potassium is reached,
    As the data in the table show, new compounds cause a 50% delay at a lower concentration than diltiazem, which indicates a better activity of the new compounds. The toxicity (LD) of diltiazem is 690 mg / kg (orally; mice). The compounds listed in the table ,, have the following dose of Lsdm, mg / kg: 700 — compounds of examples 1-3 and compounds 2, 4, 8, 9, 16, 17, and 38; 400 is compound 3; 600 is compound 39. Since the therapeutically active dose of compounds 3 and 39 is significantly less than the therapeutically active dose of diltiazem, their higher toxicity is almost irrelevant.
    权利要求:
    Claims (1)
    [1]
    The invention The method of obtaining derivatives of 1,6-naphthyridine of the general formula
    . . Tl5
    ORg Ri
    de R, is unsubstituted phenyl or phenyl substituted by halogen, nitro, cyano, difluoromethoxy, difluoromethylthio, methylenedioxy or trifluoromethyl, or unsubstituted thienyl-2; lower alkyl or benzyl; hydrogen, lower alkyl or lower alkoxycarbonyl; lower alkyl; carboxyl group or benzyloxycarbonyl, straight or branched lower alkoxycarbonyl, which may be substituted by lower alkylthio group, di-lower alkylamino group, benzylR
    R,
    R4 - R. 131395143
    lower alkylamino
    or piperidino, racemate form, or enantiomers, and their acid addition salts, different from the fact that the unity of the general formula
    il but
    fi ne meme Rj S ow n
    (Ii)
    e R ,, R and R are indicated above;
    R: .. - are above, except for the carboxyl group,
    and the alkali metal salt thereof is alkylated, followed by the need to hydrogenate the compound of the general formula (I), where is benzyloxycarbonyl, and release 15
    20
    the desired product in the form of racemates-, nil radical.
    08.25.84 when phenyl. Or phenyl, nitro, cyano, di methylthio, methyl methyl, or ne Rj — direct or C-alkyl; R, - implied C —C4-al per group, direct lower alkoxy
    01/29/85 when branched C, -C sicarbonyl p or branched bonyl radical alkylthiogroup alkylamino-group split Mules (I), where R
    14
    five
    0
    or enantiomers or in the form of acid addition salts.
    Priority featured:
    08.25.84 when R is unsubstituted phenyl. Or phenyl substituted by halogen, nitro, cyano, difluoromethoxy, difluoromethylthio, methylenedioxy or methyl trifluoro, or unsubstituted phenyl-2; Rj is my branched or branched C-alkyl; R, is hydrogen; R is unbranched C-C4 alkyl; R, is a carboxyl group, a straight or branched lower alkoxycarbonyl radical.
    01/29/85 for R - straight or branched C, -C-alkyl, lower alkoxycarbonyl radical; R is a straight or branched lower alkoxycarbonyl radical substituted by a lower alkylthio group or a di-lower alkylamino group; hydrogenolitic cleavage of a compound of formula (I), where R is benzyloxycarbo
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    引用文献:
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    RU2729998C2|2014-08-01|2020-08-13|Байер Фарма Акциенгезельшафт|Method of producing -4--5-ethoxy-2,8-dimethyl-1-4-dihydro-1,6-naphthyridine-3-carboxamide and its purification for use as pharmaceutical active ingredient|
    RU2743429C2|2015-08-21|2021-02-18|Байер Фарма Акциенгезельшафт|Method of producing -4--5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and purification thereof for use as pharmaceutical biologically active substance|US4304914A|1980-07-07|1981-12-08|Usv Pharmaceutical Corporation|Naphthyridone derivatives|
    DE3327650A1|1983-07-30|1985-02-14|Gödecke AG, 1000 Berlin|1,6-NAPHTHYRIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST VASCULAR DISEASES|DE3431303C2|1984-08-25|1989-08-10|Goedecke Ag, 1000 Berlin, De|
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    法律状态:
    优先权:
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    DE3431303A|DE3431303C2|1984-08-25|1984-08-25|
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