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    • 专利摘要:
    The invention provides a dihydropyridine compound of the followng general formular (I) or a salt thereof: …<CHEM>… wherein R<1> and R<2> are the same or different and selected from C1, to C10 alkyl groups, C1 to C5 alkyl groups interrupted by oxygen atom(s), and C1 to C5 alkyl groups substituted by C3 to C6 alicyclic group(s); R<3> and R<4> are the same or different C1 to C5 alkyl groups; R<3> and R<4> are the same or different and selected from hydrogen and halogen atoms and nitro, C1 to C5 alkyl, C1 to C5 alkoxy, C1 to C5 alkylthio, C1 to C5 alkylsulfonyl and C1 to C5 alkylsulfinyl groups; R<7> and R<8> are the same or different and are selected from hydrogen and halogen atoms and cyano, C1 to C5 alkoxy and C1 to C5 alkanoylamino groups or combine to form, with the adjacent phenyl group, a naphthyl group; A represents a single bond, or a vinylene (-CH=CH-) or ethynylene group (-C=C-); B represents a single bond or -CH2O-; and m and n are the same of different and selected from O and integers of 1 to 5, and methods of making such a compound. The compounds may be used for treatment or prevention of ischemic heart-disease and cardiovascular disorders and may show both Ca<2><+> antagonistic action and adrenergic betareceptor blocking activity.
    公开号:SU1342413A3
    申请号:SU853915847
    申请日:1985-06-27
    公开日:1987-09-30
    发明作者:Фудзикура Такаси；Ито Норики；Матсумото Юзо；Исомура Язуо
    申请人:Яманоути Фармасьютикал,Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    I13424132.
    The invention relates to the preparation of aqueous G, 4-dihydropyridine, total novel dihydropyridines, the formulas, namely, the method of producing pro-RS
    b-o-o sn b-a-csn b-nsngsn-vn
    (I)
    RlOOC
    РЗ
    COOR
    R
    SN-EX
    HE
    (I)
    R-, and R,
    R. and R and R., and H are the same or different and mean C, C, (, is alkyl or lower alkyl, which is interrupted by an oxygen atom, or lower alkyl, substituted by an alicyclic C, C-group; the same or different and mean lower alkyl;
    are the same or different and are hydrogen, nitro, halo, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, or lower alkylsulfinyl; identical or different and mean hydrogen, halogen, cyan, lower alkoxy or lower, alkanoylamino or R, and E "together with
    ( about
    neighboring phenyl obra; petroleum naphthyl; simple bond, vinylene () or ethynylene ();
    simple link or group
    type is the same or different and each is O
    R, and R A B gchili 1-5,
    possessing antagonistic sa and
    adrenergic, beta-blocker; ak-50 min. The precipitated crystals from
    tivnost,
    Pel of the invention is the creation of a method for obtaining new compounds with valuable pharmacological properties on the basis of known methods.
    Reference Example 1,
    23 g of 2- (2-bromoethoxy) -5-nitrobenzalde are dissolved in isopropanol.
    Hydrate, 11.5 g of 3-aminocrotonic acid methyl ester and 11.6 g of methyl acetoacetate, after which the mixture is boiled for 7 hours. The reaction solution is cooled, and the precipitated crystals are collected by filtration. The resulting crystals are washed with methanol and dried in air to obtain 33 g of crude crystals of dimethyl ether 4-g (2-bromoethoxy) -5-nitrophenyl -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acid. The resulting product, without purification, is directly used in the next step.
    B 25 ml of N, N-dimethylformamide are suspended 17 g of 4- (2-bromoethoxy) -5-nitrophenshG -2,6-dimethyl-1,4-dihydropyridine-3 dimethyl ester, 5-di-carboxylic acid and 7.4 g potassium phthalimide, after which the resulting suspension is heated for 3 hours at 120-130 C.
    The resulting reaction mixture was poured into 750 ml of ice-water, and the precipitated crystals were collected by filtration. The crystals obtained are washed with water and dried in air.
    emitting 19.6 g of raw crystals
    -4- (2-phthalimido-ethoxy) -5-nitrophenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester.
    A solution of 12 g of 4- (.-Phthalimidoethoxy) dimethyl ester) - 5-nitrophe-, 6-dimethyl-1, A-dihydropyridine-3,5-dicarboxylic acid and 6 ml of hydrazine hydrate in 240 ml of ethanol;
    filtered hot and the filtrate is concentrated under reduced
     pressure with solvent removal. After adding water to the residue
    gg product is extracted with ethyl acetate. The extract is washed with water and evaporated over anhydrous potassium sulfate, after which the solvent is distilled off under reduced pressure. Received Ta313
    IMM raw crystals are re-crystallized from methanol to obtain 6 g of (2-aminoethoxy) -5-nitrophenyl -2,6-dime-, 4 dihydropyridine-3,5-dicarboxylic acid dimethyl ester with a melting point of 200 ° C. 228-230 ° C.
    Calculated,%: C 56.29; H 5.72; and 10.36
    C ,, H, N ,, 0, -
    Found,%: C 56.06; H 5.82; N 10.10
    NMR (DMSO-dg) 8 (ppm): 2.24 (6H, singlet); 2.94 (2H, triplet); 3.48 (6H, singlet); 4.06 (. W, triplet); 5.24 (IH, singlet).
    Reference Example 2
    A solution of 18.3 g of 5-methylthiosalicyl aldehyde, 235 g of 1,4-dibromobutane and .1.1 g of tetra-butyl ammonium hydrogen sulphate in 18 ml of water is heated at 70-80 ° C. To the resulting solution is added with stirring a solution of sodium hydroxide containing 13.1 g of sodium hydroxide in 109 ml of water is added dropwise over 4 hours, after which the resulting mixture is heated for 2 hours. The mixture is then cooled and extracted with chloroform. The extract (separated organic layer) is washed with water,
    stitched over anhydrous magnesium sulfate and concentrated under reduced pressure to give 32.2 g of 2- (4-bromobutoxy) -5-methylthiobenzaldehyde as a crude product, which was used in the next step without further purification.
    10.9 g of 2- (4-bromobutoxy) -5-methylthiobenzaldehyde is dissolved in 55 ml of dichloromethane, after which the solution is cooled to 0 ° C. Then a solution of 15.2 is added dropwise to the cooled solution g of m-chlorobenzoic acid in 165 ml of dichloromethane. After 4 hours, complete solution of sodium bicarbonate was added to neutralize it, and the mixture was extracted with chloroform. The extract (separated organic layer) is washed with a saturated solution of sodium bicarbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product, which is recrystallized from chloroform-ether to obtain 7.8 g of 2- (4-bromobutoxy) ) 5-methylsulphonylbenzaldehyde with m.p. 103-105 ° C.
    five
    0 5 g
    five
    0
    5 0 5
    3
    7.6 g of 2- (4-bromobutoxy) -5-methylsulfonylbenzaldehyde, 2.6 g of methyl acetoacetate and 2.9 g of 3-aminocrotonic acid methyl ester are dissolved in 16 ml of isopropanol, after which the resulting solution is heated for 5 hours. Then the solution is cooled, the precipitated crystals are collected by filtration and recrystallized from methanol to obtain 3.6 g of (4-bromobutoxy) -5-methylsulfonylphenyl dimethyl ether | -2,6-dimethyl- 1, 4-dihydropyridine-3,5-dicarboxylic acid with m.p. 191-20GS.
    6.3 g of (4-bromobutoxy) -5-methylsulfonylphenyl -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester are suspended in 8 ml of 11.1-dimethylformamide and 2, 2 g of potassium phthalimide, after which the suspension is heated for 1 h at 120-130 C. Then the reaction mixture is poured into ice-water and the precipitated solid product is filtered to obtain 7 g of (4-phthalimidobutoxy) -5-methyl- as a crude product. sulfonylphenyl -2,6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylic acid in the form of its dimethyl ether, which is used without purification in the next stage.
    A solution of 6.9 g of (4-phthalimido) -5-methylsulfononyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 5.9 g of hydrazine hydrate in 170 ml of 95% of ethanol (5% water) was boiled for 6 h. After cooling the reaction solution, it is concentrated under reduced pressure. The residue is extracted with chloroform, and the resulting extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude crystals are recrystallized from chloroform-ether to obtain 2.6 g of (4-aminobutoxy) -5-methylsulfonyl-phenyl -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonyl dimethyl ether acids, so pl. 184-186 ° C.
    Reference Example 3
    13 g of 2- (4-chlorobutytes) -5-nitro-benzaldehyde, 7.28 g of ethylpropionyl acetate, 0.2 ml of piperidine and 0.62 ml of acetic acid are dissolved in 106 ml of dry benzene, then the mixture is boiled 9 h with simultaneous 5 davleniya water in lovuiku Dean-Stark. After cooling, 6.52 g of 3-aminocrotonic acid ethyl ester is added to the solution and the mixture is boiled for 11 hours. After cooling the mixture, the precipitated crude crystals are collected by filtration and recrystallized from methanol to give 13.13 g of 2-ethyl diethyl ether -4- 2- (4-chlorobutoxy) -5-nitrophenyl-b-methyl-, 4-dihydropyridine-355-dicarboxylic acid, so pl. 147-149 ° C.
    In 8 ml of K, M-dimethylformamide, 10.26 g of 2-ETHYL-4- 2- (4-chlorobutoxy) -5-nitrophenyl-6-methyl-1,4-dihydropyridine-3.5 diethyl ester is suspended. - dicarboxylic acid and 3.84 g of potassium phthalimide, after which the suspension is heated for 1 hour at 120-130 ° C. Za-2p is lysed from a mixture of chloroform-ether with
    obtaining 6.4 g of diethyl ether (4-aminobutoxy) -5-nitrophenyl-2-ethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid, mp, 25 173.5-175.5 ° s
    Example.
    the reaction mixture is poured into ice water, the precipitated solid is filtered off to give 12.5 g of 2-ethyl-4- 2- (4-phthalimidobutoto) -5-nitrophenyl-6-methyl-, diethyl ether, as a crude product, 4 di
    hydropyridine-3,5-dicarboxylic acid, which is used without purification in the next stage.
    A solution of 12.4 g of diethyl ether
    2-ethyl-4- 2- (4-phthalimidobutoxy) -5-nitrophenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid and
    10.4 g of hydrazine monohydrate in 270 ml of 95% ethanol (5% water) are boiled for 10 hours. The cooled reaction solution is then concentrated under reduced pressure to give a residue, which is extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulphate and concentrated. triple under reduced pressure. The received, received crude crystals of recrystal
    SOOSNz
    n
    Nose
    QbO-CH CH-CH,
    about
    OCH2.CH2.NHCHn SNCH 91
    SOOSNz
    sh
    he
    4 g of dimethyl ester (2-aminoethoxy) -5-nitrophene J-2, 6-dimethyl-15 4-dihydropyridine-3,5-dicarboxylic acid (for preparation, see reference example) and 1.5 g of glycidylphenyl the ester is dissolved in 200 ml of methanol and the resulting solution is left for 2 days at room temperature. Then the reaction mixture is concentrated, the resulting residue is subjected to silica gel column chromatography using chloroform-methanol (98: 2 vol / v) as eluant. The crude crystals were recrystallized from ethanol to obtain 1.8 g of 4-, 2- 2- (2 hydroxy-3-phenoxypropyl-amino-ethoxy-3-5-nitrophenyl} -2,6-dimethyl, 4-dihydropyridine- H, 5-carboxylic acid, t, pl, 1В9-190 ° С,
    Calculated,%: C 60.53; H 5.99; N 7.56
    ,
    0
    five
    0
    five
    Found.%: C 60.43; H 6.05; N 7.42
    NMR (DMSO-dg): 2.22 (6H, singlet); 3.47 (6H, singlet); 5.21 (W, syn. Glut).
    PREMIRE 2-13. The compounds are prepared according to the procedure of Example I,
    PRI mme R 2. Dimethyl. (2-hydroxy-3-phenoxypropyl-amino) ethoxy-3-nitrophenyl -2,6-dimethyl ester, 4-dihydropyridine-3,5-dicarboxylic acid ester, m.p. 147-149 С
     calculated,%: C 60,53; H 5.99; N7.56
    Found,% N 7.5
    NMR (CDCl
    singlet); 3.68 (6H, singlet); 4.26 (2H, triplet); 5.01. (W, singlet),
    Prime, p3, Dimethyl ether .- (2-hydroxy 3-phenoxypropylS 60, 47; H 6.02; (ppm): 2.35 (6H,

    amino) ethoxy 3--2-nitrophenyl -2,6-di methyl-1,4-dihydropyridine-3,5-dicarboxylic acid, amorphous powder.
    Calcined,%: C 60,53; H 5.99; N7.56
    С, Н „И, 0,
    Found,%: C 60.41; H 6.02; N 7.41
    NMR ((rrga): 2.32 (6H, singlet); 3.58 (6H, singlet); 5.86 (1H, singlet).
    PRI me R 4. Diisobutyl ether 2-hydroxy-3-phenoxy-propylamino) -ethoxy-5 - nitrophenyl - 2,6-dimethyl - 1, 4 - dihydropyridine-3,5-dicarboxylic acid, t , pl. I 65-1 6Y1
    Calculated,%: C 63.83; H 7.09; N 6.57
    C ,, H ,, N, 0,
    Found,%: C 63.55; H 7.13; N 6,
    J77JT
    NMR (CDC10 & (ppm): 0.84 (12H, double doublet); 1.86 (2H, multiple plet); 2.32 (6H, singlet); 3.78 (4H doublet); 5.40 (1H, singlet).
    PRI me R 5. Dihexyl ester (2 hydroxy-3-phenoxypropyl amino) -ethoxy 5-nitrophenyl -2,6 dimethyl-1,4 dihydropyridine 3,5-dikonovoy acid, so pl. 89-90 ° C.
    Calculated,%: C 65.59; H.7.68; N 6.04

    Found,%: C 65.35; H 7.78; N 5 99
    . NMR (SBSl3) (ppm): 0.84. (6H, triplet); 2.30 (6H, singlet); 5.36 (1H, singlet).
    Example 6: Bis- (2-methoxyethyl) ester of (2-hydroxy-3-phenoxy-propylamino) -ethoxy-5-nitrophenyl | -2,6-dimethyl-1, 4-dihydropyridine- 3,5-dicarboxylic acid, mp 109-110 ° C.
    Calculated,%: C 59.71; H 6.42; N 6.53.
    C, H4, N, 0 ,,
    Found,%: C 59.57; H 6.36; N 6.44
    NMR (SBSl3) (ppm): 2.28 (6H, singlet); 2.6-3.2 (4H, multiplet); 3.28 (6H, singlet); 3.48 (4H, triplet); 5.36 (IH, singlet).
    Example 7,
    Oj-nv
    СНзОгС.
    H
    OSNGCHN1NSNgSN-o- cOzKHji, he


    g
    0
    five
    ABOUT

    Q
    „

    55
    13 .
    Methyl octyl ester (2-hydroxy-3-phenoxypropylamino) ethoxy-2 -5-nitrophenyl 3 -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, amorphous powder .:
    Calculated,%: C 64.3; H 7.25; N 6.43
    S., 5.N N ,, 0,
    Found,%: C 64.23; H 7.46; and 6.48.
    NMR (CDCl 3) (ppm): O, 88 (3N, triplet); 2.32 (6H, singlet); 3.64 (ЗН, - singlet); 5.40 (W, singlet),
    PRI me R 8. Dimethyl ester 4- 2-СЗ- (2-hydroxy-3-phenoxypropy-1-amino) propoxy 1-5-nitrophenyl -2,6-dimethyl-1,4-dihydropyridine-3,5-di - carboxylic acid, amorphous defect.
    Calculated,%: C 61.15; H 6.19; N 7.38
    С ,, Н „К, 0,
    Found,%: C 60.91; H 6.48; N 7.1
    NMR (CDC1,) & (ppm): 2-2.2 (2H, multiplet); 2.3 (6H, singlet); 2.8- 3 (4H, multiplet); 3.6 (6H, singlet); 4-4.2 (4H, multiplet); 5.32 (W, singlet).
    PRI me R 9. Dimethyl ester 4- (2-hydroxy-3-phenoxypropyl-amino) butoxy-5-nitrophenyl -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acids, amorphous powder.
    Calculated,%: C, 61.74; H 6.39; N 7.2
    C, joH ,,
    Found,%: C 61; 66; H 6.51 (N 7.17.
    NMR ((ppm): 1.6-2 14H, multiplet); 2.28 (bN, singlet); 2.7-2.9 (4H, multiplet); 3.56 (6H, singlet); 3.92-4.16 (4H, multiplet); 5.32 (1H, singlet).
    Example 10. Ethyl methyl ester. 4-2-4- (2-hydroxy-3-phenoxy-propylamino) -butoxy-5-nitrophenyl} -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, amorphous powder.
    Calculated: 7, С С 62.3; H 6.58; N 7.03
    With ,, nz) And, 0, i. Found,%: C 62.38; H 6.77; N 6.95.
    NMR (CDCij) (G (ppm): 1.16 (ZN, triplet); 1.6-1.9 (4H, multiplet); 2.3 (6H, singlet); 2.6-2.9 (4H multiplet); 3.94 (3N, singlet); 3.8-4.2 (6H, multiplet); 5.28 (1H, singlet
    PRI me R 11. Methyl ether
    913
    4-1.- l 0- (2-hydroxy-3-phenoxypropyl-amino) decyloxy 5- Nitrofeyl -2,6-methylmethyl-1,4-dihydropyridine 3,5-di carboxylic acid, amorphous powder. , Calculated,%: C 64.75; H 7.4 ;; W 6.29 C5feH, NjO,
    Found,%: C 64.27; H 7.65; N 6.25 NMR CCDCl) 4 (ppm): 1.2-1.6 (16H, - multiplet); 2.3. (BN, singlet); 2.5 2.9 (4H, multiplet); 3.56 (6H, singgling); 3.96-4.1 (4H, multiplet); 5.34 (1H, singlet).
    Example 12. 4-5-dimethyl ester (2-hydroxy-3-phenoxypropylamino) pentyl ox; 5-nitrophenyl -2,6-dimethyl-1, -dihydropyridine-3, 5-dicarboxylic acid, amorphous powder.
    Calculated,%: C, 62.3; H.6.58; N 7.03.
    . ,,
    Found,%: C 62.43; H 6.87; N 7.18
    NMR (CDCl 3) § (ppm): 1.4-1.6 (6H, multiplet); 2.3 (6H, singlet); 2.6-2.9 (4H, multiplet); 3.56 (6H, singlet); 3.9-4.2 (4H, multiplet); 5.3 (W, singlet).
    Example 13 (2-Hydroxy-3-phenoxypropyl-amino) hexyloxy-5-nitrophenyl -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, amorphous powder.
    Included in%: C 62, 83; H 6.76; N 6.8
    C7, H4, .N, 0,
    Found,%: C 62.58; H 6.83; N 6.88
    NMR (CPC1) (ppm): 1, 4-1.6 (8H, multiplet); 2.3 (6H, singlet); 2.6 - 2.9 (4H, cartoon 1); 3.6 (6H, singlet); 3.9-4.1 (4H, multiplet); 5.32 (IH, singlet) .-
    Example 14. In 30 ml of I, N-dimethylformamide, 2 g of dimethyl (2-aminoethoxy) -5-nitrophenyl-2 -2-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic dimethyl ester are dissolved. acid and 0.6 g of styrene oxide, after which the resulting solution is left for 2 days at room temperature. Then the reaction mixture is concentrated under reduced pressure, the resulting residue is subjected to silica gel column chromatography using chloroform-methanol (95: 5 v / v) as eluent. The crude crystals are recrystallized from ethyl acetate to give 500 mg of (p-hydroxyphenylethylamino) ethoxy-5-nitrophenyl-2, b-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
    13 .10,
    its dimethyl ether, so pl. 135137 ° C.
    Calculated,%: C, 61.71; H 5.95; N 8
    C ,, H ,, N, 08
    Found%: C, 61.88; H 5.84; N 7.94
    NMR (DMSO-d) f (ppm): 1.34 (3N, singlet); 3.58 (SA, singlet); 4.2 (2H, triplet); 4.82 (W, triplet); 5.36 (W, singlet).
    Example 15. 13 g of (4-aminobutoxy) -5-nitrophegate, 6-dimethyl-1,4-dihydropyridine 3,5-dicarboxylic acid and 4.5 g of glycidylphenyl ester are dissolved in 1300 ml of methanol and then the resulting solution boil for 16 h. Then the solvent is distilled off under reduced pressure. The residue obtained is subjected to silica gel column chromatography using; chloroform-methanol (96: 4 v / v) as eluent. The crude crystals are recrystallized from ethanol to obtain 9 g of (2-hydroxy-3-phenoxy-propylamino) -butoxy-5-nitrophene 1 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, m. square 131- 133 ° C.
    Calculated,%: - C 61.74; H 6.39; N 7.2
    ,
    Found,%: C 61.61; H 6.49; N 7.21
    NMR (CDCl 3); 5 (ppm): 1.6-2 (4H, multiplet); 2.28, (6H, singlet); 2.7-2.9 (4H, multiplet); 3.56 (6H, singlet); 3.9-4.2 (.5Н, multiplet); 5.3 (1H, singlet); 6.6-7.1 (3N, multiplet); 7.1-7.4 (3N, multiplet); 7.9-8.2 (2H, multiplet).
    The resulting product is treated with an ethanolic solution of hydrogen chloride to obtain its hydrochloride, which is recrystallized from ethnol to obtain dimethyl ester hydrochloride (2-hydroxy-3-phenoxy-prop-shamino) butoxy-5-nitrophenyl -2,6-dimethyl-1,4-dihydro-pyridine-3 , 5-dicarboxylic acid, so pl. 117-120 s.
    Calculated,%: C 56.47; H 6.32; N 6.59; 01 5.56
    , N, 0, HCl HzO
    Found,%: C 56.68; H 6.38; N 6.32; 01 5.53
    Example 16. According to the procedure of Example 15, using (3) -glycidylphenyl ether, (h) - (-) - dimethyl ester of (2-hydroxy-3-phenoxypropylamino) -butoxy-3-nitrophenylJ-2,6 was obtained. -dimethyl-1,4-dihydropyridine 3.5 dicarboxylic acid.
    m.p. 144-l46 ° C. / oi /, 2.1
       D
    Meon).
    ,, 08,
    Calculated N 7.2
    C, H, N, Og
    %: C, 61.74; H 6.39;
    C, 61.57; H 6.55;
    Found% N 7.2j
    A rainbow obtained at the preceding stage is treated with an ethanolic solution of hydrogen chloride to form its hydrochloride salt, which is recrystallized from ethanol to give (h) - (-) - dimethyl ester (2-hydroxy-2-phenoxypropylamino) butox and - 5-nit-rophenyl 3, b-dimethyl 1, 4-dihydropyridine-3,5-dicarboxylic acid, m.p. 187-189 ° C. / (// 5 -12.5 ° (, 04 MeOH)
    Calculated,%: C 58.11; H 6.18; N6.78
    HC1
    30 37
    C 58; H 6.31;
    Found N 6.71
    Example 17. According to the method of Example 16, using (c) -glycidylphenyl ether, (B) - (+) -dimethyl ester (2-hydroxy-3-phenoxypropylamino) butoxy-5-nitrophenyl - 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 144-146 ° C. / oi / 2.2 (, 07, MeOH).
    Calculated,%: C, 61.74; H 6.39; N 7.2
    C, 61.58; H 6.56;
     0 37
    Found,%; N 7.17.
    The product obtained in the above step is treated with an ethanolic hydrochloric acid solution to obtain the corresponding hydrochloric salt, which is recrystallized from ethanol to give pure (P) - (+) - dimethyl ester of (2-hydroxy-3-phenoxy-propylamino) butoxy-5 -nitrophenyl -2,6-dimethyl-I, 4-dihydropyridine-3,5-dicarboxylic acid, mp 191-193 ° C.
    Calculated,%: C 58.11; And 6.18; N 6.75
    C} pHz, N, 0, .HC1
    Found,%: C 58.04; H 6.29; N 6.67.
    M + 12.1 ° (., 01, MeOH).
    Example 18. In 500 ml of methanol, 5.2 g of diethyl 4-C2- (4 aminobutoxy) -5-nitrophenyl3 2,6 Dimethyl-1,4 dihydropyridine-3,5-dicarboxylic acid and 1.7 g of glycine are dissolved. Diphenyl ether. After that, the resulting solution was boiled for 16 hours. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (95:: 5 v / v.) As eluent. ). The crude crystals are recrystallized from ethanol to obtain 2.2 g of 4- (2Hydroxy-3-phenoxypropylamino) diethyl ester of butoxy-5-nitrophenyl -2,6-dimethyl-1,4-dihydropyridine 3,5-dicarboxylic acid, t .pl. 141-143 S. , Calculated,%: C 62.83; H 6.76; N 6.87
    five
    0.2
    4, N, 0,
    0
    five
    0
    five
    0
    five
    Found,%: C 62.85; H 6.86; N 6.86
    NMR (CDCl,) S (ppm): 1.14 (6H, triplet); 2-28 (6H, singlet); 1.5-2 (4H, multiplet); 5.24 (W, singlet).,
    Examples 19-22. By the method of example. 18, the following compounds have been obtained. .
    Example 19. Nis-cyclopropyl-methyl ester of (2-hydroxy-3-phenoxypropylamino) butoxy-5-nit-; prophenyl 3-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, t. square 148-151 ° C.
    Calculated,%: C 65,14-; H 6.83; N 6.33
    CH - S N O,
    Found,%: C 64.96; H 6.94; N 6.32
    NMR (CDC1,) 5 (ppm): 0-0.6 (8H, multiplet); 0.8-1.3 {2E, multiplet); 1.4-2 (4H, multiplet); 2.3 (6H, multiplet); 5.28 (W, singlet).
    PRI me R 20. Dipropyl ester of (2-hydroxy-3-phenoxy-propylamino) butoxy-5-nitrophenyl} - 2,6-dimesh-1-I, 4-dihydropyridine-3,5-dicarboxylic acid, mp . 148-151 ° C.
    Calculated,%: C 63.83; H 7.09; N 6.75
    C ,, N ,, КЗО,
    Found,%: C 63.6; H 7.01; N 6.5
    1313424
    NMR (CDCl 2). (Ppm): 0.84 (6H, triplet); 1.2-2 (8H, multiplet); 2.3 (6H,. Singlet); 5.28 (W, singlet).
    EXAMPLE 21 Dimethyl ester of (2-hydroxy-3-phenoxypropyl amino) butoxy-4 nitrophenyl -2,6-dimethyl- 1, 4-dihydropyridine-3.5 dicaroic acid, t. square 22 124 s.
    Calculated,%: C 60.8; H 6.46; N 7.09
    C 5 ,, - 0,
    Found,%: C 60.71; H 6.42; N 7.04., 5
    NMR (CDC1,) & (ppm): 1.6-2 (4H, multiplet); 2.3 (6H, singlet); 3.58 (6H, singlet); 5.32 (W, singlet).
    EXAMPLE 22 Diisopropyl 2o ether (2-hydroxy 3-phenoxy-propyl amino) butoxy 5-nitg) of phenyl 25b-dimethyl 1, 4-dihydropyridine-3.5 carboxylic acid hydrochloride, mp 212-213 ° С.25
    Calculated,%: C 60.39; H 6.86; K 6.21
    ,, 0, C1
    Found,%: C 60,19; H 6.92; N 6.2430
    Zh1R (DMSO-d) (ppm) 0.9 (- bC, doublet); 1.16 (6H, doublet); 2.24 (6H, singlet); 3.32 (6H, singlet); 4.74 (2H, multiplet); (1H,
    singlet)
    35
    Example 23, B44 ml of methanol dissolved 2.57 g of dimethyl ester (4-aminobutoxy} -5-methylsulfonylphenyl -2, b-dimethyl-1,4-di d hydropyridine-3,5-dicarboxylic acid (for obtaining The reference example 2) and 0.83 g of glycidylphenyl ether, after which the resulting solution is left at room temperature for 43 hours. Then the reaction solution is concentrated under reduced pressure, the resulting residue is subjected to column chromatography on silica gel using chloroform-methanol mixture (95:: 5 v / s). The crude crystals recrystallize watered from aqueous ethanol to obtain 1.05 g of dimethyl ester (2-hydroxy-3-phenoxy-propylamino) butoxy | -5-methylsulfonylphenyl 3 2,6-dimethyl-1,4-dihydropyridin-5 5-dicarboxylic acid , t, pl., 145-146 ° C,
    45
    five
    0
    five
    q q
    five
    13 .14.
    Calculated,%: C 59.5; H 6.6; N 4.48; S 5.12
    C ,, H ,,,. 0,
    Found,%: C 59.6; H 6.63; W 4.29; S 5.28
    NMR (CDC1 ,,) (ppm): 2.28 (6H, singlet); 2.98 (SA, singlet); 3.56 (6H, singlet); 5.28 (W, singlet).
    Examples 24-37.
    According to the procedure of Example 23, the following compounds were prepared.
    EXAMPLE 24 4-C-chloro-2-4- (2-hydroxy-3-phenoxy-propylamino) -butoxy-phenyl -2,6-dimethyl-1,4-dihydropyridine-3,5-dicar dimethyl ether - bonoic acid, amorphous powder.
    Calculated,%: C, 62.88; H 6.51; N 4.89
    C ,, H ,,
    Found,%: C 62.71; H 6.43; N 4,8
    NMR (CTC1-) 6 (ppp): 1.5-1.9 (4H, multiplet); 2.28 (6H, singlet); 3.6, (6H, singlet); 5.24 (1H, singlet).
    Example 25: 4- (2-hydroxy-3-phenoxypropyl-amino) ethoxy-5-methoxyphenyl -2, 6-dimethyl-1,4-dihydropyridine-3, 5-dicarbnovoic acid dimethyl ester, m.p. 141-143 ° C.
    Calculated,%: C 64.43; H 6.71; N 5.18
    C, H ,, N, 0,
    Found,%: C 64.09; H 6.68; N 5.8
    NMR (CDClJS (ppm): 2.23 (6H, singlet); 3.56 (bN, singlet); 3.68 (MH, syringe); 5.28 (W, singlet).
    PRI me R 26. Dimethyl ester 4- (2-hydroxy-3-phenoxy-1-amino) butoxy 3 5-methoxyphenyl -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acid, amorphous powder.
    Calculated,%: C 64.46; H 7.15j N1.4,83
    C, H4oNiOg 0.5H,
    Found,%: C 64.49; H 7.27; N 4.72
    NMR (pyridine-d5) 5 (ppm): 2.51 (6H, singlet); 3.65 (9H, singlet-like); 5.85 (W, singlet).
    PRI me R 27. DimethylBYTE ester (2-hydroxy-3-phenoxypropane 1-amino) butoxy-5-methylphenyl -2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acid, amorphne powder .
    Calculated,%: C, 66.29; H, 7.36; N 4.99
    C ,, E, 0, -0,
    15
    Found,%: C 66.38; H 7.36; N 4.95
    NMR (CDC1,) S (ppm): 2.21 (3N, singlet); 2.27 (6H, singlet); 3.57 (6H, singlet); 5.22 (1H, singlet); 6.17 (1H, singlet).
    EXAMPLE 28 Dimethyl ester hydrochloride (2 Hydroxy-3 phenoxypropyl Iamino) butoxy thylthiophenyl -2,6-dimethyl 1, 4 - pyridine-3,5 dihydroxycarboxylic acid dihydrate, amorphous powder.
    Calculated,%: C 58.58; H, 6.76; N 4.41; C1 5.58; S 5.04
    C ,, .O-HCl-0,8H.jO
    Found,%: C 58.6; H 6.91; N 4.25; C1 5.79; S 5.24NMR (SBSI3) U (ppm): 2.3 (6H, siglet); 2.39 (SA, singlet); 3.54 (6H singlet); 5.14 (W, singlet).
    EXAMPLE 29 4-5-chloro-2-1 2 dimethyl ester (2-hydroxy-3-phenox-propyl-amino) is syphenyl -2.6 dime-, 4-dihydropyridine-3.5 dicarbo - new acid, so pl. 184-186 ° C.
    Calculated,%: C 61.7; H 6.1; N 5, 14
    ,
    Found,%: C 60.91; H 6.23; N 4.94
    NMR (CBCI) (ppm): 2.3 (6H, singlet); 3.62 (6H, singlet); (1H, singlet).
    5.26
    EXAMPLE 30 Dimethyl ether (2-hydroxy 3-phenoxy propyl amino) butoxy - 5 - methylsulfonylphenyl -2,6-dimethyl 1,4 - dihydropyridine - 3.5-- dicarboxylic acid, so pl. 83-86 ° C.
    Calculated,%: C 61.07; H 6.78; N 4.59; S 5.26
    WITH,, ,
    Found,%: C 61.02; H 6.89; N 4.41; S 5.28
    NMR (CDC1) S (ppm): 2.28 (6H, singlet); 2.65 (SA, singlet); 3.55 (6H, singlet); 5.28 (W, singlet).
    PRI me R 31. Dimethyl ester 4-5 bromo-2-f4 (2-hydroxy-3-phenox propylamino) butoxy phenyl -2,6-dime TS 1-1.4-dihydropyridine 3,5-dicarboxylic acids, so pl. 83-85 ° C.
    Calculated,%: C 58.35; H 6.04; N 4.54; Bg 12.94,
    Found,%: C 58.5; H 6.28; N 4.35; .Вг 12,44
    four
    13
    sixteen
    five
    0
    five
    0
    five
    0
    five
    0
    five
    NMR (CDClJS (ppm)): 2.27 (6H, singlet); 3.58 (6H, singlet); 5.21 (W, singlet); 6.46 (W, singlet).
    Example 32. 4- 3,5-dichloro-2- 4- (2-hydroxy-3-phenoxypropylamino) butoxy-phenyl-2,6-dimethyl-1,4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester, vol. square 72-74 S.
    Calculated,%: C57.6; H6.12; N 4.48; C1 11.34 .N O Clj-H O
    Found,%: C 57.9; H 6.35; N 4.33; C1 11.42
    NMR (CDC1,) S (ppm): 2.28 (6H, singlet); 3.62 (6H, singlet); 5.22 (W, singlet); 6.07 (1H, singlet).
    Example 33. Dimethyl ester, 5-dibromo-2- 4- (2-hydroxy-3-phenoxypropylamino) 6yTOKCHj phenyl-2,6-dimesh1-1,4-dihydropyridine-3,5-dicarboxylic acid, amorphous powder.
    Calculated,%: C 51.61; H 5.23; N 4.01; Br 22.89
    C „H, BM, 0, Br.O, 1H20
    Found,%: C 51.38; H 5.36; N 3.91; Вг 23,21
    NMR (CDCl 3) (ppm): 2.28 (6H, singlet); 3.64 (6H, singlet); 5.26 (W, singlet); 6.12 (IH, singlet).
    PRI me R 34. (2-Hydroxy-3-phenoxypropyl-amino) butoxy-phenyl-3-dimethyl ester, b-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester, mp. 129-130 ° C.
    Calculated,%: C, 66.9; H 7.11; N 5.2
    C, oH,
    Found,%: C 66.7; H 7.34; N 5.04
    NMR (CDC1 ,,) S (pp): 1.5-U9 (4H, multiplet); 2.28 (6H, singlet); 3.56 (6H, singlet); 5.2 (W, singlet).
    Example 35 4-3-G 2- (2-hydroxy-3-phenoxy-propylamino) ethoxy-phenyl-2,6-dimethyl-1,4-dihydropyridine-3 d-5-dicarboxylic acid dinethyl ester hydrochloride, mp . 136-139 ° C.
    Calculated,%: C, 61.48; H 6.45; N 5.12
    .HCl
    Found,%: C 61.27; H 6.44; N 5.09
    NMR (CDCl 3) (ppm): 2.28 (6H, singlet); 3.6 (6H, singlet); 5.24 (1H, singlet).
    PRI me R 36. Dimethyl ester 4- 3-C4- (2-hydroxy-3-phenoxyprosh
    - 17
    amino) butosk phenyl -2,6-dimethyl-1,4 dihydropyridine-3,5-dicarboxylic acid. mp. lOe-IO / jS C.
    Calculated,%: C65.8; H7.18; N5,12
    Found,%: C 65.72; H 7.32; N 4.97
    NMR (CDClO (ppin): 2.31 (6H singlet); 3.65 (6H, singlet); 5 (1H, singlet); 6.04 (1H, singlet).
    PRI me R 37. 4- (2-hydroxy-3-phenoxypropyl-amino) butoxy (5-jenyl-2,6-dimethyl-1, 4 dihydropyridine-3,5-dicarboxylic acid dimethyl ester, mp 83-85 ° s
    Calculated,%: C, 66.9; H 7.11; N5,2

    Found,%: C 66.64; H 7.2; N 5.08
    NMR (CDC1,) & (ppm): 2.3 (6H, singlet); 3.64 (6H, singlet); 4.95 (1H, singlet); 5.78 (1H, singlet).
    Example 38 In 2 ml of methanol, 2 g of Z- (4-aminobutoxy) -5-nitrophenyl-3 dimethyl ester 4 56 dimethyl-1,4-dihydroli dine-3,5-dicarboxylic acid and 0.84 g of glycylide- are dissolved in 200 ml of methanol. (4-methoxyphenyl) ether, the resulting solution is boiled for 3 hours. Then the solvent is distilled off under reduced pressure, the resulting residue is subjected to silica gel column chromatography using chloroform-methanol (95: 5 ob / v) as eluant . The crude crystals are recrystallized from a mixture of methanol and ethyl ether to obtain 0.85 g of 4-L2-4-2-hydroxy-3- (p-methoxyphenoxy) dimethyl ester of pro-pshlamino butoxy-5-nitrophenyl -2,6-dimethyl -1,4-dihydropyridine-3, 5-dicarboxylic acid, so pl. 154-155 ° С
    Calculated,%: C 60.68; H 6.41; N 6.85
    С ,, Нз, Г1,0, о
    Found,%: C 60.57; H 6.49; N 6.75
    NMR (00013) 5 (ppm): 2.28 (6H, singlet); 3.56 (bN, singlet); 3.76 (SA, singlet); 5.3 (1H, singlet).
    PRI me R s 39-45. According to the procedure of Example 38, the following compounds are prepared.
    Example 39. Dimethyl ester hydrochloride (o-chlorophenoxy) 2-hydroxy propyl amnos3. Si-5-nitrophenyl-2,6-dimethyl-1,41342413
    18
    0
    five
    0 5 0
    five
    0
    five
    dihydropyridine-3,5-dicarboxylic acid, amorphous powder.
    Calculated,%: C 57.88; H 5.99; N 6.75
    C, OH, BSSh, 0- ,. HC1
    Found,%: C 58.13; H 5.87; N 6.69
    NMR (DMSO-d) 5 (ppm): 1.4-1.8 (4H, multiplet); 2.32 (6H, singlet); 3.64 (6H, singlet); 5.26 (1H, singlet).
    PRI me R 40. Dimethyl ester of (o-cyanophenoxy) -2-hydroxypropylamino-butoxy-5-nitrophenyl -2,6-dimethyl-1, 4-dihydropyridine-3,5-dycanoic acid, t .pl. 169-171 ° C.
    Calculated,%: C 61.18; H 5.96; N 9.21
    Сз, H, 6N, 0,
    Found,%: C 61.06; H 5.91; N 9.08
    NMR (CDC1,) S (ppm): 2.32 (6H, singlet); 2.76 (2H, triplet); (6H, singlet); 5.24 (1H, singlet).
    EXAMPLE 41 4- 2-4-C2-hydroxy-3- (1-naphthyloxy) dimethyl ester propyl amino-butoxy-5-nitrophe-, 6-dimethyl-1,4-dihydropyridine , 5-dicarboxy ki slots, so pl. 180-18GS.
    Calculated,%: C 64.44; H 6.2; N 6.63
    C, H3, N, 0,
    Found,%: C 64.17; H 6.35; N 6.46
    NMR (CDCl 3) (ppm): 2.26 (6H, singlet); 3.34 (6H, singlet); 5.3 (1H, singlet).
    Example42. Dimethyl ester of (p-acetamidophenoxy) -2-hydroxypropylamino-butoxy-5-nitrophenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, m.p. 75-176 ° C.
    Calculated,%: C 59.99; H 6.29; N 8.74
    C5iH (, N40, (,
    Found,%: C 59.98; H 6.39; N 8.64
    NMR (CDCl2 + DMSO-d) S (ppm): 2.08 (3N, singlet); 2.28 (6H, singlet); 3.54 (6H, singlet); 5.28 (W, singlet).
    EXAMPLE 43: 4-2-G4- (2-hydroxy-3-frnoxypropyl-amino-J-2-butynyloxy-5-nitrophenyl-J-2,6-dimethyl-1,4-di-dimethyl ester dimethyl ester, 51913
    dicarboxylic acid, amorphous powder.
    Calculated,%: C 58.53; H 6.06; N 6.83
    С, „Н, зК, 0, -2Н20
    Found,%: C 58.73; H 6.35; N 7.09
     NMR (CDC1,) 8 (ppm): 2.3 (6H, singlet); 3.6 (6H, singlet); 4 (2H,. Singlet); 5.3 (1H, singlet).
    Example 44. (E) 4- (2-hydroxy-3phenoxypropyl amino) -2-butenyloxy-5-nitrophenyl 3 2,6-dimethyl -1,4-dihydropyridine 3,5-dicarboxylic acid hydrochloride, m.p. 171-173 S.
    Calculated,%: C 58.3; H 5.87; N 6,8. C ,, H ,, N, 0, C1
    Found,%: C 57.97; H 5.95; N 6.78
    NMR (DMCO-dJR (ppm): 2.24 (6H, singlet); 3.46 (6H, singlet); 5.24 (1H, singlet).
    PRI me R 45. Dimethyl ester hydrochloride (2) -4- (2-hydroxy-3-phenoxy-propylamino -2-butenyloxy-5-nitrophenyl-2,6-dimethyl-1,6- dihydropyridine-3,5-dicarboxylic acid, mp 191-193 ° C.-
    Calculated,%: C 58.3; H 5.87; N 6,8
    SzoN, C1
    Found,%: C 58.05; H 5.87; N 6.88
    NMR (CDCli) S (ppm): 2.28 (6H, singlet); 3.58 (6H, singlet); 4.7 (2H, doublet); 5.34 (1H, singlet).
    Example 46. 4.62 diethyl ether (4-aminobutox si) -5-nitrophenylJ-2-ethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid and 1, are dissolved in 46 ml of methanol; 46 g of glycidylphenyl ether, after which the resulting solution is boiled for 15 h. The cooled reaction solution is concentrated under reduced pressure, the resulting residue is subjected to column chromatography on silica gel using chloroform-methanol (95: 5 v / v .). The crude crystals were recrystallized from ethanol to obtain 1.22 g of 2-ethyl-4- 2- 4- (2-hydroxy-3-phenoxypropylamino) -butoxy-5-nitrophenyl-6-methyl-1-diethyl ether. , 4-dihydropyridine-3,5-dicarboxylic acid, so pl. 159-159.5 ° C.
    1320
    Calculated,%: C 63.35; H 6.93; N 6.72
    35 N, N, 0,
    Found,%: C 63.18; H 6.78; N 6,62
    NMR (CDCl 2) (ppm): 2.3 (EH, singlet); 5.3 (IH, singlet); 6.57 (1H, singlet).
    The pharmacological effect of the proposed compounds is illustrated by the following test results as well as test methods.
    Test methods.
    Hemodynamic action.
    Outbred dogs of both sexes are anesthetized with penta-barbital sodium (30 mg / kg i.v.). Animals are artificially ventilated with ambient air. Measured arterial blood pressure (ACS), heart rate (SS), left-ventricular pressure (DL), max, d DL / dt mean pulmonary arterial blood pressure (SLAD), cardiac output min (but), and venous velocity blood (Ven. UK). Test compounds are injected as an injection into the femoral vein. The hemodynamic effect of the test compounds is compared with the action of well-known Ca antagonists.
    The table (column 1) shows the percentage change in ACS and Ven. SC - from control values, caused by intravenous injection of test compound.
    Coronary vasodilating action.
    Mongrel dogs are anesthetized and ventilated as described above. Trachotomy is performed in the fourth intercostal space. Following intravenous injection of Hepraine (1000 U / kg), blood from the distal end of the cannulated carotid artery is pumped through a servo-controlled peristaltic pump to a circular branch of the left coronary artery at a constant pressure of 120 mm HQ blood that is controlled by a pump regulator. Electromagnetic flow sensor for recording blood flow velocity in the channeled coronary artery. Test compounds are inserted directly into the vascular tube attached adjacent to the coronary cannula. Crown
    211
    the vasodilatory effect of the test compounds is calculated on the basis of the dose required for an increase of 100% vein. SC (pap), when the maximum response to the administration of papaverine at a dosage of 300 µg is expressed as a 100% response. The table (column 2) shows (the popes and the duration of the coronary vascular of the widening effect of the tested compounds.
    Beta-adrenoceptor blocking effect,
    The beta-adrenoceptor blocking effect of the tested compounds was determined by the method of Tachikava and Takenaka (Pharmacological Testing of I- (7-indenyloxy) -3-iso-cropyl-aminopropan-2-ol hydrochloride (HC-2-), Apch. I pharmacodyn, 202, 79 -92, (1973) on male Wistar rats. Previously, rats were given reserpine (8 mg / kg i.M.) 18 hours before the test. Rats were anesthetized with sodium pentabarbital (55 mg / kg.M. .), then subjected to bilateral vagotomus-sh in the neck. Heart rate is measured by a cardiotachometer triggered simultaneously with the ventricle. after the control response to the intravenous administration of isoproterenol at a dose of 0.1 mg / kg was administered by intravenous injection, the test compound in an increasing dosage with an interval of 20 min. The average dose leading to the polygraph. to a 50% block of a positive chronotropic response to isoproterenol (), mouth
    3
    22
    five
    0
    five
    0
    five
    0
    This is based on the dosage-response curves obtained by depositing the percentage inhibition versus log cumulative dose of the test compound (table, column 3).
    In a series of experiments, own activity with respect to the sympathetic nervous system (CAC) was also found. The results obtained are shown in the table (column 4), where the sign indicates the almost complete absence of an increase in heart rate, the + sign means an increase in CC by 10-19 beats / min, a ++ sign means that an increase in SS by 20-29 beats / min was observed, a +++ sign means that an increase in CC was observed by more than 30 beats / min.
    The required dosage is established on a case-by-case basis, taking into account such factors as the symptom, age, and sex of the patient. A total of 1–200 mg in one or more doses are administered daily to an adult patient by intravenous injection, it is well known that many known compounds very close to the proposed compounds do not show any significant toxicity.
    Thus, as can be seen from the data in the table, the method allows to obtain new derivatives of 1,4-dihydropyridine, which possess a complex of valuable pharmacological properties.
    Form of the invention
    The method of obtaining 1,4-dihydropyridine derivatives of the general formula:
    0 (CHr, m-A- (CH l -NHCH2CH-B
    COOR2.
    R
    R (and RJ are the same ihsh different and mean C, -C, o-alkyl or lower alkyl, which is interrupted by an oxygen atom, or alkyl. Ni5IIl alkyl substituted by an alicyclic C, -Cg group;
    R, and R
    same or different and mean lower alkyl;
    R j. and Rg is the same or different and means hydrogen, nitro, halogen, lower alkyl, lower
    23134241324
    an alkoxy group, lower, characterized in that
    compound of general formula
    alkylthio, lower alkylsulfonyl or lower alkylsulfinyl; R and R are the same or different and represent hydrogen, halogen, cyan, lower alkoxy group or lower I.OOC alkanoylamino group, Q or R-, and Rg together with Yao R it form naphthyl with the adjacent phenyl;
    A is a simple bond, vinyl () or ethynylene (GG V
      / 9
    B is a simple bond or
    Group
    type- same or different-CHO-CH-B
    ny and kakdy is equal
    or 1-5
    15
    R
    6- 0- (cNg) t-A- (SNg) COOR
    -RV n.
    are reacted with a compound of the general formula
    RT 8
    I.OOC Yao R it
    R
    6- 0- (cNg) t-A- (SNg) COOR
    -RV n.
    are reacted with a compound of the general formula
    RT 8
    Diltiazem Propranolol -
    NT
    nt - not tested
    nt
    0.063
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives
    1,4-dihydropyridine of the general formula:
    0 (CH2 m -A- (CH 2 ') n -NHCH 2 CH-B- <Q ^ R 8
    OH r 7 or difference— '' Gio
    N ι n where R (and R { are the same and mean C, alkyl or lower alkyl, which is interrupted. 55 by an oxygen atom, or. Lower alkyl substituted by an alicyclic C 3 -C 6 group;
    R „and R. are identical or □ Ύ and mean alkyl;
    R c and R, are identical or different and mean a nitro group, lower alkyl, differences in hydrogen, halide, lower ι
    R 7 and R g shea η alkoxy, lower alkylthio, lower alkylsulfonyl or lower alkylsulfinyl; the same or different and mean hydrogen, halogen, cyan, a lower alkoxy group or a lower alkanoylamino group, or R 7 and R g together with the adjacent phenyl form naphthyl; single bond, vinyl (-CH = CH-) or ethynylene (-C = C-);
    single bond or group —CH 2 O—; the same or different, and each is O or 1-5, which is characterized in that the compound ι
    general formula
    Rioc
    C00R 2
    OFSN g ^ -A- (CH g ) p -YAN g
    R ^ is subjected to a general formula by reaction with a compound—
    Experience (connection)(1) (2) -(3) Betablock.mg / kgV.V. (4)САС mg / kg iv• skd% Ven.sk,% ED t00 dad Duration min 1 0.1 -7 21 75 fifteen 0.13 +++ 0.3 -17 69 - - - - 8 1,0 -29 . 10 645 60 < 0.31 + 10 0.3 -12 26 400 60 < 0.73 - 12 0.3 -18 14 475 60 < 2.58 ' - fifteen - 1.0 -33 96 228 60 < 0.70 - 16 1,0 -31 97 162 60 < 0.39 - 17 1,0 -35 94 158 60 3.53 18 0.3 -thirteen ' 20 285 6 (X s and - 23 1,0 -32 64 780 60 0,03 - 24 1,0 -33 62 245 60 1,50 26 1,0 -38 43 600 40 0.53 - 28 1,0. -28 70 555 thirty 0.27 - 34 0.3 -18 3 175 60 < 0.90 42 1,0 -thirteen 8 515 60 < 0.50 - 0.3 -thirty 90 51 20 NT - Diltiazem Propranolol - ' nt - NT - 0,063 -
    NT - not tested
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    US5514803A|1996-05-07|2,6-disubstituted 4-quinolyl-dihydropyridines
    EP0106276B1|1988-10-26|1,4-dihydropyridine derivatives
    CZ177892A3|1993-02-17|AMINOMETHYL SUBSTITUTED 2,3-DIHYDROPYRAN|PYRIDINES, PROCESS OF THEIR PREPARATION AND THEIR USE IN MEDICAMENTS
    同族专利:
    公开号 | 公开日
    JPH0123463B2|1989-05-02|
    ES544647A0|1987-09-01|
    ES552335A0|1987-04-16|
    MX7533E|1989-08-15|
    DE3581967D1|1991-04-11|
    ES8704899A1|1987-04-16|
    PT80714B|1986-12-11|
    EP0167371A3|1987-06-16|
    ES8707933A1|1987-09-01|
    KR860000261A|1986-01-27|
    ES552336A0|1987-04-16|
    AU4396785A|1986-01-02|
    EP0167371A2|1986-01-08|
    CA1312085C|1992-12-29|
    EP0167371B1|1991-03-06|
    CA1300157C|1992-05-05|
    US4727082A|1988-02-23|
    JPS6112662A|1986-01-21|
    KR900005019B1|1990-07-18|
    ES8704898A1|1987-04-16|
    MX26687A|1994-03-31|
    GR851568B|1985-11-25|
    AU569161B2|1988-01-21|
    AT61356T|1991-03-15|
    PT80714A|1985-07-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2753946A1|1977-12-03|1979-06-13|Bayer Ag|1-N-ARYL-1,4-DIHYDROPYRIDINE AND THEIR USE AS A MEDICINAL PRODUCT|
    US4285955A|1978-10-31|1981-08-25|Bayer Aktiengesellschaft|1,4-Dihydropyridinecarboxylic acids|
    NZ201395A|1981-07-30|1987-02-20|Bayer Ag|Pharmaceutical compositions containing 1,4-dihydropyridines and certain of these dihydropyridines|
    DE3207982A1|1982-03-05|1983-09-08|Bayer Ag, 5090 Leverkusen|NEW 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN MEDICINAL PRODUCTS|
    HU192166B|1982-08-06|1987-05-28|Banyu Pharma Co Ltd|Process for producing 2-carbamoyl-oxy-alkyl-1,4-dihydro-pyridine derivatives|
    US4500527A|1983-06-22|1985-02-19|Usv Pharmaceutical Corporation|Antihypertensive 4[-oxyiminomethyl phenyl]-1,4-dihydropyridines|
    NO854021L|1984-10-26|1986-04-28|Bayer Ag|1,4-DIHYDROPYRIDINE HYDROXYAMINES AND PROCEDURES FOR PREPARING THEREOF.|
    GB8503425D0|1985-02-11|1985-03-13|Ici Plc|Alkanolamine derivatives|GB8503425D0|1985-02-11|1985-03-13|Ici Plc|Alkanolamine derivatives|
    GB8503427D0|1985-02-11|1985-03-13|Ici Plc|Basic compounds|
    EP0276552A1|1986-12-08|1988-08-03|Yamanouchi Pharmaceutical Co. Ltd.|1,4-dihydropyridine derivatives and their production|
    CA1312611C|1987-07-01|1993-01-12|Yamanouchi Pharmaceutical Co., Ltd.|Pyridine derivatives, process for production thereof and pharmaceutical composition containing them|
    GB9102031D0|1991-01-30|1991-03-13|Fujisawa Pharmaceutical Co|Dihydropyridine compounds,and process for their preparation|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP59133650A|JPH0123463B2|1984-06-28|1984-06-28|
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