• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    The invention relates to substituted 1,4-dihydropyridines (HG), in particular, a compound of formulas 1 ha-C (CH 3): CH-St-CC 2 C (CH 3), where R is C (0) ORg or R4; R-, - СH j, N0.- CjH,, NC-CfH, CF3-CgH4, CHj-CH,, H, 3CO-Cj-H-., CjHjCl, (((СНз), chlornitrophenyl, pyridyl , nitrothienyl; R - 1,2,4-oxadiazolyl-5 (substituted in the 3rd position by C.-alkyl or benzyl), 1,2,4-oxadiazolyl-3 (replaced in the 5th position by CHg, meth- Lxmethyl or benzyl), 1,3,4-oxadiazol-1-2 (or substituted in the 5th position by C-alkyl or aminocarbonylmethylthio, isopropylthio); 1,2,4-thiadiazolyl-5 (substituted in 3 - i-position of CI j or methylthiogroup or R); Rj-C .j-alkyl, alkoxy-alkyl (total number of C-atoms 3-6); cyclohexyl, dimethylaminoethyl, N-methyl-K-benzylaminoene TylJ R-, 4-oxadiazolyl-2 5-methyl-1,2,4-oxadiazolyl-3, 5-methoxymethyl-1,2,4-oxadiazolyl-35 3-benzyl-1,2,4-oxa- diazolyl-5; 3-methyl-1,2,4-thiadiazolyl-, 5; 4-methyl-5-ethoxycarbonyl-1,3-thiazolyl-2 or their acid addition salts, which can be used to treat diseases or to prevent calcium penetration into muscle cells of overpressure, angina pectoris, cerebral or peripheral circulatory disorders. The goal is to create new active substances of the specified class. Synthesis of HPP lead from compounds of formulas ii, b and ly; H3C-C (0) CH2-R 2 (li); R-CH-0 (w) H2N-C (CH CHR (.W), where R, R, R, have the indicated values (molar ratio u, In, (1: 1: 1). The process is carried out in organic solvent at temperatures from ambient to the boiling point of the solvent. The release of HP is carried out in a free form or in the form of an acid addition salt. The antagonistic effect on the calcium of new known HP of nephedepine with an LDso toxicity of 22-118 mg / kg (intravenously). 2 table i CO 00 05 about ate 00 JV
    公开号:SU1360585A3
    申请号:SU833675005
    申请日:1983-12-19
    公开日:1987-12-15
    发明作者:Шенафингер Карл；Бон Хельмут；Юст Мелитта；Марторана Риеро
    申请人:Касселла Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing substituted 1,4-dihydropyridines of the total ({Yurmula
    RI
    , HjC Sj CH3 /
    n
    Similarly, the following compounds can be made, with the reaction temperature and solvent deviating temperatures being enclosed in brackets:
    a) 1,4-dihydrogde methyl ester R - QOjRg or or, phenyl, nitrophenyl,: shororfen1, methoxyphenyl, cyanophenyl, trifluoromethylphenyl, methyl-phenyl, bromophenyl, dichlorophenyl, di-15 2,6-dimethyl-4- (2, 3-dichlorophenyl) -5- .methoxyphenyl, dimethylphenyl, chloro- (3-methyl-1,2,4-oxadiazol-5-yl) -pyr nitithenyl, pyridyl, nitrothienyl; R is 1,2,4-oxadiazolyl-5, substituted in position 3 With, -C. alkyl or ben3 C.-C
    7 tons
    zyl, 1,2,4-oxadiazol-3, substituted in position 5 by methyl, methoxymethyl, benzyl, 1,3,4-oxadyasolyl-2, unsubstituted or substituted in position 5 by alkyl, aminocarboxymethyl; 1thio, isopropylthio, 1,2,4-thiadiazoles; -5, substituted in position 3, is methyl or methylthio, or R, Rj is alkoxyalkyl with a total number; carbon volumes from 3 to 6, cyclohex1; L, -dimethylaminoethyl, N-methyl-I-benzylaminoethyl, R4 - 1,3,4-oxadiazolyl-2, 5-methyl-1,2,4-oxadiazol1-3, 5-metorsimesh1-1,2, 4-oxadiazole : Il-3, 3-benzyl-1, 2,4-oxadiazolyl 5, 3-methyl-, 2,4-thiadia-ZOLSH1-5, 4-metsh1-5-ethoxycarbonyl-1-1,3-thiadiazolsh1-2 or them acid additive salts, KOTopble can be used for the treatment of diseases or their prevention caused by i penetration of calcium in the minor. cells, for example, increased blood pressure, angina pectoris, cerebro-. peripheral and circulatory disorders.
    The aim of the invention is a method for producing new 1,4-dihydropyridine derivatives having an antagonistic effect on calcium.
    Example 1. 1,4-Dig Idro-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) pyridine- methyl ester 3-carboxylic acid.
    din-3-carboxylic acid, Tpl „252-254 ° С (ethanol, reflux temperature);
    20 b) 2-methoxy-ethyl ester 1) 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-met.yl-1, 2,4-oxadiazol-5-yl) - pyridine-3-carboxylic acid. Mp 214-216 0 (ethylene glycol mono methyl ether,);
    c) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (3-methyl1, 2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester, T pl. 220-222 0 30 (methanol, reflux temperature);
    d) 1,4-dihydro-2,6-dimesh1-4- (2,3-dichloro-phenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) 2-methoxy-ethyl ester ) -pyridine-3-carboxylic acid. T. pl. 96-199 ° C (ethylene glycol monomethyl ether, reflux temperature);
    d) 1,4-dihydro-2,6-dimethyl-4- (pyrid-3-yl) -5- (3-methyl1, 2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester , T, pl, 248-250 ° C (methanol, 40 ° C);
     a) 1,4-dihydro-2,6-dimethyl-4-phenyl-5- (3-methyl-1,2,4- 45 oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester, mp , 198-200 0 (methanol, 40 ° C);
    g) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) 2-methoxy-ethyl ester pyridine-3-carboxylic acid, T.
    mp, 177-180 ° C;
    h) 1,4-dihydro-2,6-dimethyl-4- (3-methoxyphenyl) -5- (335
    40
    50
    3.02 g of 3-nitrobenzaldehyde, -2.3 g of 55 ethyl-1,2,4-oxadiazol-5-yl) pyridine-methyl methyl aminocrotonic acid-3-carboxylic ester. T, pl, 180183 C
    lots and 2.8. g 3-methyl-5-acetonyl-I, 2,4-oxadiazole is heated to boiling for 5 hours in 30 ml of isopropano (
    methanol
    50 ° C);
    i) 1,4-DIGIDRO-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-tert methyl ester.) After cooling, the solid injected is sucked off and recrystallized from ethanol, mp 239-240. C, Output 3.8 g
    Calculated: About 21.6.
    Found: C 58.6; H
    C 58.4; H 4.9; 4.9; N
    N 15.1; 15.3;
    ABOUT
    21.1
    Similarly, the following compounds can be made, with the reaction temperature and solvent deviating temperatures being enclosed in brackets:
    a) 1,4-dihydro2, 6-dimethyl-4- (2,3-dichlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) pyr methyl ester
    2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) pyr
    din-3-carboxylic acid, Tpl „252-254 ° С (ethanol, reflux temperature);
     b) 2-methoxy-ethyl ester 1) 4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-met.yl-1, 2,4-oxadiazol-5-yl) - pyridine-3-carboxylic acid. Mp 214-216 0 (ethylene glycol monomethyl ether,);
    c) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (3-methyl1, 2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester, T pl. 220-222 0 (methanol, reflux temperature);
    d) 1,4-dihydro-2,6-dimesh1-4- (2,3-dichloro-phenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) 2-methoxy-ethyl ester ) -pyridine-3-carboxylic acid. T. pl. 96-199 ° C (ethylene glycol monomethyl ether, reflux temperature);
    d) 1,4-dihydro-2,6-dimethyl-4- (pyrid-3-yl) -5- (3-methyl1, 2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester , T, pl, 248-250 ° C (methanol, 40 ° C);
     a) 1,4-dihydro-2,6-dimethyl-4-phenyl-5- (3-methyl-1,2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester, mp, 198-200 ° C (methanol, 40 ° C);
    g) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) 2-methoxy-ethyl ester pyridine-3-carboxylic acid, T.
    mp, 177-180 ° C;
    h) 1,4-dihydro-2,6-dimethyl-4- (3-methoxyphenyl) -5- (3
    183 С
    (
    methanol
    50 ° C);
    i) 1,4-DIGIDRO-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-ter31360585 4 methyl ester)
    butyl-1,2,4-oxadiazol-5-yl) pyridine-yl) pyridine-3-carboxylic acid.
    3-carboxylic acid. T. pl. (toluene,);
    a) 1,4-dihydro-2,6-dimethyl-4- (2-chlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester . T. pl. 211-213 ° C (ethanol, reflux temperature);
    l) 1,4-dihydro-2,6-dimethyl-4- (3-chlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester m.p. 228-230 ° C (methanol, reflux temperature);
    m) 1,4-dihydro-2,6-dimethyl-4- (4-chlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester . T. pl. 227197-: So. 165-167 (:;,
     x) 1,4-dihydro-2,6-dimethyl-4 - (2,3-dichlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) isopropyl ester; 3-carboxylic acid. T. pl. 194-19b C;
    v) isobutyl ester I, 4-dihydro-10 2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (3-methyl-1,2,4-oxadiazol-5-yl) -pyridine -3-carboxylic acid. M.p. 158- (i-butanol, 90 C);
    h) 1,4-15 hydroxyethyl-2,6-dimethyl-4- (3-chlorophenyl) -, 5- (3-methyl 1-1, 2,4-oxadiazol-5-yl) - .- pyridine-3-carboxylic acid. M.p. 185-187 ° C;
    x) 2-methoxy-ethyl ester 1,4229 ° C (methanol, temperature reflux-20 Dihydro-2,6-dimethyl-4- (2,3-dimethoxygation);
    n) 1,4-dihydro-2,6-dimethyl-4-fench 1-5- (3-isopropyl-1,2,4-oxadiazol-5-yl) pyridine-3-carboxylic acid 3-methoxypropyl ester. M.p. 194-196 ° C (toluene, 100 ° C);
    o) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichloro-NILE) -5 (tert-butyl-1,2,4-oxadiazol-5-yl) -pyridin-3 2-butoxyethyl ester -carboxylic acid. M.p. 211-213 ° C (t-butanol 80 s);
    p) 2-dimethylaminoethyl ether 1., 4-DIGIDRO-2,6-dimethyl-4- (3-trifluoromethyl-phenyl) -5- (3-benzyl-1,2,4-oxadiazol-4- yl) -pyridin-3-carboxylic acid. T. pl. 205-207 ° Cj
    p) 2-dimethylaminoethyl ester of 1y4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (3-methyl-, 2,4-oksa-diazol-5-yl) -pyridine-3 -carboxylic acid. T, pl. 170-172 ° C;
    c) 1, 4-dihydro-2,6-dimethyl-4- (2,3- - d-esphenyl) -5- (3-methyl-1 2,4-oxadiazol-5-yl) 2-iso-propoxyethyl ether ) -pyridine-3-carboxylic acid. T. pl. 147-149 ° C;
    t) 1,4-dihydro-2,6-dimethyl-4- (2, 3-dichlorophenyl) -5- (3-methyl-1,2,4-yxadiazol-5-yl) -pyridine-3- butyl ether carboxylic acid. T. pl. 221-223 ° C (p-butanol, 85 s);
    s) 1,4-dihydro-2,6-dimethyl-4- (3-cyanophenyl) -5- (3-methyl-l, 2,4-oxadiazol-5-yl) -pyridine-2-methoxy-ethyl ester; 3-carboxylic acid. M.p. 175-178 ° C;
    f) 2-methoxy-ethyl ester 1,4-dihydro-2,6-dimethyl-4- (2, 3-dimethoxy-phenyl) -5- (3-methyl-1,2,4-oxadiazole-5phenyl) - 5- (1,3,4-oxydiazol-2-yl) -pyridine-3-carboxylic acid. M.p. 205-207 ° C;
    y) 1,4-dihydro-25 2,6-dimethyl-4- (3-nitrophenyl-5- (1, 3, 4-oxadiazol-2-yl) pyridine-3-carboxylic acid isobutyl ester). T Pl. 213-215 0 (i-butanol,);
    y) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (2-aminecarbonyl-methylthio-1,3,4-oxadiazol-5-yl) -pyridine- methyl ester 3-carboxylic acid. M.p. 246-248 ° С (dioxane, temperature of reflux);
    yl) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (2-aminocarbonylmethylthio-1,3,4-oxa-diazol-5-yl) pyridine- 3-carbon
    thirty
    35
    40
    acids, so pl. 216-218 C (methanol, reflux temperature);
    Example 2. Hydrochloride of 2-dimethylamino-ethyl ester of 1,4-dihydro-2,6-dimethyl-4- (2,3-dichloro-45 phenyl) -5- (3-metth-1,2,4-oxadiazole- 5-yl) pyridin-3-carboxylic acid.
    5 g of the compound of Example 1 (p) is dissolved in 30 ml of hot isopropanol. To the still hot solution, 5 ml of the saturated methanolic hydrochloric acid solution are carefully added. The mixture is brought to room temperature with stirring, it is stirred for another 1 hour and the precipitate is filtered off with suction. T. pl.
    50
    55
    225 ° C (with decomposition), yield 4,2 g
    ABOUT
    Calculated: C 9,8; C1 21.8.
    Found: C, 51.5; 9.9; C1 21.9.
     H 5.1; N 11.5; H 5.3; N 11.3;
    Dihydro-2,6-dimethyl-4- (2,3-dimethoxyphenyl) -5- (1,3,4-oxydiazol-2-yl) - pyridine-3-carboxylic acid. M.p. 205-207 ° C;
    y) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl O-5- (1,3, 4-oxadiazol-2-yl) -pyridine-3-carboxylic acid isobutyl ester). T. pl 213-215 0 (i-butanol,);
    y) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (2-aminecarbonyl-methylthio-1,3,4-oxadiazol-5-yl) -pyridine- methyl ester 3-carboxylic acid. M.p. 246-248 ° С (dioxane, temperature of reflux);
    yl) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (2-aminocarbonylmethylthio-1,3,4-oxa-diazol-5-yl) pyridine- 3-carbon
    40
    acids, so pl. 216-218 C (methanol, reflux temperature);
    Example 2. Hydrochloride 2-dimethylamino-ethyl ester 1,4-dihydro-2,6-dimethyl-4- (2,3-dichloro-5 phenyl) -5- (3-metth-1,2,4-oxadiazole- 5-yl) pyridin-3-carboxylic acid.
    5 g of the compound of Example 1 (p) is dissolved in 30 ml of hot isopropanol. To the still hot solution, 5 ml of the saturated methanolic hydrochloric acid solution are carefully added. The mixture is brought to room temperature with stirring, it is stirred for another 1 hour and the precipitate is filtered off with suction. T. pl.
    0
    five
    225 ° C (with decomposition), yield 4,2 g
    ABOUT
    Calculated: C 9,8; C1 21.8.
    Found: C, 51.5; 9.9; C1 21.9.
     H 5.1; N 11.5; H 5.3; N 11.3;
    Example 3, 2-Methoxy-ethyl ester, 4-dicydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazol-2-yl) -pyridin-3-carboxylic acid . §
    3.02. g of 3-nitrobenzaldehyde, 3.18 g of aminocrotonic acid 2-methoxy-ethyl ester and 2.52 g of 2-acethos1-1,3,4-oxadiazole are heated for 5 hours to boil in 30 ml of ethane-10 la After cooling, the solid is stripped and recrystallized from ethyl acetate. After repeated recrystallization from ethanol, 2.3 g of a solid are obtained.
    3-carboxylic acid. T. pl. 214-216 C (methanol, 50 s);
    h) 1,4-dihydro-2,6-dimethyl-4- (3-methoxyphenip) -5- (5-methyl-1,2,4-oxydiazol-3-yl) pyridine-3 isopropyl ester - carboxylic acid. T. pl. 180-182 C (isopropanol, reflux temperature);
    i) 1,4-DIGIDRO-2,6-dimethyl-4- (3-methylphenyl) -5- (5-methoxymethyl-1,2,4-oxadiazol-3-yl) pyridine ester ethyl ester 3-carboxylic acid. T. pl. 165-168 S.
    15
    M.p. 208 C.
    Calculated: About 24.0.
    Found: C About 23.8.
    Similarly
    C 57.0; H 5.0; 56.7; H 5.2; N
    The following compounds can be prepared, with deviating reaction temperatures and other solvents enclosed in brackets: a) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1, 3,4- oxadiazol-2-yl) pyridin-3-carboxylic acid. T. pl. 266-268 ° C (methanol, room temperature);
    a) 1,4-dihydro-2,6-dimethyl-4- (5-nitrophenyl) -5- (5-N 1.0; benzyl-1,2,4-oxadiazol-3-yl) -pyri isobutyl ester -:
    din-3-carboxylic acid. T. pl. 14.3; 201-203 C (i-butanol,);
    20 2-metroxypropyl ester 1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -5- (3-methyl-1,2,4-thiadiazol-5-yl) pyridine-3-carboxylic acid. T. pl. 185-188 s (isopropanol, temperature 25 reflux);
    m) 1,4-dihydro-2,6-dimesh1-4- (3-cyanophenyl) -5- (3-methylthio-, 2,4-thiadiazol-5-yl) -pyridin-3 p-butyl ester -carboxylic acid. M.p. 170h) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5g (1,3-4-oxadiazol-2-yl) -pyridine-3-carboxylic acid isopropyl ester. T. pl. 190- (isopropanol, 40 ° C).
    b) 1,4-dihydro-2,6- 30 172 ° С methyl ester (butanol, 80 °); dimethyl-4- (3-nitrophenyl) -5- (5-methyl1, 3,4-oxadiazol-2-yl) pyridine-3-carboxylic acid. M.p. 267-269 ° C (methanol, room temperature);
    c) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid methyl ester. T. pl. 260-262 ° C (methanol, reflux temperature);
    d) 1,4-40 dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (5-methyl-, 3,4-oxadiazole-2-sh1) 2-methyloxyether ether 1, 4, 40; pyridine -3-carboxylic acid. T. pl. 234-236 0 (diethyl ether, rooms45
    on temperature);
    d) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) -pyridine-3 methyl ester methyl ester -carboxylic acid. T. pl. 238-240 ° C (dibutyl ether,);
    e) 1,4-dihydro2,6-dimethyl-4- (3-trifluoromethylphenyl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) pyridine-3-.carboxylic acid methyl ester .T. square 207-208 C (methanol, reflux temperature);
    g) 1,4-dkgidro2, 6-dimetsI-4-t 2-chlorophenyl) -5- (5-methyl-l, 2,4-oxadiazol-3-yl) methyl ester). pyridine50
    55
    o) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophensh1) -5- (1Z3, 4-oxadiazol-2-yl) -pyridine-3-carboxylic acid 2-methoxyethyl ester. T. pl. 168- (dimethoxyethane, 75 s);
    p) 1,4-dihydro-2,6-dimethyl-4- (2-dichlorophenyl) 2-methoxyethyl ester; 5r- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid; . M.p. 173-175 ° C (dimethoxyethane 75 s);
    p) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3, 4-oxadiazol-2-yl) pyridine-3-carboxylic acid neopentyl ester. T. pl. 19b-198 C (toluene, PO);
    c) 1,4-dihydro-2,6 dimethyl-4- (3-nitrophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) pyridine-3-carboxylate methyl ester acid. T. pl. 145-147 ° C (isopropanol, reflux temperature);
    t) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) methyl ester; -5-., (3-benzyl-1,2,4-oxadiazole-5-sh1) 3-carboxylic acid. T. pl. 214-216 C (methanol, 50 s);
    h) 1,4-dihydro-2,6-dimethyl-4- (3-methoxyphenip) -5- (5-methyl-1,2,4-oxydiazol-3-yl) pyridine-3 isopropyl ester - carboxylic acid. T. pl. 180-182 C (isopropanol, reflux temperature);
    i) 1,4-DIGIDRO-2,6-dimethyl-4- (3-methylphenyl) -5- (5-methoxymethyl-1,2,4-oxadiazol-3-yl) pyridine ester ethyl ester 3-carboxylic acid. T. pl. 165-168 S.
    n) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5g (1,3-4-oxadiazol-2-yl) pyridine-3-carboxylic acid isopropyl ester. T. pl. 190- (isopropanol, 40 ° C).
    0 172 ° C (butanol, 80 °);

    0
    five
    0
    five
    o) 1,4-dihydro-2,6-dimethyl-4- (2-nitrophensh1) -5- (1Z3, 4-oxadiazol-2-yl) -pyridine-3-carboxylic acid 2-methoxyethyl ester. T. pl. 168- (dimethoxyethane, 75 s);
    p) 1,4-dihydro-2,6-dimethyl-4- (2-dichlorophenyl) 2-methoxyethyl ester; 5r- (1,3,4-oxadiazol-2-yl) -pyridine-3-carboxylic acid; . M.p. 173-175 ° C (dimethoxyethane 75 s);
    p) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3, 4-oxadiazol-2-yl) pyridine-3-carboxylic acid neopentyl ester. T. pl. 19b-198 C (toluene, PO);
    c) 1,4-dihydro-2,6 dimethyl-4- (3-nitrophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) pyridine-3-carboxylate methyl ester acid. T. pl. 145-147 ° C (isopropanol, reflux temperature);
    t) 1,4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) methyl ester; -5-., (3-benzyl-1,2,4-oxadiazole-5-sh1)
    pyridine-3-carboxylic acid. Mp, 205-207 0 (isopropanol, reflux temperature);
    s) 1,4-dihydro-2,6 dimethyl-4- (2-nitrophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) pyridine-3-carboxylate methyl ester acid. T. pl. 189- (isopropanol, reflux temperature);
    f) 1,4-dihydro-2,6-dimethyl-4- {3-trifluoromethyl-phenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) methyl ester.) pyridine-3-carboxylic acid. M.p. 179-181 ° C (isopropanol, reflux temperature);
    x) 2-methoxyethyl ester 1,4-dihydro-2,6-dimesh-1-4- (3-nitrophenyl) 5- (3-benzyl-1,2,4-oxadiazol-5-yl) - pyridine-3-carboxylic acid. M.p.
    108-111 s (simple ethylene glycol mono methyl ether,);
    | c) 1,4-dihydro-2,6 dimethyl-4- (2-chlorophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) -pridine-3-carboxylic acid methyl ester . T. pl. 143-145 ° C (isopropanol, reflux temperature);
    h) 1,4-dihydro-25b-dimethyl-4- (2,3-dichlorophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) -pyridine- 2-methoxyethyl ester 3-carboxylic acid. T. pl. 101-103 s (isopropanol, reflux temperature);
    x) isopropyl ester 1., 4-dihydro-2,6-dimesh-1-4- (pyrid-3-yl) -5- (3-benzyl-, 2,4-oxadiazol-5-yl) -pyri- din-3-carboxylic acid. T. pl. 157-160 ° C (isopropanol, reflux temperature);
    y) 2-isopropoxyethyl ether 15 4-dihydro-2,6-dimethyl-4- (2,3-dichlorophenyl) -5- (2-methyl-1,3,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid. T. pl. 163-165 C (dibutyl ether, 80 ° C);
    y) 1,4-dihydro-2,6-dimethyl-4- (2, 3-dichlorophenyl) -5- (1,3,4-oxadiazole-2-sh1) pyridine-3-carboxylic acid isopropyl ester . T. pl. 166-168 ° C (isopropanol, reflux temperature);
    4l) 1,4-dihydro-2,6-dimethyl-3,5-di- (1,3,4-oxadiazol-2-yl) -4- (3-nitrophenyl) -pyridine. M.p. 254-256 0 (methanol, reflux temperature);
    y h) 1,4-DIHIDRO-2,6-dimethyl-3,5-di- (5-methyl-1,2,4-oxadiazol-3-yl)
    0
    five
    0
    five
    0
    five
    4- (p-toluene) -pyridine. M.p. 304-306 ° C (isopropanol, 30 ° C);
    Yi ij) 1,4-dihydro-2,6-dimesht-3,5-di (3-methyl-1,2-4-diadiazol-5-nl) -4- (2, 3-dichlorophenyl) -pyridine. T. pl. 231-233 s (methanol, reflux temperature).
    Edj) 1,4-dihydro-2,6-dimethyl-3,5-di (5-methoxymethyl-1,2,4-oxadiazol-3-yl) -4- (2-trifluoromethylphenyl) -pyridine. T. pl. 196-198 C (methanol, reflux temperature);
    u (,) 1,4-DIHIDRO-2,6-dimethyl-3,5-di- (3-benzyl-1,2,4-oxadiazol-5-sh1) - 4- (pyridin-2-yl) - pyridine. T. pl. 248-249 ° C;
    y,) 1,4-dihydro-2,6-dimethyl-3,5-di- (4-methyl-5-ethoxycarbonyl-1,3-thiazol-2-yl) -4- (3-nitrophenyl) -pyri - din. T. pl. 227-229 s.
    Example 4. 1,4-DIHIDRO-2,6-dimethyl-4- (3,5-dichlorophenyl) -5- (3-ethyl-1,2,4-oxadiazol-5-yl) 2-methoxyethyl ester pmridine-3-carboxylic acid.
    0.93 g of 3-ethn-1-5-acetonyl-1,2,4-okadiazole, 0.96 g of methoxyethyl ester / s-aminocotocic acid and 0.95 g of 3.5-dichlorobenzaldehyde are heated for 8 hours at reflux temperature in 30 ml of isopropanol. After concentration, the oily residue is dissolved with diethyl ether, and crystallization gradually begins. The solid is filtered off with suction and recrystallized from isopropanol. Output 1.7 g, so pl. 178-180 C.
    Calculated: C 55.9; H 4.9; N 9.3; O 14.2; C1 15.7.
    Found: C 56.1; H 5.1; N 9.1; O 14.0; C1 15.5.
    The following compounds can be prepared in a similar way, with deviating reaction temperatures and other solvents enclosed in brackets:
    a) 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (3-ethyl-1,2,4-oxadiazol-5-yl) -pi 2-methoxyethyl ester 0 reedin-3-carboxylic acid. M.p. 206-208 ° C;
    6} 1,4-dihydro-2,6-dimethyl-4- (2, 3-dichloro-NILE) -5- (3-ethyl-1,2,4-oxadiazole-5-s 2-methoxyethyl ester yl) -pyridin-3-carboxylic acid. T. pl. 153-155 “C;
    c) 1,4-dihydro-2,6-dimethyl-4- (2, 3-dichlorophenyl) -5- (3-ethyl-1,2,4-oxadiazol-5-yl) -pyridine 5 methyl ester
    0
    R
    3-carboxylic acid. T, pl. 190-192 ° C (methanol, reflux temperature);
    d) 2-methoxyethyl ether 1, A-di-: hydro-2/6-dimethyl-4- (4-nitrophenyl) -5- (3-ethyl-1,2,4-ok sadiazo L-5-IL) - pyridine-3-carboxylic acid. T
    square 171-173 ° C;
    d) 1,4-dihydro-2,6-dimethyl-4- (2,4-dichlorfe-1 NILE) 2-methoxyethyl ester 1 -5) -5- (3-ethyl-1,2,4-oxadiaeol-5- yl) -pyridin-3-carboxylic acid.
    T. pl. 165-167 0;
    (e) 1,4-dihydro-2, 6-dimethyl-4- (3,4-di-1-sphe-phenyl) -5- (3-ethyl-1-1,2,4-oxadiazol-5-yl) -pyridine- 2-methoxyethyl ether 3-carboxylic acid. T. pl. nS-lSO C;
    g) 1,4-dihydro-2,6-dimethyl-4- (3-bromophenyl) -5- (3-ethyl-1,2,4-oxadiazole-5-sh1) -pi-2-methoxyethyl ester Ridin-3-carboxylic acid. T. pl. 184-186 0;
    h) 1,4-dihydro-2,6-dimethyl-4- (2,5-dimethylphenyl) -5- (3-ethyl-G, 2,4-oxadiazole-5-Sh1) - 2-methoxyethyl ether pyridine-3-carboxylic acid.
    T. pl. 157-159 0;
    and 1,4-dihydro-2,6-dimethyl-4- (2-chloro-6-nitrophenyl) -5 2-methoxyethyl ester: (3-ethyl-1,2,4-oxadiazole. 5- yl) -pyridin-3-carboxylic acid. T. pl. 162-164 ° C;
    k) 2-methoxyethyl ester 1,4-di-: hydro-2 6-dimethyl-4- (3-nitrophenyl) - .. 5- (2-ethyl 1-1,3,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid. T. pl. 224-22b C;
    l) 1,4-dihydro-2,6-ymetsh-1-4- (3-nitrophenyl) -5- (2-ethy-1-1,3,4-oxadiazol-5-yl) -pyridine-3-carboxylic acid methyl ester . T. pl. 236-23 C (dimethoxyethane, reflux temperature) ;;
    m) 1,4-ihydro-2,6-, 1 -methyl-4- (2,3-dichloro- fide) -5- (2-eth1-w-1,3,4-oxadiazole-5- 1) -pyridine-3-carboxylic acid. . square 166-I) 8 C;
    n) 1,4-dihydra-2,6-dimesh1-4- (3-nitrophenyl) -5- (2-ethyl-1,3,4-oxadiazol-5-yl) pyridine isobutyl ester
    :

    .
    ;: ..
    -
    36058510
    3-carboxylic acid. T. pl. 204- (Isobutanol, 80 ° C);
    o) 2- (K-benzyl-N-methylamino) -ethyl-1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (1,3,4-oxadiazole) ester 2-Sh1) -pyridin-3-carboxylic acid. T. pl. 166-168 ° C;
    p) 1,4-dihydro-10 2,6-dimethyl-4 (3-nitrophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) pyridine-3 isobutyl ester carboxylic acid. T. pl. 121- (Isobutanol, 80 C);
    p) 1,4-dihydro-15 2,6-dimethyl-4- (3-nitrophenyl) -5- (3-benzyl-1,2,4-oxadiazol-5-yl) pyridine-3 tert-butyl ether -carboxylic acid. T. pl. 131-133 ° C (t-butnol, 80 s);
    c) 1,4-di-20-hydro-2,6-dimethyl-4- (3-nitrophenyl) -5- (5-1-propylthio-1,3,4-oxadnazol-2-yl) -cyclohexyl ester; pyridine-3-carboxylic acid. T. pl. 189-191 С (chlorobenzene, 95 ° С);
    The antagonic action relative to calcium of compounds of general formula 1 was determined by the following method.
    Spiral-shaped strips of the pulmonary artery of a guinea pig after equilibrating 30 hangings in calcium-free
    Tyrode solution was depolarized with 40 mmol of potassium. Then add 0.5 mmol of calcium chloride
    caused a reduction strips. Then, the 2g relaxing effect of the test substance was calculated by cumulative stepwise administration of concentrations at 1/2 log 10.
    From the concentration effect curve 40 (on the abscissa: log mol / l of the test substance, on the ordinate:% inhibition of the maximum contraction, average of the contraction of 4-6 strips. Vessel)
    The concentration of the test 4g substance that suppresses a 50% reduction (ICj, mol / l) is calculated. Table 1 shows the corresponding values of 1C 50 When comparing the value of 1C jo
    50
    3-10 of the known nephedipine compound (1,4-dihydro-2,6-dimethyl-4- (2-nitrophenyl) -pyridine-3,5-di- (carboxylic acid) methyl ester), it is clear that the compounds of the general formula more active than nephedipine.
    Continuation of table 2
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining substituted 1,4-dihydropyridines of the general formula
    where N - CO-gKz or K i
     - phenyl, nitrophenyl, chlorophenyl, methoxyphenyl, cyanophenyl, trifluoromethylphenyl, mets1fensh1, bromophenyl, dichlorophenyl, dimethoxyphenyl, dimethylphenyl, chloronitrophenyl, pyridyl, nitrothienyl;
    RJ is 1,2,4-oxadiazolyl-5, substituted in position 3 by C -C-alkane or benzyl, 1,2,4-oxadiazol-1-3.
    substituted in position 5 by methyl, methoxymethyl, benzyl, 1,3,4-oxadia30ilyl-2, unsubstituted or substituted in position 5 by C -C-alkyl, aminocarbonylmethylthio, isopropylthio, 1,2,4-thiadiazolyl-5, substituted in positions 3 by methyl or methylthio
    or R.,
    R - With, -C, -alksh1, apkoxyalkyl with
    the total number of carbon atoms from 3 to
    6, cyclohexyl, dimethylaminoethyl,
    N-methyl-N-benz ilamino ethyl,
    R4 is 1,3,4-oxadiazolyl-2, 5-methyl-1,2,4-oxadiazol-3-3, 5-methoxy-methyl-1,2,4-oxadiazolyl-3, 3-beieyl-1, 2,4-oxadiazolyl-5,3-met l-1,2,4
    thiadiazolyl 5, 4-methyl-5-ztox carboxy-1, 3-thiazolyl-2,
     acid addition salts.
    characterized in that 1 mole of the compound} of the general formula
    H3C-COCHj-R2,
    where Rj has the indicated meanings, is reacted with 1 mole of aldehyde of the general formula
    ,
    where R has the indicated meanings, and with 1 mole of the compound of the general formula
     HjC - C g CHR G
    Well
    where R has the indicated values, in an organic solvent at temperatures from room to the boiling point of the solvent, followed by isolation of the desired product in a bold form as an acid addition salt.
    Compiled by G.Gul eva Editor Yu, Sereda Tehred M.Hodanich Proofreader I.Musk
    Order 6166/57 Circulation 372Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, Projecto st., 4
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    同族专利:
    公开号 | 公开日
    AU2253383A|1984-06-28|
    KR840006969A|1984-12-04|
    PL245200A1|1985-02-27|
    CS961383A2|1985-07-16|
    FI834451A|1984-06-21|
    HU194556B|1988-02-29|
    DK562683D0|1983-12-06|
    AU562583B2|1987-06-11|
    FI834451A0|1983-12-05|
    EP0116708B1|1986-05-14|
    GR79484B|1984-10-30|
    ES8406193A1|1984-08-01|
    ES528175A0|1984-08-01|
    CS241144B2|1986-03-13|
    DE3247118A1|1984-06-20|
    CA1194480A|1985-10-01|
    AT19776T|1986-05-15|
    DD215548A5|1984-11-14|
    EP0116708A1|1984-08-29|
    PL140526B1|1987-05-30|
    DK562683A|1984-06-21|
    PH20327A|1986-12-02|
    ZA839382B|1984-08-29|
    US4558058A|1985-12-10|
    NO834480L|1984-06-21|
    DE3363545D1|1986-06-19|
    JPS59118783A|1984-07-09|
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    法律状态:
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