• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel compounds having vasodilation and hypotensive effects are represented by the formula where R' is halogen, nitro, cyano or lower alkoxy; each of R2 and R3 is lower alkyl, lower haloalkyl, lower alkoxyalkyl, aralkyloxyalkyl, aryloxyalkyl, lower alkenoxyalkyl, N,N-di-lower alkylaminoalkyl, N-lower alkyl-N-aralkylaminoalkyl, piperidylalkyl, 4-lower alkyl piperazinylalkyl, norpholinoalkyl or 1-pyrrolidinylalkyl; R' is lower alkyl; A is lower alkylene; and R5 is hydrogen, lower alkyl, cycloalkyl of 3 to 7 carbon atoms, or aryl unsubstituted or substituted by one or two substituents selected from halogen, nitro, lower alkyl, lower alkoxy, di-lower alkylamino and cyano. Also disclosed are processes for their preparation.
    公开号:SU1097195A3
    申请号:SU823425004
    申请日:1982-04-22
    公开日:1984-06-07
    发明作者:Мияно Тецудзи；Сузуки Кунио；Нарада Нобуо
    申请人:Баниу Фармасьютикал Ко.,Лтд (Фирма)；
    IPC主号:
    专利说明:

    f10 The invention relates to a process for the preparation of new derivatives of 2-aminocarbonyloxyalkyl-1, 4-dihydropyridine of the general formula RjjOOC where R is nitro or 2-cyano, 2-chloro, 2-low, p1Iy alkoxy; each of Rj and Rj is lower alkyl, lower alkoxy (C ,, -C) -alkyl, lower chloralkyl, phenyloxy () -alkyl, phenyl () alkyloxyCC-C U-alkyl, lower alkenoxy () -alkyl; methyl; methylene; hydrogen, lower alkyl, hexyl cycle, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, which can be used in chemical and pharmaceutical industry. 3.5-dimethyl ester 2,6-dimethyl-4- (2-nitrophenyl) is known 1, 4-dihydropyridine-3, 5-dicarboxylic acid (nifedipine), which has vasodilating activity and hypotensive action. C J However, the toxicity of this compound is LDcg 11.5 mg / kg. It is also known to use in medical practice the drug papaverine with a vasodilating effect 2. The drug in high doses reduces the excitability of the heart muscle and slows intracardiac conduction. A known method for the preparation of various aminocarbonyloxyalkyls (urethan by reacting compounds with an oxyalkyl group with isocyanates. The reaction is usually carried out in an inert solvent at room temperature or, if necessary, with heating or cooling. To obtain unsubstituted aminocarbonyl oxides, an additional reaction product with a labile amide bond is obtained This is done by hydrolyzing the NW. The aim of the invention is to obtain new compounds with less toxicity and better vasodilating properties. Since the objective is achieved by the method of producing 2-aminocarbonyloxyalkyl-1,4-hydropyridine compounds of the formula (I) 2-oxyl-1, 4-dihydropyridine of the general formula COOR, where the radicals and A have the indicated meanings, is subjected to reaction with the isocyanate of the general formula Kb - NCO (III) where Rg is chlorosulfonyl, lower alkyl, cyclohexyl, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, and the desired product is isolated or hydrolyzed if necessary. The starting compounds are known or may be. easily obtained by known methods. The reaction conditions are selected depending on the nature of the specific reagents used. Usually, the isocyanate of formula () is used in an amount of 1-5 mol, preferably in an amount of: 1-2 mol per 1 mol of 1,4-dihydropyridine of formula (II). The reaction is carried out with cooling, at room temperature or with heating. Benzene, toluene, chloroform, dichloromethane, chlorobenzene, dioxane, tetrahydrofuran, diethyl ether, acetonitrile, pyridine, dimethylformamide, ethyl acetate, or acetone can be used as the solvent used in the reaction. The reaction may preferably be carried out in the presence of a catalyst. As a catalyst, a tertiary amine can be used, such as triztilamine, trimethylamine, N-alkylpiperidine, N-alkylmorpholine; N, N-dialkylaniline or pyridine, or sodium hydroxide, sodium carbonate or sodium hydrogencarbonate. In that case, if chlorosulfonyl isocyanate is used as isocyanate, it is necessary to hydrolyze the product by adding water to the reaction mixture after completion of the reaction. Compounds of formula (I) can be cleared and isolated using lime
    methods such as Exraction treatment using an organic solvent, chromatography using silica gel or alumina or crystallization. In that case, if the resulting compounds are capable of forming a salt, they can be converted to the corresponding salts by using an inorganic acid, such as hydrochloric acid, or an organic acid.
    The compounds of formula (T) are low toxic and possess vasodilating and hypotensive activity. In particular, these compounds have a strong activity on the expansion, veins.
    Preparation of starting 4- (3-nitrophenyl) -2- (hydroxymethyl-6-methyl-3-ethoxycarbonyl-5- ((1-ethoxyetrxy; carbonyl 1, 4-dihydropyridine.
    4.5 g of were-nitrobenzaldehyde, 5.5 g of | e-of -toxy ethyl acetoacetate and 0.4 ml of pyridine were dissolved in 30 ml of benzene and the resulting mixture was refluxed by heating for 4 hours under azeotropic dehydration. After cooling, the reaction mixture is washed with water, dried and concentrated under reduced pressure to distill off the solvent.
    The oily residue and ethyl-4,4-dimethyl xi-3-aminocrotonate (5.7 g) are dissolved in 30 ml of ethanol and the mixture is stirred for 8 hours at. After cooling the reaction mixture, the solvent was separated by distillation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract is washed with water and dried, then concentrated under reduced pressure to distill off the solvent. The oily residue is separated and purified by chromatography on a column filled with silica gel using a mixture consisting of hexane and ethyl acetate in a ratio of 8; 5 as eluent. An oily yellow product is obtained that is 4- (3-nitrophenyl) -2-dimethoxymethyl-6-methyl-3-ethoxycarbonyl 5- ((L) ethoxy-ethoxy) carbonyl-1,4-dihydropyridine in an amount. 8.95 g.
    This yellow oily product is dissolved in P acetone (100 ml), 6N.
    954
    hydrochloric acid was added in an amount of 20 ml, and the mixture thus obtained was reacted with stirring for 5 hours at room temperature. The reaction mixture is neutralized with acidic sodium carbonate to pH 7, the acetone is removed by concentration under reduced pressure, and the residue is extracted with ethyl acetate. The extract obtained is washed with water, dried and concentrated under reduced pressure to distill off the solvent. The residue (aldehyde compound) is dissolved in 20 ml of ethanol, then 860 ml of sodium borohydride is added with stirring, and the mixture is stirred for 1 hour. The reaction mixture is adjusted to pH 4 by addition of 1N hydrochloric acid and then the reaction mixture is concentrated under reduced pressure. The residue is extracted with ethyl acetate and the extract is washed with water, dried and concentrated under reduced pressure to distill off the solvent. The residue obtained is purified by chromatography on a column filled with silica gel using a solvent which is a mixture consisting of hexane and ethyl acetate in a 1: t ratio. The result of 4.2 g of 4- (3-nitrophenyl) -2-hydroxymethyl-6-methyl-3-ethoxycarbonyl-5- (D) -ethoxyethoxy) carbonyl-1,4 dihydropyridine in crystalline form.
    Ultraviolet spectrum (in MeOH): Yamax 236.356 nm.
    Preparation of 4- (3-nitrophenyl) -2-hydroxymethyl-6-methyl-3-methoxycarbonyl-5 (-chloroethoxy) carbonyl-1,4-di1-hydropyridine.
    4.5 g of meta-nitrobenzaldehyde, 5 g / J-chloroethyl acetoacetate, 0.2 ml of piperidine and 0.2 ml of glacial acetic acid are dissolved in 30 ml of benzene and the mixture is refluxed under heating for 4 hours under azeotropic dehydration conditions. . The reaction mixture is then washed with water, dried and concentrated under reduced pressure to distill off the solvent. The residue and 5.5 g of methyl 4,4-dimethyl-3-aminocrotonate thus obtained in an amount of 5.5 g are dissolved in 50 ml of propanol and stirred for 8 hours at. The solvent is distilled off and the reaction mixture is mixed with 50 ml of acetone. After removing the insoluble materials by filtration, 10 ml of 6 and hydrochloric acid are added to the filtrate and the resulting mixture is reacted for It h with stirring and at room temperature. The reaction mixture is then neutralized with sodium hydrogencarbonate and the solvent is distilled off. The resulting residue is extracted with ethyl acetate and the extract is washed with water and dried. The solvent was distilled off, the oily residue was dissolved in 50 ml of ethanol, 1.3 g of sodium borohydride was added with cooling and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 4 and concentrated. The residue is extracted with ethyl acetate. The extract is washed with water, dried and concentrated. The resulting residue is separated and purified on a column filled with silica gel using a mixture of hexane: ethyl acetate in a 1: 1 ratio. The result is 6.8 g of 4- (3-nitrophenyl) -2-hydroxymethyl-6-methyl-3-methoxycarbonyl-5-C-chloroethoxy) carbonyl 1,4-dihydropyridine in crystalline form. Infrared Spectrum (KBG), 3380, 2940, 1670, 1530, 1470, 1350, 1210, 1100, 900.780, 740, 705. 10. Example 1. Preparation of 2-aminocarbonyloxymethyl-6-methyl-4- (2-nitrophenyl) -3,5-diethoxycarbonyl-1,4-dihydropyridine (compound 1). 2-Oxymethyl-6-methyl-4- (nitrophenyl) 3, 5-diethoxycarbonyl-1,4-dihydropyridine (390 mg) is dissolved in benzene (10 ml). Then chlorosulfonyl isocyanate (O, 2. ml) is added to this mixture and stirred for 30 minutes at room temperature. After that, while cooling, 10 ml of water is added and stirred for 30 minutes at room temperature for hydrolysis. The reaction mixture is extracted with ethyl acetate and the extract is concentrated under reduced pressure. The resulting residue is recrystallized from ethyl acetate-hexane. Obtain crystals in the amount of 210 mg (48.5%) with so pl. 128-132 ° C. Ultraviolet spectrum (in MeOH): Dutax 235.350 nm. The infrared spectrum (KBG), 3540, 3400, 3000, 1710, 1690, 1535, 1495, 1340, 1205, 1120, 1100, 1095. In a similar way, compounds 2-6 are obtained as indicated in Table. one.
    RgOOC
    Iff02
    Table 1
    COOR:
    bNz- SNGOSo
    34 110-114. 235,355
    sn
    ck
    3 CjHj
    63 144-148 235,355
    3540,3360,2980,1715,
    01690,1495,1355,1340,
    1210,1105,1090,830,
    805,790,755,710
    3340,3380,3000,1710,
    1690,1490,1355,1335,
    1210,1105,1090,790,
    / 60,720
    INSPIRED SOOVZ
    Sch J CHgOCOHHK,
    1685, 1480, 1355, 1280, 1205, 1105, 790, 760, 720 nOZIQZriZiE-TI 9 CHj 39 151-153 10 (CHj) - CHj 26 194-196 11Cl (CHj) 2 CHj CHj 72 194-195 12 (CHj ), -. C2H5. 78 153 13 (CH). - With Hj. С H 90 150,5PH1 S7 U (CH,) - C-H ,. C, H 62 157ГН 3 n 1SQ S 15 (CHj) - 71,134-136. 16 (CH), j-,. 4-SbH 1 70,113,116.5 17 CHj 4-CjH4C165 2 --- 235, 335 3350, 2950, 1700.1685, 1530, 1480, 1350.1210, 1096, 780, 705 235.355. 3380, 3290, 2980, 1680,. 1525, 14iBO, 1350,1275,. 1250, 1205, 1100,780, 715 236.355 3400, 3300, 2960.1690, 1640, 1610, 1530.1480, 1.350, 1280, 1260.121010, 1110, 905, 830.780, 760, 715 235.355 3350, 2980, 1685, 1530, 1480, 1350, 1275.1250, 1205, 1095, 780.715 235.355 3350, 2980, 1685.1530, 1480, 1355, 1270.124040, 1207, 1100, 780.715 235.355 3350, 2940, 1680.1530, 1480, 1350, 1275.1207, 1095, 780, 710 238.356 3350, 2980, 1685.1530, 1480, 1350, 1205.1100, 740, 710, 690 235.1530, 1380, 1680, 1695.1530, .1350, 1220, 1100.825 740, 705 243.355 3400, 3000, 1750.1690, 1670, 1600, 1530.1480, 1350, 1220, 1100.900, 805, 750, 700
    eleven
    Example 3. Preparation of 2-amino carbonyloxymethyl-6-methyl-4- (3-nitro-enyl) -3-ethoxycarbonyl-5- ((S-ethoxy-ethoxy) carbonyl-1,4-dihydropyridine (compound 18).
    To a solution of 420 mg of 2-hydroxymethyl-6methyl-4- (3-nitrophenyl) -3-ethoxycarbyl-5- (1-ethoxyethoxy) carbonyl-1,4-dihydropyridine in 20 ml of benzene was added 0.2 ml of chlorosulfonyl isocyanate. The resulting mixture was reacted with stirring for 30 minutes at room temperature. Add 10 ml of water to the reaction mixture while cooling and stir at room temperature for 30 minutes to hydrolyze. The resulting re09719512
    the mixture is extracted with ethyl acetate and the extract solution is washed with water, dried and then concentrated under reduced pressure. The residue 5 is subjected to recrystallization from a mixture of diisopropyl zfir-hexane. Get crystals in the amount of 290 mg (62.5%) with so pl. 135-138 ° C.
    Ultraviolet spectrum (in Meon):
    0 «« N0 236, 355 nm.
    Infrared spectrum (KVg), cm: 3520, 3360, 2990, 1705, 1690, 1645, 1610, 1525, 1485, 1350, 1205, 1120, 1105, 1085, 905, 830, 780, 755, 720.
    Compounds 19-32 are prepared analogously (Table 3).
    Table 3 19 S-rNOj S-NOj i-C-jH OCH CH 65 139. CHjCH OCH SZ 121-125 a-NGjCjHj 71 147149 236.355 3520.3350.2950, 1700, 1645.1610.1520, 1480, 1350.1330.12270, 1200, 1120.1100.1080, 905, 830.780, 755, 720 142 235.355 3520.3360,2980, 1702, 1685,1645,1610, 1525 1485.1350.1330, 1270, 1200.1120.1080, 900, 825.780, 755, 720 236.355 3480.3380.2990,1690, 1645, 1610, 1530, 1490, 1350, 1275, 1210, illO, 1095, 1080, 905, 830, 780, 755, 720 233-NO CH, CHCH S 135 OCH CH 243-N02 CgHyOCH - pu 253-N02 CgHjCH, OCH5-SHy 56 58 , 5 Cfj 263-NO С H OCH - CHjCH 83 91-99., „L27 3-NO CH OCH - CHjCH 76 110 OCH 1490, 1350, 1275, 1210, 1095, 905, 830, 780, 760, 715 36.355 3520 , 3360, 2990, 1705, 1485.1350.1330.12.1270, 1200.1120.1100.1080, 1000.920.900.825, 780.755.720 35.355 3480, 3420, 3360, 2950, 1710, 1690, 1615, 1600, 1530, 1490, 1350, 1335, 1250, 1200, 1125, 1080, 930, 915, 780, 755, 720, 690 36.355 3500.3360.2950.20, 1700.1685.164040.1610, 1530.1485.1350.1330, 1280, 1210.1120.1095 1085.905.830.780, 740.700 36.355 3510, 3400, 3330, 2960, 28 70, 1740, 1696, 1665, 1525, 1475, 1345, 1325, 1275, 1220, 1200, 1120, 1090, 1070, 1015, 905 830, 785, 755, 710 236,355 3500,3400, 3000,1690, 1640,1610 , 1530.1485, 1350.1330, 1280.1210, 1110.1095, 905.830, 780.755, 720 15109. 282-N02 ..-. 65 CH 294-NO / C, H OSI- C. H, 47 237 Z / e CH 302-CN CHjOCH -: CH2CH 65 CH OCHj 312-OCH CHjOCHj- 52 CH2. 322-C1 CHjOCHj-CKjCH - 72 CH OCH3. Example 4. Obtaining 2-Nmethylaminocarbonyloxymethyl-6-methyp4- (3-nitrophenyl) -3-ethoxycarbonyl-5 (/ 3-ethoxyethoxy) carbonyl-1,4-dihydropyridine (compound 33), To a solution of 420 mg of 2-hydroxymethyl-6methyl -4- (3-nitrophenyl) -3-ethoxycarbonyl-5- (4-ethoxyethoxy) carbonyl1, 4-dihydropyridine in 20 ml of benzene was added 0.1 ml of methyl isocyanate and 0.3 ml of triethylamine. The resulting mixture was reacted by diffluxing for 1 hour. After cooling, the reaction mixture was extracted with ethyl acetate and the extract solution 719516 continued. Table. 3j -. 20-126234,340 3400,2970,1710,1690, 640,1605, 1530,1490, 1335,1320, .1280,1205, 1110,1100, 1080, "60, 830,780, 755,710 17-121 233,280, 3500, 3400 , 3000, 1690,.,. 1640,1610,1530,1485, 1350,1330,1280,1210, 1110,1095,905,830, 780,755,720 62-166 235,365 3540, 3380, 3000, 2230, 1710,1690,1640,1605, 1490,1390,1335,1275 , 1200,1120,1090,1040, 940,840,775 235,355 3420, 3350, 2980, 1720, 1680, 1605, 1490, 1380, 1320, 1280, 1210, 1110, 1095, 860, 750 22-128 237,357 3420, 2980, 1705, 1685, 1640, 1605, 1490, 1385, 1370, 1330, 1280, 1205, 1110, 1100, 1080, 1040, 830, 755, rinse with water, dry, and then concentrate under reduced pressure. The residue is subjected to recrystallization from a mixture of: diisopropyl ether and hexane to obtain crystals in an amount of 200 mg (42%) with m.p. 148149 p. , Ultraviolet spectrum (in MeOH): t / "e" cs 236, 355 nm. Infrared Spectrum (KBG), 3390, 3280, 2980, 1680, 1640, 1610, 1535, 1480, 1355, 1280, 1205, 1120, 1095, 905, 830, 780, 760, 715. 3S Similarly, compounds 34-42 are obtained ( Table 4).
    17
    18
    Table 4 CHj 67 13634 CjH OCH2CH € 21) 5 j 65 119120152152 137 236,355 3380,3290,2970,1680, 1640,1610,1530,1480, 1350,1275,1200,11,120, .1100905,830,780, 760,715 122 235,355 3370, 2980,1680,1640, 1610,1530,1480,1350, 1275,1205,1120,1095, 905, 830, 780, 760, 156235,355 3370,3280,2980,1680, 1640,1610,1530,1480, 1350 , 1275.1205.1100, 905, 830, 780, 760, 236.355 3380.2980.1680.1640, 1610.1530.1485.1355, 1280.1205.1100, 910, 830, 780, 760, 715 120236.355 3350,3300,2960,2870, 1685,1635,1600, .1530, 1480,1350,1275,1250, 1200,1130,1100,1015, 990, 900, 830, 780o 760, 750, 710
    nineteen
    i ::: ii: i :::: ii :: tEiiia: Cj, H 61148-1 39 С, Н, 40 С2НуОСН2СН2 4-CgH Cl 67 14041 CHjCH42 CjH OCHjCH СН2СИ20Сз, 4-СНзС12бО 128H
    Example 5. Preparation of 2-Ncyclohexylaminocar, bonyloxymethyl-6methyl-4- (2-nitrophenyl) -3-ethoxycarbonyl-5-isopropyl-6 hydroxycarbonyl-1, 4-dihydropyridine (compound 14).
    2-Oxymethyl-6-methyl-4- (3-nitrophenyl) -3-ethoxycarbonyl-5-isopropoxy-g carbonyl-1,4-dihydropyridine (404 mg), methyl cyclohexyl-thiocarbamate (600 mg) and triethylamine (0.4 ml) was added to a stirred solution of pyridine 5 (10 ml) and acetonitrile (2 ml) and the resulting mixture was stirred. With cooling and stirring, 220 mg of silver nitrate is added dropwise to the mixture. The resulting mixture is heated at 50 for 4 hours. After cooling, ethyl acetate is added to the reaction mixture, and after removing the precipitate by filtration, the filtrate is washed with water and dried. The solvent is distilled off by concentration 55 under reduced pressure. The residue is recrystallized from a mixture: Diisopropyl ether - hexa-
    20
    1097195 Continuation of the table. four
    8 69 138
    San with obtaining crystals in the amount of 250 mg (47.2%).
    The compound obtained in accordance with this example, had so pl. 157-159 ° C, and the analytical data obtained from the ultraviolet and infrared spectrum: absorption and 1H nuclear magnetic resonance correspond to the product obtained in example 2 (compound 14).
    Example 6. Pharmacological activity.
    Test methods:
    1. Expansion of veins.
    In accordance with the Langendorff method (1895), the effect on the expansion of the vessels of the veins was tested using separated rabbit hearts. The degree of vein dilation was estimated by the value (1 CDj, g / ml), i.e. sample dose required to increase blood flow from a vein by 50%.
    2. Acute toxicity. 52 235,355 3350,29,1680,1640,1610,1530,1480,1350,11310,1210,1095,1060,100,830,780,740 ,, 710,142,238,356 3350,3000, 1685,1645 1,600,1530,1480,1350,1310 , T205,1100, 1080, 1070,905,850, 825, 770,740,710, 690 145 242,357 3400,3000,1700,1600, 1530,1490,1480,1350, 1280,1220,1100,1070, 1030,900,825,770, 740,705 135 243,355 3420 , 3300,3100,3000, 1750,1690,1670,1610, 1,595,1530,1480,1350, 910,810,755,710. Samples of the compounds were administered intravenously to male mice weighing between 18 and 22 g, and the values were obtained in accordance with the increase and decrease method. 3. Venous effects on dogs. Hound breed dogs (weighing 316 kg) underwent surgery — a chest opening was cut by anesthesia with centobarbital sodium, and the sample was inserted into the heart left coronary anterior descending artery of each animal, while blood flow in the vein (CF) was measured using an electromagnetic flow meter. On the other hand, the sample was injected into the exposed right femoral artery, and the blood flow in the femoral artery (FAF) was measured using an electromagnetic flow meter. Gender needle (cannula) was injected into the left femoral artery, and the general (somatic) shelter
    2,6-Dimethyl-4- (2-nitrophenyl) 3, 5-dimethoxycarbonyl-1,4-dihydropyridine (nifedipine)
    2-Aminocarbonyloximetr-1-6methyl-4- (3-nitrophenyl) -3,5-diethoxycarbonyl-1, 4 dihydropyridine
    2-Y-Metsh1 aminocarbonyloxymethyl-methyl-4 (3-nitrophenyl) -3,5 diethoxycarbonyl-1, 4-dihydropyridine
    2-Aminocarboxymethyl-6methyl-4 (3-nitrophensh1) -3,5dimethoxycarbonyl-1, 4-dihydropyridine
    2-M-Methylaminocarboxy-1-methyl-6-methyl-4- (3-nitrophenyl) -3,5 dimethoxycarbonyl-1, 4-dihydropyridine
     2-Aminocarbonsyl-oxymethyl-6 methyl-4- (2-nitrophenyl) -3,5distoxycarbon-1, 4-dihydro. Pyridine 109
    gt
    2.9x10
    11.5
    .-
    2.4x10
    207
    g 7
    71
    3.2x10
    -7
    167
    3.6x10
    -7
    84
    3.6x10
    -7
    104
    The 4.8 x 10 522 pressure (BP) was measured with a sensor. Heart rate (HP) was measured with an electrocardiograph and recorded on a cardiogram. A sample of 1 solution was injected intravenously into the right femoral vein. Blood flow in a vein (CF), blood flow in the femoral artery (FAF) and heart rate (HP) are expressed as a percentage increase after injection of each of the samples relative to the corresponding control values obtained after injection of saline. Total blood pressure (BP) was increased as a percentage increase compared with the control specimen. The effects of the expansion of the vein obtained on the separated hearts of rabbits and the data on acute toxicity obtained in mice are presented in Table. 5. .TablitsaZ 2-N-Metilaminokarboniloksimetil6-methyl-4- (2-nitrophenyl) -3,5dietoksikarbonil-1, 4-dihydropyridin-2 Aminokarboniloksimetil-6-methyl-4- (3-nitrophenyl) -3-ethoxycarbonyl-5-izopropiloksikarbonil1 , 4-dihydropyridine 2-K-Methylaminocarbonyloxymethyl-6-methyl-4- (3-nitrophenyl) -3-ethoxy carbonyl-5-isopropoxycarbonyl 1, dihydropyridine 2-aminocarbonyloxymethyl-6-methyl 4- (3-nitrophenyl) -3-ethoxycarbonyl-5 / L-propoxyethoxy) -carbonyl1, 4-dihydropyridine 2-aminocarbonyloxymethyl-6-methyl4- (2-nitrophenyl) -3-ethoxycarbonyl5- (p-propoxyethoxy) -carbonyl1, 4-dihydropyrid n 2-Aminocarbonyloxymethyl-6methyl-4- (3-nitrophenyl) -5-ethoxycarbonyl-3- (y-propoxy-ethoxy) -carbonyl-1,4-dihydropyridine 2-aminocarbonyloxy-imtil-6-methyl4- (3-nitrophenyl) -3,5- bis (| 5-propoxy-ethoxy) -carbonyl) -1,4-dihydropyridine 2-Y-Metnlaminocarboxy-1-methyl-6-methyl-4- (3-nitrophenyl) -3,5-bis ((fi-propoxy-ethoxy) -carbonyl) 1, 4 -dihydropyridine 2-Y-Cyclohexylaminocarbonyloxymethyl-6-methyl-5-ethoxycarbonyl-3- (p-methoxyethoxy) carbonyl1, 4-dihydropyridine 2-aminocarbonyloxymethyl-6-methyl4- (2-chlorophenyl) -3,5-bis ((/ 1-ethoxy) carbonyl) -1,4-dihydropyride 2- (4-chlorophenyl) -am nokarboniloksi methyl-6-methyl-4- (3-nitrophenyl) 3-5-etokcikapbonil izoppopokcikap Bonilla-1,4-dihydropyridin-2-N-Fenilaminokapbonilokcimetil6-methyl-4- (3-nitrophenyl) -3-ethoxy carbonyl-5 -isopropoxycarbonyl 1, 4-dihydropyridine
    Continued table. five
    .. ...
    I 4.5x10 2.4x10 2.3x10 3.4x10, 0x10 2.5x10 1.5x10 4.0x10 3.5x10 3.6x10 2.8x10 3.3x10 2510971 From the table. 5, it follows that the compounds of the formula have a strong effect of dilating the veins with respect to the venous system. The acute toxicity of these compounds is low and is 1/6-Fydipine.
    13
    -3 3
    -four
    10 1 3
    ten
    7
    10 24 13 25 65
    10 1 3
    26
    ten
    Table 7
    0.6
    2
    four
    ABOUT
    2
    four
    00
    -2 95 1/17 of the acute toxicity of nifedipine. The effect of dose on blood flow in a vein, femoral artery, total blood pressure and heart rate of beagle dogs is shown in Table. 6 and 7.
    13
    10 25
    10 1 3
    35 82
    ten
    From tab. 6 and 7, it follows that the present compounds increase the blood flow through the vein (CF) in accordance with an increase in their dosage, and their efficiency is equivalent to or exceeds the corresponding efficiency of nifedipine. It also follows from these data that these effects on the venous system are achievable without any significant effect on the heart rate (HP). Thus, the heart does not experience additional stress, which, in combination with minimal toxicity, makes the compounds of the formula -I valuable venoscale medications.
    ABOUT .
    ABOUT
    -five
    ABOUT
    ABOUT
    -ten
    Based on the results of a separate pharmacological test, in accordance with which 1-10 mg / kg of live weight of compounds 3.26 and 38 were administered intravenously, it was found that they cause an increase in the blood flow of the brain and the flow of peripheral blood
    by 40-50%, which indicates that compounds of formula I can also be used as cerebral vasodilators and peripheral vasodilators.
    Thus, the proposed method makes it possible to obtain compounds with lower toxicity and more vasophilic vasodilator properties than an honest substance in structure (nifedepine).
    权利要求:
    Claims (2)
    [1]
    METHOD FOR PRODUCING DERIVATIVES
    2-AMIN0KARB0NIL0XIALKYL-1,4-DIHYDR
    Pyridine of the general formula
    N * 1 II L ^ (JOORj II 1]* n a0CGNHR§
    where Rf is nitro or 2-cyano, 2-chloro,
    2-lower alkoxy; each of
    Rj ^ and Rj are lower alkyl, lower alkoxy (C ^ -C ^) is alkyl; lower chloralkyl, phenyloxy (C p -C 4 ) -alkyl, phenyl (C ^ -Cd) alkyloxy (C ^ -C ^ -alkyl, lower alkenoxy (C 4 -C 4 ) -alkyl; R ^ _ -methyl;
    A is methylene;
    R ^ .- hydrogen, lower alkyl, cyclohexyl. phenyl, 4-chlorophenyl,
    3,4-dichlorophenyl, characterized in that
    [2]
    2-hydroxyalkyl-1,4-dihydropyridine of the general formula where R ^ -R and A are as defined, are reacted with an isocyanate of the general formula 'R 6 ~ NC0, where Rg is chlorosulfonyl, lower alkyl, cyclohexyl, phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, and the desired product is isolated or hydrolyzed if necessary.
    SU <„> 1097195
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    同族专利:
    公开号 | 公开日
    JPH0128746B2|1989-06-05|
    AT31297T|1987-12-15|
    US4404378A|1983-09-13|
    KR890001147B1|1989-04-25|
    HU186583B|1985-08-28|
    KR830010074A|1983-12-26|
    JPS57175166A|1982-10-28|
    EP0063747A1|1982-11-03|
    DE3277809D1|1988-01-21|
    SU1169531A3|1985-07-23|
    EP0063747B1|1987-12-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1552911A|1975-07-02|1979-09-19|Fujisawa Pharmaceutical Co|1,4 dihydropyridine derivatives and the preparation thereof|
    DE2658183A1|1976-12-22|1978-07-06|Bayer Ag|2-POSITION SUBSTITUTED 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS A MEDICINAL PRODUCT|
    DE2844595A1|1978-10-13|1980-04-30|Bayer Ag|2-Acylamino:alkyl-di:hydro-pyridine derivs. - useful as cardiovascular agents acting as coronary dilators, hypotensives, antiarrhythmics, vascular spasmolytics and hypolipaemics|EP0094159B1|1982-05-10|1990-03-14|Takeda Chemical Industries, Ltd.|Dihydropyridine derivatives, their production and use|
    EP0100189B1|1982-07-22|1986-05-28|Pfizer Limited|Dihydropyridine anti-ischaemic and antihypertensive agents|
    HU192166B|1982-08-06|1987-05-28|Banyu Pharma Co Ltd|Process for producing 2-carbamoyl-oxy-alkyl-1,4-dihydro-pyridine derivatives|
    JPH0129187B2|1983-12-02|1989-06-08|Otsuka Pharma Co Ltd|
    GB8401288D0|1984-01-18|1984-02-22|Pfizer Ltd|Therapeutic agents|
    US4672068A|1984-05-04|1987-06-09|Fujirebio Kabushiki Kaisha|Antihypertensive 1,4-dihydropyridines having a conjugated ester|
    IT1201476B|1985-10-04|1989-02-02|Yason Srl|DIHYDROPYRIDINE DERIVATIVE, PROCEDURE FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT|
    IT1197012B|1986-07-29|1988-11-25|Boehringer Biochemia Srl|2-METHYL DIHYDROPYRIDINE, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP56060677A|JPH0128746B2|1981-04-23|1981-04-23|
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