• 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:
    1. Dihydropyridinelactones of the general formula I see diagramm : EP0158138,P14,F1 in which R represents halogen, alkyl having 1 to 10 C atoms or cyano, R**1 represents hydrogen, halogen or C1 -C10 -alkyl or C1 -C10 -alkoxy, R**2 represents a C1 -C20 straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical which can optionally be interrupted by 1 or 2 oxygen atoms or -SOn - (n = 0, 1 or 2) and which can optionally be substituted by one or more fluorine, chlorine, bromine or iodine atoms, phenyl, -NO2 , -O-, NO2 , C3 -C12 -trialkylsilyl, -OH, -CN, amino, C1 -C6 -monoalkylamino, dialkylamino in which each alkyl is C1 -C6 , or benzyl-C1 -C6 -alkyl-amino, R**3 represents hydrogen, NH2 , CHO, CN or a C1 -C8 straight-chain or branched, saturated or unsaturated hydrocarbon radical which can be interrupted in the chain by oxygen, -NH- or -N-alkyl (1 to 6 C atoms), and R**4 represents a C1 -C10 straight-chain or branched alkyl or C2 -C10 -alkenyl radical which can optionally be interrupted by one or two oxygen atoms in the alkyl chain and which can optionally be substituted by one to six fluorine atoms, Cl, br, I, CN, NH2 , OH, phenyl, naphtalyl, hydroxycarbonyl, alkoxycarbonyl (1 to 10 C atoms in the alkoxy radical), -CHO, morpholino or C1 -C4 -dialkylamino, in the form of isomers, isomer mixtures, racemates and optical antipodes.
    公开号:SU1319785A3
    申请号:SU853865401
    申请日:1985-03-15
    公开日:1987-06-23
    发明作者:Гольдманн Зигфрид；Боссерт Фридрих；Бишофф Гильмар；Петцинна Дитер；Пульс Вальтер；Шлоссманн Клаус
    申请人:Байер Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to novel compounds with valuable pharmacological properties, in particular, to a process for preparing 1,4-dihydropyridine lactone derivatives of the general formula
    R R.
    Ro rx 25
    thirty
    de R - halogen, methyl, methylthio,
    trifluoromethyl, diano, nitro; hydrogen, chlorine, fluorine; C-C-alkyl, C-Cd-alkyl interrupted by an oxygen or sulfur atom, or sulfinyl, phenethyl;
    methyl, methoxymethyl, dimethylaminoethyl; , -alkyl, allyl, oxy-carbonylmethyl, ethoxycarbonylmethyl, hydroxyethyl, diethylaminoethne,
    R does not mean trifluoromethyl, if Rj is ethyl, which decrease the concentration of glucose in the blood.
    The purpose of the invention is a method for the preparation of 1,4-dihydropyrhylactone derivatives which exhibit a higher activity for reducing blood glucose.
    Suitable solvents for decaponization and subsequent alkylation are all common inert solvents, preferably acid amides, such as dimethylformamide, hexamethylphosphoric triamide, ethers, such as tetrahydrofuran, dioxane, sulfoxides, such as dimethyl sulfoxides, such as dimethyl sulfoxide or sulpholane. As bases, for example, metal hydrides such as sodium hydride, potassium hydride or amides, such as sodium amide, 4-diisopropylamide, potassium diethylamide or metal alkyls, such as butyl lithium, phenyl lithium or hydroxides, such as j potassium hydroxide, sodium hydroxide; or alcohols, such as potassium t-butanol t, potassium methylate or carbonates, such as potassium carbonate.
    50 m ra 2 -me 5-oxo; 20 b) pyridium is added with rofuran and sodium at room temperature of 55 mmol with water and lysing, m.p. one
    Russ
    C ,, H Found 35 N 3.8.
    Pr ether 1ti.
    40 FUR- (lots.
    What are they doing
    45 alkyl li.pbrom tplo
     H 2.4 (c 4.7 (s (m, 1H
    Ras N 3.6.
    C ,,,
    Nay N 3.4.
    P r ether 4
    N 3 7
    Alkylation is carried out at -20-ISO C. (preferably at room temperature and up to the boiling point of the solvent used).
    Alkylation is usually carried out at normal pressure, but if necessary the pressure can be increased. The reagents can be used in any proportion, preferably they are used in a molar proportion.
    Example 1. Methyl 1-etrch-2-methyl-4- (2-trifluoromethyl-phenyl) -5-oxo-1,4,5,7-tetrahydrofuro- (3,4-b) pyridine-3-carbonyl ester acid.
    50 mmol of 2-methyl-4- (2-trifluoromethylphenyl) -5-oxo1,4,5,7-tetrahydrofuro- (3,4b) pyridine-3-carboxylic acid methyl ester is dissolved in 100 ml of anhydrous tetrahydrofuran and 50 mmol of sodium hydride is added. After 10 minutes, 55 mmol of ethyl iodide is added at room temperature and the mixture is heated under reflux for 1 hour. After concentration, it is washed with water, dried, concentrated and recrystallized. Output 4.9 g (2 6% of theory), so pl. 150-152 ° C.
    Calculated,%: C 59.8; H 4.8;
    3 7
    C ,, H, g. Found,%: C 3.8.
    59.7; H 4.6;
    50 j
    EXAMPLE 2 1-Allyl-2-methyl-4- (2-trifluoromethy.phenyl) -5-oxo-1,4,5,7-tetrahydro40 FUR- (3,4-b) methyl ester methyl ester ) pyridine-3-carboxylic acid.
    Repeat the example. 1 with the difference that dimethylformamide is used as a solvent. and as
    45 alkylating agents use ally.bromide. Vkod 5.3 g (27% of theory), tplo amorphous substance.
     H - NM (CDC1,), h / m: 2.4 (s, ZN), 3.5 (s, ZN), 4.1 (m, 2H), 4.7 (s, 2H), 5.4 (d, 2H), 5.8-6.0 (m, 1H), 7.3-7.7 (m, 4H).
    Calculated,% "C 61.1; H 4.6; N 3.6.
    C ,,, H | gF, N04.
    Found,%: C 61.4; H 4.4; N 3.4.
    EXAMPLE 3 4- (2-chlorophenyl) -1-ethyl-2-methyl ethyl 13 5-OXO-1,4,5,7-tetrahydrofuro- (3,4-b) pyridine ethyl ester 3-carboxylic acid.
    50 mmol of 4- (2-chlorophenyl) -2-methyl-5-oxo-1,4,5,7-tetrahydrofuro- (3,4-b) pyridine-3-carboxylic acid ethyl ester is dissolved in tetrahydrofuran 50 mmoles of lithium diisopropylamide are added at -78 ° C and 50 mmoles of ethyl dyl are added successively. It is then heated to room temperature, stirred for 1 h., As in Example 1, is further processed. Output 9.6 g (53% of theory), so pl. 140-141 ° C.
    Calculated,%: C 63.0; H 5.6; N 9.8.
    С ,, Н, „С1М04.
    Found,%: C 62.4; H 5.9; N 9.8.
    EXAMPLE 4 4- (2-chlorophenyl) -1,2-dimethyl-5-oxo-1,4,5,7-tetrahydrofuro- (3,4-b) pyridine-3- propyl ester carboxylic acid.
    50 mmol of 4- (2-chlorophenyl) -2-methyl-5-cc-1,4,5,7-tetrahydrofuro- (3,4-b) pyridine-3-carboxylic acid propyl ester is dissolved in 150 ml of dimethyl sulfoxide, then 7 g of potassium hydroxide powder and 50 mmol of methyl iodide are added. After 2 hours at room temperature, they are poured on ice-cold water, extracted, dried, concentrated and recrystallized. Output 10.8 g (60% of theory), so pl. 173-177 ° C.
    Calculated,%: C 63.0; H 5.6; N 9.8.
    C ,, H, „С1ЫО ,.
    Found,%: C 62.8; H 5.9; N 10.0.
    The compounds of examples 5-39 (Table 1) are prepared in the same way, the data on the gross formula and elemental analysis of these compounds are given in Table. 2
    EXAMPLE 40: 4- (2-chlorophenyl) -1-oxyethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-isopropyl ester (3, 4- B) pyridine-3-carboxylic acid.
    50 mmol of 4- (2-chlorophenyl) -2-methyl-5-ox-so-1,4,5,7-tetrahydrofuro- {3,4-b) pyridine-3-carboxylic acid isopropyl ester is dissolved in dimethylformamide , deprotonate with 50 mmol of sodium hydride and then 100 mmol of acetaldehyde-ethyl- (2-bromoethyl) -ketal are added, heated for 1 hour until condensed, added
    54
    hydrochloric acid and precipitated by a soda. The output of 9.8 g, so pl. 140-143 C (from methanol).
    Calculated,%: C, 61.3; H 5.7; N 3.6.
    C ,, H ,, C1NO ,.
    Found,%: C 61.0; H 5.9; N 3.6. Biological experience. The blood glucose lowering effect is tested on Wistar rats weighing 140– 190 g. For this, rats 18 hours before application of the test substances are weighed, divided into groups of 6 animals and kept on an empty stomach. Directly before the application, the test substances are suspended in an aqueous 0.75% tragic suspension. The application of a tragic suspension (on control animals) or the test substances suspended in the tragant is carried out by means of a gastric probe.
    Blood sampling from the retroorbital venous plexus is carried out in each rat 30, 60 and 120 minutes after application.
    Each time 30 µl of blood is taken and protein is removed from it with 0.3 ml of uranyl acetate (0.16%). After centrifugation, the glucose content in the supernatant is photometrically determined using 4-amino-phenazone paint reagent.
    The evaluation of the results is carried out by the method according to the Student, and p: 0.05 is taken as the limit of significance.
    Substances that at some point in rats caused a significant decrease in the concentration of glucose in the blood by at least 10% compared with the control group that received only tragic suspension, are recognized as active.
    In tab. 3 shows the data on the change in blood glucose concentration as a percentage of the control group of animals at a dose of 30 mg / kg, oral dacha.
    The data table. 3 indicate that the novel compounds exhibit better activity than the known are non-toxic - LD (orally; rats) is 5 g / kg.
    权利要求:
    Claims (1)
    [1]
    Formula of gain
    The method of obtaining derived 1,4 - dihydropyridinone general formula
    de R - halogen, methyl, methylthio,
    trifluoromethyl, cyano, nitro;
    R, is hydrogen, chlorine, fluorine;
    R is C, -C-alkyl, C, -Su-alkyl, interrupted by an oxygen or sulfur atom or sulphinyl, phenethyl;
    R is methyl, methoxymethyl, dimethylaminoethyl;
    Rj - C, -C5 alksh1, allyl, oxycarbonylmethyl, ethoxycarbonylmethyl, hydroxyethyl, diethypaminoethyl, and R is not trifluoromethyl, if Rj. - ethyl.
    1319785 6
    characterized in that the compound of the general formula
    R, OOC
    where, R, R,, Rj, R have the indicated meanings, is subjected to deprotonization with a base in an inert solvent, followed by alkylation with a compound of the general formula
    four
    where R has the indicated meanings;
    Hal - means halogen, and the selection of the target product.
    Table 1
    Me: 423 (M), 406 (90), 378, 332, 316, 312, 288, 248, 222, 177, 75. Mcs (DCl, isovut) 415 (50Z), 387 (iDOZ), 369 (20X) , 355 (10X), 327 (101).
    table 2
    29 С, Н „КО,
    thirty ,
    31 Cj, Hj ClNOj
    32 C, H, j ClNOt
    33 Cj
    FOR C.2, H C1N04
    35 C,,
    36 C ,,, 0,
    37, N, 0
    38 C, H ,,
    39 ,, ,, FC1NO
    Order 2537/59 Circulation 371. Subscription 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:
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    DE3565541D1|1988-11-17|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2005116C3|1970-02-05|1980-02-14|Bayer Ag, 5090 Leverkusen|Symmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid esters|
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    US4284634A|1975-07-02|1981-08-18|Fujisawa Pharmaceutical Co., Ltd.|1,4-Dihydropyridine derivatives, and pharmaceutical method of the same|
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    DE3206671A1|1982-02-25|1983-09-01|Bayer Ag, 5090 Leverkusen|Dihydropyridines having positively inotropic action, novel compounds, their use in medicaments and processes for their preparation|
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    DE4430092A1|1994-08-25|1996-02-29|Bayer Ag|2,3-Cyclically condensed 1,4-dihydropyridines, process for their preparation and their use as medicaments|
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    WO2021253180A1|2020-06-15|2021-12-23|Novartis Ag|Methyl-2--5-oxo-4-phenyl-4, 5, 6, 7-tetrahydro-1h-cyclopenta [b] pyridine-3-carboxylate and methyl-2--5-oxo-4-phenyl-1, 4, 5, 7-tetrahydrofuro [3, 4-b] pyridine-3-carboxylate as cav1.2 activators|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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