• 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:
    Compounds are described of the formula <CHEM> wherein R1 and R4 independently represent a C1-4 alkyl group; R2 and R3 independently represent a C1-6 straight or brached alkyl chain or alkoxy group; R4 represents a C1-4 alkyl group; R5 represents a group CH=CR6R7 where R6 is a hydrogen atom or C1-3 alkyl group and R7 represents an aryl, pyridyl or cyano group; or R5 represents the group C IDENTICAL CR8 where R8 is an aryl group. The compounds represented by formula (1) reduce intracellular calcium ion concentration by limiting transmembranal calcium ion influx and thus may be useful for the treatment of cardiovascular disorders such as hypertension.
    公开号:SU1731049A3
    申请号:SU884356934
    申请日:1988-12-05
    公开日:1992-04-30
    发明作者:Семераро Клаудио；Микели Дино；Пьераччьоли Даниэле；Гавираги Джованни；Дэвид Бортвик Алан
    申请人:Глаксо С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    cardiovascular agents. til 5 and 2,6-dimethyl-4- (2-methylphenyl) -1,4) -dihydropyridine-carboxylic-3,5-lilo ester is condensed by the condensation of an elidene-p ester of ketocarboxylic acid or an enaminocarboxylic ester or with p-ketocarboxylic ester and ammonia
    The aim of the invention is to obtain new 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives exhibiting a more effective antihypertensive effect than the known related compounds.
    The goal is to obtain compounds of general formula I
    Rl
    Yishkv
    1 $$
    five
    (No. -V AlkKRify i
    R3H R4
    where 1C is methyl; RЈ is methyl; Alk is methylene;
    ethyl is independently represented; RЈ alkyl with 1-4 carbon atoms;
    Rg tret-butyl; R7 is hydrogen
    and their pharmaceutically acceptable salts by the interaction of tf, | 3 unsaturated ketone of formula (II) with a diamino ether of formula (III). The reaction usually takes place in a solvent, such as a limiting alcohol, for example ethanol or isopropanol, preferably with heating, and at 40-150 ° C.
    (01 7
    S-SOGKb VDchuhSN
    Rerc-0
    Pc CH
    and
    ten
    H2lT CHiKRiRz
    five
    0
    five
    To obtain compounds of formula I in which R and / or R2 are hydrogen nitrogen, it is necessary to use the diamino ether of formula III, where Rf and R2 are a group that can be removed to form a hydrogen atom.
    Compounds represented by formula I may be in more than one isomeric and / or enantiomeric form. The invention includes all isomers, enantiomers, and mixtures thereof.
    The compounds of formula I form salts with inorganic and organic acids. The invention also includes salts in its scope. Salts of physiologically acceptable inorganic and organic acids (hydrochlorides, hydrobromic acid salts, sulfates, tosylates, methanesulfonates, acetates, maleates, fumarates, formates, succinates, phosphates, citrates, benzoates, tartrates and dibenzoyl tartrates) are particularly useful salts. Preferred salts are hydrochloric and hydrobromic acids "
     The group -CH CRTC02RgB of compounds of formula I may exist in the cis and trans configuration. Preferred compounds are compounds in which a hydrogen atom and a group
    S
    R is in trans configuration with respect to the rest, i.e. trans isomers.
    The compounds according to the invention have an asymmetric carbon atom at the 4th position in the dihydropyridine ring. Formula I includes both enantiomers and their mixtures. Two individual enantiomers can be represented by formulas 1a and 1c. The enantiomer represented by formula 1c, hereinafter referred to as the 5th S-enantiomer, is preferred. The enantiomer represented by formula 1a; hereinafter referred to as R-Enantiomer
    C02R
    (CH2) 0NR, R2
    R602C
    R302C- 4YxC02Rv R aNCCH n
    4N
    H
    (Ib)
    - S-enantiomer
    The desired product may be obtained and / or isolated in the form of a salt, preferably in the form of a physiologically acceptable salt. Such salts can be converted to the corresponding free base of formula I using conventional methods.
    Physiologically acceptable salts of the compounds of the formula I can be prepared by reacting the compound of the 66 formula I with a suitable acid in a suitable solvent, such as acetone, ethyl acetate or an alkanol, for example ethyl alcohol.
    If a specific enantiomer of formula 1a or 1b is required, they can be obtained by separating the mixture of enantiomers of the corresponding compound of general formula I using conventional methods. Thus, in one case, a suitable optically active acid may be used to form salts with a mixture of enantiomers of a compound of general formula (I). The resulting mixture of isomeric salts can be separated, for example, by fractional crystallization into individual diastereomeric salts, of which the desired enantiomer of formula 1a or 1b can be isolated either as a free base or as something else.
    five
    five
    The starting compounds III are either new compounds or can be prepared by methods similar to those used for the preparation of known compounds.
    The following examples illustrate the invention. Temperatures are given in ° C. In all examples, TLCing means thin-layer chromatography on silica plates, unless otherwise specified, using a mixture of ethyl acetate, cyclohexane and methanol as a solvent in the ratio of 7: 3: 2.
    Intermediate compounds 1 - 1,1 - dimethyl ethyl ester (E) -3- (2 formylphenyl) 2-propenoic acid.
    Intermediate compound 2 is 3-amino-4-dimethylamino-2-butenoic acid ethyl ester.
    Pyridine perbromide bromohydrate (48 g) was added to a solution of acetoacetic acid ethyl ester (19.4 g) in anhydrous methylene chloride (500 ml) at room temperature for 20 minutes. The mixture was stirred for two hours and then a solution of dimethylamine (48.8 g) in anhydrous methylene chloride (100 ml) was added dropwise at -15 ° C for one hour. The resulting mixture was cooled to 20 ° C and ammonia was bubbled through the mixture with stirring for an hour and two hours at room temperature. The reaction mixture was left overnight to complete the reaction at 5 ° C. After evaporating the solvent, the residue was treated with ether, the solid was filtered, the solution was evaporated to obtain
    0 Brown oil, which was purified by silica gel column chromatography, afforded intermediate compound 2 (10.8 g) as an orange oil. TLC. Rf 0.4.
    5 Intermediate 3 „
    A) 2- (2- (3- (1,1-Dimethylethoxy) -Z-oxo-1-propenyl) phenyl) - methylene-3-oxo-butanoic acid methyl ester. Piperidine solution (0.11 g) and
    0 of hydrochloric acid (0.078 g) in isopropanol (1 ml) was added to a solution of intermediate 1 (5.2 g) and methyl acetoacetate (2.55 g) in isopropanol (15 ml).
    stirred at 60 ° C for one hour, then the solvent was evaporated, and the residue was dissolved in ether (100 ml). The solution was washed with 1N hydrochloric acid, water, saturated bicarbonate solution,
    five
    then again with water and dried over sodium sulfate. Evaporation of the solvent gave an oil, which was purified by column chromatography (a mixture of gasoline and ether in ratios from 7; 3 to 1: 1), to give intermediate (11a) as a slightly colored oil ( 4.2 g) (mixture of E and Z isomers).
    The following compounds were prepared in a similar manner.
    E) 2- (2- (3- (1,1-Dimethylethoxy) 3-oxo-1-propenyl) phenyl) methylen-3-oxo-butanoic acid ethyl ester was obtained from intermediate 1 and ethyl ether acetoacetic acid.
    Example 1. 2-Dimethylaminomethyl-6-methyl-4- (E) diethyl ester hydrochloride (2- (3- (1,1-dimethylethoxy) -3-ok6o-1-propenyl) phenyl) -1, 4-di-hydro-3,5-pyridinedicarboxylic acid
    Intermediate compound 2 (6.25 g) was added to a solution of intermediate compound Sv (5 g) in isopropyl alcohol (50 ml) and then the mixture was heated at 40-45 ° C for 48 hours. The solvent was removed by evaporation in vacuo to obtain an orange residue, which was dissolved with methylene chloride (100 ml) and washed twice with diluted water with hydrochloric acid. The organic layer was concentrated under vacuum, and the residue was eluted on a silica gel column (ethyl acetate – methanol in a ratio of 9; 1) and obtained name of example connection in de yellow solid substance (0.9 g), Tspl. 190 - 193 ° С „TLC (ethyl acetate – methanol mixture, 8: 2), 43.
    EXAMPLE 2 (d) Ethyl chlorohydrate () (S) - (€) -4- (2- (3- (1,1-dimethylethoxy) -3-oxo 1 propenyl) phenyl-2- dimethylamino-methyl-6 methyl-1 "4-dihydro-3, 5-pyridinecarboxylic acid
    (-) - Dibenzoyl-β-tartaric acid monohydrate (8.0 g) was added to a solution of (E) -4- (2- (3- (1, 1 dimethylethoxy) -oxo-1-propenyl) phenyl) - 3.-dimethylaminomethyl-6-methyl-1,4-dihydro 3,5-pyridinecarboxylic acid 1 Example 1) (10.6 g) in isopropyl alcohol (360 ml) and the mixture warmed to room temperature and stirred
    five
    It was filtered and purified by recrystallization three times from isopropanol. The solid (1.5 g) was dissolved in dichloromethane (50 ml) and treated with 10% sodium hydroxide (40 ml). The organic layer is evaporated, the residue
    s
    was dissolved in ethyl acetate (20 ml) and acidified with 1.2 hydrochloric acid in ethyl acetate (2 ml). The solid phase was filtered off, dried, and the title compound was obtained (0.63 g), mp, 202-203 ° C.
    TLC, (ethyl acetate – methanol mixture, 8: 2). Rt 0.43.
    C "0 69.2 (from 1.04 in 95% ethanol),.
    In the same way obtained the following connection
    c) (+) (K) (6) -4 (2- (3- (1,1-dimethylethoxy) -3-oxo-1-propenyl (phenyl) -2-dimethyl-aminomethyl-6-methyl) diethyl ester hydrochloride -1,4-dihydro-3, 5-5 pyridinecarboxylic acid (0.65 g) „TLC (ethyl acetate – methanol mixture, 8: 2) Rf 0.43.
    (/ G) +68.5 (from 1.04 in 95% ethanol) from the compound of Example 3 0 (10.6 g) with (+) - dibenzoyl-D-tartaric acid monohydrate (8.0 g) . T „pl. 203 ° C.
    c) diethyl ether bromhydrate
    2-dimethylaminomethyl-6-methyl-4- (E) - (2- (3- (1,1-dimethylethoxy) -3-oxo-1 propenyl) phenyl-1,4-dihydro-3,5 pyridinecarboxylic Acids, mp 192-194 ° C. TLC, R 0.33.
    d) 2-dimethylamino methyl 6-methyl-4- (E) - (2- (3- (1, tylotoxy 3-oxo-propenyl) phenyl) diethyl ester); 1, 4 dihydro-3,5-pyridinecarboxylic acid at interaction with maleic acid gives maleate, t „pl„ 154 - 156 ° С.
    e) In the treatment of 2-dimethyl-aminomethyl-Chromethyl-4 (E) - (2- (3- (1,1-dimethylethoxy) 3-oxo-1 propenyl) phenyl) diethyl ether bromide, -1.4 dihydro-3,5-pyridinecarboxylic acid with a solution of sodium hydroxide was obtained free base (so pl. 146 - 148 C, TLC, (mixture of ethyl acetate and methanol 9: 1), R "0.38.
    The ability of the compounds obtained according to the invention to limit or suppress the effect of calcium ions on the tone of the vascular smooth muscle is determined
    0
    S
    0
    S
    20 v- Yellow crystals collected and divided using depolarized
    v
    Noah's ear artery of a rabbit prepared according to Tovarte
    The antihypertensive activity of the compounds according to the invention has been demonstrated by intravenous or oral administration of the compound to male rats with spontaneous hypertension.
    The compounds of formula I were compared with nitrendipine, a derivative of digiridine-3-methyl ester of 5-ethyl ester of 2,6-dimethyl-4- (3 nitrophenyl) 1i4-dihydropyridine-3i of 5-dicarboxylic acid as an antihypertensive agent.
    The compounds of the invention and nitrandin were compared under the action of spontaneously hypertective male rats. The compounds were administered orally and the effects on blood pressure were measured, using the tail strike procedure. Each compound was administered to animals in three different doses and the maximum response was determined for each dose. Determined the dose required to reduce blood pressure in an animal by 25% using a conventional linear regression analysis. In this experiment, the compounds of the invention all had an ED in the range of 0.25 to 4.2 mg / kg (for example, the compound of Example 1 had an ED25 of 0.75 mg / kg, while the ED25 of nitndipine was 11 , 4 mg / kg. Thus, the compounds of the invention are noticeably more active, the non-lived related compound nitrendipine,
    In these experiments, the compounds of the invention have a particularly advantageous activity profile, including a relatively long duration of action.
    The compounds of the invention are of interest in the treatment of hypertension and diseases characterized by reversible blockage of airways such as asthma and chronic bronchitis. They are also potentially useful in the treatment of other cardiovascular diseases, including angina myocardial ischemia, congenital heart disease, and vascular diseases of the brain and peripheral vessels.
    权利要求:
    Claims (1)
    [1]
    Compounds I can be classified as compounds with low toxicity. Invention Formula
    Method for preparing symmetric 4 ester of substituted 1,4-dihydropyridine-3 5-dicarboxylic acid of general formula I

    ten
    :about
    CH icooRf
    hell
    "Y yCOtRj
    n
    where RJ is methyl; R2 is methyl; Alk is methylene;
    1C and 1C independently denote this RJ-alkyl; R,
    R7
    tert-butyl;
    hydrogen atom
    or its physiologically acceptable leu, wherein the compound of general formula II
    7 CH C-C02Rf
    K.5-C-0
     where is kc. have the indicated meanings, are reacted with diamclo-ether of general formula III
    № СН}
    Hjif skdag
    where R, - - K has the indicated meanings, and the target product is isolated or, if necessary, the corresponding cis or trans isomer of the target product is separated into S and / or R enantiomers using an optically active acid, or the compound of general formula I or its salt is converted into a physiologically acceptable salt.
    类似技术:
    公开号 | 公开日 | 专利标题
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    KR950011410B1|1995-10-04|A process for the preparation of heterocyclic compounds
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    同族专利:
    公开号 | 公开日
    IT8619481D0|1986-02-20|
    EP0245918B1|1993-05-05|
    EP0245918A1|1987-11-19|
    JPS62252768A|1987-11-04|
    DE3785695T2|1993-08-19|
    DE3785695D1|1993-06-09|
    AT88997T|1993-05-15|
    IT1204459B|1989-03-01|
    US4946851A|1990-08-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1409865A|1973-02-13|1975-10-15|Science Union & Cie|Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them|
    ZA776989B|1976-12-22|1978-09-27|Ciba Geigy Ag|A caustic-free process for the production of monochloro-diamino-s-triazines|
    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|US5514693A|1988-12-15|1996-05-07|Farmitalia Carlo Erba S.R.L.|Imidazolyl and pyridyl derivatives of phenyl substituted 1,4-dihydropyridines and process for their preparation|
    IL92646D0|1988-12-15|1990-08-31|Erba Carlo Spa|Imidazolyl and pyridyl derivatives of phenyl substituted 1,4-dihydropyridines,their preparation and pharmaceutical compositions containing them|
    US5158963A|1989-08-02|1992-10-27|Kaken Pharmaceutical Co., Ltd.|1-4-dihydropyridine derivative, process for preparing the same and pharmaceutical composition containing the same|
    CA2048668A1|1989-12-29|1991-06-30|Michio Nakanishi|Ethynylphenyl derivative, process for preparing the same and medicament for circulatory disease containing the same as an effective ingredient|
    GB9119983D0|1991-09-19|1991-11-06|Erba Carlo Spa|Dihydropyridine derivatives useful in antitumor therapy|
    PT657432E|1993-12-10|2003-07-31|Bayer Ag|PHENYL-SUBSTITUTED 1,4-DIHYDROPYRIDINES WITH CEREBRAL ACTIVITY|
    US20080089947A1|2006-08-18|2008-04-17|Knox Clayton D|Calcium Influx Inhibitors in the Treatment of Ischemia|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT19481/86A|IT1204459B|1986-02-20|1986-02-20|HETEROCYCLIC DERIVATIVES|
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