• 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 5-acyl-2-(1H)pyridinones of formula I <CHEM> and their use as cardiotonic agents. They are prepared by reacting a 1-R5-3-R6-2-(dimethylamino-1-R4-methylidenyl)-1,3-propanedione with an appropriate R3-substituted acetoacetamide.
    公开号:SU1299505A3
    申请号:SU843732701
    申请日:1984-04-28
    公开日:1987-03-23
    发明作者:Д.Джоунз Винтон；А.Шнеттлер Ричард；С.Дейдж Ричард
    申请人:Меррел Дау Фармасьютикалз Инк (Фирма)；
    IPC主号:
    专利说明:

    1 12995052
    The invention relates to organic 0.05 mm and produces 10.1 g (73%) of a light yellow liquid. . Example 4. 4-Dimethylaminomethyl-3,5-decandion.
    3,5-decandion (10.00 g, O, 067 mol) and N, M-dimethylformamide dimethyl acetal (8.97 g, 0.075 mol) are stirred at room temperature overnight in an argon atmosphere. The mixture is concentrated on a rotary evaporator to obtain the desired compound.
    Getting the resulting connections.
    chemistry of nitrogen-containing heterocyclic compounds, in particular, to a new method of producing new 5-acyl -2 -2 (1H) -pyridinones of the general formula
    ABOUT
    tt
    in Oh
    (one)
    sh
    where R is normal pentyl or hexyl,
    Rj is methyl or ethyl,
    possessing increased inotropic akpprimer 5. 5- (1-Oxopentyl) - activity, which can be used - 15 -i, 2-dihydro-6-methyl-2-oxo-3-pyrized in medicine as cardiodinocarbonitrile. tonic agents in the treatment of heart failure and other diseases that require cardiac enhancement with a cardiotoxic agent.
    The aim of the invention is to search for a series of pyridinone compounds of new compounds possessing enhanced inotropic ak-3-dimethylaminomethylene-2, 4-octanedione (7.29 G; 0.037 mol) added to a stirred suspension of cyanoacetamide (3.36 g, 0.04 mol) and sodium hydride (1.0 g, 0.04 mol). The reaction mixture is stirred and heated at 50 ° C overnight. Reactionary
    tivnost.
    Obtaining intermediate compounds. Example 1. 1-Dimethylaminomethylene-3,5-non-dione.
    A mixture of K, N-dimethylformamide dimethyl acetal (16.68 g, 0.136 mol) and 3.5–30 nonanedione (21.2 g, 0.136 mol) is stirred overnight at room temperature under argon atmosphere. The resulting red oil is concentrated to neutralize the pH to 6 with acetic acid and concentrate on a rotary evaporator. The residue is triturated with a mixture: 50:50 and collected. Approximately 3.0 g of this powder is mixed with 8.0 g of silica gel having a particle size of 60-200 mixture, and are chromatographed once using 35% ethyl acetate and 65% methylene chloride as eluant and collecting fractions of 65% ml. Of
    35 fractions 5 and 6 are collected. 600 mg of 5- (1- 4-dimethylaminomethylene-3,5-nonadione .. -oxopentyl) -, 2-dihydro-6-methyl-2 Example 2 are obtained. 3-Dimethylamine- Tylenyl-2,4-octandion.
    A mixture of 2,4-octanedione (7.11 g, 0.50 mol) and H, N-dimethylformamide dimethyl acetal (7.15 g, 0.60 mol) was stirred overnight at room temperature under argon atmosphere. The resulting red oil concentrate40
    -oxo-3-pyridinecarbonitrile with so pl. 216-217 ° C. Continuing the described single-use chromatography from fractions 12-25 yields 1.8 g of 5-acetyl-1,2-dihydro-6-butyl-2-oco-3-pyridine-bo-nitropyl, m.p. 195-197 C.
    EXAMPLE 6 5- (1-Oxopentyl) is run on a rotary evaporator and Ne-45 -1,2-dihydro-6-ethyl-2-oxo-3-pyridinecarbonitrile.
    4-Dimethylaminomethylene-3, 5-nonadione (7.8 g, 0.037 mol) was added to a stirred suspension of cyanoacyl-50 tamide (3.36 g, 0.04 mol) and sodium hydride (1.0 g, 0 , 04 mole). React over kugelror at 140-150 C 15 mm to obtain 860 g (87%) of 3-dimethylaminomethylene-2,4-octanedione.
    Example 3. 3-Dimethylaminomethyl-2,4-non-dione.
     2,4-Nonandione (10.00 g, O, 0649 mol) and S, H-dimethylformamide dimethyl acetal acetal (8.97 g, 0.075 mol) are stirred overnight at room temperature under argon atmosphere. Acetic acid is 55% concentrated and the concentrated orange liquid is concentrated to a dry residue. The residue is triturated with a rotary evaporator, then distilled over a kugelror at 140 ° C,
    The mixture is stirred and heated at 50 ° C. for one night. The reaction mixture is neutralized to pH 6 with
    a mixture of methylene chloride: water 50: 5 and get a solid compound, which is a primer and 5. 5- (1-Oxopentyl) - - i, 2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile.
    3-Dimethylaminomethylene-2,4-octanedione (7.29 G; 0.037 mol) was added to a stirred suspension of cyanoacetamide (3.36 g, 0.04 mol) and sodium hydride (1.0 g, 0 , 04 mole). The reaction mixture is stirred and heated at 50 ° C overnight. Reactionary
    the mixture is neutralized to pH 6 with acetic acid and concentrated on a rotary evaporator. The residue is triturated with a mixture: 50:50 and collected. Approximately 3.0 g of this powder is mixed with 8.0 g of silica gel having a particle size of 60-200 mixture, and are chromatographed once using 35% ethyl acetate and 65% methylene chloride as eluant and collecting fractions of 65% ml. Of
    -oxo-3-pyridinecarbonitrile with so pl. 216-217 ° C. Continuing the described single-use chromatography from fractions 12-25 yields 1.8 g of 5-acetyl-1,2-dihydro-6-butyl-2-oco-3-pyridine-bo-nitropyl, m.p. 195-197 C.
    Example 6. 5- (1-Oxopentyl) carbonitrile.
    4-Dimethylaminomethylene-3, 5-nonadione (7.8 g, 0.037 mol) was added to a stirred suspension of cyanoacyl-50 tamide (3.36 g, 0.04 mol) and sodium hydride (1.0 g, 0 , 04 mole). React55 with acetic acid and concentrate to dryness. The residue is ground with
    acetic acid and concentrated to dryness. The residue is ground with
    The mixture is stirred and heated at 50 ° C. for one night. The reaction mixture is neutralized to pH 6 with
    acetic acid and concentrated to dryness. The residue is ground with
    a mixture of methylene chloride: water 50:50 and get a solid compound, which chromatograph on silica gel and obtain the target compound.
    Example 7. 5- (1-Oxohexyl) -6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile.
    3-Dimethylaminomethyl-2,4-nonan-dione (10.1 g, 0.0475 mol) was dissolved in dry tetrahydrofuran (20 ml) and the whole solution was simultaneously added to a suspension of cyanoacetam-fg (4.20 g, 0.050 mol ) and sodium hydride (2.5 g, 0.05 mol) in dry tetrahydrofuran (175 ml) at room temperature under argon atmosphere. After that, the reaction mixture is heated to 50 ° C. and stirred overnight. The reaction mixture is cooled to room temperature and neutralized with glacial acetic acid (5.5 ml).
    )five
    The resulting viscous orange blend20 as cardiotonic agents
    concentrated under vacuum and separated with a mixture of methylene chloride and water. The methylene chloride layer is separated, extracted with 5.0% sodium bicarbonate solution, separated, washed with a 25-minute pharmaceutical carrier brine, separated, dried over sulfa in a mongrel dog (of any gender), the volume is sodium, filtered, concentrated on rotary evaporator and get a solid connection. Solid can be determined by intravenous, intraperitoneal, intraduodenal or intragastric administration — the test compound (0.01–10 mg / kg) with
    Test dogs are anaesthetized and, under isolation, suitable arteries (for example, femoral or
    Disinfection is triturated with hexane (300 ml), the zone of the artery) and veins (for example, poorly filtered, and 8.9 g (81%) of a mixture of compounds are obtained, mp 155–159 C. Single chromatography using 15% ethyl acetate and 85% hexane receive the target compound, j mp. 178-180 ° C.
    Example 8. 5- (1-Oxohexyl) -6-ethyl-2 -oxc-1, 2-dihydro-3-pyridine-carbonitrile.
    venous or external strap veins) and the introduction of polyethylene catheters filled with 0.1% sodium heparinate solution, respectively, to record arterial blood pressure and to inject the joints. The chest cell is opened by a sternum incision in the middle or by a slit of the left fifth intercostal spaces
    The solution is 4-dimethylaminomethylene- 40 and form a pericardial support for
    -3,5-decandion (10.7 g, 0.0475 mol) in dry tetrahydrofuran was added in one portion to a suspension of cyanoacetate-amide (4.20 g, 0.050 mol) and hydride
    Sodium (2.50 g, 0.05 mol) in a dry 45 Electromagnetic flow meter tetrahydrofuran at room temperature can be placed around an upstream column in an argon atmosphere .. After this, the reaction mixture is stirred at 50 ° C in an argon atmosphere overnight. The reaction mixture is allowed to cool to room temperature and neutralized with glacial acetic acid. The resulting liquid is concentrated on a rotary evaporator and the distribution of extraction-55 is carried out by subsequent continuous infusion of its co-generation with a mixture of methylene chloride and a rate of 0.18 mg / kg / min into the blood and water. A layer of methylene chloride is an extrawashable heart. After administration, 5.0% sodium bicarbonate of these agents, which suppress heart support, is lucked. The Walton-Brodie deformation sensor is attached to the right or left ventricle to record the contractile force of the myocardium.
    aorta for measuring the flow of small coronary blood flow from the heart. Heart failure is caused by the administration of sodium pentobarbital (20–40 mg / kg) and its subsequent continuous infusion at a rate of 1–2 mg / kg / min or the administration of propranalol hydrochloride (4 mg / kg) followed by fg those).
    2995054
    and washed with brine, separated, dried over magnesium sulfate and concentrated. The residue is chromatographed and the title compound is obtained. The yield of the target products is 45-50%. Compounds of general formula (I) can be used to treat heart failure, including cardiac abnormalities associated with overfilling of the heart with blood, slowing the heart to return or direct blood flow, disrupting the right or left ventricle of the heart, or can be used to treat any other conditions that require cardiac enhancement with a cardiotonic agent.
    The suitability of compounds of formula (I)
    walking a pharmaceutical carrier to a mongrel dog (of either sex),
    can be determined by intravenous, intraperitoneal, intraduodenal, or intragastric administration of a test compound (0.01-10 mg / kg) with an appropriate pharmaceutical carrier to a mongrel dog (of either sex),
    Test dogs are anaesthetized and prepared by isolating a suitable artery (e.g., femoral or sonar or external vein vein) and inserting polyethylene catheters filled with 0.1% sodium heparinate solution, respectively, to record arterial blood pressure and to inject connections. The thorax is opened by an incision in the middle of the sternum or by a section of the left fifth intercostal space.
    heart support. The Walton-Brodie deformation sensor is attached to the right or left ventricle to record the contractile force of the myocardium.
    The electromagnetic flow meter can be placed around the upstream, continuous infusion of it at a rate of 0.18 mg / kg / min into the blood washing the heart. After the introduction of any of these agents, inhibit eraort to measure the flow of small coronary blood flow from the heart. Heart failure is caused by the administration of sodium pentobarbital (20–40 mg / kg) and its subsequent continuous infusion at a rate of 1–2 mg / kg / min or by the administration of propranalol hydrochloride (4 mg / kg) with a-rhythmic activity, the normal blood pressure increases and the work of the heart is strongly oppressed. A reduction in these effects with the test compound indicates cardiotonic activity,
    The table shows comparative data showing increased positive activity on anesthesia-tO solutions, suspensions or emulsions.
    dogs for the compound of example 5, compared with the cardinotonic compound Amerinone, which is known at the known level, namely 3-am. The solid unit dosage forms can be capsules which can be of the type of ordinary gelatin capsules and contain, for example, 5- (4 -pyridinyl) 2- (1H) -pyridinone. t5 measures, lubricants and inert fillers such as lactose, sucrose and corn starch. In another embodiment, the compounds of formula (I) may be included in tablets along with
    20 such common tablet ingredients as lactose, sucrose, corn starch in combination with dispersing agents such as potato starch or alginic acid and with lubricants such as stearic acid or magnesium stearate. When administered internally, the compounds can be administered in dosage forms for injection, which is Amrion
    Compound 5
    0.38
    0.18
    1.0
    2.11
    To achieve the desired effect of the compound, various
    in ways. Compounds to a patient can be 30% soybean solution or suspension, either alone or in the form of pharmaceutical formulations, by mouth or parenteral, i.e. intravenously or intradermally. The amount of compound administered may vary depending on the patient, the degree of cardiac failure, and the mode of administration.
    When administered by mouth or when parenterally administered, a cardiotonically effective amount of the compound is approximately 0.01-500 mg / kg of patient body weight per day, preferably approximately 0.10 dins in a physiologically acceptable diluent with a pharmaceutical carrier, which may be sterile. liquid such as
    35 water, alcohols, oils, and other acceptable solvents, either with or with a surfactant or other pharmaceutically acceptable additives.
    40 powerful agents. Examples of oils that can be used in these formulations are oils of petroleum, animal, vegetable sludge of synthetic origin, for example
    200 mg / kg patient body weight per day. 45 measures coconut oil, soybean oil When administered through the mouth, a single dose may contain, for example, 1.0-250 mg of the active ingredient. For parenteral administration, the unit dose may contain, for example, 5,500 mg of the active ingredient, preferably about 10-250 mg. Repeated daily administration of the compounds may be required, which varies depending on the condition of the patient and the route of administration.
    By the term patient as used herein is meant a warm-blooded animal, for example birds such as chickens and turkeys, mammals such as primates, humans, sheep, horses, cows and bulls, pigs, dogs, cats, rats and mice,
    When administered orally, the compounds can be used in the form of solid and liquid formulations, such as capsules, pills, tablets, dragees, powders.
    Solid dosage forms can be capsules that can be of the type of conventional gelatin capsules and contain, in a physiologically acceptable diluent, with a pharmaceutical carrier, which can be a sterile liquid, such as
    Water, alcohols, oils, and other acceptable organic solvents, without or with the addition of a surfactant compound or other pharmaceutically acceptable auxiliary agents. Examples of oils that can be used in these formulations are those of petroleum, animal, vegetable or synthetic origin, for example, mineral; butter. As a rule, as liquid carriers, especially for solutions for injection, it is preferable to use water, saline
    50 solution, an aqueous solution of dextrose and solutions of the corresponding sugars, ethanol, glycols such as propylene glycol or polyethylene glycol, as well as 2-pyrrolidone.
    55 Compounds can be administered as a me, as a resorbable injection or in the form of an implant formulation that can be formulated as follows.
    way to prevent the rapid release of the active ingredient. The active ingredient can be compressed in the form of pills or small cylinders and implanted subcutaneously or intramuscularly as slow-absorbable injections or implants. For: implants, inert compounds such as biodegradable polymers or synthetic silicones, such as Si-lastic, which is a silicone rubber manufactured by Dow-Corninp Corporation, can be used.
    As well as in the case of many large classes of compounds, some types of compounds of this class or some specific compounds included in this class are preferable from the point of view of their pharmaceutical activity for the treatment of lulea disease. From this point of view, preferred compounds of the formula () Are those compounds in which R is n-butyl or n-pentyl. Particularly preferred compounds are 3-cyano-6-methyl-5-n-pentanoyl-2 (H) pyridinone and 3-cyano-6-ethyl by G. Volkov.
    Compiled by P. Narushkova
    Tehred L. Serdyukova Proofreader E. Roshko
    Order 905/63 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
    9505
    with fO 8
    -5-n-pentanoyl-2- (1H) -pyridinone. Of the remaining members of the general class, other preferred compounds are those compounds in which R is hexyl, for example specific compounds such as 3-cyano-6-methyl-n-hexanoyl-2- (1H) pyridinone and 3 -cyano-6-ethyl-5-n-hexanoyl-2- (1H) -pyridinone.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 5-ac1-2 (1H) -pyridinones of the general formula
    he
    about
    where R is normal pentyl or hexyl;
    R, is methyl or ethyl.
    1R J LC
    that is, 2-dimethylamino-methyl-thydenyl-1,3-propanedione, where the values of R and Rj have the indicated meanings, is reacted with cyanacetamide and the reaction product is separated by a single graph.
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    同族专利:
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    EP0124089B1|1987-03-04|
    NZ207961A|1986-09-10|
    DE3462889D1|1987-05-07|
    HUT34006A|1985-01-28|
    PT78493A|1984-05-01|
    DK213584A|1984-10-30|
    AU2714184A|1984-11-01|
    JPS59206356A|1984-11-22|
    DD223444A5|1985-06-12|
    EP0124090A1|1984-11-07|
    GR81990B|1984-12-12|
    NZ207960A|1987-05-29|
    ES531911A0|1985-06-01|
    DK159425B|1990-10-15|
    HU191928B|1987-04-28|
    DK159424B|1990-10-15|
    JPH0579668B2|1993-11-04|
    KR840008323A|1984-12-14|
    HU191753B|1987-04-28|
    DK159425C|1991-03-18|
    DK213584D0|1984-04-27|
    IE841047L|1984-10-29|
    DK213284D0|1984-04-27|
    NO164415C|1990-10-03|
    US4568751A|1986-02-04|
    DK159424C|1991-03-18|
    KR840008322A|1984-12-14|
    IE57285B1|1992-07-15|
    AU2713184A|1984-11-01|
    GR81967B|1984-12-12|
    CA1242443A|1988-09-27|
    AU571219B2|1988-04-14|
    IE57273B1|1992-07-01|
    NO841691L|1984-10-30|
    KR900005011B1|1990-07-16|
    PT78491B|1986-05-22|
    ES531910A0|1985-06-01|
    HUT34007A|1985-01-28|
    NO164416C|1990-10-03|
    ZA843034B|1984-11-28|
    IL71648A|1987-11-30|
    NO841690L|1984-10-30|
    AT26262T|1987-04-15|
    AT25678T|1987-03-15|
    PT78493B|1986-05-20|
    CA1256880A|1989-07-04|
    ES8505955A1|1985-06-01|
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    IL71649A|1987-10-30|
    NO164415B|1990-06-25|
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    IE841046L|1984-10-29|
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    AU557543B2|1986-12-24|
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    IL71648D0|1984-07-31|
    DK213284A|1984-10-30|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2531035C2|1975-07-11|1988-03-31|Basf Ag, 6700 Ludwigshafen, De|
    US4072746A|1975-10-14|1978-02-07|Sterling Drug Inc.|3-Amino-5--2-pyridinones|
    GB1596887A|1977-07-15|1981-09-03|Rohm & Haas|2-pyridone derivatives and their use as plant growth regulators|
    DE3005069A1|1980-02-11|1981-08-20|Cassella Ag, 6000 Frankfurt|2-Oxo-6-hydroxy-1,2-di:hydro-pyridine-5- carboxylic acid derivs. - prepd. by reaction of alkoxy:methylene-malonate cpds. with substd. acetamide cpds.|
    DE3106460A1|1980-03-03|1982-01-28|Sandoz-Patent-GmbH, 7850 Lörrach|2 -PYRIDINONE DERIVATIVES, THEIR PRODUCTION AND THE PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME|
    US4412077A|1982-03-15|1983-10-25|Sterling Drug Inc.|Process for preparing 5--6--2-pyridinone|
    US4524149A|1982-03-15|1985-06-18|Sterling Drug Inc.|5-Alkanoyl-6-alkyl-2-pyridinones, their preparation and their cardiotonic use|
    US4568751A|1983-04-29|1986-02-04|Merrell Dow Pharmaceuticals Inc.|5-Acyl-2--pyridinones|
    DE3406329A1|1984-02-22|1985-08-22|Merck Patent Gmbh, 6100 Darmstadt|PYRIDONE|US4568751A|1983-04-29|1986-02-04|Merrell Dow Pharmaceuticals Inc.|5-Acyl-2--pyridinones|
    US5118696A|1983-04-29|1992-06-02|Merrell Dow Pharmaceuticals Inc.|5-Acyl-2--pyridinones useful for treating cardiac failure|
    US4992452A|1983-04-29|1991-02-12|Merrell Dow Pharmaceuticals Inc.|Certain 5-acyl-2--pyridinones useful in treating cardiac failure|
    US4853395A|1983-04-29|1989-08-01|Merrell Dow Pharmaceuticals Inc.|Certain 3-carboxylate or 3-carbamyl-5-acyl-2--pyridinones having cardiotonic properties|
    US5428045A|1983-04-29|1995-06-27|Merrell Dow Pharmaceuticals Inc.|5-acyl-2--pyridinoes|
    US5212314A|1983-11-03|1993-05-18|Merrell Dow Pharmaceuticals Inc.|Alkoxyimino ether derivatives of 5-acyl-2-pyridinones|
    US4732982A|1983-11-03|1988-03-22|Merrell Dow Pharmaceuticals Inc.|Novel alkoxyimino ether derivatives of 5-acyl-2-pyridinones|
    US4731371A|1984-03-29|1988-03-15|Merrell Dow Pharmaceuticals Inc.|Certain 5-acyl-1,2-dihydro-2-oxo-3-pyridinecarbonitriles which are useful as cardiotonic agents|
    US4657919A|1984-08-03|1987-04-14|E. I. Du Pont De Nemours & Co.|Pyridone esters as inotropic agents|
    US4650806A|1985-01-14|1987-03-17|Sterling Drug Inc.|Cardiotonic 5--pyridones|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/490,081|US4568751A|1983-04-29|1983-04-29|5-Acyl-2--pyridinones|
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