• 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:
    Quinolone cardiac stimulants of the formula:- …<CHEM>… or a pharmaceutically acceptable salt thereof,… wherein "Het" is a 5-membered monocyclic aromatic heterocyclic group containing at least one nitrogen atom in the aromatic ring and attached by a nitrogen atom to the 5-, 6-, 7- or 8- position of the quinolone;… "Het" being substituted by a group selected from - @-(C1-C4 alkyl), -R<1>, - @-R<1> and -@-R<2> wherein R<1> is a phenyl group optionally substituted by 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, trifluoromethyl, -CONR<3>R<4>, -SO2NR<3>R<4>, -N(R<3>)SO2(C1-C4 alkyl) and-S(O)n(C1-C4 alkyl) where R<3> and R<4> are each H or C1-C4 alkyl and n is 0, 1 or 2, and R<2> is a heterocyclic group selected from thienyl, furyl, imidazolyl, triazolyl and tetrazolyl, said heterocyclic group being attached to the adjacent carbonyl group by a ring carbon atom and being optionally substituted by up to two substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo;… "Het" also being optionally substituted by up to two C1-C4 alkyl groups;… and R, which is attached to the 5-, 6-, 7- or 8- position of the quinolone, is H, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, CF3, halo, cyano or hydroxymethyl.
    公开号:SU1470190A3
    申请号:SU864028546
    申请日:1986-11-27
    公开日:1989-03-30
    发明作者:Фрейзер Кемпбелл Саймон；Энтони Робертс Дэвид
    申请人:Пфайзер Лимитед (Фирма)；
    IPC主号:
    专利说明:

    (21) 4028546 / 23-04
    (22) 11/27/86
    (31) 8529362
    (32) 11/28/85
    (33) GB
    (46) 03/30/89. Bksh number 12
    (71) Pfizer Limited (GB)
    (72) By Sima Fraser Keetbell and David Anthony Roberts (GB)
    (53) 547.781.785.07 (088.8) (56) Weigand - Hilgetag. Experimental methods in organic chemistry. M .: Himi, 1968, p. 728.
    (54) METHOD FOR OBTAINING 6- (4-ACETYL-2-METHYLIMIDAZOL-1-IL) -8-METHYL-2- (1H) -CARBOSTYRENE
    (57) The invention relates to heterocyclic compounds that can be used in medicine. The goal is to get new, more active compounds. They are obtained by the interaction of 6- (4-cyano-2-methylimidazol-1-yl) -8-methyl-2 (1H) -carbostyril with Grignard reagent of formula CHj-MgX, where X is C1 Br, I, followed by treatment an aqueous solution of acid. The resulting compound has a T 306-Sr8 ° C. Gross fsf-la, jN ,, 02.
    i
    one
    The invention relates to methods for the preparation of 6- (4-acetyl-2-methylimidazol-1-yl) -8-methyl-2 (1H) -carbostyril, which selectively increases the force of the contraction of the heart muscle without causing a significant increase in the number of heartbeats. . These compounds can be used for the treatment or prophylaxis of various heart diseases, in particular for the treatment of heart failure.
    The purpose of the invention is the synthesis of a substituted quinoline derivative, which in its activity exceeds a structural analogue possessing the same type of biological activity.
    Example 1. Preparation of 6- (4-acetyl -2-methylimidazl-1-yl) -8-methyl-2- (1H) -carbostyril 0.17 NgO.
    Bromomethylmagnesium (1.11 cm ZM solution in diethyl ether) was added dropwise to a stirred solution of 6- (4-cyano-2-methylimidazol-1-yl) -8-methyl-2- (1H) -carbostyril (0.15 g ) in tetrahydrofuran (25 cm) at 0 ° under nitrogen. The mixture was heated under reflux for 2 hours, then cooled to room temperature, filled with water (10 cm), after
    which was mixed with 30 M hydrochloric acid. The mixture was basified with 10% sodium carbonate solution and extracted with dichloroethane (3x100 cm). The combined and dried (MgS64) organic extracts were evaporated in vacuo and a solid was obtained which was subjected to silica gel chromatography (MeRCK W 609385 / Trademark). Elution with methanol and dichloromethane4
    WITH

    sn
    ten
    i31470190
    HJOM in a ratio of Vt 19 by volume, followed by compounding and evaporation of the corresponding fractions gave a solid which was recrystallized from ethyl acetate metric-i nola, which gave the target compound, mp. 306-308 (0.05 g),
    Found,%: C, 67.4; H, 5.4; C (14.8.
    I C, gH, 5N ,, 0 0.17
    I Calculated,%; C, 67.6; H, 5.4; l4, 14.8.
    I The biological activity of the compounds obtained is shown in one or | t 1 | the following several experiments} (a) increasing the force of the contraction of the heart of the dog — KJH lung preparation; hp through the left ventricular catheter; (| b) an increase in contractility of the heart muscle (left ventricle dp (dt.) phytaxia tetanicular contraction iacc, in a dog under anesthesia, measured through a left ventricular catheter; b) an increase in contractility of the heart20
    25
    25
    thirty
    compared to which the proposed compound has a greater election; power-frequency, i.e. selectivity with an increase in the force of contraction of the heart muscle without a significant increase in the rate of contraction of the heart. For the proposed compound is the heart rate. does not change with the dose, which gives 50% of the dog in a creature, with the implanted sensor
    Ventricular ventricle (dp / dt) max.) or ct outwardly looped carotid Yrteria (systolic intervals and time).
    In experiment (a) positivi1:, the effect of the test compound in a change in the contractility of the young tissue after jjie with food was measured i | heart-lung preparation - Star-35 Increase by 10 beats / min at
    liing dogs Byp obtained a selectivity of increase in strength compared to the frequency of contraction of the test with;
    HER
    An increase of -1% in comparison with
    the same dose in a known compound, which is a very significant advantage for the proposed compounds that have been tested for toxicity (g) with a positive change and at a dose of 30 mg / kg, i .e. dose
    much more than what is required when used to treat a person, did not show signs of toxic contractility of the tiny tissue of the compound to be injected after intravenous administration was measured in a dog under anesthesia. The magnitude and duration of this effect and the selectivity of the test compound were increased to increase the force compared to the frequency of contractions as peripheral Actions, such as the effect on blood pressure.
    In the experiment (s), a positive action in changing the contractility of the bone tissue after intravenous or oral administration on a dog in condition with an implanted left ventricular transducer (dp / dt, Kt.) Or with an outward projection.
    45
    50
    55
    and they can be classified as low-toxic compounds.
    The compound of the formula may be used in pure form, but is usually used in a mixture with a pharmaceutical carrier selected depending on the method of application and the usual pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such an integral part as starch or lactose, either in capsules, directly or together with an integral part of the drug, or in the form of zlexirov or suspensions containing flavoring or coloring agents. They can be entered into parient
    the loop of the carotid artery (systolic intervals) was measured. The values obtained for the change in contractility of constricted tissue, the selectivity for the increase in strength compared to the frequency of contractions and the duration of action on the change in contractility of the muscle tissue of the test compound.
    As a proof of the advantages of the proposed compound, a compound of the formula
    compared to which the proposed compound has a greater election; power-frequency, i.e. selectivity with an increase in the force of contraction of the heart muscle without a significant increase in the rate of contraction of the heart. For the proposed compound is the heart rate. does not change at a dose giving 50% Increase by 10 strokes / min at
     Increase by 10 beats / min at
    HER
    An increase of -1% in comparison with
     Increase by 10 beats / min at
    the same dose in a known compound, which is a very significant advantage for the proposed compounds that have been tested for toxic
    and they can be classified as low-toxic compounds.
    The compound of the formula may be used in pure form, but is usually used in a mixture with a pharmaceutical carrier selected depending on the method of application and the usual pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such an integral part as starch or lactose, either in capsules, directly or together with an integral part of the drug, or in the form of zlexirov or suspensions containing flavoring or coloring agents. They can be entered into parient
    for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution, which may contain other soluble substances, such as enough salts or glucose, to make the solution isotonic.
    When using lkdma for therapeutic or prophylactic purposes for heart diseases such as heart failure, accompanied by stagnation, oral dose of the proposed compounds will be 1-250 mg daily with 1–3 single doses per day for an average adult. ) (70 kg). The dose of intravenous administration will be 0-1-100 mg, as required for acute cardiac insufficiency. Thus, for a typical adult patient, tablets or capsules may contain 1; 0-100 mg of active compound in a suitable pharmaceutically acceptable medium or carrier. Of course there may be variations depending on the weight and condition of the patient.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 6- (4-acetyl 2-methylimidazol-1-yl) -8-methyl-2 (1H) - carbostyril of the formula
    sns
     „
    SNDS CHS1
    characterized in | compound of formula
    what
    e
    h5i
    25
    I is reacted with a reagent of the general formula, where X is chlorine, bromine or iodine, followed by treatment with an aqueous solution of an acid.
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    同族专利:
    公开号 | 公开日
    KR890002795B1|1989-07-31|
    AU6575486A|1987-06-11|
    PT83810B|1988-12-09|
    NO864782D0|1986-11-27|
    DD265403A5|1989-03-01|
    CN1004205B|1989-05-17|
    YU44603B|1990-10-31|
    EP0226357A1|1987-06-24|
    US4740513A|1988-04-26|
    ZA868978B|1988-07-27|
    DD270710A5|1989-08-09|
    GB8529362D0|1986-01-02|
    CN86108133A|1987-09-09|
    AU569200B2|1988-01-21|
    DK570486A|1987-08-03|
    PL270983A1|1988-09-15|
    PL151696B1|1990-09-28|
    HUT42082A|1987-06-29|
    PH23868A|1989-11-23|
    NZ218428A|1989-03-29|
    DK570486D0|1986-11-27|
    FI864814A0|1986-11-26|
    IL80799D0|1987-02-27|
    YU202686A|1987-12-31|
    PL262599A1|1988-07-07|
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    FI864814A|1987-05-29|
    HU196989B|1989-02-28|
    JPS62138490A|1987-06-22|
    KR870004975A|1987-06-02|
    引用文献:
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    US3993656A|1974-11-19|1976-11-23|Merck & Co., Inc.|1,8-Naphthyridine compounds|
    JPS5728710B2|1977-11-15|1982-06-18|
    DE2815956A1|1978-04-13|1979-10-18|Bayer Ag|PROCESS FOR PRODUCING 2-POSITION SUBSTITUTED TRIAZOLEN-1,2,3|
    JPS6155514B2|1978-09-01|1986-11-28|Otsuka Pharma Co Ltd|
    US4258185A|1978-10-17|1981-03-24|Yoshitomi Pharmaceutical Industries, Ltd.|Pyridazinone compounds|
    JPS6257625B2|1978-12-06|1987-12-02|Yoshitomi Pharmaceutical|
    JPH0143747B2|1980-10-31|1989-09-22|Otsuka Pharma Co Ltd|
    CA1164459A|1980-11-11|1984-03-27|Yung-Hsiung Yang|Process for preparing -carbostyril or -3,4-dihydrocarbostyrylderivatives|
    EP0102046A1|1982-08-26|1984-03-07|Schering Corporation|Tricyclic lactams, method for making them, pharmaceutical compositions containing them|
    CH655110A5|1982-09-03|1986-03-27|Otsuka Pharma Co Ltd|CARBOSTYRILE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM.|
    PT79031B|1983-08-20|1986-08-22|Boots Co Plc|Therapeutic agents|
    US4532250A|1983-11-23|1985-07-30|American Hospital Supply Corporation|5-Heteroarylimidazol-2-ones having cardiotonic activity|
    US4710507A|1983-12-22|1987-12-01|Pfizer Inc.|Quinolone inotropic agents|
    US4591591A|1984-03-08|1986-05-27|Eli Lilly And Company|Pyridazinone derivatives as inotropic agents|
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    JP5473783B2|2009-06-22|2014-04-16|三菱電機株式会社|Antenna position setting device for radiated EMI measuring device|
    JP5576872B2|2010-03-31|2014-08-20|パナソニック株式会社|Communication device, communication system, communication method, integrated circuit|DK111387A|1986-03-05|1987-09-06|Otsuka Pharma Co Ltd|CARBOSTYRIL DERIVATIVES AND SALTS THEREOF, MEDICINE CONTAINING SUCH DERIVATIVES AND PROCEDURES FOR THE PREPARATION OF THE DERIVATIVES|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858529362A|GB8529362D0|1985-11-28|1985-11-28|Quinolone cardiac stimulants|
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