• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    9-Carbamoyl-9-(2-cyanoethyl)fluorenes (I) are intermediates for synthesis of 9-aminoalkyl-9-carbamoyl- fluoroenes (II), which are antiarrhythmic agents. In (I) and (II) R and R' are independently hydrogen, C1-C4 alkyl, fluoro of chloro; R4 and R5 are independently hydrogen or C1-C6, alkyl, and R2and R3 independently are hydrogen, C1C6 alkyl, CH2 (C2-C5 alkenyl), phenyl (C1-C3 alkyl), or taken together with the nitrogen to which they are attached are a cyclic group of the formula wherein R6 is hydrogen or C, - C4 alkyl; A is -CH2-, oxygen or -NH-; and Y is zero or one; or a pharmaceutically acceptable salt thereof.
    公开号:SU1297724A3
    申请号:SU813310061
    申请日:1981-04-16
    公开日:1987-03-15
    发明作者:Ральф Лавагнино Эдвард；Джозеф Пайк Эндрю；Бьюфорд Кемпбелл Джек
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a process for the preparation of new fluorene derivatives of the formula
    NC # 2
    where is R; R - H; IU, which can be used in obtaining medical supplies.
    The aim of the invention is to obtain new compounds of the above formula, which are intermediate 97724, 2
    It is concentrated under vacuum until a solid forms, which is purified as in Example I. This is obtained in order to obtain the desired product.
    Example 3. 9 Carbamoyl-9- (2-cyanoethyl) fluorene.
    500 g of 9-carbamoylfluorene is mixed with 13 l of tetrahydrofuran in a nitrogen atmosphere to obtain a slurry, then the mixture is stirred and heated to. 50 MP of Triton B are added, followed by 131 g of acrylonitrile. Mixture mix
    acrylonitrile is watered at 50 ° C for 6 hours, then 65 g of acrylonitrile and 25 mp are added
    compounds in the synthesis of the production of 15 Triton B. The mixture is stirred at
    fluorene with antiarrhythmic activity.
    Example 1. 9-Carbamoyl-9- (2-cyanoethyl) fluorene,
    A portion of 4.2 g of 9-carbamoylfluorene is dissolved in 300 ml of dioxane at 45 ° C. To the solution add 0.4 g of Triton B (40% solution of benzyl triethyl ammonium hydroxide in methanol) and 1.1 g of acrylonitrile. The reaction mixture was stirred at 70 ° C for 1 h, then cooled to ambient temperature and incubated overnight. Dioxane is removed under vacuum, and ethyl acetate-water is poured into the remaining oil. The organic layer is separated and washed three times with water and once with a saturated solution of sodium chloride. The organic layer is then dried over magnesium sulfate, filtered, and evaporated under vacuum to a foam, which is then placed in dichloromethane. The solution is boiled and hexane is added until the crystallization begins. The mixture is cooled, incubated overnight, the precipitated crystals are separated by filtration, washed with hexane and dried under vacuum at 40 ° C, resulting in 3.2 g of the left product, m.p. 148-152 seconds, which is sintered at 43 ° C,
    Example 2. 9 Carbamoyl 9- (2-. Ianoethyl) dinyopeH,
    100 g of 9-carbamoylfluorene is mixed with 3375 ml of tetrahydrofuran in a 5-liter flask to obtain a slurry. The mixture is heated with stirring to 45 ° C and 10 ml of Triton B is added. The mixture is stirred for 15 minutes at constant temperature and then 26.2 g of acrylonitrile are added in one portion. The mixture is stirred at boiling point for 3 hours and then cooled to room temperature. Mixture
    TO
    0
    five
    0
    50
    35
    40
    45
    55
    50 C during the night. The reaction mixture is cooled, filtered, and the filtrate is evaporated to form a solid under vacuum. The solid is dissolved in ethyl acetate-water, the desired product is isolated from the organic layer, as in Example 1. The resulting product is crystallized from methanol, yielding 433 g of a substance identical to that obtained in Example 1.
    Example 4. 9- (2-Cyanoethyl) - 9- (N, W-dimethylcarb amoyl) fluorene.
    28 g of 9- (I, I-dimethylcarbamoyl) fluorine are placed in a three-liter flask, filled with 1 l of tetrahydrofuran. The mixture is heated to 45 ° C, 10 ml of Triton B are added. The mixture is stirred at a constant temperature for 15 minutes, then one 8 g of acrylonitrile are added in a portion. The mixture is stirred at boiling point for 3 hours, cooled and concentrated in vacuo. 51.8 g of oil. The product is isolated as in example 1, Crystallized from hexane. The result is 15 g of the product with so pl. 109-110 ° C.
    Example 5, 9- (2 Pianoethyl) - 9- (I-methylcarbamoyl) fluorene,
    36.8 g of 9- (H-metsh1carbamoyl) fluorene in Example 4 are mixed with 10.6 g; Acrylonitrile in tetrahydrofuran in the presence of Triton B in an amount of 10 g. The reaction mixture is maintained in the mode described in Example 4. Then the reaction mixture concentrated under vacuum to a semi-solid state and placed in ice water mixed with ethyl acetate.
    The organic layer is separated, washed with water, dried over sodium sulfate. Then the solution is evaporated to dryness, with the result that receive
    45.8 g of crude product, which is purified by crystallization from a mixture of ethyl acetate - hexane
    Obtain 30 g of the desired product with so pl. 185-187 ° C.
     As indicated above, compounds of formula I are used as intermediates for the synthesis of an important series of anti-arrhythmic agents of formula
    %
    R
    /
    ; NiCHzl3 col1H1
    where R, R, are as defined above;
    .RJ and E are independently hydrogen or C, -C-alkyl.
    Antiarrhythmic agents can be obtained from intermediates of formula I by reduction in the presence of an amine, containing E and R substituents, or by reducing the nitrile to a primary amine, followed by E and Rj-rpynn.
    9-Aminoalkenfluorene is used as antiarrhythmic agents. Such use is confirmed by testing for anti-arrhythmic activity on dogs in which cardiac arrhythmia is caused. After applying the compound, it is observed whether normal heart function is restored and, if so, for how long,
    five
    five
    0
    0
    50
    In a general experiment to determine the activity of the compounds, one or more dogs are anesthetized using sodium pentobarbital. A Butterfly 23 infusion needle is placed in a radial vein for the purpose of administering an arrhythmia drug to the dog, as well as administering the test compound to the dog. During the experiment, each dog was continuously monitored using an electrocardiogram. After 30 minutes of continuous, artificially induced arrhythmia, using a needle or infusion, the Butterfly flux is administered at a dose of 200 mg / kg per minute.
    If arrhythmias do not stop within 10 minutes from the time the test compound is started (as determined using an electrocardiogram), the infusion dose of the test compound is increased to 500 mg / kg per minute. The amount of test compound that was required to stop the arrhythmia and restore normal cardiac activity is recorded as a reducing dose. After completion of the administration of the test compound, the dog's heart is continuously monitored by an electrocardiogram for a period of time, and the arrhythmia recovery time is recorded. The maximum observation time is 2 hours, after which the test ends. The duration of normal heart activity is expressed in minutes.
    The results of the experiments are shown in the table.

    /
    R2
    H
    In another biological experiment, known as the Nodal Electrogram for HIS dogs, the effect of anti-arrhythmic agents on the conduction intervals and the resistance period of different regions of the heart was determined. When comparing 9- (2-isopropylaminopropyl) -9-carbamoyl-fluorohydrochloride with the known anti-arrhythmic agent aprindine using the nodal electrogram for dogs HIS, it was found that the first of these compounds at least twice the duration of the intervals conductivities and periods of resistance
    The proposed compounds can be used to restore normal cardiac activity in animals by administering to the animal an anti-arrhythmic amount of one or more aminoalkylfluorenes. These compounds are effective as anti-rhythmic agents.
    with their introduction into the cardiovascular system of the animal.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives orena General formula
    flu conrri
    whereR; Rf is H; Me, characterized in that the 9-carbamohepfuoren formula
    CONHRi
    where R, P. - have the indicated meanings, are reacted with acrylonitrile at 45-70 seconds in the solvent medium in the presence of a base.
    Editor I. Rybchenko
    Compiled by I. Zavarzin Tehred M. Hodankch
    Order 800/64 Circulation 372
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production polygraph (} c ical enterprise, Uzhgorod, Proektna st., 4
    Proofreader M. Samborska Subscription
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    同族专利:
    公开号 | 公开日
    PL131122B1|1984-10-31|
    IE51221B1|1986-11-12|
    DD158395A5|1983-01-12|
    EP0038676B1|1984-10-17|
    US4282170A|1981-08-04|
    DK172181A|1981-10-18|
    IL62669A|1984-06-29|
    PT72854B|1982-03-30|
    JPH01125363A|1989-05-17|
    FI75337C|1988-06-09|
    AU543345B2|1985-04-18|
    EP0038676A1|1981-10-28|
    BG35464A3|1984-04-15|
    GR73824B|1984-05-03|
    CA1172646A|1984-08-14|
    JPH0153267B2|1989-11-13|
    KR840001071B1|1984-07-31|
    ZA812482B|1982-11-24|
    PT72854A|1981-05-01|
    FI75337B|1988-02-29|
    JPS574954A|1982-01-11|
    DE3166679D1|1984-11-22|
    IL62669D0|1981-06-29|
    GB2074161A|1981-10-28|
    PH15857A|1983-04-13|
    NZ196814A|1984-07-06|
    ES501339A0|1983-01-16|
    RO82739B|1984-01-30|
    JPH0149701B2|1989-10-25|
    KR830005110A|1983-07-23|
    AT9897T|1984-11-15|
    PL230714A1|1982-08-02|
    CS225833B2|1984-02-13|
    AR228596A1|1983-03-30|
    FI811176L|1981-10-18|
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    IE810873L|1981-10-17|
    GB2074161B|1984-03-14|
    RO82739A|1984-01-14|
    AU6961181A|1981-10-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2280058A|1942-04-21|Cyanoethylation of carbocycijc |
    CH407092A|1962-12-21|1966-02-15|Boehringer & Soehne Gmbh|Process for the preparation of basic fluorene derivatives|
    US3325544A|1965-06-10|1967-06-13|Upjohn Co|9- fluoren-9-ol and salts thereof|
    US3660485A|1970-10-05|1972-05-02|Searle & Co|Fluorene-9-carboxylic acid hydrazides|
    US3843657A|1972-12-08|1974-10-22|Searle & Co|9-dialkylamin oalkyl-n-substituted fluorene-9-carboxamides|US4552982A|1983-08-01|1985-11-12|Eli Lilly And Company|Synthesis of 9-carbamoyl-9-fluorenes|
    US4508735A|1983-09-21|1985-04-02|Eli Lilly And Company|Anti-arrhythmic N-alkanoylaminoalkyl fluorenes|
    US4486592A|1983-10-19|1984-12-04|Eli Lilly And Company|9-Carbamoylfluorene derivatives|
    FI844067L|1983-10-19|1985-04-20|Lilly Co Eli|FOERFARANDE FOER FRAMSTAELLNING AV 9-KARBAMOYLFLUORENDERIVAT.|
    US4585894A|1983-10-19|1986-04-29|Eli Lilly And Company|Process for producing 9-carbamoyl fluorene derivatives|
    US4842420A|1987-12-14|1989-06-27|Mobil Oil Corporation|Variable-width draw tape for thermoplastic bags|
    US5736578A|1995-06-06|1998-04-07|Bristol-Myers Squibb Company|Ethylamido fluorenes and improved method of making same|
    HU9902133A3|1996-01-16|2000-04-28|Bristol Myers Squibb Co|Aromatic inhibitors of microsomal triglyceride transfer protein|
    US5760246A|1996-12-17|1998-06-02|Biller; Scott A.|Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method|
    CN100463249C|2006-01-24|2009-02-18|吉林大学|Preparing organic light emitting film by electrochemical deposition and use in electroluminescence device|
    US7520124B2|2006-09-12|2009-04-21|United Technologies Corporation|Asymmetric serrated nozzle for exhaust noise reduction|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/141,229|US4282170A|1980-04-17|1980-04-17|9-Carbamoyl-9-fluorenes|
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