• 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:
    PCT No. PCT/HU84/00004 Sec. 371 Date Sep. 20, 1984 Sec. 102(e) Date Sep. 20, 1984 PCT Filed Jan. 20, 1984 PCT Pub. No. WO84/02906 PCT Pub. Date Aug. 2, 1984.Compounds are disclosed of the formula (I) <IMAGE> wherein A1 is a valence bond or a C1 to C5 straight or branched chain alkylene group unsubstituted or substituted by hydroxy or aminocarbonyl; B is a valence bond or a double bond; R3 is hydrogen or C1 to C4 alkyl; R2 is a phenyl or phenoxy group unsubstituted or substituted by one or two C1 to C4 alkyl groups, C1 to C4 alkoxy groups, or halo substituents; or R2 is an amino group, a diphenylmethyl group, or an R4 -NH-CO- group in which R4 is 2,6-dimethyl-phenyl; or a pharmaceutically acceptable acid addition salt thereof. The compounds possess anti-arrhythmic activity and exert little or no hypotensive side effects.
    公开号:SU1333236A3
    申请号:SU843800100
    申请日:1984-09-20
    公开日:1987-08-23
    发明作者:Хидег Кальман；Х.Ханковски Ольга；Франк Ласло；Боди Илона；Чак Йожеф
    申请人:Алкалоида Ведьесети Дьяр (Инопредприятие)；
    IPC主号:
    专利说明:

    The invention relates to the production of new pyrrolidine derivatives of the general formula
    sn
    v-so
    SS 1 CH
    and
    -N-A- 1
    g
    -El.
    de a
     - a valence bond, straight or branched C, -C4-alkylene, which may be substituted by a hydroxyl or aitinHOKaponyl group, B is single or double bond; R, is phenyl, pyridyl, hydroxyphenyl, which can be mono- or di-substituted by a lower ally, cyclic or lower alkoxy group, or by a single Halogen atom, or an amino, diphenylmethyl or R —NH — CO— group, where R is unsubstituted or substituted by lower alkyl phenyl,
    R is hydrogen or C, -C, -alkyl, or their salts with an inorganic acid, possessing antiarrhythmic: action.
    The purpose of the invention is to create, on the basis of known methods, a method for the preparation of new compounds with valuable pharmacological actions with low toxicity.
    Example 1.4.31 g of 2-amino- -3- (2,6-dimethylphenoxy) propane hydrochloride is dissolved in 60 ml of acetone and the resulting solution is diluted with 20 ml of water. After 8.3 g of potassium carbonate is added to the solution, 7.88 g of hydrobromic 3,5-dibromo-2,2,6,6-tetramethyl-4-pi-Peridone is added in portions at room temperature to it. After 3 hours, the solution is saturated with about 120 g of potassium carbonate and the extraction with chloroform is carried out four times in 20 ml portions of chloroform. The extract is washed with water, dried over magnesium sulfate and filtered, then evaporated to dryness, and the residue is dissolved in 30 ml of ether and the solution is diluted with 40 ml of n-hexane. The precipitate is filtered off at low temperature and dried. The result of 5.24 g (yield 82%) (2,2,5,5 tetramethyl-2.5 3332362
    -dihydro-3-pyrrolin-3-carbonyl) -3- - (2,6-dimethylphenoxy) -aminopropane (compound 9, Table 1.; therefore, using the corresponding amines as starting compounds, compounds 1-10 are obtained shown in Table 1.
    Example 2, 3.29 g of the product obtained in accordance with Example 1 is dissolved in 20 ml of chloroform, after which hydrogen is passed through it in the presence of a palladium catalyst on a high activity carbon until the absorption of hydrogen ceases. The resulting solution filter5
    are evaporated and then treated as in Example 1. The resulting product is 2-s (2, 2,5,5-tet: ramethyl-3-pyrrolidine-3-carbonyl) 3 -3 - (2,6-dimethylphenoxy) -aminopropane (compound j1, Table 1).
    Examples 3-5. 31.30 g of 2,2- 6,6-tetramethyl-3, 5-dibromopyropid-4-one is added over 1 hour to the following solutions, cooled to O C: solution 27, -04 g 1.3 -diamino-2-propanol in 500 ml of water; a solution of 2.01 g of 1, 3-diamino-2-propanol and 9.01 g of triethylamine in 500 ml of water, a solution of 9.01 n of 1,3-diamino-2-propanol and 13.82 g of potassium carbonate in 500 ml of water; a solution of 9.01 g of 1,3-di-5 amino-2-propanol and 15.9 g of sodium carbonate in 500 ml of water; a solution of 9.01 g of 1, 3-diamino-2-propanol and 25.20 g of sodium bicarbonate in 500 ml of water.
    0
    40
    The reaction mixture is stirred for 1 h at O With, after which
    Potassium arbonate (about 200 g) is added to it until the resulting product appears on the surface of the aqueous phase. After extraction of its chloroform (three times in 100 ml portions), the chloroform solution was dried over magnesium sulfate. The solvent as well as the excess amine (if it is contained in the solution) is distilled off under reduced pressure. The residue is dissolved in 15 C1 ml of ether. Crystalline precipitate of N- - (2-hydroxy-3-aminopropy) -2, 2.5, 5-tetramethyl-3-pyrrolidine-3-carboxamide
    filtered, washed and dried (compound 15, PL. 1).
    Example 6-8. 39.39 g of the 2,2,6,6-tetramethyl-355-dibromo-piperid-4-bromide hydrobromide is added
    to the following solutions, cooled to a solution of 36.05 g of 1,3-diamino -2-propanol in 500 ml of water, a solution of 9.01 g of 1, 3-diamino-2-propanol and 3.03 g of triethylamine in 500 ml of water; a solution of 9.01 g of 1, OZ-diamino-2-propanol and 20.73 g of potassium carbonate in 500 ml of water.
    The process is then carried out as described in examples 3-5. The resulting product corresponds to the product obtained in these examples (compound 15, Table 1).
    Example 9. 22.53 g of N- (3-aminopropyl) -2,2,5,5-tetramethyl-3-pyrrolidine-3-carboxamide (compound 13, Table 1) is dissolved in 300 ml of chloroform and hydrogen is passed through black in the presence of a palladium catalyst on a high activity coal until the absorption of hydrogen ceases. Next, the reaction mixture is recycled in the same manner as in Example 1. The resulting product, in the form of an oily liquid, is N- (3-aminopropyl) -2,2,5,5-tetramethyl-pyrrolidin-3- carboxamide (compound 18, table. 1), can be directly used for the synthesis of other compounds.
    The compounds obtained by this method are listed in Table. one.
    The pharmacological effect of compounds (I) is demonstrated by the example of arrhythmias caused in rats with aconitine.
    Wistar rats (200-220 g) are anesthetized with a urethane. The jugular vein is connected to a polyethylene cannula. Using a standard ECG tap, a control ECG is taken. The test compounds and the physiological saline solution used as a control were administered intravenously 5 minutes before the aconitine infusion. The aconitine solution is injected continuously in an amount of 5 µg / kg at a rate of 0.1 ml (100 g / min) into the vein vein. The process continues until the appearance of isoelectric lines on the ECG.
    During the experiment, the moments of the occurrence of extrasystoles and cardiac ventricular tachycardia, as well as treptanil fibrils, are determined. Some results related to different types of compounds are given in Table. 2

    In tab. 2 shows changes in the time of occurrence of ECG changes (in rats) caused by the administration of aconitine (min, X + S.E.M.).
    On the delayed appearance of extrasystoles of the ventricle of the heart, the ED values are determined. and ED, yp. Acute toxicity (95% confidence interval) is determined on a mass (CFLP) and is calculated over copper with the results obtained.
    In the control animals, which were injected with physiological saline, the effect of aconitine in the amount of 5 µg / kg after 6.1 min causes the ventricle extrasystole. The s-o values correspond to the duration of the infusion. 7.6 and a, 2.
    Antiarrhythmically effective doses, and | also LDjjj of some compounds of various types are given in table. 3
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining pyrrolidine derivatives of the general formula
    gn gvt-COsU
    I n
    SNS
    A is a valence bond, straight or branched C, -C-alkylene, which may be substituted by a hydroxyl or aminocarbonyl group, B is single or double, R is phenyl, pyridyl, oxyphenyl ,. which may be mono- or di-substituted by a lower alkyl or lower alkoxy group, or by a single halogen atom, or by an amino, diphenylmethyl or Rj — NH — CO— group, where R is unsubstituted or substituted by lower alkyl phenyl,
    R is hydrogen or C4-C4-alkyl, their salts with an inorganic acidic differing from that derived from piperidino on the total
    formulas
    Vg
    sns
    BUT
    .D.VG J Bs
    J I SNZ
    - n
    or its hydrobromide salt is reacted with an amine of the formula
    HN-X-RI
    R2
    Where A, R, and R
    have the indicated meanings.
    in the presence of an acid binding agent, followed by isolation of the carboxamide obtained, or in the case when B is a double bond, reduction with hydrogen in the presence of palladium and separation of the target product in free form or in the form of a salt with an inorganic acid.
    17
    1333236
    18
    table 2
    Editor S.Pekar
    Compiled by I. Bocharova
    Tehred L.Serdyukova Proofreader V.Girn to
    Order 3853/58 Circulation 371 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Project, 4
    Table 3
    类似技术:
    公开号 | 公开日 | 专利标题
    US2441498A|1948-05-11|Alkyl glycinanilides
    PL117155B1|1981-07-31|Method of manufacture of novel n-alkylated derivatives of 2-aminoethanol 2-aminoehtanola
    DE3623941A1|1988-01-28|SUBSTITUTED AMINO-5,6,7,8-TETRAHYDRONAPHTHYL OXYACETIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE USE AS A MEDICINAL PRODUCT
    SU1333236A3|1987-08-23|Method of producing the derivatives of pyrrolidine or their salts with inorganic acid
    EP0192829B1|1990-09-26|Amino propanol derivatives, process for their preparation, medicines containing these compounds and intermediates
    CH637933A5|1983-08-31|METHOD FOR PRODUCING NEW DERIVATIVES OF PERHYDRO-AZA-HETEROCYCLEN.
    CH643809A5|1984-06-29|AMINO ALCOHOL DERIVATIVES.
    SE436027B|1984-11-05|NEW ESTARS OF QUARTERLY AMMONIUM SALTS WITH ANTICOLINERG ANTI-SECRETARY EFFECT AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE SALTS
    DE2362278C2|1983-03-24|5- | propoxycarbostyril compounds, their salts with acids, processes for their preparation and pharmaceuticals containing these compounds
    SU598557A3|1978-03-15|Method of preparing 1-phenoxy-3-aminopropane-2-ol derivatives or salts thereof
    DE2549889C2|1985-06-05|3,4-Dihydrocarbostyril derivatives, processes for their preparation and pharmaceuticals containing them
    DE3642105A1|1988-06-16|SUBSTITUTED AMINOMETHYL-5,6,7,8-TETRAHYDRONAPHTYL-OXYACETIC ACIDS, NEW INTERMEDIATE PRODUCTS, PROCESS FOR THEIR PRODUCTION AND THEIR USE IN MEDICINAL PRODUCTS
    EP1245561B1|2005-12-28|N-substituted benzyl or phenyl aromatic sulfamides compounds and the use thereof
    DE1543693A1|1969-09-11|Alkanolamine derivatives and processes for their preparation
    US2704284A|1955-03-15|Therapeutic compounds
    US2483435A|1949-10-04|Beta-benzohydryloxyethylamines and process for preparing
    US2459217A|1949-01-18|Alkamine esters of para amino benzoic acid
    SU1064869A3|1983-12-30|Process for preparing 1-oxide-n-|ethyl)-3-pyridinecarboxamide or its pharmaceutically acceptable salts
    US4058534A|1977-11-15|Therapeutically effective nicotinates and N-oxide nicotinates of aliphatic amines
    US3426034A|1969-02-04|Omega-phenyl-omega-pyridyl alkylamine derivatives
    US3983169A|1976-09-28|Phenoxypropylamine derivatives
    DE2450161B2|1977-12-01|N-BETA- | - GLUTAMINE AND ITS ALKYLESTERS AND THEIR PHARMACOLOGICALLY COMPATIBLE ACID ADDITION SALTS, PROCESS FOR THE PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE
    SU1574170A3|1990-06-23|Method of obtaining derivatives of pyrrolidine or salts thereof with inorganic acid
    US3629442A|1971-12-21|Sulphonamides for treating hypertension
    EP0196648A1|1986-10-08|Novel diamine derivatives
    同族专利:
    公开号 | 公开日
    JPH0471067B2|1992-11-12|
    WO1984002906A1|1984-08-02|
    DK447284D0|1984-09-19|
    FI71127B|1986-08-14|
    FI843667A0|1984-09-19|
    FI71127C|1986-11-24|
    HU189214B|1986-06-30|
    US4731376A|1988-03-15|
    DK447284A|1984-11-20|
    JPS60500668A|1985-05-09|
    DK166776B1|1993-07-12|
    FI843667L|1984-09-19|
    EP0134795A1|1985-03-27|
    EP0134795B1|1988-08-17|
    DE3473443D1|1988-09-22|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE109345C|
    DE109346C|
    DE109347C|
    US3020288A|1962-02-06|Hypotensive compounds |
    GB190004799A|1900-03-13|1900-05-19|George William Johnson|The Manufacture of Para-amidophenyl Glyoxylic Acid, its Substitution Products and Homologues.|
    CH336068A|1955-04-06|1959-02-15|Bofors Ab|Process for the preparation of amides of N-alkyl-piperidine-monocarboxylic acids or N-alkyl-pyrrolidine-α-monocarboxylic acids|
    GB983134A|1962-06-13|1965-02-10|American Cyanamid Co|Cyclic nitroxides and process for preparing same|
    US3250771A|1962-12-17|1966-05-10|Geigy Chem Corp|5-monocarbocyclic aryl-n-lower alkyl-2-pyrrolidine carboxylic acid, esters, amides and derivatives thereof|
    US3299097A|1963-04-29|1967-01-17|Upjohn Co|4-alkylhygric acid hydrazides|
    US3313801A|1965-10-18|1967-04-11|Upjohn Co|Process for inhibiting n-alkylation of pyrrolidines and substituted pyrrolidines by microorganisms, and products produced thereby|
    US3624081A|1967-02-15|1971-11-30|Sterling Drug Inc|1-acyl-2-ethylidenepyrrol-idine-3-carboxamides|
    US4111901A|1977-06-06|1978-09-05|Borg-Warner Corporation|Hindered five-membered nitrogen rings as polyolefin stabilizers|
    US4302383A|1980-05-19|1981-11-24|Borg-Warner Chemicals, Inc.|Stabilized olefin polymers|EP0134225B1|1983-01-21|1988-08-17|ALKALOIDA VEGYéSZETI GYáR|New alkyl diamine derivatives|
    US5047555A|1988-12-13|1991-09-10|Tanabe Seiyaku Co., Ltd.|4-aminophenol derivatives and processes for preparing the same|
    HU9700392A1|1997-02-10|1999-09-28|ICN Magyarország Részvénytársaság|Cardioprotective pharmaceutical compositions containing one or two active ingredients|
    TWI243162B|2000-11-10|2005-11-11|Taisho Pharma Co Ltd|Cyanopyrrolidine derivatives|
    US6827226B2|2002-12-09|2004-12-07|Wmc Holdings Incorporated|Storage apparatus for sportboards with variable widths|
    RU2606622C2|2010-08-31|2017-01-10|Бионуре Фарма, С.Л.|Agonists of neurotrophin receptors and their use as medicaments|
    WO2017038552A1|2015-09-04|2017-03-09|Dic株式会社|Stabilizer compound, liquid crystal composition, and display element|
    KR20180052599A|2015-09-04|2018-05-18|디아이씨 가부시끼가이샤|Liquid crystal composition and liquid crystal display element using same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU83178A|HU189214B|1983-01-20|1983-01-20|Process for preparing pyrroline and pyrrolidine carboxamide derivatives|
    [返回顶部]