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    • 专利摘要:
    Novel carbostyril derivatives and their salts having antihistaminic effects and are useful as antihistaminic agents, represented by the general formula (1), <IMAGE> (1) wherein R1 is a hydrogen atom, a lower alkenyl group, a lower alkynyl group or a lower alkyl group which may have phenyl group(s) as the substituted group(s); R2 is a hydrogen atom, a lower alkyl group or a phenyl group; R3 is a lower alkyl group having phenyl group(s) as the substituted group(s), or a phenyl group which may have 1 to 3 substituted groups selected from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups; R4 is a hydrogen atom, a hydroxyl group or a lower alkanoyl group; X is a halogen atom; Y is a lower alkylene group which may have hydroxyl group(s) as the substituent(s); n is 0, 1 or 2; the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single or double bond; provided that when R3 is a lower alkyl group having phenyl group(s) as the substituted group(s), then R4 should be neither a hydroxyl group nor a lower alkanoyl group.
    公开号:SU1091857A3
    申请号:SU802982853
    申请日:1980-09-16
    公开日:1984-05-07
    发明作者:Банно Казуо；Фудзиока Такафуми；Осиро Ясуо；Накагава Казуюки
    申请人:Оцука Фармасьютикал Ко, Лтд (Фирма)；
    IPC主号:
    专利说明:

    have the indicated meanings, B is hydrogen or the group X -Y-, where Y has the indicated meanings and X is halogen, is reacted with a piperidine derivative of total III
    -about
    U
    at
    where RT and R have the indicated meanings, Z is hydrogen or a group, where Y has the indicated meanings, and halogen, provided that if B is hydrogen, then 2. is a group, and if B is X-, then Z is hydrogen, followed by isolation of the desired product in the form of a base or an acid additive salt or by treatment
    compound of general formula IV
    RFiQ,
    where Pv5H Q is as defined, and isolating a quaternary salt of formula 1a.
    Priority featured:
    09.18.79
    with R-, - all values, R. - all values, Rj C, | -C-alkyl 5 which can be replaced by phenyl, phenyl; R is hydrogen, Q is halogen.
    09.28.79
    when Rj is phenyl, substituted with 1-3 substituents from among halogen, C - C, - alkyl or C - C alkoxyl, RC C | - C |; -alkyl
    one
    The invention relates to a method
    obtaining carbostyril derivatives and their salts with antihytamine activity and which can be used in medicine,
    The reaction of 0-alkylation of carbostyril derivatives Cl is known.
    The purpose of the invention is a method for the preparation of carbostyril derivatives having valuable pharmacological properties.
    The goal is achieved based on a known reaction method for the preparation of carbostyyl derivatives of the general formula I
    hydrogen, alkenyl or
    de R alkynyl, C —C-alkyl, which may be substituted with phenyl,
    hydrogen, alkyl or
    R is phenyl;
    , -alkyl, which can
    3 be substituted with phenyl, or phenyl substituted with 1-3 for 2
    halogen, C-Cg-alkyl or C -C alkoxy 5
    Tj
    hydrogen, hydroxyl or
    C-C-alkanoyl,
    X p Y
    halogen
    O, 1 or 2;
    C-Cg-alkylene, which can
    to be substituted by hydroxyl-, the bond between positions 3 and 4 can be single or double, provided that RJ is alkyl substituted by phenyl, then it can be hydroxyl or alkanoyl, or their pharmacological acid addition or quaternary salts of the general formula 1a
     R, X,
    and u have specified
    P
    value; Rg is C.-C, -alkyl, Q is halogen. 5109 perurature of the bath is maintained and a gas mixture consisting of 5% CO and 5% Og is passed into it. After a 10-minute passage, 10 M histamine is added to the bath, tissue sensitivity is examined and a histamine dose-response curve (control) is obtained. Upon reaching a constant curve for the reaction of a histamine dose (control), 10 g / ml of the test compound is added to the bath and after 5 minutes another histamine is obtained to obtain a dose-dependency curve. The wrinkling of the ileum is recorded by a recorder through an isotonic signal transducer. The anti-histamine activity of the test compound is defined as the pA2 value by the Van Rossam method with: provided that the maximum retraction shown in the control curve is 100%. The results are presented below. Test results Dinene (compounds obtained according to the invention, examples 1-15): 1 (4-benzyl-1-piperidyl) propoxyJ-3, 4-dihydrocarbostyryl 1-methyl-7-C3- (4-benzyl-1-piperidyl monooxalate) propoxy J-3,4-dihydrocarbostyril; 1-propargyl-5- 3 (4-benzyl-1-piperidyl) -propoxy} 3,4-dihydrocarbostyryl monohydrochloride; 4-methyl-5-Hz- (4benzyl-1-piperidyl) -propoxy-3,4 dihydrocarbostyryl monohydrochloride, 54-metsh7-7-C3- (4-benzyl-1-piperidyl) propoxy carbostyryl; 6 monooxalate-1-allyl-4-G.2-hydroxy- (4benzyl-1-piperidyl) -propoxy J-3 Dihydrocarbostyryl 7 monooxalate 1-ethyl-5-2-hydroxy-3 (4-benzyl-1-piperidyl) -propoxy J3 , 4-dihydrocarbostyril; 8-bromo-5-C2-hydroxy-3- (4-becyl 1-piperidyl) propoxy J-3,4-dihydrocarbostyryl; 97-C 2-hydroxy-3- (4-phenyl-1 -piperid.p) propoxy 3-3 5 4-dihydrocarboxyles 1, 10 monooxalate 1-methyl-5-2-hydroxy-3 (4-benzyl-1-piperidyl) propoxy} 3, 4-dihydrocarbostyril; 11. 4-phenyl-1- (2-hydroxy-3-C 2oxo-1, 2,3,4-tetrahydroquinolin-5yloxy) propyl iodide 1-benzyl-4-2-hydroxy 1-benzyl-4-2-hydroxy (4- benzyl-1-piperidyl) propoxy J3, 4-dihydrocarbostyril; 4-phenyl-7-ch3- (4l-1-piperidyl) propoxy carboyl hydrochloride, (4-hydroxy-4-phenyl) -1-piperidv-3 5 4-dihydrocarbostyryl; 3-G4- (4-aC tsh1-4-phenyl) -1-eridyl-3, 4-dihydrocarbostyryl. Organic compounds: enylhydramine hydrochloride; Chlorpheniramine eat. rA2 t9.52 210.70 39.73 411.00 59.59 69.54 79.65 88.39 99.89 acological test 2. division of acute toxicity. t in male rats administered orally. Results below. Acute toxicity, mg / kg 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 15 1,000 Example 1 (reference). 20.5 5-acetyloxy-3, 4-dihydrocarbostyryl is dissolved in 200 ml of acetic acid and a solution of 16 g of bromine in 60 ml of acetic acid is added dropwise to the solution while cooling with water and stirring for 30 minutes, then mixing continue for 2 hours at the same temperature. 300 ml of water are added to the reaction mixture and left for 3 hours. The resulting crystals are separated by filtration and recrystallized from methanol. 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyrol are obtained in the form of colorless needle-shaped crystals, m.p. 237-239 ° C. “21 g of the obtained 8-bromo-5-acetyl oxy-3,4-dihydrocarbostyril is dispersed in 150 ml of 8 n. hydrochloric acid and refluxed for 3 hours. After cooling the reaction mixture, the precipitated substance was separated by filtration, washed with water, dried and recrystallized from a mixture of methanol and water. 14 g of 8-bromo-5-hydroxy73,4-dihydrocarbostyril are obtained in the form of colorless needle-shaped crystals, m.p. 212-213 C. Note 2 (reference). 35.4 7-methoxy-3,4-dihydrocarbostyril is dissolved in 300 ml of acetic acid, and while cooling in an ice bath and with stirring, 27 g of chlorine sulphuryl dissolved in 100 ml of acetic acid are added dropwise to this solution. acid, then the reaction mixture is left overnight. The reaction mixture is extracted into 1 liter of ice-water, the precipitate formed is filtered off, washed with water, dried and recrystallized from methanol. Obtain 30 g of 6-chloro-7-methoxy-3, 4-dihydrocarbostyril in the form of colorless needle-shaped crystals with so pl. 212 ° C. 30 g of the 6-chloro-7-methoxy-3, 4-dihydrocarbostyril obtained are dispersed in 300 ml of hydrobromic acid and refluxed for 4 hours. After cooling the reaction mixture, the resulting substance is filtered out, rinsed with water and crystallized from the mixture methanol with chloroform. 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril are obtained in the form of colorless needle-shaped crystals with m.p. 264-266 C. PRI me R 3 (reference). 16.4 g of 5-hydroxy-3, 4-dihydrocarbostyril are dissolved in 300 ml of acetic acid and 80 ml of acetic acid containing 14 g of chlorine are added dropwise to this solution with stirring at room temperature, then continue stirring for another 3 hours. The reaction mixture is poured into 500 ml of water and left to stand for 1 hour. The precipitate formed is separated by filtration, taken up in water, dried and recrystallized from methanol. 16 g of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril are obtained in the form of colorless crystals with m.p. 259-260 ° C. EXAMPLE 4 20.0 and 8-bromo-5-oxy-3, 4-dihydrocarbostyril and 18 g of potassium carbonate were dispersed in 160 ml of isopropanol, then 40 ml of epichlorohydrin was added and heated at 80 ° C for 6 hours. The reaction mixture was concentrated under reduced pressure, to the resulting residue was added 100 ml of 2N. sodium hydroxide and mix thoroughly. The resulting substance is separated by filtration, washed with water, dried, recrystallized from methanol, to obtain 18.5 g of 8-bromo-5- (2,3-epoxypropoxy) 3, 4-dihydrocarbostyril as colorless needle-shaped crystals with m.p. 220-222 ° C. PRI me R 5 (reference). 16.4 g of 5-hydroxy-3, 4-dihydrocarbostyril and 3.7 g of sodium hydroxide are added to 100 ml of methanol and stirred at AO-SO for 3 hours, then 150 ml of epichlorohydrin is added to the mixture and boiled refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure to dryness and the semi-residue was recrystallized from cm 2 methanol with water in a ratio of 1: 1. 18.5 g of 5- (2, 3-epoxypropoxy) 3,4-dihydrocarbostyryl were obtained ; 1e colorless crystals with t.pl, 172173 ° C. Example 6 (denomination) 16.3 5-hydroxy-3, 4-dihydrocarbostyril and 9. Potassium hydroxide are mixed with 150 m of isopropanol and stirred at 7080 ° C for 30 minutes. Then, 25 g of 1,3-bromochloropropane is added to the mixture and refluxed for 6 hours. After completion of the reaction, the reaction mixture is poured into 200 ml of 2N. an aqueous solution of sodium hydroxide and the formed solid are separated by filtration, washed with water, dried and recrystallized from ethanol to obtain 18.5 g of (3-chloropropoxy) -3, 4 dihydrocarbostyril in the form of colorless needle-shaped crystals with m.p. 176-178 seconds. Example (reference) 4-Fensch1piperidine, 24 g-chloro-3-bromopropane and 15 g of triethylamine are mixed with 100 ml of dimethylformamide and stirred at 50-60 0 1 h. The reaction mixture is mixed into 200 ml of a saturated aqueous solution of chloride sodium and organic layer are extracted with chloroform. Then the chloroform layer is washed with water, dried and the chloroform is removed by distillation. The residue is purified by chromatography on a column of silica gel. 15.3 g of 1-chloro-3- (4-phenylpiperyl dil) propane are obtained in the form of a colorless oily substance, which is distilled and 11 g are obtained from a bale, 112-115 ° C / 0.1 mm Hg. Art. A portion of this distillate is converted to the hydrochloride and recrystallized from ethanol. 1-chloro-3- (4-phenyl-1-pipa15idyl) propane monohydrochloride is obtained with m.p. 167-169 ° C in the form of colorless needle-shaped crystals, EXAMPLE 7 Example 1, 1-chloro-2-methyl-3- (4 phenyl-1-piperid; yl) propane is obtained in the form of a colorless oily 3 t.kip, 114-1Tb C / O, 1 mm Hg 7 10 9 (sync). EXAMPLE EI 4-hydroxy-4-fensch: shiperidine 5 24 g of chlorine-3-bromopropane and 15 g of triethylamine are mixed with 100 ml of dimethylformamide and stirred at 50-60 C for 1 h. The reaction is taken in 200 ml of saturated aqueous solution of chloride sodium and the organic layer is extracted with chloroform, washed with water, dried, and the chloroform is removed by distortion. The residue obtained is purified by chromatography on a column of silica gel. 14.3 g of 1-chloro are obtained. 3- (4-hydroxy-4-phenyl-1-piperidyl) propane as a colorless oily substance. This oil is distilled at low pressure. The distillate is transferred to the hydrochloride, recrystallized from atanol, and 1-chloro-3- (4-hydroxy-4-phenyl-1-piperidyl) propane monohydrochloride is obtained, m.p. | 92195 C, as colorless needles} of suspended crystals. Example 1, 4.8 g of 5- (3-chloropropoxy) -3,4-dihydrocarbostyril and 4.2 g of 4-benzylpiperidine are mixed with 40 ml of toluene and heated under reflux for 24 hours. After cooling the reaction mixture, the precipitate formed is filtered off, washed with water, recrystallized from ethanol, and 6.3 g (76%) of 5-C3- (4-6enzyl-1-piperidyl) propoxy-3, 4 dihydrocarbatiryl in the form of colorless needle-like crystals are obtained with mp.143 .45 ° C. EXAMPLE 2 4j9 g of 1-methyl-7 (3-chloropropoxy) -3,4-dihydrocarbostyril, 4.2 g of 4-benzylpiperidine, and 3 g of riethylacine are mixed with 60 ml of diethylformamide. The mixture is heated at 70-80 ° C for 8 hours. After the completion of the reaction, the reaction mixture is concentrated under reduced pressure to dryness. The resulting residue is dissolved in% aqueous sodium bicarbonate and is constructed with chloroform. The chloroform layer is washed with water, dried, and then the chloroform is removed by distillation. The resulting residue is dissolved in 0 ml of acetone and, while stirring, a 5% solution of alkaline acid in acetone is added to it to pH 4.5. Then maintain the reaction mixture. The precipitate formed at the same time is otlivat by filtration, washed with acetone, recrystallized from smears of ethanol and ether to obtain 7.9 g (yield 86%) of 1-methyl-7-C3 (4-benzyl-1-piperidyl) propoxy1-3,4 dihydrocarbatiryl monooxalate as a colorless powder, so pl. 175177 0. . In a similar manner as described in Example 2, the compounds of Examples 3-16 are prepared. Note 3.-Propargyl-5- 3 (4-6enzyl-1-piperidyl) propoxy-3,4 dihydrocarbostyryl hydrochloride monohydrate. Colorless needle-shaped crystals (from a mixture of methanol and ether) So pl. 172 ° C (with decomp.). PRI me R 4. 1-Methyl-5-СЗ- (4benzyl-1-piperidyl) propoxy-3,4-dihydrocarboxyryl monohydrochloride. Colorless needle-shaped crystals (from a mixture of methanol and ether) So pl. 130-133 0. Example 5. 1-Hexyl-7- 3- (4phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl monooxalate. Colorless needle-shaped crystals (from isopropanol). T. pl. t68-170 ° C. EXAMPLE 6 1- (3-Phenylpropyl) (4-phenyl-1-piperidyl) propoxy3, 4-dihydrocarbostyryl monooxalate. Colorless needle-shaped crystals (from a mixture of methanol and water. So pl.210 213 ° C. PRI me R 7. 6,8-Dichloro-5-2methyl-3- (4-phenyl-1-piperidyl) propoxy - 3,4-dihydrocarboxystyrene 1. Colorless needle-shaped crystals (from ligroin): Tpl 125-126 ° C. Example 8. (4-Benzyl-1piperidyl) propoxy-3,4-dihydrocarbatiryl monohydrochloride. Colorless needle-shaped crystals (methanol ), Mp 213-215 ° C. EXAMPLE 9 (4-Benzyl-1-piperidyl) propoxy J-3,4-dihydrocarbo styryl, Colorless needle-shaped crystals (from a mixture of ligroin and benzene). mp 143-145 ° C. Example 10. Monooxalate (4-benzyl-1-piperidyl) propoxy -3.4 d ihydrocarbostyril. Colorless prisms (from ethanol), mp 175-177 ° C. Example 11. 7-3- (4 -felyl-1-piperidyl) propoxy J3, 4-dihydrocarboxyryl monohydrochloride. Yellowish needle-like crystals (from ethanol) Mp 252-254 ° C. 109 Example 12 4-methyl-7-- f 3- (4-benzyl-1-piperidyl) propoxy carbostyryl dihydrate monohydrochloride. Colorless needles (from ethanol). T. mp 241-242c. Example 13. 5-СЗ- (4-phenyl-1-piperidyl) propoxy} 3, 4-dihydrocarbostyryl monohydrochloride. Colorless needle-shaped crystals (from methanol). M.p. 200 ° C. EXAMPLE 14 4-Methyl-6- {3-4- (4-methylphensh1) -1-piperidyl) propoxy carbostyryl monohydrochloride. Colorless needle-shaped crystals (from methanol). M.p. 256-259 ° C (with decomp.). Example 15. 4-methyl-6-3-4- (4-chlorophenyl) -1-piperidyl propoxy carbostyryl monohydrochloride. Colorless needle-shaped crystals (from methanol). M.p. 263-265 C. Example 16. 1-isopentyl-2-hydroxy-3-4- (3,4, 5-trimethoxyphenyl) -1-piperidyl propoxy-3,4-dihydrocarbostyril monooxalate. Colorless flaky crystals (from ethanol). M.p. 199-20lc. Example 17. 2.1 t of 7- (5-bromoethoxy) -3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperidine and 1.5 g of triethylamine are mixed with 30 ml of dimethylformamide and the mixture is heated at 6070 ° C for 6 hours. Then the reaction mixture is concentrated under reduced pressure to dryness and to the resulting residue is added 5% aqueous sodium bicarbonate solution and stirred. The solid formed is separated by filtration, washed with water and dried. By recrystallization from ligroin, 3.6 g (yield 88%) of (4-benzyl-1-piperidyl) pentoxyJ3, 4-dihydrocarbostyryl are obtained in the form of colorless plate crystals. M.p. 100-102C. Example 18. 2.5 g of 4-methyl-6 (3-chloropropoxy) carbostyril, 1.8 g of sodium iodide are mixed with 50 ml of acetone and stirred at 50 for 1 hour, then 50 ml of dimethylformamide is added and the acetone is removed by distillation at reduced pressure. 1.5 g of triethylamine and 1.6 g of 4-benzylpiperidine are added to the obtained residue and the mixture is heated with stirring for 7 hours at 7080 ° C. Then the reaction mixture is concentrated under reduced pressure
    60 ml of 5% aqueous sodium bicarbonate solution are added to dryness and to the residue. The resulting substance is separated by filtration, washed with water, then recrystallized from methanol and 3.2 g (yield 82%) of 4-methyl-6- 3- (4-benelyl-1-pyperidyl) propoxy-jacarbatir are obtained in the form of yellowish prismatic crystals Tpl , l / t-iyS C.
    By the method similar to Example 18 described, the following compounds of Examples 19-24 are prepared.
    PRI me R 19. A-Methyl-U-3-Sabenzyl 1-piperidyl) propoxy carbostyl.
    Colorless needle-shaped crystals (from methanol), m.p. 183-184 ° C.
    Example 20. 4-Phenyl-7- 3- (4-phenyl-1-piperidyl) propoxy carbostyryl monohydrochloride.
    Colorless needle-shaped crystals (from a mixture of methanol and ether). M.p. 238-24lc.
    Example 21, 4-Methyl-6- 3- (4benzyl-1-piperidyl) propoxy carbostyryl.
    Yellow-brown prism-shaped crystals (from methanol). M.p. 177-178 C.
    Example 22. 4-Methyl-6- 3- (4-benzyl-1-piperidyl) propoxy-3-carbostyryl monohydrochloride.
    Colorless crystalline powder (from a mixture of ethanol, acetone and ether.). T. pl. .
    Example 23. 4-Methyl-6-W- (4-methylphenyl) -1 -pitseridyl-propoxy-1-carbostyryl monohydrochloride.
    Colorless needle-shaped crystals from methanol. M.p. 256-259С (with decomposition).
    Example 24. 4-Methyl-6-f3- (4-chlorophenyl) -1-piperidyl1-propoxy carbostyril monohydrochloride.
    Colorless needles
    (from methanol). M.p. 263-265 S.)
    Example 25. 2.6 g of 1-Allyl 5- (2-hydroxy-3-chloropropoxy) -3,4-dihydrocarbostyril, 1.5 g of triethylamine and 2.0 g of 4-benzylpiperidine are mixed with 30 ml of dimethylformamide and the mixture is stirred at 80 -90 C 5 The reaction mixture was poured into 80 ml of a 5% aqueous solution of sodium bicarbonate and extracted with chloroform, washed with water, and dried. Then chloroform is removed by distillation and the residue is dissolved in 30 ml.
    acetone and add 5% solution of oxalic acid in acetone to pH 4.5. The resulting crystals are separated by filtration and washed with acetone. By recrystallization from ethanol, 4.3 g (82% yield) of 1-allyl-5-C2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarbostyrene monooxalate are obtained in the form of colorless needle crystals. M.p. 178-180s.
    In a manner similar to that described in Example 25, the compounds of Examples 26-36 were prepared.
    PRI me R 26. Monooxalate 1-benz1-4-4-2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarbostyril.
    Colorless crystalline powder (from ethanol-ether). M.p. 213214s (with diff.).
    PRI me R 27. Monooxalate-1ETHYL-5-C2-OXI-3- (4-benzyl-1-piperidyl) - nponoKQH 3-3,4-dihydrocarbostyril.
    Colorless needle-shaped crystals (from ethanol). M.p. 164-169 0.
    Example 28. 8-Bromo-5-2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl.
    Colorless needle-shaped crystals (from ethanol). M.p. 165-166 With,
    EXAMPLE 29 5- 2-Oxy-3- (4phenyl-1-piperidyl) propoxy-3, 4-dihydrocarboxyryl.
    Colorless acicular crystals (from ethanol), m.p. 207-208 S.
    PRI me R 30, 6- 2 Oxy-3- (4-phenyl-1-piperidp) propoxy-3,4-dihydrocarbostyryl.
    Colorless lamellar crystals (from ethanol). M.p. 170-171 ° C.
    EXAMPLE 31 7-C2-Oxy-3- (4-phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl.
    Colorless needle-shaped crystals (from isopropanol). M.p. 149-150 C.
    Example 32. 1-Allyl-5- 2-hydroxy-3- (4-fench-1-piperidyl) propoxy-3,4 dihydrocarbostyryl.
    Colorless needle-shaped crystals (from ligroin). M.p. 92 C.
    PRI me R 33. Monooxalate 1-allyl-5 - 2-hydroxy-3- (4-fe NIL-1-piperidyl) propoxy 3,4-dihydrocarbostyril.
    Yellowish needle-shaped crystals (from methanol). M.p. 208s (with different). Example 34, 1-methyl-5-2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy 3-3,4-dihydrocarbostyril monooxalate. Colorless powder (from a mixture of ethanol and ether). T, pl. 150152 S. PRI me R 35. 1-Benzyl-5-C2-hydroxy-3- (4-benzyl-1-piperidyl) propokcHj-3, 4-dihydrocarbostyryl. Colorless needle-shaped crystals (from ethanol, mp. 141-143 ° C. Example 36. Monooxalate 1-iso-pentyl-6-- 2-hydroxy-3- 4- (3,4,5-trimethoxyphenyl) -1-piperidyl1propoxy 3, 4-dihydrocarbostyril, colorless flaky crystals (from ethanol), mp 199-201 ° C. Example 37: 2.4 g of 7-hydroxy-4phenylcarbostyril and 0.8 g of potassium hydroxide are mixed with 60 ml of methanol and concentrated dry under reduced pressure. To the obtained residue, 60 ml of dimethylformamide are added and thoroughly mixed, then 5 g of 1- (3-chloropropyl) -4 phenylpiperidine is added to the mixture and the mixture is heated at 70-80 ° C with stirring The reaction mixture is concentrated under reduced pressure to dryness, and 60 ml of a 5% aqueous solution of sodium bicarbonate is added to the resulting residue and extracted with chloroform. The chloroform layer is washed with water, dried and the chloroform removed by distillation. 30 ml of methanol and 5 ml of concentrated hydrochloric acid are concentrated under reduced pressure, the residue is crystallized from ethanol and recrystallized from methanol to give 2.8 g (58% yield) of 4-phenyl-7-C3- (4-phenyl- 1-piperidyl) propoxy} carbos tiril monohydrochloride in the form of colorless needle-shaped crystals. Melting point 288-241 C In a manner similar to that described in Example 55, the compounds of Examples 49-69 were prepared. Example 38. Monooxalate 1-methyl-7-C3- (4-benzyl-1-piperidyl) propoxy-3, 4-dihydrocarbostyryl. Colorless powdery substance (from a mixture of ethanol and ether). T. pl. 175-177С. Example 39. Monohydrochloride, 1-propargyl-5-H- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarboxytes 10 16 la monohydrate. Colorless needle-shaped crystals (from a mixture of methanol and ether). M.p. (directly). PRI me R 40. 1-Methyl-5- 3- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl monohydrochloride. Colorless needle-shaped crystals (from a mixture of ethanol and ether). M.p. 130-133 ° C. EXAMPLE 41 Monooxalate 1-hexyl-7-f3- (4-phenyl-1-piperidyl) propoxy-3, 4-dihydrocarbostyril. Colorless needle-shaped crystals (from isopropanol). M.p. .168-170 C. Example 42. 1- (3-phenylpropyl) (4-phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl monooxalate. Colorless needle-shaped crystals (from a mixture of methanol and water). T.pl.210213 ° C. Example 43. Manoxalate 1-all-1-5-2-hydroxy- (4-benzyl-1-piperidyl) propoxy) -3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 178-180 ° C. EXAMPLE 44 1-Methyl-4-2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl monooxalate. Colorless crystals (from ethanol and ether). M.p. 150-152 0. Example 45. 1-Benzyl-5-2-oxy-3- (4-benzyl-1-piperidyl) propoxy 3, 4-dihydrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 141-143C. PRI me R 46. 5-СЗ- (4-benzyl-1-piperidyl) propoxy 3,4-dihydrocarbostyril monohydrochloride. Colorless needle-shaped crystals (from methanol). M.p. 213-215 0. EXAMPLE 47. Monooxalate (4-benzyl-1-piperidyl) propoxy-3,4 dihydrocarbostyryl. Colorless needle-shaped crystals (from a mixture of ligroin and benzene). - 1 3-145 С (with diff.). Example 48 Monooxalate (4-benzyl-α-piperidyl) propoxy J-3,4 dihydrocarbyl. Colorless prism-shaped crystals (from ethanol). M.p. .175-177 ° C. EXAMPLE 49. 1-Allyl-5-2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy-3,4 dihydrocarbostyryl. Colorless needle crystals (from ligroin). M.p. 92 ° C. Example 50, Allyl-4-2-hydroxy-3 (4-phenyl-1-py11-idridyl) propoxy 3-3,4-dihydrocarbyl monooxalate monooxalate. Yellowish needle-shaped crystals (from methanol), mp 208 ° C (with,). Example 51: 4-Methyl-6- {3- (4 benzyl-1-piperidyl) propoxy carboxyryl. Yellow-brown prism-shaped crystals (from methanol). M.p. 177-178s, Example 52. 4-Methyl-6- 3- (4-benzyl-1-piperidyl propoxy carbostyryl monohydrochloride. Tandem-free crystalline powder (from a mixture of ethanol, acetone and ether). Mp. 217 C. P. EXAMPLE 53 Monohydrochloride (4-phenyl-1-piperidyl) propoxy 3,4-dihydrocarbostyril Yellowish needle-shaped crystals (from ethanol) T. pl. 252-254 p. EXAMPLE 54. Monogram of hydrochloride 4-methid1-7 - (- 3- (4-benzshst-1-piperidyl propoxy carbostyryl dihydrate. Colorless needle-shaped crystals (from ethanol). So pl. 241-242 ° C, PRI mep 55. Monohydrochloride ( 4-phenyl-1-piperidyl) propoxy carbostyril. Colorless needle-shaped crystals (from methanol), mp 200c. Example 56. 4-methyl-6-3-4- (4-methylphenyl) -1-piperidyl propoxy carbostyril monohydrochloride. Colorless needle-like crystals (from methanol). mp 256 -259 Q (with decomp.). EXAMPLE 57. 4-Methyl-6- {3-G4- (4-chlorophenyl) -1-piperidyl propoxy | carbostyril monohydrochloride. Colorless needle-shaped crystals (from methanol), Mp 263-265 C. EXAMPLE 58. Monooxalate 1-isopentyl-6-2-hydroxy-3- 4- (3,4, methoxyphenyl) -1-piperidyl propoxy 3,4-dihydrocarbostyril. colorless flaky crystal (from ethanol). M.p. 199-201 ° C. Example 59 2.4 g of 6,8-dichloro 5-hydroxy-3, 4-dihydrocarbostyril and 0.8 g of granulated potassium hydroxide are mixed with 60 ml of methanol and concentrated under reduced pressure to dryness. The resulting residue is added to 60 ml of dimethylformamide and thoroughly mixed, then 5 g of 1-chloro-2-methyl-3- (4-phenylpiperidyl) propane are added and the mixture is heated at 70-80 ° C for 8 hours with stirring. The reaction mixture is concentrated under reduced pressure to dryness, then 60 ml of 5% aqueous sodium bicarbonate solution is added and extracted with chloroform. The chloroform layer is washed with water and dried, then the chloroform is removed by distillation and the residue thus obtained is purified by silica gel column chromatography, recrystallized from ligroin, and 1.6 g are obtained (yield 35%) of 6.8-dichloro-5-2- methyl 3 (4-phenyl-1-piperidyl) propoxy-3,4 dihydrocarbostyril in the form of needle-like colorless crystals. M.p.125126 ° C. By a method similar to that described in Example 7, the following compounds of Examples 60-64 were prepared, P e im p 60. (4-Benzyl1-piperidyl) propoxy J-3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 143-145p. Example 61. (4-Benzyl1-piperidyl) pentoxy2-3,4-dihydrocarbostyryl. Colorless lamellar crystals (from ligroin). M.p. 100-102s. EXAMPLE 62. 4-Methyl-6- 3- (4benzyl-1-piperidyl) propoxy carboxyryl. Yellowish prism-shaped crystals (from methanol). M.p. 177-178 ° C. Example 63: 4-Methyl-7- 3- (4benzyl-1-piperidyl) propoxy carboxyryl. Colorless needle-shaped crystals (from methanol). M.p. 183-184c, EXAMPLE 64. 8-Bromo-5-2-hydroxy-3- (4-benzyl-1-piperidyl) propoxy 3, 4-dihydrocarbostyryl. Colorless needles (ethanol). M.p. 165-166 C. PRI me R 65. 2.0 g of 5- 2-hydroxy-3- (4-phenyl-1-piperidyl) propoxy 3, 4-dihydrocarbostyril and 3 g of methyl iodide are mixed with 30 ml of dimethylformamide and mixed at 50 ° C for 5 hours. The reaction mixture is concentrated under reduced pressure, and the resulting residue is added to 50 ml of acetone and stirred. The precipitate formed is collected by filtration, washed with acetone and recrystallized from a mixture of methanol and ethanol. 1.7 g of 4-phenyl-1-C2-hydroxy-3- (2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy) propyl iodide are obtained. -1-methylpiperidini in the form of a colorless powder. M.p. 242-43 0. By a method similar to that described in Example 65, the following compounds of Examples 66 and 67 are prepared. Example 66: 4-Phenyl-2-hydroxy-3- (1-allyl-2-Oxo-1) iodide 2,3,4 tetrahydroquinolin-5-yloxy) propyl 1-methylpiperidinium. Colorless needle-shaped crystals (from a mixture of isopropanol and acetone). M.p. ng-iso c. EXAMPLE 67 4-benzyl iodide 1-C2-hydroxy-3- (1-benz1-1-oxo-1,2,3,4 1 tetrahydroquinolin-6-yloxy) propyl 1-methylpiperidinium. Yellowish crystals in the form of needle (from a mixture of ethanol and ether). M.p. 135-139 0. Example 68. 2, O g of 4-phenyl-1-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yloxy) propyl -1-methylpiperidine hemihydrate iodide is dissolved in 150 ml of methanol and 100 ml of water, then 3.0 g of silver chloride is added to the solution and stirred in the dark in the refrigerator for 24 hours. The reaction mixture is filtered and the mother liquor thus obtained is concentrated under reduced pressure to dryness. The residue is recrystallized from a mixture of isopropanol, acetone and ether to obtain 1.0 g of 4-phenyl-1t chloride 3- (2-oxo-1,2,3,4-tetrahydroquinolin-7-Sh1Oxy) propyl 3-1-metstpiperidine hemihydrate in the form of a colorless crystalline powder. Mp 211213C. Example 69 2.4 g of 7- (3-chloropropoxy) -3.4 dihydrocarbostyril and 4.0 g of 4-hydroxy-4-phenylpiperidine are mixed with 15 C1 ml of toluene and boiled for 24 hours under reflux. After cooling the reaction mixture, the resulting precipitate is collected by filtration and washed with water, then recrystallized from ethanol. 2.8-g (4-hydroxy-4-phenyl-peridyl) propoxy 2-3,4-hydrocarbyls of the reel are obtained in the form of colorless flaky crystals. M.p. 215 C. In a manner analogous to that described in Example 69, the compounds of Examples 70-77 are prepared. PRI me R 70. 5-C3- (4-hydroxy-4phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl. Colorless needle-like crystals (from methanol). M.p. 265-26bs. EXAMPLE 71 7- 3- 4-Oxy-4- (4 chlorophenyl) -1-piperidyl propoxy-3,4 diggdrocarbostyryl. Colorless needle-shaped crystals (from ethanol). M.p. 189-190 ° C. PRI me R 72. (4-Acetyl-4-phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl. Light yellowish prism-like crystals (from ethanol). M.p. PRI me R 73. (4-Acetyl-4-phenyl-1-piperidyl) propoxy-3,4-dihydrocarbostyryl. Colorless needle-shaped crystals (from isopropanol). M.p. 159-160 ° C. PRI me R 74. (4-Acetyl-4phenyl-1-piperidyl) ethoxy carbostyryl. Colorless acicular crista. Shy (from ethanol). M.p. 158-160 C. Example: 75- 7- {3- (4-Oxy-4- (4-methylphenyl) -1-piperidyl propoxy-3,4 dihydrocarbostyryl. Colorless flocculent crystals (from ethanol). So pl. 188-189 ° C. PRI me R 76. 7- 3-4-hydroxy-4- (2-methoxyphenyl) -1-piperidyl-propoxy 1-3, 4-dihydrocarbostyryl monohydrochloride. Colorless crystalline powder (from a mixture of methanol and water ), Mp 239-24lc., Example 77, 4-Methyl-3-G4- (4 acetyl-4-phenyl) -1-piperidyl propoxy carbostyryl. Light yellowish needle-shaped crystals (from methanol). Mp 212-213 C. Example 78 1.43 g 1-methyl6- (2-bromoethoxy) -3,4-dihydrocarbostyril, 1.3 g 4-acetyl-4-phenylpiper Dine and 1.0 g of triethylamine are mixed with 30 ml of dimethylformamide and the mixture is heated at 60-70 ° C for 6 hours. The resulting reaction mixture is concentrated under reduced pressure to dryness and to the residue is added 5% aqueous sodium bicarbonate solution and stirred. The solid is collected by filtration, washed with water, dried and recrystallized from ethanol / water to obtain 1.3 g 1
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of carbostyril of the general formula I / Where R ^ is hydrogen, alkenyl or Cg-Cg. Alkynyl, C-j-Cg-alkyl, which may be substituted with phenyl;
    ~ hydrogen, C ^ -Cg alkyl or phenyl;
    R ^ is C-j-Cg-alkyl which may be substituted by phenyl or phenyl substituted by 1-3 substituents from halogen, C ^ -Cg-alkyl or C ^ -Cg-alkoxyl;
    - hydrogen, hydroxyl or C ^ -Cg-alkanoyl;
    X is halogen;
    η = 0, 1 or 2;
    Y is C ^ -Cg alkylene with 1-6, which may be substituted with hydroxyl;
    the relationship between positions 3 and 4 may be single or double provided that, if Rj is alkyl substituted with phenyl, then it cannot be hydroxyl or alkanoil, or their pharmacologically acceptable acid addition or quaternary salts of the general formula 1a
    Ry - C ^ -Cg-alkyl}
    Q is halogen, characterized in that carbostirol of the general formula II
    SU, „> 1091857 where 1C, R 2 , X, n and carbon are the carbon bonds between positions 3 and 4
    1091857.
    have the indicated meanings, B is hydrogen or a group X — Y—, where Y has the indicated meanings, and X ^ is halogen, is reacted with a piperidine derivative of the general formula III where R ^ and R ^ have the indicated meanings, Z is hydrogen or the group X 2 -Y ~, where Y has the indicated meanings, and X 2 is halogen, provided that if В is hydrogen, then the Z-group is Χ ^ -У-, and if В is a group X 1 -У-, then 2 - hydrogen, followed by isolation of the desired product in the form of a base or an acid addition salt or by asking application of the compounds of general formula IV d e R ^ h Q have the abovementioned meaning, and quat release tertiary salt of the formula 1A.
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    同族专利:
    公开号 | 公开日
    AR230280A1|1984-03-01|
    AR230059A1|1984-02-29|
    IT8068445D0|1980-09-18|
    GB2063869B|1983-05-25|
    DK158984C|1991-01-14|
    NO154841B|1986-09-22|
    ES495163A0|1981-11-16|
    NO802762L|1981-03-19|
    FI802905A|1981-03-19|
    FI76322C|1988-10-10|
    IT1129263B|1986-06-04|
    GB2063869A|1981-06-10|
    FR2465732A1|1981-03-27|
    DE3034237A1|1981-04-16|
    MX6806E|1986-07-30|
    PT71810B|1981-07-07|
    FR2465732B1|1983-06-24|
    US4482560A|1984-11-13|
    NL187912B|1991-09-16|
    DK394080A|1981-03-19|
    CA1151172A|1983-08-02|
    SE439632B|1985-06-24|
    NL8005188A|1981-03-20|
    ES8200679A1|1981-11-16|
    ATA465780A|1984-06-15|
    PT71810A|1980-10-01|
    DE3034237C2|1988-04-21|
    AT376972B|1985-01-25|
    AU518144B2|1981-09-17|
    FI76322B|1988-06-30|
    AU6238180A|1981-05-28|
    SE8006498L|1981-03-19|
    NL187912C|1992-02-17|
    NO154841C|1987-01-07|
    DK158984B|1990-08-13|
    CH645892A5|1984-10-31|
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    法律状态:
    优先权:
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