• 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:
    The compounds of formula in which R' is hydrogen, halogen, hydroxy, or alkyl; R2 is substituted or unsubstituted pyridinyl, pyrazinyl, quinolinyl or quinoxalinyl and said substituents are alkyl, alkoxy, alkoxycarbonyl, halogen, cyano or nitro; and n is 2, 3, 4, 5 or 6; and the pharmaceutically acceptable salt thereof, are antipsychotic and anxiolytic agents.
    公开号:SU1442074A3
    申请号:SU864028180
    申请日:1986-09-12
    公开日:1988-11-30
    发明作者:Абдель-Меджид Абоу-Гхарбиа Маджид
    申请人:Американ Хоум Продактс Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining new derivatives of --carbolinum of the general formula
    (CH2) Rj
    where R is hydrogen or halogen, R 2 is a group of the formula

     -O ™
    n 2,3 or 4,
    or their pharmaceutically acceptable salts with antipsychotic and antidepressant properties.
    The aim of the invention is the development of a method based on the known methods for the preparation of new compounds with valuable pharmacological properties with increased activity.
    After each example, a pharmaceutical evaluation of the compound obtained is given. Experiments on conditional {1 run are given as comparative activity {for jumping to the shelf (PP) at the intraperitoneal dose, mg / kg (ib), and ABje for lever reaction (PP) at the oral (ode) dose, mg / kg Permanent inhibition is given for limbic D-2 binding, expressed in jL (M concentration. Similarly, the inhibition constant for cortical 5HT1 -. Binding is given as permanent inhibition in pM concentration. All compounds that were inactive as opposing apomorphine.
    Example 1. 8-Fluoro-2,3,4,5-tet rahydro-2-G4- (4-pyridinyl) butyl -1H- -pyridi- (4,3-b) indole.
    To the mixed suspension of 8-fluoro--2,3,4,5-tetrahydro-1H-pyrid (453-b) -indole (1.5 g, 0.0079 mol), freshly dried anhydrous sodium carbonate (1.7 g, 0.016 mol) and a catalytic amount of cesium carbonate in 70 MP of dimethylformamide, 2-, 33 g (0.016 mol) of 4-pyridinylbutyl bromide hydrobromide are added.
    The reaction is carried out with stirring at a scientific research institute at room temperature overnight, then the solvent is removed in vacuo and a solid suspension cake
    o
    five
    0
    five
    d
    five
    five
    five
    N
    N
    100 MP of water and extracted with methylene chloride (3x100 ml). The methylene chloride extracts are combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The target compound is separated by horizontal preparative thin layer chromatography using ethyl acetate as the solvent to obtain 2.3 g of the expected product, which is converted to the salt: ... dichlorohydrate, mp 210-212 C.
    Calculated,%: C 59.97 H H 6.3; 10.14.
     2HC1-H, 0
    Found,%: C 57.67-H 5.78 10.29.
    PP active (20).
    RR 15.11 od (tO, 38-34., 33).
    Limbic D-2 143 (92-214).
    Cortical 5-NTG 480 (140-980).
    Example 2. 8-Fluoro 2,3,455-tetrahydro-2-G2- (2-pyridinyl) ethyl 7-1H-pyridin (4,3-b) indole.
    A mixture of 3.2 g (0.016 mol) of 8-fluoro--2,3,4,5-tetrahydro-1H-pyrid (4,3-b) indole, 2-vinylpyridine (1.79 g 0.017 mol) and 2 ml glacial acetic acid is heated under reflux for 48 hours in 30 ml of methanol. The solvent is removed in vacuo and the separated solid is purified by horizontal or preparative thin layer chromatography and converted into the dihydrochloride salt to obtain 2.5 g. (38% yield) of the desired product, m.p. 199-201 6.
    Calculated,%: C 55.96; H 5.7; N 10.88.
    ScN fgNj-2HC1-NgO
    Found,%: C 56.51j H 5.39; N 10.96.
    PP active (20).
    PP 37.64 od (20.86-322.08).
    Limbic D-2 26 (13-42).
    Cortical 5 - HT2 173 (139-220).
    Example 3. 2,3,4,5-Tetrahydro -2 (2-pyridinyl) ethyl -1-H-pyridol- (4,3-b) indole.
    The target compound was prepared according to Example 2, except that instead of the 8-fluoro-2,3s4,5-tetrahydro-1H-pyrid (4,3-b) indole, 2,3,4,5-tetrahydro-1H-pyrid (4,3-h) indole. The product is converted to the dihydrochloride salt. M.p. 189-19GS.
    Calculated,%: C 57.29; H 6.4) N 11.18; C1 18.79.
    With fjH ,, Мз-2НСЫ / 2НгО
    Found,%: C 57.4j H 6.36, - N 10.97; C1 18.95.
    PP active (40) ..
    PP is very weak (40 od).
    Limbic D-2 33% at 1.
    EXAMPLE 4 8-Fluoro-2,3,4,5-tet rahidro-2-H2- (2-quinolinyl) ethyl J-1H-pyrid (4,3-b) indole.
    The target compound is prepared according to Example 2, except that 2-α-vinylquinoline is used instead of 2-vinylpyridine. The product is converted to the dihydrochloride salt, mp. t92-194
    Vyisland,%: C 62.63, - H 5.45 N 9.96.
    C iHipN, F-2HCl
    Found,%: C 62.57 H 5.30 | N 9.43.
    PP active (20).
    Limbic D-2 185.
    Example 5: 2,3,4,5-Tetrahydro -2-t2- (2-quinolinyl) ethyl} -1H-pyrid- (4,3-b) indole.
    The target compound was prepared according to Example 2 with the exception that instead of 8-fluoro-2,3,4,5-tetrahydro-1H- -pyrid (4,3-b) indole, use 2,3,4 5-tetrahydro-1H- pyrid (4,3-b) ivdol, and instead of 2-vinylpyridine-2-vinylquinoline. The product is converted to dichlorohydrate, so pl. 195-197 C.
    Calculated,%: C, 61.83; H, 6.13; N, 9.83; C1 16.6.
    CiiHiiN, 2HCl t1 / 2H2P
    Found: C, 62.24; H, 5.89; N, Cl, 16.12.
    PP active (40).
    PP is weak (40 od).
    Limbic D-2 331 (238-410).
    Example 6..2,3,4,5-Tetrahydro (4-pyridinyl) butyl J-IH-pyrid-: (4,3-b) indole.
    The target compound was prepared according to Example 1, except that instead of 8-fluoro-2,3,4,5 1 etrahydro-1H- -pyrid (4,3-b) indole, use 2,3,4 | 5-tetrahydro-1H pyrid (4,3-b) indole. The product is converted to the salt dichlorohydrata salt, T.Sh1. 204-206 S.
    "H
    Calculated,%; C, 60.60; H 6.80; N 10.60.
    C7oH7 N3-2HCl-H O
    Found,%: C 60.87; H 6.79; N 10.62,
    PP active (20,40).
    PP 7 20 od.
    Limbic D-2 41% at 1 f / M.
    Example 7. 2,3,4,5-Tetrahydro-2f3- (3-pyridit1l) propyl -1H-pyrid- (4,3-b) indole.
    The target compound was prepared as described in Example 1, except that, instead of 8-fluoro-2,3,4,5-tetrahydro-1H- -pyrid (4,3-b) indole, 2,3,4, 5-tetrahydro- 1H-pyridine (4,3-b) is indole, and instead of the salt of 4-pyridinyl-butyl bromide, hydrobromium is used; The product is converted to the dihydrochloride salt, m.p. 223-225 C.
    Calculated,%: C 59.68; H 6.54} N 10.99; C1 18.58.
    C, jHi, N5 2HClVHiO
    Found,%: C 60.78; H 6.26} N 11.08; C1 18.80. Ш1 active (40). RR 33.09 od (25.58-60.65). 5 Limbic D-2 43% at 1 M. Cortical 5-NT7. 252 (197-341). EXAMPLE 8 8-Chloro-2,3,4,5-tetrahydro-2-4- (4-pyridinyl) butyl -1H- -pyrid (4,3-b) indole. 0 The target compound is prepared as in example 1, except that instead of 8-fluoro-2,3,4,5-tetrahydro-1H- -pyrid (4,3-b) indole, 8-chloro--2,3,4 is used. , 5-tetrahydro-1H-pyrid (4,3-b) - indole. The product is converted to the dihydrochloride salt, m.p. 227-228 s.
    Calculated,%: .C 55.74j H 6.03-, N 9.75.
    C7oH iClN3 2HCl-H O 0 Found: C 55.74; H 5.86; , N 9.61.
    PP active (40).
    RR 36.08 od (21.51-59.35).
    Limbic D-2 106 (26-263).
    Cortical 5-HTA 60 (29-132).
    EXAMPLE 9 8-Chloro-2,3,4,5-tetrahydro-2 2- (2-pyridinyl) ethyl J-1H-pyridine (4,3-b) indole.
    The target compound is prepared according to Example 2, except that instead of 8-FTOR-2,3,4,5-tetrahydro-1H- -pyrid (4,3-b) indole, 8-chloro--2,3,4 is used, 5-tetrahydro-1H-pyridine (4,3-b) 45
    50
    indole The product is converted to the dihydrohydrate salt, m.p. 198-200 ° C. Calculated,%: C 53.67; H 5.5; N 10.43.
    Ci HaiClN3-2HCl-HaO
    Found: C 53,32; H 5.3; N 10.21.
    PP active (AO).
    RR JSC odL
    Limbic 103 (72-1A1).
    Example 10. 8-Chloro-2,3, A, 5- -tetrahydro-2C2- (2-quinolinyl) ethyl 3 -1 H-nitride (4,3-b) indole.
    The target compound was prepared according to Example 2, except that instead of 8-fluoro-2,3, A, 5-tetrahydro-1H- -pyrid (A, 3-b) indole, 8-chloro-2,3, A, 5-tetrahydro-1H-pyrid- (A, 3-b) indole, and 2-vinylquinoline is used instead of 2-vinylpyridium. The products are converted to the dihydrochloride salt, m.p. IBT-igO C.
    Calculated,%: C 58.37; H 5.19 N 9.27.
    С2гН., СС1Нз 2НС1-Н20
    Found.%: C 58.3Aj H 5.30; N 9.29. .
    PP active (AO).
    PP AO one ..
    Limbic D-2 82 (A7-136).
    Example 11. 8-Fluoro-2,3, A, 5- -tetrahydro-2-СЗ- (3-pyridinyl) propyl -1 H-pyrid (A, 3-b) INDOL,
    The target compound is prepared as described in Example 1 with the exception that hydrobromide bromide 3-pyridinyl propyl is used instead of hydrobromide of A-pyridinyl butyl bromide. The product is converted to the salt of diclorohydrate, mp. 215 218 C.
    Calculated,%: C 55.7A; H 6.11 N, 10.26.
    With tgHioFNa-HCl -1 1/2
    Found,%: C 56.06; H 5.60 N 10.51.
    PP active (20).
    РР 1А.42 one (9.9A-30.7A).
    Limbic D-2 395 (165-8A8) cortical (76-299).
    Example 12. 8-Chloro-2,3, A, 5- -tetrahydro-2 Sz- (2-pyridinyl) -sh1l3 -1H-pyridi (A, 3-b) indole.
    The target compound was prepared according to Example 1, except that instead of hydrobromide of methyl A-pyridinylbutyl, hydrobromide of methyl bromide 3-pyridinylpropyl was used and instead of 8-fluoro-2,3, A, 5-tetrahydro-1H-pyrid (A, 3 -B) indole using 8-chloro--2.3, A, 5-T8 trahydro-1H-pyrid (A, 3-b) - indole.
    The product is converted to the dichloromethane salt. M.p. 2AO-2A2 ° C.
    five
    0
    five
    about
    0
    five
    0
    five
    Calculated,%: C 57.22; H 5.56; N 10.5A.
    C gH oClNr 2HCl
    Found,%: C 57.60, H 5, A9 N 10.68.
    PP active (AB WB).
    PP AO one
    Limbic D-2 126 (85-183).
    Cortical 5-HTi 28 (12-66).
    Example 13. 8-Fluoro-2,3, A, 5- - heterrahydro-2-C2- (A-pyridinyl) ethyl J- -1H-pyridine (A, 3-b) indole.
    The target compound was prepared according to Example 2, with the exception that jBMecTO 2-vinylpyridine is used as A-vinylpyridine. The product is converted to the dihydrochloride salt, mp. 233-23L.
    Calculated,%: C 58.69; H 5, A3i N11.41.
    C, 8FN3-2HC1
    Found,%: C 58.55} H 5, A2; N 11-, 18.
    PP active (AB WB).
    RR 22.85 (11.34-80.89).
    Limbic D-2 110 (39-274).
    Cortical 5-HT2 211 (165-263).
    Example14. 8-Fluoro-2,3,4,5-tetrahydro-2 C2- (2-pyrazinyl) ztilJ-1H-pyrido (A, 3-b) indole.
    A mixture of 8-fluoro-2,3,4,5-tetrahydro-3-pyrido (4,3-b) indole (3.2 g, 0.016 mol), 2-vinylpyrazine (1.7 g, 0.01 mol ) and 2 ml of glacial acetic acid are refluxed for 48 hours in 30 ml of methanol.
    The solvent was removed in vacuo and the separated solid was purified by high-liquid chromatography and converted to its dihydrochloride. M.p. 200-202 C.
    Calculated,%: C 54.62; H 5.25; N 14.99.
    С Н i7FN4 2HC-1 / 4HiO
    Found,%: C 54,32; H 5.11; N 14.93.
    (S - I) asset (AO).
    Limbik D-2 63% in 1 | uM.
    Example 15. 8-Fluoro-2,3, A, 5- -tetrahydro-2- 3- (3-hydridinyl) propyl-1J-1H-pyrido (4,3-b) indole, monohydrochloride. ,
    0.9 g of the compound in the form of free base is dissolved in 15 ml of thermal ethanol and 1.1 g of the compound in the form of dihydrochloride in 30 MP of hot methanol is added to the stirred solution.
    The solution is brought to a boil, concentrated to 40 ml, cooled and the solid monohydrochloride is separated by filtration and dried. T. Gsh. 217-218 C.
    Vyisleno: C 65.99; H 6.07; N 12.15. .
    C, 9H j Nj HCl
    Found,%: C 66.06 H H 6.09 J N 11.8.
    Example 16. 8-Fluoro-2,3,4,5-tetrahydro-2-C3- (3-pyridinyl) propyl -1 -1H-HYDRIDE (4,3-b) indole hemi-ethyl.
    1 g of compound in the form of free
    electric current. The rat can avoid electric current by suppressing the reaction lever (lever-reaction) or in another study by jumping on the shelf (jump reaction). In each study, the reaction during the initial warning signal is considered an avoidance reaction, Q and the reaction during current-reaction-time shocks cue escape. The avoidance response is determined and expressed as a percentage of the total number of tests of the corresponding number of tests and 50% blockade in
    bases are dissolved in hot ethano-15 Avoiding reactions (AB5o) is achieved
    whether regression of the effect of dose.
    For the study of the extrapyramidal side effects, the compounds of the invention have been studied to counteract the 2Q stereotypical behavior caused by apomorphine, where CF-1 mice (Charles River) receive the test compound intraperitoneally (ib) six mice per dose and after 30 minutes receive 10 mg / kg apomorphine sc. Five minutes after the injections, the presence or absence of rearing-head-bobbing-licking syndrome caused by apomorphine was observed in each animal. 3Q Checks were carried out every 5 minutes for a 30 minute run.
    The AfljoC value is 95% interval. confidence is determined to suppress stereotypical behavior caused by apomorphine by simple linear regression analysis. In this study, the compounds of the invention were inactive, demonstrating low potential for side effects accompanying long-term treatment with conventional antipsychotic medications such as haloperidol and chlorpromazine.
    As a further confirmation of the low potential for side effects exhibited by the compounds, they were investigated according to a method where homogenized marginal brain tissue is incubated with H-spiroperidol and various concentrates (15 mp) and added 0.3 g methane - sulfonic acid in 5 ml of ethanol. The solution is boiled and then cooled rapidly. A few drops of diethyl ether are added and the solution is heated and gradually cooled. The separated solid precipitate is isolated by filtration, dried and the specified hemisylate is obtained, m.p. 204-205 ° C.
    Calculated,%: C 50.29 J H 5.58; .and 8.38.
    CiiHijFSjOt
    Found,%: C 50.17; H 5.57.-, N 8.07.
     PRI me R 17. 8-FTOR-2,3,4,5- -tetrahydro-2- 3- (pyridine) -1H-pyrido (4 J 3 -b) indole, hemofumarate.
    1 g of the compound in the form of the free base is dissolved in hot acetone and 0.37 g of fumaric acid in 25 ml of boiling acetone is added. The solution is boiled and made up to a volume of 20 ml and a few drops of diethyl ether are added to give a cloudy solution, which is then gradually cooled. The precipitated solid is filtered, dried to give a semi-fumarate. M.p. 190-191 ° C.
    Calculated,%: C 65.99; H 6.07; N 12.15.
    CieHitFN 3-1 / 2 C4H404
    Found,%: C 64.59i H 6.06; N 11.85.
    The antipsychotic properties of the compounds of the invention are established as usual.
    40
    45
    pharmaceutically acceptable methods of test compound, fil "
    mi
    bami, including two conditional avoidance studies, in which prepared male rats of diabetes (Charles River) weighing 400-450 g are subjected for 15 s with a warning signal (conditioned stimulus) for 15 s for an additional signal and accompanying strokes
    55
    is scrubbed, washed, agitated, and scintillated toroys are counted.
    Binding in the presence of the test compound is expressed as a percentage of specific binding (total binding is less than binding in the presence of 1 L M (+) (butaclamol).
    electric current. The rat can avoid electric current by suppressing the reaction lever (lever-reaction) or in another study by jumping on the shelf (jump reaction). In each study, the reaction during the initial warning signal is considered an avoidance reaction, and the reaction during current shock-reaction escape The avoidance response is determined and expressed as a percentage of the total number of tests of the corresponding number of tests and 50% blockade in
    35
    40
    45
    55
    is scrubbed, washed, agitated, and scintillated toroys are counted.
    Binding in the presence of the test compound is expressed as a percentage of specific binding (total binding is less than binding in the presence of 1 L M (+) (butaclamol).
    Permanent suppression (Ki) is calculated for the compound of each test to classify the limbic D-2 binding potential. The larger the number, the lower the potential for dopamine receptor binding and the presence of side effects when taking an antipsy. Permanent suppression (95% confidence intervals) for side antipsychotics: haloperidol - 4.0 (3.0-5.6) fi clozapine - 34 (23-54) flufenazine - 4.5 (3.6-5.6 ) PM and sulpiride - 376
    ; (174-5000) PM.
    i In a similar experiment involving cortical tissue of the brain, the compounds of the present invention that were tested showed equal or greater strength than serotonin for binding to serotonin-2 receptors. In this test, Ki of serotonin shows 20 (14-30), while tsapaman is inactive.
    From these data, it can be seen that the activity profile of the compounds of the present invention is a profile of antipsychotic agents with much less potential for extrapyramidal side effects, such as when using main tranquilizers (sedation, pseudoparkinsonism, ataxi, muscle relaxation, etc. .). This activity profile resembles the & depressive compound buspirone.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives -carbolin of the general formula
    HI lj (CHs) -Rz
    Where
    Rf - R N
    H
    hydrogen or halogen; formula group
    .
    one
    P
    7.3 nl 4,
    or their pharmaceutically acceptable icortefi-, characterized in that, u-carboline of the general formula
    RI
    1G-G ""
    where R has the indicated meanings, is N-alkylated in position 2 with a compound of the general formula
    CH,
    CH - R-i or
    X - vCH 7 / n 5
    where X is bromine or chlorine
     n have the indicated meanings, with the subsequent allocation of the desired product in free form or as a physiologically acceptable salt,
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    MX3681A|1993-10-01|
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    NZ217580A|1988-07-28|
    ZA866258B|1988-04-27|
    FI863692A|1987-03-17|
    AT55770T|1990-09-15|
    NO163619B|1990-03-19|
    AU6181386A|1987-03-19|
    GB2180536A|1987-04-01|
    DK440686A|1987-03-17|
    GB8621226D0|1986-10-08|
    US4636563A|1987-01-13|
    AR242208A1|1994-08-31|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/776,180|US4636563A|1985-09-16|1985-09-16|Antipsychotic γ-carbolines|
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