• 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 invention relates to condensed heterocyclic systems, in particular hexahydropyrrolo (1,2-a) quinoline derivatives. or hexahydro-pyrido (1,2-a) quinoline, or octahydrophenanthrene of the general formula: HO-CH2-CH2, it p I -0-C-CCNg) xX2), RI (IJ where R and RX are one methyl, and other hydrogen, M is N or CH, and when M is N, Tq or 2j when M is CH, then those that have analgesic activity and can be used in medicine. The goal is to create active substances of the above class .The preparation of these substances is carried out by the reduction of compounds of the general formula (II) or (III) HO-C (0) -CH, OI K W -o-9- (cnb- {§ H (U) RI (III); o-func2 ) s-ho). 2 where R, R / and p are indicated above, using lithium aluminum hydride in tetrahydrofuran or lithium in anhydrous liquid ammonia. The activity of substances above caffeine and morphine. 1 tab. SO with SAZ JV ate 00 04
    公开号:SU1355130A3
    申请号:SU833665902
    申请日:1983-11-28
    公开日:1987-11-23
    发明作者:Фредерик Егглер Джеймс；Росс Джонсон Майкл；Шерман Мелвин Лоренс (младший)
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    one
    The invention relates to a process for the preparation of new chemical compounds, namely, derivatives of hexapodro pyrrolo (1,2-a) quinoline or hexahydro-pyrido (1,2-a) quinoline, or octahydrophenanthrene of the general formula
    HE
    sn,


    L
    (I)
    С-СНгШ СН С Нe Б-,
    Where
    R and
    R, one of the radicals is methyl, and the other is hydrogen M is nitrogen or the CH group, and when M is nitrogen, or 2, when M is the CH group,
    which possess avalgic activity. The purpose of the invention is to develop, on the basis of a known method, a method for producing new chemical compounds having analgesic activity.
    Example 1. 6-hydroxy-5- (2-hydroxyethyl) -8- (5-phenyl-2К-pentyloxy), 3,3aS, 4,5Е-hexahydro-1-rolo (1,2-a) quinoline (1a).
    A mixture of 10 ml of dry tetrahydrofur and 340 mg (0.87 mmol) of 2-} b-hydroxy-8- (5-phenyl-2E-pentyloxy) -1,2,3,3aS, 4,5K-hexahydropyrrolo (1, 2-a) Quinoline 2-yl-acetic acid is stirred until a solution is formed, after which 33 mg (0.87 mmol) of lithium aluminum hydride is added to the mixture and the mixture is stirred at room temperature for 2 hours. Then the reaction mixture is quenched by adding several The pH of the droplets of water is adjusted to 6.0 by the addition of normal hydrochloric acid thereto and subjected to extraction treatment with ethyl acetate. The combined extract {s1 is washed with brine, dried over magnesium sulphate and the solvent is evaporated in vacuo to give 344 mg of an oil-like residue. This oil-like material is placed on a silica gel column and a mixture of methylene chloride and ethyl acetate is eluted, followed by stripping with methanol. The fractions containing the product are combined and you
    15

    20
    25
    thirty
    35
    40
    45
    50
    55
    soared to dryness under vacuum to obtain 323 mg of an oil-like product, Cet3j +46.5 (s-1, chloroform).
    PMR spectrum (CDClI), S, m, d : 1.20 (g, 3N); 3.60 (t. 2H,); 4.10 (m, 1H); 5.65 (m, 2n); 7.10 (s, 5H).
    Example 2. Bb-6- (2-Hydroxyethyl) - 7OXY-9- (5-pent; L-2-pentilloxy) -2.3, 4, 4aS5,6-hexahydropyrido, (1,2-a) quinoline (16 ).
    In a stream of nitrogen and in anhydrous conditions, a solution of 263 mg (0.65 mmol) of the lactone Bb-6-carboxymethyl-7-hydroxy-9- (5-phenyl-2-pentene-1) -2,3,4,4a, 5 is dissolved in 6-hexahydro (1H) pyrido (1,2-a) quinoline in 20 ml of tetrahydrofuran (THF), 25 mg (0.66 mmol) of lithium aluminum hydride are added in portions over 3 minutes. The mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of water, the pH was adjusted to 6.0 by the addition of normal hydrochloric acid, and the mixture was partitioned between water and ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulphate and evaporated to dryness to give 275 mg of the desired dioxy compound as an oil.
    Mass spectrum (t / e): 409 (M), 364 ().
    H-NMR (CDCl1), & ppm: 1.30 (g, 3N); 5.90 (s, 2H); 7.20 (s, 5H).
    Example 3. DL-4a, YU-trans-7-hydroxy-b- (2-oxystil) -9- (5-fensch-1-2-pentyloxy) -1,2,3,4,4a, 5,6,1Ob octa-hydrofenanthrene (1c).
    A solution of 2.1 g (5.2 mmol) of DL-4a, 10-trans-7-hydroxy-6-carboxymethylene-9- (5-phenyl-2-pentesh10xi) -2,3,4,4a, 5,10 - hexahydro-1H-phenanthrene lactene in 100 ml of diethyl ether is added to 400 ml of liquid ammonia. Then, in separate portions, 84 mg (12 mmol) of lithium metal is added to the solution and a blue color remains for 2 minutes. The reaction was quenched by the addition of 2.1 g of ammonium chloride, the ammonia was evaporated in a stream of nitrogen, the residue was dissolved by adding water, the solution was acidified to pH 3 by the addition of normal hydrochloric acid and subjected to its extraction treatment with ethyl acetate. The extracts were dried over sodium sulfate and evaporated in vacuo to give 2.1 g of crude product, which is subjected
    31355130
    chromatographic processing on silica gel, eluting with mixtures of isopropyl ether and hexane, resulting in 440 mg of compound (1c).
    five
    PMR spectrum (CDCl, j), S, ppm : 1.15 (g, 3N, CH); 3.80 (t, 2H,); 4.25 (m, 1H, OSI); 6.25-6.50 (m, 2H); 7.20 (s, 5H).
    Study the analgesic activity of the compounds being offered (I),
    Suppression of seizures caused by feilbenzoquinone.
    Groups consisting of five mice are pretreated subcutaneously or orally with physiological saline, morphine, codeine, or compounds (1). 20 minutes (if treated subcutaneously) or 40 missions (if treated orally) after each group are treated with an intraperitoneal injection of phenylbenzoquinone, an irritant known for abdominal contractions. Muscles are examined for 5 minutes for the presence or absence of seizures that begin 5 minutes after the administration of the stimulus. The dose required to provide 50% of the maximum positive effect (MPE) of pretreatment drugs to block seizures is established.
    ten
    15
    20
    sign up
    not me
    sa sa
    25
    thirty
    gd
    The analgesic activity of the compounds is presented in the table.
    The analgesic activity is compared with morphine, codeine, and phenanthridine derivatives (11), which have analgesic activity.
    0.32 0.16
    0.28
    0.76 (bp)
    0.91
    Continued Tables
    one
    Codeine 11
    6.7 0.1-100
     Substances were injected subcutaneously, except as indicated orally (p.o.).
    Compounds (I) show no signs of toxicity at the tested doses (upper limit 56 mg / kg).
    权利要求:
    Claims (1)
    [1]
    Thus, the proposed compounds (I) possess high anaphygetic activity, superior to morphine, codeine, and known phenanthridine derivatives. Invention Formula
    The method of obtaining derivatives of hexa-hydropyrrolo (1,2-a) quinoline or hexa-hydropyrido (1,2-a) quinoline, sh1i ok- i taghydrofenanthrene of the general formula
    in
    25
    0
    (
    0-C-CH CH2CH C6Hj
    where R. and R- 5
    M group CH, different
    g
    one of the radicals is methyl, and the other is hydrogen; nitrogen or CH group, and when M is nitrogen, or 2 when M is, by
    40
    compound of general formula
    soon
    Ш20Н
    45
    Rl 0-С-СН2СН2СН2СбН5
    one,
    50
    0-С-СН2СН СН2СбН5
    (CHiV R.
    55
    where r, rj, m and n have the indicated
    meanings
    is reacted with lithium aluminum hydride, in tetrahydrofuran or with lithium in anhydrous liquid ammonia.
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    同族专利:
    公开号 | 公开日
    NZ203577A|1985-09-13|
    IE54897B1|1990-03-14|
    GR77127B|1984-09-07|
    ES520630A0|1985-03-01|
    FI76334B|1988-06-30|
    PL141640B1|1987-08-31|
    US4476131A|1984-10-09|
    FI830857A0|1983-03-15|
    DK85183D0|1983-02-24|
    HUT34146A|1985-02-28|
    AR240936A2|1991-03-27|
    RO88221B|1986-01-02|
    JPS63183542A|1988-07-28|
    YU175785A|1986-08-31|
    AR240936A1|1991-03-27|
    DE3377280D1|1988-08-11|
    AU543215B2|1985-04-04|
    NO162385B|1989-09-11|
    RO85382B|1984-11-30|
    KR840004111A|1984-10-06|
    PL240989A1|1984-06-18|
    PH19998A|1986-08-28|
    FI76334C|1988-10-10|
    PT76390A|1983-04-01|
    CA1254567A|1989-05-23|
    KR870001126B1|1987-06-09|
    ES527075A0|1985-04-16|
    ES8504097A1|1985-04-16|
    PT76390B|1986-02-03|
    ZA831781B|1983-11-30|
    IE830559L|1983-09-16|
    DK85183A|1983-09-17|
    JPS58170724A|1983-10-07|
    PL245846A1|1984-08-27|
    EP0090516A1|1983-10-05|
    HU189906B|1986-08-28|
    AU1244883A|1983-09-22|
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    DD219765A5|1985-03-13|
    CS249126B2|1987-03-12|
    JPH0260653B2|1990-12-17|
    KR880002412B1|1988-11-08|
    IL68131D0|1983-06-15|
    ES8503510A1|1985-03-01|
    KR880006969A|1988-07-25|
    FI830857L|1983-09-17|
    YU44736B|1991-02-28|
    YU60683A|1986-04-30|
    YU44899B|1991-04-30|
    EP0090516B1|1988-07-06|
    DD210270A5|1984-06-06|
    RO88221A|1985-12-30|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3045020A|1962-07-17|x xcooa |
    FR1490023A|1965-08-17|1967-07-28|Sandoz Sa|Isoquinoline derivatives and their preparation|
    US4260764A|1976-12-22|1981-04-07|Pfizer Inc.|9-Hydroxyoctahydrobenzo [C] quinolines and intermediates therefor|
    US4188495A|1977-11-14|1980-02-12|Pfizer Inc.|1,9-Dihydroxyoctahydrophenanthrenes and intermediates therefor|US4576964A|1982-03-16|1986-03-18|Pfizer Inc.|Substituted hexahydrobenzo[e]indene and octahydrophenanthrene CNS agents and pharmaceutical compositions thereof|
    US4670562A|1985-03-13|1987-06-02|Hoechst-Roussel Pharmaceuticals Inc.|Dihydropyrrolo[1,2-b]isoquinolinedione oximes|
    US5965620A|1993-07-23|1999-10-12|Vide Pharmaceuticals|Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure|
    US5629345A|1993-07-23|1997-05-13|Vide Pharmaceuticals|Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure|
    CA2187257A1|1995-10-12|1997-04-13|Enrique Luis Michelotti|Aryl-substituted cycloalkanes and cycloalkenes and herbicidal use thereof|
    CN1075498C|1997-05-08|2001-11-28|车庆明|New compound and its derivatives and their use|
    US6316734B1|2000-03-07|2001-11-13|3M Innovative Properties Company|Flexible circuits with static discharge protection and process for manufacture|
    ITGE20080051A1|2008-06-04|2009-12-05|Matteucci Francesco|METHOD FOR THE REALIZATION OF DIAMOND-REINFORCED CABLES FOR CUTTING STRUCTURES AND MATERIALS IN STEEL, CONCRETE, STEEL AND CONCRETE, LITOIDI OR SIMILAR MATERIALS AND REINFORCED DIAMOND CABLE OBTAINED THROUGH THIS METHOD.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/358,569|US4476131A|1982-03-16|1982-03-16|Substituted hexahydropyrrolo[1,2-a]-quinolines, hexahydro-1H-pyrido[1,2-a]-q|
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