• 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:
    Compounds of the formula (I): <CHEM> or salts, esters or amides thereof; wherein R1 is a C1-7 bivalent aliphatic hydrocarbon group or a single bond; R2 and R3 are the same or different and are each hydrogen, C1-4 alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members; R4 is hydrogen, halogen, hydroxy, cyano, C1-4 acyloxy, C1-4 alkoxy or C1-4 alkyl optionally substituted by one to three halogen atoms, X is -N= or -CH=; and A and B each represents hydrogen atoms or -CA-CB= represents -C=C- are useful in the symptomatic treatment of allergic conditions. Processes for preparing the compounds, intermediates useful in their preparation, pharmaceutical compositions containing them and their use in the symptomatic treatment of allergic conditions are also described.
    公开号:SU1301312A3
    申请号:SU833652410
    申请日:1983-10-17
    公开日:1987-03-30
    发明作者:Джордж Кокер Джиоффри；Вилльям Аддисон Файндли Джон
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a process for the preparation of new pyridyl or phenyl compounds of the general formula
    CH CH-COORi
    W / H A-; C-C-CH2NR R., B
    where RI is hydrogen, methyl, ethyl;
    Rj and
    Rg - each C, - C-alkyl or together with the nitrogen atom to which they are attached, form pyrrolidine or piperidine; RX - C ;, - Cx-alkyl, halogen;
    X is nitrogen or CH; A and B are each hydrogen atom either
    SA-CB means -. The purpose of the invention is to develop, on the basis of a known method, a method for the preparation of new compounds possessing valuable pharmacological properties with reduced toxicity.
    Example 1, (E) -3- (3-pyrrolidino-1- (4-tolyl) prop-1-enyl) cinnamic acid,
    To a stirred suspension of lithium aluminum hydride (330 mg) in ether (62 ml) was added 3- (3-pyrrolidino-1- (4-toln)) prop-1-enyl-benzoic acid methyl ester (mixture (E) - and (Z) -isomers) and the mixture is heated under reflux for 6 hours. Water (0.33 ml) is added, then sodium hydroxide solution (15%, 0.33 ml) and finally water (1 ml), and the solid is filtered and washed with ether. The ether filtrate is evaporated to give an oil (4.1 g), which is then cooled, filled into a mixture of ether and petroleum ether (b.p. 40-60 ° C), precipitated by crystals (1.43 g); By recrystallization from petroleum ether (t, bale, 60-80 ° C), pure (E) -3- (3-pyrrolidino-1- (4-tolyl) prop-1-enyl) benzyl alcohol is obtained in the form of colorless needles, t, melt, 96-97 ° C. The filtered mixture of ether-petroleum ether was mixed and the residue was separated by high-performance liquid chromatography (silica, dichloromethane:
    013122
    methanol: triethylamine 98.5: 1.25: 0.25), obtaining an additional amount of the indicated (E) -isomer, as well as (Z) - 3- (3-pyrrolidino-1- (4-tolyl) prop-15 enyl) ) benzyl alcohol, which forms colorless prisms, t, melt. 67-69 C, during crystallization from petroleum ether (t, kip. 60-80 C). To a stirred solution of fused (E) -3- (3-pyrrolidino-1- (4-tolyl) prop-1-enyl) benzyl alcohol (1.1 g) in dichloromethane (75 ml) is added to barium manganate, holding the mixture at 40 ° C for 5 hours 7 hours and left at room temperature for 6 hours. The solid is removed by filtration, and the filtrate is evaporated, yielding a crude (E) -3- (3-pyrrolidino-1- (4-tolyl)
    20 prop-1-enyl) benzpidedehyde (1.09 g), which is used without purification, To a stirred suspension of sodium hydride (107 mg, 80% oil per suspension) in 1,2-dimethoxyethane (3.7 ml) added Methoxycarbonylmethylphosphonic acid diethyl ester (740 mg) in 1,2-dimethoxyethane (3.7 ml) is used. After 1 5 minutes of stirring, a solution of this is added dropwise.
     (E) -aldehyde (1.09 g) in 1, 2-dimethoxyethane (3.7 ml) and the mixture is stirred for 18 hours at room temperature. After adding water and acidifying with dilute hydrochloric
    35 The acidic suspension is washed with ether, the clear aqueous solution is basified with sodium carbonate solution, and the precipitated oil is extracted into ether. Washed and dried ethereal rast25
    40
    the thief is evaporated, leaving a solid (800 mg), which is dissolved in ethanol and heated under reflux with Grignard reagent (200 mg) for 1 hour. The solvent
    45 is evaporated, water is added and the ether and the ether extract is washed, dried and evaporated to give (E) -3- (E) -3-pyrrolidino-1- (4-tolyl) prop-1-enyl3 cinnamic acid methyl ester,
    50 t.plav, 102-107 ° C (620 mg).
    This ester (620 mg) was dissolved in ethanol (7 ml), 2N was added, sodium hydroxide solution and the mixture was stirred for 4 hours at room temperature. Add 2n. hydrochloric acid (2.85 ml) and the solution is evaporated to dryness. Extracted solid residue with ethanol and evaporated from the bright brownish t, melting, 190 C (decomposed.)
    filtered extract, to obtain a solid (600 mg), which is recrystallized from aqueous isopropanol, to obtain plates,
    (E) -3- (E) -3-pyrrolidino-1- (4-tolyl) prop-1-enyl cinnamic acid. The hydrochloride salt of the compound is obtained, t, melt, 240-245 ° C (decomposed)
    Example 2, (E) -6- (1- (4-Chlorophenyl) -3-dimethylaminopropyl) -2-pyridyl acrylic acid,
    To a cold (-70 s) solution of 2-bromo-6- (1- (4-chlorophenyl) -3-dimethylaminopropyl) pyridine (1.44 g) under nitrogen atmosphere in anhydrous tetrahydrofuran (50 ml) is added with stirring n-butyl lithium solution (2.4 ml, 1.7 M in hexane). After another 5 minutes at -70 ° C, anhydrous dimethylformamide (1.5 ml) is added dropwise over 2 minutes. The solution was allowed to warm, and then 5 ml of water was added. The solvents are removed under reduced pressure, and the residue is dissolved in methylene chloride (50 ml). This solution is extracted with water (3x25 ml), dried (.) Sodium sulfate, concentrated and the crude 6- (1- (4-chlorophenes 1 ) -3-dimethylaminopropyl) - 2-pyridinecarboxaldehyde, which is chromatographed on a reversed phase (to 6.3 on C18 with an adonitrate mixture: 70:30 water).
    By reacting the aldehyde with the sodium salt (from sodium hydride) of triethylphosphonoacetic acid in anhydrous toluene under nitrogen with
    antagonist,
    the subsequent separation of the ester-40 product of the antagonist, a / B / - by extraction by extraction of crude ethyl ester of 6- (1- (4-chlorophenyl) -3-dimethylaminopropyl) -2-pyridyl acrylic acid (K 8.3 in C, in a mixture of acetonitrile: water 70: 30, 5 NMR (80 MHz, CDQ,), S: 1.32 (t, 3N);, 2.15 (m, YN); 4.25 (gp, 3N); 6, 75 - 7.80 (p}, 9H). The ester is hydrolyzed with sodium hydroxide (4-equiv.) In aqueous methanol. Reactor 50
    concentration
    evaluate RA, i.e. negate the antag concentration harithm due to which the control response of the concentrate shifts by 2 times
    Table 1 summarizes the in vitro antihistamine studies.
    The mixture is neutralized with aqueous hydrochloric acid (1 N,), and the solvents are removed under reduced pressure. The residue is treated with methanol, filtered and the methanol is removed under vacuum, obtaining a crude acid. Reverse phase chromatography gives (E) -6- (l- (4-chlorophenyl) -3-dimethylaminopropyl-2-pyridyl acrylic acid (K 5.7 per with methanol: water 30: 70), TLC: Rf 0.40 (silica gel, methanol), NMR (30 MHz, CDC1,), 5: 2.40
    (ё Н is imposed on 2.0-3.0 (and, 4Н); 3.97 (wide triplet); 6.65-7.70 (gt), 9H); 11.5 broad singlet, exchangeable,
    Antihistamine activity,
    A. Antihistamine activity in vitro. The longitudinal muscle was isolated from the intact ileum of the guinea pig (male, 250-400 g) and placed in an organ bath under tension.
    300 mg. After establishing equilibrium for 1 h, the dependence of the cumulative concentration — reaction to histamine is obtained. After blinking, the tissues are incubated for 1 hour.
    with the test compound, and then the histamine concentration – reaction is carried out with the second dependence. Shifting to the right depending on the concentration of antagonist - the reaction obtained by the action of antagonists is used to plot Schild, Regression loa (dp-l) from 1аа / В /, where ded means equal reaction in the presence and presence of antagonist,
    vii antagonist, a / b / -
    molar allows
    concentration
    evaluate RA, i.e. the negative logarithm of the antagonist concentration, due to which the control dependence of the reaction on the histamine concentration is shifted 2x to the right.
    Table 1 shows the results of an in vitro study of antihistamine activity.
    Table 1
    five
    B. Antihistamine activity in vivo. Guinea pigs (Hartley, males 300–350 g) were not fed for 20 hours, and then were administered through the mouth or intrabrigth dose of the test compound. 1 hour after the dose was administered, the pigs were placed in a clean plastic chamber, which was saturated and continuously gassed 0, 25% histamine from aerosol dispenser. Signs of histamine anaphylaxis in guinea pigs (for example, coughing, sneezing, abdominal heavy movements, dianose, or loss of orientation) were detected. Under the conditions studied, control animals collapsed for an average of 33 seconds. The effective dose of Eflj for protection against histamine was calculated on the basis of the analysis. In this experiment it shows that at a specific dose, 50% of the animals are completely protected from being exposed to histamine during the test (1 hour after dosing). Full protection is defined as the absence of histamine symptoms for 6 minutes in an aerosol chamber (approximately 10X collapse time of control animals). An antihistamine preparation, triprolidine -1- (4-methylphenyl) -1- (2- pyridyl) -3-pyrrolidinoprop-1-ene,
    Table 2 shows the results of antihistamine tests.
    Table 2
    3013126
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining pyridyl or phenyl compounds of the general formula
    CH CH-COORi
    / n
    A-; C-C-CH T RiRj
    ABOUT "
    where R is hydrogen, methyl, ethyl; R and
    R 5 - each C, - Cd-alkyl or together with the nitrogen atom to which they are attached form pyrrolidine or piperidine;
    4 halogen. C, - C-alkyl; X is nitrogen or CH;
    A and B - each individually a hydrogen atom or CA-CB means -,
    characterized in that the compound of the general formula
    cf °
    /
    35
    A-C-C-CH2NK2
    AT
    The resulting compounds are therapeutic in therapeutic terms. Thus, for a compound with UDso, 1000 mg / kg for rats is peritoneal).
    VNIIPI Order 1163/58 Circulation 372
    Subscription
    Random polygons pr-tie, Uzhgorod, st. Project, 4
    40
    45
    50
    where (), K, Au and have the indicated values, interact with the Wittig reagent of the formula
    (RgOl PiobCHCOjR ,,
    where R is methyl, ethyl; Ry-methyl, ethyl,
    and, if necessary, with the subsequent transfer of the obtained ester to carboxylic acid.
    Priority signs: 04,02,82 with X -N; SA-SV -
    10/18/82 when X - CH; SA-SV -
    03.02.83 when SA-SV - CH-CH,
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1301312A3|1987-03-30|Method for producing pyridyl or phenyl compounds
    US5231101A|1993-07-27|Benzo[5,6]cyclohepta[1,2-B]pyridine derivatives and antiallergic agents comprising same
    US5919932A|1999-07-06|Biphenylamide derivatives as 5HT1D antagonists
    SU1380614A3|1988-03-07|Method of producing derivatives of aryltriazoles or hydrochloride or hydrobromic salts thereof
    JPH05194513A|1993-08-03|Chemical intermediate
    CH678427A5|1991-09-13|
    US7271168B2|2007-09-18|Piperazine derivatives having SST1 antagonistic activity
    CS247094B2|1986-11-13|Preparation method of 5,11-dihydro-11-|amino)carbonyl)-6h-dibenz|-azepin-6-on
    AU617988B2|1991-12-12|Hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds
    US4377576A|1983-03-22|5-|-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones
    US4424225A|1984-01-03|Thienobenzodiazepinones, pharmaceutical compositions thereof and method of use thereof
    EP0389425B1|1995-04-26|Benzotiopyranyl amines
    BG99253A|1995-09-29|Epi - epibatydine derivatives
    EP0635012B1|1996-07-10|Unbridged bis-aryl carbinol derivatives, compositions and methods of use
    US5137894A|1992-08-11|4-(4-Piperidinyl-thieno[3,2-c]pyridine derivatives of n-alkylglutarimides
    EP0213080B1|1992-05-20|Hydrogenated pyridine derivatives
    SU1048985A3|1983-10-15|Method of producing octahydro-1h-pyrrolo-/2,3g/-isoquinolines or salts thereof, racemates or cis-or transisomers
    EP0266308A1|1988-05-04|Indolo-pyrazino-benzodiazepine derivatives
    US4690933A|1987-09-01|Pyridylvinyl-1H tetrazole having antihistamine activity
    DK160049B|1991-01-21|6-PHENETHYLAMINOALKYL-FURO- | -PYRIDINE DERIVATIVES AND MEDICINALS CONTAINING SUCH COMPOUNDS
    KR840002139B1|1984-11-23|Process for preparing benzoquinolizines
    CS226743B2|1984-04-16|Method of preparing new 1,4,9,10-tetrahydropyrazolo |pyrido | l,4)diazepin-10-ones
    US6166034A|2000-12-26|Spiro piperidine derivatives as 5HT1D receptor antagonists
    EP0187619A2|1986-07-16|1,3-Disubstituted tetrahydropyridines
    FI102276B|1998-11-13|A process for the preparation of novel therapeutically useful 5-N, N-dialkylsulfoyl-1H-6,7,8,9-tetrahydro-1 H indole-2,3-dione 3-oximes
    同族专利:
    公开号 | 公开日
    BG41821A3|1987-08-14|
    IE830213L|1983-08-04|
    DK164662C|1992-12-14|
    KR880001466B1|1988-08-11|
    KR870001927B1|1987-10-22|
    AU555083B2|1986-09-11|
    YU22183A|1986-02-28|
    ES523416A0|1984-10-01|
    GB8302971D0|1983-03-09|
    IE54600B1|1989-12-06|
    PL140810B1|1987-05-30|
    ES519491A0|1984-04-01|
    FI82450C|1991-03-11|
    PT76192B|1986-01-24|
    CA1275102A|1990-10-09|
    ES523418A0|1984-10-01|
    AU1098283A|1983-08-11|
    YU44821B|1991-02-28|
    PL140809B1|1987-05-30|
    JPH0468B2|1992-01-06|
    NO830368L|1983-08-05|
    PL140811B1|1987-05-30|
    EP0085959B1|1989-04-19|
    ES8500233A1|1984-10-01|
    ES8403872A1|1984-04-01|
    NL930057I2|1994-02-16|
    KR870001918B1|1987-10-22|
    IL78419A|1989-01-31|
    PT76192A|1983-03-01|
    SI8310221A8|1995-10-31|
    BG42003A3|1987-09-15|
    FI830380L|1983-08-05|
    AT64596T|1991-07-15|
    PL245843A1|1985-01-30|
    NO874330D0|1987-10-16|
    FI82450B|1990-11-30|
    JPH0251897B2|1990-11-08|
    GB2114565A|1983-08-24|
    NO172341B|1993-03-29|
    DK43683A|1983-08-05|
    PL245845A1|1985-01-30|
    KR840003628A|1984-09-15|
    PL245842A1|1985-01-30|
    KR870001917B1|1987-10-22|
    FI830380A0|1983-02-03|
    IL67829A|1988-06-30|
    HU189223B|1986-06-30|
    ES523414A0|1984-10-01|
    EP0249950A1|1987-12-23|
    PL240412A1|1985-01-30|
    DK43683D0|1983-02-03|
    ES523415A0|1984-10-01|
    NL930057I1|1993-09-01|
    IL67829D0|1983-06-15|
    MC1498A1|1983-11-17|
    DD209446A5|1984-05-09|
    GR77407B|1984-09-13|
    SG106091G|1992-03-20|
    ES8500232A1|1984-10-01|
    JPS6479153A|1989-03-24|
    PH21348A|1987-10-13|
    DE3379654D1|1989-05-24|
    PL140708B1|1987-05-30|
    EP0085959A2|1983-08-17|
    JPH01301661A|1989-12-05|
    CA1275102C|1990-10-09|
    PL245844A1|1985-01-30|
    EP0249950B1|1991-06-19|
    UY23404A1|1992-10-19|
    HK25892A|1992-04-16|
    BG41822A3|1987-08-14|
    KR870001916B1|1987-10-22|
    AT42282T|1989-05-15|
    BG42004A3|1987-09-15|
    NO162556B|1989-10-09|
    CS235306B2|1985-05-15|
    EP0085959A3|1984-07-18|
    PL245841A1|1985-01-30|
    ES523417A0|1984-10-01|
    ES8500231A1|1984-10-01|
    PL140812B1|1987-05-30|
    CA1249830A1|1989-02-07|
    KR870001915B1|1987-10-22|
    ES8500234A1|1984-10-01|
    DE3382321D1|1991-07-25|
    NO874330L|1983-08-05|
    BG42005A3|1987-09-15|
    NO162556C|1990-01-17|
    NZ203171A|1986-12-05|
    ES8500235A1|1984-10-01|
    GB2114565B|1985-06-26|
    BG42185A3|1987-10-15|
    CY1627A|1992-07-10|
    NO172341C|1993-07-07|
    PL141639B1|1987-08-31|
    DK164662B|1992-07-27|
    IL78419D0|1986-08-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2567245A|1948-05-10|1951-09-11|Schering Corp|Aryl--amino alkanes and their production|
    DE1227464B|1951-09-10|1966-10-27|Wellcome Found|Process for the preparation of the trans form of the new 1- -1- -3-pyrrolidinopropens- |
    FR1228802A|1954-05-03|1960-09-02|Farbwerke Hoechst Ag Vomals Me|Process for the preparation of tertio-amino-ketone compounds|
    FR2197583B1|1972-09-07|1975-10-17|Rhone Poulenc Ind|US4562258A|1982-02-04|1985-12-31|Findlay John W A|6-[3-Amino-1-prop-1E-enyl]pyridine-2-carboxylic acid derivatives having antihistaminic activity|
    US4610995A|1984-07-27|1986-09-09|Coker Geoffrey G|Certain 1,1-diaryl-propenyl-3-(1-pyrrolidino-2-carboxylic acids, derivatives thereof and their anti-histaminic properties|
    LU86387A1|1986-04-04|1987-12-07|Oreal|AROMATIC COMPOUNDS, THEIR PREPARATION PROCESS AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSMETICS|
    GB8707416D0|1987-03-27|1987-04-29|Wellcome Found|Pharmaceutical formulations|
    DE3711866A1|1987-04-08|1988-10-27|Hoechst Ag|SYNTHESIS OF PEPTIDAMIDES BY SOLID PHASE METHOD USING SAEURELABILE ANCHOR GROUPS|
    GB8914060D0|1989-06-19|1989-08-09|Wellcome Found|Agents for potentiating the effects of antitumour agents and combating multiple drug resistance|
    DE69003200T2|1989-06-19|1994-01-20|Wellcome Found|Aryl-substituted amine derivatives can be used in cancer therapy.|
    GB8914040D0|1989-06-19|1989-08-09|Wellcome Found|Agents for potentiating the effects of antitumour agents and combating multiple drug resistance|
    FR2711651B1|1993-10-28|1995-12-22|Adir|New cyclized analogs of fatty acid metabolites, process for their preparation and pharmaceutical compositions containing them.|
    US5420866A|1994-03-29|1995-05-30|Scientific-Atlanta, Inc.|Methods for providing conditional access information to decoders in a packet-based multiplexed communications system|
    GB9508748D0|1995-04-28|1995-06-14|British Biotech Pharm|Benzimidazole derivatives|
    GB2308593B|1995-08-05|1999-01-27|British Biotech Pharm|Imidazopyridine derivatives|
    IT1277597B1|1995-09-15|1997-11-11|Smithkline Beecham Spa|DIARYLALKENYLAMINE DERIVATIVES|
    CN101838235B|2009-06-12|2013-08-07|重庆华邦制药有限公司|3-phenyl-3'-pyridylallylamine compound and synthesis method thereof|
    CN103124723A|2010-09-23|2013-05-29|先正达参股股份有限公司|Novel microbiocides|
    WO2013159884A2|2012-04-23|2013-10-31|Saudi Basic Industries Corporation|Solar energy based countinuous process and reactor system for the production of an alkene by dehydrogenation of the corresponding alkane|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB8203261|1982-02-04|
    GB8229705|1982-10-18|
    [返回顶部]