• 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:
    Novel tetrahydrofuro- and -thieno[2,3-c]pyridines, a process for their preparation and their use as medicaments having cholinomimetic properties.
    公开号:SU1657064A3
    申请号:SU884356747
    申请日:1988-10-28
    公开日:1991-06-15
    发明作者:Гарреус Альбрехт；Вебер Карл-Гейнц；Вальтер Герхард；Штрански Вернер；Кун Франц-Йозеф；Шингнитц Гюнтер；Энзингер Гельмут
    申请人:Берингер Ингельгейм Кг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the chemistry of heterocyclic compounds, in particular, to a process for the preparation of new tetrahydro (furo or thieno)-2,3-c pyridine derivatives of the general formula
    H
    (I)
    Kg
    R, irV vVs
    n
    where RI is hydrogen, chlorine, bromine, Ci-Ce-alkyl, acetyl;
    R2 is hydrogen, bromine or C1-C4-alkyl;
    R3 is hydrogen or St-C-alkyl;
    R4 is hydrogen or C1 C4 alkyl;
    X is oxygen or sulfur, or their hydrochlorides or their quaternary salts with methyl iodide, which can be used as medicines, in particular as cholinomimetic agents.
    The purpose of the invention is to obtain new compounds with a higher cholinomimetic activity compared with the known drug arecoline.
    Os
    ate
    vj o o 4

    WITH
    The goal is achieved by the proposed method of obtaining derivatives of tetrahydro (furo or thieno) - 2,3-e pyridine of the given general formula (I) or their hydrochlorides or their quaternary salts with methyl iodide, which means that the compound of the general formula
    % N
    S about.
    (Ii)
    X
    3
    where Ri-Rj and X are the indicated values, are subjected to reduction followed, if necessary, by alkylation of the obtained compound, where Pz is hydrogen, or by acylation of the obtained compound, where RI is hydrogen, or by halogenation of the obtained compound, where RI or R2 is hydrogen , and the selection of the target product in free form, in the form of hydrochloride or in the form of a quaternary salt with methyl iodide.
    Recovery is carried out by known techniques. The reaction is preferably carried out with tin (II) chloride at a temperature from room temperature to the boiling point of the reaction mixture, preferably at 50-70 ° C. in glacial acetic acid or concentrated hydrochloric acid, or a mixture thereof. In addition, the process can be carried out in the presence of a mixture of hydroiodic acid and red phosphorus in glacial acetic acid at the boiling point of the reaction mixture.
    The following examples illustrate the invention.
    Example 1. 2,6-Dimethyl-4,5,6,7-tetrahydrofuro-2,3-e pyridine.
    10 g (49 mmol) of 2,6-dimethyl-4-hydroxy-4,5,6,7-tetrahydrofuro- (2,3-c pyridine is dissolved in a mixture of 120 ml of glacial acetic acid and 60 ml of concentrated hydrochloric acid and mixed with 19.1 g (99 mmol) of tin (II) chloride, then stirred for 2.5 h at 65 ° C. Next, the reaction mixture is concentrated and the residue is taken up in water, alkalinized with concentrated ammonia under ice cooling and extracted with ethyl acetate After drying and thickening the solvent, the residue is purified by chromatography (silica gel, ethyl ether is used as eluent acetic acid, methanol and ammonia 10: 1: 0.5). The purified base is converted to hydrochloride and recrystallized from ethanol. The above compound as hydrochloride has a yield of 2.6 g (28% of theory), mp. 256-258 ° C (decomposition).
    Calculated,%: C 57.59: H 7.51; N 7.46: CI 18.89.
    Found,%: C 57.31; H 7.56; N 7.65; CI 18.65.
    Example 2. 2,5,6-Trimethyl-4,5,6,7 tetrahydrothieno-2,3-e pyridine.
    10.2 g (50 mmol) of 2,5, b-trimethyl-4-hydroxy-4,5,6,7-tetrahydrothieno-2,3-c pyridine is reacted with 18.9 g (100
    0 mmol) anhydrous tin (II) chloride in 60 ml of anhydrous glacial acetic acid. After 6 hours, the mixture is subjected to hydrolytic processing (NH / jOH). From the organic phase (CH2CI2), after recrystallization from ethyl acetate and ether (8: 2), 5.6 g (51% of theory) of the above compound with m.p. 165-166 ° C.
    Analogously to Examples 1 and 2, the following compounds are obtained:
    3,6-dimethyl-4.5,6,7-tetrahydrofuro-2,3-e pyridine in the form of hydrochloride with so pl. 287-288 ° C (compound 1);
    5 2,6-dimethyl-4,5,6,7-tetrahydrothieno-2,3-e-pyridine in the form of hydrochloride with so pl. 226 ° C (compound 2);
    2,4,6-trimethyl-4,5,6,7-tetrahydrothieno-2,3-c pyridine in the form of hydrochloride with so pl.
    0 200-202 ° C (compound 3);
    6-ethyl-2-methyl-4,5,6,7-tetrahydrothieno-2,3-c pyridine with m.p. 210-211 ° C (compound 4);
    2-chloro-6-methyl-4,5,6,7-tetrahydrothieno5 2,3-c pyridine with m.p. 247-248 ° C (compound 5);
    2-acetyl-6-methyl-4,5,6,7-tetrahydrothieno-2,3-c pyridine in the form of hydrochloride with m.p. 256-257 ° C (compound 6);
    02- (1-hydroxyethyl) -6-methyl-4,5,6,7-tetrahydrothieno-2.3-e pyridine in the form of the hydrochloride with so pl. 131-132 ° C (compound 7);
    2-bromo-6-methyl-4,5,6,7-tetrahydrothio-but-2.3-c pyridine as hydrochloride
    5 m.p. 260-261 ° C (compound 8);
    3-bromo-2.6-dimethyl-4.5.6.7-tetrahydrothieno- {2,3-c pyridine as hydrochloride with m.p. 300-302 ° C (compound 9).
    Example 3. (NE-2-Util-4.5.6,7,7-tet0 rahydrothieno-2,3-c pyridine.
    2.5 g (13 mmol) of 2-methyl-4,5,6,7-tetrahydrothieno-2.3-c pyridine hydrochloride are dissolved in 100 ml of anhydrous dimethylformamide. add 2.8 g (18 mmol)
    5 Ethyl iodide. 1.2 g of potassium iodide and 4.2 g of sodium carbonate and the mixture is stirred for 3 hours at 100 ° C. then concentrated, absorbed in water and dichloromethane, the aqueous phase is alkalinized and processed by known methods. The residue thus obtained is subjected to chromatography on
    silica gel using dichloromethane and methanol (97 3) as eluent. The isolated base is converted into hydrochloride, which is recrystallized from ethanol. The yield is 1 2 g (13%) with a melting point. 210-211 ° C
    Example 4 2-Chloro-6-methyl-4 567-tetrahydrothieno-2,3-c pyridine
    2.7 g (14 mmol) of hydrochloride 6 methyp-4.5 6 7-tetrahydrothie1 o | 2,3-c | pyridine is dissolved in 90 ml of glacial acetic acid and 2.2 g (16 mmol) is added dropwise at 15 ° C sulfuryl chloride, then stirred for 48 hours at room temperature, fed to ice, alkalinized, and extracted with dichloromethane. The crude product obtained from the organic phase by drying and thickening is subjected to chromatography on silica gel using dichloromethane and methanol as eluent. The single fractions are concentrated and converted into hydrochloride . Output 0.5 g. T PL 247-248 ° C (ethanol).
    Calculated,%: C, 42.87; H 4.95; N 6.25, 0131.63; S 14.31.
    CsHioCINS x HCI (224.15)
    Found,%: C 42.65; H 4.95 N 6.07, CI 31.27; S 14.38.
    Example 5 Iodide 2-methyl-C 6-N.N di methyl-4,5,6 7-tetrahydro- (2 3-c pyridinium
    0.5 g (2.7 mmol) of 2,6-dimethyl-4 5,6 7-tetrahydrofuro-2,3-c pyridine is dissolved in 10 ml of ethanol and mixed with 0 72 g of methyldido After stirring for 3 At room temperature, the precipitated crystals are sucked off and recrystallized from ethanol. Yield 0 b2 gm 190-193 ° C
    Calculated,%. C 40.97, H 5 50 N4.78 I 43.29
    SyuntzMO (293,15)
    Found% C 41.00, H 5 57 N 4 95 I 43.04
    Example 6. Iodide-2-methyl-6 6-N N-dimethyl-4,5,6,7-tetrahydrothieno-2,3-e-pyridine
    Analogously to example 52.7 mol of 2,6-dimethyl-4,5,6,7-tetrahydro i yeno-2 3-e pyridine, dissolved in 10 ml of ethanol, is mixed with 0.8 g of methyl iodide. After the treatment, the corresponding quaternary ammonium salt as white crystals with m.p. 160 161 ° С
    Example 7. 2-acetyl-b-methyl-4,5,6,7-tetrahydrothieno-2,3-cj pyridine hydrochloride.
    3.2 g (21 mmol) of 6-methyl-4 5 6,7-tetrahydrothieno- (2,3-c pyridine) are dissolved in 10 ml of dichloroethane and mixed with 3 of 3 g of three-houred aluminum. 1.7 g of acetyl chloride, dissolved in 20 ml of dichloroethane, are added and measured for 16 h. Then the reaction mixture is fed to ice alkalinized and the base
    extracted with dichloromethane
    After conventional work-up by chromatography, subsequent conversion into hydrochloride and recrystallization from ethanol, 0.5 g of the above compound is obtained.
    0 mp 256 257 ° С
    Example 8 2-bromo-6-methyl-4 5 6,7-tetra hyd yen, 3rd pyridine
    To a solution of 3.0 i (0016 mol) of 6-methyl-4,5,6,7-tetrahydrothieno-2,3-e pyridine in
    5 65 ml of water are added dropwise at 0 ° C a solution of 4.6 g (0.038 mol) of potassium bromide and 2.4 g (0.017 mol) of bromine in 30 ml of water, then further stirred for 3 hours at 10-15 ° C and the resulting crystals are filtered with ice water. These crystals are absorbed in a dilute solution of ammonium hydroxide and extracted with dichloromethane. After the usual processing, the residue of the organic phase is dissolved in 20 ml of methanol.
    5 and acidified with 2N ethanolic hydrochloric acid. 1.7 g (40% of theory) of hydrochloride of the above compound are obtained in the form of colorless crystals with a melting point of 260-261 ° C. Example 9 3-Bromo-2,6-dimethyl0 4.5 6 7-tetrahydrothieno {2 3-c pyridine
    Analogously to Example 8, by brominating 2 6-dimethyl-4 with 5.6,7-tetrahydrothieno-3-pyridine, the above compound is obtained as a light yellow crystalline hydrochloride with a melting point of 300-302 ° C. Yield 49%
    Analogously to examples 1-9, compounds of the general formula (I) are prepared in gabl 1
    0Biologically experiments
    Experiments were carried out on the study of receptor binding in muscarinated-polar-ergic systems of three subtypes 8 in accordance with known data
    5 The results of the experiments are summarized in table 2
    A well-known methyl 1-methyl-1 2.5,6-tetra hydro-nicotinic acid (arecoline) with cholinometic activity is used as a reference standard.
    II. Experiments were carried out to study the degree of displacement of a muscarinic agonist from its site of binding in accordance with data in the literature (Kloss Aidr Naunin Shmi5 Deber C Arch Pharmacol 1987 with 335, 372-377).
    The results of the experiment are summarized in Table 3. Comparison of the data in Tables 2 and 3 suggests that the new compounds exhibit better biological activity compared with the known
    The novel compounds of general formula (I) are classified as medium toxic substances.
    Thus, the proposed method allows to obtain new pyridine derivatives of general formula (I) with cholinomimetic activity, which is higher compared with the known drug arecoline.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of tetrahydro (furo or thieno) - (2,3-e pyridine of the general formula (I) R H
    ,
    RI
    vvH
    s
    where RI is hydrogen, chlorine, bromine, Cu-Cd-alkyl. acetyl;
    Ra is hydrogen, bromine or C1-C4-alkyl;
    Ra is hydrogen or C, B, C H alkyl;
    RA is hydrogen or Ci-Ci-alkyl;
    X is oxygen or sulfur, or their hydrochlorides or their quaternary salts with methyl iodide, characterized in that the compound of general formula (II)
    H
    where RI-RI and X are the indicated values, are subjected to reduction followed by, if necessary, by alkylating the resulting compound, where Ra is hydrogen, or by acylating the resulting compound, where RI is hydrogen, or by halogenating the obtained compound, where RI or Ra is hydrogen, and isolating the desired product in free form, as hydrochloride, or as a quaternary salt with methyl iodide.
    Table 1
    25
    table 2
    Continuation of table 2
    Table 3
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19873736664|DE3736664A1|1987-10-29|1987-10-29|TETRAHYDRO-FURO- AND -THIENOPYRIDINE, THEIR USE AS A MEDICAMENT AND METHOD FOR THE PRODUCTION THEREOF|
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