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    • 专利摘要:

    公开号:SU786903A3
    申请号:SU782694551
    申请日:1978-12-08
    公开日:1980-12-07
    发明作者:Фреель Даниель；Маффран Жан-Пьер
    申请人:Паркор (Фирма)；
    IPC主号:
    专利说明:

    the presence of an organic solvent, preferably acetone, and the resulting ketones of the general formula and CHN
    ®2
    , y- $ OjB5
    ijCj
    OR,
     TO
    $ -V
    about wl
    treated with the base agent of the formula “OI, in which R is branched or non-branched; C” -C-alkyl and M is an alkali metal cation, preferably sodium or potassium alcohols — for example, potassium tert-butylate, in an alcohol of general formula R -OH, where the R values are given above, preferably tert-butyl alcohol, at the boiling point of the reaction mass, and the target product is isolated in free form or in the form of its pharmaceutically acceptable acid salt.
    The starting compounds are prepared in a known manner (2.
    Preparation of starting 4-hydroxy-2-methyl-4, 5,6,7-tetrahydrothieno (2,3-c) -pyridine.
    In a flask equipped with a Dean-Stark nozzle, a mixture of 30 g (O, 237 mol) of 5-methyl-2-thiophenkercarboxaldehyde, 27.4 g (0.261 mol of aminoacetaldehyde methyl acetate in 250 cm of benzene) is refluxed for 2 hours. The mixture was evaporated to dryness, the residue was dissolved in 250 cm of ethanol, 13.5 g (0.355 mol) of sodium borohydride were added in portions, decomposed by adding acetone and the mixture was evaporated to dryness. The residue was treated with water and extracted with methylene chloride. The organic extracts were dried over sodium sulfate the solvent is distilled off to dryness. distilled under reduced pressure, bp / 2 Nw Hg, yield 90% N- (5-methyl2-thienyl) methylaminoacetaldehyde dimethyl acetal, which is heated at 60 ° C for 1 h in 250 ml of 6N hydrochloric acid.
     The reaction mass is evaporated to dryness and the residue is triturated with acetone. Whitish crystals of the desired chlorohydrate are crystallized from acetonitrile, so pl. 120s, total yield 61%.
    Example 1. 7-Oxitieno- (3,2-c) -pyridine. ()
    a) 7-Oxy-5ttosyl-4,5, b, 7-tetrahydrothieno- (3, 2-e) -pyridine (R Ri H
    R "P-TOLIL).
    To a mixture of 45 g (0.234 J small) of 7-hydroxy-4,5,6,7-tetrahydrothieno- (3,2-c) -pyridine hydrochloride, 100 ml of chloroform and 150 ml of a saturated aqueous solution of potassium carbonate are added dropwise at room temperature
    and With intensive mechanical stirring, stretch 45 g (0.234 mol) of p-toluenesulfone l. chloride in 250 ml of chloroform and continue stirring for. After decanting, the chloroform phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue is chromatographed on a column filled with silica (eluent:
    toluene-ethyl acetate 7: 3) and recrystallized from isopropanol. White crystals are obtained, mp. 120 ° C, yield 74%.
    b) 7-OXO-5-TOZIL-4,5,6,7-tetrahydrothieno- (3, 2-e) -pyridine (W:
     R p-tolyl.
    To a solution of 20.3 g (0.064 mop) of 7-OXY-5-TOZIL-4, -5,6,7-tetrahydrothieno- (3,2-e) -pyridine, obtained in a), in 250 cm of acetone 28.4 ml of 1-Jones reagent (D, 5 N solution of chromic anhydride in 8.35 N of sulfuric acid), the reaction mixture is added dropwise with good stirring and at room temperature.
    the mass is stirred at room temperature for 2 hours, the precipitated mineral salts are filtered off, the filtrate is evaporated to dryness and the residue is dissolved in methylene chloride. Organic
    the phase is washed with aqueous 5% sodium bicarbonate solution, then with water, dried over sodium sulfate and evaporated to dryness. The solid residue is crystallized from benzene. Creamy crystals are obtained, mp., Yield 79%.
    c) 7-Oxitieno- (3, 2-e) -pyridine (n). A solution of 19.6 g (0.064 mol) of 7-OXO-5-TOZIL-4,5,6,7-tetrahydrothieno- (3,2-e) -pyridine (obtained in paragraph b), 28.6 g (0.255 mol a) Potassium tert-butylate in 300 ml of tert-butanol is boiled for 2 hours under reflux under nitrogen. After distillation of the solvent under vacuum, the precipitated precipitate is dissolved. The reaction mixture is extracted with 2N hydrochloric acid, the aqueous phase is extracted with ether, then made basic by addition of concentrated ammonia and evaporated to dryness. The residue is extracted four times with boiling ethyl acetate. The organic extracts are filtered through a layer of two; silica and evaporated to dryness. The precipitate is recrystallized19 from ethanol-acetonitrile. I get grayish crystals, so pl. , yield 72%.
    Example 2. 4-Oxythieno (2,3-c) -pyridine (R),
    a) 4-OXI-6-TOZIL-4,5,6,7-tetrahydrothieno- (2, 3-e) -pyridine (R, RJ p-tolyl.
    The title compound was prepared as described in Example 1a from 4-hydroxy-4,5,6,7-tetrahydrothieno- (2,3-e) -pyridine hydrochloride. Beige crystals are obtained, mp. (isopropanol), yield 86%.
    b) 4-Oxo-6-tosyl-4,5,6,7-tetrahydrothieno {2, 3-e) -pyridine (lu) g

    This compound is obtained according to the method of Example 1b) from the tooelate described in a). Get white crystals, so pl.172 ° C (rung / ol), Jycho 98%.
    c) 4-Oxitieno- (2, 3rd) -pyridine (I) j 2
    This compound is prepared according to the procedure of Example 1c) from the tosylate described in item 6} (yield 78%). White crystals, mp, (ethanol-cyclohexane).
    Example 3. 4-Oxy-7-methylthieno- (2,3-e) -pyridine (T): R.H; Rj СНза) 4-Oxy-7-methyl-b-tozip-4,5,6,7-tetrahydrothieno-C2,3-c) -diene (V):
    R N; P, - CH; To p-tolil.
    This compound is prepared according to the procedure of Example 1a) from 4-hydroxy-7-methyl-4, 5,6,7-tetrahydrothieno- (2,3-e) -pyridine hydrochloride. White crystals are obtained, m.p. (benzene-cyclohexane), yield 96%.
    b) 7-Methyl-4-oxo-6-tosyl-4,5,6,7-tegrahydrothieno- (2, 3rd) -pyridine (AND (); H; Rj CH; K p-tolyl.
    This compound is prepared according to the procedure of Example 16) from the tosylate described in a) as white crystals, mp. (benzene-acetone), yield 90%.
    c) 4-hydroxy-7-methylthieno- (2,3-c) -pyridine (I): R H; .
    This compound is obtained according to the procedure of Example 1 c) from the tosylate described in paragraph b) as white crystals, mp. 220 ° C (cyclohexane-ethanol), yield 50%.
    Example 4. 4-Oxy-2-methylthieno- (2,3-e) -pyridine (1) R CH-; R, j, N.
    a) 4-Oxy-2-methyl-6-tosyl-4,5,6,7-tetrahydrothieno- (2,3-e) -pyridine (V) R eHu R-H; R, p-tolyl.
    This compound is prepared according to the procedure of Example 1 a) from 4-hydroxy-2-methyl-4,5,6,7-tetrahydrothieno- (2,3-e) -pyridine hydrochloride (preliminary) in the form of white crystals, m. square (benzse :), yield 48%.
    b) 2-Methyl-4-OXO-6-TOZIL-4,5,6,7-tetrahydrodieno- (2,3-e) -pyridine
    (Iii): R H; R1 p-tol.
    This compound is prepared according to the procedure of Example 1 b) from the 6ejaiDC tosylate crystals described in a), T.PL.124 ° C, yield 83%.
    c) 4-Oxy-2-methylthieno- (2,3-c) -pyridine (I): and R N.
    This compound is obtained according to the method of example 1 c) from the tosylate described in b) as sulfur-containing crystals, m.p. (ethanol-acetonitrile), yield 36%.
    Example 5. 4-Oxythieno- (2,3-e) -pyridine.
    This example represents an alternative version of the method for producing the derivative described in Example 2c).
    a) 4-Oxy-6-mesyl-4,5,6,7-tetrahydrothieno- (2,3-c) -pyridine (V):
    Rj 2,
    to a mixture of 50 g (0.26 mol) of 4-hydroxy-4, 5,6, 7-tetrahydro-thieno- (2, 3-e) -pyridine hydrochloride, 200 ml of chloroform and 100 ml of water, saturated with potassium carbonate solution dropwise at the temperature of the pellet and, with intensive mechanical stirring, a solution of 30 g (O, 26 mol) of methanesulfonyl chloride B is added with 50 ml of chloroform. Stirring is continued for 2 hours at room temperature. After decantation, the chloroform phase is washed with dilute hydrochloric acid, then with water, and dried over anhydrous sodium sulfate. Evaporation under vacuum
    a precipitate which is crystallized from methanol.
    Crystals of a light brown color are obtained, mp.140c, yield 76%.
    b) 6-Mesyl-4-oxo-4,5,6,7-tetrahydrothieno- (2, 3-e) -pyridine (lt ():
    Rj-ra hj.
    This compound is prepared as described in example 1 b) of the methanesulfonate described in a) as beige-colored crystals, mp. 120c (isopropanol-ethyl acetate), yield 70%.
    c) 4-Oxitieno- (2,3-e) -pyridine (I):.
    This compound is obtained according to the method of example 1 c) from the methane sulfonate described in paragraph b). Output 80% (in the form of white crystals), T.PL.206 C (ethanol-cyclohexane).
    The results of the toxicological and pharmacological and testing are given below.
    Toxicological and seizure. Compounds of formulas 1 are well tolerated and have relatively low toxicity. Thus, LDR-c is above 800 mg for all derivatives when orally administered to mice.
    Intravenously, as an example, the LD 50 determined in a mouse is 131 mg for the derivative synthesized in Example 1.
    Pharmacological studies on anti-inflammatory activity were carried out using two methods.
    a) The method of localized edema caused by carrageenin.
    A 1% solution of carragenin (0.1 MP) is administered by injection into
    metatarsal flexors of the right hind g, -gltl rats during O. givotnne-processed batch receive, in addition, orally 100 mg / kg body weight of the test derivative, respectively 1 hour before the injection, simultaneously with the injection of the phlogogenic agent, then after 1, 2 5 h after injection. Measurements performed with a ROCH micrometer 0.1, 2, 3, and 5 hours after carrageenin administration allow the percentage of anti-inflammatory activity to be determined compared to the control lot. The results are presented in table 1. Table 1
    The results of biological tests indicate low toxicity and interesting anti-inflammatory properties of the synthesized compounds of general formulas.
    These compounds may be administered orally in the form of tabla. . , with, coated tablets, capsules, drops and syrup. They are also suitable for rectal administration, in the form of suppositories, and for parenteral administration, as injectable solutions.
    Each single dose preferably contains from 0.010 to 0.250 g of the active principle, from 5 doses up to 5 doses can be applied in 5 daily doses.
    0.750 g of active principle depending on. of the patient’s age and disease to be cured.
    权利要求:
    Claims (4)
    [1]
    1. A method for producing thieno- (2, 3-th) - or thieno-{3, 2-th) pyridine derivatives of the general Formulas I
    b) The method of edema generalized by ovalbumin. A rat was given a simultaneous intraperitoneal injection of 1 ml of ovalbumi and 0.5 ml of an aqueous 1% solution of Evans blue. One hour before the test, the animals of the test batch were orally administered 100 mg / kg body weight of the test compound at the same time as ovalbumin. The intensity of the induced effect is indicated by numbers from 1 to 5, depending on the progression of the inflammatory syndrome. The average intensity of the edema and the percentage reduction of the edematous reaction as compared with the control are also determined depending on time. The percentages of anti-inflammatory activity obtained at the 2nd and 3rd hours after the injection of ovalbumin are presented in the following table.2. table 2
    50 58 61 60
    44 4953 48
    T
    2 IV where R and R2 are the same different and denote a hydrogen atom or C-C-alkyl, or their pharmaceutically acceptable salts with an acid, characterized in that the compound of the general formula II and III O I is.t L. -V R. it tn interacting with chlorine Tbtt-i sulfonyl of the formula in which alkyl or phenyl substituted in the para-position with C-C-alkyl in a mixture of water and an organic solvent which is not miscible with it in the presence of sodium carbonate and intermediate alcohols of the general formula IV or V
    oxidized in the presence of an organic solvent and the resulting ketones of the general formula C1 or VII, respectively
    SIG
    N-sO; i "3 VNM P 1 ni-sOzR
    Lchs - xx
    Ri
    process the main agent with a formula in which R is a branched or unbranched C-C-alkyl and M is an alkali metal cation, in an alcohol medium of the general formula R-OH, where the R values are given above, when the reaction mass boils and the target products are isolated in in free form or in the form of their pharmaceutically acceptable salts with acids.
    [2]
    2. Method POP.1, characterized in that the reaction of the compounds of the general formula K or 1 and
    with R-jSOji, Cl is carried out in mixtures of water and chloroform.
    [3]
    3. A method according to claims 1 and 2, characterized in that the oxidation of alcohols of general formula W or V is carried out with chromic anhydride in sulfuric acid in the presence of acetone.
    [4]
    4. The method according to claims 1 to 3, about tl and the fact that sodium or potassium alcoholates, for example potassium t-butylate, are used as the main agent of the last stage of the process in an alcohol environment, for example t-butyl alcohol.
    Sources of information taken into account in the examination
    1. Buhler K., Pearson D. Organic syntheses. M., 1973, Vol.2, p.92. 2. I.P.Maffrann, et F .E 1ou.Nouve11 syntheses de thienoC3i2-c} -...-. I.Het .Chem.M976, 2, 1347.
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    同族专利:
    公开号 | 公开日
    DK149627B|1986-08-18|
    IT7852313D0|1978-12-15|
    PH15475A|1983-01-27|
    PH15141A|1982-08-24|
    DK149627C|1987-02-02|
    AU4258778A|1979-06-28|
    HU176145B|1980-12-28|
    FI69077C|1985-12-10|
    FI783761A|1979-06-20|
    RO75933A|1981-02-28|
    GB2031428A|1980-04-23|
    DK568078A|1979-06-20|
    GB2031428B|1982-08-11|
    FI69077B|1985-08-30|
    NO150207B|1984-05-28|
    YU41323B|1987-02-28|
    FR2411838B1|1980-06-20|
    PL211885A1|1979-08-27|
    CA1113470A|1981-12-01|
    YU291778A|1982-10-31|
    BE872836A|1979-06-18|
    EP0002635B1|1980-08-20|
    IL56179A|1981-07-31|
    EP0002635A1|1979-06-27|
    DE2860244D1|1980-12-04|
    GB2010249B|1982-08-18|
    PL117941B1|1981-09-30|
    JPS6241234B2|1987-09-02|
    GB2010249A|1979-06-27|
    JPS5495595A|1979-07-28|
    CH635843A5|1983-04-29|
    IE782444L|1979-06-19|
    IT1109342B|1985-12-16|
    LU80562A1|1979-03-22|
    IE47794B1|1984-06-27|
    FR2411838A1|1979-07-13|
    AU517124B2|1981-07-09|
    IL56179D0|1979-03-12|
    ATA870978A|1981-10-15|
    NO784251L|1979-06-20|
    DD139856A5|1980-01-23|
    ZA786891B|1979-11-28|
    MX5753E|1984-06-20|
    PT68928A|1979-01-01|
    ES476033A1|1979-04-16|
    AT367057B|1982-05-25|
    AR221711A1|1981-03-13|
    NZ189199A|1982-03-16|
    US4496568A|1985-01-29|
    NO150207C|1984-09-05|
    GR65360B|1980-08-20|
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    WO2021050994A1|2019-09-13|2021-03-18|Aerie Pharmaceuticals, Inc.|Heterobicyclic carboxamides and uses thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7738308A|FR2411838B1|1977-12-19|1977-12-19|
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