• 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 the preparation of heterocyclic compounds, in particular derivatives of 1H, 3H-pyrrolo [1,2-c] thiazole @ general formula wherein AR - naphthyl or methylnaphthyl, AR- or pyridyl monosubstituted with halogen, CN 3, CH 3 O, methoxy group or disubstituted CH 3 , which have a inhibitory effect on PAF - ACETHER, which can be used in medicine. The purpose of the invention is the creation of new, more active and less toxic substances of the specified class. The synthesis is carried out by the reaction of the amine AR-NH 2 with racemic or optically active acid chloride 7-chloroformyl-3- (3-pyridyl) -1H, 3H-pyrrolo- [1,2-c] -thiazole-hydrochloride, followed by isolation of the target product in racemic or optically active isomer. New substances have low toxicity, LD 50 = 300-900 mg / kg.
    公开号:SU1510719A3
    申请号:SU874202824
    申请日:1987-07-02
    公开日:1989-09-23
    发明作者:Фабр Жан-Луи；Жам Клод；Лаве Даниель
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new derivatives of 1H, 3H-pyrrolo-β-2-c-thiazole of the general formula
    CO JH-Ar

    N
    where Ar is pyridyl monosubstituted with halogen, methyl, ethyl, methoxy or disubstituted with methyl, or naphthyl, unsubstituted or substituted with methyl,
    in the form of racemates or optically active isomers, which have a certain inhibitory effect on PAF-acether.
    The purpose of the invention is to obtain new compounds that have a certain inhibitory effect on PAF-acether at lower doses and have weak toxicity.
    Example 1. To a solution of 3.9 g of 2-amino-6-chloropyridine and 6.1 g of triethylamine in 200 cm of dioxane heated to 60 ° C is added in 5 minutes at a temperature of 60-68 ° C 9 g of 7-chloro - formyl-3- (3-pyridyl) -1H, 3N-pyrrolo-.
    SP
    about
    with

    om
    fl, 2-c3-thiazole hydrochloride. The resulting suspension is heated with stirring for 5 hours and 45 minutes, then stirred at 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg, CT.i 2.7 kPa) at a temperature of about. The residue is dissolved in
    of sodium and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, 0.5 g of bleaching charcoal is added, filtered and concentrated under reduced pressure (20 mm Hg, 2.7 kPa) at about 50 C. In this way, 11.4 g of crude is obtained.
    500 cm methylene chloride. Received-10 product, which is dissolved in 70 cm.
    boiling 1-butanol. The resulting solution is added to 0.5 g of bleaching charcoal and filtered in
    The aqueous solution is washed with 2 times 300 cm of distilled water, 2 times with 300 cm of an aqueous solution of 2N. alkali sodium and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, add 0.5 g of bleaching charcoal, filter and concentrate to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at about 50 C. In this way 9.5 g of crude product is obtained, which is dissolved in 140 cm of boiling 1-butanol. The resulting solution is added to 0.5 g of bleached charcoal and filtered while hot. The filtrate is cooled to a temperature of about 4 ° C. for 16 v. The crystallized crystals are separated by filtration, washed 3 times with 30 cm of 1-butanol and 3 times with 150 cm of diethyl ether, then dried under reduced pressure (20 mm Hg; 2.7 kPa) at about potassium in pills. In this way, 5.6 g of M- (6-chloro-2-pyridyl) -3- (3-pyridyl) -1H, 3H-pyrrolo 1,2-cJ -7-thiazolecarboxamide are obtained in the form of cream-colored crystals with a dot melting 18b with.
    Example 2. To a solution of 4.5 g of 2-amino-6-fluoro-pyridine and 8.1 g of triethylamine in 250 cm of dioxane, heated to a temperature of about, is added over a period of 5 minutes at a temperature of 60 - 12 g 7- chloroformyl-3- (3-pyridyl) -1H, 3N-pyrrlo 1,2-cJ-thiazole hydrochloride. The resulting suspension.-, penzia is heated to a temperature of about 100 ° C for 6 hours and 45 minutes, then stirred at 20 ° C for 16 hours. The solvent is ground under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60 C. The resulting residue is dissolved in 500 cm-methylene chloride and the resulting solution is washed with 2 times 300 cm of distilled water, 2 times with 300 cm of an aqueous solution of 2N. over 20
    25
    thirty
    hot condition. The filtrate is cooled to about 4 ° C for 2 hours. The crystallized crystals are separated by filtration, washed 3 times with 45 cm of 1-butanol, 2 times with 50 cm of ethanol and 3 times with 90 cm of diethyl ether, then dried. under reduced pressure (20 mm Hg 2.7 kPa) at a temperature of about in the presence of potassium tablets. 5.3 g of N- (6-fluoro--2-pyridyl) -3- (3-pyridyl) -1H, 3N-pyrrolo G1, 2-c} -thiazolecarboxamide are obtained in the form of beige-colored crystals with a dot melting 198 C.
    Example 3. To a solution of 2.2 g of 2-amino-6-picoline and 4.05 g of triethyl amine in 130 cm of dioxane, heated to a temperature of about 60 s, is added in 5 minutes at a temperature of 60-66 ° C, 7- chloroformyl-3- (3-pyridyl) -1H, 3N-35-pyrrolo 1,2-c} thiazol hydrochloride. The resulting suspension is heated with stirring at a temperature of 100 ° C for 7 hours 30 minutes, then stirred at a temperature of about 20 ° C for 40 hours. The solvent is evaporated under reduced pressure (20 mm PT.CT.J 2.7 kPa) at . temperature is about. The residue is dissolved in 300 cm of methylene chloride and the resulting 45 solution is washed with 2 times 300 cm of distilled water, 2 times with 300 cm of an aqueous solution of 2N. alkaline sodium and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate; 0.5 g of bleaching charcoal is added, filtered and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of about 60 ° C. In this way, 5.6 g of crude product is obtained, which is dissolved in 60 cm of boiling acetonitrile. The resulting solution is added to 0.5 g of bleaching charcoal and sodium filtrate and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulfate, 0.5 g of bleaching charcoal is added, filtered and concentrated under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of about 50 ° C. This way 11.4 g of crude is obtained.
    product that is dissolved in 70 cm
    hot condition. The filtrate is cooled to a temperature of about 4 ° C for 2 hours. The crystallized crystals are separated by filtration, washed 3 times with 45 cm of 1-butanol, 2 times with 50 cm of ethanol and 3 times with 90 cm of diethyl ether, then dried at reduced pressure (20 mm Hg 2.7 kPa) at a temperature of about in the presence of potassium tablets. 5.3 g of N- (6-fluoro--2-pyridyl) -3- (3-pyridyl) -1H, 3N-pyrrolo G1, 2-c} -thiazolecarboxamide are obtained in the form of beige-colored crystals with a dot melting 198 C.
    Example 3. To a solution of 2.2 g of 2-amino-6-picoline and 4.05 g of triethyl amine in 130 cm of dioxane, heated to a temperature of about 60 s, is added in 5 minutes at a temperature of 60-66 ° C, 7- chloroformyl-3- (3-pyridyl) -1H, 3N- β-pyrrolo 1,2-c} thiazol hydrochloride. The resulting suspension is heated with stirring at a temperature of 100 ° C for 7 hours 30 minutes, then stirred at a temperature of about 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm PT.CT.J 2.7 kPa) at. temperature is about. The residue is dissolved in 300 cm of methylene chloride and the resulting solution is washed with 2 times 300 cm of distilled water, 2 times with 300 cm of an aqueous solution of 2N. sodium alkali and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, 0.5 g of bleaching charcoal is added, filtered and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at temperature of about 60 ° C. Thus, 5.6 g of crude product is obtained, which is dissolved in 60 cm of boiling acetonitrile. The resulting solution is added to 0.5 g of bleaching charcoal and filter51.
    are hot. The filtrate is cooled to a temperature of about 2 hours. The crystallized crystals are separated by filtration, washed with 2 times 20 cm of acetonitrile, cooled to about c, then 2 times with 50 cm of diethyl ether and dried under reduced pressure (20 mm Hg). at 2.7 kPa) at a temperature of about in the presence of potassium tablets. In this way, 2.5 g of K- (6-methyl-2-pyridyl) -3- - (3-pyridyl) -1H, 3N-pyrrolo1,2-cJ-7-thiazolecarboxamide are obtained in the form of light-beige crystals. colors with melting point.
    Example 4. To a solution of 2.5 g of 2-amino-6-methoxy-pyridine and 4.1 g of triethylamine in 80 cm of dioxane, heated to a temperature of about 40 ° C, is added in 15 minutes at a temperature of about 40 ° C 6 g of 7- chloroformyl-3- (3-pyridyl) -1H, 3N-pyrrolo D, 2-c-thiazole hydrochloride. The resulting suspension is heated with stirring at a temperature of about 6 hours, then stirred at a temperature of about 20 ° C for 12 hours. The solvent is evaporated under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of about 60 ° C The residue is dissolved in 300 cm of methylene chloride and the resulting solution is washed with 2 times 200 cm of distilled water, 2 times with 200 cm of an aqueous solution of 2N. alkali. sodium, and 5 times 500 cm of distilled water, then dried with not anhydrous magnesium sulphate, 0.5 g of bleaching charcoal is added, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50 C. Thus, 5.6 products are obtained, which are subjected to chromatography on a column with a diameter of 6 cm, containing 480 g of silica (0.04-0.063 mm). Elute with a mixture of ethyl acetate and methanol (95-5 by volume) at a pressure of 0.4 bar (41 kPa), selecting fractions of 75 cm. The first nine fractions are removed. The next six fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg
    2.7 kPa) at a temperature of about 50 ° C. Thus, 3.6 g of a crude product with a melting point are obtained. This product is dissolved in 50 cm of boiling ethanol. The resulting solution
    Q 5
    0 5 Oh l. Q
    five
    nineteen
    attached to 0.5 g of bleaching charcoal, filtered while hot. The obtained filtrate is cooled to a temperature of about 4 ° C for 2 hours. The crystallized crystals are separated by filtration, washed with 2 times 10 ethanol, cooled to a temperature of about 4 seconds, and 2 times with 20 cm of diethyl ether, then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20 s in the presence of potassium in tablets. Thus, 3 g of N- - (6-methoxy-2-pyridyl) -3- (3-pyridyl) -1 -1 H, 3H-pyrrolo l, 2-e-7 thiazolcarboxamide in the form of white crystals with a melting point are obtained. .
    Example 5. To a solution of 2.9 g of 1-naphthyl-amine and 4.1 g of triethylamine in 100 cm of dioxane heated to a temperature of about 6 ° C, 6 g of 7-chloroformyl acid are added in 5 minutes at a temperature of 60 - 65 ° C. H- (3-pyridyl) -1H, 3H-pyr-, 2-c-thiazole hydrochloride. The resulting suspension is heated with stirring at a temperature of about 100 ° C for 5 hours, then stirred at a temperature of about 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about. The resulting residue is dissolved in 300 cm of methylene chloride and the resulting solution is washed with 2 times 200 cm of distilled water, 2 times with 200 cm of an aqueous solution of 2N. sodium alkali and 2 times 200 cm of distilled water, then dried on anhydrous magnesium sulphate, add 0.5, g of bleaching charcoal, filter and concentrate to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about. Thus, 7.5 g of crude product is obtained. This product is dissolved in 50 cm of boiling ethanol. The resulting solution is added to 0.5 g of bleaching charcoal and filtered while hot. The filtrate is cooled to a temperature of about 4 ° C for 16 hours. By vivshies krys-. The talles are separated by filtration, washed with 2 times 20 cm of ethanol, 3 times with 90 cm of diethyl ether and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium salts. In this way, 3.9 g of product are obtained.
    with a melting point of 3.7 g of this product, is dissolved in 55 cm of boiling isopropanol. The resulting solution was filtered hot. The filtrate is cooled to a temperature of about 4 ° C for .16 hours. The crystallized crystals are separated by filtration, washed with 2 times 10 cm of isopropanol, then 3 times with 45 cm of diethyl ether and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium tablets. In this way, 3.3 g of N- (1-naphthyl) -3- (3-pyridyl) -1H, 3N-pyrrolo (1,2-c} -7-thiazolecarboxamide) are obtained in the form of cream-colored crystals with a dot melting.
    Example 6. To a solution of 2.6 g of 2-amino-4-chloro-pyridine and 4.05 g of three ethylamine in 150 cm of dioxane, heated to a temperature of about, is added in 15 minutes at a temperature of about 6 g of 7-chloroformyl-3 - (3-pyridyl) -1H, 3N-pyrrole about 1,2-e-thiazole-hydrochloride. The resulting suspension is heated with stirring to a temperature of about 7 hours and 30 minutes, then stirred at a temperature of about 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg 2.7 kPa) at a temperature of about . The residue is dissolved in 350 cm of methylene chloride. The obtained 1 & w solution is washed with 2 times 200 cm of distilled water, 2 times with 200 cm of an aqueous solution of 1N. alkali sodium and 3 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, 0.5 g of bleaching charcoal is added, filtered and concentrated under reduced pressure (20 mm Hg 2.7 kPa) at about. In this way, 5 g of crude product is obtained, which is dissolved in 200 cm of boiling acetonitrile. The resulting solution is combined with 0.5 g of bleaching charcoal and filtered while hot. The filtrate is cooled to about 2 hours. The crystallized crystals are separated by filtration, washed with 2 times-10 cm of acetonitrile, cooled to about 2 times, and 2 times with 20 cm of diethyl ether, then dried under reduced pressure (20 mm). Hg 2.7 kPa), at a temperature of about in the presence of potassium tablets. So get
    2.6g N- (4-chloro-2-pyridyl) -3- (3-pyridyl) -1H, 3N-pyrrolo 1, 2-c-7-thiazole carboxamide. In the form of cream-colored crystals with a melting point
    ,
    Example 7. To a solution of 2.45 g of 2-amino-6-ethyl-pyridine and 4.05 g of triztilamine in 150 cm of dioxane, heated to a temperature of about 68 ° C, is added in 5 minutes at a temperature between 68 and 75 ° C , 6 g of 7-chloroformyl-3- - (3-pyridyl) -1H, 3N-pyrroloG1, -thiazol hydrochloride. The resulting suspension is heated with stirring to a temperature of about 100 ° C for 6 hours and 15 minutes, then stirred at 20 ° C for 16 hours.
    The solvent is evaporated under reduced pressure (20 mm Hg).
    2.7kPa) at a temperature of about 60 ° C. The residue is dissolved in 300 cm of methylene chloride. The resulting solution was washed 2 times. 300 cm of distilled water, 2 times 300 cm of an aqueous solution of 2N. alkali sodium and 2 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, add 0.5 g of bleaching charcoal, filter
    and concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about. 6.5 g of crude product are obtained in this way, which is dissolved in 75 cm of boiling acetonitrile. The resulting solution is combined with 0.5 g of bleaching charcoal and filtered while hot. The filtrate is cooled to a temperature of about 16 hours. The crystallized crystals are separated by filtration, washed with 2 times 10 cm of acetonitrile, cooled to a temperature of about 4 s, 3 times with 90 cm of diethyl ether, then dried under reduced pressure (20 MM p T.cT.i 2.7 kPa) at a temperature about 20 seconds in the presence of potassium tablets. 2.3 g of N- (6-ethyl-2-pyridyl) -3, - (3-pyridyl) -1H, 3H-pyrrolo Cl, 2-c3-7-thiazole carboxamide are obtained in the form of cream-colored crystals. with a melting point of 150 s.
    Example 8. To a solution of 3., 9 g of Z-methyl-1-naphthylamine hydrochloride and 6.1 g of tristilla in 200 cm of dioxane, heated to a temperature of about, are added in 5 minutes at a temperature of 70 - 76 ° C 6 g 7 -chlorfrmyl-3- - (3-pyridyl) -. 1H, 3N-pyrrolo tl, -thiazole-hydrochloride, the resulting suspension is heated with stirring to a temperature of about 100 ° C for 7 h, then stirred at a temperature of about 20 ° C for 16 The solvent is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60 ° C. The residue is dissolved in 500 seconds of methylene chloride and the solution obtained is wash 2 times 400 cm of distilled water, 2 times 400 cm of an aqueous solution of 2n. sodium alkali and 2 times 400 cm of distilled water, then dried on anhydrous magnesium sulphate, 0.5 g of decolorizing carbon is added, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 60, C. In this way, 7.6 g of product are obtained, which is chromatographed on a lia column with a diameter of 6 cm, containing 480 g
    dioxide (0.02-0.045 mm). Elute with mixtures of ethyl acetate and cyclohexane at a pressure of 0.4 bar (41 kPa), selecting fractions of 200 cm. The first 14 fractions from the elution with a mixture of ethyl acetate and cyclohexane (80-20 by volume) are removed, the 11 fractions from the elution with a mixture of ethyl acetate and cyclohexane (80-20 by volume) and the seven following fractions from the elution with ethyl acetate are removed , are combined and concentrated to dryness under reduced pressure (20 mm Hg, st, 2,7 kPa) at a temperature of about 60 ° C. Thus, 6.8 g of a crude dope are obtained and cooled to about 4 ° C for 1 hour. - crystals are separated by filtration, washed with 2 times 10 cm acetonitre la, OX, ennogo to a temperature of about 4 C and then dried under reduced pressure (20 mm Hg, 2.7 kPa) at tempe50
    It is with a melting point of 170 ° C. This product is dissolved in a 50 cm boiling 45 temperature of about 20 ° C in the presence of tabacetonitrile. The resulting solution is combined with 0.5 g of bleaching charcoal and filtered hot. The resulting filtrate is cooled to about 4 ° C for 16 hours. The crystallized crystals are separated by filtration, washed with 2 times 30 cm of acetonitrile and 3 times 9, 0 cm of diethyl ether, then dried under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of about 20 ° C in the presence of potassium tablets. In this way, 3.5 g of N- (3-methyl-1-naphthyl) -3- (3-pi55) are obtained.
    potassium year. In this way, t, 5 g of K- (4-methyl-2-pyridyl) -3- (3-pyridyl) -1H, 3N-pyrrolo G1, J 2-CJ-7-thiazolecarboxamide in the form of cream-colored crystals is obtained. With a melting point of 163 ° C,
    Example 10 To a solution of 4.3 g of 2-a-IHO-4-methylpyridine and 8.1 g of triethylamine in 300 cm of dioxane, heated to a temperature of about 60 ° C, 12 g of acid chloride are added in 5 minutes at a temperature of 65 - 72 ° C. chlorine hydrate (+) 3- (3-pyridyl) -1H, 3N-pyrrolor, 2-c7 - / - thiazolecarboxylic acid) -1H, 3N-pyrrolo f1,2-c} -7 thiazolecarboxamide in the form crystals of pale yellow color with a melting point of 172 C.
    Example 9. To a solution of 2.15 g of 2-amino-4-methyl-pyridine and 4.05 g of triethylamine in 100 cm of dioxane, heated to a temperature of about, are added over 20 minutes at a temperature of 65 - 72 ° C 6 g of 7- chloroformyl-3- (3-pyridyl) -1H, 3N-pyrrolo 1,2-cJ-thiazole hydrochloride. The resulting suspension
    15
    heated with stirring at about 5 h
    45 minutes, then stirred at a temperature of about 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg, Art.; 2.7 kPa)
    at a temperature of about, the residue is dissolved in 250 cm of methylene chloride. The resulting solution was washed with 100 cm of distilled water, then 100 cm of an aqueous solution of 4N. alkalis
    sodium and 3 times 450 cm of distilled water, then dried on anhydrous magnesium sulphate, 0, L g bleach charcoal 5 is added and filtered and concentrated to dryness at
    reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50 ° C. In this way, 4.8 g of crude product is obtained, which is dissolved in 50 cm of boiling a1 = etonitrile. Received by
    the solution is added to 0.5 g of bleaching charcoal and filtered while hot, the filtrate is cooled to a temperature of about 4 ° C for 1 hour. By gravity, the crystals are separated by filtration, washed with 2 times 10 cm of acetonitrile, oh -, to a temperature of about 4 ° C, then dried under reduced pressure (20 mm Hg, 2.7 kPa) at a temperature of about 20 ° C in the presence of a tab
    a temperature of about 20 ° C in the presence of
    potassium year. In this way, t, 5 g of K- (4-methyl-2-pyridyl) -3- (3-pyridyl) -1H, 3N-pyrrolo G1, J 2-CJ-7-thiazolecarboxamide in the form of cream-colored crystals is obtained. With a melting point of 163 ° C,
    Example 10 To a solution of 4.3 g of 2-a-IHO-4-methylpyridine and 8.1 g of triethylamine in 300 cm of dioxane, heated to a temperature of about 60 ° C, 12 g of acid chloride are added in 5 minutes at a temperature of 65 - 72 ° C. (+) 3- (3-pyridyl) -1H, 3H-pyrrolorum, 2-c7 - / - thiazolecarboxylic acid, chlorine hydrate
    you. The resulting suspension is heated with stirring to OKOlo temperature for 7 hours, then stirred at a temperature of about 20 ° C for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about. The residue is dissolved in 500 cm of methylene chloride. The resulting solution is washed with 2 times 300 cm of distilled water, 2 times with 300 cm of a saturated aqueous sodium bicarbonate solution and 2 times with 300 cm of distilled water, then dried on 1M of magnesium sulphate, 0.5 g of bleaching charcoal is added, filtered and the mixture is concentrated. under reduced pressure (20 mm Hg; 2,) at a temperature of about 60 s. In this way, 13.3 g of the product are obtained, which is dissolved in 140 cm of boiling acetonitrile. The resulting solution is combined with 0.5 g of bleaching charcoal and filtered while hot. The filtrate is cooled to about 20 ° C for 2 hours. The crystallized crystals are separated by filtration, washed 3 times with 75 cm of acetonitrile and 3 times with 90 cm of diethyl ether, then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 10 in the presence of tablets. Kali. In this way, 3.1 g of (+) H- (4-methyl-2-pyryl) -3- (3-pyridyl) -1H, 3H-pyrrolol, 2-c3-7-thiazole-carboxamide is obtained in the form cream colored crystals with melting point Mk ° G.
    .0
    z
       ° 09 dimethylformamide) .. 1. Example 11. To a solution of 2.4 g
    2-amino-4,6-dimethyl-pyridine and 4.1 g of triethylamine in 100 cm of dioxane, heated to a temperature of about 60 ° C, are added in 25 minutes at a temperature of 60.- 70 ° C to 6 g of 7-chloroformyl 3- (3-pyri dil) -1H, 3H-pyrrolo P, 2-c-thiazole-chloro hydrate. The resulting suspension is heated with stirring to temperatures of about 5 hours and 30 minutes. Then it is stirred at a temperature of about 20 seconds for 16 hours. The solvent is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 50 ° C. The residue is dissolved in 400 cm of methylene chloride.
    - Yu 15 20 25 30 g 40

    45 -5o 55.
    The resulting solution was washed with 100 cm-distilled water, 2 times with 200 cm of an aqueous solution of 1N. alkaline sodium and 3 times 300 cm of distilled water, then dried on anhydrous magnesium sulphate, add 0.5 g of bleaching charcoal, filter and concentrate to dryness under reduced pressure (20 mm pT.CT.J 2.7 kPa) at about 50 ° C. 6.3 g of crude product are obtained in this way, which is dissolved in 140 cm of boiling acetonitrile. The resulting solution is added to 0.5 g of bleaching charcoal and filtered while hot. The filtrate is cooled to a temperature of about 20 ° C for 1 hour. The crystallized crystals are separated by filtration, washed with 2 times 20 cm of acetonitrile, cooled to a temperature of about 4 seconds, then dried under reduced pressure (20 kM Hg; 2.7 kPa ) at a temperature of about in the presence of potassium tablets. Thus, 3.9 g of S- (4,6-dimethyl-2-pyridyl) -3- - (3-pyridyl) -1H, 3H-pyrrolo, -thiazolecarboxamide are obtained in the form of white crystals with a melting point of 171 ° C.
    The compounds obtained are active with a brake on concentrations of (Cljo) that are between 1 and 1000 nM in the fixation antagonism test (H) 0-1-octadecyl-0-2-acetyl-pZ-3-glycerophosphorylcholine (PAF- tritirovanny acether) on platelet receptor centers.
    Test method. The drug is from diluted rabbit platelets.
    Male rabbits weighing approximately 2.5 kg are punctured by the ear artery. Blood is placed in a mixture of citric acid (1.9 mmol), three-sodium citra (9 mmol), primary acidic sodium phosphate (1.75 mmol) and dextrose (5.6 mmol). The blood is centrifuged at 150 g for 20 minutes at 15 ° C to obtain a platelet-rich plasma (PRP). This plasma is centrifuged at 1000 g for 15 minutes at 15 ° C. The platelet precipitate thus obtained is washed for the first time with a solution of Tyrode (modified) containing 0.35% serum albumin bovine (BSA)., 2 mmol MgCl2.0.2 mmol ESTA then Tyrode solution without ESTA. Platelets form a suspension
    in an experimental buffer solution (buffer solution A), which has the following composition; mmol: NaCl 140; KC1 2.7, NaH2PO 0.4; MgCl 2; NaHCOj 12; tris buffer solution; HC1 10, dextrose 6.2 and BS.A 0.25%. The final suspension concentration is adjusted to 4 x l 10 platelets / cm with this buffer solution.
    The implementation of the test. A test buffer A, test substance, PAF-tritiated acether (0.5 mmol — specific activity: 80 inch / mmol) and platelets, prepared as described above (0.5–10 thrombocytob), are introduced successively into a 5 cm tube. get a final volume of 0.5 cm, and leave the mixture to incubate for
    ABOUT
    1 hour at 20 ° C. Then add 2 cm of buffer solution A, cooled until, quickly filter the contents of the tube on the VATMAN PF / C filter, and very quickly rinse the tube 3 times 2 cm of buffer A, cooled to 4 C. The filter is placed in a flask containing 4.5 cm of READY SOLY liquid scintillator, and radioactivity is measured using a RACK BETA 1218 universal counter. NKB. In this way, the total combined radioactivity is determined.
    The specific fixation of tritiated PAF-acether is determined by subtracting from the total combined radioactivity the radioactivity remaining on the filter after adding 10 mmol of N- (3- methoxy phenes1) -3- (3-pyridyl) -1H, 3N-pyrrol, 2C } -7-zol carboxamide. For each product that was tested, the test was replicated 3 times with increasing concentrations reaching from up to 10 mol. Clso is graphically determined for each product by analyzing the log Probit deceleration curve i
    The proposed compounds displace PAF-acether at its site of communication. After
    Indeed, they compete with him and are antagonists to one another. The known pyrrolothiazoles have an inhibitory effect on PAF-acether, but the products offered are fixed on platelet receptors at lower doses and, therefore, more suitable for inhibiting the effects of PAF-acether.
    The compounds obtained have a low toxicity. Wfff with oral administration is 300-900 mg / kg in mice.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of 1H, 3H-pyrrolo-D, 2-c-thiazole of the formula.
    CONH-Ar
    B
    where Ar is pyridyl monosubstituted with halogen, methyl, ethyl, methoxy or disubstituted with methyl, or naphthyl, unsubstituted or substituted with methyl,
    in the form of racemates or optically active isomers, characterized in that the amine of the formula
    Ar - NH ,,
    where Ar has the indicated meanings, is reacted with a racemic or optically active acid chloride formula
    SOS1
    2nd j
    ABOUT
    with the subsequent selection of the target product in the form of a racemate or an optically active isomer.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1510719A3|1989-09-23|Method of producing derivatives of 1n,3n-pyrrolo-/1,2-c/-thiazole as racemates or optically active isomers
    DK167573B1|1993-11-22|SOLID FORMS OF 2-ETHOXY-4-OEN- | -3-METHYL-1-BUTYL) -AMINOCARBONYLMETHYLA-BENZOIC ACID, PHARMACEUTICALS CONTAINING THESE SUBSTANCES, PROCEDURES, FOR THE PREPARATION OF A MEDICINE
    ES2071919T4|2011-08-30|Antianginal agents of pyrazolopyridimine.
    AU2018232071A1|2019-10-17|Hepatitis B virus surface antigen inhibitor
    AU2005245400A1|2005-12-01|Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
    CN105518005A|2016-04-20|Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors
    SK31793A3|1993-09-09|Pyridine and pyridine n-oxide derivatives of diaryl methyl piperidines and piperazines and compositions and methods of use thereof
    DE3614132A1|1986-11-27|1,3-DIHYDRO-2H-IMIDAZO | CHINOLIN-2-ONE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
    AU8177198A|1999-01-19|Substituted N-|phenyl) propyl amides
    RU2065859C1|1996-08-27|2-|-1-alkanol derivatives and 2-|-1-alkanone derivatives
    KR102200264B1|2021-01-11|PPAR agonist pyrrolidine derivative
    DE60011269T2|2005-06-23|AZAIDOLE WITH SEROTONIN RECEPTOR AFFINITY
    KR20200027989A|2020-03-13|ROCK's 5-membered-aminoheterocycle and 5,6- or 6,6-membered bicyclic aminoheterocyclic inhibitors for the treatment of heart failure
    US5760230A|1998-06-02|4, 4'-bridged bis-2, 4-diaminoquinazolines
    US20040006065A1|2004-01-08|Bicyclic pyrimidinones as coagulation cascade inhibitors
    DE4427838A1|1996-02-08|Condensed azepine derivatives, pharmaceutical compositions containing them and methods for their preparation
    ES2437166T3|2014-01-09|Bicyclic thiazoles as allosteric modulators of mGluR5 receptors
    KR100195368B1|1999-06-15|Selective adenosine receptor agents and process for their preparation of them
    AU2017317123A1|2019-04-11|PDE4 inhibitor
    JPH0660183B2|1994-08-10|Intermediate for the preparation of pyrazoloquinolines with alkylated pyrazole ring
    EP3466946A1|2019-04-10|Thiophene, manufacturing method thereof, and pharmaceutical application of same
    US5719145A|1998-02-17|Amidine derivatives and platelet aggregation inhibitor containing the same
    DE60204468T2|2006-04-27|THIOPYRAN-4-ONE AS INHIBITORS OF DNA PROTEIN KINASE
    EP3072882A1|2016-09-28|Substituted methyl amines, serotonin 5-ht6 receptor antagonists, methods for the production and use thereof
    CZ20014696A3|2002-05-15|Tricyclic spiro compounds and pharmaceutical preparations comprising them
    同族专利:
    公开号 | 公开日
    CS264349B2|1989-07-12|
    PL150646B1|1990-06-30|
    NZ220930A|1989-10-27|
    ES2016375B3|1990-11-01|
    AU598560B2|1990-06-28|
    HU196414B|1988-11-28|
    TNSN87084A1|1990-01-01|
    FI872932A|1988-01-05|
    IE60772B1|1994-08-10|
    KR880001680A|1988-04-26|
    PT85236B|1990-03-30|
    MA21028A1|1988-04-01|
    FI84728C|1992-01-10|
    KR950012680B1|1995-10-20|
    PT85236A|1987-08-01|
    JP2517725B2|1996-07-24|
    AU7504187A|1988-01-07|
    NO170583C|1992-11-04|
    NO872780D0|1987-07-02|
    IL83067D0|1987-12-31|
    GR3000637T3|1991-09-27|
    DK340187D0|1987-07-02|
    IE871768L|1988-01-04|
    CS501487A2|1988-11-15|
    DE3763630D1|1990-08-16|
    PL266581A1|1988-09-01|
    US4786645A|1988-11-22|
    BG47037A3|1990-04-16|
    MX173699B|1994-03-23|
    HUT44790A|1988-04-28|
    DD263774A5|1989-01-11|
    NO872780L|1988-01-05|
    FR2601016B1|1988-10-07|
    IL83067A|1991-01-31|
    ZA874815B|1988-03-30|
    EP0252823B1|1990-07-11|
    AT54454T|1990-07-15|
    FI872932A0|1987-07-02|
    NO170583B|1992-07-27|
    MX7190A|1993-10-01|
    FI84728B|1991-09-30|
    DK340187A|1988-01-05|
    JPS6322588A|1988-01-30|
    EP0252823A1|1988-01-13|
    CA1294967C|1992-01-28|
    FR2601016A1|1988-01-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2541280B1|1983-01-13|1985-06-21|Rhone Poulenc Sante|NEW DERIVATIVES OF 1H, 3H-PYRROLO THIAZOLECARBOXAMIDE-7, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM|
    FR2601015B1|1986-07-04|1988-08-05|Rhone Poulenc Sante|NOVEL 1H, 3H-PYRROLO THIAZOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|FR2601015B1|1986-07-04|1988-08-05|Rhone Poulenc Sante|NOVEL 1H, 3H-PYRROLOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    FR2617484B1|1987-07-02|1989-10-20|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF ACID-3 1H-3H-PYRROLOTHIAZOLECARBOXYLIQUE-7 DEXTROGYRE|
    FR2626004B1|1988-01-20|1991-08-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF-3 1H, 3H-PYRROLOTHIAZOLECARBONITRILE-7|
    FR2644456B1|1989-03-17|1991-07-05|Rhone Poulenc Sante|NOVEL 1H, 3H-PYRROLOTHIAZOLECARBOXAMIDE-7 DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    DE3915450A1|1989-05-11|1990-11-15|Gerd Prof Dr Dannhardt|SUBSTITUTED PYRROL COMPOUNDS AND THEIR USE IN PHARMACY|
    US5260451A|1989-05-11|1993-11-09|Merckle Gmbh|Substituted pyrrole compounds and use thereof in pharmaceutical compositions|
    JP3061631B2|1989-10-11|2000-07-10|山之内製薬株式会社|Novel heterocyclic compound and method for producing the same|
    US5120749A|1991-02-20|1992-06-09|Abbott Laboratories|Platelet activating antagonists|
    US5530141A|1992-03-04|1996-06-25|Center For Innovative Technology|2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase|
    US5639782A|1992-03-04|1997-06-17|Center For Innovative Technology|Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors|
    US5120751A|1991-03-29|1992-06-09|Abbott Laboratories|Benzoylphenyl pyridinylthiazolidine compounds as platelet activating antagonists|
    US5149704A|1991-05-03|1992-09-22|Abbott Laboratories|Platelet activating antagonists|
    US5648486A|1992-07-13|1997-07-15|Cytomed, Inc.|Compounds and methods for the treatment of inflammatory and immune disorders|
    US5358938A|1992-07-13|1994-10-25|Cytomed, Inc.|Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase|
    ES2152952T3|1992-07-13|2001-02-16|Millennium Pharm Inc|2,5-DIARIL TETRAHYDRO-THIOPHENS, -FURANS AND ANALOGS FOR THE TREATMENT OF INFLAMMATORY AND IMMUNE PROBLEMS.|
    US5463083A|1992-07-13|1995-10-31|Cytomed, Inc.|Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders|
    US5434151A|1992-08-24|1995-07-18|Cytomed, Inc.|Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase|
    US5792776A|1994-06-27|1998-08-11|Cytomed, Inc.,|Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders|
    US5750565A|1995-05-25|1998-05-12|Cytomed, Inc.|Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders|
    US5703093A|1995-05-31|1997-12-30|Cytomed, Inc.|Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8609729A|FR2601016B1|1986-07-04|1986-07-04|NOVEL 1H, 3H-PYRROLOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    [返回顶部]