• 专利附录
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  • 权利要求
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  • 优先权
    • 专利摘要:
    A method for preparing heterocyclic amides of general formula 4; -O where A is a methylene group; p O or; Р - 0; 1 R or A - p «P RI or p p RI or R, - R, R, - R3 is a sulfur atom; I; 0; R. R, hydrogen. hydrogen. 0; O or 1; RJ is hydrogen, hydrogen; hydroxyl or, alkane, substituted by morpholinyl, imidazolyl. 4-methylpiperazine, diethylamino or oxyethylamino group, or R and RJ together with the nitrogen atom — morpholinyl or piperazinyl, substituted in position 4 with methyl, benzyl, hydroxyethyl or 1-pyrrolidinylcarbonylmethyl; Rj is hydrogen, methyl or phenyl, or their salts, characterized in that the acid of the general formula C (X) H N A p L N 3 (cng, where A, p, p, RJ have the indicated meanings, is reacted with chloride thionyl and an acid chloride of the general formula with where A, p, p, RJ have the indicated meanings, react with the amine of the general formula HN: .1 R2 CM where R, and Rj have the indicated values, in methylene chloride and separate the target product in free form or in salt form.
    公开号:SU1251805A3
    申请号:SU843692010
    申请日:1984-01-12
    公开日:1986-08-15
    发明作者:Фабр Жан-Луи；Фарж Даниель；Жамес Клод；Лаве Даниель
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    125
    The invention relates to a process for the preparation of new chemical compounds, namely, heterocyclic amides of the general formula
    CCfN


    A (SNg) p
    -Ri
    H2
    1СН
    where A is a methylene group; p O or 1; P 0;
    R, RJ RJ is hydrogen or A is a sulfur atom; n 1; p 0;
    , R, j is hydrogen, or n 0;
    p O or I;
    R, R J is hydrogen, or R I H;
    R is hydroxyl or C.-C-alkyl substituted with morpholinyl, imidazolyl 4-methylpiperazinyl, diethylamino and pi hydroxyethylamino, or R and R together with nitrogen atom - morpholinyl, or piperazinyl, substituted in position 4 by methyl, benzyl, hydroxyethyl or 1-pyrrolidinylcarbonylmethyl;
    R, is hydrogen, methyl or phenyl, or their salts, which exhibit biological activity and can be used in medicine.
     The aim of the invention is to develop, on the basis of a well-known method, a method of obtaining new chemical compounds with valuable pharmaceutical properties.
    Example I. Suspension of 8.8 g of 5- (3-pyridyl) -1H, 3N-pyrrolo-1, -thiazole-7-carboxylic acid in a mixture of 6.25 cm of thionyl chloride, 0.05 cm of dimethylformamnz and 100 cm 1, 2-dichloroethane is heated with a reflux condenser with stirring for 2 h 30 min. The reaction mixture is cooled at 20 ° C and concentrated to dryness under reduced pressure (20 mm Hg) at 60 ° C. The resulting precipitate is suspended in 150 cm of cyclohexane, and the solvent is evaporated under reduced pressure (20 mm Hg) at 70 ° C. The operation is repeated 2 times. Obtain 10 g of hydrochloride 7-chloroformyl-5- (31805
    -pyridyl) -1H, 3N-pyrrolo tl, 2-c-thiazol in the form of cream crystals, gsa-SYAlCH1HSCYa at.
    This product is extracted with 200 cm 5 of methylene chloride. In the solution thus obtained, a solution containing 6.2 g of H- (3-aminopropyl) -morpholine and 8.7 g of triethylase in 70 cm of methylene chloride is added during 20 minutes. The resulting solution was stirred at 20 ° C for 16 hours. 250 ml of methylene chloride and 250 cm of distilled water were added to the solution. The organic phase is separated, washed 2 times with 500 cm (total) of distilled water, to which 0.5 g of vegetable black is added, dried over anhydrous magnesium sulphate, filtered and concentrated
    0
    20
    dry under reduced pressure
    (20 mm Hg) at 60 ° C. 1.6 g of pure oil is obtained, which is mixed with 2.7 g of the product previously prepared in the same manner and dissolved in 150 cm of boiling 2-propane. la 0.5 g of vegetable black is added to the resulting solution and filtered while hot. The filtrate is cooled at 4 seconds for 1 hour. The crystallized crystals are separated by filtration, washed 3 times 30 cm (total) 2-propanol, 3 times 75 cm (total) isopropyl oxide and dried under reduced pressure (20 mm). Hg) at 20 s in the presence of granular caustic
    thirty
    35
    Kali. 11.6 g of product are obtained, melting at 156 ° C. It is then dissolved in 50 cm of boiling ethanol. Add 0.5 g of vegetable black
     and filter the solution hot. The filtrate is cooled at 4 ° C for 1 h. The crystallized crystals are separated by filtration, washed with 2 times 10 cm (total) ethanol, then 3 times
     75 cm (in total) of isopropyl oxide and dried under reduced pressure (20 mm Hg) at 20 ° C in the presence of granular caustic potash. 10.5 g of product are obtained, melting at 158 C. Then, it is dissolved in 200 cm of boiling acetonitrile. The resulting solution is filtered hot, then the filtrate is cooled at 4 ° C for 15 minutes. By vivshies
    55 crystals are separated by filtration, washed 3 times 45 cm (total) of acetonitrile and 3 times 75 cm (total) of isopropyl oxide and dried at
    25
    31251
    reduced pressure (20 mm Hg) with in the presence of granular potassium hydroxide.
    9 g of N- (3-morpholino-propyl) -5- (3-pyridyl) -1H, 3H-pyrrolo-j-1,2-c-thiazole-7-carboxamide are obtained in the form of cream crystals, melting at} 58 ° s
    5- (3-Pyridyl) -1H, 3H-pyrrolo-, 2-c3-thiazole-7-carboxylic acid o can be prepared as follows.
    A mixture of 18.7 g of 5- (3-pyridyl) -1H, 3N-pyrrolo-G1,2-c1-thiazole-7-carbonitrile, 16.3 g of granulated caustic potash and 160 cm of ethylene glycol is heated with stirring 2 hours. After 16 hours of stirring at 20 ° C, the solvent is evaporated under reduced pressure (2 mm Hg) at 100 ° C. The residue is dissolved in 100 cm of distilled water and the resulting solution is brought to pH 5 by adding 2N aqueous hydrochloric acid . The crystallized crystals are separated by filtration, washed 3 times with 150 cm (total) of acetone and dried under reduced pressure (20 mm Hg) at 20 With the presence of granulated potassium hydroxide. 17.7 grams of pure product, melted at. This product is mixed with 1.3 g of the product previously prepared in the same way, and dissolved in a mixture of 650 cm of 1-but-35 yola and 150 cm of dimethylformamide, previously heated at 15 ° C at 15 ° C. 0.5 g of vegetable black is added to the resulting solution and filtered hot. The filtrate is cooled at 16 hours. The crystallized crystals are separated by filtration, washed twice with 50 cm (total) of dimethylformamide, 3 times with 150 cm (total) of ethanol, 3 times with 150 cm (total) of isopropyl oxide, then 3 150 cm times (in total) diethyl ether and dried under reduced pressure (20 mm Hg) at 20 ° C in the presence of granular potassium hydroxide. 16.1 g of product are obtained, melting at. This product is suspended in 250 cm of distilled water, and then it is stirred at 20 ° C for 2 hours. The crystals are separated by filtration, 55 are washed with 150 cm (total) of distilled water, 3 times 90 from) ethanol, 3 times 90 cm oxide
    five
    one
    j

    8054
    isopropyl, then - 3 riza 90 cm (in
    the amount of) distil ether and suca-H under reduced pressure (20 mm Hg) at 100 C in the presence of granulated caustic potash.
    15.5 g of 5- (3-pyridyl) -1H, 3H-pyrrolo-1,2-e-thiazole-7-carboxylic acid are obtained in the form of cream crystals, melted at 266 C.
    5- (3-Pyridyl) -1H, 3H-pyrrolo-tl, 2-e-thiazole-7-carbonitrnl can be prepared as follows.
    A suspension of 403 g of N-nicotyshthiazoline dinocarboxylic acid in a mixture with 1250 cm of 2-chloroacrylonitrile and 1750 cm of acetic anhydride is heated at 90 C for 2 hours and 40 minutes. A transition is observed during this period: after 30 minutes a clear homogeneous phase is formed, and 10 minutes later a precipitate is formed. After cooling at 4 ° C for 16 hours, the crystallized crystals are separated by filtration, washed with 2 times 200 cm (total) acetic anhydride, 3 times 300 cm (total) acetone and dried under reduced pressure (20 mm Hg). Art.) at 20 C in the presence of granular potassium hydroxide. The resulting product is suspended in a 2400 cm 2N aqueous solution of sodium hydroxide. After stirring at 20 ° C for 1 hour and 30 minutes, the precipitated crystals are separated by filtration, washed 5 times with 1250 cm (in total) of distilled water, 3 times with 1200 cm (in total) ethanol, 3 times with 900 cm ( in total) diethyl ether and dried under reduced pressure (20 mm Hg) at 20 ° B in the presence of granulated caustic potash.
    159.7 g of 5- (3-pyridyl) -1 -1, 3H-pyrrolo-1,2-c-thiazole-7-carbonitrile are obtained in the form of cream-colored crystals, melting LINE.
    K-Nicotinyl thiazolidine-4-carbon acid can be obtained as follows.
    To a solution of 400 g of 4-thiazolidine carboxylic acid and 613 g of triethylamine in 4300 cm of chloroform, 1 hour is added at 3-B of C, 534 g of nicotinyl chloride hydrochloride. The resulting solution is heated at 64 ° C for 4 hours. After stirring at 20 ° C for 16 hours, the crystals that have precipitated out are separated by filtration, washed 3 times with 1500 cm (total) chlorofor-.
    ma, then 3 times 1500 cm (in total) of diethyl ether and sugaat under reduced pressure (20 mm Hg) at 20 ° C in the presence of a granular caustic drip.
    403 g of N-nicotinyl-4-thiazolidine carboxylic acid are obtained in the form of white crystals, melting at
    igo c.
    Example 2. To suspension 12.5 g of hydrochloride 7-chloroformyl-5- - (3-pyridyl) -1H, 3N-pyrrolo-1,2-c | thiazole in 250 cm-methylene chloride is added for 20 minutes at 22-30 0 a solution of 13.2 g of N-methyl piperazine in 120 cm of methylene chloride. The resulting solution is stirred for 16 hours and 250 cm of methylene chloride and 150 cm of distilled water are added to it. The organic phase is separated by decantation, washed 2 times with 300 cm (total) of distilled water, dried over anhydrous magnesium sulphate, then 0.5 g of vegetable black is added, filtered and concentrated to dryness under reduced pressure (20 mm Hg) at . The resulting mass is extracted with 150 cm of isopropyl oxide with stirring for I h at. At the same temperature for 24 hours, the later cremated crystals are separated by filtration, washed 3 times with 75 cm- (total) of isopropyl oxide and dried under reduced pressure (20 mm Hg) under the presence of a granular caustic drip. 10.8 g of pure product are obtained, melting at. This product is dissolved in 250 cm of boiling carbon tetrachloride. To the resulting solution, 0.5 g of vegetable black is added and the solution is filtered hot; the filtrate is cooled at 4 ° C for 16 hours. The crystallized crystals are separated by filtration, washed
    3 times 30 cm (in total) with carbon tetrachloride, then 4 times
    100 cm (in total) of isopropyl oxide and dried under reduced pressure (20 mm Hg) at 20 ° C in the presence of granular caustic potash. 5.8 g of product are obtained, melting at 104 C. 5.4 g of this product is dissolved in 12 boiling acetonitrile. The resulting solution is cooled at
     for 2 h. The crystallized crystals are separated by filtration, washed 3 times with 6 cm (total) aceto
    five
    0
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    0
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    0
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    0
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    nitrile, 3 times 30 cm (in total) of isopropyl oxide and supersht under reduced pressure (20 mm Hg) in the presence of a granulated caustic drip.
    4 g of 7-f (4-methyl-l-piperazinyl) -carbonyl-5-3-pyridip) -1H, 3H-pyrrolo-1,2-c-thiazole are obtained in the form of cream crystals melting at
    .
    7-Chloroformyl-5- (3-pyridyl) -1H-311-pyrrolo-1, 2 -c-thiazole hydrochloride is prepared as in Example I.
    Example 3. To a suspension of 12 g of 7-chloroformyl-5- (3-pyridyl) -1H, 3H-pyrrolo-11,2-c-thiazole hydrochloride in 200 cm of methylene chloride was added a solution of 13.9 at 20 ° C. g 2-diethylaminoethylamine in 50 cm of methylene chloride. The resulting solution is stirred for 16 h at 20 ° C. The product forms a precipitate. Then 250 cm of methylene chloride and 100 cm of an aqueous solution of 2N sodium hydroxide are added; the organic phase is separated by decantation and washed with 100 cm of an aqueous solution of 2N sodium hydroxide, then 3 times 600 cm (in total) of distilled water, dried over anhydrous potassium carbonate, filtered while adding 0.5 g of vegetable black and concentrated to dryness under reduced pressure ( 20 mm Hg) at 60 ° C. 12 g of pure product are obtained. This product is then dissolved in 60 cm of boiling acetonitrile. To the resulting solution, 0.5 g of vegetable black is added and the solution is filtered hot. The filtrate is cooled at 4 ° C for 2 hours. The crystallized crystals are separated by filtration, washed with 2 times 20 cm (total) of acetonitrile, cooled at 4 ° C, then - 3 times 150 cm - (in total) isopropyl oxide and dried at reduced pressure (20 mm Hg) at 20 ° C in the presence of granulated caustic potash.
    Get 6.4 g N- (2-diethylamino-ethyl) -5- (3-pyridyl) -1 And, 3N-pyrrolo - P, 2-c-thiazole-7-carboxamide in the form of light beige crystals, melt existing at.
    7-chloroformyl-5- (3-pyridyl) -1 hydrochloride AND 3H-pyrrolo-1,2-C1-thiazole is prepared as in Example 1.
    Example 4. To a suspension of 15.7 g of 7-chloroformyl-5- (3-pyridsh1) -1H, 3H-pyrrolo-1,2-eJ hydrochloride
    thiazole and 10.9 g of hydroxylamine hydrochloride in 390 cm of methylene chloride are added for 20 minutes at 16-27 C, 26.5 g of triethylamine. The resulting solution was stirred for 16 hours at. Well, the crystals are separated by filtration, washed 3 times with 150 cm (total), methylene chloride and dried under reduced dosing (20 mm Hg), with anhydrous potassium hydroxide. The crystals transferred transferred into suspension with stirring in 250 cm of distilled water at 20 ° C for 70 minutes. The crystals are separated by filtration, washed 3 times with 150 cm (total) of distilled water, 3 times with 150 cm of acetone, 3 times with 150 cm (in total) diethyl ether and cyinaT under reduced pressure (20 mm Hg). Art.) when in the presence of anhydrous caustic potash in the granules. 11.6 g of pure product are obtained, melting at 195 s. This product is mixed with 2 g of the product obtained in the previous synthesis and dissolved in 500 cm of boiling 1-butanol. To the resulting solution was added 0.5 g of vegetable black and filtered; the filtrate is cooled at 4 ° C for hours. The crystallized crystals are separated by filtration, washed with 2 times 50 cm (total) of butanol-1, 3 times 150 cm (total)
    ethanol, then 3 times 150 cm (in total) of diethyl ether and dried under reduced pressure (20 mm Hg) in the presence of granulated caustic potash.
    8.4 g of 5- (3-pyridyl) -1H, 3N-pyrrolo-L1,2-c-thiazole-7-carboxyamic acid are obtained in the form of ocher crystals melting at 2-10 ° C.
    7-chlorophor mil-5- (3-pyridyl) -1H, 3N-pyrrolo-1,2-C1-thiazole hydrochloride is prepared as in Example 1.
    Example 5. To a suspension of 12 g of 7-chloroformyl-5- (3-pyridyl) -1H, 3H-pyrrolo-1,2-C1-thiazole hydrochloride in 200 cm of methylene chloride was added for 15 minutes at 24-33 ° C. 10.45 g of morpholine in 50 cm of methylene chloride. The resulting solution was stirred for 16 hours, then diluted with 250 cm of methylene chloride, washed 2 times with 400 cm (in total) of distilled water, 1 time with 200 ml of water.
    , y 5 20 5 o
    five

    five
    a solution of 2N sodium hydroxide, then 2 times 400 cm (in total) of distilled air of water, dried over anhydrous magnesium sulfate, filtered with the addition of 0.5 g of vegetable black, and concentrated under reduced pressure (20 mm Hg) at 60 ° C. 12.7 g of pure product are obtained, which is dissolved in 125 cm of boiling acetonitrile. To the resulting solution is added 0.5 g of vegetable black and filtered hot. The filtrate is cooled at 2 hours. The crystallized crystals are separated by filtration, washed 2 times 10 cm (in cybfMe) of acetoiitrile, cooled to 4 s, and 3 times 75 cm (total) of isopropyl oxide, then dried under reduced pressure (20 mm Hg) when in the presence of granular caustic potash.
    7.5 g of 7-morpholinocarbonyl-5- (3-pyridyl) -1H, 3H-pyrrolo- I, 2-C1-thiazole are obtained in the form of beige crystals, melting at.
    7-Chloroformyl-5- (3-pyridyl) -1 H, 3H-pyrrolo-2-2-thiazole hydrochloride is prepared as in Example I.
    Example To a solution of 26.1 g of anhydrous piperazine in 500 cm of methylene chloride, a solution of 30 g of hydrochloride of 7-chloroformyl-5- (3-pyridyl) -1H, 3N-pyrrolo-II, 2H is added in 25 minutes at 24-32 ° C. with α-thiazole and 20.2 g of triethylamine in 500 cm of methylene chloride. The resulting suspension is stirred at 20 s. for 16 hours, then diluted with 600 cm of methylene chloride and washed 2 times with 600 cm (in total) of an aqueous solution of 2N sodium hydroxide. The organic phase is decanted, washed 3 times with 1550 cm (total) of distilled water, dried over anhydrous magnesium sulphate, filtered, with the addition of 1 g of vegetable black, and concentrated to dryness under reduced pressure (20 mm Hg) at 60 ° C. 25.4 g of product are obtained, which is dissolved in 160 cm of boiling 1-butanol. To the resulting solution is added 0.5 g of vegetable black and filtered hot. The filtrate is cooled at 4 seconds for 16 hours. The crystallized crystals are removed by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at. -1 g of product is obtained which is chromatographed on a column of
    3.8 cm, containing 210 g of silica (0.063-0.2 mm). It is washed with a mixture of methylene chloride and methanol, collecting fractions from 300 cm. The first 7 fractions are removed by thrashing with a mixture of methylene chloride and methanol (95-3 vol.), The following 3 are washed when washing with a mixture of methylene chloride and methanol (93-5 vol.), 7 following are washed with a mixture of methylene chloride and methanol (90-10 vol. .) and the following 8, when washed with a mixture of methylene chloride and methanol (85-15 vol.), are collected and concentrated to dryness under reduced pressure (20 mm Hg) at 60 C. 12.2 g of product are obtained, which is converted into a suspension in 50 cm of distilled water, and the resulting suspension perempshivat when adding 100 cm 5N caustic soda and extracted 3 750 cm times (in total) methylene chloride. The organic extracts are combined, washed 2 times with 200 cm (in total) of distilled water, dried over anhydrous magnesium sulphate, filtered with the addition of 0.5 g of vegetable black and concentrated to dryness under reduced pressure (20 mm Hg) at 60 C. Obtain 11 g of product, which is extracted with 30 cm of boiling methanol. The resulting suspension is filtered hot in the presence of 0.5 g of vegetable black, and the filtrate is cooled at A C for 3 hours. The crystals formed are separated by filtration, washed 2 times with 10 cm (total) methanol, cooled to A C, and 3 75 cm times of diethyl ether (in total), then dried under reduced pressure (20 mm Hg with the presence of granulated caustic potash. 5.9 g of product are obtained, melting at. The mother liquors are concentrated to dryness under reduced pressure (20 mm Hg) 2.8 g of product is obtained which is extracted 25 cm of ethanol. The floor of the suspension is heated to boiling for 5 minutes, then cooled to 20 ° C. The crystallized crystals are separated by filtration, then washed with 2 times (in total) 10 cm-) tanol and dried under reduced pressure (20 mm Hg) when in the presence of granular potassium hydroxide. 0.3 g of product is obtained, melting at 262 C. The filtrate is poured into 28 cm of an alcohol solution.
    0
    five
    0
    five
    0
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    0
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    0.64N hydrogen chloride, the crystallized crystals are separated by filtration, washed with 2 times 20 cm (total) of ethanol and 3 times 75 cm (total) of isopropyl oxide, then sugate under reduced pressure (20 mm Hg) at 20 C in the presence of granular caustic potash. 2.5 g of product are obtained, melting at 260 ° C. This product, mixed with CO, Zg5.9 g of the product obtained earlier, is slurried into 600 cm of an alcohol solution of 5.35 N hydrogen chloride. After 35 minutes of stirring, dissolution was observed, after 10 minutes after which crystallization occurred. The resulting suspension was stirred for 16 hours. The crystallized crystals were separated by filtration, washed 3 times 75 cm (total) ethanol and 3 times 75 cm (total) diethyl ether, then dried under reduced pressure (20 mmHg). ) at 20 s in the presence of granulated potassium hydroxide.
    6.7 g of 7- (I-piperazinyl-carbonyl) -5- (3-pyridyl) -1N.H.-pyrrolo-11,2-c-thiazole are obtained in the form of trichlorohydrate monopadrate in the form of pale yellow crystals. melting at 242 C.
    5- (3-Pyridyl) -1H, 3H-pyrrolo-tl, 2-C-thiazole-7-carboxylic acid is prepared as in Example 1.
    Example 7. To a suspension of 7.8 g of 7-chlorophormyl-5- (3-hydroxy) -1H, 3H-pyrrolo-t1,2-el-1-thiazole hydrochloride in 130 cm of methylene chloride are added for 20 minutes at 21-31 C solution of 3.7 g of 1- (2-aminoethyl) -4-methylpiperazine and 5.3 g of triethylamine in 45 cm of methylene chloride. The resulting solution was stirred at 20 ° C for 16 hours, then diluted with 200 cm of methylene chloride, washed 4 times with 800 cm (total) of distilled water, dried over anhydrous magnesium sulfate, filtered by adding 0.5 g of carbon black and concentrated to dryness under reduced pressure (20 mm Hg) at 60 s. 6.3 g of product are obtained, which is dissolved in 150 cm of distilled water. The resulting solution and the previous washings are combined and alkalinized by adding 250 cm of an iodine solution of 5N sodium hydroxide. The resulting suspension is extracted 3 times 750 cm (total) of methylene chloride. The organic extracts are combined.
    washed 3 times 750 cm (total) of distilled water, dried over anhydrous magnesium sulphate, filtered by adding 0.5 g of vegetable black and concentrated to dryness under reduced pressure (20 mm Hg) at. 7.6 g of pure product are obtained, which is dissolved in 150 cm of ethanol and added to it for 15 minutes at 65 cm of an alcoholic solution of 1.26 N hydrogen chloride. 25 cm of ethanol is added to the resulting suspension, then stirred at 20 ° C for 2 hours. The crystals are separated by filtration, washed with 3 times 75 cm (total) of ethanol and 4 times 100 cm (total) of diethyl ether, then dried under reduced pressure ( 20 mm Hg) at 20 ° C in the presence of granular caustic potash.
    Get 7, And g (4-methyl-l-pi perzinyl) -ethyl-5- (3-pyridsh) -lH, 31-pyrrolo-2-C1-7-thiazolecarbox and in the form of trichlorohydrate in the form of pale yellow crystals melting at.
    7-hporoformal-5- (3-pyridyl) -1H, 3N-pyrrolo-1,2-c-thiazole hydrochloride is prepared as in Example 1.
    Example 8 To a solution of 5.3 g of 2-hydroxyethylpiperazine and 8.1 g of trizthyl amine in 250 cm of methylene chloride are added for 35 minutes at 23-30 With 12 g of hydrochloride 7-chloroformyl-5- (3-pyridyl) -1H, 3N-pyrrolo-P, 2-c-thiazole. The resulting solution was stirred for 16 hours, then diluted with 200 with methylene chloride and washed 4 times with 800 cm (total) distilled water, dried over anhydrous magnesium sulfate, filtered while adding 0.5 g of vegetable black and concentrated to dryness under reduced pressure ( 20 mm Hg) at. 14 g of pure product are obtained, which is dissolved in 130 cm of boiling ethanol. To the resulting solution, 0.5 g of vegetable black is added and filtered hot. The filtrate is cooled at 1 hour. The crystallized crystals are separated by filtration, washed 2 times 50 cm (total) of ethanol and 4 times 100 cm (total) of isopropyl oxide, then dried under reduced pressure (20 mm Hg) when in the presence of granular potassium hydroxide.
    8.3 g of G (- (2-oxystil) - I-piperazinyl) -7-carbonyl-5- (3-pyridyl) -1H, 3N-pyrrolo- (I, 2-cj-thiazole in the form of a creamy crystals melting at 140 C.
    7-Chloroforml-5- (3-pyridyl) -1H, 3H-pyrrolo-1,2-f) -thiazole hydrochloride is prepared as in Example 1.
    Example 9: To a suspension of 7-x. Porformyl-5- (3-pyridyl) -1H, 3H-pyrrolo-1, 2-C-thiazole chlorohydrate in 300 cm of methylene chloride was added for 30 minutes at 24-31 s solution 30.6 g of 1-benzylpiperazine in 150 cm of methylene chloride. The resulting solution is stirred at 20 seconds for 16 hours, then diluted with 300 cm of methylene chloride, washed 3 times with 750 cm (total) of distilled water, dried over anhydrous magnesium sulphate, filtered while adding 0.5 g of vegetable black and concentrated to dryness under reduced pressure (20 mm Hg) at 60 ° C. Get 22.7 g of the product in pure form. This product is dissolved in 100 cm.-boiling acetonitrile. To the resulting solution, 0.5 g of vegetable black is added and filtered hot. The filtrate is cooled at A C for I h. The crystallized crystals are separated by filtration, washed 2 times 50 cm (total) of acetonitrile, cooled at 4 ° C, 3 times 75 cm (total) of diethyl ether, then dried under reduced pressure (20 mm Hg) when in the presence of granular caustic potash.
    13 g of 7- (4-benzyl-l-piperazinyl) -carbonyl-5- (3-pyridyl) -IH, 3H-pyrrolo-1,2-C-thiazole are obtained in the form of cream crystals, melting at 140 WITH.
    7-Chloroformyl-5- (3-pyridyl) -1H, 3H-pyrrolo-I, 2-cT-thiazole hydrochloride is prepared as in Example 1.
    Example 10. To a suspension of 15 g of 7-chloroformyl-5- (3-pyridyl) -1H, 3H-pyrrolo-1,2-G-thiazole hydrochloride in 250 cm of methylene chloride is added for 30 minutes at 24-32 ° C. The solution 10.2 g of 1 - (1-pyrrolidinyl) -carbonylmethyl-piperazine and 10.1 g of triethylamine in 100 cm of methylene chloride. The resulting solution was stirred at 20 ° C for 16 hours, then diluted with 300 cm of methylene chloride, washed 3 times with 900 cm (total) of distilled water, and dried over anhydrous sulfate
    magnesium, filtered with the addition of 0.5 g of vegetable black, and concentrated to dryness under reduced pressure (20 mm Hg) at 60 ° C. Get 20.8. g of pure product, which is extracted 80 cm of acetonitrile. The product is crystallized. The resulting suspension is heated to boiling, then 0.5 g of vegetable black is added to the resulting solution and the solution is filtered hot. The filtrate is cooled at 4 ° C for 16 hours. The crystallized crystals are separated by filtration, washed
    2 times 20 cm (in total) of acetonitrile cooled to 4 ° C, 4 times 200 cm
    (in total) diethyl ether, then dried under reduced pressure (20 mm Hg) at 20 ° C in the presence of granular caustic potash. Obtain 13.2 g of 7- (l-pyrrolidinyl-4-carboxyl-methyl-l-piperidinyl) - -carbonyl-5- (3-pyridyl) -1H, 3N-, pyrrolo-LI, 2-c1-thiazole in the form of beige crystals melting at.
    7-Chloroformyl-6- (3-pyridyl) -1H, 3H-pyrrolo-1,2-C-thiazole hydrochloride is prepared as in Example t.
    Example 11. To a solution of 12.9 g of histamine in 360 cm of methylene chloride, 17.5.-g of 7-chloroformyl-5- (3-pyridio) -1H, 3N-pyrrolo hydrochloride is added for 15 minutes at 18-27 ° C - 1,2-C-thiazole. The resulting suspension was stirred at 20 ° C for 16 hours, then a mixture of 360 cm of methylene chloride and 300 cm of water was added to it. The crystallized crystals are separated by filtration, washed
    3 times 30 cm (total) of methylene chloride, 3 times 300 cm (total) of distilled water, 3 times 300 cm (total) of an aqueous solution of 2N sodium hydroxide and 3 times 300 cm of distilled water and dissolved in 100 cm of an aqueous solution of 2N salt Noah acid. To the resulting solution was added 0.5 g of plant black and filtered. The filtrate is adjusted to pH 10 by the addition of an aqueous solution of 10N sodium hydroxide; the crystallized crystals are separated by filtration, washed 3 times with 150 cm (total) of distilled water and 3 times with 75 cm (total) of acetone and dried under reduced pressure (20 mm Hg) npH. in the presence of granular caustic potash. 11.8 g of pure product are obtained, which is dissolved
    in 250 cm of isopropanol. To the resulting solution, 0.5 g of vegetable black is added and filtered hot. The filtrate is cooled at 4 ° C for 16 hours. The viscous precipitate is separated by filtration and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 60 ° C. 8.4 g of product are obtained, melting at. This product is dissolved in 350 cm of boiling ethanol. To the resulting solution, 0.5 g of vegetable black is added and filtered hot. The filtrate is cooled for 16 hours at. The crystallized crystals are separated by filtration, washed 3 times with 30 cm (total) of ethanol and 3 times with 75 cm (total) of diethyl ether and dried under reduced pressure (20 mm Hg) at 20 ° C in the presence of potassium hydroxide.
    5.6 g of (4-imidazolyl-ethyl-5- (3-pyridio) -lH, 3H-pyrpolo-1, 2-c-thiazole-7-carboxamide) are obtained in the form of cream crystals, melting at 226 s.
    7-chloroform-1-5- (3-pyridyl) -1H, 3N-pyrrolo-I, 2-C1-thiazole hydrochloride is prepared as in Example I.
    In the same way, but starting from the corresponding acids, the following compounds are obtained.
    Example 12. 5- (3-Pyrncyl) -1H, 3N-pyrrole-1,2-c-7-thiazole-carbox amide, m.p. 215 C.
    Example 5. 5- (3-Pyridsh1) - -2,3-dihydro-1H-7-pyrrolizinecarboxamide with t. Rai. 210 ° C.
    Example 14. b- (3-pyridl) -3,4-dihydro-1H-pyrrol-C1, 4-thiazyl-8-carboxamide with mp. .
    Example 15. (3-Pyridyl) -vinyl -1H, 3N-pyrrol-l, thiazolecarboxamide with m.p.
    Example 16. M-C (2-hydroxyethyl) -2 -2-aminoethyl-5- (3-pyridsh1) -1H, 3H-pyrrole-1, 2-C-7-thiazolecarboxamide with m.p. 163 S.
    Example 17. 3-Phenyl-5- (3-pyridyl) -1H, 3N-pyrrole-1,2-C-7-thiazole-carboxamide, the hydrochloride of which has so pl. 250 ° C.
    Example 18. 3-Methyl-5- (3-pyridyl) -1H, 3N-pyrrole-1,2-c-7-thiazole-carboxamide with m.p. 170 C.
    Example 19. H- (3-Pyridyl) -5,6,7,8-tetrahydro-I-indolizinecarb-oxamide with m.p. 184 s.
    Pharmacological tests (test description).
    with). An in vitro study of the inhibition of platelet aggregation caused by collagen.
    Platelet aggregation of rabbit platelet-rich plasma, caused by collagen suspension during agitation, is measured by the increase in light transmission through the mixture.
    Rabbit fresh and citrate blood is centrifuged at 100 G for 20 min at. In this way, platelet-rich plasma (PRP) is obtained which contains at least 500,000 platelets in I mm.
    6. Toxicity.
    Determine the dose of the product (LD j), which, after administration to the mice, causes the death of 50% of them.
    The results of biological tests are summarized in table.
    权利要求:
    Claims (1)
    [1]
    A method for producing heterocyclic amides of the general formula where A is a methylene group;
    η = 0 or 1; p is 0;
    R, "R 2 = Rj is hydrogen, or A is a sulfur atom;
    η ”1;
    p is 0;
    R, "R g = R, is hydrogen, or η ® 0;
    p is 0 or 1;
    R, = R 2 “hydrogen, or R, is hydrogen;
    R 2 is hydroxyl or C 2 -C 3 alkyl substituted with morpholinyl, imidazolyl,
    4-methylpiperazinyl, diethylamino or hydroxyethylamino, or R and R 2 together with the nitrogen atom, morpholinyl or piperazinyl substituted at position 4 with methyl, benzyl, hydroxyethyl or 1-pyrrolidinylcarbonylmethyl;
    R 3 is hydrogen, methyl or phenyl, or their salts, characterized in that the acid is of the general formula
    C0QH where A, and, p, Rj have the indicated meanings, are reacted with thionyl chloride and the resulting acid chloride of the general formula where A, p, p, R 3 have the indicated meanings, are reacted with an amine of the general formula where R t and R 2 have these values in the environment of methylene chloride and secrete the target product in free form or in the form of salt.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE649903A|1963-07-03|
    FR1401707A|1963-07-03|1965-06-04|Kodak Pathe|New dyes, new intermediates used in their preparation and photographic materials containing them|
    US3642807A|1970-06-18|1972-02-15|Schering Corp|Certain 1-/dilower-alkyl amino-loweralkyl/-2-phenyl indolizines and quaternary salts thereof|FR2557111B1|1983-12-21|1986-04-11|Rhone Poulenc Sante|NOVEL ORTHO-CONDENSES OF PYRROLE, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM|
    GB8903592D0|1989-02-16|1989-04-05|Boots Co Plc|Therapeutic agents|
    US5260451A|1989-05-11|1993-11-09|Merckle Gmbh|Substituted pyrrole compounds and use thereof in pharmaceutical compositions|
    DE3915450A1|1989-05-11|1990-11-15|Gerd Prof Dr Dannhardt|SUBSTITUTED PYRROL COMPOUNDS AND THEIR USE IN PHARMACY|
    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|
    DE4419246A1|1994-06-01|1995-12-07|Merckle Gmbh|New hetero-aryl substd. pyrrolizine derivs.|
    DE4419247A1|1994-06-01|1995-12-07|Merckle Gmbh|New pyrrolizine keto-acid, keto-ester and carboxamide derivs.|
    FR2735476B1|1995-06-14|1997-07-18|Rhone Poulenc Rorer Sa|NEW APPLICATION OF PYRROLE DERIVATIVES|
    WO2001005792A1|1999-11-23|2001-01-25|Merckle Gmbh|Anti-inflammatory oxo derivatives and hydroxy derivatives of pyrrolizines, and their pharmaceutical use|
    DE10004157A1|2000-02-01|2001-08-02|Merckle Gmbh Chem Pharm Fabrik|New pyridyl- or pyrimidinyl-substituted bicyclic pyrrole derivatives, are cyclokine release inhibitors useful for treating immune system-related disorders, e.g. cancer, multiple sclerosis or arthritis |
    US8424704B2|2004-06-02|2013-04-23|X-Pert Paint Mixing Systems, Inc.|Self-cleaning lid for a paint container fluid pour spout|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8300454A|FR2539417B1|1983-01-13|1983-01-13|
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