• 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 heterocyclic compounds, in particular to the preparation of ortho-condensed pyrrole derivatives (OPP) of the general formula: ANC CC (CH) -C (0) NH, (CH -M-CH) p-Het, where a) Het-3- pyridyl, A-heterocycle, which with a pyrrole ring fused with it forms 1H, 3N-pyr-, 2-c thiazole, 2,3-dihydro-4H- -pyrrolo-1,2-e -1,3-thiazine , 2,3-di-hydro-pyrrolo 2,1-n thiazole, R - H, halogen, CH, n O or 1, p O, b) Het - 5-thiazolyl A - 1H, 3N-pyrrolol- (1,2-c) thiazole, R i - H, n O, p O, possessing antithrombotic activity. The goal is to create new, more active and less toxic substances of the specified class. OPP synthesis is carried out by hydrolysis of the corresponding nitrile at 80-90 C in an aqueous solution of HC1 or in tert-butanol in the presence of KOH. RPP inhibits the formation of thromboxane A by 36–92% at a dose of 10–50 mg / kg and LD toxicity, p 300–900 kg / kg. 1 tab. I WITH t about OO 4ia. WITH
    公开号:SU1440349A3
    申请号:SU853954499
    申请日:1985-09-23
    公开日:1988-11-23
    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:

     CM
    The invention relates to the production of new ortho-condensed pyrrole derivatives of the general formula
    (CH2) (AGG
     () r-neg
    where Het is 3-pyrridyl A is such a heterocycle that with the pyrrole ring with which it is condensed forms a 1H, 3H-pyrrolo- (1,2-c) thiazole, 2,3-dihydro-1H-pyrrolizine cycle, substituted by a hydroxy group , 1,2-dihydro-4H-pyrrolo- (1,2-e) -1,3-thiazine, 2,3-dihydro-pyrrolo- (2,1-c) thiazole R, is hydrogen, halogen, methyl; p O or 1, p O or when Het - 5-thiazolyl A is 1H, 3H-pyrrolo- (1,2-c) thiazole, R is hydrogen, p O,
    p O with anti-thrombotic activity.
    The purpose of the invention is to develop, on the basis of known methods, a method for producing New ortho-condensed pyrrole derivatives, which possess valuable pharmacological properties with low toxicity.
    Example 1. A suspension of 3.6 g of potassium hydroxide powder and 2.6 g of methyl 6- (pyridyl-3) -5-1H, 3N-pyrrole- (1,2-c) thiazolecarbonitrile in 75 cm of tertiary butyl alcohol is heated at 81 ° C for 10 hours. The suspension is placed in boiled water, and
    , -3
    500 cm distilled
    distilled vapi reduced pressure (mm Hg, 2.7 kPa) and
    the resulting solution
    stirred at 4 ° C for 3 hours. The crystallized crystals are separated by filtration, washed five times with a total volume of 125 cm, and dried (20 mm Hg, -1., in the presence of potassium hydroxide tablets. This gives 2 , 3 g of the product melting at 212 ° C. This product is dissolved in 150 cm of boiling ethanol. 0.5 g of vegetable black is added to the resulting solution and hot filtration is carried out. The filtrate is cooled to 4 seconds for 1 h. The crystallized crystals are separated by filtration, washed twice with a total volume of 50 cm of ethanol and 3 times with a total volume of 75 see diethyl ether and dried under reduced pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of hydro
    ten
    potassium oxide in tablets. 1.6 g of 6-methyl-5- (3-pyridyl) -1H, 3H-pyrrolo- (1,2-c) -7-thiazolecarboxamide are thus obtained in the form of white crystals, melting at 222 ° WITH.
    Methyl-6- (pyridyl-3) -5-1H, 3N-pyrrol- (1,2-e) thiazolecarbonitrile-7 was prepared as follows.
    A suspension of 19 g of N-nicotinoyl thiazolidine carboxylic acid and 58.4 g of bromine-2-butene-2-nitrile in 120 cm of acetic anhydride is heated to 100 ° C for 1 hour. The resulting
    the solution is concentrated by itself at
    dry applied pressure. (20 mm Hg, 2.7 kPa) and 80 ° C. The residue is shaken to 150 cm 3 of distilled water. The suspension is added
    five
    0
    five
    0
    five
    five
    0
    0 150 cm
    in one solution of sodium hydroxide 10N and stirred at for 30 minutes. Then 300 cm methylene chloride is added. The organic phase 1 is separated by decantation, and the aqueous phase is extracted twice with a total volume of BOO cm methylene chloride. The organic extracts are combined, washed three times with a total volume of 300 cm of distilled water, dried on anhydrous magnesium sulphate, 0.5 g of vegetable black is added, filtered and concentrated by dry means at reduced pressure (20 mm Hg, 2.7 kPa) and 60 s. So get
    2.6 g of the original product. I
    This product is chromatographed on a 4 cm diameter column containing 320 g of silica (0.04-0.063 mm). Wash with a mixture of ethyl acetate and cyclohexane (70-30 by volume) at a pressure of 0.5 bar (51 kPa), collect fractions of 50 cm each. The first nine fractions are removed, the next eight fractions are combined and concentrated in a dry manner. at reduced pressure (20 mm Hg, 2.7 kPa) and 60 ° C. Thus, 1.1 g of product are obtained. This product is combined with 4 g of the product obtained in the same way by the previous operations, and dissolved in 75 cm of boiling acetonitrile. The resulting solution is hot filtered. Filtrate

    cooled to 20 ° C. The crystallized crystals are separated by filtration, washed four times with a total volume of 20 cm acetonitrile and three times with a total volume of 75 cm diethyl ether and dried under reduced pressure (20 mm Hg, 2.7 kPa) and in the presence of potassium hydroxide tablets. Thus, 2.6 g are obtained with methyl 6- (pyridyl-3) -5-1H, 3H-pyrrole- (1,2-c) thiazolcarbonitrile-7 as cream crystals, melting at 90 ° C.
    K-Nicotinoyl thiazolidine carboxylic acid-410 was prepared as follows.
    To a solution of 400 g of thiazolidinecarboxylic-4 acid and 613 g of triethylamine in 4500 cm of chloroform were added for 1 hour at 30-52 with 534 g of chlorine-15 nicotinoyl chloride hydrate. The resulting solution is heated to a temperature close to within 4 hours. After stirring at 20 ° C for 16 hours, the crystallized crystals are separated by filtration, washed with three times
    times with a total volume of 75 cm-ethanol cooled to and three times with a total volume of 75 cm diethyl ether, then dried at a pressure applied (20 mm Hg, 2.7 kPa) and 20 C in the presence of potassium hydroxide tablets. 3.4 g of 2-.C5- (3-pyridyl) -1H, 3N-pyrrol- (1,2-c) -7-thiazolyl-1-acetamide are thus obtained in the form of pale yellow crystals, melting at 176 C.
    (Pyridyl-3) -5-1P, 3N-pyrrole (1,2- -c) thiazolyl-7 -2-acetonitrile was prepared as follows.
    In a solution of 8.7 g of tertiary butyl potassium hydroxide in 140 cm of dime-tox-1,2-ethane, cooled to
    -30 ° C, added in 20 minutes at -30 ° C
    20
    for a total volume of 1500 cm of chloroform, then three times with a total volume of 1500 cm of diethyl ether and dried under reduced pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. In this way, 403 g of N-nicotinoyl thiazolidine carbonyl-4 are obtained
    solution of 7.5 g of tosylmethyl isocyanide in 50 cm of dimethoxy-1,2-ethane; The resulting solution is cooled until then a solution of 8 g of 5- (3-pyridyl) -1H, 25 is added to it in 30 minutes at -60 ° C 3N-pyrrole (1,2-c) thiazolecarboxaldehyde-7 in 70 cm of dimethoxy-1,2-ethane. The resulting solution is brought to 1 hour at 0 ° C, then held at this temperature for 1 hour 20 m.
    acids in the form of white crystals, pla-30. Then, for 15 minutes at 3-7 ° C, 105CM thief is heated
    at 190 s.
    Example 2. A suspension of 6.5 g of C (pyridyl-3 -) - 5-1H, 3N-pyrrole- (1,2-e) - thiazolyl-7 -2-acetonitrile and 8.9 g of potassium hydroxide powder in 110 cm of tertiary butyl alcohol is heated to 80 ° C for 15 minutes The suspension is taken up in 1500 cm of distilled water and the mixture is extracted 4 times with a total volume of 1200 cm of methylene chloride. The organic extracts are combined, washed three times with a total volume of 750 cm of distilled water, and dried on anhydrous sulfate.
    The solvent is vietarised at reduced pressure (20 mm Hg; 2.7 kPa) and 40 ° C. The residue is placed in a mixture of 350 cm of distilled water and 250 cm of ethyl acetate. The organic phase is separated.
    40 by decantation, and the aqueous phase is extracted 3 times with a total volume of 750 cm of ethyl acetate. The organic extracts are combined, washed three times with a total volume of 450 cm of distilled carbonate, 0.5 g of vegetable 45 is added, and dried on anhydrous sulfate
    magnesium, 0.5 vegetable - soot is added, filter-comfort and concentrated by dry method at reduced pressure (20 mm Hg, 2.7 kPa) and 50 ° C. Ta-gQ IMDs give 7.6 g of starting material.
    soot, filtered and concentrated in a dry process under reduced pressure (20 mm Hg, 2.7 kPa) and 60 C. In this way, 4.9 g of product are obtained, melting at 174 C. This product is combined with 0.6 g of an identical product obtained in the previous operation and all dissolved in 150 cm of boiling ethanol. To the resulting solution, 0.5 g of vegetable black is added and hot filtration is carried out. The filtrate is cooled to 4 ° C for 1 hour. The crystallized crystals are separated by filtration, washed with three
    55
    This product is chromatographed on a 2.7 cm diameter column containing 75 g of silica (0.063-0.2 m {m), washed with cyclohexane and ethyl acetate mixtures and collecting fractions of 200 cm each. The first two fractions disappearing. a mixture of cyclohexane and ethyl acetate
    with
    ten
    15
    times with a total volume of 75 cm-ethanol cooled to, and three times with a total volume of 75 cm diethyl ether, then dried at a pressure applied (20 mm Hg, 2.7 kPa) and 20 C in the presence of potassium hydroxide in pills. 3.4 g of 2-.C5- (3-pyridyl) -1H, 3N-pyrrol- (1,2-c) -7-thiazolyl-1-acetamide are thus obtained in the form of pale yellow crystals, melting at 176 C.
    (Pyridyl-3) -5-1P, 3N-pyrrole (1,2- -c) thiazolyl-7 -2-acetonitrile was prepared as follows.
    To a solution of 8.7 g of tertiary butyl potassium hydroxide in 140 cm of dimethox-1,2-ethane, cooled to
    -30 ° C, added in 20 minutes at -30 ° C
    solution of 7.5 g of tosylmethyl isocyanide in 50 cm of dimethoxy-1,2-ethane; The resulting solution is cooled to, then a solution of 8 g of 5- (3-pyridyl) -1H is added to it in 30 minutes at -60 ° C; 3N-pyrrole (1,2-c) thiazolecarboxaldehyde-7 in 70 cm of dimethoxy-1,2-ethane. The resulting solution is brought up to 1 ° C for 1 hour, then held at this temperature for 1 hour 20 minutes.
    Then, for 15 minutes at 3-7 ° C, 105CM thief is added.
    methanol. The resulting solution was 72 ° C for 1 h 15 min, then stirred at 20 ° C for 16 h. Three quarters of the solvent were Vietarite under reduced pressure (20 mm Hg; 2.7 kPa) and 40 ° C. The residue is placed in a mixture of 350 cm of distilled water and 250 cm of ethyl acetate. The organic phase is separated.
    decantation, and the aqueous phase is extracted 3 times with a total volume of 750 cm of ethyl acetate. The organic extracts are combined, washed three times with a total volume of 450 cm of distilled water.
    This product is chromatographed on a 2.7 cm diameter column containing 75 g of silica (0.063-0.2 m {m), washed with cyclohexane and ethyl acetate mixtures and collecting fractions of 200 cm each. The first two fractions disappearing. a mixture of cyclohexane and ethyl acetate
    (50-50 by volume) are removed. The following three fractions, vyttavayuschiysya mixture of cyclohexane and ethyl acetate (50-50 by volume), and the next fraction, g eluted with pure ethyl acetate, are combined and concentrated by dry working at a reduced pressure (20 mm Hg, 2.7 kPa) and . Thus, 6 g of t (pyridyl-3) -5-10 -1H, 3H-pyrrole- (1,2-c) thiazole1-7 -2- -acetonitrile are obtained in the form of light yellow crystals, which are right at 92 ° C. .
    (Pyridsh1-3) -5-1H, 3N-pyrrole- (1,2- -c) thiazolecarboxaldehyde-7 is obtained 15 by a known method.
    Example 3. A suspension of 6.5 g of potassium hydroxide powder and 4.6 g of a mixture (in the proportion of 20-80) cyano-6 and cyano-7- (thiazolip-5) -5-1H, 3N-pyrrole- 20 - ( 1,2-c) thiazole in 100 cm of tertiary butyl alcohol is brought to reflux in a bath preheated to. The resulting suspension is extracted into 800 cm of distilled 25 water, and the resulting crystals are separated by filtration, washed six times with a total volume of 300 cm of distilled water and three times with a total volume of 75 cm of acetone, then dried at 30 given pressure (20 mm Hg, 2 , 7 kIa) and 20 C in the presence of potassium hydroxide in tablets. Thus, 1.8 g of product is obtained, melting at 230 C. 35
    The previous filtrate is extracted three times with a total volume of 1000 cm of methylene chloride and three times with a total volume of 1000 cm of ethyl acetate. The organic extracts are combined, dried on 40 anhydrous magnesium sulphate, filtered and concentrated by dry-drying at a reduced pressure (20 mm Hg,
    2.7kPa) and 60 ° C. In this way, 1 g of product is obtained, melting at 45 215 C. This product is combined with
    1.8 tons with 1.2 g of an identical product obtained in the previous operation.
    Three sets are dissolved in 200 cm of boiling butanol-1. To the resulting 50 solution, 0.5 g of vegetable black is added and hot filtration is performed. The filter g is cooled to within 2 hours. The crystals that have precipitated are separated by filtration, washed two 55 times with a total volume of 20 cm of butanol-1, two times with a total volume of 50 cm of ethyl and three times with a total volume of 5 cm of diethyl ether, then dried
    reduced pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. Thus, 2.1 g of 5- (5-thiazolyl-) -1H, 3H-pyrrolo- (1,2-c) -7-thiazole-carboxamide are obtained in the form of orange crystals, melting at 236 ° C.
    A mixture of (20-80) cyano-6- and cyano-7- - (thiazolyl-5) -5-1H, 3N-pyrrole- (1,2-c) thiazole was prepared as follows.
    To a solution of 13.1 g of thiazolidinecarboxylic-4 acid and 9.8 g of triztilamine in 360 cm of chloroform, a solution of 14.1 g of chloroformyl-5-thiazole in 120 cm of chloroform is added in 15 minutes at 23-36 ° C. The resulting solution is heated to 64 ° C. for 2 hours and 15 minutes. After stirring for 16 hours, the solvent is evaporated under reduced pressure (20 mm Hg, 2.7 kPa) and 60 ° C, and the residue is placed in 350 cm of acetone. The resulting suspension is filtered, and the filtrate is concentrated by a dry method at a reduced pressure (20 mm Hg, 2.7 kPa) and 60 ° C. Thus, 26.4 g of product are obtained, which is dissolved in a mixture of 77 cm of chloro-2-acrylonitrile and 96 cm of acetic anhydride. The resulting solution is heated to 2 hours and 45 minutes, then stirred at 20 ° C for 16 hours. The crystals are separated by filtration, washed twice with a total volume of 150 cm of acetic anhydride and three times with a total volume of 225 cm of acetone, then dried at reduced pressure (20 mm Hg, 2.7 kPa) and 20 C in the presence of potassium hydroxide tablets. Thus, 7.2 g of product are obtained.
    This product is shaken in 150 cm of distilled water. 150 cm of an aqueous solution of sodium hydroxide 10N are added to the suspension. The crystallized crystals are separated by filtration, washed four times with a total volume of 200 cm of distilled water and dried under reduced pressure (20 mm Hg 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. Thus, 4.6 g of a mixture of cyano-6- and cyano-7- (thiazolyl-5) -5-1H, 3N-pyrrole- (1,2-c) thiazole are obtained in the form of brown crystals, melting at 155 ° C in the ratio of 20-80 (according to the spectrum of RMN).
    Example 4. A solution of 5.5 g of methyl-7- (pyridyl-3) -6-dihydro-1.2-4H 14A0 .349
    -pyrrole- (1, 2-e) thiazine-, 1,3-carbonitrile-8 in 70 cm of an aqueous solution of hydrochloric acid 12N is heated with stirring to 80-86 C for 1 h 30 min, then to 96 C in for 7 h 30 min The resulting solution was stirred at 20 ° C for 16 hours, then 20 cm of an aqueous solution of 12N hydrochloric acid was added to it and heated to 98 ° C for 6 hours and 30 minutes. To the resulting solution, 100 cm of distilled water is added and adjusted to pH 9 by addition of potassium hydroxide carbonate. The resulting suspension is extracted three times with a total volume of 450 cm of a mixture of methylene chloride and methanol (9-1 by volume). The organic extracts are combined; two
    ten
    15
    thirty
    20
    times with a total volume of 100 cm distilled water, dried over anhydrous magnesium sulphate, t added, 5 g of vegetable black, filtered and concentrated under reduced pressure (20 mm Hg, 2.7 kPa) and, Thus, 4 are obtained 8 g of the starting product, which is chromatographed on a column with a diameter of 6 cm, containing 480 g of silica (0.04-0.063 mm). Wash with a mixture of ethyl acetate and methanol (95-5 by volume) at a pressure of 0.5 bar (51 kPa), collect fractions of 200 cm each. Nine of the first 4 fractions are removed, the five subsequent fractions are combined and concentrated by the method at reduced pressure (20 mmHg, 2.7 kPa) and 50 ° C. Thus, 1.8 g of product is obtained, which is combined with 0.3 g of the product obtained during the previous operation and dissolved in 60 cm of boiling ethanol.
    0.5 vegetable black is added to the resulting solution and hot filtration is carried out. The filtrate is cooled to 4 ° C for 16 hours. The crystallized crystals are separated by a filter40
    ly 22
    -1 - about
    gi vo an 80 lu 90 te le 80 80 lu
    easy po
    25 Or shi shi soi go with p pa che from ra
    45 but for the pro ro radi
    This is washed twice with a total volume of 4 cm of ethanol cooled to, and three times with a total volume of 12 cm
    diethyl ether, then dried under reduced pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of potassium hydroxide in tablets. 1.3 g of 7-metip-6- (pyridyl-3) -1,2-dihydro-4H-pyrrole- (1,2-c) -thiazine-1,3-carboxamide-8 are thus obtained in the form of white crystals, 220 C.
    melting at
    fept-7- (pIipidyl-3) -6-dihydro--1,2-4H-pyrrole- (1,2-c) thiazine-1,3-carbonitrile-8 is prepared as follows.
    To a solution of 9 g of N-nicotinoyltetra-hydro-3,4,5,6-2H-thiazin-1,3-car bons-4 acid in 100 cm of acetic anhydride, 36 g of chlorine are added in 8 minutes at 80 ° C. 2-crotonnitrile. The resulting solution is heated to 85-90 ° C for 3 hours, then the solvent is evaporated under reduced pressure (20 mm Hg, 2.7 kPa) at 80 ° C. The residual oil is dissolved in 100 cm of distilled water, and the resulting solution is brought to pH 10
    0
    0
    five
    0
    0
    by adding solid potassium hydroxide carbonate, then 10 cm of an aqueous solution of sodium hydroxide 4N. This alkaline solution is extracted five times with a total volume of 500 cm of ethyl acetate.
    5 The organic extracts are combined, washed five times with a total volume of 400 cm of distilled water, dried on anhydrous magnesium sulphate, 0.5 g of vegetable black is added, filtered and concentrated in a dry manner at reduced pressure (20 mm Hg, 2, 7 kPa) and 50 ° C. Thus, 6.9 g of the starting product, melting at 130 ° C, is obtained. The resulting product, combined with 4.3 g of the product obtained in the same way, is dissolved in 60 cm of boiling isopropanol. 0.5 g of vegetable black is added to the resulting solution and hot filtration is carried out. The filtrate is cooled to 4 ° C for 16 hours. The crystallized crystals are separated by filtration, washed three times with a total volume of 15 cm of isopropyl alcohol cooled to 4 ° C and three times with a total volume of 30 cm of isopropyl oxide, then dried pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. Thus, 4.8 g of methyl 7- (pyridyl-3) -6-dihydro-1,2-4H-pyrrole- (1,2- -c) thiazin-1,3-carbonitrile-8 are obtained in the form of
    floating
    five
    color crystals, at 166 C.
    Example 5. A solution of 4.7 g of hydroxy-2- (pyridyl-3) -5-dihydro--2,3-1H-pyrolysyncarbonitryl-7 in 110 cm of an aqueous solution of chloro
    12N prenatal acid is heated to 80 ° C for 2 hours, then concentrated by dry method at reduced pressure (20 mm Hg, 2.7 kPa) and 60 ° C. 8 g of product are obtained in a skim manner, which is dissolved in 20 cm of distilled water . The resulting solution was adjusted to pH 8 by adding 100 cm of a saturated aqueous solution of sodium hydrogen carbonate 1.19N and then concentrated by dry method at reduced pressure (20 mm Hg 2.7 kPa) and 60 C. The resulting solid was placed for the first time. 500 cm of a mixture of methylene chloride and methanol (80-20 by volume). In this way, a solution and an undissolved substance are obtained.
    The solution is carefully decanted and poured onto a 13 cm diameter column containing 400 g of silica (0.063-0.2 mm). The undissolved substance is again placed in 500 cm of a mixture of methylene chloride and methanol (80-20 by volume) and treated in the indicated manner. In this way, the operation is repeated nine times a day. Organic solutions, which are collected in the lower part of the column, are combined and concentrated by a dry method at a pressure of 1 ft (20 mm Hg, 2.7 kPa) and 60 ° C. In this way, 4.7 g of product is obtained, which is combined with 0.5 g of product obtained by the same method, and dissolved in 140 cm of boiling ethanol. 0.5 g of vegetable black is added to the resulting solution and hot filtration is carried out. The filtrate is cooled to 4 ° C for 16 hours. The crystallized crystals are separated by fillers, rinsed twice with a total volume of 50 cm of ethanol and three times with a total volume of 75 cm of diethyl ether, then dried under reduced pressure (20 mm Hg). 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. In this way, 3.3 g of hydroxy 2- - (pyridyl-3) -5-digvdro-2, 3-1H-pyrrhot of lysine-carboxamone-7 was obtained in the form of cream crystals melting at 206 C.
    Hydroxy-2- (pyrvdil-3) -5-dip-schro--2,3-1H-pyrrolisinecarbonitrile-7 is prepared as follows.
    A suspension of 3 g of N-nicotinolyl of schroxy-4-proline in a mixture of 115 cm chlorine -2-acrylonitrile and 150 cm of acetic anhydride is heated to 90 ° C.
    five
    0
    five
    0

    five
    0
    five
    0
    five
    3 h 40 min. The resulting solution is concentrated by a dry process at reduced pressure (20 mm Hg, 2.7 kPa) and 70 ° C. The resulting residue is suspended in 500 cm of an aqueous solution of sodium hydroxide 5N, the resulting suspension is extracted four times with a total volume of 1250 cm of ethyl acetate. The organic extracts are combined, washed four times with a total volume of 1000 cm of distilled water, dried over anhydrous magnesium sulfate, 0.5 g of vegetable black are added, filtered and concentrated to dryness under reduced pressure (20 mm Hg, 2.7 kPa) at 60 ° C.
    In this way, 13 g of starting material is obtained, which is dissolved in 130 cm of boiling isopropanol. The resulting solution is hot filtered and the filtrate is cooled to 20 ° C for 2 hours. The crystals that have been added are separated by filtration, washed twice with a total volume of 50 cm of isopropanol and three times with a total volume of 50 cm of diethyl ether, 20 mm Hg, 2.7 kPa) and 20 C in the presence of potassium hydroxide tablets. Thus, 5.6 g of hydroxy-2- (pyridyl-3) -5-dihydro-2,3-1H-pyrrolizinecarbonitrile-7 are obtained in the form of beige crystals, melting at 190 ° C.
    N-Yikoinoylhydroxy-4-proline was prepared as follows.
    To a solution of 212.8 g of bis-0, M-nicotinoylhydroxy-4 ethyl prolinate in 2130 cm of ethanol is added in 25 minutes at 14–26 ° C with 346 cm of an aqueous solution of sodium hydroxide 5N. The resulting solution was stirred for 16 hours, then adjusted to pH 3 by adding 160 cm of an aqueous solution of hydrochloric acid 12N. By - . The crystallized crystals are removed by filtration, and the filtrate is concentrated by a dry method at reduced pressure (20 mm Hg, 2.7 kPa) and 70 ° C. The residue obtained is shaken in 1250 cm of boiling ethanol. After cooling to 20 ° C, the crystals are removed by filtration, and the filtrate is concentrated to half its volume under reduced pressure (20 mm Hg, 2.7 kPa) and, the resulting solution is cooled to 16 hours. The crystalline
    They are separated by filtration, washed three times with a total volume of 300 cm of ethanol and three times with a total volume of 450 cm of diethyl ether, then dried under reduced pressure (20 mm Hg, 2.7 kPa) and in the presence of potassium hydroxide tablets. Thus, 112.6 g of N-nicotinoylhydroxy-4-proline are obtained in the form of pale pink crystals, melting at 172 C.
    Bis-0, N-nicotinoylhydroxy-4-proline was prepared as follows.
    655 g of triethylamine are added to a suspension of 209.6 g of hydroxyhydroxy-4-ethylpropanol in 2800 cm of methylene chloride in 10 minutes, keeping the temperature at 24 ° C. During this period, a transition through a uniform transparent phase is observed after 5 minutes with further immediate precipitation. The resulting suspension is added over 15 minutes at 23-43 ° C, 480.6 g of nicotinoyl chloride hydrochloride. The resulting suspension is heated to 43 ° C for 3 hours, then stirred at 20 ° C for 16 hours. Then 1000 cm of methylene chloride and 2000 cm of water are added to the suspension. The organic phase is separated by decantation, followed three times by volume.
    miss
    With a volume of 3000 cm of distilled water, dried on white magnesium sulphate, 0.5 g of vegetable black are added, filtered and concentrated by dry using a reduced pressure (20 mm Hg, 2.7 kPa) and 60 ° C. Thus, 458.7 g of the starting product is obtained, melting at 80 C.
    This product is placed in 2000 cm of boiling distilled water. The resulting insoluble oil is separated by hot decantation, and the aqueous phase is filtered hot. The filtrate is cooled to 16 hours. The crystallized crystals are separated by filtration, rinsed three times with a total volume of 750 cm of distilled water, and there is air drying. In this way, 212.8 g of bis-0, N-nicotinyl hydroxyl-4-ethyl prolinate are obtained as pale yellow crystals, melting at 110 ° C,
    Example 6. Suspension 6 g smsi (in proportion 10-90) of cyano-6- and cyano-7- (pyridyl-3) -5-di-hydro-2,3-pyrrole- (2,1-in) hydrochloride and 2

    4LOZ49
    7.5
    .140
    that
    ten
    12

    :
    35
    40
    g potassium hydroxide powder in cm tertiary butyl alcohol- 82 °
    45
    50
    heated to “Z C for 1 h. min. Concentrated reaction mixture
    It is dry dried at a reduced pressure (20 mm Hg, 2.7 kPa) and 50 ° C, and the residue obtained is shaken in 100 cm of distilled water. The crystals are separated by filtration, flashed five times with a total volume of 200 cm of distilled water and three times with a total volume of 30 cm of ethanol, then dried under reduced pressure (20 mm Hg,
    2.7 kPa) and. In this way, 3 g of crude product is obtained, melted at. 1.4 g of the product obtained is added to this product.
    20 in another operation, and all together dissolved in 37 cm of dimethylformamide heated to 125 s. 0.5 g of vegetable black are added to the crawled solution and hot water is applied.
    25 filtering. The filtrate is cooled to 4 ° C for 1 hour. The crystallized crystals are separated by filtration, washed three times with a total volume of 3 cm of dimethylformamide, cooled to C, five times with a total volume of 15 cm of ethanol, cooled to 4 ° C, and five
    30 4
    cooled to
    once with a total volume of 25 cm of diethyl ether, then dried at a reduced pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of potassium hydroxide tablets. Thus, 3 g of (pyridyl-3) -5- -dihydro-2,3-pyrrole- (2,1-b) thiazole-carboxamide-7 is obtained in the form of cream crystals, melting at 253 ° C.
    A mixture (in the proportion of 10-90) chloro-hydrate of cyano-6- and cyano-7- (pyridyl-3) -5-dihydro-2,3-pyrrole- (2,1-b) thiazole is obtained as follows .
    Suspension 9.5 g of N-nicotinoylthiazolidinecarboxylic-2 acid and 35 g
    100
    88- this
    period, a transition through a homogeneous transparent phase is observed after 30 minutes with a further precipitation after 25 minutes. After cooling to 20 ° C for 16 hours, the enlarged crystals are separated (by filtration, removing twice the total volume of 10 cm of acetic anhydride and twice the total volume of 20 cm of diethyl ether, then dried with over-acid and 35 chlorine-2- acrylonitrile in 100 cm of acetic anhydride is heated to 108 ° C for 2 hours. For
    pressure (20 mm Hg, 2.7 kPa) and 20 ° C in the presence of ka.pi hydroxide tablets. Thus, 8.6 g of a mixture of chloro-hydrate cyano-6- and cyano-7- (pyr-shchil 3) -5-DIHYDRO-2,3-pyrrole- (2) thiazole as brown crystals, melting at, in a ratio of 10-90 (according to the spectrum of RMN).
    N-Nicotinoylthiazidinecarboxylic--2 acid was prepared as follows,
    To a suspension of 77 g of thiazolidinecarboxylic acid-2 in 700 cm of chloroform, 133.6 g of triethylamino are added over 5 minutes at 22-30 ° C. To the resulting solution is added for 1 hour at 23-40 ° C 117.5 g of nicotinoyl hydrochloride
    chloride. The resulting solution is heated to 64 ° C. for 2 hours. After cooling to 20 ° C. for 16 hours, then to 4 ° C. for 1 hour, the crystals that have formed are separated by filtration, washed three times with oborm 300 cm of chloroform, cooled to 4 ° C, and removed. The filtrate is concentrated by a dry process at a reduced pressure (20 mmHg, 2.7 kPa) and, the residue is shaken in 1000 cm of acetone, and the formed crystals are separated by filtration, washed three times with a total volume of 750 cm of acetone and removed. The filtrate is concentrated by a dry process at reduced pressure (20 mm Hg, 2.7 kPa) and. 150 g of product are obtained. This product is dissolved in 500 cm of distilled water and the solution is adjusted to pH 9 by adding an aqueous solution of sodium hydroxide 10N, the solution is poured onto a 6 cm diameter column containing 1 kg of resin. Dotex 5WX2 form H (50-100 mesh). Pull in distilled water to collect 1000 cm fractions. The first two fractions are removed. The four following fractions are combined and the end of the HTI-fut to a volume of 150 s at a reduced pressure (20 mm Hg 2.7 kPa) and 60 ° C. The resulting solution was allowed to stand for 16 hours. The product precipitated. The crystals are separated by filtration, washed twice with a total volume of 10 cm of distilled water, twice with a total volume of 10 cm of ethanol, then dried under reduced pressure (20 mm Hg; cent. 2.7 kPa) and 20 ° C in the presence of potassium hydroxide

    in tablets Thus, 9.5 g of N-nicotinoyl thiazolidine carbonic-2 acid are obtained in the form of white crystals melting at 180 ° C.
    Example 7. By proceeding analogously to Example 1, but using the corresponding starting compounds, 6-bromo-5-3-pyridyl) -1H, - 3H-pyrrolo- (1,2-c) -7-thiazolecarboxamide in the form of light - yellow crystals melting at.
    The resulting compounds have antithrombotic activity, which is determined by the following 1HEAL tests.
    Study of the inhibitory ability to form thromboxane A ex vivo in rats.
    To male rats (C.O.B.S, CD) weighing 200 g, either gum arabic (control) or the test compound was administered, taken as a suspension in gum arabic, at the rate of 5 ml / kg.
    Two hours after the administration, blood is taken at the level of the abdominal aorta after anesthesia of the rats with pentobarbital containing the administration (the infusion is carried out intraperitoneally at a rate of 50 mg / kg). Thus, the blood was coagulated spontaneously for analysis. The temperature is maintained at 37 ° C for 30 minutes, after which the centrifugation is carried out for 15 minutes at 15 ° C. Thus, a serum containing thromboxane EI (thromboxane metabolite A) is obtained. Thromboxane B is examined by radioimmunology.
    The results, which are expressed as a percentage of the change in the amount of thromboxane B and compared to the control, show a change in the content of thromboxane Aq, which was initially formed during coagulation.
    Toxicity,
    The dose of the compound (DLj) is determined, which, after the injection of mice, orally causes the death of 50% of the animals.
    The results of biological tests are shown in the table.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    Method of propagating orthocondensed pyrrole derivatives of the general formula
    (CH2) n-CONH2
    (
     N - () p-Hel5
    where at Het - 3 pyridyl L - such a heterocycle, which with the pyrrole ring, with which it forms a scodensirovan-.n, forms a cycle zine, hydroxy substituted, 1,2-di-hydro-4H-pyrrolo- (1,2-c) -1,3-thiazine, 2,3-dihydropyrrolo (2,1-b) -thiazole, R - hydrogen, halogen, methyl, p About 15
    or
    1, p O or at Het - 5-thiazolyl A - 1H, 3N-pyrrolo- (1,2-с) thiazole, R - hydrogen, n 0, p 0, detached-i due to the fact that the compound
    general formula
    (but
    (CH ln-CN RI
    N- (CH-CH) p-Hel
    where Het, R, A, pyr have the indicated meanings, are hydrolyzed with BO-EO C in aqueous hydrochloric acid or in tert-butyl alcohol in the presence of potassium hydroxide.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1440349A3|1988-11-23|Method of producing orthocondensed derivatives of pyrrole
    SU1436871A3|1988-11-07|Method of producing pyridyl or phenyl compounds or hydrochlorides thereof or esters
    DE3614132A1|1986-11-27|1,3-DIHYDRO-2H-IMIDAZO | CHINOLIN-2-ONE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS
    FR2652579A1|1991-04-05|HYDROXY-2 THIOPHENE AND FURANNE DERIVATIVES CONDENSED WITH NITROGEN CYCLE, PREPARATION METHOD AND THERAPEUTIC USE THEREOF
    DE3724164A1|1988-01-28|Novel 1,4-benzodiazepines, their preparation and use
    FR2703051A1|1994-09-30|New pyridothiadiazines, processes for their preparation, and pharmaceutical compositions containing them
    DE3239157A1|1983-05-05|DERIVATIVES OF 3-AMINO-2-AZETIDINONE-1-SULPHONIC ACID, THEIR PRODUCTION, INTERMEDIATE PRODUCTS AND PHARMACEUTICAL COMPOSITIONS
    EP0041215B1|1986-01-29|Imidazoazolalkenyl carboxamides, intermediates for their preparation, their preparation and their use as medicaments
    SU873887A3|1981-10-15|Method of preparing derivatives of imidazo-/2,1-b/-thiazoline or imidazo-/2,1-b-thiazine or their acid-additive salts in form of isomer mixture or individual isomers
    SU1282818A3|1987-01-07|Method of producing orthocondensed derivatives of pyrrole
    DE2705582A1|1977-08-11|NEW DERIVATIVES OF 1,2-DITHIOL, THEIR PRODUCTION AND THE COMPOSITIONS THAT CONTAIN THEM
    EP0255028A2|1988-02-03|1,4-Benzodiazepines, their preparation and use as PAF antagonists
    FI80457B|1990-02-28|NYA SAOSOM MELLANPRODUKTER ANVAENDBARA 3-PYRIDYLPYRROLOTIAZOLE- OCH TIAZINDERIVAT OCH FOERFARANDE FOER FRAMSTAELLNING DAERAV.
    FR2496666A1|1982-06-25|NOVEL CEPHALOSPORINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME
    SU1731046A3|1992-04-30|Method for synthesis of dextro-rotatory derivatives of hydroxyisoindolinyle and theirs pharmaceutically acceptable salts
    DE3246757A1|1984-06-20|NEW 2-AZABICYCLO | HEPTAN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF, AND 2-AZABICYCLO | HEPTAN DERIVATIVES AS INTERMEDIATE PRODUCTS AND METHOD FOR THE PRODUCTION THEREOF
    EP0267432A1|1988-05-18|Antibacterially active pyrido-benzothiazine derivatives with long term action
    SU1705287A1|1992-01-15|Derivatives of 2-amino-1,2,3,4-tetrahydroisoquinoline with saluretic effect
    SU793398A3|1980-12-30|Method of preparing thiazoline derivatives
    US3303195A|1967-02-07|Methylated deserpidine
    RU1838313C|1993-08-30|Method of synthesis of spirocompound azolone or its n-oxide derivative or its basic salt with pharmacologically usable cation
    BE896159A|1983-09-15|1H-PYRAZOLO | SUBSTITUTED PYRIMIDINES AND THEIR PREPARATION
    SU1402264A3|1988-06-07|Method of producing derivatives of pyrimidoisoquinoline
    DE3040258A1|1981-05-21|4,5-DIHYDROPYRAZOLE COMPOUNDS, MEDICINAL PRODUCTS AND THEIR USE
    DE2646445A1|1977-04-21|BICYCLOHEPTAN DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THESE
    同族专利:
    公开号 | 公开日
    FR2557111A1|1985-06-28|
    DK616584A|1985-06-22|
    ZA849958B|1985-08-28|
    JPS60172977A|1985-09-06|
    US4684658A|1987-08-04|
    EP0147317A3|1986-06-25|
    IL73888A|1987-11-30|
    IL73888D0|1985-03-31|
    FI76809C|1988-12-12|
    FR2557111B1|1986-04-11|
    DK616584D0|1984-12-20|
    AU3696084A|1985-07-04|
    CS251782B2|1987-08-13|
    EP0147317A2|1985-07-03|
    KR850004768A|1985-07-27|
    CS251790B2|1987-08-13|
    FI76809B|1988-08-31|
    CS251791B2|1987-08-13|
    NZ210671A|1989-08-29|
    FI845064A0|1984-12-20|
    HU194238B|1988-01-28|
    CS524985A2|1986-12-18|
    HUT40435A|1986-12-28|
    CS524885A2|1986-12-18|
    SU1436883A3|1988-11-07|
    AU573666B2|1988-06-16|
    CA1250286A|1989-02-21|
    FI845064L|1985-06-22|
    HU196801B|1989-01-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3429885A|1965-10-22|1969-02-25|American Home Prod|Pyridylethyl and piperidylethyl pyrroles|
    GB1174124A|1967-06-30|1969-12-10|Beecham Group Ltd|Pharmacologically Active Indolizine Compounds|
    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|
    US4539400A|1983-01-13|1985-09-03|Rhone-Poulenc Sante|Pyridin-3-yl substituted ortho-fused pyrrole derivatives|
    FR2539417B1|1983-01-13|1985-03-15|Rhone Poulenc Sante|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|
    JPH05501103A|1989-06-26|1993-03-04|
    US5395846A|1993-06-25|1995-03-07|Rhone-Poulenc Rorer Pharmaceuticals Inc.|Amino Bi- and tri-carbocyclic aklane bis-aryl squalene synthase inhibitors|
    DE4419315A1|1994-06-01|1995-12-07|Merckle Gmbh|New hetero- and oxo-pyrrolizine derivs.|
    DE4419247A1|1994-06-01|1995-12-07|Merckle Gmbh|New pyrrolizine keto-acid, keto-ester and carboxamide derivs.|
    DE4419246A1|1994-06-01|1995-12-07|Merckle Gmbh|New hetero-aryl substd. pyrrolizine derivs.|
    FR2735476B1|1995-06-14|1997-07-18|Rhone Poulenc Rorer Sa|NEW APPLICATION OF PYRROLE DERIVATIVES|
    FR2757166B1|1996-12-12|1999-01-29|Rhone Poulenc Rorer Sa|PYRROLE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    FR2757059B1|1996-12-12|1999-01-29|Rhone Poulenc Rorer Sa|NEW THERAPEUTIC APPLICATION OF PYRROLE DERIVATIVES|
    US6191925B1|1999-06-18|2001-02-20|Storage Technology Corporation|Dual element read with shaped elements|
    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 |
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8320474A|FR2557111B1|1983-12-21|1983-12-21|NOVEL ORTHO-CONDENSES OF PYRROLE, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM|
    [返回顶部]