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    • 专利摘要:

    公开号:SU923365A3
    申请号:SU782690452
    申请日:1978-11-24
    公开日:1982-04-23
    发明作者:Форбрюгген Хельмут；Скубалла Вернер；Радюхель Бернд；Лозерт Вольфганг；Логе Олаф；Мюллер Бернд；Маннесманн Герда
    申请人:Шеринг Аг (Инофирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing prostane derivatives of the general formula I
    R.COB CN λ l m AWDEP 2f 'where R ^ is hydroxyl, lower alkoxyl or the group -NHR *;
    R4 is lower alkanoyl or lower alkylsulfonyl;
    B is a linear alkylene group with 1-5 carbon atoms,
    A is ethylene, cis or transvinylene, or the group —CiC—;
    W is a free or substituted C ιχ-C acyl oxymethylene group, or a free or substituted Cq-C ^ acyl group. and wherein hydroxyl may be in the f or β position,. t. D and E - together mean a direct bond, or a D-linear or branched alkylene group with 1-5 carbon atoms *, 5 E - oxygen or a direct bond;
    Ri ^ is lower alkyl or phenyl; R ^ is a free or substituted Cq-Cd, acyl hydroxyl group.
    You can use their salts with pharmacological activity.
    A known method of obtaining derivatives of 5-halogen-6, 9 tL-oxide of prostaglandin, PG3q_, which consists in the fact that To a compound of General formula
    where R g hydrogen or alkyl, treated with iodine in pyridine or
    N-bromosuccinimide in methylene chloride [1].
    However, a method for producing derivatives of prostanoic acid of the general formula (I) or their salts, which may find use in medicine as pharmaceuticals, is not known.
    The purpose of the invention is the preparation of new pharmacologically active derivatives of prostanoic acid of the general formula (I) or their salts.
    The goal is achieved. a method for producing derivatives of prostanoic acid of the general formula (I) or their salts, namely, a compound of the general formula 11
    R.COB
    I (0) where
    E and W are as defined above, is reacted with a compound of general formula (III) RgSOqNCO, wherein R ζ - chlorine or bromine, at a temperature of from -70 to 0 ° C and then with a tertiary amine and, if necessary 30 bridges, they are subjected to alkaline hydrolysis to obtain compounds of the general formula (I), where Rg is hydroxyl, which, if necessary, is reacted with a compound of the general formula (IV) R4NCO, where R4 is lower alkanoyl or lower alkylene sulfonyl, followed by isolation of the target 'product in free form or in the form of salt.
    Compounds of the general formula (1) lower blood pressure and inhibit platelet aggregation.
    Example D. Complex methyl- 5-cyano-prostacyclin-11.15-diacetate ester.
    To a solution of 320 mg of prostacyclin-1 1, 15-diacetate methyl ester in 4.2 ml of absolute ether was added dropwise at minus 70 ° С a 3.55 mp solution of chlorosulfonyl isocyanate (preparation: dissolve 2.3 ml of chlorosulfonyl isocyanate in 50 mp abs. Ether ), slowly heated to 0 ° C and 3.55 ml of a solution of triethylamine are added dropwise (obtain: 100.2 mg of triethylamine are dissolved in 5 ml of methylene chloride). Stirred for 1 h at 0 ° C, 15 min at 20 ° C, poured onto
    70. next 5.6 g complex4, a mixture consisting of a solution of sodium bicarbonate and ice water was extracted three times with ether, the organic extract was shaken twice with brine, dried with magnesium sulfate and evaporated in vacuo. After purification using preparative thin-layer chromatography PTX (silica gel, ether), 60 mg of the compound (indicated in the title) are obtained as a colorless oil.
    IR (SNEC), cm * 2959; 2930; 2860; 2203, 1730; 1650; 1372, 1245,
    The starting material is prepared in a suitable manner.
    1a. Methyl ester '' Hidrido-5-iodine-prostacyclin.
    To the mixture consisting of 2.16 methyl prostaglandin methyl ester - Fqj. ” 5.4 g of sodium bicarbonate, 50 mp ether and 90 ml of water are added dropwise with stirring at 0 ° C for 3 hours, 65.2 ml of 2.5% ether solution of iodine. After 22 hours at 0 ° C, it is diluted with ether, shaken with a dilute sodium thiosulfate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo. After filtering through silica gel in a mixture of ether and ethyl acetate (1: 1), 2.81 g of the compound are obtained in the form of a colorless oil.
    IR (CHCEj), cm * 3600; 3400; 2932; 1730; 975.
    16. Methyl ester of 5,6-dihydro-5-iodo-prostacyclin-11,15-diacetate.
    400 mg of the compound obtained according to example 1a are dissolved in 0.8 ml of acetic anhydride and 3 ml of pyridine and left to stand for 18 hours at room temperature *. After evaporation in vacuo, 467 mg is obtained according to thin layer chromatography of a diacetate in the form of a colorless oil.
    IR (CHCEj), cm'1 2958; 2948; 2860; 1732; 1245; 976
    Guards Prostacyclin 11.15-diacetate methyl ester.
    To a solution of 200 mg of the diacetate obtained according to Example 16 in 2 ml of benzene, 1 ml of diazabicyclo 14,3,0} non-5-one (DBN) was added and stirred for 20 hours at 40 ° C. de argon. Dilute with ether, shake three times with ice water, dry with sodium sulfate and concentrate in vacuo at 20 ° C. At the same time, 5 9 2 3 365 lu is added to the oily (indicated in the name) compound, which is used without further purification.
    Example 2. Methyl ester of 5-cyano-prostacyclpin.
    250 mg of the compound obtained according to example D, 150 mg of potassium carbonate and 10 mp methandle are stirred for 3.5 hours at room temperature in argon. Then it is diluted with ether, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo at 25 ° C.
    IR (LNGS 3 ) cm ' 1 : 3600 } 3430, 2937} 2860} 2212} 1650; 972.
    Example 3. 5-Cyano-prostacyclin.
    0.25 ml of 1N are added to a solution of 25 mg of the compound obtained according to example 2, 1.5 mp methanol. sodium hydroxide solution and stirred for 4 hours at 25 ° C in argon. It is then concentrated in vacuo, treated with 3 ml of brine and the solution is adjusted to pH 7 with 0.5% citric acid. It is extracted four times with methylene chloride, the organic extract is shaken once with brine, dried over magnesium sulfate and evaporated in vacuo. In this case, 22 mg was obtained according to the data of TX, (indicated in the name) of the compound in the form of an oil, which crystallized upon storage at minus 20 ° С. • IR (CHCEj), cm ' 4 : 3600; 2930; 2862; 2211; 1710; 1650; 973.
    Example 4. Methyl ester of 5-cyano-15-methyl-prostacyclin-11,15-diacetate.
    To a solution of 644 mg of methyl ester of 15-methyl-prostacyclin-11.15-diacetate in 9 mp abs. ether is added dropwise at minus 70 ° С a 7.2 mp solution of chlorosulfonyl isocyanate (preparation: dissolve 2.3 ml of chlorosulfonyl isocyanate in 50 mp abs. ether), slowly heated to 0 ° C and 7.2 mp solution of triethylamine is added dropwise (preparation: 200 mg triethylamine in 10 mp methylene chloride). Stirring 1 hour at 0 C, 15 min at 20 * C, poured! · On ice-cooled sodium bicarbonate solution, extracted three times with ether, shake the organic extract twice with brine, dried with 1 magnesium sulfate and evaporated in vacuo. After 55 purifications using PTX (ether) get! 35 mg (indicated in name) compound as a colorless oil.
    to
    IR (SSCC), cm -1 : 2960; 2930, 2203;
    1730; 1650; 1245, 9/2.
    The starting material for the (indicated in the name) compound is obtained in the wake of $. in a general way.
    4a. 5,6-dihydro-5-iodo-15-methyl-prostacyclin methyl ester.
    To a mixture consisting of 1.1 g of I5-methyl-prostaglaidin ester “ffoV” 2.7 g of sodium bicarbonate, 30 mp of ether and 50 mp of water was added dropwise while stirring at 0 ° C for 3 hours 33 mp 2.5% ethereal solution of iodine. After 23 hours at 0 ° C, it was diluted with ether, shaken with sodium thiosulfate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo. After filtering through silica gel in a mixture of ether and ethyl acetate (1: 1), 1.35 g (indicated in the name) of the compound are obtained in the form of an oil.
    IR (SSCC), cm 4 : 3600-, 3400; 1730; 976
    4b. Methyl ester 5,6-. dihydro-5-iodo-I5-methyl-prostacyclin-I1,15-diacetate.
    1.3 g of the compound obtained according to example 4a are dissolved in 12 mp of pyridine and 3 mp of acetic anhydride, 100 mg of 4-dimethylaminopyridine are added and left to stand for 16 hours at 25 ° C. Then it was evaporated in vacuo and the residue was filtered through silica gel in a mixture of pentane and ether (8: 2) to obtain 1.41 g (indicated in the title) of the compound as a colorless oil.
    IR (CHCtj), cm: 2960; 2360; 1733; 1245; 976
    4c. Methyl ester of 15-methyl-prostacyclin-1i, 15-diacetate.
    A mixture consisting of 600 mg of diacetate obtained according to example 46, 6 mp benzene and 3 mp DBN is stirred for 20 hours at 45 ° C in argon. Then it is diluted with ether, shaken three times with ice water, dried with sodium sulfate and concentrated in vacuum - at 20 ° С ·. An oily (indicated in the title) compound is obtained which is used without further purification.
    II r. Me R 5. 5-4tHaHO-15-methyl-prostacyclin,
    To a solution of 100 mg of the compound obtained according to example 4 ,; in ml of methanol, I ml of 2N sodium hydroxide solution is added and stirred for 5 hours at 25 ° C in argon. It is then concentrated in vacuo, treated with 5 ml of brine, adjusted to pH 7 with 0.5% citric acid and extracted four times with methylene chloride, the organic extract is shaken once with brine, dried with magnesium sulfate and evaporated in vacuo. The crude product is purified by filtration through silica gel in a mixture of methylene chloride with isopropanol (85:15). Obtain 56 g (indicated in the name) of the compound as a colorless oil.
    IR (SNCH 3 ), cm 4 : 3600; 3300; 2930; 2862; 2210; 1712; 1650, 974.
    Example 6. Methyl ester of 5-cyano-16,16-dimethyl-prostacyclin-1I, I5-diacetate. *
    To a solution of 320 mg of 16.16-dimethyl-prostacyclin-11.15-diacetate methyl ester in 4.5 ml of ether was added dropwise at minus 70 ° C. 3.5 ml of a solution of chlorosulfonylisocyanate (preparation: according to Example 1), heated slowly to O ^ C and 3.5 ml of a solution of triethylamine are added dropwise (preparation: Example I), stirred for 1 hour at 0 ° C, 15 min at 20 ° C, poured onto ice-cold sodium bicarbonate solution, extracted three times with ether, and the organic extract is shaken twice with brine, dried with magnesium sulfate and evaporated in vacuo. After purification using PTX (ether), 72 ml (indicated in the name) of the compound are obtained as a colorless oil.
    IR (CHCE 3 ), cm 4 : 2960; 2930; 2204; 1732, 1650, 1245, 972.
    The starting material for the (indicated in the title) compound was prepared as follows.
    bah. 5,6 • dihydro-16,16-dimethyl-6-iodo-prostacyclin methyl ester.
    Analogously to example 1a, 16.16-dimethyl-prostaglandin-Go ^ 1.5 g (indicated in the title) compound is obtained from 1.2 g of the compound in the form of an oil.
    IR (CHCEi), cm ' 4 : 3600; 3400; 1730; 975. 'bb, 5,6-Dihydro-16,16-dimethyl-5-iodo-prostacyclin methyl ester · ^ ·! 1,15-diacetate.
    A solution of 820 mg of the diol obtained in Example 6a in 6 ml of pyridine and 1.5 ml of acetic anhydride is left to stand at room temperature for 18 hours, evaporated in vacuo and filtered in a mixture of pentane and ether (1: 1) through silica gel . 800 mg (indicated in the name) of the compound are obtained in the form of a colorless oil. IR (CHCEj), cm ' 4 : 2900; 2948; 1732; 1245; 975.
    6s Methyl ester of 16.16-dimethyl-prostacyclin-11,15-diacetate.
    Analogously to example 1B, 800 mg of diacetate obtained according to example 66 and 4 ml of DBN (indicated in the name) of the compound in the form of an oil are obtained
    PRI me R 7. 5-cyano-16,16-dimethip-prostacyclin.
    To a solution of 400 mg of the compound obtained according to example 6, 4 mp 2n are added in 25 mp methanol. sodium hydroxide solution and stirred for 6 h at 25 ° C in argon. · Then concentrated in vacuo, treated with 15 ml of brine, set with 1% citric acid pH 7 and extracted four times with methylene chloride. Shake the organic extracts once with brine, dry with magnesium sulfate and evaporate in vacuo. The crude product is purified by filtration through silica gel (methylene chloride: isopropanol 85:15). Receive 240 mg (indicated in the name) of the compound as a colorless oil.
    IR (SSCC), cm 4 : 3600; 3300; 2930; 2860; 2210; 1710; 1650; 975.
    Example 8. 5-Cyano-16-methyl-pro-Staticpin-11.15-diacetate methyl ester.
    To a solution of 1.3 g of methyl ester of 16-methylprostacyclin-11.15-diacetate in 18 ml of abs. ether is added dropwise at minus 70 ° С 14.4 ml of a solution of chlorosulfonyl isocyanate (preparation: dissolve 2.3 ml of chlorosulfonyl isocyanate in 50 ml of abs. ether), slowly heated to 0 ° C for 30 minutes and 14.4 ml of a solution of triethylamine are added dropwise (preparation : 400 mg of triethylamine in 20 mr of methylene chloride). Stirred for one hour at 0 ° C, 15 min at 20 ° C, drunk on an ice-cold sodium bicarbonate solution, extracted three times with ether, and shaken
    923365 ΙΟ extracts twice with brine, dried over magnesium sulfate and evaporated in vacuo. After purification with 1HHC (ether), 290 mg (indicated in the name) of the compound are obtained in 5 form of a colorless oil.
    IR. (SNCE } ), cm * '': 2960; 2932; 2203; 1730; 1650; 1260; 972.
    The starting material for the title compound was prepared as follows.
    8a. 5,6-dihydro-5-iodo-16-methyl-prostacyclin methyl ester.
    Analogously to example 1a, 'is obtained from 4.3 g of 16-methyl-prostaglandin-G methyl ester (2 £ ^ 5.6 g (indicated in the name) of the compound as a colorless oil.
    IR (CHCEj), cm * 3600; 3400; 2930; χ 1732; 975.
    86. Methyl ester of 5,6-dihydro-5-iodo-16-methyl-p0ostacyclin-11,15-diacetate.
    5.51 g of the compound obtained according to Example 8a are dissolved in 30 ml of pyridine and 8 ml of acetic anhydride and left to stand for 18 hours at 25 ° C. After evaporation in vacuo and filtration, through silica gel (pontane: ether 7: 3), 6 g (indicated in name) of the compound are obtained in the form of a colorless oil.
    IR (CHCEj), cm * 4 : 2960; 2950-, 2860; 1730-, 1245; 975.
    8c. Methyl ester of 16-methyl-prostacyclin-11,15-diacetate.
    A mixture of 3 g of the compound obtained according to example 86, 30 mp benzene and 15 mp DBN. stirred for 20 hours at 45 ° C in argon, diluted with ether, shaken four times with looking water, dried with sodium sulfate and concentrated in vacuo at 20 ° C. An oily (indicated in the name) compound 45 is obtained, which is used without further purification.
    Example 9. 5-Cyano-16 — methyl-. - prostacyclin.
    To a solution of 1 g of the compound obtained according to Example 50 chennogo 8, in 50 ml of methanol was added 10 ml of 2N. sodium hydroxide solution and stirred for 7 hours at 25 ° C in argon. Then concentrated in vacuo,. 55 is treated with 50 ml of brine, the pH is adjusted to 7 with 1% citric acid and extracted four times with methylene chloride. Shake the organic extracts once with brine, dry with magnesium sulfate and evaporate in vacuo. After filtering the crude product through silica gel, 590 mg (indicated in the title) of the compound are obtained as a colorless oil using a mixture of methylene chloride and isopropanol (85:15).
    IR (CHS £ 3 ), cm ~ and : 3600; 3300; 2933; 2860; 2210; 1710; 1650; 976
    Example 10. 5-Cyano-16-phenyl-17,18,19 methyl ester; 20-tetranor-prostacyclpin-11,15-diacetate.
    To a solution of 300 mg of methyl ester of 16-phenyl-17,18,19, 20-tetranor-prostacyclin-11,15-diacetate in 4 mp ether, a 3.4 mp solution of chlorosulfonyl isocyanate is added dropwise at minus 70 ° C. (preparation; as an example 1), heated for 30 min to 0 ° C and 3.4 ml of a solution of triethylamine in methylene chloride are added dropwise (preparation: according to Example 1). It is stirred for one hour at 0 ° C, 15 min at 20 ° C, poured onto ice-cold sodium bicarbonate solution, extracted with ether, the extract is washed with brine until neutral, dried with magnesium sulfate and evaporated in vacuo. After purification using PTX (ether), 80 mg (indicated in the name) of the compound are obtained in the form of an oil.
    IR (CHCSE3), cm ^ : 2960; 2205; 1733, 1651; 1602; 1245; 974.
    The starting material for (indicated above in the name) of the compound is prepared as follows. .
    10a. 5,6-Dihydro-5-iodo-I6-phenyl-17,18,19,20-tetranor-prostacyclin methyl ester.
    Analogously to Example 1a, 16-phenyl-17,18,19,20-tetranor-prostaglandin-Gd ^ !, 16 g of methyl ester is obtained, 38 g (indicated in the title) of the compound as a colorless oil.
    IR (SSCC), CM-'S 3600; 3410; 1732; 1602; 975.
    106. Methyl ester of 5,6-dihydro-5-iodo-16-phenyl-17,18,19, 20-tetranor-prostacyclpin-11,15-diacetate.
    A solution of 1.2 g of the diol obtained according to example 10a, in 9 mp
    Pyridine and 2.4 mp acetic anhydride are allowed to stand at room temperature for one hour. Then it is evaporated in vacuo and the residue 11 923365 is filtered with a mixture of pentane: ether (1: 1) through silica gel. This gives 1.31 g (indicated in the name) of the compound as a colorless oil.
    IR (CHCEj), cm ' 5 : 2958; 2950; 1732; 1602; 1245, - 976.
    10th century The methyl ester of 16-phenyl-17,18,19,20-tetranor-prostacyclin-11,15-diacetate.
    Analogously to example 1c, 1.25 g of diacetate obtained according to example 106 and 6 ml of DBM are obtained from an oily (indicated in the name) compound, which is used as a raw material in the future.
    Example 11. 5-Cyano-16-phenyl-17,18,19,20-tetranor-prostacyclin.
    To a solution of 610 mg of the compound obtained according to Example 10 in 28 ml of methanol was added 6 ml of 2N. sodium hydroxide solution and stirred for 6 hours at 25 ° C in argon. It is then concentrated in vacuo, treated with 15 ml of brine, adjusted with a 12th citric acid solution, pH 7 n, extracted four times with methylene chloride. Shake the organic extracts once with brine, dry with magnesium sulfate and evaporate in vacuo. After purification of the crude product by filtration through silica gel (methylene chloride: isopropanol 9: 1), 390 mg '(indicated in the name) of the compound are obtained as a colorless oil. ·
    YK (CHC1 3 ), cm; 3600; 3310; 2930, 2860; 2212; 1712; 1650, 1602; 976
    Example .12i 5-cyano-13,14-dihydro-16-methyl-prostacyclin-11,15-diacetate methyl ester.
    To a solution of 1.15 g of 13.14-diHydrΰ-16-methyl ether-prostacyclin-methyl-11.15-diacetate in 15 mp abs. ether is added dropwise at minus 70 ° С 13 mp of a solution of Chlorosulfonylieocyanate (preparation: according to Example 1), heated * for 30 minutes to 0 ° С, 13 ml of a solution of trinethylamine are added dropwise. in methylene chloride (see example 1), stirred for 1 h at 0 ° C, poured into ice-cold sodium bicarbonate solution and extracted with ether. The extract is washed with brine, dried with magnesium sulfate and evaporated in vacuo | mind at 25 ° C. By PTX (ether), 10 mg of the compound are obtained in the form of a colorless oil.
    IR (CHECS), cmL 2960-, 2932-, 2203; 1730; 1650; 1250.
    12a. 5,6-dihydro-13,14-dihydro-5-iodo-16-methyl-prostacyclin methyl ester.
    Analogously to example 1a, 2.1 g of complex 13.14-dihydro-16-methyl-prostaglandin-G <2 ( £ 2.6 g (indicated in the name) of the compound in the form of a colorless oil are obtained.
    IR (CHCtj), cm: 3600 ·, 3400-, 2930-, 1730.
    126. Methyl ester of 5,6-dihydro-13,14-5-iodo-16-methyl-prostacyclin-11,15-diacetate.
    Analogously to example 16 is obtained from 2.5 g of the diol obtained according to example 12a, after chromatography 2.7 g (indicated in the title) of the compound in the form of an oil.
    IR (CHC1 3 ), cm ^ 2958; 2950; 2855; 1732; 1245. ·
    12th century Methyl ester 13,
    14-dihydro-16-methyl-prostacyclin-11,
    15- diacetate,
    Dialogically to example 1c, a compound is obtained from 2 g of the compound ’obtained according to example 126 and 10 mp DBN (indicated in the name), which is used as a raw material in the future.
    Example 13. 5-Cyano-13,1435-dihydro-16-netyl-prostacycles and.
    Analogously to example 5, 250 mg of the compound obtained according to example 12 and 2.5 ml of 2N are prepared from 250 mg. pa-. a solution of caustic soda in 5 ml of methanol 145 mg (indicated in the names) of the compound as a colorless oil.
    IR cif 4 : 3600; 3300; 2930;
    2862; 2212; 1710.
    Example 14 * 5-Cyano-M-methanesulfonyl-prostacyclin-carboxamide.
    377 mp 5-cyanb-prostacyclin (preparation: as in Example 3), 3 ml of pyridine and 1 ppm acetic anhydride. the slots were left to stand for .16 hours at room temperature and evaporated in vacuo. The residue is dissolved in 10 ml of abs. acetonitrile, add 120 mg trnethylamine and mix with a solution of 150 mg methylsulfonylisocyanate in 8 ml of acetonitrile. It is stirred for 4 hours at 20 ° C, concentrated in vacuo, mixed with 10 ml of water, adjusted with an iX citric acid solution!
    > 3 923365 pH to 7 and extracted with ether. Shake the organic extract with brine, dry with magnesium sulfate and evaporate in vacuo. After purification using PTX (ether), 34Ό mg of methanesulfonylcarboxamide is obtained. To remove the protective acetate groups, they are dissolved in 10 ml of methanol, mixed with 240 mg of potassium carbonate and stirred for 3 hours at 20 ° C in argon. It is then diluted with brine, adjusted with 1% citric acid solution pH 7, extracted with methylene chloride, the extracts are brushed with brine, dried over magnesium sulfate and evaporated in vacuo.
    After filtering through silica gel in a mixture of methylene chloride with isopropanol (9: 1), 203 mg (indicated in the name) of the compound are obtained as a colorless oil.
    IR (CHCEj), cm * 1 : 3400; '2935;2865;22I;1720;1650;1340; 975.
    Example 15. 5-Cyano-I6-methyl-I-methanesulfonyl-prostacyclin-carboxamide.
    . Analogously to example 14, 173 mg (indicated in the name) of the compound are obtained in the form of an oil from 250 mg of 5-cyano-16-methyl-prostacyclin.
    IR (SNHS 5 ), cm · ' 1 : 3400; 2940; 2865; 2210; 1718; 1650; 972
    Example 16. 5-Cyano-M-acetyl-prostacyclin-carboxamide.
    190 mg of 5-cyano-prostacyclin (see Example 3), 1.5 ml of pyridine and 0.5 ml of acetic anhydride are allowed to stand for .16 hours at room temperature and then evaporated in vacuo. The residue is dissolved in 6 ml of acetonitrile, a solution of 75 mg of triethylamine in 6 ml of acetonitrile is added and at 0 ° C, mixed with a solution of 55 mi-acetypisocyanate A in 6 mp acetonitrile. It is stirred for 2 hours at 20 ° C, concentrated in vacuo, mixed with 10 ml of water, adjusted to pH 7 with a 1% citric acid solution and extracted with ether. Shake the extract with brine, dry with magnesium sulfate and evaporate in vacuo. After purification using PTX (ether: pentane 7: 3), I60 mg of acetylcarboxamide is obtained. To remove the protective acetate groups, they are dissolved in 5 ml of methanol, mixed with 105 mg of potassium carbonate and stirred for 3 hours at '25 i 14
    20 ° С in argon medium is brine, the citric acid solution is brought up to .pH 7,
    Then, diluting with 1% non-acid acid, the mixture was extracted with methylene chloride, the extract was shaken with brine, dried with magnesium sulfate and evaporated in vacuo. After filtering with silica gel cheree (methyl chloride: isopropanol 9: 1), 105 mg (indicated in the name) of the compound are obtained in the form of an oil.
    IR (CHCKj), cm * 1 : 3600; 3400 ', 2960; 22 ';1733;1705; 1650, 973.
    Example I 7. 5 — Cyano-I5 — methyl-N-acetyl-simple acycline — carboxamide.
    Analogously to example 16 receive from 225 mg of 5-cyano-15-methyl-prostacyclin (see example 5) 152 mg (indicated in the name) of the compound in the form of oil.
    IR (CHCt ^), cmA 3600; 3400; 29551 2212; 1733; 1706; 1650; 973..
    Example 18. 5-Cyano-1b | 16-dimethyl-M-acetyl-prostacyclin-carboxamide.
    Analogously to Example 16, 95 mg (indicated in the name) of the compound in the form of an oil are obtained from 170 mg of 5-cyano-16-16-dimethyl-protacyclin (see Example 7).
    IR (CHCEj), cm * 3600; 3410, 2960; 2210; 1732; 1705, 1650; 976
    EXAMPLE 19 5-Cyano-16-methyl-K-acetyl-pr-wedge-carboxy atm mid. .
    Analogously to example 16, from 152 mg of 5-cyano-16-methyl-prostacyclin (see example 9), 102 mg (indicated in the name) of the compound are obtained in the form of an oil.
    IR (CHCl3), cm- 1 : 3600; 3410; 2955; 2210; 1735; 1708; 1650; 974.
    Example 20. 5-Cyano-M-acetyl-16-phenyl-17,18,19,20-tetranor-prostacyclin-carboxamide.
    Analogously to example 16, from 165 mg of 5-cyano-16-phenyl-17.18, 19.20-tetranOp-prostacyclin 100 mg (indicated in the name) of the compound are obtained as a colorless oil.
    IR (CHCBj), cm * 1 : 3600; 3400-, 2945; 2212; 1734; 1708; 1650; 1602; 975.
    P r and. MER 21. 5-Cyano-13,14-dihydride o-16-methyl-N-acetyl-pros tacicline-carboxamide.
    Analogously to example 16 receive from 95 mg of 5-cyano-13,14-dihydro-16-methyl-prostacyclin 57 mg (indicated in the name) of the compound in the form of oil, f
    IR (CHCE 3 ), cmL · 3600-, 3400; 2955; 2210; 1734; 1706; 1650..
    Example 22. Tris- (oxymethyl) -aminomethane salt of 5-cyano-prostacyclin. 5
    To a solution of 190 mg of 5-cyano-prostacyclin in 7 ml of acetonitrile, a solution of 60 mg of tris (oxymethyl) aminomethane in 0.2 ml of water is added at 80 ° C with stirring, and it is stirred for 16 hours at room temperature. After removal of the solvent, 185 mg (indicated in the name) of the compound are obtained.
    权利要求:
    Claims (2)
    [1]
    3 However, the method of preparing prostanoic acid derivatives of general formula (1) or their salts, which can be used in medicine as pharmaceutical preparations, is not known. The purpose of the invention is to obtain new pharmacologically active derivatives of prostanoic acid of general formula (O or their salts. The goal is achieved. The method of obtaining prostanoic acid derivatives of general formula (I) or their salts is that the compound of the general formula AND RjOOB H OA- WDE-Bg, where R, RQ, RjA, B, D, E and W are as defined above, is reacted with a compound of the general formula (Ml) RgSOij NCO, where R 5 is chlorine or bromine, at a temperature of from -70 to, and then with tertiary amine and, if necessary, I is subjected to alkali gi Rolysis to obtain compounds of the general form (0 where Rg is hydroxyl, which, if necessary, is reacted with a compound of general formula (IV), where (4 lower alkanoyl or lower alkylsulfonyl, with subsequent selection of the target product in free form or as a salt. Compounds of the general formula (1) lower blood pressure and inhibit platelet aggregation. Example D 5-cyano-prostacyclin-1,15 methyl diacetate methyl ester. To a solution of 320 mg of prostacyclin-1 1, 15-diacetate methyl ester in 4.2 ml of absolute ether, 3.55 ml of chlorosulfonyl isocyanate solution are added dropwise at minus 70 ° C (preparation: dissolve 2.3 ml of chlorosulfonyl isocyanate in 50 ml of abs. Ether ), slowly heated to and added dropwise with 3.55 ml of a solution of triethylamine (preparation: 100.2 mg of triethyl mine is dissolved in 5 ml of methylene chloride). The mixture is stirred for 1 h at 15 minutes, the mixture consisting of sodium bicarbonate solution and ice water is poured onto 54, extracted three times with ether, shaken the organic extract twice with brine, dried over magnesium sulfate and evaporated in vacuo. After purification using preparative thin layer chromatography (PTX) (silica gel, ether), 60 mg of the compound (indicated in the title) are obtained as a colorless oil. IR (SNCES),, 2930; 2860, 2203-, 1730; 1650; 1372, 1245, 970. The starting material is obtained as follows. 1a Methyl ester of 5,6-hydrido 5-iodine-prozacyclin. To a mixture consisting of 2.1 bg of prostaglandin methyl ester-, 5.4 g of sodium bicarbonate, 50 MP of ether and 90 ml of water, 65.2 ml of 2.5% - under stirring iodine solution. After 22 hours at O, it is diluted with ether, shaken with a dilute sodium thiosulfate solution, washed with water until neutral, dried with magnesium sulfate and evaporated in vacuo. After filtration through silica gel in a mixture of ether and ethyl acetate (1: 1), 2.81 g of compound are obtained in the form of a colorless oil. IR (SNCES), cm-: 3600; 3400; 2932; 1730; 975. 16. Methyl ester of 5,6-di hydro-5-iodine-prostacyclin-11,15-diacetate. Dissolve 400 mg of the compound obtained according to Example 1a in 0.8 ml of acetic anhydride and 3 ml of pyridine and leave to stand for 18 hours at room temperature. After evaporation in vacuo, 467 mg is obtained according to thin layer chromatography of diacetate in the form of a colorless oil. IR (CUCEj), cm-1 2958; 2948; 2860; 1732; 1245; 976. Gu. Prostacyclin-11,15-diacetate methyl ester. To a solution of 200 mg of diacetate prepared according to Example 16 in 2 ml of benzene was added 1 ml of diazabicyclo 14,3,01-non-5-one (DNN) and stirred for 20 hours at 40 ° C with argon. Dilute with ether, shake three times with ice water, dry with sodium sulfate and concentrate in vacuo at. In this way, an oily (indicated in the title) compound is obtained, which is used without further purification. Example
    [2]
    2  Methyl ester of 5-cyano-prostacyclin.  250 mg of the compound obtained according to Example I, 150 mg of potassium carbonate and 10 ml of methanol are stirred for 3.5 hours at room temperature in argon.  Then it is diluted with ether, dried with water until neutral, dried with magnesium sulfate and evaporated in vacuo at.  IR (CHCIj) cm 3600} 3430, 2937; 2860; 2212i 1650; 972.  Example 3  5-Cyano-prostacyclin.  To a solution of 25 mg of compound,. The methanol obtained according to Example 2, 1.5, No. 1 was added 0.25 ml of 1N.  caustic soda solution and stirred for 4 h at 25 ° C in argon.  It is then concentrated in vacuo, treated with 3 kp of brine, and the solution is adjusted to pH 7 with 0% citric acid.  Extract four times with metipenhporidom, shake the organic extract once with brine, dry with magic sulphate and evaporate in vacuo.  Thereby, 22 mg is obtained according to TX, (indicated in the title) of the compound as an oil, which crystallizes upon storage at minus.  -.  IR (CHCEj), cm-: 3600; 2930; 2862 2211; 1710; 1650; 973.  Example 4  Methyl ester of 5-cyano-15-methyl-prostacyclin-11, 15-diacetate.  To a solution of 644 mg of 15-methyl-prostacyclin-1t, 15-diacetate netil ester in 9 ml of abs.  ether was added dropwise at minus 70 with 7.2 ml of chlorosulfonyl isocyanate solution.  (preparation was dissolved with 2.3 ml of chlorosulfonyl isocyanate in 50 ml of abs.  ether, heated slowly to and with a drop of 7.2 MP of triethylamine solution (preparation: 200 mg of triethylamine in 10 MP of methylene chloride.  I stirred for 1 h at 15 scientific research institutes at, poured onto an ice-cold sodium bicarbonate solution, extracted three times with ether, shaken the organic extra twenty with brine, dried with magnesium sulfate and evaporated from under vacuum.  After purification with PTH (ether), 1 35 mg (indicated in the title) are obtained to combine HeitiUi as a colorless oil.  9 5 IR (CHCtj), 2960; 2930; 2203 1730i 1650i 1245, 9:72.  The starting material for (indicated in the title) of the compound is prepared as follows.  4a.  Methyl ester of 5,6-dihydro-5-iodine-15-mePSh-prostacyclin.  To a mixture consisting of 1.1 g of 15-methyl-prostaglandin-F ester, 2.7 g of sodium bicarbonate, 30 mp of ether and 50 MP of water, is added dropwise with stirring at 3 hours 33 MP 2.5% - Ny ethereal solution of iodine.  After 23 hours, the mixture is diluted with ether, shaken with sodium thiosulfate solution, dried with water until neutral, dried with magnesium sulfate and evaporated in vacuo.  After filtration through silica gel. mixtures of ester with ethyl acetate (1: 1) give 1.35 g (the title indicates) of the compound as an oil. .  IR (CHCl1), cm: 3600; 3400; 1730; 976.  4b.  Methyl ester 5,6-.  -dihydro-5-iodine-15-methyl-prostacycly-11, 15-diacetate.  1.3 g of the compound obtained according to Example 4a is dissolved in 12 ml of pyridine and 3 ml of acetic anhydride, 100 mg of 4-dimethylaminopyridine are added and the mixture is left to stand for 16 hours at 25 ° C.  It is then evaporated in vacuo and the residue is filtered through silica gel in a mixture of pentane and ether (8: 2) to obtain 1.41 g (indicated in the title) of the compound as a colorless oil.  IR (CHCtj), cm: 2960; 2360; 1733; 1245; 976.  4c.  Methyl ester 15-methyl-prostacyclin-1I, I5-diacetate.  A mixture consisting of 600 mg of diacetate prepared according to Example 4b, 6 ml of benzene and 3 4p DBN is stirred for 20 hours while in argon. Then it is diluted with ether, shaken three times with ice water, taken up in sodium sulfate and concentrated in vacuum - at 20 ° C.  Oily oil is obtained (indicated in on-.  This is a compound that is used without further purification.  .  Example 5  5-Cyano-15-methyl-proticyllia, To a solution of 100 mg of the compound obtained otherwise according to Example 4, in 6 M7I methanol was added I ml of 2N sodium hydroxide solution and stirred for 5 hours at 25 ° C in argon .  Then it is concentrated in vacuo and treated with 5 ml of brine, set up with P5 7 with 0.5% citric acid and extracted four times with metal chloride, shaken the organic extract once with brine, dried with magnesium sulfate and evaporated in vacuo.  The crude product is purified by filtration over silica gel in a mixture of methylene chloride and isopropanol (85; 15).  56 g (as indicated in the title) of the compound are obtained in the form of a white oil.  IR (SNSIZ) cm 3600 3300 293 2862; 2210; 1712; 1650, 974.  Example 6  Methyl ester of 5-cyano-16,16-dimethyl-prostacyclin-1I, 15-diacetate.  , To a solution of 320 mg of 16,16-dimethyl-simple cyclin-11,15-diacetate methyl ester in 4.5 ml of ether was added dropwise at minus 3.5 m solution of chlorosulfonyl isocyanate (preparation: according to example 1), heated Slowly add and drop by drop 3.5 ml of a solution of triethylamine (preparation: an example). Stir for 1 h at 0 ° C, 15 min., pour into sodium bicarbonate solution cooled with ice, extract three portions of ether, shake organic extract twice with dissolve, dried with magnesium sulfate and evaporated in vacuo. After purification with PTX (ether), 72 are obtained. ml (indicated in the title) of the compound as a colorless oil.  IR (SNCES), see : 2960; 2930-, 220 1732, 1650, 1245, 972.   The starting material for (title) compound is prepared as follows.  ba Sophisticated methyl. ether 5,6-dihydro-16, 16-dimethyl-6-iodine-prostacyclic a.  In analogy to Example 1a, 1.2 g of methyl methyl ester 16,16-dimethyl-prostaglandin-Po G, 5 (indicated in the title) of the compound are obtained in the form of an oil.  IR (CHCEi), 3600-, 3400; 173 975.   bb, Methyl ester 5,6-dihydro-16, 16-dimethyl-5-iodo-prostacyclin-11, 15-diacetate.  A solution of 820 mg of the diol prepared in Example 6a in 6 ml of pyridine and 1.5 ml of acetic anhydride is left to stand for 18 hours at room temperature, evaporated in vacuo and filtered in a mixture of pentane and ether (1: 1 through silica gel.  800 mg (indicated in the title) of the compound are obtained in the form of a colorless oil.  , IR (CHCEj), cmL 2900; 2948; 1732; 1245-, 975.  6c.  Methyl ester 16,16-dimethyl-prostacyclin-11, 15-diacetate, analogously to example 1c, is prepared from 800 mg of diacetate prepared according to example 6b and 4 cl dbn (indicated in the title) of the compound as an oil. 7  5-cyano-16,16-dimetip-prostacyclin.  To a solution of 400 mg of the compound obtained according to Example 6 in 25 MP of methanol was added 4 ml of 2N.  caustic soda solution and stirred for 6 h under argon.  Then it is concentrated in vacuo, treated with 15 ml of brine, adjusted with 1 (1% citric acid, pH 7 and. extracted four times with methyl chloride.  Inoculate organic extracts once with brine, sulphate magnesium sulfate and evaporate in vacuo.  The crude product is purified by filtration over silica gel (methylene chloride: isopropanol 85:15).  240 mg (indicated in the title) of the compound are obtained in the form of a colorless oil.  IR (CHCl1), 3600; 3300, 2930; 2860; 2210; 1710; 1650; 975.  Example 8  Methyl ester of 5-cyano-16-methyl-protectClean-11, 15-diacetate.  To a solution of 1.3 g of the methyl ester of 16-methylprostacyclin-11, 15-diacetate in 18 ml abs.  14.4 ml of a solution of chlorosulfonyl isocyanate is added dropwise at minus 70 ° C (preparation: dissolve 2.3 ml of chlorosulfonyl isocyanate in 50 ml of abs.  ether), slowly heated to within 30 minutes and 14.4 ml of pactBOpa triethylamine are added dropwise (production: 400 mg of triztilamine in 20 mr of methylene chloride).  It is stirred for one hour at 15 minutes, poured onto an ice-cooled sodium bicarbonate solution, extracted three times with ether, shaken the organic extracts twice with brine, dried with magnesium sulfate and evaporated in vacuo.  After purification with 1GHG (ether), 290 mg (the title indicated) gives the compound as a colorless oil.  IR (SNCE}), 2960; 2932 2203 1730; 1650; 1260-, 972.  The starting material for the title compound is obtained as follows. .  8a.  Difficult Me. 5,6-dihydro-5-iodo-16-metsh1-prostacyclin methyl ester.  Analogously to Example 1a, from 4.6 g of methyl ester of 16-metst-prostaglandin-Pn 5.6 g (indicated in the title) of the compound in the form of a colorless oil.  IKTSSNSE), cm-- 3600-, 3400; 2930 1732; 975.  86  Methyl ester 5,6-dihydro-5-iodo-I6-metsh1-shch1ostacycpin-11,15-diacetate.  5.51 g of the compound obtained according to Example 3A is dissolved in 30 ml of pyrcine and 8 ml of acetic anhydride and left to stand for 18 hours at 25 ° C.  After evaporation in vacuo and filtration, over silica gel (pentane: ether 7: 3), 6 g (as indicated in the title) of the compound are obtained as a colorless oil.  IR (SNCES), cm-2960} 2950-, 2860 1730} 1245; 975.  8c.  Methyl ester of 16-methyl-prostacyclin-11, 15-diacetate, a mixture of 3 tons of the compound obtained according to example 86, 30 ml of benzene and 15 ml of DBN.  stirred for 20 hours at 45 ° C in argon, diluted with ether, shaken four hands with fresh water, dried with sodium sulfate, and concentrated in vacuo at.  An oily (indicated in the title) compound is obtained, which is used without further purification.  Example 9  5-Cyano-16-methyl-prostacyclin.  To a solution of 1 g of the compound boiled according to Example 8 in 50 mp of methanol was added 10 mp 2n.  caustic soda solution and stirred at 7 h at 25 ° C in argon.  Then it is concentrated in vacuo and the mixture is treated with 30 ml of brine, the value of p is brought to 7 with 1% lmonic acid and extracted with methylene chloride four times.  Inject the organic extracts once with brine, dry with magnesium sulfate and evaporate in vacuo. After filtering raw material through silica gel using a mixture of methylene chloride and isopropanol (85:15), 590 mg (indicated in the title) of the compound are given as. colorless oil.  IR (CHCEj), 3600; 3300; 2933; 2860; 2210; 1710; 1650; 976.  Example 10  Methyl ester of 5-cyano-16-fench1-17,18,19 20-tetranor-prostacyclin-11, 15-d1 acetate.  To a solution of 300 mg of 16-fensh1-17,18,19, 20-tetranor-prostacyclin-1I methyl ester, 4 kp of ether, I5-diacetate in a 4 kp ether solution is added dropwise at minus 70 ° С to a 3.4 MP solution of chlorosulfonyl isocyanate (preparation; by example 1), heated for 30 minutes before and 3.4 mp solution were added dropwise. RA of triethylamine in methylene chloride (preparation: according to example 1).  Stir for one hour at 15 minutes at 20 ° C, pour into an ice-cooled sodium bicarbonate solution, extract with ether, extract the extract with brine until neutral, dry with magnesium sulfate and evaporate in vacuo.  After purification with PTH (ether), 80 mg (indicated in the title) of the compound are obtained in the form of an oil.  IR (CHCEj), cm-: 2960-, 2205; 1733, 1651; 1602; 1245; 974.  The starting material for (above in the title) of the compound is prepared as follows.  10a.  Methyl ester 5,6-dihydro-5-iodo-16-fennp-17, 18,19,20-tetranor-prostacyclin.  Analogously to Example 1a, 16-phenyl-17, 18,19,20-tetranor-prostaglandin-P (, 38 g (indicated in the title) of the compound as a colorless oil) is prepared from methyl ester 16.  IR (CHCt), ctr 3600; 3410; 1732,160; 975.  106  Layer W) 1 st methyl ester 5,6-di hydro-5-iodo-16-fesh-17,18,19, 20-tetranor-prostacyclin-11,15-diacetate.  A solution of 1.2 g of diol, obtained according to the example of Sha, in 9 ml. pyridine and 2.4 MP acetic anhydride are left to stand for 18 hours at room temperature.  It is then evaporated in vacuo and the residue is filtered with pentane: ether (1: 1) over silica gel.  In this way, 1.31 g (indicated in the title) of the compound are obtained in the form of a colorless oil.  IR (SNCES).  cm: 2958-, 2950-, 173 1602j 1245, - 976.  10c.  Methyl ester of 16-phenyl-17, 18,19,20-tetranor-prostacyclin-11, 15-diacetate.  Analogously to Example IB, 1.25 g of diabstat obtained according to Example SB and 6 ml of DBM oily (as indicated in the title) compound, which is subsequently used as a raw material, are obtained.  Example P.  5-Cyano-16-fe shl-17, 18,19,20-tetranor-prostacyclin.  To a solution of 610 mg of the compound obtained according to Example 10 in 28 MP of methanol was added 6 ml of 2N.  caustic soda solution and stirred for 6 h at 25 C in argon.  It is then concentrated in vacuo, treated with 15 ml of brine, adjusted to tZ-uoro with a solution of citric juice, pH 7, and extracted four times with methylene chloride.  Inject the organic extracts once with paccon m, dry with sulphate and evaporate in vacuo.  After purification of the cbipoiO product with the aid of filtration, the snipicagel methylene chloride: H3oit onanolol 9: 1) obtains 390 mg (indicated in the title) of the compound as a colorless oil JC (CHCl 3), cfd: 3600; 33fO; 2930 2B60i 2212; 1712; 1650, 1602; 976.  An example. 12 Methyl ester of 5-Sch1a about-13,14-dihydro-l6 methyl-prostacyclin-l 1,15-diacetate.  To a solution of 1.15 g of 13,14-dip dr 16-methyl ester-prostacyclin-methyl-11, I5-diacetate in 15 ml of abs.  The ester is pressed with g "Nus 70C 13 MP solution of chlorosulfonyl isocyanate (preparation: as in example I), Ha is heated for 30 minutes to 0 ° C, and I3 ml of a solution of triethylamine in methylene chloride is dripped (see Example 1), stirred for 1 hour at, poured into a solution of sodium bicarbonate and cooling with ice and extracting with ether.  The extract is washed with brine, dried over magnesium sulfate and evaporated in vacuo at.  By PTX (ether) 300 mg (indicated in the title) of the compound are obtained in the form of a colorless oil.  IR (SNCES) cm-2960-, 2932-, 2203; 1730; 1650; 1250.  12a.  Methyl ester 5,6-dihydro-13, I4-DIHYDRO-5-IODE-16-methyl-prostacyclin.  As in Example 1a, 2.1 g of complex 13,4-dihydro-16-methyl-prostaglandin-P (, 6 g (indicated in the title) of the compound as a colorless oil) are obtained.  IR (sneEl), cm: 3600-, 3400, 2930-, 1730.  126.  Methyl ester 5,6-dihydro-g 13,14-5-iodo-16-methylprostacyclin-i 1,15-di acetate ail In analogy to example b, it is obtained from 2.5 g of diol, prepared according to example 12a, after chromatography 4 , 7 g (indicated in the title) of the compound as an oil.  IR (CHClj), CM-- 2958; 2950-, 2855-; 1732; 1245.  12th century  Methyl ester of 13, 14-dihydro-16-methi-gprostacic-11, 15-diacetate.  Analogously to example 1c, it is obtained from 2 g of the compound obtained according to 1fim 126, Yu DM DM (indicated in the title of you) coeai Hetme, which as c |  Example 13  5-Ibiavo-3.14 digishch about 16- "1fnp-osta11 kPii.  Similarly, npmtepy 5 is obtained from 250 mg of the compounds, obtained according to primsfu 12, and 2.5 MP 2n.  solution of Haffui in 5 mp of methanol 145 14G (of Asano Azano in Na G) compound as a colorless liquid.  IR (CHCtj), 3600; 3300; 2930; 2862; 2212-, 1710.  PRIUME 1 14 5- Cyano-N-methanesulfonyl LPrOstacyclinLine-carboxy amide.  377 ml of 5-cyanO-prostate cyclin (preparation: according to Example 3), 3 ml of pyridine and 1 MP of acetic anhydride ki.  CX slots are allowed to stand for 16 hours at room temperature and evaporated in vacuo.  The residue is dissolved in to ml of abs. . acetonitrile, 120 mg of triztilamine are added and mixed with a solution of 150 mg of methylsulonyl isocyanate in 8 ml of acetonitrile.  Stir for 4 hours at 20 ° C, concentrate in vacuo, mix 10 ml of water, adjust pH to 7 with iZ-Horo solution / monoacid acid and extract with ether.  Inject the organic extract with brine, dry with magnesium sulfate and evaporate in vacuo.  After purification with PTH (ether), 340 mg of methanesulfonylcarboxamide are obtained.  To remove the protective acetate groups, they are dissolved in 10 ml of methanol, mixed with 240 mg of potassium carbonate and stirred for 3 hours at 20 ° C in argon.  It is then diluted with brine. The solution is adjusted to pH 7 with a 1% citric acid solution, extracted with methylene chloride and then extracted with brine, dried over magnesium sulfate and evaporated in vacuo.  After filtration through silica gel in a mixture of methylene chloride and isopropanol (9: 1), 203 mg (indicated in the title) of the compound are obtained as a colorless oil.  IR (CHCEj), 3400; 2935; 286 2211; 1720; 1650, - 1340; 975.  Example 15  5-Cyano-16-methyl-N-methanesulfonyl-prostacyclin-carboxamide.  .  Analogously to Example 14, 173 mg (indicated in the title) of the compound as an oil are obtained from 250 mg of 5-cyano-16-metsh1-prostacycpine.  IR (CHCBj), 3400; 2940; 286 2210; 1718; 1650, - 972.  Example 16  5-Cyano-M-acetyl-prostacyclin-carboxamide.  190 mg of 5-cyano-prostacyclin (see Example 3), 1.5 ml of pyridine and 0.5 ml of acetic anhydride are allowed to stand for. 16 h at room temperature and then evaporated in vacuo.  The residue is dissolved in 6 ml of acetonitrile, a solution of 75 mg of triethylamine in 6 m of acetonitrile is added and mixed with a solution of 55 mg of acetylisocyanate in 6 MP of acetonitrile.  Stir for 2 hours at 20 ° C, concentrate in vacuo, mix with 10 ml of water, adjust pH to 7 with 1% citric acid solution and extract with ether.  Inject the extract with brine, dry with magnesium sulfate and evaporate in vacuo.  After purification with PTX (ether: pentane 7: 3, half of I60 mg of acetylcarboxamide) To remove the protective acetate groups, dissolve in 5 ml of methanol, mix with -105 mg of potassium carbonate, and stir for 3 hours under argon. ; The mixture is then diluted with brine, the mixture is adjusted to pH 7 with 1% citric acid solution, extracted with methylene chloride, the extract is shaken with brine, dried over magnesium sulfate and evaporated in vacuo.  After filtration over silica gel (methylesquoride: isopropanol 9: 1), 105 kg (indicated in the title) of the compound are obtained in the form of an oil.  IR (CHCEj), 3600j 3400, 2960V 2210; 1733; 1705; 650, 973.  Example 17  5-Cyano-I5-MetAL-N-acetyl-prostate acin-carboxam d.  In analogy to Example 16, 225 mg of 5-cyano-5-methyl-prostacyclin is obtained (see  Example 5) 152 mg (indicated in the title) of the compound as an oil.  IR (CHCt), cmL 3600; 3400; 2955, 2212; 1733; 1706; 1650; 973.  .  Example 18  5-Cyano-16 16-dimethyl-N-acetyl-prostacycpin-carboxamide.  In analogy to Example 16, 170 mg of 5-cyano-16-16-dimethyl-prostacyclin is obtained (see  Example 7: 95 mg (indicated in the title) of the compound as an oil.  IR (CHCEj), cm 3600; 3410, 2960; 2210; 1732; 1705, 1650; 976.  Example 19  5-Cyano-16-metsht-M-acetyl-prostacyclin-carboxes In analogy to example 16, 152 mg of 5-cyano-16-metsh1 Prostacycline is obtained (see  Example 9: 102 mg (indicated in the title) of the compound as an oil.  IR (СНС1з), cm-: 3600; 3410; 2955; 2210; 1735; 1708; 1650; 974.  Example 20  5-Sch4ano-M-acetyl-16-phenyl-17, 18,19,20-tetranor-prostacyclin-carboxamide.  Analogously to Example 16, 165 mg of 5-cyano-16-phenyl-17.18, 19,20-tetran or prostacyclin 100 mg (indicated in the title) of the compound are obtained as a colorless oil.  IR (CHCEj), 3600; 3400-, 2945; 2212; 1734; 1708; 1650; 1602; 975.  P p i.  me er 21.  5-Cyano-13,14-dihydro-16-methyl-M-acetyl-prostacyclin-carboxamide.  Analogously to Example 16, 95 mg of 5-cyano-3,14-DIHIDRO-16-methyl-prostacyclin 57 mg (indicated in the title) of the compound are obtained in the form of an oil.  5 IR (SNCES), 3600-, 3400-, 295 22IO-, 1734; 1706; 1650.  .  Example 22  Tris- {hydroxymethyl-aminomethane salt of 5-cyano-prostacyclin,.  To a solution of 190 mg of 5-cyano-pro-stacyclin in 7 ml of acetonitrile was added at 80 ° C while stirring a solution of 60 mg of tris (oxymethyl) aminomethane in 0.2 ml of water, stirred for 16 hours at room temperature. temperature  After removal of the racer, 185 mg (indicated in Plzvankk) dinene are obtained.  The invention method for producing prostano derivatives of general formula KjCOB H (AWDE-Rg hydroxyl, lower alkoxy or group R - lower alkanoyl or lower alkylsulfonyl; B - linear alkylene group with 1-5 carbon atoms, A - ethylene, cis or trans -vinyl ene or group W - free or substituted C (2-C 4 dyl or oxymethylene group or free or substituted acyl group - C ", and hydroxy is hydroxy.   be in d-- or (i-position.  5 Oi E together means a direct bond or D is a linear or branched alkyl group with 1-5 carbon atoms; E is oxygen or a direct bond; Rf is lower alkyl or phenyl, Rij is a free or substituted CQJ-C acyl hydroxyl group, or their salts, characterized in that the compound of the general formula II is RtCOB H C AWDE-Bg where R, R, R, A, B, D , E and W, these values are reacted with a compound of the general formula) RgSOj NCO where R 5 is chlorine or bromine, at a temperature of minus 70 C to O C and then with a tertiary amine and, if necessary, is subjected to alkaline hydrolysis to obtain the compounds of formula (I), where R5 is hydroxyl, which, if necessary, is reacted with the compound s of formula IV, wherein R -lower alkanoyl or lower alkylsulfonyl, posleduiltsim vscheleniem with the desired product. in with a free-form; or in the form of salt.  .  Sources of information taken into account during the examination 1.  Tomoskozi et aE.  A SimpEe Synthesis of PGir.  Tetrahedron Lett.  1977, 2627.
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    US5164519A|1992-11-17|Process for the separation of R and S-2,2-R1,R2 -1,3-dioxolane-4-carboxylic acid
    US5153330A|1992-10-06|Thiapentanamide derivatives
    KR790000983B1|1979-08-16|Process for preparing of pthalidylester of aminobenzyl penicillanic acid
    US5256807A|1993-10-26|Process and intermediates for chiral epoxides
    同族专利:
    公开号 | 公开日
    AU523420B2|1982-07-29|
    ATA836478A|1982-11-15|
    IT1160264B|1987-03-11|
    DD140042A5|1980-02-06|
    AU4191278A|1979-05-31|
    NO783964L|1979-05-28|
    HU181518B|1983-10-28|
    EP0002234A1|1979-06-13|
    NZ188976A|1979-12-11|
    ES475377A1|1979-04-01|
    CA1180701A|1985-01-08|
    AT371455B|1983-06-27|
    DE2860486D1|1981-03-26|
    JPS5481257A|1979-06-28|
    EP0002234B1|1981-02-11|
    JPS6220989B2|1987-05-11|
    IE782321L|1979-05-25|
    NO148642C|1983-11-16|
    IL56017A|1983-03-31|
    IT7830174D0|1978-11-24|
    IL56017D0|1979-01-31|
    FI68621B|1985-06-28|
    FI783590A|1979-05-26|
    ZA786622B|1979-10-31|
    FI68621C|1985-10-10|
    DK153482B|1988-07-18|
    DK522578A|1979-05-26|
    YU271078A|1983-01-21|
    NO148642B|1983-08-08|
    CS209909B2|1981-12-31|
    PH20276A|1986-11-14|
    IE47497B1|1984-04-04|
    GR72772B|1983-12-05|
    DE2753244A1|1979-06-07|
    DK153482C|1988-12-27|
    US4219479A|1980-08-26|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4178367A|1977-02-21|1979-12-11|Ono Pharmaceutical Co. Ltd.|Prostaglandin I2 analogues|
    DE2902809A1|1979-01-25|1980-08-07|Hoechst Ag|NEW PROSTACYCLIN ANALOGS|
    DE3004795A1|1980-02-07|1981-08-13|Schering Ag Berlin Und Bergkamen, 1000 Berlin|NEW PROSTACYCLINE DERIVATIVES, THEIR PRODUCTION AND USE|
    DE3041601A1|1980-10-31|1982-06-16|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW PROSTACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3041602A1|1980-10-31|1982-06-16|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW 5-CYAN PROSTACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3322893A1|1983-06-23|1985-01-03|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW PROSTACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3427797C2|1984-07-25|1988-08-11|Schering Ag, 1000 Berlin Und 4709 Bergkamen, De|
    DE3448256C2|1984-07-25|1988-08-18|Schering Ag, 1000 Berlin Und 4709 Bergkamen, De|Cytoprotective action of prostacyclin derivatives on the pancreas|
    DE3740838A1|1987-11-27|1989-06-08|Schering Ag|CYCLODEXTRINCLATHRATE OF 5-CYANO-PROSTACYCLINE DERIVATIVES AND THEIR USE AS MEDICINAL PRODUCTS|
    EP2043629A1|2006-07-18|2009-04-08|Bayer Schering Pharma Aktiengesellschaft|5-cyano-prostacyclin derivatives as agents for the treatment of autoimmune diseases|
    CA2669763C|2006-11-16|2015-02-17|Bayer Schering Pharma Aktiengesellschaft|Ep2 and ep4 agonists as agents for the treatment of influenza a viral infection|
    US20080242713A1|2007-03-28|2008-10-02|Bayer Schering Pharma Aktiengesellschaft|Novel 5-cyano-prostacyclin derivatives as agents for the treatment of autoimmune diseases|
    EP1988087A1|2007-03-28|2008-11-05|Bayer Schering Pharma Aktiengesellschaft|Novel 5-cyano-prostacyclin derivatives and their use as agents for the treatment of autoimmune diseases|
    US7776896B2|2007-03-28|2010-08-17|Bayer Schering Pharma Aktiengesellschaft|5-cyano-prostacyclin derivatives as agents for the treatment of influenza a viral infection|
    EP1975163A1|2007-03-28|2008-10-01|Bayer Schering Pharma Aktiengesellschaft|Novel 5-cyano-prostacyclin derivatives and their use as agents for the treatment of influenza a viral infection|
    KR20160042039A|2013-08-09|2016-04-18|알데릭스, 인코포레이티드|Compounds and methods for inhibiting phosphate transport|
    US20200368223A1|2019-05-21|2020-11-26|Ardelyx, Inc.|Methods for inhibiting phosphate transport|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19772753244|DE2753244A1|1977-11-25|1977-11-25|NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION|
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