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    • 专利摘要:
    New 2,3,4-trinor-1,5-inter-m-phenylene-PGI2 derivatives (wherein A stands for carboxy, cyano, tetrazolyl or -COOR<3> or -CONR<1>R<2>; R<3> is C1-4 alkyl or an equivalent of a pharmacologically acceptable cation: R<1> and R<2> each stands for hydrogen, phenyl; C1-5 alkyl, optionally substituted by carboxy, hydroxy, phenyl or C2-5 alkoxycarbonyl; or C1-4 alkyl-sulfonyl; or R<1> and R<2> together form an alpha , omega -alkylene chain containing 3-6 carbon atoms; B stands for oxygen or methylene; Y is optionally bromo-substituted vinylene or a -C=C- group: R<4> stands for hydrogen or tetrahydro-pyran-2-yl; R<5> represents an alkyl group containing 5-9 carbon atoms, which can be optionally interrupted by one or more oxygen atom(s) or -CH=CH- or -C=C- group(s) and/or optionally substituted by halogen; or a phenoxymethyl group optionally substituted by halogen or trifluoromethyl; or an alkenyloxymethyl group containing 3-5 carbon atoms; R<6> is hydrogen or C1-4 alkyl; R<7> stands for hydrogen, halogen, cyano, C1-4 alkyl or C1-4 alkoxy; R<8> is hydrogen, halogen, cyano, nitro, hydroxy or C2-5 alkanoylamido; with the proviso that if R<5> stands for an alkyl group containing 5-9 carbon atoms which is unsubstituted or not interrupted by an oxygen atom or a -CH=CH- or -C=C- group; or a phenoxymethyl group optionally substituted by halogen or trifluoromethyl, then either R<7> or R<8> is other than hydrogen, or A is other than carboxy or -COOR<3>) and a process for the preparation thereof. The new compounds of the general Formula I exhibit prolonged cytoprotecting and aggregation inhibiting and a low hypotensive effect and are superior to prostacycline in the prolonged duration of their activity.
    公开号:SU1382834A1
    申请号:SU833681400
    申请日:1983-12-28
    公开日:1988-03-23
    发明作者:Секели Иштван；Ловас Марианна；Ботар Шандор；Долгош Кристина；Бенток Бела；Гайари Антал；Саболчи Тамаш；Ковач Габор
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт., (Инопредприятие)；
    IPC主号:
    专利说明:

    one
    The invention relates to new derivatives of the class of prostacyclin, specifically to derivatives of 2,3,4-three-nor-1,5-inter-m-phenylene prostacycl on the general formula


    BUT
    (I)
    where a
    RICOONa,
    n-hexyl-n-heptyl-2-methyl, 4-1-phenyl-1-yl, 6-methyl-5-hepten-1-yl, n-octyl, n-pentile, methoxyethoxymethyl, ethoxymethyl, hex-5- enoxymethyl, pent-4-enmethyl, phenoxy methyl, pentyloxymethyl, chloro-phenoxymethyl; R is fluoro, chloro, methoxy, cyano or methyl group; hydrogen, fluorine, chlorine, cyano, nitro, methoxy or acetyl-amino group,
    possessing cytoprotective properties. The purpose of the invention is to obtain new prostacyclin class derivatives that are more stable in comparison with the known prostacyclin analogues, which increases their pharmacological activity.
    Example 1. Preparation of 3-bromomethylbenzoic acid.
    10 g (73.4 mmol) of t-toluic acid is dissolved in 75 ml of carbon tetrachloride, after which 0.2 g of 2,2-azo bis (2-methylpropionitrile) and 13.72 g ( 77.07 mmol) of N-bromoxynimide. AT
    tatna mixture at a ratio of 1: 1).
    Methyl ether formed in noMODiH diazomethane gives a Rj value of 0.38 (a mixture of benzene and hexane in a 2: 1 ratio).
    H-NMR (CDCl ,,): 4.51 (S, 2H, CH); 7.25-7.6 (m, 2H, aromatic protons); 7.75-8.25 (t, 2H, aromatic protons.
    The following compounds were obtained: 3-bromomethyl-6-nitr-benzoic acid at Rf 0.07 (benzene and ethyl acetate in a 1: 1 ratio);
     H-NMR (CDC1 ,, ./): 4.54 (S, 2H, CHP; 7.5-8.1 (t, 3N, aromatic protons); 3-bromomethyl-4-fluoro-benzoyl0
    Q
    0
    five
    : 0.36 (benzene and
    on acid,
    ethyl acetate in a ratio of 1: 1); 2-chloro-3-bromomethylbenzoic acid, R 0.35 (benzene and ethyl acetate in the ratio: 1), 3 bromomethyl-6-5 cyano-benzoic acid, R. 0.32
    (benzene and ethyl acetate in the ratio; 1: 1); 3-bromomethyl-5-hydroxy-benzoic acid, Rr 0.15 (benzene and ethyl acetate in the ratio 1: 1); 3-bromomethyl-6-acetylamine benzoic acid, Rr 0.05 (benzene and ethyl acetate 1: 1).
    PRI mme R 2. Preparation of 3-methoxymethylbenzoic acid.
    12 g (55.77 mmol) of 3-bromomethylbenzoic acid are dissolved in 10 ml of anhydrous methanol, after which sodium methoxide is added to the solution at room temperature in an amount of 22.3 ml (concentration 5 mmol / ml). The reaction mixture is stirred for 5-10 minutes and the methanol is removed under reduced pressure. The precipitate is dissolved in 10 ml of ethyl acetate.
    for 20 min, the reaction mixture nag., that. After the addition of 2 ml of water, it is milled with countercurrent, then the formed suksinamid is filtered off in the form of heat. The organic phase, obtained in the form of a filtrate, is washed with 13 ml of water, dried with sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The resulting crude product crystallizes out from five times the amount of carbon tetrachloride. 12.72 g of compound are obtained, yield 80.5%.
    By thin layer chromatographic method Rj. 0.39 (benzolace50
    55
     2N sodium bisulfate solution at a pH of 2-3 is adjusted. The phases are separated from each other, the organic layer is dried, filtered and the solvent is filtered off under reduced pressure. 8.55 g of compounds are obtained, yield 92.3%.
    According to the thin-layer chromatographic method, Rf 0.13 (benzene and methyl acetate in the ratio 1: 1); Rr 0.6 (benzene, dioxane and acetic acid in the ratio 20: 10: 1).
    PRI me R 3. Preparation of 3-fluoromethylbenzoic acid.
    0
    five
     2N sodium bisulfate solution at a pH of 2-3 is adjusted. The phases are separated, the organic layer is dried, filtered and the solvent is filtered off under reduced pressure. 8.55 g of compounds are obtained, yield 92.3%.
    According to the thin-layer chromatographic method, Rf 0.13 (benzene and ethyl acetate in the ratio 1: 1); Rr 0.61 (benzene, dioxane and acetic acid in the ratio 20: 10: 1).
    PRI me R 3. Preparation of 3-fluoromethylbenzoic acid.
    2.945 g (11.15 mmol) of 1, 4.7, 10, 13,16-hexanonacycloctadecane (18-crown-6) are dissolved in 30 ml of anhydrous acetonitrile, after which 6.48 g (111.54 mmol) are added. a) dehydrated potassium fluoride. The mixture is stirred for half an hour. After adding 12 g (55.77 mmol) of 3-bromomethylbenzoic acid, the reaction mixture is stirred for another 3 hours at 50 ° C, filtered, and then the filtrate is concentrated under reduced pressure. The precipitate is placed in 100 ml of ethyl acetate, the suspension is washed with 15 ml of water and 15 ml of saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated under reduced pressure. 7.3 g of compounds are obtained, yield 85%.
    By the method of thin-layer chromatography Kg 0.3 (benzene, dioxane and acetic acid in the ratio 50: 10: 1).
    For methyl ester obtained with an ether solution of diazomethane, the Rp value is 0.37 (benzene and hexane 2: 1).
    PRI me R 4. Preparation of 3-cyano-methylbenzoic acid.
    10 g (43.66 mmol) of 3-bromomethylbenzoate of methyl ether are dissolved in 50 ml of anhydrous acetone, after which 3.2 g (65.5 mmol) of sodium cyanide (dried at 105 ° C) and 0.327 g (dried 2.18 mmol) sodium iodide. The reaction mixture is heated for 10 hours under countercurrent, then cooled and carefully filtered. Acetone is filtered off under reduced pressure. The precipitate is placed in 120 ml of ethyl acetate and the suspension is washed twice with 20 ml of water. The organic solvent is distilled off under reduced pressure and the residue is dissolved in 20 ml of methanol. To the solution is added a solution prepared from 5.24 g of sodium hydroxide and 20 ml of water. The reaction mixture was stirred at room temperature for one night. Under reduced pressure, the methanol is distilled off and the precipitate is washed with 20 ml of water and 20 ml of saturated sodium bisulfate solution and acidified to pH 1-2. The mixture is extracted three times with 60 ml of ethyl acetate. The organic phase is dried.
    filtered and the solvent is removed under reduced pressure. The resulting product is then subjected to halogenation as in Example 5. Yield 5.62 g (80%) of the crude product.
    By the method of thin-layer chromatography R 0.3 (benzene and ethyl acetate in the ratio 1: 1).
    PRI me R 5. Preparation of 3- (bromofluoro-methyl) benzoic acid.
    11.3 g (73.4 mmol) of 3-fluoromethylbenzoic acid are dissolved in 75 ml of anhydrous carbon tetrachloride. 0.2 g of azo-bis- (2-methylpropionitrile) and 13.72 g (77.07 mmol) of N-bromoxyxinimide are added to the solution. The reaction mixture is heated under countercurrent for 30 minutes. Formed by succinim id filtered off in a warm form. The resulting organic filtrate was washed with 15 ml of water, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The resulting crude product crystallizes out from five times the amount of carbon tetrachloride. In the end, get 13,65 g of substance, yield 79.5%.
    By the method of thin layer chromatography Rr 0.3 (benzene, dioxane and acetic acid in the ratio of 50:10:
    :one).
    The following compounds were obtained in a similar way: 3- (fluorocyano-methyl) benzoic acid at Rt 0.25 (benzene, dioxane and acetic acid in a ratio of 50: 10: 1); H- (fluoro-methoxy-methyl) benzoic acid with Rr 0.32 (benzene, dioxane and acetic acid in the ratio 50: 10: 1).
    EXAMPLE 6 Preparation of Trifenyl- (3-carboxy-4-nitrobenzyl phosphonium bromide.
    15 g (57.7 mmol) of 3-bromomethyl-6-nitrobenzoic acid and 15.17 g (57.7 mmol) of triphenylphosphine are heated for 70 hours in 70 ml of anhydrous toluene. The precipitated product is filtered off, washed with ether and dried. 21.15 g of compounds are obtained, the yield is 71%.
    Analysis: HNMR (CDC1 ,, (): 5.45 (d, 2H, CH, P +, j 16 Hz); 7.5-7.8 (t, 3N, aromatic protons).
    The following compounds are prepared analogously: triphenyl- (3-carboxyB
    benzyl) phosphonium bromide; triphenyl- (3-carboxy-phenyl-cyanomethyl) phosphonium phosphonium; triphenyl- (3-carboxy-4-chlorobenzyl) phosphonium bromide at R. 0.6 (methanol, water, and acetic acid in the ratio 5: 5: 1); triphenyl- (2-fluoro-5-carboxy-benzyl) phosphonium bromide at Rr 0.61 (methanol, water and acetic acid in the ratio 5: 5: 11; triphenyl- (3-carboxy-4-cyano-benzyl a) phosphonium bromide at Rf 0.55 (methanol, water and acetic acid in the ratio 5: 5: 1); triphenyl- (2-hydroxy-3-carboxy-benzyl) phosphonium bromide at Rf (methanol, water and acetic acid in the ratio 5: 5: 1).
    EXAMPLE 7 Preparation of triphenyl-3- (carboxy-phenyl-fluoromethyl-phosphonium bromide.
    A solution of sodium methyl sulfonidmethyl (DIM SYL-sodium) obtained by the reaction of 0.15 ml of anhydrous dimethyl sulfide and 0.151 g of sodium hydride solution at 20 ° C in a nitrogen atmosphere, 1.5 g (3.13 mmol) of solid triphenyl- (3 —Arboxybenzyl) phosphonium bromide, eluted at 80–90 ° С and reduced pressure. D; then perchlorylfluoride was added to the resulting dark red color solution at room temperature until the red color of the solution disappeared and the pH reached a value close to neutral. 30 ml of water were added to the reaction mixture, after which The 2N sodium bisulfate solution is adjusted to pH 1 to 2. The mixture is washed three times with methylene chloride in an amount of 25 ml each time and twice with ethyl acetate in an amount of 25 ml each time, subjected to extraction, the organic extracts are combined and concentrated under reduced pressure. pressure. The resulting raw, if necessary, crystallized from a mixture of ethanol and ethyl acetate. With this, 0.91 g of compound, the yield is 70%.
    According to the method of thin-layer chromatography, Rf 0.6 (methanol, water and acetic acid in the ratio 5: 5: 1), Example 8, Preparation of 3- (t-chlorophenoxy) acetonylphosphorane.
    From 5.76 g (0.25 mol) of metallic sodium and 200 ml of methanol, sodium methoxide is obtained. After the addition of 32 g (0.25 mol) t-chlorfeno a polu20
    25

    -
    ten
    15
    thirty
    The cooled solution is heated in countercurrent for 1 hour, then evaporated. The resulting solid precipitate is suspended:) That in 200 ml of benzene, where 88 g (0.25 mol) of chloroacetonephosphorane are introduced. This reaction mixture is heated under reflux for 3 hours. The precipitated sodium chloride is filtered hot, and the benzene solution is concentrated under reduced pressure. Sex: 7-membered solid crude product, triturate, ayut 50 ml of ether, the resulting crystals are filtered and dried. 97 g of crystalline compound are obtained, the yield is 87.2%.
    Analysis: Melting point 240-242 ° C.
    On thin layer chromatography Rf 0.5 (acetone and ethyl acetate 3: 1).
    1R cm-3350, 1590, 1523, 1405, 1240, 1100, 1045, 890, 860, 740, 705, 690.
    The following compounds are prepared analogously: 3-propargyloxyacetonylphosphorus; 3- (2-methoxyethoxy) acetonylphosphorane with Rj 0.4 (acetone and ethyl acetate 3: 1); 3-crotyloxyacetonylphosphorane with ethyl acetate 3;
    ethoxy) acetonylphosphorane at Rp - 0.52 (acetone and ethyl acetate 3: 1).
    J 1 nJlW141-n ijU, C i IjnWJl
     Rp 0.51 (acetone and G :); 3- (2, 2, 2-trifluoro-.
    five
    0
    five
    0
    five
    PRI me R 9. Preparation of triphenyl- (3,4-didehydrohexanoyl) methylenephosphorane.
    Prepare a suspension of the salt with ethyl acetate in 0.5 molar; ammonium hydroxide. A solution of 166.75 g of triphenylchloroacetonylphosphorane and 100 ml of tetrahydrofuran is added to the suspension at -33 ° C, and it is introduced below the surface of liquid ammonium. The mixture is allowed to stand for one hour, after which the ammonium is evaporated. The solid residue is dissolved in 300 ml of methylene chloride, the suspension is washed with water, dried with anhydrous sodium sulfate, filtered, and the solvent is then distilled off under reduced pressure. The compound obtained is crystallized by trituration with petroleum ether. 134.4 g of the expected product are obtained, the yield being 70%.
    On thin-layer chromatography R g O ,, 61 (acetone and ethyl acetate in the ratio 3: 1).
    Similarly, the following compounds can be obtained: triphenyl- (3,4-didehydro-5-methoxy-pentaoyl) methylene-deprofan with Rr 0.55 (acetone and ethyl acetate 3: 1); triphenyl- (3,4-dide hydro-octanoyl) methylenephosphorane with R | - 0.60 (acetone and ethyl acetate 3: 1)
     PRI me R 10. Obtaining dimethyl- {2-oxo-5-heptin-1-yl) phosphonate
    20 g (12.9 mmol) of dimethylacetoni phosphonate is dissolved in 100 ml of non-verbal tetrahydrofuran, after which the solution is cooled to -78 ° C. After the addition of 23.1 g (219 mmol) of hexamethylphosphoric triamide, 12.9 ml of a solution of butyl lithium with hexane (concentration 2 mmol / ml) are introduced into the solution at a temperature of -78 ° C. At this temperature, the reaction mixture is stirred for half an hour. After the subsequent addition of 17.15 g of 1-bromo-2-butin and 5 ml of tetrahydrofuran to the solution, the reaction mixture is stirred for another hour at (-60) - (-70) C. Next, add 20 ml of a saturated solution of sodium chloride after which the temperature is raised to a value of room temperature. The reaction mixture is diluted with 50 ml of water and 50 ml of ether. The phases are separated from each other, the water layer is extended by treating with ether three times, the amount of which is 30 ml for each treatment. The organic phases are combined, washed with 15 ml of saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the solvent is distilled off under reduced pressure. 22 g of compound are obtained, the yield being 82.5%.
    In a similar way, dimethyl- (2-oxo-5-heptin-1-yl) phosphonate can be obtained.
    Example 11 Preparation of 3.3a, 4,5,6,6a / -hexahydro-2-oxo-4/5 4-t-chlorophenoxy-3-oxo-1-trans-butenyl (p-phenylbenzyloxy) -2H-cyclopent s (lurana.)
    20 g (53.9 mmol) 3.3a, 5, 4,5,6, 6a fb-hexahydro-2-oxo-4-formalne-5 s / - (p-phenyl-benzoyloxy) -2H-cyclopenta in furan is dissolved in 20 ml of anhydrous dichloromethane. 24.0 g (53.9 mmol of solid triphenyl- (t-chlorophenoxy-adetonylphosphorane and 0.64 g of benzoic acid) are added to the solution. The reaction mixture is agitated
    Yu
    5 20 25 zo Q
    ds
    city,
    35
    five
    The mixture is heated at room temperature for 8 hours. Then it is diluted with 00 ml of dichloromethane and washed twice with 10 ml of 1N hydrochloric acid each time. The organic phase is dried with anhydrous magnesium sulphate and the solvent is distilled off under reduced pressure. The crude product is chromatographed on a column of silica gel and elui P3, using a mixture of 3: 1 benzene and ethyl acetate. The fractions, which in the benzol ethyl acetate mixture (4: 1) show R ~ 0.2-6, are collected and concentrated under reduced pressure. In total, 21.48 g of compound are obtained, with a yield of 77%. The product may crystallize from anhydrous ethanol.
    Analysis: Rr 0.26 (benzene and ethyl acetate 4: 1).
    Similarly to the described method, p-hexahydro-2-oxo-4/3 - (3-oxo-1-trans-nonyl) -5-o1 (p-phenylbenzoyl-aloxy Si1-2H-cyclopenta b furan.
    Example 12. Preparation of 3.3a, i i4, 5, 6, - hexahydro-2-hydroxy-4/3 (35-hydroxy-1-trans-nonyl) -5 o - hydroxy-2H-cyclopentane b of furan.
    63.7 g (0.117 mol) 3.3av, 4.5, 6, 6ar-hexahydro-2-oxo-4 / s- (3-oxo-1-trans-nonynyl) -5- (p-phenylbenzoyl-oxy) ) -2H-cyclopenta L of furan is dissolved in 200 ml of anhydrous ethanol. The solution is cooled before and 240 ml of a 0.5 molar ethanolic solution of sodium borane is added to it. The reaction mixture is stirred for 30 minutes at temperatures ranging from -20 to, after which it is poured into 500 ml of 0.1N hydrochloric acid. The resulting mixture is extracted four times with. 100 ml of ethyl acetate each time. The collected organic phases are dried with sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product is separated by silica gel column chromatography and washed with a mixture of 1: 1 ethyl acetate and benzene. The two isomers formed correspond to the less polar isomer of the S-configuration (R. - 0.33, benzene and ethyl acetate 1: 1). The fractions for which Rr has a value of from 0.33 to 0.28 are collected separately and
    concentrated. 25.6 g of less molar S allyl alcohol and 23.2 g of more polar R allyl alcohol are obtained.25, 6 g of less polar S-allyl alcohol is dissolved in 130 ml of anhydrous tetrahydrofuran. The solution is cooled in a dry ice bath - acetone to -78 ° C. 45.5 ml of a solution of diisobutylaluminium hydride with hexane (concentration 2.28 mmol / ml) are instilled into a solution with an inert gas at a rate that does not exceed the temperature. After completion of the instillation, the reaction mixture is stirred for 30 minutes. Next, 50 np of 2N aqueous sodium bisulfate solution is added to the mixture, after which its temperature rises to room temperature. The reaction mixture is acidified to pH values from I to 2 and 300 ml of ethyl acetate are poured into it. The phases are separated from each other. The aqueous layer is extracted three times with 20 ml of ethyl acetate each time, the combined organic phases are dried, filtered and concentrated under reduced pressure. 24.8 g of bicyclic lactol are obtained (Rr. 0.455 ethyl acetate and benzene 3 :).
    In order to remove the p-phenylbenzoyl protecting group, the product obtained is dissolved in 00 ml of anhydrous methanol and 6.53 g (0.047 mol) of dry potassium carbonate are introduced into the solution. The suspension is stirred for half an hour, filtered, and the solvent is distilled off under reduced pressure . The resulting product is chromatographed on a silica gel column and washed with ethyl acetate. The fractions for which the P value is at the level of 0.28 are collected and concentrated under reduced pressure. 9.44 g of compounds are obtained, yield 71% (relative to the S-alcohol).
    According to the thin layer chromatography method, Rj O, 28 (ethyl acetate), Rr 0.3 (benzene, dioxane and acetic acid).
    By analogy with the method described above, the following compounds can be obtained: 3, Over, A, 4,5,6,6A, r-hex sagidro 2-hydroxy-4 p- (33-hydroxy-trans-decenyl-5c / -hydroxy-2H -cyclopenta-b-furan at Rg 0.3 (benzene, dioxane and acetic acid 20:: 10: 1); 3, For,} - 4.5, 6.6a l-hexagid
    ten
    20
    25
    thirty
    35
    40
    45
    50
    55
    ro-2-hydroxy-4b- (38-hydroxy-4- (t-chloro-phenoxy) -1-trans-butenyl-5) -hydroxy-2H-cyclopenta-t-furan with R | - 0.23 {ethyl acetate ); 3.3a | 54.5, 6, 6a l-hexahydro-2-hydroxy-4 /} - (3: 5-hydroxy-4-methoxyethoxy-1-trans-butenyl) -5 s (hydroxy-2H-cyclopentane 1 1: -furan at Rf 0.26 (benzene, dioxane and acetic acid 20: 10: 1); 3, 3a / i, 4,5,6, 6a /} - hexahydro-2-hydroxy-4 - (35-hydroxy-1-trans-6,7-didehydro-octenyl} -5 ° (-hydroxy-2H-cyclopent G bfuran at Rp 0.27 (ethyl acetate).
    Example 13, Preparation of 3.3a /) 4,5,6,6a p-hexahydro-2-hydroxy-4 (38-hydroxy-1-decynyl) -5o / -hydroxy-2H-cyclopenta B of furan.
    55.9 g (0.1 mol) 3, Over /, 4,5,6, ba fi -hexahydro-2-oxo-4 / i (3 oxo-1-trans-decenyl-5s / -) p-phenyl-benzoyl - hydroxy-3H-cyclopenta HF furan is dissolved in 200 ml of anhydrous dichloromethane, then 5.5 ml of bromine are added to the solution at room temperature and 25, 6 ml (0.3 mol) pyridine is added. The reaction mixture is heated for three hours under countercurrent. After adding 100 ml of methylene chloride, the mixture is washed with 50 ml of 1N hydrochloric acid and then 75 ml of methylene chloride are extracted twice with the aqueous phase. The organic solutions are combined, washed with 50 ml of 5% sodium bicarbonate solution, dried, filtered and concentrated under reduced pressure. 64 g of crude product are obtained, RJ-0.3 (benzene and ethyl acetate 4: 1).
    This crude product is dissolved in 200 ml of anhydrous ethanol. The solution is cooled to and added with 190 ml of an Oh, 5-molar ethanolic solution of sodium borate. The reaction mixture at temperatures from -20 to -25 ° C is stirred for 30 minutes, poured into and 500 ml of O, 1N hydrochloric acid and the resulting mixture is extracted four times with 100 ml of ethyl acetate. The organic phases are combined, dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained as a result of this treatment is subjected to chromatography on a column of silica gel, and the benzene-acetate mixture is eluted. Two isomers are formed with a less polar isomer of S configuration
    eleven
    (R |. 0,2, benzene and acetate 3: 1). The fractions for which Rr values are from 0.2 to 0.3 are collected separately and concentrated under reduced pressure. 26.1 g (40%) less polar S allyl alcohol and 25 g more polar R - allyl alcohol are obtained.
    26.1 g of the less polar S allyl alcohol is dissolved in 150 ml of anhydrous tetrahydrofuran. The solution is cooled to -78 ° C in a bath of dry ice and acetone. 17.55 mp of diluent formed from diisobutylaluminum hydride and hexane (2.28 mmol / ml at a rate at which the temperature of the solution does not exceed) is instilled into the solution under inan gas. After the instillation, the reaction mixture is stirred for 30 minutes and 20 ml of an aqueous 2N sodium bisulfate solution are added, the temperature is raised to room temperature, the pH is adjusted to 1 to 2 and 300 m of ethyl acetate is added. The phases are separated and the aqueous suspension is extracted three times with 20 ml of ethyl acetate. ml, the residue is dried , filtered and distilled off under reduced pressure.
    24.3 g of bicyclic lac tol are obtained (K 0.15, benzene and .. ethyl acetate
    at. the ratio of 3: 1).
    To remove the p-phenylbenzoyl protecting group, the product obtained is dissolved in 100 ml of anhydrous methanol. After the addition of 5.66 g (0.041 mol) of anhydrous potassium carbonate, the suspension is stirred for half an hour, filtered and the filtrate is concentrated under reduced pressure. The crude product obtained is subjected to chromatography on a column of silica gel and washed with ethyl acetate. Fractions that have an Rj value. 0.25, collected and evaporated under reduced pressure. 10.48 g of bromovinyllactol is obtained, yield 73.5% (calculated as S-alcohol).
    By the method of thin-layer chromatography R 0,25 (ethyl acetate).
    10.48 g of the brominovyl lactol so formed was dissolved in 50 ml of anhydrous dimethyl sulfoxide and 3.12 g (0.027 mol of tertiary potassium butylate) was added to this solution at room temperature.


    0
    5 0 5
    0
    five
    0
    five
    0
    five
    The suspension was stirred at room temperature for 30 minutes, diluted with 300 ml of ethyl acetate, the aqueous phase was extracted with 100 ml of water and washed with 50 ml of water twice, dried, the filter and concentrated under reduced pressure. The crude product is chromatographed on a silica gel column and eluted with an ethyl acetate-acetone mixture (4: 1). Fractions with an Rf value of 0.33 (ethyl acetate) are collected and concentrated under reduced pressure. 6.22 g of compound are obtained.
    By the method of thin-layer chromatography R i 0,33 (ethyl acetate).
    PRI me R 14. Obtaining 2,3,4, 17,18,19,20-hectanor-1,5-inter-t-phenylene-13,14-didehydro-16-methoxyethoxy-PgF 7, / methyl ester.
    23.6 g (0.06 mol) of anhydrous triphenyl- (3-carboxybenzyl) phosphoeniumbromde was placed in a 150 ml round flask, after which, with nitriding, cooling and stirring, 58 ml of sodiummethylsulphenylmethide with dimethylsulfoxide (instilled 2 mmol / ml). The resulting red phosphorane solution is stirred at room temperature for 30 minutes and then diluted with 5 ml of dimethyl sulfoxide. After the addition of 5.72 g (0.02 mol) of 3.3a, 34, 5, 6, 6a l-hexahydro-2-hydroxy-4 / 3- (3H-hydroxy- (4-methoxyethoxy) -1-butynyl) -5 -hydroxy-2H-cyclopent L of furan, the reaction mixture was stirred at 40 ° C for two hours, then it was poured into a mixture of 30 g of ice and 100 ml of water and adjusted to pH 1 with a solution of sodium bisulfate. 3-4. The solution is extracted with 30 ml of ethyl acetate four times. The combined organic extracts are extracted three times with 1N sodium hydroxide 16 ml three times. The combined alkaline extracts using Na sodium bisulfate solution reach a pH in the range of 3.5 to 4. After adding 80 ml of diethyl ether and O ml of the molar ether diazometh solution, the ether phases are separated, washed with a saturated solution of sodium chloride, dried and under reduced pressure, 5.6 g of the obtained crude product is distilled to expose 13J
    Chromatography is carried out on a column of Silkgel and extracted with a mixture of ethyl acetate and benzene (3: 1). The fractions for which R | .equal is 0.23 (3: 1 ethyl acetate benzene) are collected and concentrated under reduced pressure. 5 g of compound yield 60% are obtained.
    On thin-layer chromatography Rf 0,23 (ethyl acetate and benzene in the ratio 3: 1).
     H-NMR (CDCij,): 7.3-8.1 (m,
    4H, aromatic protons) | 652- 6.7 (t, 2H, trans H-5, H-6) | 5.7-5.95 (t, 2H, cis H-5, H-6); 4.0-4.35 (t, 3Н, Н-9, Н-П, Н-15) 3.92 (S, ЗН, СНл); 3.65 (S, NN, CHj Oether)
    Similarly, the following compounds can be prepared:
    2,3,4,17,18,19,20-gentanor-1,5-inter-t-phenylene-5-fluoro 16- (w-chloro-pheno phenoxy) -PgF o / methyl ester, R 0,3 (benzene-dioxane-acetic acid 20: 10: 1);
    2,4,4,17,18,19,20-heptanor-, 5-inter-t-phenylene-16-propargyl-hydroxy-methyl ester, Rf (benzene, dioxane and utric acid in the ratio 20: 10: 1 ) |
    2,3,4,17,18,9.20 teptanor-1, 5-inter-t-phenylene-16-crotyl-hydroxy-PgF / (./- methyl ester, Rp O 5 39 (benzene, dioxane and utssous acid 20 ;);
    2,3,4,17,18,19,20-heptanor-1, 5-inter-t-phenylene-6- (2,2,2-trifluoroethoxy CK) - Pg 1 methyl ester, f- 0,27 (benzene dioxane and acetic acid (20: 10: 1);
    2,3,4-trinor-1jS-HHTep-t-phenylene-17 J1 8-didehydro-PgF j -methyl ester R 0.41 (benzene S dioxane and acetic acid 20: 10: 1);
    2, 3,4-trinor-1 W-icter-w-phenylene
    -PgF {(-methyl ether, el (benzene, dioxane and acetic acid; acid 20: 10: 1);
    2,3,4-trinor-i, 5-inter-a-phenylene-5 cyano-20-methyl-P§E-methyl ether, R | 0.4 (benzene 5 dioxane and acetic acid 20: 1 0: 1) j
    2,3,4-trinor-1 5-inter tz-zylene-14-bromo-17,18-didehydro-20-ethyl-FgF 2 methyl ester of R: 0-6 (benzole, dioxane and acetic acid 20 :: 10: 1);
    2,3,4-trinor 135 inter-phenyleK 13,1 4,1 7 81 8-bic-didehydro-PgF
    i. i
     /,

    )
    five
    g;
    five
    d
    ,;
    ; Q
    ;
    T1 low ester 5 Rf o ,, b (benzene 5 dioxane and acetic acid 20: 10; 1);
    2,3; 4-triner 1,5-nter-t-phenylene- 1 3. 1 4-Didegndro L -PgF 3 -methyl ester, Rr 0.6 (benzene, dcoxane and;, cyclic acid 20: 10: 1,).
    Example 15. Obtaining 2s3,4-trinor-1,5-inter-t-phenylene-13, i 4 didehydro-PoF-amide.
    2.5 g (6.3 mmol) 2.354-trinor-15 5-inter-t-phenylene-3,14-didehydro-20-thyl-PoF 7 ° (methyl ester is dissolved in 36 ml of ethanol and 1 , 26 g (3.15 mmol of sodium hydroxide in 12 ml of water. The reaction mixture was stirred overnight and the methanol was distilled off under reduced pressure. To the residue was added 10 ml of water 10 ml of a saturated solution of sodium chloride, resulting in a pH of 2 and then the aqueous layer is extracted five times with 20 ml of ethyl acetate. The organic phases are combined, dried, filtered and concentrated Under reduced pressure, the floor of the crude as a result of the carbopic acid (2.5 g) is dissolved in 20 ml of anhydrous β1-tylene chloride. After 3 solution, 1.3 g (1256 mmol) of triethylamine and 860 g (6, , 3 mmol) of isobutyl chloroformate ester, the mixture is stirred for half an hour at room temperature. At -5 ° C, 30 ml of acetonitrile and ammonium are added to the mixture, which is stirred for another 10 minutes. After the 31T of which the reaction mixture is diluted with 50 ml of saturated Patric chloride solution and 10 ml of water. The resulting mixture was extracted five times with ethyl acetate in an amount of 20 ml each. The combined organic orbits 5 are washed twice with 2 ps hydrochloric acid in an amount of 20 ml each, with an aqueous solution of 5- bicarbonate; atri in an amount of 20 ml each and 20 ml of a saturated solution of sodium chloride, then dried with sodium sulfate, filtered and concentrated under reduced pressure . The raw material is chronographised;.; And the column with silica gel and you; 1-with a mixture of adone-ethyl acetate (3: 1). The fractions for which Kg Raano is 0.25 (benzene; dioxac and ulustic acid 20: 20: i) are combined and concentrated from reduced pressure. In the end, get 2j24 g of the product, yield 93%.
    By thin layer chromatography R 0,25 (benzene, dioxane and acetic acid 20: 20: 1).
    EXAMPLE 16. Preparation of 2-de-carboxy-2-cyano-2,3,4-trinor-1,5-inter-phenylene-13,14-didehydro-20-ethyl-PgF j.
    4 g (9.64 mmol) of 2,3,4-trinor-1,5-inter-t-phenylene-13,14-didehydro 20-ethyl-PgF-amide is dissolved in 40 ml of anhydrous dimethylformamide, after which the solution 1.21 (48 mmol) of dimethyltributylsilyl chloride and 7.9 g (115 mmol) of imidazole are added.
    The mixture is stirred overnight, then 400 ml of a mixture of petroleum ether and ether (1: 1) is poured into it. The organic phase is washed three times with water, 50 ml each time, and 50 ml of a saturated solution of sodium chloride, then it is dried, filtered and concentrated under reduced pressure. The resulting tris-silyl (10 g) is dissolved in 40 ml of pyridine and 2.2 g (10.6 mmol) of N, M-dicyclohexylcarbodiimide is added to the solution. The reaction mixture is stirred at room temperature for one hour and diluted with 250 ml of ether. The precipitated dicyclohexyl urea is filtered off and the filtrate is concentrated under reduced pressure. The residue is placed in 16 ml of a tetra-p-butylammonium fluoride in tetrahydrofuran molar solution and the mixture is stirred at room temperature for 2 hours. Next, 300 ml of ethyl acetate is added to the reaction mixture, washed three times with water, 40 ml each time, and 50 ml of a saturated solution of sodium chloride, then dried, filtered and concentrated under reduced pressure. Z, 6 g of compound, yield 68%.
    By the method of thin layer chromatography RP 0.3 (benzene, dioxane and acetic acid 20: 10: 1);
     H-NMR (CDCl ,,, cf): 0.85 (t, 3H; CH1,); 5.45-6.5 (m, 2H, olefinic protons); 7.2-8.1 (t, 4H, aromatic protons).
    Example 17. Preparation of 2-de-carboxy-2- (1H-tetrazol-5-yl) -2.3, 4-trinor-1.5-inter-t-phenylene-13,14-didehydro-20-ethyl- Pgf,.
    The experiment was carried out as in Example 16, however, instead of adding tetra-p-butylammonium fluoride, 50 ml of tilformamide was used as a solvent, and then 1.22 (9.3 mmol) of sodium azide and 5.15 g of ammonium chloride were added. . The reaction mixture is heated for 3 hours at temperatures ranging from 110 to 120 ° C, then cooled to room temperature, diluted with 100 ml of chloroform, washed twice with 20 ml of water each time, dried at room temperature and concentrated at reduced temperature. pressure. The residue is taken up in 20 ml of anhydrous tetrahydrofuran and 116 ml of tetrabutylammonium fluoride are introduced thereto. Mixture at. Stir for 3 hours at room temperature, dilute with 100 ml of chloroform, wash three times with water, 100 ml each time, dry, filter and concentrate under reduced pressure. 2.7 g of compound is obtained, yield 65%.
    According to the thin layer chromatography method: Rr-0.03 (benzene, dioxane and acetic acid 20: 10: 1).
    Example 18. Preparation of 2,3,4-trinor-1, 5-inter-t-fennlen-13,14-didehydro-20-ethyl-PgF, α-methanesulfo amide.
    In Example 15, 2,3, 4-trinor, 5-inter-t-phenylene-13,14-didehyde-po-20-ethyl-PgF, methyl ester and chlorobutyric acid isobutyl ester receive the corresponding mixed anhydride. A solution of this mixed anhydride in 10 ml of anhydrous dimethylformamide is mixed with methanesulfonate and sodium amide sodium, prepared from 2.8 g of methane sulfonate amide and 1.36 g of sodium ethoxide and purified from methanol with benzene.
    The mixture is mixed with 2 ml of triamide hexyl phosphate and this mixture is stirred for 24 hours at room temperature. Using a molar cold solution of sodium bisulfate, the mixture is adjusted to a pH of 3, and then extracted three times with ethyl acetate in an amount of 30 ml each time. The organic phases are combined, washed with water, dried, filtered, and concentrated
    17
    under reduced pressure. 2.25 g of compound are obtained, yield 75%.
    Analysis: for thin-layer chromatography: 0.05 (toluene, dioxane and
    acetic acid 20: 10: 1.
    Example 19. Preparation of 2,3,4-trinor-1, 5-inter-1n-phenylene-5-iodo-13-14,18,19-bis-di-hydroxy-20-ethyl-PgF-methyl ester .
    2.2 g (5.13 mmol) of 2,3,4-trinor-155-inter-t-phenylene-13,14,18,19-bic-didehydro-20-ethyl-PgF-methyl ether is dissolved with stirring in 10 ML1 of methylene chloride, after which 52 ml (52.0 mmol) of sodium bicarbonate solution (concentration 1 mmol / ml) are added with stirring. To this biphasic mixture, 103 ml of iodide solution with methylene chloride (concentration 0.1 mmol / ml) Within an hour, the reaction mixture was vigorously stirred at room temperature, diluted with 300 ml of ethyl acetate, and the content of excess iodine was lowered with a 5% sodium thiosulfate solution. The organic layer is separated and extracted twice each time with 25 ml of ethyl acetate. The organic phases are collected, washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulphate, filtered and distilled off under reduced pressure. 2.9 g of the title compound are obtained.
    According to the method of thin layer chromatography Rf.0,65 and 0,58 (ethyl acetate and benzene 3: 1).
    Example 20 p. Preparation of 2,3,4-trinor-1,5-inter-1p-phenylene-5-bromo-16-fluoro-13,14-didehydro-20-etl; l-PgF methyl ether,
    470 mg (1.1 mmol) 2,3,4-trinor-1,5-inter-t-phenylene-5-bromo-16-fluoro-13,14-didehydro-20-ethyl-PgF2 methyl ether solution 1: 1. The solution is cooled to (a mixture of acetone and dry ice and stirred in inert gas. The mixture is introduced into a portion of 215.4 mg of H-bromo-succinimide "for 10 The reaction mixture is stirred at -78 ° C for 1 min, the acetone and dry bath is removed and the temperature is raised to room temperature. The mixture is stirred at this temperature.
    ten
    15
    20
    thirty
    25
    50 azz
    38283418
    half an hour, diluted with 50 ml of chloroform and washed three times with water in an amount of 20 ml each time. The organic phase is dried with sodium sulfate, filtered and concentrated under reduced pressure. 560 mg of the title compound are obtained.
    By the method of thin-layer chromatography P, 0.59 and 0.54 (ethyl acetate).
    Pr and m p 21, Preparation of 2,3,4-trinor-1, 5-inter-g1-phenylene-5-phenyl-selenyl-5-methyl-13j14-didehydro-20-ethyl-PgF, methyl the ether.
     carried out in the same manner as in example 20, however, instead of N-bromoxy-imide imide, a solution of phenylselenyl chloride and methylene chloride (1.21 ml. 1 mmol / ml) is used. 650 mg of compound are obtained.
    Analysis:, 62, and 0.57 (ethyl 35
    40
    45
    tat).
    EXAMPLE 22 Preparation of 2,3, 4-trinor-1,5-inter-t-phenylene-13,14-dihydro-15-methyl-16-fluoro-20-ethyl-Pgl2- methyl ester,
    K 471 mg (0.85 mmol) 2,3,4-trinor-1, 5-inter-p-phenylene-5-iodo-1 3 "14-didehydro-15-methyl-16-fluoro-20- ethyl Pgl, methyl ester is added 5 ml of distilled 1,5-diazabicyclo (4, 3,0) non-5-one. The resulting mixture is stirred for an hour and then cooled to room temperature. The reaction mixture is diluted with 100 ml of ether, the organic phase is washed twice with water, 25 ml each time, dried with sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude product (390 mg) is chromatographed on a column of silica gel and washed with a mixture composed of ether and acetone in a ratio of 3 :, Fractions, for which R ,. 0.5 (benzene and ethyl acetate 3: 1), collected together and concentrated under reduced H1-1: pressure. 300 mg of compound are obtained. Yield 85%. By the method of thin layer chromatography, 5 (benzene ethyl and acetate 3 :, three times).
    H-mvffi (CDClI,; /): 7.25-8.1 (m, 4H; aromatic protons); 5.95-5.3 (S, 1H, E or H-5); 4.05-4.5 (2H, H-11 and H-15); 4.75 (dt, 1H, H-9); 3.95 (3N, ester CHj); 0.85 (t, 3N, CH ,,).
    Similarly, the following compounds can be obtained:
    nineteen
    2,3, D-trinor-1, 5-inter- (4-chloro-1, 3-phenylene) -1 3, 1 4-didehydro-20-e. Pb12-methyl ester, 64 and 0.6 (ethyl acetate);
    2,3,4-trinor-1,5-inter- (4-fluoro-1,3-phenylene) -13,14-didehydro-20-et Pgl.2-methyl ester, R., 64 and 0.6 (ethyl acetate);
    2,3,4-trinor-1,5-inter- (6-cyano 1,3-phenylene) -13,14-didehydro-20-et Pglj-methyl ester, R | .0.49 and 0.4 ( ethyl acetate);
    2,3,4-trinor-1,5-inter- (6-nitro 1,3-phenylene) -13,14-didehydro-20-et Pgl2-methyl ester, P.0.53 and 0.5 (ethyl acetate );
    2,3,4-trinor-1,5-inter- (6-acetyl amino-1,3-phenylene) -13,14-didehydro 20-ethyl-Po15-methyl ester,, (dichloromethane and acetone 2: 1) ;
    2,3,4-trinor-1,5-inter- (6-hydro-si-1,3-phenylene) -13,14-didehydro-20 ethyl 1-P51 methyl ether, 34 (dichloromethane and acetone 2: 1 );
    2,3,4,17,18,19,20-hepranor-1, 5-inter-t-phenylene-5-fluoro-13,14-didero-16- (3-chlorophenoxy) -Pgl, methyl ester, 68 and 0.66 (dichloro methane and acetone 3: 1);
    2,3,4,17,1B, 19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-16 propargyloxy-PgI methyl ester, R.0.55 and 0.51 ( dichloromethane and acetone 2: 1);
    2,3,4,17,18,19,20-heptanor-1,5-inter-ha-phenyl-13,14-didehydro-16-crotyloxy-PgI-methyl ester, R, 0.6 and 0, 55 (dichloromethane and acetone 2: 1);
    2,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-16-methoxyethoxy-PgI methyl ester, 41 and 0.37 (dichloromethane and acetone 2: 1);
    2,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-13, G4-didehydro-16- (2,2, 2-trifluoroethoxy) -P 17 -metsh10- ether, 52 and 0.48 (dichloromethane and acetone 3: 1);
    2,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-16- (2-butyn-1-yl-oxy) -PgI methyl ester ,, 59 and 0.56 (dichloromethane and acetone 2: 1);
    2,3,4-trinor-1, 5-inter-1p-phenylene 13,14,17,18-bic-didehydro-PgIo-methyl ether,, 67 and 0.62 (dichloromethane and acetone 3: 1) ;








    2,3,47 trinor-1,5-inter-t-phenylen-1 3, 14-didehydro-20-met1-m-Pg1 ,, - methyl ester, 69 and 0.66 (dichloromethane and acetone 3: 1);
    2,3, 4-trinor-1, 5-inter-1p-phenylene-5fluoro-1 3,1 4-dIihydrogen-PgI j-methyl ester, 6 and 0.55 (ethyl acetate);
    2,3,4-trinor-1,5-inter-t-phenylene-Q 5methoxy-13,14-didehydro-PgIj-methyl ester, 61 and 0.58 (dichloromethane and acetone 3: 1);
    2,3,4-trinor-1,5-inter-t-phenylene-5 cyano-13,14-didehydro-PgI2-methyl ester, 56 and 0.52 (dichloromethane and acetone 3: 1).
    II p. And measure 23. Preparation of 2,3,4-tririor-1, 5-inter-gp-phenylene-13,14-didehydro-20-ethyl-P21, -amide. Q 1.8 g (3.16 mmol) 2,3,4-trinor-1, 5-inter-I1-phenylene-5-phenyl-selenyl-13,14-didehydro-20-ethyl-PgI, -amide solution in 29 ml of tetrahydrofuran, after which 5 are added to the solution at 3.5 ml of 30% hydrogen peroxide. The mixture was stirred for one hour, stirred, the temperature was raised to room temperature and then stirred again for one hour. 20 ml of water and 20 ml of a saturated solution of sodium chloride are then poured into the reaction mixture. This mixture is extracted three times with 15 ml of ether each time and three times with 15 ml of ethyl acetate each time. 5 The organic phases are combined, washed twice with sodium bicarbonate solution at a flow rate of 20 ml each time and 20 ml of water, sulphate sodium sulfate, filtered and concentrated under reduced pressure. Get
    957 mg of compound, yield 71.5%.
    By the method of thin layer chromatography, 28 (benzene, dioxane and acetic acid 20: 20: 1).
    PRI me R 24. Obtaining 2,3,4-trinor-1,5-inter-t-phenylene-13,14,17, 18-bis-didehydro-20-methyl-6a-carba-prostaglandin-11 - methyl ether.
    A solution of 40 mmol sodium methylsulfenylmethyl and 40 ml of dimethyl sulfoxide, (prepared from 960 mg of sodium hydride and 40 ml of anhydrous dimethyl sulfoxide) cool 5 JOT to 15-20 C. After the addition of 9.54 g (20 mmol) of triphenyl-3 -carboxybenzylphosphonium bromide red solution obtained 30 minutes stir0
    0
    2
    wate when and then cool; "1; ayut to room temperature. Then 2.62 g (3 mmol) of 7- | (tetrahydropyran-2-yl-oxy} -6 / g (3fi- (tetrahydropyran-2-yl-oxy) -1) is added thereto, 4-nonnyl-bicyclo (3.3.0) octane 3-one in 2 m of anhydrous tetrahydrofuran. The reaction mixture is stirred at 40 ° C for 48 h, then cooled to room temperature j.
    10 ml of water and using a solution of 1 n sodium bisulfate establish a neutral pH. The mixture is extracted three times with ethyl acetate, 20 ml each time. The organic extracts are filtered, washed three times with water, 10 ml each time and once with 10 ml of a saturated solution of sodium chloride, dried with anhydrous sodium sulfate and filtered. The solution is cooled to 0 ° C and 10 ml of ether solution of diazomethane (concentration 1 mmol / ml) are poured into it. The solvent under reduced pressure is distilled off and the crude product (4 g) is chromatographed on a silica gel column with a mixture of benzene and ethyl acetate in a 4: 1 ratio. The fractions for which Ef is in the range from 0.40 to 0.36. (Benzene and ethyl acetate C :) are combined and concentrated.
    Yield: product with R0 0540-1.3 g (48%) -, product c, 38-2.36 g (40%) The obtained fractions are separately dissolved in 20 ml of a mixture composed of acetic acid, water and tetrahydrofuran in the ratio of 3; 1: 1.5,
    and stirred for 3 h at% o

    40 ° C. The reaction mixture is cooled to room temperature and then 40 ml of a saturated solution of sodium chloride and 40 ml of ethyl acetate are added to it. The organic phase is separated, the aqueous layer is extracted twice with ethyl acetate, 5 ml each time. The organic phases are combined and twice, washed with a saturated solution of sodium bicarbonate in an amount of 10 ml each time. They are further dried with anhydrous sodium sulphates, filtered and the solvent is distilled off under reduced pressure. The crude product is chromatographed on a silica gel column and the ethyl acetate is washed out. 782.5 mg (32%) and 843.5 mg (34.5%) of the 5 (Z) - and 5 (, E) -isomers of the compound are obtained.
    By the method of thin-layer chromatography, Kg - 0.20 and Oj, 1 7 ((ethyl acetate-. Tat).
    15
    283422
    II p and me R 25. Obtaining 2,3,4-e 5-inter- (4-fluoro-1, 3-phenyl flax) -135 4-didehydro-20-ethyl-PgF - sodium salt
    813.5 mg Us83) 2,3,4-triorin 1s5-MHTep- (4-fluoro-1,3 phenylene) -; 3 p 1 4-dc, ehydro-20-ethyl-p G methyl ester is dissolved in 5 ml of JQ methanol, and then 11 ml of 0.5 mol% is added to the solution at room temperature. sodium hydroxide solution. At room temperature, the mixture is stirred overnight and the methanol is distilled off under reduced pressure. The residue was dissolved in 3 ml of water, 10 ml of a saturated solution, sodium chloride and 50 ml of eth: acetate were added to this solution. after which the mixture is cooled to 0 ° C. With a molar solution of oxalic acid, the pH is set between 4 and 5. The phases are separated from each other, the aqueous layer is extracted three times with ethyl acetate, the amount of which is 20 ml each time. The organic phases are combined, dried with sodium sulfate, filtered and the solvent is distilled off under reduced pressure. The remaining acid is dissolved in 3-1 h of methanol. A 1jB ml methanol solution of sodium hydroxide concentration mmol / ml Methanol is distilled into the solution at O C under reduced pressure. The residue is suspended in petroleum 1-th ether, which is then removed.
    20
    25
    when decanting. 679.2 mg of compound are obtained, yield 82%,
    By the method of thin-layer chromatography R, .0.46 (benzene 5 dioxane and acetic acid in the ratio 20: 20: 1). Н-Ш - Ш (deuteronmethanol, ff 0.9 (tj ЗН, С.,); 5.3 (Е, Н-5 5 isomer); 5.86 (нН-55 Е-isomer); 6.7-7.3 (t, IHj aromatic protons,); 7.5-8515 (t, 2H5 aromatic proton-,).
    Similarly, the following compounds can be obtained:
    2s3.4,, 17,18, i9,20-heptanor-1, 5-inter-ha-fentchlen-1 3, 4-didegid, ro-1 5 fluoro-1 6 (3: tor-phenoxy) - dicyclo-hexestamine salt,, 46 and Oj44 (benzol; dioxane and acetic acid 20: 10: 1); ,
    2,3,4,17,18,19,20-heptakor 1,5-nter-t-phenylene-13 4-didehydro-16-crotyloxy-rgl, tetrabutylammonium salt,, 49 and 0.43 (benzene, dioxane and vinegar: acid 20: 10: 1);
    2,3,4,17,18,19,20-heptanor-1,5-inter-1gphenylene-13,14-didehydro-16-methoxyethoxy-PdTt-tris-hydroxymethylamino-methane salt, Rf.0,56 and 0.53 (benzene, dioxane and acetic acid 20: 20: 1);
    2,3,4,18,19,20-heptanor-1-inter-t-phenylene-13,14-didehydro-16- (2,2,2 t-ortho-ethoxy) -PgI /) - pyrrolidine salt, and 0.55 (benzene, dioxane and acetic acid 20:20 :);
    1,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-16- (2-butyn-1-yl-oxy) -P21-morpholine- wah salt,, 51 and 0.50 (benzene, dioxane and acetic acid 20: 10: 1)
    2,3,4-trinor-1,5-inter-p phenylene 5-fluoro-13,4-dihydro-PgI -triethanolamine salt,, 50, and 0.48 (benzene, dioxane, and acetic acid 20:10: one);
    2,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-5-fluoro-16- (3-tri-fluoromethyl-phenoxy) -PgI calcium salt,, 44 and 0.37 (benzene, dioxane and acetic acid 20: 10: 1);
    2,3,4-trinor-1,5-inter-t-phenylene 13,14,17,18-bis-didehydro-20-methyl-6a-carbaprostaglandin-1 sodium salt, and 0.58 (benzene, dioxane and acetic acid 20: 20: 1);
    2,3,4,17,18,19 ,, 20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-15-crotyloxy-PgIo-yl) glycin sodium salt, 39 (benzene, dioxane and acetic acid 20: 10: 1),
    PRI me R 26. Preparation of 2,3,4, 17,18,19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-16-methoxy-ethoxy C-PgI5- carbethoxymethylamide.
    The experiment was carried out as in Example 15, however, the mixed anhydride obtained from 2,3,4,17,18,19,20 heptanor-1,5-inter-t-phenylene-13,14-di-hydro-1 b -methoxy-ethoxy-PgI-2 and isobutyl chloroacetic acid ester, reacts with 714.5 mg (b, 93 mmo GLYCINETH1010 thiether. 2.826 g of compound are obtained, yield 91.3%.
    On thin layer chromatography E |, 0549 (benzene, dioxane and acetic acid
    . „.„, (ЗН, СНз).
    acid 20: 20: 1
    Similarly, the following compounds can be obtained:
    2,3,4-trinor-155-inter- (4-chloro-1,3-phenylene) -13,14-didehydro-P515-amide, 52 and 0.50 (ethyl acetate);

    O

    0
    five

    0;
    2,3,4-trinor-1,5-inter-4-fluoro-1,3-phenylene), 14-didehydro-20-ethyl-PgI, .- diisopropyl amide, 63 and 0.50 (ethyl acetate);
    2, 3,4-trinor-1,5-inter- (6-acetamido-1,3-phenylene) -13,14-didehydro-20-ethyl-PgI-methyl benzyl amide, Rf 0.37 and 0 34 (ethyl acetate);
    2,3,4,17,18,19,20-heptanor-1, 5-inter-ha-phenylene-16- (3-chlorophenoxy) - Pgl-pyrrolidine, 55 (ethyl acetate);
    2,3,4,17,18,19,20-heptanor-1,5-inter-In-phenylen-l6-covery-PgI -, - anilide,, 58 and 0.52 (dichloromethane and acetone 1: 1) ;
    2,3,4,17,18,19,20-heptanor-1-inter-t-phenylene-13,14-didehydro-16-meth-oxyethoxy-PgIl-l-hydroxy-2-acetyl-amide, , IB and 0.11 (ethyl acetate).
    Example 27: Preparation of 2-dek: arboxy-2-cyano-2, 3,4-trinor-1,5-inter-t-phenidene-13,14-didehydro-16-methoxyethoxy-PgI .
    The experiment was carried out analogously to example 16, however, 680 mg (169 mmol) of 2,3,4-trinor-1, 5-inter-1p-phenylene-13,14-didehydro-16-methoxyethoxy-Pglo- amide. 413.75 g of compound are obtained, yield 63.7%,
    But thin layer chromatography


    50
    five
    60 and 0.55 (ethyl acetate)
     H-No. 1B (CDCl,): 7.2-8.25 (t, 4H, aromatic H); 5.9-5.27 (S or m H-5, E and Z isomers); 3.45-4.3 (and, 9H, GR),
    EXAMPLE 28, Preparation of 2-de-carboxy-2- (1H-tetrazol-5-yl) -2.3, 4,17,18519,20-heptanor-16-crotyloxy-PgI.
    The experiment is carried out analogously to the example
    17, but 2,3,4,17,18,19,20-heptanor-1,5-inter-t-phenylene-1b-crotyloxy-PgIj-amide is taken as the starting material. 2.38 g of compound are obtained, yield 60.3%.
    By the method of thin layer chromatography, 04 (benzyl, dioxane, and acetic acid 20: 10: 1).
    Er and mep 29. Preparation of 2,3,4-trinor-1,5-inter-y-phenylene-13,14-didehydro-20-ethyl-Pe17-methanesulfon-amide.
    The experiment is carried out analogously to the example
    18, but 2,3,4-trinor-1, 3-inter-t-phenylene-13,14-didegdro-20-ethyl-P512-me
    solid ether. 2, .5 g of compound are obtained. 71% yield
    According to the method of thin layer chromatography Rr-O, (benzene, dioxane and acetic acid 20: 10: 1),
     (ShS1z, f): 7p25-8.3 (w, 4H, aromatic H); 5, 2-5.9 (S, H-5,. E and Z isomers); 3.0 (S, ZN, CHO; 0.87 (t, ZN, SI,) /
    Example 30: Preparation of 3-pheno-hydroxyacetonyl phosphorane
    The experiment was carried out analogously to example 8. However, 23.5 g (0.25 mol of phenol instead of p-chlorophenol were used. 93.27 g (91%) of compound was obtained; boiling point was 108-1 ° C; Coefficient, 45 (acetone and ethyl acetate in the ratio of 3: 1).
    EXAMPLE 31, Preparation of 3-ptyloxy-acetonyl-phosphorane,
    Analogously to Example 8, however, 22.0 g (0.25 mol) of pentyl alcohol is used instead of t-hturphenol.
    In this way, 86.9 g (86%) of the compound, coefficient B, are obtained (acetone and ethyl acetate 5: 2),
    Example 32. Preparation of triphenyl- (3-carbox-methylben-eyl) phosphonium bromide
    Analogously to Example 6, however, 13.2 g (57.7 mmol) of 3- (1-bromo-ethyl) -benzoic acid are used instead of 3-bromomethyl-6-nr1-trobenzoic acid.
    In this way, 20.1 g (71% of compound, coefficient P.0.7 are obtained (methanol, water and acetic acid in the ratio 5: 5: 1).
    PRI me R 33, Obtaining 4,5,6o / p-Hexahydro-2-oxo-4 / e-phenoxy-3-ox-1-trans-butenyl (5 s) - (p-fe nilbenzoyloxy) -2H-cyclopenta b furan.
    As in Example 11, however, 22 g (53.9 mmol) of 3-phenoxyacetonyl-phosphorane are used as phosphorane.
    In this way, 19.4 g (78% of compound are obtained. The coefficient P, (ethyl acetate and petroleum ether with a ratio of 2: 1),
    Example 34, Preparation of 3j3c / fl f 4,5,6,6s. (L-hexahydro-2-oxo 4 / b pentyloxy-3-oxo-1 trans-butenesh- (5) - (p Fensch1-benzyloxy) -2H zkklopenta b furan.
    As in Example 11. However, 21.77 g (53.9 mmol) 3 was used. 20
    25
    ten
    ). |
    thirty
    35
    45
    50
    55
    pentyloxyacetonyl phosphorane as phosphorane.
    In this way, 18.7 g (76%) of compound are obtained, the ratio, 6 (ethyl acetate and petroleum ether 1: 1),
    PRI me R 35. Getting 3,3 o / L 4, 5 s6 5bo | y-hexahydro-2-hydroxy-4 - (33-hydroxy-4-phenoxy-1-trans-1-butynyl) -5o-hydroxy-2H-cyclopentaG1 furan.
    Analogously to example 13, however, 46.2 g of 0.1 mol) 3.30 (4.5,. B5bo / 5-hexahydro-2-oxo-4 5- (phenoxy-) 3-oxo-1 -trans- butenyl) - (p-phenylbenzyloxy) -2P-cyclopenta b furan.
    Obtain 8.2 g of compound, a ratio of 3 (ethyl acetate).
    Example 36, Preparation of 4 J 5, 6, 6o (l-hexahydro-2-hydroxy-4 / 5- (35-hydroxy-4-pentyloxy-1-trans-butenyl) -5 a-hydroxy-2H-piclopent Gy furana.
    In analogy to Example 13, however, 45.6 g 3, 301.44, 5, 6, 6 o fl-hex-hydro-2-oco-4 | fi (pentyloxy-3-ox- with 1-transbutenyl) -5o ( - (p-phenylbenzyl-oxy) -2H-cyclopenta b furan.
    8 ,, 6 g of compound are obtained, the coefficient R is 0.35 (ethyl acetate).
    PRI me R 37, Preparation of 2,3,4, 1 7 j 1 8 J, 1 9 5 20-heptanor-1, 5-inter-t-feni.pen-13,1 4-didehydro 1 6-phenoxy-PCP methyl ester.
    Analogously to Example 4, however, 6.08 g (0.02 mol) 3 ,, 3 (X, d4.5, 6, 6 o B-hexahydro-2-hydroxy-4 / g (P- g1adroxy-4-phenoxy-I-trans-1-butynyl) -5c / -hydroxy-2H-cyclopentaGo furan instead of 3.3c / p 4,5,6,6c // 1-hexahydro-2-hydroxy-4 / | - (35-hydroxy-4-methoxyethoxy-1-butynyl) -5 -hydroxy-2H-cyclopenta in furan.
    Get 5 ,, 3 g (61%) of the compound ratio, 55 (benzene, dioxane and acetic acid 20: 10: 1),
    PRI me R 38, Preparation of 2,3,4, 1 7 ,, 18, 1 9 5 20-heptanor-1, 5-inter-gp-phenylene-I3 514-didehydro-16-pentyloxy POP2 „ {-methyl ester.
    Analogously to example 14, however, 5.76 g (0.02 mol) of 3 3; / s4.5, 6 ,, 6c (/ 5-hexahydro-3-hydroxy-4 / s- (3S-hydroxy-4- pentyloxy-1-trans-butynyl / 5o; -hydroxy-2H-cie; lopentaG j j furan instead of 3.3 (), 5, 6, 6 o p-hexa-hydro-2-hydroxy-4, b- ( 33-hydroxy-4-
    methoxyethoxy- -butnyl) -5c -hydroxy-2H-cyclopenta b furan.
    5.23 g are obtained (62% of compound ratio, 6 (benzene, dioxane and acetic acid 20: 10: 1).
    PRI me R 39. Preparation of 2,3,4, 17,18,19,20-heptanor-1, 3-inter-n-phenyl-5-methyl-13,14-didehydro-16- (methoxyethoxy ) -PGF. - methyl ester.
    As in Example 14, however, 25.5 g (0.06 mol) of triphenyl- (3-carboxymethylbenzyl) -phosphonium bromide is used instead of methyl three-phenyl- (3-carboxybenzyl) -phosphonium.
    5.3 g (62%) of the compound are obtained, a ratio of 26 (ethyl acetate and benzene in a ratio of 3: 1).
    EXAMPLE 40 Preparation of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodo-13 14-dehydro-15-methyl-20-ethyl-PC1, -methyl ester .
    As in Example 19, however, 2.26 g (5.13 mmol) of 2,3,4-trinor-1, 5-inter-p1-phenylene-1 3, 14-didehydro-15-methyl-20-ethyl -ROG of g-methyl ester instead of 2,3,4-three nor-1,5-inter-sh-phenylene-13,14,18,19-bis-di-hydro-20-el-PGF-methyl ester .
    In this way, 2.8 g of compound are obtained, the coefficient Rj is 0.6 and 0.62 (ethyl acetate and benzene in a ratio of 3: 1).
    EXAMPLE 41 Preparation of 2,3,4-trinor-1, 5-inter-t-phenylene-5-iodo-13, 14,18,19-bis-dihydro-16-fluoro-20-ethyl-PGI, - methyl ester.
    As in Example 19, however, 2.26 g (5.13 mmol) of 2,3,4-trinor-1,5-inter-t-phenylene-13,14, 18,19-bis-di-dihydro-16- fluorine-20-ethyl-ROG-methyl ester instead of 2, 3,4-trinor-1, 5-inter-tri-phenylene-13,14,18,19-bis-di-hydro-20-ethyl-PGF 1 - methyl ester about.
    3.05 g of compound are obtained, a ratio of 61 and 0.59 (ethyl acetate and benzene 3: 1).
    Example42. Getting 2,3,4, 17,18,19,20-heptanor-1,5-inter-t-phenylene-5-methyl-5-iodine-13,14-didehydro-1 6- (methoxyethioxy) -PGI, - methyl ester.
    As in Example 19, however, 2.20 g (5.13 mmol), 2.3.4, 17.18, 19.20-heptanor-1.5-inter- (r5



    five
    about 5
    phenylene-5-methyl-13,14-didehydro-16- (methoxyethoxy-PGr, -methyl it ester instead of 2,3,4-trinor-1, 5-inter-1n-phenylene- 13,14,18, 19-bis-dihydro-20-ethyl-POP.-methyl ester.
    3.0 g of compound are obtained, a ratio of 0.63 and 0.59 (ethyl acetate and benzene 3: 1).
    EXAMPLE 43 Preparation of 2,3,4, 17,18,19-heptanor-1,5-inter-t-phenylen-13,14-didehydro-1b-phenoxy-PGI - methyl ester .
    Analogously to Example 22, however, 479 ml (0.85 mmol) 2,3,4, 17,18,19-heptanor-1,5-inter-t-phenylene-5-iodo-13,14-didehydro are used. -1b-phenoxy-PGI, methyl ester instead of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodo-13,14-dihydro-15-methyl-16-ftorop 20-ethyl-PGI, methyl ester.
    Obtain 319 mg (86%) of the compound, a ratio of 56 (benzene and ethyl acetate in the ratio 3: 1, twice).
    Example 44. Preparation of 2,3,4, 17,18,19-heptanor-1,5-ypter-t-phenylene-13,14-didehydro-16 (pentyloxy) - PGF i.j-methyl ester. Analogously to example 22, however, 465 mg (0.85 mmol) 2,3,4, 17,18,1 9-heptanor-1,5-inter-1p-phenylene-5-iodo-13,14- didehydro-16-pentyloxy-PGI-methyl ester instead of 2,3,4-trinor-1,5-inter-haphenylene-5-iodo-13,14-didehydro-15-methyl-16- fluoro-20-ethyl-P01, methyl ester.
    300.5 mg (84%) of the compound are obtained, a ratio of 3.0.57 (benzene and ethyl acetate 3: 1, twice).
    EXAMPLE 45 Preparation of 2,3,4-trinor-1,5-inter- (6-acetylamino-1,3-phenylene) -13,14-didehydro-20-ethyl-PGI l-methyl complex the ether.
    As in Example 22, however, 516 mg (0.85 mmol) of 2,3,4-trinor-1, 5-inter- (6-acetylamino) -1, 3-phenylene-5-iodo-13,14-didehydro - 20-ethyl-P01, -methyl ester instead of 2,3,4-trinor-1,5-inter-h1-phenylene-5-iodo-13,14-didehydro-15-methyl-6-otor; 20-ethyl-PGI methyl ester.
    348.2 mg (85%) of compound are obtained, a ratio of 22 (dichloromethane and acetone in a 2: 1 ratio).
    PRI me R A6. Preparation 2, trinor-1,5-inter-t-phenylene-13,14-dihydro-PGI-aniline,
    Analogously to example 15, however, 253,4-trinor-1,5-inter-t-phenylene-13 „14-dihydro-PGI mixed anhydride is converted to chloroisobutyl formate with 0.65 g (6.93 mmol) of aniline ..
    3.5 g (92%) of compound are obtained, a ratio of 38 and 0.552 (dichloromethane and acetone in a 1: 1 ratio),
    EXAMPLE 47, Preparation of 2,3,4-trinor-1,5-inter-t-phenylene-13,4-di dehydro-15-methyl-20-ethyl-PC1. tmeti-
    W
    Lovoy ester.
    As in Example 22, however, 482.8 mg (0.85 mmol) 2, 3,4-trinor-1,5-inter-t-phenylene-5-iodo-13,14-didehydro-15-methyl-20 are used. -ethyl PGI, -methyl ester instead of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodo-13,14-didehydro-15-methyl-16-fluoro-20-ethyl -PC1-methyl ester.
    323.1 mg (86%) of the compound, a ratio, and 0.67 (acetone and dichloroethane 1: 2) are obtained.
    PRI me R 48. Preparation of 2,3, 4, 17,18,19,20-heptanor-1, 5 — inter-t-phenylene-13,14-didehydro-16-methoxyethoxy- PGI-cyclopropyl-methylamide.
    Analogously to example 26, however, 492 mg (6.93 mmol) of cyclopropylmethylamine are used instead of glycine ethyl ester.
    2.8 g (90%) of the compound are obtained; the coefficient is 62 and 0.55 (ethyl acetate).
    PRI me R 49, Getting 2,3,4. 17,18,19-heptanor-1 5,5-inter-t-phenylene-5-iodo-13,14-didegndro-J 6-phenoxy-PGI, -methyl ester.
    Analogously to Example 9, however, 2.24 g (5.13 mmol) 2,3,4sl7j 18,19,20-heptanor-1,5-inter-t-phenylene-13,14-didehydro-6- fecox: i-P01 methyl ester instead of 2,3 4-trinor-1,5-inter-ha-phenylene-13,14, 18,19-bic-didehydro-20-ethyl-PGF, - methyl ester.
    2.92 g of compound are obtained, the ratio Rj.0.53 and 0.55 (benzene and ethyl acetate 1: 3).
    EXAMPLE 50 Preparation of 2,3,4, 17,18,1 9-heptanor-1, 5-inter-t-phenylene-5-iodo-13,14-didehydro-16-pentyl- hydroxy-PGI-methyl ester
    Analogously to example 19, however, 2.16 (5, 13 mmol) 2,3,4,17,
    1 8 p 20-heg1-1-1, 5-inter-p1-phenylene-13,14-didehydro b-pentyloxy-PGF methyl ester instead of 2,3,4-trinor-15 5 inter-t-phenylene-13 145185 9-bis-didehydro-20-ethyl-RPG methyl ester.
    2.8 g of compound are obtained, the coefficient Rj, 0.54 and 0.56 (benzene and ethyladetate 1: 3).
    P r and m-e p 51. Preparation of 2,3,4-trinor-1, 5 inter-1p-phenylene-5-iodo-1 3 14-didehydro-17,18-dehydro-20-ethyl-PGI-methyl ester.
    Analogously to Example 19j, however, 2.23 g (5.13 mmol) of 2,3,4-trinor-1 55-inter-1G1-phenylene 5 13514-didehydro-17,8-dehydro-20-ethyl-PGFj-methyl complex ether instead of 2,3,4-trinor-1, 5-inter-gt1-phenylene-13 514 J18,19-bis-didehydro-20-3T 4ji-PGFjjj-methyl ester
    Compound g, a ratio of 66 and 0.6 (ethyl acetate and benzene) are obtained.
    Example52. Preparation of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodo-1 3, 1 4 - didehydro-1 6-fluoro-i 7, 18-dehydro-20-ethyl-PGI. , - methyl ester.,
    As in Example 19, however, g (5.13 mmol) 2,3,4-trinor-15 5-inter-t-phenylene-13,14-didehydro-1 6-fluoro-I 7, 1 8-dehydro-20 are used. - ethyl-PGF.-methyl ester instead of 25354-trinor-1 55-inter-1g-phenylene-1 3, 14 .. 1 8, 1 9-bis-dihydro-20-ethyl-PGF-methyl ester.
    Obtain 3.0 g of compound, a ratio and 0; 54 (ethyl acetate and Beisol).
    PRI imper 53. Obtaining 2,3,4-tricor-1,5-inter-p-phenylene-13,14, 1 B, I9-bis-didehydro-1b-fluoro-20-ztil-PGI, - methyl ester.
    Analogously to Example 22, however, 482.8 mg (0.85 mmol) 2, 3, 4-trinor-1, 5-inter-y-phenylene-5-iodine 135145185 9-bis-didehydro-16 (fluorine 20-ethyl) -PGI, -methyl ester instead of 2, 354-trinor-1,5-inter-phenylene-5-iodo-135) 4-didehydro-15-methyl-16-ftorop-20-ethyl -PGI, -metsh-juvogo ester.
    Obtain 323.5 mg (86.5%) of Neni, a total of 63, and 0.64 (acetone and dichloroethane I2).
    PRI me R 54 o Obtaining 2,354, 17,18, i 9, 20-heptanor-1, 5-inter-gg. Fe31g
    Nilen-5-methyl-3,14-didehydro-I6-methoxyethoxy-PGIj-methyl ester.
    In analogy to Example 22, however, 471.8 mg (0.85 mmol) 2,3,4, 17,18,1 9,20-heptanor-1, 5-inter-gp-phenylene-5-methyl-5 iodine-13,14-didehydro-1b-methoxyethoxy-PC, methyl ester instead of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodine-13,14-dide hydro -1 5-methyl-16-fluoro-20-ethyl-PC11, - methyl ester.
    309 mg (85%) of the compound are obtained, a ratio of 62 and 0.6 (acetone and dichloroethane 1: 2).
    EXAMPLE 55 Preparation of 2,3,4-trinor-1,5-inter-t-phenylene-13,14-didehydro-17,18-dehydro-20-metsh-PGIj-methyl ester.
    As in Example 22, however, 466.6 mg (0.85 mmol) of 2,3,4-trinor-1, 5-inter-p1-phenylene-5-iodo-1 3, 14-didehydro-17,8- dehydro-20-ethyl-PGI-methyl ester instead of 2,3,4-trinor-1,5-inter-ha-phenylene-5-iodo-13,14-didehydro-15-methyl-16-fluoro-20- ethyl P01, methyl ester.
    313 mg (87%) of the compound are obtained, a ratio of 63 and 0.66 (acetone and dichloroethane 1: 2).
    Example 56, Preparation of 2,3,4-trinor-1,5-inter-t-phenylene-13,14-didehydro-1 6-fluoro-17,18-dehydro-20-ethyl-PGI methyl ester.
    The operation is carried out as in Example 22, however 482.8 mg (0.85 mmol) 2,3, 4-trinor-1,5-inter-t-phenylene-5-iodo-13,14-didehydro-16-fluorine are used. -17,18-dehyd-po-20-ethyl-PGI, -methyl ester instead of 2,3,4-trinor-1,5-inter-t-phenylene-5-iodo-13,14-didehydro-15- methyl-16-fluorop-20-ethyl-PGI, methyl ester.
    323 mg of C86%) compound, a ratio of 52 and 0.55 (acetone and dichloroethane 1: 2) are obtained.
    Unexpectedly, it has been found that the new 2,3,4-trinor-1,5-inter-t-phenylene-PgI derivatives corresponding to the invention have significant advantages over the known Pgl analogs of this structure. The novel compounds of general formula I have a more effective cytosagg action, the duration of their effect is higher on an15
    20
    25
    281432
    The speckle model of Speckeres exhibits a reciprocal effect for 5 hours after intravenous infusion. Compounds of the general formula I are used as test of 1x compounds, where A means - COOKa, R, - hydrogen and R, -n - hexyl.
    In tab. Figure 1 shows the required doses to provide a significant cytoprotective effect depending on the K1 value.
    From tab. 1, it follows that the novel compounds corresponding to the invention of 1B have a significantly stronger cytosopharyngeal effect in comparison with the known analogues.
    In cats, Pgl at an intravenous dosage of 10 mg / kg body weight is known to cause a short-term decrease in blood pressure of about 1.5 min to 6.6 kPa / 50 mmHg, st. Duration of action is easy to determine with the aid of measuring instruments. Taking into account that the novel compounds of general formula I according to the invention lower blood pressure more weakly than Pgl, intravenous doses are taken up to 100 and g / kg body weight. A period of time was determined during which the blood pressure level of the cats returned to its original value.
    In tab. 2 shows the results of 35 of these measurements in minutes.
    As experimental compounds of the general formula (l), compounds in which A is -COONa, R is hydrogen are used.
    40 Table. 2 shows the meanings of the symbols R and R,.
    Such an increase in the period of influence could be proved also in e5 experiments on a living organism on an antiaggregative model,
    The antiaggregative effect of the compounds of general formula (I) is approximately analogous to that of prostaglandin. To illustrate this, the following shows the 1C values measured for human PRP and (, the values measured for guinea pig PR for some compounds of general formula (l) (in pg / ml): 2,3,4-trinor-1 , 5-inter-t-phenylene-13,14-didehydro-20-methyl-l -) and 6; 2,3,4-trinor-1,5-inter-i-phenylene-13,14,17,18-bis-dide30
    0
    hydro-20-methyl-P-1 sodium salt, 6 and 8.2; 2,3,4-trinor-1,5-inter- (4-fluoro-1,3-phenylene) -13,14-didehydro-20-methyl-P51 g sodium salt; 6.2 and 10.
    The stability of the proposed compounds is also higher. In the case of using compound c), there is almost no decomposition; This is of particular importance, since compounds of the general formula (l) can be introduced into a physiological saline solution, for example, in contrast to prostacyclin, which due to alkaline reaction can cause angiitis. The hemodynamic effect of the compounds of general formula (l) is significantly weaker than the same effect exerted by prostacyclin;
    The biological activity of the proposed compounds is close to the biological activity of prostacyclin. At the same time, these compounds have a significantly greater stability, as well as days stabilized with respect to the so-called p-Oxidation and 15- PgDH metabolisms, which cause the rapid decomposition of biologically active substances.
    The proposed compounds of general formula (l) possess a number of valuable pharmacological properties. They are able to slow down the formation of clusters of blood plates and the release of sour
    Doses, mg / kg body weight, causing a tangible protective effect
    600 Structural equivalent
    25
    25
    125
    five
    1 (30
    gastric juice, reduce the undesirable effects on the gastrointestinal tract of pharmaceutical preparations containing prostaglandins synthetase, have a calming effect on asthmatic bronchial spasms and thus facilitate breathing.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    2,3,4-trinor-1,5-inter-t-phenyleneprostacycline derivatives
    mules
    R
    -BUT
    where A is COONa; R. BUT
    Rj OH
    CHC-CH-RI
    n-hexyl, n-heptyl, 2-methyl-4-pentyl-1-yl, 6-methyl-5-hepten-1-yl, n-octyl, n-pentyl, methoxyethoxymeth w, ethoxymethyl, hex-5 -enoxymethyl, pent-4-enmethyl, phenoxymethyl, pentyloxymethyl, chlorphenoxymethyl j fluorine, chlorine, methoxy, cyano or methyl group; hydrogen, fluorine, chlorine, cyano. nitro, methoxy or acetylamino, possessing cytoprotective properties.
    Table 1
    R, Kz 35
    n-Hexyl .4
    p-heptyl 10
    p-Octyl6
    p-heptylI2
    p-Octyl16
    2-Methyl-4-pentyl-1-yl10
    6-Methyl-5-hepten-1-yl16
    -CH-0-CH-SNG-O-CH319
    -CH -O-CH -C, 16
    38283D36
    table 2
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    同族专利:
    公开号 | 公开日
    EP0107693B1|1988-07-27|
    US4638002A|1987-01-20|
    JPS59500767A|1984-05-04|
    DE3377491D1|1988-09-01|
    WO1983004021A1|1983-11-24|
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    IL68680A|1986-07-31|
    EP0107693A1|1984-05-09|
    AT382372B|1987-02-25|
    ATA902383A|1986-07-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE795200A|1972-05-10|1973-08-09|Ciba Geigy|NEW OXABICYCLOOCTANES AND THEIR PREPARATION METHODS|
    SU944502A3|1978-01-31|1982-07-15|Куреха Кагаку Когио Кабусики Кайся |Process for producing derivatives of prostaglandin|
    HU179001B|1978-05-29|1982-08-28|Chinoin Gyogyszer Es Vegyeszet|Process for preparing 5-halo-6,9alpha-oxido-prostaglandin derivatives|
    JPS5931510B2|1979-09-03|1984-08-02|Toray Industries|
    CA1201712A|1980-02-28|1986-03-11|Paul A. Aristoff|Carbacyclin analogs|
    DE3029984C2|1980-08-08|1983-12-15|Grünenthal GmbH, 5190 Stolberg|2-Oxabicyclo [3.3.0] octane derivatives and medicinal products containing them|
    US4349689A|1980-12-22|1982-09-14|The Upjohn Company|Methano carbacyclin analogs|
    CH648556A5|1981-03-11|1985-03-29|Hoffmann La Roche|FLUORPROSTACYCLINE.|
    IL65387D0|1981-04-14|1982-05-31|Chinoin Gyogyszer Es Vegyeszet|2,3,4-trinor-m-inter-phenylene-prostaglandin derivatives and a process for the preparation thereof|
    HU188559B|1981-12-01|1986-04-28|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu|Process for preparing new inter-m-phenylene-prostacyclin derivatives|DE3408699A1|1984-03-08|1985-09-12|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3428266A1|1984-07-27|1986-01-30|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    US5312958A|1992-01-31|1994-05-17|Takeda Chemical Industries, Ltd.|Process for producing 4-bromomethylbiphenyl compounds|
    WO1994007838A1|1992-10-05|1994-04-14|Teijin Limited|ISOCARBACYCLIN WITH MODIFIED α-CHAIN AND PROCESS FOR PRODUCING THE SAME|
    DE69822665T2|1997-11-14|2005-02-17|United Therapeutics Corp.|USE OF 9-DESOXY-2 ', 9-ALPHA-METHANO-3-OXA-4,5,6-TRINOR-3,7--13,14-DIHYDROPROSTAGLANDIN-F1 FOR TREATMENT OF PERIPHERAL VASCULAR DISEASES|
    KR20020022798A|1999-08-13|2002-03-27|후미에 사토|Prostaglandin Derivatives|
    HU231203B1|2011-12-21|2021-10-28|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Zrt|Novel process for the preparation of travoprost|
    MX2016006325A|2013-11-15|2016-12-02|Wistar Inst|Ebna1 inhibitors and their method of use.|
    KR20180003615A|2015-05-14|2018-01-09|더 위스타 인스티튜트 오브 아나토미 앤드 바이올로지|EBNA1 inhibitors and methods for their use|
    US11242338B2|2018-05-17|2022-02-08|The Wistar Institute|EBNA1 inhibitor crystalline forms, and methods of preparing and using same|
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    申请号 | 申请日 | 专利标题
    HU821421A|HU190007B|1982-05-06|1982-05-06|Process for producing new aromatic prostacylin analogues|
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