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    • 专利摘要:
    The method of obtaining the derivatives of 9-chloroprostane of the general formula L where C1 is in the 9-position can be Oi, - or Ib-configuration; R, residue where R 2 is hydrogen, lower alkyl, or R residue NHRj, where Rg is hydrogen Or the residue is “izd of aliphatic carboxylic acid or sulfonic acid with 1-4 carbon atoms, A is the group -CHp-CHn-cisCHH-; In the group - CHL-CHL trans CHN CH-; W is a free or protected by a tetragidropyran-2-yl group hydroxymethylene group, or a free or protected tetrahydropyran CHj 2-ILNA group -ft- - G is a group, and the OH group can have the CO - or p-configuration; 3) and form together a carbon-carbon bond or D - Alkylene g supp with 1-6 carbon atoms, possibly substituted by methyl groups or fluorine, and B - oxygen; R4 is a free or protected tetrahydropyran-2-yl, hydroxy group; d RS is lower alkyl, phenyl, M S chlorophenyl, or their salts if RI is a hydroxyl group, it differs with Ausch and also with the fact that the compound has the general form of shl To K) O5 where is the group can be OSI or configuration o : RoBfB, E sd, and RC have the indicated values; when it is free, the hydroxy groups in R and W are protected; X1Ryu: through the non-daily sulfonic acid ester with chloride, total RfiCl, where R is lytic, sodium, potassium, or with carbon tetrachloride / triphenylphosphine a and in the obtained target products, if necessary, be released in any sequence lnosti protected hydroxy and / or eterifytsiruyut free hydroxy and / or Guidry
    公开号:SU1026652A3
    申请号:SU803221450
    申请日:1980-12-09
    公开日:1983-06-30
    发明作者:Скубалла Вернер；Радюхель Бернд；Форбрюгген Хельмут；Эльгер Вальтер；Логе Олаф；Шиллингер Эккехард
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    double bonds, etherify and / or clarify the esterified carboxyl group, and / or esterify the free carboxyl group, and / or convert the free carboxyl group to amide, after which the target products are isolated in free form or in the form of salts. .
    The invention relates to a method for producing novel derivatives of the analogue of natural prostaglandins, namely, derivatives of 9-chloroprostane of the general formula B-W-D-B-Bj in the 9-position may be of a C-C or L-configuration; OR2 residue / where H is hydrogen, lower alkyl, or R is NHR residue, where R is hydrogen or a residue of a lower aliphatic carboxylic acid or sulfonic acid with 1-4 carbon atoms; the group —CH —CH — or cis CH-CH-; group - CH- -CH-, trans CH CH-; a free or protected tetrahydropyran-2-yl group is a hydroxymethylene group, or a free or protected tetrahydropyran is a 2-yl group - c - pa, and the OH group may be in the - or p-configuration; jointly form a carbon-carbon bond or D - Alkylene group with 1-6 carbon atoms, possibly substituted by methyl groups or fluorine, and E - oxygen free or protected oxyl group; lower alkyl, phenyl, m-chloro-phenyl, or their salts if V. is a hydroxyl group with pharmacological data. Semisynthetic analogs of natural prostaglandins F and E, obtained by multistage synthesis according to Wittig i, are known. There is also known a method of producing sulfonic acid esters by esterifying hydroxyl compounds with alkylsulfonyl chloride or arylsulfonyl chloride 2. The purpose of the invention is to obtain new derivatives of 9-chloroprosta, possessing pharmacological activity. The goal is achieved by the fact that according to the method, consisting in the fact that a compound of the general formula where the OH group can have o (, - or / 5 is a configuration; Ri (, B, D, E and Rj - have the indicated values while the free hydroxy groups in and W. are protected, chlorinated through an intermediate sulfonic ester with a chloride of the general formula where R is lithium, sodium, potassium, or with carbon tetrachloride / triphenylphosphine and the obtained target products, if necessary, sequences protected hydroxy groups and / or whether free hydroxy groups are esterified, and / or double bonds are hydrogenated, esterified carboxyl group is esterified and / or washed, and / or the free carboxyl group is converted to amide, after which the target products are isolated in free form or as salts., Derivatives 9 -chloroprostane have a different specificity of action, have a greater activity and duration of action than their natural counterparts. New analogues of prostaglandins have a strong luteolytic effect, i.e. significantly lower dosages are required to release luteolysis. , To remove miscarriages, especially after oral administration, much smaller amounts of blood are also required.
    The number of new analogues of prostaglan dinov compared to natural prostaglandins.
    When registering isotonic contractions of the rat uterus under anesthesia and the isolated rat uterus, it appears that the effect of the proposed substance is much more effective and longer than the action of natural prostaglandins.
    New prostaglandin derivatives are used by single intestinal or parenteral administration to induce menstruation or abort pregnancy, to synchronize the sexual cycle in female mammals (rabbits, cattle, horses, pigs, etc.), to dilate the cervix in preparation for diagnostic or therapeutic interventions.
    The effect of the proposed substances is also observed when examining other organs with smooth muscles, such as, for example, in the ileum of the guinea pig or on the isolated trachea of the rabbit, where less stimulation is observed than under the action of natural prostaglandins. Substances have a. Also bronchospasmolytic effect, in addition, they reduce the swelling of the nasal mucosa.
    The active substances inhibit the secretion of gastric acid, exhibit a cytoprotective and healing sound effect, and thus counteract the undesirable consequences of nonsteroidal inflammatory substances.
    Some compounds reduce arterial blood pressure, regulate heart rhythm and inhibit plaque aggregation.
    For medical use, the active substances may be formulated for inhalation, oral parenteral or topical administration.
    For inhalations, it is advisable to use aerosol solutions. For oral administration, for example, tablets, dragees or capsules for parenteral — sterile injectable aqueous or oily solutions, for the vaginal tongue, etc. are used.
    The active substances in combination with the known galenic preparations 1 and and ordinary and auxiliary substances can be used, for example, to obtain preparations for removing miscarriages, regulating the cycle, initiating labor or treating hypotension, while the content of the active compound is 0.01-50 mg.
    Example. Methyl complex, esters (52,13E) - (9K, 11K, 15K) -9-chlor11, 15-dihydroxy-16-phenoxy-17.18, 19,20-tetranor-30.30-prostadiene acid. V
    To a solution of 5.72 g of methyl ester (5Z, 13E) - (9S, llR, 15R) -9-hydroxy-11, 15-bis- (tetrahydropyran2-yloxy) -16-phenoxy-17,18,19,20 tetranor-5 , 13-prostadiene acid, obtained from the corresponding acid in methylene chloride with O, 5 M ethereal solution of diazomethane at 17 ml of pyridine, is added at 0 ° C with 3.8 g of c-tolu-5-sulfonic acid chloride, stirred for 16 hours at ice temperature Noah bath and 48 „h at room temperature. Then mixed with 15 ml of water, stirring, for 2.5 hours at room temperature, mixed with 1 l of ether,
    0 shaken in turn with water, 5% sulfuric acid, 5% sodium bicarbonate solution and water. Dry over magnesium sulfate and evaporate in vacuo. At the same time, 6.56 g are obtained.
    5 9-tosylate as a colorless oil. IR spectrum, 2950, 2875, 1733, 1600, 1590, 1496, 1365, 1240.974.
    A solution of 3.6 g of 9-tosylate in 150 ml of dimethylformamide is stirred for 4 hours with
    0 2.1 g of lithium chloride at 60 C in an argon atmosphere. Then it is poured onto a 10% solution of sodium chloride, extracted three times with ether: hexane (1: 1), the organic extract is mixed with water three times, dried over magnesium sulphate and evaporated in vacuo.
    This gives 2.9 g of compound 9 p-chloro as a colorless oil.
    IR, 2955, 1734, 1603,
    0 1591, 973.
    2.9 g of the crude product obtained above is stirred for 16 hours at room temperature for the cleavage of tetrahydropyranylgrone ether.
    5 with 80 ml of a mixture of acetic acid + vod da + tetgrahydrofuran (65 + 35 + 10) and then evaporated in vacuo. The residue is purified by chromatography on silica gel. Using a SIMPLE ether as a solvent, 1.1 g of compound are obtained in the form of a colorless oil.
    IR spectrum, cm: 3600, 3400 (wide), 2940, 1730, 1603, 1591, 975. P p and M e p 2. 5Z, 13E) - (9R, 11R,
    5 15R) -9-Chloro-11,15-dihydroxy-16-phenoxy-17, 18,19,20-tetranor-5,13-prostadiene acid.
    450 mg of methyl ester prepared in Example 1 are stirred for 5 hours with 15 ml of a solution of potassium hydroxide in ethanol and water (2 g of potassium hydroxide is dissolved in 75 ml of ethanol and 25 ml of water). Then acidified with a 10% citric acid solution to pH 4, extracted with
    three times with methylene chloride, the organic extract is washed once with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with methylene chloride / methanol as the solvent, 405 m of compound are obtained as a colorless oil.
    IR spectrum, 3600, 3400 (broad), 2930, 2855, 1710, 1600, 1590, 971.
    Example 3. Methyl ester (13E) - (9K, 11H, 15K) -9-chloro-11,15 dihydroxy-16-phenoxy-17, 18, -19, 20 tetranor-13-prostoic acid.
    Into a solution of -1.15 g of methyl (13E) - {9S, 11R, 15R) -9-hydroxy-II, 15-bic- (tetrahydropyran2-yloxy) -16-phenoxy-17,18,19,20 methyl ester (13E) α-tetranor-13-prostoic acid, obtained from the corresponding acid l in methylene chloride with 0.5 M ether, with a solution of trisomethane at 0 ° C, in 3.5 ml of pyridine was added at 720 mg of p-toluenesulphonic acid chloride, stirred for 16 hours at 0 ° C and 48 hours at 25 ° C. Then it is mixed with 0.30 ml of water, stirred for 2.5 hours, mixed with ether, shaken in turn with water, 5% sulfuric acid, 5% sodium bicarbonate solution and water. Dry over magnesium sulfate and evaporate in vacuo. 1.4 g of 9-tosylate are obtained as a colorless oil.
    IR Spectrum CMS 2950, 2873, 1732, 1600, 1591, 1495, 1365, 1240, 975.
    A solution of 0.92 g of 9-tosylate in 60 ml of dimethylformamide is stirred for 4 hours with 550 mg of lithium chloride at 60 ° C. argon atmosphere. Then it is poured onto a 10% solution of sodium chlorine, extracted three times with a mixture of ether (1: 1) and hexane, and the organic extract is shaken three times. water, dried over magnesium sulphate and evaporated in vacuo. Thus, 0.72 g of 9p-chlorine is obtained in the form of a colorless oil.
    IR spectrum, cm: 2955, 1733, 1602, 1590, 976.
    ;.
    To remove the tetrahydropyranyl ether, mix 0.72 g of the crude product obtained above for 16 hours at 25 seconds with 15 ml of a mixture of acetic acid + water + tetrahydrofuran (65 + 354-10) and then evaporate it in vacuo. The residue is purified by chromatography on silica gel. With solid ether, 0.29 g of the compound is obtained as a colorless solvent.
    IR spectrum, cm: 3600, 34.00 (wide), 2945 1731, 1602, 1590, 976.
    PRI me R 4. (13E) - (9R, 11R, 15R) —9-Chloro-11., 15-dihydroxy-16-phenoxy-17, 18,19,20-tetranor-13-prostoic acid .
    Analogously to Example 2, from 0.25 g of methyl ester prepared according to Example 3, 0.19 g of compound is obtained in the form of a colorless oil.
    IR spectrum, cm 3600, 3420 (wide), 2935, 2857, 1710, 1600, 1592, 972.
    PRI me R 5. Methyl ester (52, 13E) - (9R, HR, 15R) -9-chloro 11, 15, -dihydroxy-16- (m-chlorophenoxy) 17, 18,19,20-tetranor -5,13-prostadiene acid.
    In a solution of 2.95 g of methyl ester (5Z, 13E) - (9S, llR, 15R) -9 hydroxy-11, 15-bis- (tetrahydropyran 2-ILOXI-16- (m-chlorophenoxy) -17,18, 19, 20-tetranor-5,13-prostadiene acid, obtained from the corresponding acid in methylene chloride with a 0. 5 M solution of diazomethane — in 8 ml of pyridine is added at 1.9 g of p-toluenesulfonic acid chloride, stirred for 16 hours at a temperature ice bath and 48 hours at room temperature. Then mixed with 5 ml of water, stirred for 2.5 hours at room temperature, mixed with 0.4 liters of ether, shaken in turn with water, 5% sulfuric acid, 5% aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate and evaporated in vacuo. This gives 3.4 g of 9-tosylate as a colorless oil.
    IR spectrum, 2955, 2873, 1733, 1600, 1588, 972.
    A solution of 3.4 g of 9-tosylate in 150 ml of dimethylformamide is stirred for 4 hours with 2.0 g of lithium chloride under an argon atmosphere. It is then poured onto a 10% sodium chloride solution, extracted three times with an ether: hexane mixture (1: 1), the organic extract is shaken with water three times, dried over magnesium sulfate and evaporated in vacuo. As the crude product, 2.7 g of compound 9 f-chlorine is obtained as a colorless oil.
    IR Spectrum, CMS 2955, 1733, 1600, 1587, 975.
    To remove the tetrahydropyranyl ether, mix 2.7 g of the resulting crude product for 16 hours at room temperature with 70 ml of a mixture of acetic acid + water + terrahydrofuran (65 + 35 + 10) and then evaporate it in vacuo. After purification of the residue on silica gel, using a simple ether as solvent, 0.95 g of the compound as a colorless oil.
    IR spectrum, 3600, 3420 (broad), 2940, 1732, 1600, 1588, 976.
    PRI me R 6.  (5Z, 13E) - (9R, 11R, 15R) -9-Hlop-ll, 15-DIHYDROXI-16- (mhlorphenoxy) -17,18,19,20-tetranor5, 13-prostadiene acid.  Analogously to Example 2, out of 510 mg of methyl ester prepared according to Example 5, 460 mg of the compound are obtained as a colorless oil.  IR spectrum, 3600, 3400 (broad), 2940, 2860, 1710, 1600, 1588, 973.  Example 7 Methyl ester (13E) - (9K, 11H, 15K) -9-chloro-11.1 dihydroxy-16- (m-chlorophenoxy) -17.18 19.20-tetranor-13-prostoic acid Solution 600 mg of methyl ester (WE) - (9S, llR ,. 15R) -9-hydroxy-I, 15-bis- (tetrahydropyran-2yloxy) -16- (m-chlorophenoxy) -17,18, 19,20-tetranor-13-prostoic acid obtained by hydrogenation from methyl ester from a southern ester (52 , 1ЗЕ) (9S, llR, 15R) -9-hydroxy-ll, 15-bis (tetrahydropyran-2-yloxy) -16- (mhlorphenoxy) -17 / 18,19,20-tetranor5, 13-prostadiene acid in vinegar Doroda is mixed with 10% ether at a day on coal and one equivalent in 2 ml of pyridine, 390 mg of acid chloride II, lolsulfonic acid, are mixed at 0 ° C, stirred 16 at ice bath temperature and 48 at room temperature.  Then it is mixed with 0.5 ml of water, stirred for 3 hours at room temperature, diluted with ether, stirred in turn with water, 5% sulfuric acid, 5% bicarbonate sodium and water, dried over magnesium sulfate and evaporated in vacuo.  680 mg of 9-tosylate are obtained as a colorless oil.  IR spectrum, 2955, 2873, 1732 1600, 1588, 974.  A solution of febO mg 9-tosoate in 15 m of schimethylformamide is stirred.  4 hours with 220 mg lithium chloride under an argon atmosphere.  Then it is poured onto 10% sodium bicarbonate solution, extracted three times with a mixture of ether and hexane (1: 1), the organic extract is shaken three times with water, dried over magnesium sulfate and evaporated in vacuo.  As a crude product, 520 mg of 9/3 -chloro is obtained as a colorless oil.  IR spectrum, 2955, 1732, 1600 1588, 975.  For the cleavage of simple tetrahydropyranyl ether, 520 mg of the resulting crude product was stirred at room temperature for 16 hours with 10 ml of acetic acid. acid + water + tetrahydrofuran (65 + 35 + 1) and then evaporated in vacuo.  After purification of the residue on silica gel, 225 mg of the compound is obtained as a colorless oil using ether as the solvent.  Example.  (13E) - (9R, 11R, 15K) -9-Chlor-I, 15-dihydroxy-16- (Mlorfenoxy), 19,20-tetranorostenoic acid.  Analogously to example 2, out of 200 mg of the methyl ester prepared according to example 7, 165 mg of solids are obtained (colorless oil).  IR, 3600, 3420 (broad), 2944,. 2860, 1710, 1600, 1588, 975.  PRI me R 9.  Methyl ester (5Z, 13E) - (9R, 11R, 15K) -9-chloro11, 15-DIHYDROXI-16,16-dimethyl-5,13-prostadiene acid A solution of 1.3 g of methyl. (5Z, 13E) - (9S, 11R, 15R) ester of 16, 16-dimethyl-9-hydroxy-11,15-bis (tetrahydropyran-2-yloxy) -5,13-prostadiene acid, 800 mg of triphenylphosphine and 370 mg of carbon carbon tetrachloride in 6 ml of acetonitrile is stirred for 2 hours at 80 ° C.  It is then diluted with water, extracted three times with a mixture of ether and hexane (1: 1), the organic extract is washed with water, dried over magnesium sulfate and evaporated in vacuo.  After chromatography, the residue on evaporation on silica gel is obtained using a mixture of hexane and ether (4 + 1 0.55 g of 9-chloro in the form of a colorless oil.  IR spectrum, 2960, 1733, 976.  For the cleavage of the tetrahydropyranyl ether, 0.5 g of the obtained compound, 9fJ-chlorine above, is mixed with 5 ml of mixed acetic acid + water + tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo.  The residue is purified by chromatography on silica gel:.  Using ether as the solvent, 0.35 g of compound is obtained as a colorless oil.  IR sp € KTP, cm 3600, 3400 (wide), 2945.  1732.  976.  Example 10  (5Z, 13E) - (9R, HR, 15R) -9-Chloro-I, l5-dihydroxy 6,1 6-dimethyl-5113-prostadiene acid.  . .  .  Analogously to Example 2, out of 0.3 g of the methyl ester prepared according to Example 9, 0.24 g of compound is obtained as a colorless oil.  JK spectrum, 3600, 3. 420 (wide), 2944, 1709 ,.  975.  Note 11.  Methyl ester (5g, lЗE) - (9R, llR, lбRS) -9-hlopll, -15 L -dihydroxy-16-methyl-5,13 prostadiene acid.  In a solution of 1.1 g of methyl ester (5Z, 13E) - (9S, llR, 16RS) -9 hydroxy-1b-methyl-11, 15c6-bis- (tetrahydropi) an-2-yloxy) -5,13-prostadiene acid, obtained from the corresponding acid in methylene chloride with a 0.5 M solution of diazomethane at 0 ° C, is added to ml of pyridine.  at 0 ° C, 760 mg of p-toluenesulfonic acid chloride are stirred. 16 at and 48 h at 25 ° C.  After processing as in example 1, 1.4 g of 9-tooelate are obtained in the form of a colorless oil. IR spectrum, cm S 2955, 2870, 1732, 975.  A solution of 1.4 g of 9-tosylate in 60 ml of dimethylformamide is stirred for 4 hours with 840 mg of lithium chloride at 60 ° C under argon atmosphere.  After the usual processing, 1.1 g of compound 9 | 3-chloro are obtained in the form of an oil.  IR spectrum, cm: 2960, 1732, 975.  To remove the simple tetrahydropyranyl ether, 1.1 g of the resulting crude product was stirred at room temperature for 16 hours with 35 ml of acetic acid + water + + tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo.  After chromatography of the residue on silica gel, using ether as the solvent, 0.6 g of the compound is obtained as an oil.  IR, 3600, 3420 (wide), 2960, 1733, 976.  PR and ME 12.  (5Z, 13E) - (9R, 11R, 16RS) -9-Chloro-11.15 about -dihydroxy 16-methyl-5,13-prostadiene acids Analogously to example 2 of 0.5 g from the methyl ester prepared according to example 11 0.39 g of compound is obtained in the form of a colorless oil.  IR, 3600, 3400 (broad), 2945, 1710, 976.  Example 13  Methyl ester (5Z, l3E) - (9R, llR, 15S) -9 chlor-11, 15, dihydroxy-15-methyl-5.13 prostadiene acid.  In a solution of 1 g of methyl ester (5Z, 13E) - (9S, HR, 15S) -9 hydroxy-15-methyl-11, 15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadiene acid, obtained from the corresponding acid in methylene chloride with a 0.5 M solution of diazomethane, in 3.5 ml of pyridine, 691 mg of p-toluenesulfonic acid chloride are added at 0 ° C, stirred 16 at 0 ° C, then 48 hours at 25 ° C.  After processing in accordance with Example 1, 1.25 g of 9-tosylate are obtained as a colorless oil.  IR spectrum, 2950, 2870, 1735 1601, 1365, 1175, 978, 905.  A solution of 1.20 g of 9-tosylate in 50 m of dimethylformamide is stirred for 4.5 hours with 720 mg of lithium chloride at 60 ° C. in an argon atmosphere, is processed analogously to example 1 and 900 mg of compound 9p-chlorine are obtained in the form of oil, IR spectrum, cm: 2955, 2868, 1735, 978.  For the cleavage of the protective groups, 800 mg of the 9/3-chloro compound obtained in this way are mixed with 20 ml of a mixture of acetic acid + water + tetrahydrofuran (65 + 35 + 10) for 20 hours at 25 ° C.  After evaporation in vacuo and chromatography of the residue on silica gel with methylene chloride, 400 mg of the compound are obtained as an oil.  IR spectrum, cm: 3600, 3420 (broad), 2955, 2870, 1735, 976.  Example 14  (5Z, 13E) - (9R, 11R, 15S) -9-Chloro-11,15-dihydroxy15-methyl-5, 13-prostadiene acid.  Analogously to Example 2, out of 800 mg of the methyl ester prepared according to Example 13, 230 mg of the compound are obtained as an oil.  IR spectrum, cm 3600, 3400: 2950, 1710, 978.  Example 15  Methyl ester (5Z, 13E) - (9R, llR, l5R, 16RS) -9 chloro-11, 15-dihydroxy-16-fluoro-5.13 pro. stadenoic acid.  A mixture of 1.2 g of methyl ester (5Z, 13E) - (9S, 11R, 15R, 16RS) -9-hydroxy-16-otorop-II, 15-bis (tetrahydropyran-2-yloxy) -5 ,, 13 prostadiene acid.  The acid obtained from the corresponding acid in methylene chloride with a 0.5 M solution of diazomethane at 0 ° C, 800 mg of p-toluenesulfonic acid chloride and 4 ml of pyridine mixture is mixed for 16 hours at OS, then 48 hours at 25 seconds.  Processing according to Example 1 yielded 1.45 g of 9-tosylate as an oil.  IR spectrum, cm 2952, 2870, 1601, 1360, 1170, 978, 906.  1.25 g of the tosylate thus obtained is heated with 725 mg of lithium chloride in 50 ml of dimethylformamide with stirring until.  After processing in accordance with Example 1, 925 mg of compound 9 chlorine is obtained in the form of an oil.  IR spectrum, CMS. 2950, 1735, 976.  To remove the protecting groups, 900 mg of the thus obtained 9/5-chloro compound are mixed with 25 ml of a mixture of acetic acid + water + tetrahydrofuran (65 + 35 + 10) for 20 hours at.  After evaporation in vacuo and chromatography of the residue on silica gel with methylene chloride,.  450 mg of compound are obtained as an oil.  IR spectrum, 2605.3420, 2952, 2868, 1735, 978.  PRI and MER 16.  (5Z, 13E) - (9R, 15R, 16RS) -9-Chloro-11,15-Dihydroxy-16-fluoro-5, 13-prostadiene acid.  Analogously to example 2, 400 mg of methyl ester prepared according to example 15 is obtained. 310 mg of compound as an oil.  IR spectrum, 3600, 3400, 2952, 2860, 1712, 978.  PRI me R 17.  Methyl ester (5Z, 13E) - {9S ,. HR, 15R) -9 chloro-11, 15-dihydroxy-16-phenoxy, 17, 18, 19, 20-tetranor-5, 13-prostadiene acid.  A solution of 910 mg of methyl {5Z, 13E) ester - (9R, llR, l5R) -9 hydroxy-11, 15-bis- (tetoagipropioan 2-yloxy) -16-phenoxy-17,18,19,20 tetranor-prostadiene acid, 560 mg of triphenylphosphine and 260 mg of carbon tetrachloride in 5 ml of acetonitrile are heated to 80c for 2 hours.  It is diluted with 100 for processing.  water, extracted three times, each with 50 ml of heptane, the organic extract is washed with brine, dried over sulfate, magnesium and evaporated in vacuo.  The residue is chromatographed on silica gel with hexane / ether (2: 1) to give 510 mg of 9% chlorine as an oil.  IR spectrum, cm 2955, 2870, 1735 1600, 1590, 1100, 980.  To remove the protective groups, the substance is treated with a mixture of acetic acid in accordance with Example 1 and 300 mg of compound are obtained as an oil.  IR Spectrum, H & O, 3400, 2950 1735, 1601, 1590, 976.  Methyl ester (5Z, ЗE) - (9R, llR, 15R) -9-hydroxyl 11, 15-bis (tetrahydropyran-2-yl-g-si) -16-phenoxy-17,18,19 is used as the starting material , 20-tetranor of prostate acid. receive as follows.  A solution of 3 g of 9-tosylate obtained in Example 1 in 100 ml of dimethyl sulfoxide is heated from 6 g of potassium nitrite for 3 hours to 60 ° C, after cooling it is diluted with 800 ml of water, extracted three times with 100 ml of a mixture of hexane and ether ( 2: 1), the combined extracts are washed twice, each time with 20 ml of brine, dried over magnesium sulfate and evaporated in vacuo.  The residue is purified on silica gel with hexane and an increasing gradient of ethyl acetate.  1.5 g of (9R) -9 (i-hydroxy compounds in the form of Meela are obtained.  Example 18.  5Z, 13E) - (9S, 11R, 15R) -9-Chloro-11,15-dihydroxy16-phenoxy-17, 18,19,20-tetranor5, 13-tprostadienic acid.  Analogously to Example 2, out of 250 mg of the substance prepared according to Example 17, 190 mg of the compound were obtained.  IR spectrum, 3600, 3410, 296 2870 ,.  1710, 1600, 1588, 978.  Example 19  Methylsulfonam (5Z, 13E) - (9R, llR, 15R) -9-xlQp-ll, 15 diHydroxy-1b phenoxy-17,18,19,20 tetranor-5, 13-prostadiene acid.  A solution of 200 mg of (5Z, 13E) - (9R, 11R, 5R) -9-HLOR-11,15-dihydroxy-16-feoxi-17, 18,19,20-tetranor-5,13-protadienoic acid in 5 ml dimethylormamide mixed with p. 80 mg of the utilized chloroforic acid ester and 60 mg of triethylamine.  After 30 minutes, 234 mg of nathium salt of methylsulfonamide, prepared from methylsulfonamide and sodium methiate, and 2 ml of triamide hexamethylphosphoric acid are added and stirred for 3 hours at 20 ° C.  The reaction mixture is then fed to a buffer citrate solution pH 5, extracted several times with ethyl acetate, the organic phase is washed with brine, dried over magnesium sulphate and evaporated in vacuo.  After chromatography of the residue on silica gel with methylene chloride, 80 compounds are obtained in the form of an oil.  IR spectrum, cm: 3600j 3400, 1718, 1600, 1590, 1125, 972.  Example 20  Methylsulfonamide {13E) - (9R, 11R, 15R) -9-chloro-11,15-dihydroxy-16-phenoxy-17, 18,19, 20-tetranor-13-prostanoic acid.  Analogously to Example 19, the compound prepared according to Example 4 is obtained as an oil.  IR spectrum, CMS 3605, 3410, 1720, 1600, 1588, 1125, 970.  PRI me R 21.  Methylsulfonamide (5Z, lЗE) - (9R ,, i5R) -9-XLOp-ll, 15 dihydroxy-16- (m-chlorophenoxy) -17,18, 19,20-tetranor-5,13-prostadiene acid.  - Analogously to Example 19, the compound prepared according to Example 6 is obtained in the form of an oil.  IR spectrum, cm3 3602, 3400, 1720, 1602, 1590, FROM, 970.  PRI me R 22.  Methylsulfonamide (13E) - (9K, 11H, 15E) -9-chloro-11,15-dihydroxy-16- (w-chlorophenoxy) -17,18, 19,20-tetranor-13-prostoic acid.  .  Analogously to Example 19, the compound prepared according to Example 8 is obtained in the form of an oil.  IR-SP, 3602, 3400, 2960, 2870, 1720, 1601, 1590, 1125, 970.  Example23.  Methylsulfonamide) - (EK, 11H, 15K) -9-chloro-11,15-, dihydroxy-16,16-dimethyl-5,13 prostadiene acid.  To a solution of 585 mg (5Z, 13E) - (9R, llR, 15R) -9-hlop16,16-dimethyl-ll, 15 bis (tetrahydropyran-2-yloxy) -5,13 prostadienic acid {from methyl ester - example 9 - by saponification with 1 M sodium hydroxide in methanol) in 25 ml of tetrahydrfuran, 0.75 mg of methanesulfonyl isocyanate in 10 ml of tetrahydrofuran is added and stirred for 6 hours at 20 ° C. .  It is then neutralized with acetic acid, concentrated in vacuo, the residue is dissolved in 100 ml of methylene chloride, shaken with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated in vacuo.  To remove the protective groups, the residue is mixed with 10 ml of ice / acetic acid + water + tetra hydrofuran (65 + 35 + 10) for 4 hours at 40 ° C, evaporated in vacuo and the residue is absorbed on 20 g of silica gel.  Elution with hexane / ethyl acetate was used to make the contaminants.  With ethyl acetate, 200 mg of the compound is then eluted as an oil.  IR spectrum cm: 3600, 3420, 2955 2868, 1718, 1120, 972. .  .  PRI me R 24.  Methylsulfonamide (5Z, 13E) - (9E, 11E, 16K5) -9-chloro-11,15 e6-dihydroxy-1b-methyl-5,13-prostate enoic acid.  By analogy with Example 19, the compound prepared according to Example 12 was obtained as an oil. IR spectrum, 3602.3400.1718, 1120, 972.  Pr and m er 25.  Isopropylsulfonic {5Z, 13E) - (9R, 11K, 15K) -9-chlor11 g15-dihydroxy-16-phenoxy-17.18, 19.20-tetranor-15.13 prostadiene acid.  200 mg (5Z, 13E) - (9R, llR, 15R) -9 chloro-11, 15-igidroxy-16-phenoxy-17 18,19,20-tetranor-5,13-prostadiene acid (according to example 2) solution in 5 ml of dimethylformamide and mixed with 80 mg of isobutyl layered chloroformate and 60 mg of triethylamine.  After 30 minutes, add 290 mg of isopropylsulfonamide sodium salt, prepared from isopropylsulfonamide and sodium methylate, and 2 ml of hexamethylphosphoric triamide and stir 3 at 25 s.  For processing, the mixture is fed to 100 ml of a buffer citrate solution (pH 5), extracted several times with ethyl acetate, the organic phase is washed with brine, dried over magnesium sulfate and evaporated in vacuo.  After chromatography of the residue on silica gel with methylene chloride, 91 mg of compound are obtained in the form of an oil.  IR spectrum, cmH 3600, 3410, 2960 2870, 1722, 1601, 1588, 1120, 974.  For example 26.  isopropylsulfonamide {13E) - {9R, llS, 15R) -9-hlopll, 15-dihydroxy-. 16-phenoxy-17,18, 19,20-tetranor-13-prostoic acid.  Analogously to example 25, 200 mg (1ZE) - (9R, 11R, 15R) -9-HLOR-11,15-dihydroxy-16-phenoxy-17, 18 19,20 13-prostoic acid tetranor (according to example 4) are obtained 85 mg of compound as an oil.  IR, 3605, 34. 10, 2955 2865, 1722f.  1600, 1588, 1125, 974.  Example 27.  Acetyl amide (5Z, 13E) - (9H, 11K, 15H) -9-chloro-11 ,. 15-dihydroxy-16-phenoxy-17, 18, 19,20-tetranor-5, 13-prostadiene acid.  To a solution of 575 mg (5Z, 13E) - (9R, llR, l5R) -9-hlop-ll, 15-bic- (tetrahydropyran-2-yloxy) -16-phenoxy-17,18, 19,20-tetranor-5 , 13-prostadiene acid, obtained from the corresponding methyl ester — Example 1 — saponification with 1 M sodium hydroxide in methanol; JB 15 ml of acetonitrile are added at 150 mg of triethylamine, cooled before and instilled a solution of 106 mg of acetyl isocyanate in 10 ml of acetonitrile.  Then it is stirred for 2 hours at, concentrated in vacuo, diluted with 100 ml of water, adjusted to pH 5. addition of 1N sulfuric acid. Extract several times with npocTfciiM ether, wash the organic phase with brine, dry over magnesium sulfate and evaporate in vacuo.  To remove the protective group, the residue is stirred with 15 ml of a mixture of ice and acetic acid + water + tetrahydrofuran (65 + 35 + 10) for 5 hours at 40 ° C and then evaporated to dryness in vacuo.  The residue kromatografat5to silica gel with methylene chloride 1% isopropyl alcohol.  220 mg of compound are obtained as an oil.  IR spectrum, 3600, 3400, 2945, 2862, 1708, 1600, 1588, 976.  Example 28  Acetylamide (13E) (9R, 11R, 15I) -9-chloro-11,15-dihydroxy-1b-phenoxy-17, 18,19,20-tetranor13-prostoic acid.  analogously to Example 27, of 450 mg of (13E) - (9R, llR, 15R) -9-xlop-ll, 15-bic (tetrahydropyran-2-yloxy) -1b-phenoxy-17, 18,19,2 0-tetranoro 13-prostoic acid, prepared from the corresponding methyl ester — Example 3 — by hydrofluoride with 1 M sodium and ethanol in methanol, gives 200 mg of the compound as an oil.  JK-spectrum, 3600, 3410, 2950, 2860, € 170, 1600, 1590, 976.  PRI me R 29.  The acetyls (HSE) (9R, llR, 15R) -9-hlop-ll, l5-dihydroxy, 16- (m-chlorophenoxy) -17,18,19,20-tetranor-13-prostoic acid.  Analogously to Example 27 of 485 mg of C13E), 15R) -9-chloropl, 15-Bic {tetragidropyran-2-yloxy) -16- (mhlorphenoxy) -17,18,19,20-tetranor13-prostanic acid, made from the corresponding methyl ester — Example 7 — saponification with 1 M sodium hydroxide in methanol, yields 225 mg of the compound as an oil.  IR spectrum, 3600, 3400, 2948, 2858, 1706, 1602, 1590, 976.  PRI me R 30.  Amide (5Z, 13E) - (9R, llR, l5R) -9-xlop-ll, 15-dihydroxy-161 phenyxy-17, 18,19,20-tetran-5,13 prostadiene acid.  400 mg (5Z, 13E) - (9R, llR, 15R) -9 chloro-11, 15-dihydroxy-16-phenoxy17, 18,19,20-tetranor-5,13-prostadiene acid (prepared according to example 2) are dissolved in 10 ml of tetrahydrofuran and mixed with OS with 140 mg of triethylamine and 17. 1 mg of iso-butyl ester of chloroformic acid.  After 1 hour, gaseous ammonia was introduced at 0 ° C for 10 minutes, then the mixture was kept at Then for 1 hour. the mixture is diluted with 50 ml of water, extracted three times, each time with 50 m of methylene chloride, the combined extracts are shaken once with 20 ml of brine, dried over magnesium sulphate and concentrated in vacuo.  For purification, the residue is chromatographed on silica gel with a mixture of chloroform and ethyl acetate.  310 mg of compound are obtained in the form of a waxy mass.  IR spectrum, 3600, 3535, 3415, 2995, 2930, 2860, 1675, 1600, 1588, 972.  PRI am 31.  Amide (13E) - {9H, 11E, 15K) -9-chloro-11,15-DIHYDROXI-16phenoxy-17, 18,19,20-tetrapanop-13-pro-stenthenic acid; Analogously to example 30, an acid prepared according to example 4 is obtained in the form of an oil.  IR spectrum, 3600.3535, 3410, 2996, 2930, 2860, 1670, 1601, 1588, 972.  Example 32  Amide (5Z-13E) - (9R, lR, 15R) -9-hlop-ll, 15-DIHYDROXI-16 (M-chlorophenoxy) -17,18,19,20-tetranoprop 5, 13-prostate acid.  Analogously to example 30, an acid prepared according to example 6 is obtained in the form of an oil.  IR spectrum, cmH 3600, 3450, 2998, 2930, 2862, 1670, 1600, 1585, 974.  Example 33  Amide (13E) - {9R, 11R, 15R) -9-HLOR-11,15-DIGYDROXI-16 (M-chlorophenoxy) -17,18,19,20-tetranor13-prostoic acid.  Analogously to example 30, an acid produced according to example 8 is obtained in the form of an oil.  IR spectrum, 3600, 3420, 2998, 2935, 2860, 1672, 1600, 1588, 972.  PRI me R 34.  Trisoxymethylaminomethane salt of (13E) - (9R, 11R, 5R) -9-chlor-II, 15-digxtx-16 phenoxy-17, 18,19,20-tetranor-13-prostoic acid.  To a solution of 410 mg of (13E) - (9R, 11R, 15R) -9-HLOR-11,15-dihydroxy-16-phenoxy-17, 18,19,20-tetranor-13-prostoic acid (prepared by rto example 4) in 70 ml of acetonitrile is added with a solution of 122 mg of Tris (hydroxymethyl) aminomethan in 0.4 ml of water, cooled with stirring, decanted from the solvent after 16 hours and the residue is dried in vacuo. 365 mg of the compound is obtained as a white, waxy mass.
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of 9-chloroprostane of the general formula substituted with methyl groups or fluorine, and E is oxygen;
    R 4 is free or protected tetrahydropyran-2-yl. a hydroxy group;
    Rg is lower alkyl, phenyl, d chloronyl, or their salts in case R <is a hydroxyl group, different from the fact that the compound of the general formula
    C1 "1 where C1 - in the 9-position can be 01 - or p-configuration;
    R ( is the OR2 residue, where R2 is hydrogen, lower alkyl, or the NHRj residue, where Rg is hydrogen or a residue of a lower aliphatic carboxylic acid or sulfonic acid with 1-4 carbon atoms;
    A is the group —CH ^ —CHn — or cisCH = CH ~;
    B — group — CHl — CHl, transCH — CH—;
    W is a free or protected tetrahydropyran-2-yl group hydroxymethylene 'group, or a free or protected tetrahydropyranghe OH group can have an ol or p - configuration R 4 , B, B, E.
    and B. have the indicated meanings, while the free oxy groups in I 4 and W are protected, chlorinated through an sulfonic acid intermediate with chloride of the general formula
    R 6 C1, where R ^ is lithium, sodium, potassium, or with the help of carbon tetrachloride / triphenylphosphine and in the obtained target products, if necessary, protected hydroxy groups are released and / or free hydroxy groups are esterified and / or hydriSU-1026652>
    double bonds, etherify and / or saponify the esterified carboxyl group, and / or esterify the free’s carboxyl group,
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    同族专利:
    公开号 | 公开日
    JPS5692860A|1981-07-27|
    US4444788A|1984-04-24|
    EP0030377B1|1984-02-22|
    IE51212B1|1986-11-12|
    IE802572L|1981-06-10|
    AU543797B2|1985-05-02|
    DK153944B|1988-09-26|
    IL61669D0|1981-01-30|
    CS226419B2|1984-03-19|
    DK573687A|1987-11-02|
    CA1196327A|1985-11-05|
    DK526080A|1981-06-11|
    ES8200336A1|1981-11-16|
    US5079259A|1992-01-07|
    AU6519080A|1981-06-18|
    ES497589A0|1981-11-16|
    AT6364T|1984-03-15|
    DK153944C|1989-02-20|
    HU183263B|1984-04-28|
    EP0030377A1|1981-06-17|
    DK573687D0|1987-11-02|
    JPS6224422B2|1987-05-28|
    IL61669A|1986-08-31|
    DE2950027A1|1981-06-11|
    DE3066726D1|1984-03-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE4229050A1|1992-08-31|1994-03-03|Schering Ag|New esters and amides of 9-chloro-prostaglandins - useful, e.g., in treatment of glaucoma and as diuretic agents|
    DE4229048A1|1992-08-31|1994-03-03|Schering Ag|New ester of 9-chloro-prostaglandin - useful in treatment of glaucoma and as diuretic agents|DE2517773A1|1975-04-18|1976-10-28|Schering Ag|NEW 11-OXO-PROSTAGLANDIN DERIVATIVES AND METHOD FOR THEIR PRODUCTION|
    US4163016A|1977-07-05|1979-07-31|Hoffmann-La Roche Inc.|16-Substituted prostaglandins|
    US4192799A|1977-09-21|1980-03-11|The Upjohn Company|Conjugates formed by reacting a prostaglandin mimic compound with a carrier molecule|
    DE2950027A1|1979-12-10|1981-06-11|Schering Ag Berlin Und Bergkamen, 1000 Berlin|9-CHLORINE PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|DE2950027A1|1979-12-10|1981-06-11|Schering Ag Berlin Und Bergkamen, 1000 Berlin|9-CHLORINE PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|
    US5204371A|1979-12-10|1993-04-20|Schering Aktiengesellschaft|Pharmaceutically active 9-chloroprostaglandins|
    DE3126924A1|1981-07-03|1983-01-20|Schering Ag, 1000 Berlin Und 4619 Bergkamen|9-FLUOR PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|
    DE3148743A1|1981-12-04|1983-06-09|Schering Ag, 1000 Berlin Und 4619 Bergkamen|9-BROM PROSTAGLAND IN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3325175A1|1983-07-08|1985-01-17|Schering AG, 1000 Berlin und 4709 Bergkamen|11-HALOGEN PROSTANE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3337450A1|1983-10-12|1985-04-25|Schering AG, 1000 Berlin und 4709 Bergkamen|PROSTAGLANDINE AND ANTIGESTAGE FOR PREGNANCY ABORT|
    DE3347128A1|1983-12-22|1985-07-11|Schering AG, 1000 Berlin und 4709 Bergkamen|9-HALOGEN- 2-PROSTAGLAND IN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3414509C2|1984-04-13|1992-07-02|Schering Ag Berlin Und Bergkamen, 1000 Berlin, De|
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    DE3510978A1|1985-03-22|1986-09-25|Schering AG, Berlin und Bergkamen, 1000 Berlin|NEW 9-HALOGEN PROSTAGLANDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3608088C2|1986-03-07|1995-11-16|Schering Ag|Pharmaceutical preparations containing cyclodextrin clathrates of carbacyclin derivatives|
    DE3724189A1|1987-07-17|1989-01-26|Schering Ag|9-Halo-- DELTA <4>-prostaglandin derivatives, process for their preparation and their use as medicaments|
    US5891910A|1987-07-17|1999-04-06|Schering Aktiengesellschaft|9-halogen- prostaglandin derivatives, process for their production and their use as pharmaceutical agents|
    AU624078B2|1987-07-17|1992-06-04|Schering Aktiengesellschaft Berlin Und Bergkamen|9-halogen--prostaglandin derivatives, process for manufacturing them, and their use as drugs|
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    HU206084B|1987-07-17|1992-08-28|Schering Ag|Process for producing 9-halogen-/z/-prostaglandin derivatives and pharmaceutical compositions comprising such active ingredient|
    DE4036140A1|1990-11-09|1992-05-14|Schering Ag|9-HALOGEN-11SS-HYDROXY-PROSTAGLANDIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    EP0652211A1|1992-07-24|1995-05-10|Taisho Pharmaceutical Co. Ltd|Prostaglandin derivative|
    DK0656889T3|1992-08-31|1999-03-22|Schering Ag|9-chloro-prostaglandin esters and amides and their use in the manufacture of drugs|
    US5972991A|1992-09-21|1999-10-26|Allergan|Cyclopentane heptan oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents|
    IT1257479B|1992-12-01|1996-01-25|PROSTAGLANDINIC DERIVATIVES WITH RADIOPROTECTIVE EFFECTS|
    DE4330177A1|1993-08-31|1995-03-02|Schering Ag|New 9-chloro prostaglandin derivatives|
    US5721273A|1993-12-15|1998-02-24|Alcon Laboratories, Inc.|Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension|
    US5807892A|1994-09-30|1998-09-15|Alcon Laboratories, Inc.|Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension|
    US6235780B1|1998-07-21|2001-05-22|Ono Pharmaceutical Co., Ltd.|ω-cycloalkyl-prostaglandin E1 derivatives|
    DE602005005355T2|2005-11-21|2009-03-26|Bayer Schering Pharma Ag|9-Chloro-15-deoxyprostaglandin derivatives, process for their preparation and their use as medicaments|
    US7563924B2|2005-11-21|2009-07-21|Schering Aktiengesellschaft|9-chloro-15-deoxyprostaglandin derivatives, process for their preparation and their use as medicaments|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792950027|DE2950027A1|1979-12-10|1979-12-10|9-CHLORINE PROSTAGLAND DERIVATIVES, METHOD FOR THE PRODUCTION AND USE AS A MEDICINAL PRODUCT|
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