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    • 专利摘要:
    Carbacylin derivatives of the general formula I <IMAGE> in which R1 denotes a hydrogen atom or the radical OR2, in which R2 can denote hydrogen, alkyl, cycloalkyl, aryl, the radical <IMAGE> or a heterocyclic radical, or R1 can denote the radical NHR3 where R3 denotes an acid radical or the radical R2, n can denote the number 2, 3, 4 or 5, X denotes a hydrogen atom or a fluorine atom, A denotes a -CH2-CH2-, a trans -CH=CH- or -C IDENTICAL C- group, W denotes a free or functionally modified hydroxymethylene group or a free or functionally modified <IMAGE> group, in which the OH group can be in the alpha or beta position, D denotes the group <IMAGE> a straight-chain, saturated alkylene group having 1-5 C atoms, a branched saturated or a straight-chain or branched unsaturated alkylene group having 2-5 C atoms, which may be substituted by fluorine atoms, m can denote the number 1, 2 or 3, E represents a direct bond, a -C IDENTICAL C- group or a -CR6=CR7- group, in which R6 denotes a hydrogen atom or an alkyl group having 1-5 C atoms and R7 denotes a hydrogen atom, an alkyl group having 1-5 C atoms or a halogen atom, R4 denotes an alkyl, cycloalkyl or a substituted or unsubstituted aryl group or a heterocyclic group, R5 denotes a free or functionally modified hydroxyl group, and, if R2 denotes a hydrogen atom, the salts thereof with physiologically acceptable bases, a process for their preparation and their use as pharmaceuticals.
    公开号:SU1316555A3
    申请号:SU833615553
    申请日:1983-07-12
    公开日:1987-06-07
    发明作者:Скубалла Вернер；Радюхель Бернд；Форбрюгген Хельмут；Казальс-Штенцель Хорхе；Маннесманн Герда；Шиллингер Эккехард；Харолд Таун Майкл
    申请人:Шеринг Аг (Фирма)；
    IPC主号:
    专利说明:

    t13
    Image 1) Etenie refers to a process for the preparation of new carbacyline derivatives
    (CH l rCORi
    about
    CH2
    X
    TA-CH-D-E-Hu OH OH
    where with R Н, ОН А means trans or -СГС-group, D means group CRjR, CHj X where Rj, CH ,, R, H, CHj or -Rj-R, - - (CHj), -, E means trans -CH C (CH,) - or -CsC-group,,; CjHy, X H, F, or with A - trans-CH CH-, E, D - CH (CH) - CH,;,, F, R, CR, - H, CH, jCH (OH) CH it) , or at R, OH or their additively basic salts of tris- (hydroxymethyl) -aminomethane.
    The purpose of the invention is to synthesize new carbacline derivatives, which reduce blood pressure more effectively than the known ones.
    Example 1. (5E) - (l6RS) -2- -Descarboxy-1a, 1b-dihomo-2-formyl-16-methyl-3-oxa-18,18, t9,19-tetra-dehydro-6-a -carbaprostaglandin-1,
    To a solution of 700 mg of (E) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-sh1oxy) -6- (E) - (3S, ARS) -4-methyl-3- (tetra- hydropyran-2-yloxy) -oct-1-en-6-inyl-bicyclo (3.3; o) octan-3-ylidene-α-ethan-1-ol in 15 ml of tetrahydrofuran at 0 ° C 77 mg of a 55% sodium hydride suspension in mineral oil and stirred for 30 minutes at 24 ° C in an argon atmosphere. A solution of 1.15 g of 2- (3-bromo-propyl) -1,3-dioxolane in 7 ml of tetrahydrofuran is then added dropwise and boiled for 21 hours under reflux in an argon atmosphere. The mixture is diluted with ether, washed with water until neutral, dried over magnesium sulphate and evaporated in vacuo. After chromatography of the residue on silica gel, 480 mg of an oxide compound are obtained with a mixture of hexane and ether (7 + 3), which are stirred for 16 hours at 24 ° C with 40 ml of mixture
    acetic acid with water and tetrahydrofuran (65 + 35 + 10). It is then evaporated in vacuo and the residue is chromatographed on silica gel. With a mixture of acetic ether and hexane (4 + 1), 270 mg of the compound are obtained as a colorless oil.
    IR (CHCl1): - 3600, 3420 (wide), 2970, 2862, 2730, 1725, 1603.970 cm.
    Used for the above esterification to the 2- (3-bromo-propyl) -1,3-dioxrlan ether, was prepared as follows.
    To a solution of 9.6 g of ethyl ether
     Bromobutyric acid in 595 ml of toluene slowly, at -70 ° C, is added 50 ml of a 1.2 M solution of diisobutylaluminium hydride in toluene, stirred for 15 minutes at -70 ° C and then mixed
    0 dropwise with 10 ml of isopropyl alcohol and 25 ml of water. The mixture is stirred at room temperature for 2 hours, filtered, the filtrate is dried over magnesium sulfate and concentrated in vacuo at 25 ° C. The residue is dissolved in 500 ml of toluene, 10 ml of ethylene glycol and 100 mg of p-toluenesulfonic acid are added and boiled for 6 hours. reflux and water separator. Then, add 500 ml of ether once, shake it once with 5% sodium bicarbonate solution, dry the organic extract three times with magnesium sulfate and concentrate in vacuo at
    5 to 30 ° C. Distillation of the residue at 0.6 torr and 43-45 ° C gives 6.8 g of 2- (3-bromo-propyl) -, 3-dioxolane as a colorless liquid.
    Example 2. (5E) - (16RS) -1a, 160 -Digomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-ba-carba-prostaglandin-lj.
    To a solution of 500 mg of the aldehyde obtained in Example T in 5 ml of pyridine, add 2 ml of acetic anhydride and leave to stand at room temperature for 18 hours. Then concentrate in vacuo, the resulting 11, Q 15-diacetate is dissolved in 25 ml acetone and when mixed dropwise with 2.1 ml of Jones reagent. The mixture is stirred at 0 ° C for 30 minutes, 2 ml of isopropyl alcohol is added, diluted with ether, shaken three times with water, dried over magnesium sulphate and evaporated in a vacuum. After chromatography of the residue on silica gel using hexane-acetic ether (1 + 1) to 3
    410 mg of (5E) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-those of hydrohydro-6-a-carba-prostaglandin-Ij-11 are obtained , 15-diacetate as a colorless oil.
    IR: 3650, 3400 (wide), 2960, 1730, 1600, 1245, 968.
    For cleavage of the protecting groups, 410 mg of 11,15-diacetate in 20 ml of methanol is stirred for 16 hours at 24 ° C with 520 mg of potassium carbonate. It is then concentrated in vacuo, acidified with 10% citric acid solution to., Extracted three times with methylene chloride, washed twice with water, dried over magnesium sulphate and evaporated in vacuo. The residue is chromatographed with acetic acid ethyl acetate (99.5 + 0.5) on a silica gel. 305 mg of the title compound are obtained in the form of a colorless oil.
     IR: 3950, 3420 (wide), 2960, 2930, 2865, 1720, 1600, 970.
    Example 3. (5Z) - (16RS) -2- -Descarboxy-1 a, 1b-dihomo-2-formyl-16-methyl-3-oxa-18,18,19,19-tetra-dehydro-6a -carba-prostaglandin-1.
    By analogy with example 1, out of 320 ml of 2- (Z) - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (Е) - (3S, -4Е8) -4 -methyl-3- (tetrahydropyran-2- -yloxy) -oct-1-en-6-in-yl-bicyclo (3.3, o) -octan-3-ylidene-ethane-1-ol gives 125 mg of the compound as colorless oil.
    IR: 3610, 3400 (wide), 2965, 2730, 1736, 1602, 968.
    Example 4. (5Z) - (l6RS) -1a, 1b-Digomo-16-methyl-3-oxa-18,18,19, 19-tetradehydro-6-a-carba-prostaglandin-12.
    By analogy with example 2, out of 125 mg of aldehyde obtained in example 3, 90 mg of (5Z) - (16RS) -1-1, 1b-dihomo-1b-methyl-3-oxa-18.18 and 19.19-tetradehydro-6a are obtained. -carba-prostaglandan-1 -11,15-diacetate. After cleavage of the protecting groups, 57 mg of the title compound are obtained in the form; colorless oil.
    IR: 3600, 3410 (wide), 2960, 2866, 1718, 1600, 968 cm.
    Example 5. (5E) - (16RS) -2- -Descarboxy-1a, 1b-dihomo-16,20-dimethyl-2-formyl-3-oxa-18.18, -tetradehydro-6-carba- prostaglandin-.
    554
    By analogy with example 1, from 1.35 g of 2- (E) - (1S, 5S, 6R, 7R) -7- (TeT-rahydropyran-2-yl-oxy) -6- (E) - (35, 4RS) -4-methy l-3- (tetrahydropyran-2-yl-oxy) -ion-1-en-6-in-yl-bicyclo (3. 3) O-octane-3-ylidene-ethane- 1-α-ol gives 610 mg of the title compound as a colorless oil.
    IR: 3600, 3410 (wide), 2967, 2862, 2731, 1725, 1601, 970 cm
    The starting compounds for the title compound are prepared as follows.
    (5a) - (1R, 5S, 6R, 7R) -3,3-ethIenedioxy-7-benzoyloxy-6- (E) - (3S, 4RS) -Z-oxy-4-methyl-non-1 -en-6-in-yl - -bicyclo- (3.3, o-octane.
    To a suspension of 1.46 g of sodium hydride (55% in oil) in 130 ml of dimethoxyethane (DME) at 0 ° C, a solution is added dropwise from 9.02 g of 3-methyl-2-oxo-oct-5-ins-dimethyl ether the background acid in 67 ml of DME and stirred for 1 h at O C. Then it is mixed at -20 C with a solution of 9.4 g (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzo-Sh1oxy -6-formyl-bicyclo- (3,3,0) -octane in 130 ml of DME, stirred for 1.5 hours at -20 ° C, added to 600 ml of a saturated solution of ammonium chloride - and extracted three times with ether. The organic extract is washed with water until. neutral, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, using a mixture of ether and hexane (1 + 1), 9.1 g of c6, p-unsaturated ketone as an oil.
    To a solution of 9.1 g of ketone in 300 ml
    5.2 g of sodium borohydride are added in portions of methanol at -40 ° C and stirred for 1 hour at -40 ° C. Then it is diluted with ether, washed with water until neutralized, dried over magnesium sulfate and evaporated in vacuo . By column chromatography on silica gel using a mixture of ether and hexane, first, 3.9 g of the title compound (PG nomenclature: 15 ° C -oxy) - and also 3.2 g of the isomeric -oxy compound are obtained as a polar component.
    IR: 3600, 3400 (wide) 2942, 1711, 1603, 1588, 1276, 968, 947cm
    (5b) - (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-idoxy) -6- (E) - (3S, 4RS) -3- - (tetrahydropyran-2-yloxy) -4 -mёSh1
    -I
    five
    -non-1-en-6-in-yl-bicyclo (3,3,0) - -octan-3-one.
    A mixture of 3.6 g of the 5aot-alcohol obtained in Example 1 and 1.5 g of potassium carbonate in 120 ml of methanol was stirred for 16 h. At room temperature under an argon atmosphere. It is then concentrated in vacuo, diluted with ether and washed with brine until neutral. Dry over magnesium sulfate and evaporate in vacuo. The residue after evaporation is stirred for 16 hours at room temperature. With 75 ml of a mixture of acetic acid, water, and tetrahydrofuran (65 + 35 + 10) and then evaporated in vacuo. After filtration of the residue through silica gel, 2.2 g of ketone is obtained in the form of an oil with a mixture of ethyl acetate and hexane (7 + 3).
    A solution of 2.2 g of ketone; 2.4 ml of dihydropyran and 23 mg of p-toluenesulfonic acid in 75 ml of methylene chloride are stirred for 30 minutes at 0 ° C. It is then diluted with ether, shaken with a dilute sodium bicarbonate solution, washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo. 3.4 g of bistetrahydropyranyl ether are obtained, which is used without purification.
    IR: 2960, 2865, 1738, 970 cm.
    (5c) -2 (E) - (. 1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (E) - (3S, 4EZ) -4-methyl-3- (tetrahydropyran-2- -yloxy) -ion-1-en-6-in-yl) -bicycdo (3,3,0) -octan-3-ylidene-ethan-1-ol.
    To a solution of 8.1 g of phosphonooacetic acid triethyl ester in 170 ml of tetrahydrofuran at O ° C is added 3.5 g of potassium t-butylate, stirred for 10 minutes, mixed with a solution of 9 g of ketone prepared according to Example 56 in 90 ml of toluene and stirred for 16 h. at room temperature in an argon atmosphere. Dilute with 1000 ml of ether, shake with water until neutral, dry over magnesium sulfate and evaporate in vacuo. The residue is filtered with a mixture of hexane and ether (3 + 2) through silica gel. In this case, 8.2 g of unsaturated ester are obtained in the form of a colorless oil.
    IR: 2950, 2870, 1700, 1655, 968 cm-.
    165556
    2.2 g of lithium aluminum hydride are added in portions at 0 ° C to a stirred solution of 8 g of the ester obtained. In 280 ml of ether and stirred for 30 minutes at 0 ° C. The excess reagent is decomposed by adding dropwise ether acetic acid, then 12 ml of water is added, stirred for 2 hours at 22 ° C, filtered and evaporated in
    W vacuum. The residue is chromatographed using a mixture of ether and hexane (3 + 2) on silica gel. In this case, 2.8 g of 2- (g) - (15.53, bK, 7U-7-tetrahydrof5 pyran-2-yloxy) -6- (E) - (3S, 4RS) -4 are obtained as a non-polar compound. - -methyl-3- (tetrahydropyran-2-yloxy) - -non-1-en-6-in-yl-bicyclo (3.3.0) - -octan-3-ylidene 1-ethan-1-ol and 4, 2 g. Chitouz compound in the form of a colorless oil.
    IR: 3600, 3430, 2942, 2863, 1600, 972 cm.
    Example 6. (5E) - (16RS) -1a, 1b-Digomo-16,20-dimethyl-3-oxa-18.18,
     19,19-tetradehydro-6a-carba-prostag-glandin-.
    By analogy with example 2, from 380 mg of aldehyde obtained according to example 5, 305 mg of (5E) - (16RS) -1a, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetrahydro -6a-carba-prostaglandin-12-11,15-diacetate.
    After cleavage of the protecting groups, 210 mg of the title compound are obtained.
    35 nor as a colorless oil.
    IR: 3600, 3400 (wide) 2962, 2865, 1720, 1601, 970 cm.
    Example 7. (5E) -2-descarb-40 hydroxy-1a, 1b-dihomo-2-formyl-20-methyl-3-oxa-1b, 16-trimethylene-18,18,19, 19-tetradehydro-6a -carba-prostaglandin-.
    45 By analogy with example 1 and example 5 from 0.9 g of 2- (E) -1S, 5S, 6R, (tetrahydropyran-2-yloxy) -6- (E) - (ZR) -3- (tetrahydropyran-2 -yl-oxy) -4,4-trimethylene-non-1-en-6-in50 il | -bicyclo (3.3.0) -octan-3-ylidene-ethane-1-ol (prepared according to example (5a c) from dimethyl zfir (2-oxa-3, 3-trimethylene-non-5-in-phosphonic acid), 0.5 g of the titanium compound are obtained in the form of a colorless oil.
    IR: 3610, 3400 (wide), 2968, 2864, 2730, 1725, 1602, 970 cm.
    7
    The starting material for the title compound is prepared as follows.
    (7a) -2 (E) - (15.55.6K, 7K) -7- (tetrahydropyran-2-yloxy) -4.4, -trimethyl-non-1-ene-6-in- il-bicyclo (3,3,0) -octane-3-ylidene-ethan-1-ol.
    By analogy. With example 5c from 3 g (III, 58.6K, 7K) -7- (tetrahydropyran-2- -yloxy) -6- (E) - (3R) -3- (tetrahydropyran-2-yloxy ) -4,4-trimethylene-non--1-en-6-ynyl-bicyclo (3.3.0) -octane-3-one after chromatographic separation of the isomers as a nonpolar compound, 470 ml of 2- (Z) - - (1S, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -4,4-trimethylene-non-1-ene-b-ynyl-bicyclo (3.3.0) -octane-3- ylyden-ethan-1-ol and 690 mg of the title compound as a colorless oil.
    IR: 3600, 3400 (wide), 2945, 2862, 1602, 972 cm.
    Example 8. (5E) -1a, 1b-Digomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19,19-tetradehydro-6a carba-β-prostaglandin-1.
    By analogy with example 2, from 400 mg of aldehyde obtained according to example 7, 295 mg of (5E) -1 a, 1b-dihomo-20-methyl-3-oxa-16,16-trimethylene-18,18,19 are obtained. , 19-tetradehydro-ba-carbaprostaglandin-1 - -11,15-diacetate.
    After cleavage of the protecting groups, 220 mg of the title compound are obtained as a colorless oil.
    IR: 3610, 3400 (wide), 2960,
    2864, 1721, 1602, 970.
    Example 9. (5E) -2-Dezcarboxy-1a, 16-DIGOMO-16,16-dimethyl-2-formyl-3-oxa-18,18,19,19-tetradehydro-b-carba- prostaglandin-12.
    By analogy with example 1 and example 5, prepared from 0.5 g of 2- (E) - (1S, 53.6K, 7K) - (7-tetrahydropyran-2-yl-oxy) -6- (E) - (3R ) -4,4-dimethyl-Z- - (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl-bicyclo- (3.3.0) -octane-3- -sh1iden-ethane-1-ol 0.28 g of the title compound as colorless.
    oils.
    I
    IR: 3600, 3400 (wide), 2965, 2732, 1724, 1600, 970 cm.
    When im 10, (5E) -1a, 16-dihomo-16,16-dimethyl-3-oxa-18,18,19, 19-tetradehydro-6a-carba-prostaglandin-1.
    16555 8
    By analogy with Example 2 of Example, 2 7g of aldehyde obtained according to Example 9, 180 mg of (5E) -1a, 1b-.-Dihomo-16,16-dimethyl-3-oxa-18,18 is obtained,
    5 19,19-tetradehydro-6a-carba-prostapa-glandin-1, -11,15-diacetate. After cleavage of the protecting groups, 120 mg of the title compound are obtained as a colorless oil.
     About IR: 3600, 3400 (wide), 2962, 2865, 1720, 1600, 971.
    Example 11. (5E) -2-Descarboxy-1a, 1 b-digomo-2-formyl-3-oxa-16, 16,20-trimethyl-18,18,19,19-tetrade 5 hydro- 6a-carba-prostaglandin-1,.
    By analogy with example 1 and example 5 of 1.1 g 2 - {(E) - (1S, 5S, 5R, 7R) -7- (tetrahydropyran-2-yloxy) -6: - - - (E) - (ЗR ) -4,4-dimethyl-3- (tetragide 20 ropiran-2-yloxy) -non-1-en-6-ynyl) -bicyclo (3.3.0) -octan-3-yliden-1-ethane-1-ol 0.6 g of the title compound is obtained as a colorless oil. IR: 3610, 3420 (wide), 2964,
    5 2730, 1725, 1602, 972 cm.
    Example 12. (5E) -1a, 1b-Dihomo-3-oxa-16,16,20-trimethyl-18,18, 19,19-tetradehydro-6a-carba-prostaglandin-1.
     By analogy with example 2, from 0.4 g of an aldehyde obtained according to example 11, 0.3 g of (5E) -1,1b-dihomo-3-oxa-16,16,20-trimethyl-18, 18,19 are obtained, 19-tetradehydro-6a-carba-pro35 tagglandin-1 -11,15-diacetate. After cleavage of the protecting groups, 0.22 g of the title compound is obtained as a colorless oil.
    IR: 3610, 3400 (wide), 2964,
    40 2864, 1721, 1600, 972.
    Example 13. (5E) - (l6RS) -2- -Descarboxy-18,19-didehydro-1a, 16- -digomo-16,19-dime, tyl-2- formyl-3- -oxa-ba-carb prostaglandin-1.
     By analogy with examples 1 and 5 of 0.7 g of 2- (E) - (1S, 5S, 6R, 7R) -7- - (tetrahydropyran-2-shyoxy) -6- (E) - (3S, 4RS) -4,7-dimethyl-3- (tetrahydropyran-2-Sh1oxy) -oct-1,6-dienyl-bicyclo (3.3.0) -yctan-3-ylidene-ethane-1-ol get 0.4 g of the title compound as a colorless oil.
    “IR: 3600, 3400 (wide), 2966, 2732, 1725, 1601, 972 cm.
    Example 14. (5E) -1a, 16-digomo-16,19-dimets1-18,19-dnehydro-3-oxa-b-a-carbaprostaglandin-.
     By analogy with example 2 from 0.2 aldehyde obtained according to example 13, 0.14 g of (5E) -1a, 1b- -digomo-16,19-dimethyl-18,19-didehyd ro-3-oxa-6a-carba is obtained -prostaglandin-1 -11,1 5-diacetate. After cleavage of the protecting groups, 90 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2960, 2860, 1720, 1601, 972 ..
    Example 15. (5E) - (16RS) -2- -Decarboxy-13,14-didehydro-1a, 16- -digomo-2-formyl-16-methyl-3-oxa-18,18,19,19- tetrahydro-6a-carba- -prystaglandin-.
    By analogy with example 1 and pri-. measure 5 of 0.6 g of 2- (E) - (1S, 5S, 6S, 7U-7- (tetrahydropyran-2-yloxy) -6- (38.4K8) -4-methyl-3- (tetrahydro- Pyran-2-yloxy) octa-1,6-diynyl-bi-cyclo (3.3.0) -octan-3-ylidene-ethane--1-ol gives 0.29 g of the title compound as a colorless oil.
    IR: 3610, 3410 (wide), 2966, 2730, 2225, 1725.
    The starting material for the title compound is prepared as follows.
    (15a) -2- (E)) - (1S, 5S, 6S, 5R) -7- - (tetrahydropyran-2-yloxy) -6- (33, 4K8) -4-methyl-3- (tetrahydropyran-2 - -yloxy) -oct-1,6-diynyl-bicyclo-. (3.3.0) -octane-3-ylidene-ethane-1-ol.
    By analogy with example 5c from 1.8 g (1I, 58, b8.7K) -7- (tetrahydropyran-2- -Sh1oxy) -6- (35.4KZ) -4-metsh-3-tetra hydropyran-2- Iloxy-octa-1,6-diynyl-bicyclo (3.3.0) -octan-3-one, after chromatographic separation of the isomers, as a non-polar compound, receive 380 mg of 2- (Z) - (1S, 58, B8.7E ) -7- (tetrahydropyran-2-yl-oxy) -6- (38.4R8) -4-methyl-3- (tetrahydropyran-2-yloxy), 6-diynyl-bicyclo (3.3.0) -octane -3-ylidene-ethane-1-ol and 610 mg of the title compound as an oil.
    IR 3600, 3400 (wide), 2945, 2860, 2225 cm-.
    PRI me R 16. (5E) - (16R8) -13, 14-Didehydro-Ta, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a carba prostaglandin-1,.
    By analogy with example 2, 0.21 g of (5E) - - (16K8) -13,14-didehydro-1a, 1b-dihomo-16-methyl-3-oxa-18 is obtained from aldehyde prepared according to example 15 from 0.4 g , 18,19,19-tetradehydro-bagcarbaprostaglandin-1 - 11,15-diacetate.
    After cleavage of the protecting groups
    5, 150 mg of the title compound are obtained as a colorless oil. IR: 3600, 3410 (wide), 2960, 2864, 2226, 1718 cm.
    Example 17. (5E) - (16RS) -20 -Descarboxy-13,14-didehydro-1a, 16-digomo-16,20-dimesh1-2-formyl-3-oxa-18,18,19, 19-tetradehydro-6a-carba-prostaglandin-12.
    By analogy with example 1 and example 15 r. 5 from 0.8 g of 2-G (E) - (18,58,68,7R) - -7-tetrahydropyran-2-yloxy) -6- (38, 4К8) - 3-methyl-3- (tetrahydropyran-2- -yloxy) -nona-1,6-diynyl-bicyclo- (3, 3.0) -octan-3-ylidene-ethan-1-ol
    0, 0.42 g of the title compound is obtained in the form of a colorless oil.
    IR: 3600, 3400 (wide), 2965, 2732, 2227, 1724 cm.
    Source material for the specified
    5 title compounds are prepared as follows.
    (17a) -2- (E) - (18,58,68,7R) -7- - (tetrahydropyran-2-yloxy) -6- (38, 4R8) -4-methyl-3- (tetrahydropyran-2 - yloxy) -nona-1,6-diynyl-bicyclo- (3.3.0) -octan-3-ylidene) -ethan-1-ol.
    By analogy with example 5c from 2.1 g (1R, 58.68.7R) -7- (tetrahydropyran-2-yloxy) -6- (38.4R8) -4-methyl-3-5-tetrahydropyran- 2-yloxy-nona-1,6-dienyl-bicyclo (3.3.0) octan-3-one after chromatographic separation of the isomers as a non-polar compound, 450 mg of 2- (Z) - (18,
    0 5S, 68, 7E) -7- (tetrahydropyran-2-yl-oxy-6- (ZR, 4R8) -4-mets-l-3- (tetra-hydropyran-2-yloxy) -non-1,6-di- ynyl-bicyclo (3.3.0) -octane-3-or-den-ethane-1-ol and 740 mg of the title
    5 Compounds as colorless oil. I
    IR: 3600, 3420 (wide), 2947, 2862, 2223 cm.
    Example 18. (5E) - (16R8) -13, P 14-didehydro-1a, 1b-dihomo-16,20-dimethyl-3-oxa-18,18,19,19-tetradehydro-6a prostaglandin-1 carba.
    By analogy with example 2, out of 620 mg of al- and dehyd obtained according to example 17, 340 mg of (5E) - (16R8) -13,14-didehydro-1a, 1b-dihomo-16,20-dimethyl-3-oxa is obtained -18,18,19,19-tetra-hydro-6a-carba-prostaglandin-1 -11, 15-diacetate. After cleavage of the protecting groups, 260 mg of the title compound are obtained as a colorless oil.
    IR: 3610, 3400 (wide), 2962, 2865, 2225, 1720.
    Example 19. (5E) -2-Dezcarbok si-13,14-didehydro-1a, 1b-dihomo-2-formyl-20-methyl-3-oxa-18,18,19,19- -tetrahydro-16, 16-trimethylene-6a-carba-prostaglandin-.
    By analogy with example 1 and example 5 of 0.41 g of 2- (E) - (1S, 5S, 6S, 7K) -7- (tetrahydropyran-2-yloxy-6- - (38) - (tetrahydropyran-2- iloxy) nor as a colorless oil.
    IR: 3600, 3400 (wide), 2963, 2865, 2225, 1720 cm.
    Example 21. (5Е) -2-Dezcarbok-5 si-13,14-didehydro-1a, 1b-dihomo-16, 16-dimethyl-2-formyl-3-oxa-18,18,19, 19-tetradehydro 6a-carba-prostaglandin-1 ,,.
    By analogy with example 1 and example 0 0 5 of 0.9 g 2 {- (E) - (1S, 5S, 6S, 7R) - -7- (tetrahydropyran-2-yloxy) -6- - (38) -4,4-dimethyl- (tetrahydrapiran--2-yloxy) -bkta-1, b-diynyl-bicyclo- (3.3.0) -octan-3-ylidene-ethane-1-ol
    -4,4-trimethylene-non-1,6-diynyl-bi- 5 get 0.47 g of the title compound
    the cycle (3.3.0) -octan-3-ylidene-ethane--1-ol gives 0.18 g of the title compound as a colorless oil
    IR: 3600, 3400 (wide), 2965, 2732, 2227, 1724 cm.
    The starting material for the title compound is prepared as follows.
    nor as a colorless oil.
    IR: 3600, 3410 (wide), 2966, 2730, 2225, 1725.
    The starting material for said title compound 20 is prepared as follows.
    (21a) -2- (E) - (1S, 5S, 6S, 7S) -7- - (tetrahydropyran-2-sh10ksi) -6- (3S) (19a) -2- (E) - (1S, 5S , 6S, 7R) -7- (Tet- - -4,4-dimethyl-3- (tetrahydropyran-2-regihydropyran-2-yloxy) -6- (3S) -3-yloxy) octa-1.6 -dienylZ-bicyclo-(tetrahydropyran-2-yloxy) -4,4-trimethylene-ion-1,6-diynyl-bicyclo- (3.3.0) -octan-3-ylidep-ethan-1-ol.
    By analogy with example 5c from 3.1 g (1K, 58.65.7K) -7- (tetrahydropyran-2- -yloxy) -6- (35) -3- (tetrahydropyran-2-yloxy) -4, 4-trimethylene-non-1,6-dienyl-bicyclo (3.3.0) -octan-3-one after chromatographic separation
    - (3.3.0) -octane-3-ylidene-ethane-1 -ol.
    By analogy with example 5c from 2.5 g (1R, 5S, 65.7U-7- (tetrahydropyran-2-yloxy) -6- | 3C) -4,4-dime.-30 -3- ( tetrahydropyran-2-yloxy) -oct-. -1,6-diynyl-bicyclo- (3.3.0) -octane-3-ol after chromatographic separation of isomers as a nonpolar
    compounds receive 625 mg of 2-f (Z) - isomers as a non-polar compound- 35, - (1S, 5S, 6S, 7R) -7- (tetrahydropyrane 2-neither get 890 mg 2- (Z) - (1S, 5S, 6S, -yloxy) -6- (3S) -4,4-dimethyl-3- (tet-7R) -7- (tetrahydropyran-2-yloxy) -6- - (3RS) -3- (tetrahydropyran- 2-yloxy) - -4,4-trimethylene-non-1, b-diinyl-bi40
    cyclo (3.3.0) -octane-3-ylidene-ethane-1-α-ol and 1.3 g of the title compound as an oil.
    IR: 3610, 3420 (wide), 2945, 2862, 2226 cm
    l1
    rahidropyran-2-yloxy) -octa-1,6-diynyl-bicyclo- (3.3.0) -octan-3-yl-d-α-ethane-1-ol and 1.1 g of the title link with oil.
    IR: 3600, 3400 (wide), 2946, 2865, 2225.
    Example 2I. (5E) -13,14-Di dehydro-1a, 1b-dihomo-1b, 1b-dimethyl. Example 20. (5E) -13,14-Dide-45-3-oxa-18,18,19,19-tetrahydro 6a hydr. O-1a, 1b-dihomo-20-methyl-3-oxa-carba-prostaglandin-1. -18,18,19,19-tetradehydro-16; 16-trimethylene-6a-carba-prostaglandin-1 J-.
    By analogy with example 2 out of 0.31 g obtained according to example 21 al. By analogy with example 2 out of 0.42 g 50, 0.21 g of (5E) -13.14 -4 obtained obtained according to example 19 al-dehydro-1a , 1b-dihomr-16,16-dimethyl-3-oxa-18, 18,19,19-te trade hydro- -ba-carba-prostaglandin-1 -11,15-di-
    dehydrate get 0.32 g of (5E) -13,14-dehydro-1a, 1b-dihomo-20-methyl-3-rx-18,18,19,19-tetradehydro-16, 16-trimethylene-6a carba-prostaglandin-lj-l1,15-diacetate.
    After cleavage of the protecting groups, 210 mg of the title compound-acetate are obtained.
     . After cleavage of the protecting groups, 0.14 g of the title compound is obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2964,
    2865, 2225, 1720 cm
    -one
    nor as a colorless oil.
    IR: 3600, 3400 (wide), 2963, 2865, 2225, 1720 cm.
    Example 21. (5E) -2-Dezcarboxy-13,14-didehydro-1a, 1b-dihomo-16, 16-dimethyl-2-formyl-3-oxa-18,18,19, 19-tetradehydro-6a -carba-prostaglandin-1 ,,.
    By analogy with example 1 and example 5 of 0.9 g 2 {- (E) - (1S, 5S, 6S, 7R) - -7- (tetrahydropyran-2-yloxy) -6- - (38) - 4,4-dimethyl- (tetrahydrapiran--2-yloxy) -bkta-1, b-diyl-bicyclo- (3.3.0) -octan-3-ylidene-ethane-1-ol
    0.47 g of the title compound are obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2966, 2730, 2225, 1725.
    The starting material for the title compound is prepared as follows.
    (21a) -2- (E) - (1S, 5S, 6S, 7S) -7- - (tetrahydropyran-2-sh10xy) -6- (3S) - -4,4-dimethyl-3- (tetragapripyran-2 - -yloxy) -octa-1,6-diynyl-3-bicyclo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -oct-1,6-diine 3-bicyclo-(3.3.0) -octane -3-ylidene-ethane-1 -ol.
    By analogy with example 5c from 2.5 g (1R, 5S, 65.7 U-7- (tetrahydropyran-2-yloxy) -6- | 3C) -4,4-dime.-3- (tetrahydropyran -2-yloxy) oct. -1,6-diynyl-bicyclo- (3.3.0) -octane-3-ol after chromatographic separation of isomers as a nonpolar
    compounds receive 625 mg of 2-f (Z) -, - (1S, 5S, 6S, 7R) -7- (tetrahydropyran 2- yloxy) -6- (3S) -4,4-dimethyl-3- (tet-
    rahidropyran-2-yloxy) -octa-1,6-diynyl-bicyclo- (3.3.0) -octan-3-yl-d-α-ethane-1-ol and 1.1 g of the title link with oil.
    IR: 3600, 3400 (wide), 2946, 2865, 2225.
    Example 2I. (5E) -13,14-Di dehydro-1a, 1b-dihomo-1b, 1b-dimethyl-3-oxa-18, 18,19,19-tetrahydro-6a-carba-prostaglandin-1.
    acetate.
    . After cleavage of the protecting groups, 0.14 g of the title compound is obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2964,
    2865, 2225, 1720 cm
    -one
    131
    Example 23. (5Е) -2-Dezkar6ok si-13,14-didehydro-1 a, 1b-dihomo-2-α-formyl-3-oxa-18,18,19,19-tetra-dehydro-16,16, 20-trimethyl-6a-carba-prostaglandin-1.
    By analogy with example 1 and example 5 from 0.8 g 2 (E) - (1S, 5S, 6S, 7R) - -7- (tetrahydropyran-2-yloxy) -6- - (38) -4,4- dimethyl-3- (tetrahydropyran-2-yloxy) -ion-1, b-diynyl-bicyclo (3.3,0) -octan-3-ylidene-ethane-1-ol get 0.31 g of the title compound in - as colorless oil.
    IR: 3610, 3420 (wide), 2965, 2730, 2226, 1724 cm.
    The starting material for the title compound is prepared as follows.
    (23a) -2- (E) - (15.53,63,7K) -7- (tetrahydropyran-2-yloxy) -6- (3S) -4,4-dimethyl-3- (tetrahydropyran-2 -yloxy) -nona-1,6-diynyl D-bicyclo (3.3.0) - -octane-3-ylidene-ethane-i-ol.
    By analogy with example 5c from 1.3 g of (1K, 55, b5.7K) -7- (tetrahydropyran-2- -yloxy) -6- (3s) -4,4-dimethyl-3- (tetrahydropyran- 2-shyloxy) nona-1,6-di-ynyl-bicyclo (Z.O.O.) octane-3-one after chromatographic separation of the isomers as a non-polar compound, 300 mg of 2- (Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yl-oxy) -6- (3S) -4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -n6-1,6-di -. ynyl-bicyclo- (3.3.0) -octan-3-or-7-ethane-1-ol and 430 mg of the title compound as an oil.
    IR: 3610, 3400 (wide), 2945, 2865, 2225.
    Example 24.: (5E) -13,14-dihydro-1a, 1b-dihomo-3-oxa-18,18, 19,15-tetradehydro-16,16,20-trime-tsh1-6a-carba- prostaglandin-1.
    By analogy with Example 2, 0.1 g of (5E) -13,14-dihydro-1a, 1b-dihomo-3-oxa-18,18, 19,19 are obtained from 0.16 g of aldehyde obtained according to example 23. - tetradehyde-16,16,20-trimethyl-6a-carba-prostaglandin-1 -11, 15-diacetate.
    After cleavage of the protecting groups, 60 mg of the title compound are obtained as a colorless oil. . IKG 3600, 3400 (wide), 2965, 2864, 2224, 1718.
    Example 25. (5Z) - (l6RS) -2- -Descarb6xy-1a, 1b-digmo-5-fluoro-2- -formyl-16-metsht-3-oxa-18,18,19,195. 14
    -tetradehydro-ba-carba-prostaglaidin- 2 .. To a solution of 420 mg 2-f (Z) - (1S, 5S, bK, 7K) -7- (tetrahydropyran-2-yloxy) -6- (E) - (38.4a5) -4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-b-ynyl - bicyclo- (3.3.0) -octan-3-ylidene-2- -fluoro-ethane-1-ol in 80 ml of 1-furan tetrahydhen at O C is added 42 mg of a 55% suspension of sodium hydride in mineral oil and stirred for 30 minutes at 24 C under argon atmosphere. A solution of 630 mg of 2- (3-bromopropyl) -, 3-dioxolane in 8 ml of tetrahydrofuran is then added dropwise and the mixture is heated under reflux for 20 hours under argon atmosphere. It is diluted with ether, washed with water until neutral, dried over magnesium sulphate and evaporated.
    drew in a vacuum. After chromatography of the residue on silica gel, 340 mg of the oxa compound is obtained with a mixture of hexane and ether (3 + 2), which together with 30 ml of a mixture of acetic acid and ethyl acetate
    acids, water and tetrahydrofuran (65 + 35 + 10) are stirred for 16 hours at 24 ° C. They are then evaporated in vacuo and the residue is chromatographed on silica gel. Using a mixture of ethyl acetate
    hexane (4 + 1), 280 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3420 (wide), 2960, 2930, 2870, 2730, 1730, 1603,970 cm 1
    Example 26. (5Z) - (16RS) -1a, 1 b-digo mo-5-fluoro-16-methyl-3-oxa-18, 18,19,19-tetradehydro-6a-carba-prostaglandin-1 .
    By analogy with example 2 of 205 mg
    aldehyde prepared according to Example 25 — 110 mg of (5Z) - (16RS) -1 -1, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetradehydro-6a is obtained. carta-prostaglandin-1-, 15-diacetate.
    After cleavage of the protecting groups, 78 mg of the title compound b are obtained in the form of a colorless oil.
    Example 27. (5Z) - (l6RS) -2- -Descarboxy-1a, 1b-dihomo-16,20-dimethyl-5-fluoro-2-formyl-3-oxa-18, 18, 19-19-tetradehydro 6a-carba-prosta-glandin-lj,
    By analogy with example 24, out of 610 mg of 2- (E) - (1S, 5S, 6R, 7R) -7- (tetropyridine-2-yloxy) -6- (3S, 4RS) -4-methyl-3 - (tetragamine-2-Shioxi) -non-1-en-6-ynyl-bicyclo (3.3.0) - -octane-3-yliden-2-fluoro-ethane-1-ol
    370 mg of the title compound are obtained as a colorless oil.
    IR: 3610, 3400 (wide), 2963, 2930, 2868, 2731, 1630, 1602.971 cm.
    Example 28. (5Z) - (16RS) -1a, 1b Digomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a-carba-prostaglandin-12.
    By analogy with example 2 of 230 mg
    obtained according to example 27 al-tO mo-1b, 1b-dimethyl-5-fluoro-3-oxa-18,18,
    125 mg of (5Z) - (16RS) -1 a, 1b-dihomo-16,20-dimethyl-6-fluoro-3-oxa-18,18,19,19-tetradehydro-ba-carba-prostaglandin - -11,15-diacetate.
    After cleavage of the protecting groups, 85 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2965, 2930, 2870, 1720, 1602, 970 cm.
    Example 29. (5g) -2-Descarboxy-1a, 1b-dihomo-5-fluoro-2-formyl-2019, 19-tetradehydro-6a-carba-prostaglandin-.
    Analogously to example 2, out of 220 mg of aldehyde 15 obtained according to example 31, 120 mg are obtained (5Z-19.1b-digomo-16, T6-dimethyl-5-fluoro 3-oxa-18.18, 19.19-tetradehydro -6a-carba-prostaglandan-1 -11,15-diacetate.
    After cleavage of the protecting groups 20, 92 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2964,
    2931, 2870, 1720, 1601, 971.
    Example 33. (5Z) -2-Dekkabbok-25 si-1 a, 1 B.-digomo-5-fluoro-2-formsh1-3-oksa-18,18,19,19-tetradehydro-16, 16, 20-trimethyl-6a-carba-prostaglandin-12.
     vv-t -Mt - - - -.-.... / - ,, -, Analogously to example 25 of 0.7 g -trimethylene-non-1-en-6-yn bicyc-2- (Z) - ( 1S, 5S, 6R, 7R) -7- (tetrahydrogen (3.3.0) -octan-3-ylidene -2-fluoropyran-2-yloxy) -6- (E) - (3RS) -4, 4-dimethyl-3- (tetrahydropyran-2-yloxy) - -non-1-en-6-ynyl-1-bicyclo- (3.3.0) - -octane-3-sh-iden-2-fluoro-ztan-1-ol 35 0.38 g of the title compound are obtained as a colorless oil.
    -methyl-2-oxa-18,18,19,19-tetradehyde-16,16-trimethylene-6a-carba-prostag glandin-.
    By analogy with example 25, out of 390 mg of 2- (Z) - (1S, 5S, 6R, 7R) -7- (TeT-rahydropyran-2-Sh1oxy) -6- (E) - (3R) -3- ( tetrahydropyran-2-yloxy) -4,4. -Stan-1-ol gives 165 mg of the title compound as a colorless oil.
    IR: 3600, 3410 (wide), 2965, 2931, 2870, 2730, 1630.1601.970cm.
    Etc. and measure 30. (5Z) -1a, 1b-digo-mo-5-fluoro-20-methyl-3-oxa-18,18,19, 19-tetradehydro-16,16-trimethylene-6a -carba Prostaglandin-12
    Analogously to Example 2, out of 190 mg of aldehyde obtained in Example 29, 105 mg of (5Z) -1a, 1b-dihomo-5-fluoro-20-metip-3-oxa-18,18,19,19- -tetradehydro-16, are obtained 16-trimethylene-6a -carba-prostaglandin-11,15-diacetate. I
    After cleavage of the protecting groups
    IR: 3610, 3400 (wide), 2965,
    2980, 2870, 2730, 1601, 970 cm
    -one
    40
    Example 34. (5Z) -1a, 1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetrahydro-16,16,20-trimetesh1 6a-carba-prostaglandin-. Analogously to example 2 of 0.3 g-. 45 aldehyde radiated according to example 33 is obtained 0.16 g of (5Z) -1a, 16-dihomo-5-fluoro-3-oxa-18,18,19,19-tetradehydro-16,16,20-trimetsh-1-6- prostaglandin-1 carba. -11,15-diacene- receive 70 mg of the title compound cn op-o
    JU TZTE.
    After cleavage of the protecting groups, 0.12 g of the title compound is obtained as a colorless oil.
    in the form of colorless oil.
    IR: 3600, 3400 (wide), 2965, 2930, 2870, 1718, 1602, 970.
    Example 31. (5Z) -2-Dezkarboksi-1 a, 1 b-digomo-16, 16-dimethyl-5-fluoro-55 3610, 3400 (wide), 2963, -2-formyl-3-oxa-18, 18,19,19-tetra- 2868, 1720, 1602.971 cm, dehydro-6a-carba-prostaglandin-1.
    Analogously to example 25 of 0.6 g 2 - {(Z) - (1S, 5S, 6R, 7R) -7- (tetrahydro Example 35. (5Z) - (16RS) -2- -Descarboxy-13,14-didehydro 1a, 1b- -digomo-5-fluoro-2-formyl-16-methyl-zpiran-2-yloxy) -6- (E) - (3K) -4,4-dimethyl-3- (tetrahydropyran-2 -yloxy) - -oct-1-en-b-ynyl-bicyclo- (3.3.0) - -octan-3-ylidene-2-fluoroethan-1-ol gives 0.27 g of the title compound as a colorless oil.
    IR: 3610, 3420 (wide), 2966, 2930, 2868, 2732, 1730, 1602.971 cm.
    Example 32. (57) -1a, 1b-digo19, 19-tetradehydro-6a-carba-prostag glandin-.
    Analogously to example 2, out of 220 mg of the aldehyde obtained according to example 31, 120 mg are obtained (5Z-19.1b-digomo-16, T6-dimethyl-5-fluoro 3-oxa-18.18, 19.19-tetradehyde- 6a-carba-prostaglandan-1 -11,15-diacetate.
    After cleavage of the protecting groups, 92 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3410 (wide), 2964,
    2931, 2870, 1720, 1601, 971.
    IR: 3610, 3400 (wide), 2965,
    2980, 2870, 2730, 1601, 970 cm
    -one
    Example 34. (5Z) -1a, 1b-dihomo-5-fluoro-3-oxa-18,18,19,19-tetrahydro-16,16,20-trimetesh1 6a-carba-prostaglandin-. Analogously to example 2 of 0.3 g-. 0.16 g of (5Z) -1a, 16-dihomo-5-fluoro-3-oxa-18,18,19,19- -tetradehydro-16,16,20-trimetsh-1-6a 3610 are obtained from the aldehyde which is radiated according to example 33; 3400 (wide), 2963, 2868, 1720, 1602.971 cm,
    Example 35. (5Z) - (16RS) -2- -Descarboxy-13,14-didehydro-1a, 1b- -digomo-5-fluoro-2-formyl-16-methyl-3-oxa-18, 18,19 , 19-tetradehyde-6a-carp-prostaglandin-1 j.
    Analogously to Example 25, from 0.41 g of 2 - ((7) - (15.53.68.7 SU-7- (tetrahydropyr AN-2-yloxy) -6-C (33.4EZ) -4-methyu1- -3- (tetrahydropyran-2-yloxy) -octa-1,6-diynyl I-bicyclo (3.3.0) -octane-3-ylidene-5-fluoro-3-ethane-1-ol, give 0.2 g the title compound as a colorless oil,
    IR: 3600, 3410 (wide), 2966, 2731, 2224, 1727. . Example 36. (5Z) - (16RS) -13, 14-Didehydro-1 a, 1b-dihomo-5-fluoro-16- -methyl-3-oxa-18,18,19,19-tetradehydrogen -carba-prostaglandin-12.
    Analogously to Example 2, 0.2 g of (5Z) - (16RS) - -13,14-didehydro-1a, 1b-dihomo-5-fluoro-1b-methyl-3- is obtained from 0.2 g of the aldehyde obtained according to example 35; oxa-18,18,19,19-tetradehydro-ba-carba-prostaglandin-K - -11,15-diacetate,
    After cleavage of the protecting groups, 70 mg of the title compound are obtained in the form of a colorless oil,
    IR: 3620, 3400 (wide), 2965, 2870, 2225, 1620.
    Example 37, (5Z) - (16RS) -2- -Descarboxy-13,14-didehydro-1a, 16- -digomo-16,20-dimetsh-5-fluoro-2-form-msh1-3-oksa-18 , 18,19,19-tetradehydro-6a-carba-prostaglandin-1,
    Analogously to Example 25, out of 0.7 g of 2- (g) - (13,55,65,7K) -7- (tetrahydropyran-2-yloxy) -6- (35.4KZ) -4-methyl-3- - (tetrahydropyran-2-yloxy) -ion-1,6-diyni. Cp-bicyclo- (3, 3, 0) -octan-3-yl-den-2-fluoro-ethan-1-ol get 0, 38 g of the title compound as a colorless oil.
    IR: 3600, 3400 (wide), 2968, 2730, 2225, 1728.
    Example 38, (5Z) - (16RS) -13,14-didehydro-1 a, 1b-dihomo-16,20-dimethyl-5-fluoro-3-oxa-18,18,19, | 9-tetra, adhede ro-6a-carba-prostaglandin-1 ,,
    Analogously to Example 2, from 0.35 g of the aldehyde obtained according to Example 37, 0.18 g of (5Z) - (16RS) -13, 14-didehydro-1a, 1 b-dihomo-16.20 - dimethyl-1 5-fluoro-3-oxa-18,18,19,19-tetra-dehydro-ba-carba-prostaglandin-Ij-11,15-diacetate,
    After cleavage of the protecting groups, 0.14 g of the title compound is obtained as a colorless oil.
    IR: 3600, 3420 (wide) / 2966, 2870, 2226, 1718.
    Example 39, (5Z) -2-fle3Kap6oK si-13,14-didehydro-1a, 1b-dihomo-5-fluoro-2-formyl-20-methyl-3-oxa-18, 18,19,19- tetradehydro-16,16-trimethylene-6a-carba-prostaglandin-1,
    In analogy to Example 25 of 1.2 g of 2- (Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- C (38) -3-tetrahydro pyran-2- yloxy) -4,4-trimethylene-non--1, b-diynyl-bicyclo- (3,3,0) -octane-3-stydeno | -2-fluoro-ethane-1-ol get 0.7 g the title compound as a colorless oil,
    IR: 3620, 3420 (shchi), 2970, 2731, 2224, 1730.
    Example 40, (5Z) -13,14-didehydro-1 a, 1b-dihomo-5-fluoro-20-methyl-3 oxa-18,18,19,19-tetradehydro-16, 16-trimethylene-6a prostaglandin-1 carba,
    Analogously to Example 2, from 0.6 g of the aldehyde obtained according to Example 39, 0.31 g of (5Z) -13.14-dihydro-1a, 1b-dihomo-5-fluoro-20-methyl-3-oxa is obtained. -18,18,19,19-tetradehydro-16,16-trimethylene-6a-carba-prostag-glandin-12-11,15-diacetate,
    After cleavage of the initial groups, 0.27 g of the title compound is obtained as a colorless oil.
    IR: 3620, 3425 (shchi), 2968, 2870, 2225,
    Example 41. (5Z) -2-fle3Kap6oK si-13,14-didehydro-1a, 1b-dihomo-16, - 16-dimethyl-5-fluoro-2-formyl-3-oxa-18,18,19 , 19-tetradehydro-6a-carba-β-prostaglandin-1.
    Analogously to Example 25, of 1.4 g of 2- (Z) - (1S, 5S, 6S, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S) -4,4-dimetsh-1-3 - (tetrahydropyran-2-yloxy) -oct-1, 6-diynyl-bicyclo- (3.3.0) -octane-3-ylidene-2-fluoro-ethane-1-ol, give 0.65 g of the title compound in the form of colorless oil,
    IR: 3600, 3420 (wide), 2970, 2930, 2865, 2730, 2225, 1730,
    Example 42. (5Z) -13, l4-flH-dehydro-1a, 1b-dihomo-16,1b-dimethyl-5-fluoro-3-oxa-18,18,19,19-tetradehydro-6a prostaglandin-1 carba
    Analogously to example 2, 0.22 g of (5) -13,14-dihydro-1 a, 1b-dihomo-16,16-dimethyl-5-fluoro-3-oxa-18 are obtained from the aldehyde obtained according to example 41 of the aldehyde. , 18,19,19-tetradehydro-6a-carba-prostaglandin-1 -11, 15-diacetate.
    After cleavage of the protecting groups, 0.18 g of the title compound is obtained as a colorless oil.
    IR: 3600, 3420 (wide), 2970, 2870, 2224, 1718.
    P r. Im p. 43. (5g) -2-Dezcarbok si-13,14-didehydro-1 a, 1b-dihomo-5-fluoro-2-formyl-3-oxa-18,18,19,19- -tetradehydro-16, 16,20-trimethyl-6a -carba-prostaglandin-.
    Analogously to example 25 of 0.7 g of 2- (g) - (18,53,68,7K) -7- (tetrahydropyran-2-yloxy) -6- (35) -4,4-dimethyl- -3 - (tetrahydropyran-2-yloxy) -non--1,6-diynyl-bicyclo- (3.3.0) -octane-3-ylidene-2-fluoro-ethane-1-ol gives 0.3 g of the title compounds in the form of a colorless oil.
    IR: 3600, 3420 (shchi), 2968, 2932, .2864, 2730, 2225, 1730.
    Example 44. (5g) -13,14-Didero-1a, 1b-dihomo-5-fluoro-3-oxa-18, 18,19,19-tetradehydro-16,16,20-trimethyl-6a -carba-prostaglandin-1.
    By analogy with Example 2, from 0.3 g of aldehyde obtained according to Example 43, 0.14 g of (5Z) -13.14-β-dehydro-1 a, 1b-dihomo-5-fluoro-3-oxa-18, is obtained 18,19,19-tetradehydro-16,16,20-trimethyl-ba-carba-prostaglandin-1 - -11,15-diacetate.
    After cleavage of the protecting groups, 0.1 g of the title compound is obtained as a colorless oil.
    IR: 3605, 3420 (wide), 2970, 2870, 2225, 1720 cm.
    Example 45. (5E) - (16RS) - -1a, 1b-Digomo-16-methyl-3-oxa-18.18, 19, 19-tetradehydro-6a-carba-prostaglandin-12-methyl ester .
    To a solution of 60 mg of (5E) - (16RS) -1a, 1b-dihomo-16-methyl-3-6xa-18,18,19, 19-tetradehydro-6a-carba-prostaglandin-lj in 10 MP of dichloromethane is added dropwise when, up to a non-fading yellow color, ether solution of diazomethane. After 5 minutes, evaporated in vacuo and the residue is chromatographed on silica gel. Using a mixture of ethyl acetate-hexane (4 + 1), 40 mg of the title compound are obtained as a colorless oil.
    IR: 3600, 3400 (wide), 2960, 1740, 974 cm.
    Example 46. (5E) - (16RS) -1a, 1b-Digomo-16-methyl-3-oxa-18,18,19,
    five
    0
    five
    0
    five
    0
    five
    0
    five
    19-tetradehydro-6a-carba-prostaglandin-1, j, -carboxamide.
    105 mg of (5E) - (1bK8) -1a, 1b-dihomo-16-methyl-3-oxa-18,18,19,19-tetra-dehydro-ba-carba-prostaglandin is dissolved in 3 ml of tetrahydrofuran and at 0 ° C, 40 mg of triethyl amine and 45 mg of isobutyl chloroformate are mixed. After 1 hour at 0 ° C and for 10 minutes, ammonia gas is passed, then left to stand for 1 hour at 24 ° C. After that, it is diluted with 30 ml of water, extracted three times with 30 ml of methylene chloride, and the combined organic extracts are added. Pour with 20 ml of brine, dry over magnesium sulphate and evaporate in vacuo. After chromatography of the residue on silica gel using a mixture of methylene chloride and isopropanol (9 + 1), 78 mg of the title compound are obtained in the form of an oil.
    IR: 3610, 3540, 3400 (wide), 2960, 1670, 975 cm.
    Example 47. (5Z) - (16RS) -1a,
    1 b-Ligomo-5-fluoro-16-methyl-3-ox.sa-18, 18., 19,19-tetradehydro-6a carba-prostaglandin-1 - (2, 3-dioxy-propyl) - -amide.
    195 mg of (5Z) - (16RS) -1a, 1b-digomp-5-fluoro-15-metsh-3-oxa-18,18,19,19- -theradehydro-6a-carba-prostaglandin-1g solution in 5 ml of acetone and mixed with 60 mg of triethyl amine and 75 mg of isobutyl chloroformate. After 20 minutes, a solution of 260 mg of 1-amino-2,3-β-dioxypropane in 8 ml of acetone and 8 ml of acetonitrile is added and stirred at 20 ° C for 2 hours. Concentrated in vacuo, diluted with methylene chloride, shaken with a small amount of brine, dried organic over magnesium sulfate and evaporated in vacuo. After chromatography, the residue on silica gel using methylene chloride-isopropanol (8 + 2) mixture gives 160 mg of the title compound as a colorless oil.
    IR: 3600, 3400 (wide), 2935, 1645, 974.
    Example 48. (5Z) - (16RS) -1a, 1b-Digomo-5-fluoro-16-methyl-3-oxa-18, 18,19,19-tetradehydro-6a-carba-prostaglandin-1 - ( 4-phenyl) -phenacyl ester.
    120 mg of (5Z) - (16RS) -1a, 1b-dihomo-5-fluoro-16-methyl-3-oxa-18,18,19,19-tetrahydrocarbo-carba-prostaglandin-1 is dissolved in ml of acetone and mixed with 90 mg (O-bromo-4-phenyl-acetophenone and 1 ml of triethylamine and stirred overnight at room temperature. Mix with 100 ml of ether, shake twice with water, each 10 ml each time, dried over magnesium sulphate and evaporated in vacuo. The purification is carried out by preparative thin-layer chromatography on silica gel plates, which are developed with ethyl acetate. 128 mg of the title compound are obtained.
    IR: 3610, 2940, 1740, 1703, 1602, 974.
    Example 49. (5E) - (16RS) -1a, 1b-Digomo-16-methyl-3-oxa-18,18,19, 19-tetradehydro-ba-carba-prostaglandin-12-tris- (hydroxymethyl) aminomethane salt,
    To a solution of 185 mg of (5E) - (16RS) -1a, 1b-dihomo-16-methyl-3-oxa-18, 18, 19, - 19-tetradehydro-6a-carba-simple; aglandin-lj in 35 ml of acetonitrile at 70 ° C is added a solution of 60 mg of tris- (hydroxymethyl) aminomethane in 0.2 ml of water. It is allowed to cool with stirring, after 16 hours the solvent is removed by decantation and the residue is dried in vacuo. 160 mg of the title compound is obtained in the form of a waxy mass.
    IR (K Cr isomers): 3300 (wide), 2930, 1720, 970.
    Comparative test data on the activity of the compounds obtained are given in the table.
    Systolic and diastolic pressure was measured with P.O. in awake patients with hypertension in rats at the following dosages: 0.1, 0.5 and 1.0 mg / kg.
    The maximum effect is determined in examples 2 and 18 at a dose of 0.5 mg / kg. The same maximum effect of lowering blood pressure in Example 1 of European Patent No. 55208 was obtained only at a dose of 1-2 mg / kg.
    The compound of Example 18 shows an LDjg (intragastric rat) of 10 mg / kg.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    . The method of producing carbacyclin derivatives of the general formula:
    XCH2l3o
    SNG
    CX
    l
    ten
    A-CH-D-E-Yaa
    OH OH
    where with R, H, OH, A means trans- or -CsC-rpynny, D means a group, -CH, where R CH
    3
    R,
     H, CH, or R - R, - (CH), -, E means trans-CH C (CH) - or -CnC
    group, R CH, X H, P, or when A is trans-CH CH-, E D -CH (CH) - CH, X H, F, R AISI, NHRy (Ry H, (OH)) , or with R, OH or their additive Hbjx base salts of tris (oxymethyl) aminomethane, characterized in that the compound of the general formula
    CH2, OH
    sc
    l
    V A-CH-D-E-R 6 O
    And (y
    where Rj is R, A, D, E, X have the indicated meanings, reacts with sodium hydride in tetrahydrofuran and then 2- (3-bromopropyl) -, 3-dioxolane is added, boil in an inert atmosphere 21- 24 hours, then acetal protecting groups are removed in an acidic medium to form the desired products (I) (R, H), which, if necessary, are acetylated with acetic anhydride with an yield of 11,15-diacetyl derivatives, which, if necessary, are subjected to
    oxidation followed by removal of acetyl protection and release of target products (I) (R, OH), and the obtained target product is subjected to the action of diazomethane with the formation of me23131655524
    a typical ester (R, OCH), or an active amide (R, NH, NHCH, successively isobutyl ester of chloroformic acid, ammonia and amine with the formation of the corresponding
    -CH (OH) CHjOH) or to the action of the input solution of the tris (oxymethyl) aminomete to form the basic salt.
    2 18 .
    18
    (pure 1br-methyl diastereomer)
    26
    (pure 16 p-methyl diastereomer)
     Example 1. Iloprost from European Patent No. 55208 1 (P.O.).
    Compiled by Yu. Belousov Editor E. Danko Tehred V. Kadar Proofreader M. Pojo
    Order 2375/58 Circulation 371 Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., d. A / 5
    Production and printing company, Uzhgorod, st. Project, 4
    amide (R, NH, (OH) CHjOH) or to the action of the tris (oxymethyl) -aminomethane input solution to form the basic salt.
    2 6
    ten
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    同族专利:
    公开号 | 公开日
    GR78873B|1984-10-02|
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    JPS5921636A|1984-02-03|
    CS235329B2|1985-05-15|
    FI832557A0|1983-07-13|
    NZ204875A|1986-11-12|
    FI77645C|1989-04-10|
    IE57233B1|1992-06-17|
    IL69199A|1987-08-31|
    ES524058A0|1984-04-16|
    DK321283A|1984-01-14|
    IL69199D0|1983-11-30|
    FI832557A|1984-01-14|
    PH25119A|1991-02-19|
    CA1248525A|1989-01-10|
    DK163579C|1992-08-03|
    ZA835109B|1984-08-29|
    DD210027B3|1990-07-18|
    AU571841B2|1988-04-28|
    FI77645B|1988-12-30|
    EP0099538A1|1984-02-01|
    HU191057B|1986-12-28|
    AU1671883A|1984-01-19|
    ES8403865A1|1984-04-16|
    DK321283D0|1983-07-12|
    EP0099538B1|1991-09-11|
    DD210027A5|1984-05-30|
    AT67182T|1991-09-15|
    JPH0324457B2|1991-04-03|
    DE3226550A1|1984-01-19|
    IE831630L|1984-01-13|
    DK163579B|1992-03-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB2040928B|1978-01-26|1982-12-08|Erba Farmitalia|Bicycloalkane derivatives useful as intermediates in preparing pg1 isosteres|
    US4705806A|1978-02-13|1987-11-10|Morton Jr Douglas R|Prostacyclin analogs|
    DE3048906A1|1980-12-19|1982-07-15|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    IE54303B1|1981-08-19|1989-08-16|Merrell Dow France|Fluorinated diaminoalkene derivatives|
    GR77976B|1982-03-12|1984-09-25|Schering Ag|
    DE3225287A1|1982-07-02|1984-01-05|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|DE3225287A1|1982-07-02|1984-01-05|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    DE3225288A1|1982-07-02|1984-01-19|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    JPH0414091B2|1983-02-01|1992-03-11|Sumitomo Pharma|
    DE3405181A1|1984-02-10|1985-08-22|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
    US4971987A|1984-07-27|1990-11-20|Schering Aktiengesellschaft|New carbacycline, process for their production and their use as a drug|
    DE3933523A1|1989-10-05|1991-04-11|Schering Ag|ANTIMETASTICALLY ACTIVE AGENTS|
    EP0431571A3|1989-12-05|1992-01-02|Sagami Chemical Research Center|Cis-bicyclonon-2-ene derivatives|
    DE4104607A1|1991-02-12|1992-08-13|Schering Ag|PROSTACYCLIN AND CARBACYCLINE DERIVATIVES AS A MEDIUM FOR TREATING FEVERED DISEASES|
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    KR20160042039A|2013-08-09|2016-04-18|알데릭스, 인코포레이티드|Compounds and methods for inhibiting phosphate transport|
    US20200368223A1|2019-05-21|2020-11-26|Ardelyx, Inc.|Methods for inhibiting phosphate transport|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19823226550|DE3226550A1|1982-07-13|1982-07-13|NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|
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