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    • 专利摘要:
    The present invention relates to new furyl derivatives of 16-substituted prostaglandins, to a process for their preparation and to pharmaceutical and veterinary compositions containing them. The new compounds of the invention are optically active or racemic prostaglandins of the following formula (I) <IMAGE> (I) wherein R is (1) -OH or -OR' wherein R' is C1-C6 alkyl optionally substituted by phenyl or by a monocycloalkyl group or by a pentatomic or hexatomic heteromonocyclic ring containing at least one heteroatom chosen from O, S and N; (2) <IMAGE> wherein each of R'' and R''', is independently, hydrogen; C1-C6 alkyl; phenyl; or a pentatomic or hexatomic heteromonocyclic ring containing at least one heteroatom chosen from O, S and N; or R'' and R''', together with the nitrogen atom to which they are linked, form a pentatomic or hexatomic heteromonocyclic ring optionally containing a further heteroatom chosen from O, S and N; (3) -W-(CH2)n-X wherein W is -O- or -NH-, n is an integer of 1 to 4 and X represents a group -OR' or a group <IMAGE> wherein R', R'' and R''' are as defined above; one of R1 and R2 is hydrogen and the other is hydroxy or R1 and R2, taken together, form an oxo group; one of R3 and R4 is hydrogen and the other is hydroxy; one of R5 and R6 is hydroxy and the other is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or phenyl; one of R7 and R8 is hydrogen and the other is a C1-C4 alkyl or tri-halo-C1-C4 alkyl group; m is an integer of 1 to 3; R9 is a 2-furyl or 3-furyl group, optionally substituted by one or more substituents chosen from C1-C4 alkyl, C1-C4 alkoxy, tri-halo-C1-C4 alkyl and halogen; and the symbol represents a single bond or a cis double bond.
    公开号:SU1489582A3
    申请号:SU843810695
    申请日:1984-11-02
    公开日:1989-06-23
    发明作者:Franko Faustini；Achille Pantseri；Fabritsio Ortsi；Enriko Di Salle；Roberto Tseserani
    申请人:Erba Farmitalia；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new optically active or racemic furyl derivatives of 16-substituted prostaglandins. $
    The new compounds are optically active or racemic prostaglandins of the following formula
    (I)
    10
    fifteen
    where K = H or C, -C 6 -alkyl;
    K / is a hydroxyl group; - hydrogen
    H 2 or B pu;
    and K g together form a ketogroup20
    - single or cis25
    35
    line
    double bond.
    The purpose of the invention is a method for producing new derivatives of prostaglandin with stronger pharmacological activity and fewer side effects compared to natural compounds.
    Example 1. Under argon atmosphere 30, a solution of 0.378 g of dimethyl- (G2-oxo-33-3-methyl-4- (5-methyl-2-furyl)] butyl) phosphonate in 5 ml of dry benzene was added dropwise to the stirred sludge 0.044 g of 80% CaN (dispersion in mineral oil) in 5 ml of dry benzene in the absence of moisture. Stirring is continued until the evolution of hydrogen ceases, and then a solution of 0.510 g of 1-alpha-G7 / (methoxycarbonyl) -hex-5 '(Ζ) -ethyl) -2-beta-formyl-3-alpha is added to this mixture in one portion -oxy-5-alpha-acetate · oxycyclopentane in 5 ml of dry benzene.
    The final mixture was stirred for 1 h at 25 ° C, and then neutralized by the addition of acetic acid and stirring was continued again for 30 minutes. The organic phase is washed under neutral with water, dried and the solvent is removed by evaporation in vacuo. The crude product is subjected to chromatographic purification using a 95: 5 ratio of diethyl ether and ethanol as eluent $$, as a result of which 0.51 g of pure 9.1-acetate-type ether 51.1ZE40 is obtained
    45
    fifty
    -9-alpha, 11-alpha-dioxo-15-oxo-163-methyl-18,19,20-trinor-17- (5 1 -methyl-2 7- furyl) -5,1-3-denoic acid ; (^) o - + 36.2 ° (C-1, chloroform).
    According to the same procedure, using saturated 1-alpha (7 - (methoxycarbonyl) hexyl) -2-beta-formyl-3-alpha-hydroxy-5-alpha-acetoxycyclopentane, the corresponding 9-acetate methyl ester 13e-9 alpha, 11-alpha-dioxo-15-oxo-16-methyl-18,19,20-trinor-17-5'-methyl-2'-furyl) simple-13-enoic acid, and using 1- alpha (7 7 - (methoxycarbonyl) -hex-5 7 (2) -enyl) -2-beta-formyl-5-al fa-acetoxycyclopentane and 1-alpha (7 '- (methoxycarbonyl) hexyl) 2-beta -formyl-5-alpha-acetoxycyclopentane receive respectively 9-acetate methyl ester '5Ζ, 1 ZE-9-alpha-hydroxy- s. -15-oxo-1 6-methyl-18,19,20-τρinορ-1 7- (5'-methyl-2'-furyl) -5,13-dienoic acid and 1ZE-9-alpha 9-methyl ester -oxy-15-oxo-16-methyl-18,19,20-trinor-17— (5'-methyl-2'-furyl) -simple-13-enoic acid.
    Example 2. ' A solution of 1.26 g of 9Ζ methyl acetate 5Ζ,
    1ZE-9-alpha-11-alpha-hydroxy-15-oxo-1bZ-methyl-18,19,20-trinor-17— (5 -Methyl-2'-furyl) -sim-5,13-dienoic acid in 25 ml of methanol, 0.315 g of IAHV ^ in 30 ml of methanol cooled to -30 using an external cooling bath is added dropwise to a stirred solution. After the addition is complete, the temperature is maintained at -25 to -30 ° C for 20 minutes. Then the solution is neutralized with acetic acid and the mixture is left to stand until the temperature rises to room temperature. The solution was diluted with 50 ml of ethyl acetate and washed with brine, dried and the solvent was removed by evaporation. Crude epimeric mixture of 9,1-acetate methyl ether 5,1ZE-9-alpha-11-alpha, 15 (KZ) -trioxy-16-methyl-18,19,20-trinor-17-5'-methyl-2'-furyl ) -simple-5,13-dienoic acid was separated into two epimers 153 in 15K chromatographic purification on silica gel using a mixture of ethyl acetate with n-hexane in a ratio of 9: 1 as eluent, resulting in 0.49 g
    3
    1489582
    4
    5Ζ, 13E-9-alpha, 11-alpha, 158-trioxy-1 6-methyl-18,19,20-trinor-17- (5 Ζ- methyl-2-furyl) -simple 5-methyl acetate 9-acetate , 13-dienoic acid, (· ί) β = +32.7 0 (s-1, chloroform) and 0.51 g of the corresponding 15K epimer, 5Ζ-ethyl acetate 5Ζ, 13E-9-alpha, 11-alpha, 15E-trioxy-16-methyl-18,19,20-τρΗΗθργΙ7-, θ - (5-methyl-2'-furyl) -sim-5,13-dienoic acid, ("О ^ = +9.8" ( s-1, chloroform).
    Example 3. A stirred solution of 0.25 g of 9-acetate methyl-15th ether 5Ζ, 1ZE-9-alpha, 11-alpha,
    . 153-trioxy-168-methyl-18,19,20-trinor-17- (5-methyl-2'-furyl) -simply-5,13-dienoic acid in 10 ml of methanol - solutions of 0.10 g of 20 nidrate are treated lithium oxide in 1 ml of water. This mixture was stirred at room temperature for 6 hours and then neutralized to a pH value of 6.2 by adding 10% aqueous 25% sodium hydrogen phosphate aqueous solution to it, subjected to extraction with ethyl acetate, washed with brine and dried. The solvent was removed to give 0.22 g of 5Ζ, 13E, -9-al-30
    fa, 11-alpha, 153-trioxy-1bZtmethyl-18,19,20-trinor-17- (5 1 -methyl-2'-furyl) -simple-5,13-dienoic acid,
    (<Ζ) β = + 26.8 ° (s-1, ethanol).
    . In accordance with the described procedure using 5-methyl ester 5Ζ, 13E-9-alpha,
    11-alpha, 15B-trioxy-163-metip- <
    -18, 1 9,20-trinor-17- (5 1- methyl-2``-furyl) -simply 5, 1 3-dienoic acid 40 give pure 5Ζ, 13E-9-alpha, 11-alpha , 15B-trioxy-163-methyl-18,19,20-trinor-17- (5'-methyl-2'-furyl) -sim-5,1 3-dienoic acid, (</) 0 = * 5, 5 (s-1, ethanol) .45
    Carrying out a similar procedure, the following compounds are obtained, where values (^) о are given for concentrations of C-1 in ethanol:
    5Ζ, 13E-9-alpha, 11-alpha, 153-triox-163-methyl-18,19,20-trinor-17- (2'-furyl) -simple-5,13-dienoic acid, ("Oa = + 28.2 °;
    5Ζ, 1ZE-9-alpha-11-alpha, 153-trioxy-163-methyl-13,19,20-trinor-17- (3'-furyl) -simple-5,13-dienoic acid (a /) ^ = +27.5 C ;
    5Ζ, 1ZE — 9-alpha, 11-alpha, 153 —- trioxy - 168-ethyl-18,19,20-trinor-17- (2 -Furyl) -simple-5, 13-dienoic acid (2) a = + 29 °;
    5Ζ, 1ZE-9-alpha-11-alpha, 153-trioxy — 1 68 — ethyl-18,19,20-trinor — 17- (3 ^ -furyl) —simple-5,13 — dienoic acid, (<< ) 5> - +24.8 e ;
    5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-163-ethyl-18, I9,20-trinor-17> - (5 1 -methyl-2'-furyl) -simple-5,13-diene acid (Λ) v = +27 V;
    5Ζ, 13E-9-alpha, 11-alpha, 153-three hydroxy-163-methyl-18,19,20-trinor-17- (5-ethyl-2-furyl) -simple-5,13-dienoic acid, (<) "= + 31.6 ° and the corresponding 1bK epimers, in particular;
    5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-16-K-metip-18,19,20-trinor-17- (2’-furyl) -simple-5,13-diene
    .'acid, (<) 0 = + 30, b ';
    5Ζ, 13E-9-alpha, 11-alpha, 153—-trioxy-16K-methyl-18,19,20-trinor-17- (3'-furyl) -simple-5,13-dienoic acid, (οί) a = 31 to 15K, and epimers of these compounds.
    Example 4. To a solution of 0.260 g of 9-methyl acetate 5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-163-methyl-18,19,20-trinor-17- (5 '-me type-2 '-furyl) -simple-5,13-dienoic acid in 8 ml of dry dichloromethane add 0.126 ml of DHA and 0.010 g of η-tbluolsulfonic acid. The solution was stirred at room temperature (25 ° C) for 2 hours, then it was diluted with 50 ml of diethyl ether and washed twice with 5% aqueous sodium bicarbonate, washed twice with water and then dried. The solvent is removed in vacuo, the crude product is dissolved in 10 ml of methanol and 0.1 g of potassium carbonate is added to the solution, then the solution is stirred at room temperature for 6 hours, after which it is treated with a 30% aqueous solution of sodium hydrogen phosphate (30 ml). ) and subjected to extraction processing in 4 portions of 20 ml of ethyl acetate. The organic phase is washed, dried and the solvent is distilled off in vacuo. The residue was purified by chromatography on silica gel using a 40:60 mixture of ethyl acetate and n-hexane as the eluent to give 0.265 g of pure 5Ζ, 13E-9-alpha, 11-alpha, 153-three, hydroxy-163- metip-18,19,20-trinor-17- (5-methyl-2 '-furyl) -simple-5,13-di5
    1489582
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    enic acid - methyl ether-11,15-bis-THP-ether,
    The resulting product was dissolved in 3 ml of dry benzene and 1 ml of dry DMSO, and then it was reacted with 0.144 g of DCC together with several drops of a pyridine debromoacetate solution (0.6 ml of pyridine and 0.25 ml of trifluoroacetic acid) and pyridine Yu as a catalyst. The reaction mixture is heated to 35 ° C for 1 h with stirring, diluted with 25 ml of benzene, and then 2 ml of a 6% aqueous solution of primary 15 sodium hydrogen phosphate are added. The sludge is filtered off, the solid phase is washed with 5 ml of benzene, the organic phase is separated, washed with 2 ml of water four times, then dried and the solvent is removed in 20 vacuum to obtain 0.250 g of crude 5Ζ, 1ZE-9-oxo-11-alpha, 158-dioxo- 165-methyl-18,19,20-trinor-17- (5-methyl-2-furyl)-simple-5,13-dienoic 'acid-methyl ether-11,15-bis-25-ether. The crude product is dissolved in 4 ml of a mixture of acetic acid, water and THF in a ratio of 4: 2: 1 and stirred at 40 C for 3 hours; the mixture. cool 50 ml of a mixture of water with ice 30 and four times subjected to extraction treatment with 20 ml of ethyl acetate. The organic phase is washed with 10 ml of a 5% solution of sodium dihydrogen phosphate in water, 10 ml of water and then 35, dried, the solvent is removed in vacuo and the crude product is chromatographed on silica gel to give 0.128 g of pure methyl ether 5Ζ, 1ZE-9 -oxo-11-alpha, 155-di-40 hydroxy-16-methyl-18,19,20-trinor-17— (5 - methyl-2-furyl) -simple-5,13-dienoic acid (< 2) p = -59.2 ° (s-1, chloroform).
    Example 5. To a solution of 0.53 g of 45 13E-9-alpha, 11-alpha, 15-trioxy-1b8-metip-18,19,20-trinor-17- (2'-furyl) -simple-13-diene acid-1 1,15-bis-THP-ether in 4.5 ml of dry benzene and 1.5 ml of dry DMSO add 5θ
    0.285 g of DCC together with a few drops of a pyridinium trifluoroacetate solution obtained from 0.6 ml of pyridine and 0.25 ml of trifluoroacetic acid and pyridine as a catalyst. 55 The reaction mixture is heated to 30 ° C for 1 h with stirring, diluted with 20 ml of benzene, and then 5 ml of an aqueous 6% solution of sodium hydrogen phosphate are added to it. The sludge is filtered and the solid phase washed with 20 ml of benzene. The organic phase is separated, washed with water, dried and the solvent removed in vacuo to give 0.640 g of a yellow oil-like product. This crude product was subjected to silica gel column chromatography using a mixture of ethyl acetate and n-hexane and a few drops of triethylamine as an eluent, to give 0.480 g of 13E-9-oxo-11-alpha, 158-dioxi as a clear, oil-like product. -168-methyl-18,19,20-trinor-17— (2'-furyl) -simple-13-enoic acid-11,15-6is-THP-ester, (· <) в = -85 ° (С -1, chloroform). This product is then dissolved in 10 ml of a mixture of acetic acid with water in a ratio of 2: 1 and the solution is stirred at 40 ° C for 3 hours. Then the mixture is rapidly cooled and subjected to four times extraction treatment with 20 ml of ethyl acetate. The organic phase is washed with water, dried and the solvent is distilled off in vacuo. The crude product is subjected to silica gel column chromatography using an 8: 2 mixture of ethyl acetate and n-hexane as the eluent, to give 0.230 g of pure 1ZE-9 — oxy-11-alpha, 15-dioxi-16-methyl -18,19,20-tripor-17- (2-furyl) -simple-13-enoic acid in the form of oil-like product, (2) = e -53 (C-1, ethanol). In accordance with the same procedure, the epimeric 1ZE-9-oxo-11-alpha, 15K-dioxi-165-methyl-18,19,20-trinor-17- (2 -Pheryl) -simple-1 3-ene is obtained acid, (Ό β =
    = -72 ° (C-1, ethanol).
    I
    In accordance with a similar procedure receive the following compounds, where the values of (2) th are given for the concentration of C-1 in ethanol:
    5Ζ, 1ZE-9-oxo-11-alpha-dihydroxy-155 163 ~ metip-18,19,20-trinor-17- (2 1 '-furyl) -simple-5,13-dienoic acid, ( «ί ) a = -54 ';
    5Ζ, 1ZE-9-OXO-11-alpha, 155-diox. And-1 b5-methyl-18, 1 9,20-trinor-1 7- (3'-furyl) -simple-5,13-dienoic acid , (^) a = -55.4 ';
    5Ζ, 1ZE-9-oxo-11-alpha, 155-dioxi-165-ethyl-18.19,20-trinor-177
    1489582
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    - (2'-furyl) -simple - 5,13-daynoic acid, (^) a = 53.8 °;
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-168-ethyl-18,19,20-trinor-17- (З 1- furyl) -simple-5,13-dienoic acid, (<L) L = -56 ';
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-168-methyl-18,19,20-trinor-17- (5 Ζ -methyl-2 1- furyl) -simple-5,13-dienoic acid , (° <) s - -61 °;
    5Ζ, 13E-9-oxo-11-alpha, 155-dioxi-1bZ-ethyl-18,19,20-trinor-17- (5-methyl-2 g- furyl) -simple-5,13-dienoic acid, ( "<), and = -60,4 °;
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-163-methyl-18,19,2 0-trinor-17- (5'-ethyl-2'-furyl) -simple-5,13-diene acid, (o) a = -68 '; ·
    13E-9-oxo (11-alpha, 155-dioxi-168-methyl-18,19,20-trinor-17- (3 Ζ -pheryl) -simple-13-enoic acid,
    = -56 °;
    1ZE-9-oxo-11-alpha, 158-dioxi-163-ethyl-18,19,20-trinor-17- (2 1- furyl) -simple-1 3-enoic acid, (<<) = = - 50 °;
    1ZE-9-oxo-11-alpha, 153-dioxi-1bZ-ethyl-18,19,20-trinor-17- (3'-furyl) -simple-1 3-enoic acid, (° () 0 =
    = -58 °;
    1ZE-9-oxo-11-alpha, 153-dioxo-1 63-methyl-18,19,20-trinor-17- (5 ζ- methyl-2 1- furyl) -simple-13-enoic acid, (Ch ) o = -60.5'C;
    1ZE-9-OXO-11-alpha, 153-dioxi-1 63-ethyl-18,19,20-trinor-17- (5 ζ- methyl-2-furyl) -simple-13-enoic acid, (C) a = -64 °;
    1ZE-9-oxo-11-alpha, 153-dioxo-1 68-methyl-18,19,20-trinor-17- (5'-ethyl-2'-furyl) -simple-13-enoic acid, (about () ^ = -68.7 °; as well as 15Pi and 16K epimers of all these compounds, in particular:
    1ZE-9-oxo-11-alpha, 153-dioxi-1 bK-methyl-18.19,20-trinor-17- (2 '.-Furyl) -simple-13-enoic acid, (^) ^ = = -68.5 °;
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-1bK-methyl-18,19,20-trinor-17- (2 ; -furyl) -simple-5.1 8-dienoic acid, (o0 < 2 = -71.
    Example 6. The conversion of the blocked form of compound I to another compound I,
    A solution of 1.65 g of 5Ζ, 1ZE-9-alpha-11-alpha, 153-trioxy-1b8-methyl-18,19,20-trinor-17- (2'-furyl) -prost-5,13- is carried out 163-methyl-18.19, 20-trinor-17- (2-furyl) -5,13-dienoic acid-11,15-bis-THPether in 20 ml of diethyl ether with 1 N. diazomethane solution until a stable yellow color is formed. The solvent was evaporated in vacuo to give 1.67 g of crude methyl ether, which was purified by chromatography on silica gel using a mixture of ethyl acetate with n-hexane and triethylamine in a ratio of 50: 50: 0.1, to give 1.48 g crude 5Ζ 13E-9-alpha, 11-alpha, 153-trioxy 163-methyl-18,19,20-trinor-17- (2 -furyl) -simple-5,13-dienoic acid methyl ester - 11.15 bis-THP ether, (<7) a = +36.2 (s-1, chloroform),
    11,15-bis-THP-ester protecting groups are removed by treatment with an aqueous solution of acetic acid in accordance with the procedure described in example 5, whereby methyl 5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-163 are obtained -methyl-18.19, 0-trinor-17- (2-furyl) -5,13-dienoic acid, (^) = +25.04 '(s-1, ethanol).
    Example 7. The conversion of the protected form of compound I to another compound of formula I.
    A solution of 1.12 g of 5Ζ, 13E-9-alpha,
    11-alpha, 15 ^ -trioxy-16 ^ -methyl-18, ιΐ9,20-trinor-17- (2'-furyl) -simple-5,13-dienoic acid - methyl ether-11, 15-bis-THT1 -ether in 20 ml of acetone is cooled to -25 ° C, and then treated with 1.279 ml of Jones reagent added over 10 min, maintaining the temperature in the range from -25 to -30 ° C. The reaction mixture is heated to -10 ° C and maintained at this temperature for 30 minutes. After decomposition of the excess Jones reagent by adding 1 ml of isopropanol, the mixture was diluted with 60 ml of benzene, the organic phase was washed several times with a saturated aqueous solution of ammonium sulfate until neutral, dried and evaporated to dryness, resulting in 1.0 g of crude 5Ζ, 13E-9-OXO- 11-alpha, 153-dioxi-163-methyl-18,19,20-trinor-17— (2'-furyl) -simple-5,13-dienoic acid methyl ester - 11,15-bis-TPP ester. A solution of this crude product in 4 ml of glacial acetic acid and 2 ml of water
    10
    9 1489582
    heated to AO ° C and maintained at this temperature for 90 minutes, and then sharply cooled by adding 100 ml of a mixture of water and ice, subjected to extraction processing with 200 ml of ethyl acetate, and the organic phase was washed with 5 £ aqueous sodium bicarbonate and water. The solvent was evaporated in vacuo and the crude product was subjected to silica gel column chromatography using a mixture of ethyl acetate and n-hexane in a ratio of 8: 2, whereby 0.337 g of pure methyl ether 5Ζ, 1ZE-9-οκso-11-alpha, 15 ^ -dioxio-163-methyl-18,19,20-trinor-] 7- (2'-furyl) -sim-5,1.3-d-nenoic acid, (° /) β = -53,4 *, (" () <£ = -334.3 * (c = 1, ethanol 95 °),
    NMR spectrogram (with C0C1 3 , bh.
    1,000,000 hours): 0.87 (ZN, d, CH 3 -C , ); 5.35 (2H, m, delta 5.6); 5.60 (2H, m, delta 13.14); 6.00, 6.27, 7.23 (ZN, furyl).
    In a similar way, the following compounds are obtained in which (“ί) β values are given for the concentration of C-1 ethanol:
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-163-methyl-18,19,20-trinor-17— (3'-furyl) -simple-5,13-dienoic acid methyl ester, ( <<) 0 = -52 *;
    methyl 5Ζ, 1ZE-9-oxo-11-alpha, 158-DIOXY-168-Ethyl-18,19,20-trinor-17- (2'-furyl) -prime-5,13-dienoic acid, ( 4) ϊ) = -53 °;
    methyl 5Ζ, 1ZE-9-oxo-1 1-alpha, 153-DIOXN-1bZ-ethyl-18,19,20-trinor-17- (3 7- furyl) -prost-5,13-dienoic acid, ( <) $ = -52.5 °;
    5Ζ, 1ZE-9-oxo-11-alpha, 153-dioxi-1b methyl methyl ester 18,19,20-trinor-17- (5'-methyl-2-furyl) -propa-5,13-dienoic acid methyl ester, (Ό $ =
    - -59.2 °;
    5Ζ, 13E-9 — oxo-11-alpha, 153-dioxi-168-ethyl-18,19,20-trinor-17- (5 - '-methyl-2 1- furyl) -simple-5,13-diene acid, methyl ether, ("Όε, = -57;
    5Ζ methyl ester, 1ZE-9-oxo-11-alpha, 158-dioxi-168-methyl-18,19,20-trinor-17- (5 1- ethyl-2'-furyl) -prost-5,13- dienoic acid, (e) ^ = ryl) -sim-5,13-dienoic acid;
    methyl ether 5 1, 1ZE-9-oxo-11 - as well as the analogous 15K and 16K epimers.
    alpha, 153-dioxi-163-methyl-18,19,20- Example 9. A solution of 500 μg
    -trinor-17- (2’-furyl) -simple-5.13-di. 5Ζ, 13E-9-oxo-11enoic acid methyl ester (x) b = -65 °; alpha, 153-dioxi-1bZ-methyl-18,19,2010
    fifteen
    20
    thirty
    1ZE-9-oxo-11-alpha, 155-dioxi-168-methyl-18,19,20-trinor-17- (2 7- furyl) -simple-13-enoic acid, methyl ether, (^) <a = -51.8 ';
    1ZE-9-oxo-11-alpha methyl ester, 158-DIOXY-168-methyl-18,19,20-trinor-17- (2-furyl) simple-13-enoic acid, (<) d = -54 *;
    1ZE-9-oxo-11-alpha, 153-dioxi-163-methyl-18,19,20 - trinor-17- (5 1- methyl-2 7- furyl) -propa-13-enoic acid methyl ester ( “Ί) 3 = -59; and corresponding 15 and 16 epimers.
    Example 8. The conversion of compound I to its salt.
    A solution of 0.203 g of 5, 13E-9-alpha,
    15-trioxy-16-methyl-18,19,20-trinor-1 7- (2 7- furyl) -sim-5,13-dienoic acid in 5 ml of ethanol is treated with 5 ml of 0.1 N. sodium hydroxide solution. The alcohol is removed in vacuo and the aqueous solution is lyophilized to obtain 0.210 g of dry sodium salt 25 5Ζ, '1ZE-9-alpha, 153-trioxy-1b8 ~ methyl-18,19,20-trinor-17- (2'-furyl) - simple 5,13-dienoic acid in the form of a white powder, (^) ^ = +28.7 e (c = 1, ethanol).
    The following sodium salts are prepared in a similar way:
    5Ζ, 13E-9-alpha, 11-alpha, 158-trioxy-163-metip-18,19,20-trinor-17- (3-furyl) -simple-5,13-dienoic acid sodium salt;
    5Ζ, 13E-9-alpha, 11-alpha, I53-trioxy-163-ethyl-18,19,20-trinor-17- (2 7- furyl) -sim-5,13-dienoic acid sodium salt;
    5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-163-ethyl-18,19,20-trinor-17- (3 7- furyl) -sim-5,13-dienoic acid sodium salt;
    sodium salt of 5Ζ, 13E-9-alpha, 11-alpha, 158-trioxy-163-methyl-18,19,20-trinor-17- (5'-metip-2'-furyl) -prost-5, 13- dienoic acid;
    5 соль, 13E-9-alpha sodium salt,
    11 alpha; 158-trioxy-168-ethyl-18,19,20-trinor-17- (5’-methyl-2 ’-furyl) simply 5, 13-dienoic acid;
    5Ζ, 13E-9-alpha, 11-alpha, 153-trioxy-168-methyl-18,29,20-trinor-17- (5’-ethyl-2’-fu35 sodium salt
    40
    45
    fifty
    1
    1489582
    12
    trinor-17- (2’-furyl) —simply — 5,13-dienoic acid in 6 ml of ethanol is sterilized by passing through a bacteria-retaining filter. 0.1 ml portions are placed in 1 ml ampoules, which are then sealed. The contents of the ampoule are diluted with 1 ml of Tris-hydrochloride buffer solution, the pH of which is 3.6, resulting in a solution that is ready for injection into the body.
    The pharmacological properties of the compounds indicated in the preform A to G are compared with the pharmacological properties of the known compounds E g , i.e. natural prostaglandin E g and pharmacological properties of the known β-analogous PCE compounds, i.e. 20
    2. "
    natural prostaglandin E g .
    Compound A: 5Ζ, I ZE-9-oxo-1 1o /, 15B-DIOXY-1b8-methyl-18,19,20-trinor-17- (2'-furyl) -prost-5,13-dienoic acid complex methyl ether.
    Compound B: 5Ζ, 1ZE-9-oxo-11 ^,
    155-DIOXY-165-methyl-18,19,20-trinor-1 7- (2’-furyl) simply 5,13-dienoic acid.
    Compound C: 13E-9-oxo-1 1 ^,
    155-dioxo-1b5-methyl-18.19,20-trinor-1 7— (2 * furyl) simple-13-enoic acid methyl ester.
    Connection ϋ: 1ZE-9-oxo-1Y,
    155-dioxi-163-metip-18,19,20-trinor-17- (2’-furyl) -simple-13-enoic acid. ,
    Compound E: 5Ζ, 1 3Ε-9 = (-, 11 <<,
    165-trioxy-165-methyl-18, I9,20-trinor-17- (2 ) furyl) simple-5,13-dienoic acid methyl ester.
    Compound E: 5, 13E-94, 11 ";,
    155-trioxy-165-methyl-18,19,20-trinor-17- (2’-furyl) -sim-5,13-dienoic acid.
    The compound from A to G, for example, in those cases when they are tested as antiulcer agents, have shown that they have a therapeutic index that exceeds the therapeutic index of PCE ^, which is confirmed by the values indicated in the table. 1, which presents data related to antiulcer activity in relation to ulcers caused by oral use of ethanol for rats.
    Inhibitory activity against ulcers caused by the use of
    10
    fifteen
    ethanol, defined as follows. To conduct these experiments, male rats weighing 190 * were used
    -10 g, which were not allowed to eat for 15 hours, but which had free access to water.
    Animals are treated by oral administration of the compounds 5 minutes before they are administered 95% ethanol, in an amount of 2 ml per 1 kg of live weight.
    After 1 h, after ethanol was introduced into rats, the rats were sacrificed by cervical translocation and the blood was drained, and then the stomachs pinched by the pyloric sphincter and sarsna were quickly removed, filled with brine, and immersed in 0.4% formalin for 30 s in accordance with the method of Hanson and Brody (Napzop Vgo <He, “T. Αρρί. ΡΗΪ5ΪΟ1 15, 291, 1960), which are opened along the greater curvature and examined for ulcerative 25 disease in accordance with an arbitrary scale.
    The anti-ulcer effect is evaluated by the dose response curve and expressed through ED ^, which is up to 30 dose, which reduces the effect of ethanble by 50%. Moreover, compounds E and E were investigated as luteolytic agents. Their therapeutic index is higher compared to
    2 ^ with the therapeutic index of natural prostaglandin PCP 2 , which is confirmed by the data indicated in the following table. 2.
    Luteolytic activity is determined as follows.
    Virgin hamsters (Charles River, Italy), weighing 90-120 g, are mated every night with adult males. Every morning the next day
    45 take vaginal smears on sperm and pregnant hamsters are identified as being in a state of pregnancy equal to one day.
    50 On the morning of the fifth day of pregnancy, these animals are processed using the target compounds (in the form of solutions in propylene glycol), which were administered subcutaneously,
    55 in an amount of 0.1 ml (100 g live weight). On the tenth day of pregnancy ( after laparotomy with mild anesthesia using ether, a womb check is performed
    14
    13 1489ί
    and if there is no noticeable fetus there, then the pregnancy was considered terminated.
    In order to obtain a dose that terminates pregnancy in 50% of the animals (EG ^), different doses of each of the compounds are used.
    Acute toxicity of the compounds is evaluated in male mice of the CO-1 Yu breed (Charles River, Italy).
    The target compound, dissolved in propylene glycol, is administered to animals at various dose levels (8–13 animals per dose) by an intraperitoneal injection of 15, the dose is 0.05 ml / 10 g live weight, and the dose that caused the death of 50% of the animals is estimated (bC · #) By the seventh day after processing. 20
    The data presented in table. 1 and 2, show that the target compounds are much more active in comparison with natural analogues.
    Table 1
    Compound Antiulcer activity ED L , mg / kg Acute toxicity 50 mg / kg ROE. 36 500 A 0.33 400 IN 0.25 380 FROM 0.8 380 P 0.5 370
    Table 2
    Compound Luteolytic activitymg / kg Sharptoxicity50 mg / kg RO S R 0,048 53 Έ 0.0025 81 R 0.0020 80
    权利要求:
    Claims (2)
    [1]
    (57 /: METHOD FOR PRODUCING OPTICALLY ACTIVE FURYL DERIVATIVES OF 16-SUBSTITUTED PROSTAGLANDINES of the general formula

    where K is OH hydrogen or C, -C < -alkyl;
    B, is a hydroxyl group;
    ΓΪ £ is hydrogen,
    or K, and together form a keto group;
    E ^ is C ^ -C ^ alkyl; line .... - single or cis double bond,
    characterized in that the compound of the general formula

    where .... and E ^ have the indicated meanings;
    E is C ^ -C ^ alkyl;
    E is a hydroxyl group,
    protected in vvda ester, lower aliphatic acid;
    in £ is hydrogen,
    subjected to reduction with an alkali metal hydride complex in an inert organic solvent at (-30) (~ 25) ° С followed by chromatographic separation of 158 and 15Е epimers, or to remove protective groups and obtain target products of the formula '.. (I), where Е = H, and E 1 is a hydroxyl group, treated with alkali metal hydroxide, or after protecting the hydroxy groups at 11 and 15 positions as tetrahydropyranyl groups, the 9-hydroxy group is oxidized, followed by removal of the tetrahydropyranyl protection to obtain a compound of formula (I), where E and E ^ taken e together form an oxo group, or converted compound of formula (I), where E = H, an alkyl in C ^ -C ~ 6 ether action corresponding diazoalkane.
    -311 ,,,, 1489582 AZ
    1
    1489582
    [2]
    2
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    同族专利:
    公开号 | 公开日
    SE8405514L|1985-05-05|
    NL8403307A|1985-06-03|
    FR2554448A1|1985-05-10|
    GB2149788A|1985-06-19|
    SE8405514D0|1984-11-02|
    FI844273L|1985-05-05|
    BE900959A|1985-05-02|
    IT8423390D0|1984-10-30|
    ZA848551B|1985-06-26|
    GB2149788B|1987-04-08|
    GB8427678D0|1984-12-05|
    IT1177095B|1987-08-26|
    AU3494584A|1985-05-09|
    HUT35637A|1985-07-29|
    GR80822B|1985-03-04|
    DE3439863A1|1985-05-23|
    US4585791A|1986-04-29|
    IL73395D0|1985-02-28|
    FI844273A0|1984-10-31|
    AU563999B2|1987-07-30|
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    JPS60112782A|1985-06-19|
    HU193708B|1987-11-30|
    CH663413A5|1987-12-15|
    DK524484D0|1984-11-02|
    DK524484A|1985-05-05|
    FR2554448B1|1987-07-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1386146A|1972-05-03|1975-03-05|Ici Ltd|Cyclopentane derivatives|
    ES416865A1|1972-07-13|1976-03-01|Pfizer|15-substituted-omega-pentanorprostaglandins|
    US3956284A|1972-07-13|1976-05-11|Pfizer Inc.|Heterocyclic 15-substituted-ω-pentanorprostoglandins|
    US4404372A|1977-06-13|1983-09-13|Pfizer Inc.|15-Substituted-ω-pentanorprostaglandin derivatives|
    IT1088966B|1977-11-15|1985-06-10|Erba Carlo Spa|13,14-didehydro-prostaglandins|
    US4543353A|1981-11-27|1985-09-24|Farmitalia Carlo Erba S.P.A.|Ester and amide derivatives of 13,14-didehydro prostaglandins|US5834498A|1992-09-21|1998-11-10|Allergan|Cyclopentane heptanoic acid, 2-heteroarylalkenyl derivatives as therapeutic agents|
    US5741810A|1996-02-29|1998-04-21|Allergan|Cyclopentane heptanoic acid, 2- heteroarylalkenyl derivatives as therapeutic agents|
    US8063033B2|2008-01-18|2011-11-22|Allergan, Inc.|Therapeutic beta-lactams|
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    BRPI0911543A2|2008-04-24|2015-10-13|Allergan Inc|substituted arylcyclopentenes as therapeutic agents|
    CA2731279A1|2008-04-24|2009-10-29|Allergan, Inc.|Therapeutic compounds|
    JP2011520807A|2008-05-09|2011-07-21|アラーガンインコーポレイテッド|Therapeutic substituted hydantoins and related compounds|
    AU2009244513B2|2008-05-09|2014-04-10|Allergan, Inc.|Therapeutic cyclopentane derivatives|
    US7981887B2|2008-05-09|2011-07-19|Allergan, Inc.|Therapeutic compounds|
    US8569349B2|2008-05-09|2013-10-29|Allergan, Inc.|Therapeutic compounds|
    ES2612921T3|2012-07-19|2017-05-19|Cayman Chemical Company, Incorporated|Difluorolactam compounds as selective agonists of the EP4 receptor for use in the treatment of diseases and conditions mediated by EP4|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB838329559A|GB8329559D0|1983-11-04|1983-11-04|Furyl derivatives of 16-substituted prostaglandins preparations|
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