SE460193B - 13-OXAPROSTAGLANDINES OF PGE TYPE, SET TO MANUFACTURING THESE AND A PHARMACEUTICAL COMPOSITION - Google Patents
13-OXAPROSTAGLANDINES OF PGE TYPE, SET TO MANUFACTURING THESE AND A PHARMACEUTICAL COMPOSITIONInfo
- Publication number
- SE460193B SE460193B SE8601852A SE8601852A SE460193B SE 460193 B SE460193 B SE 460193B SE 8601852 A SE8601852 A SE 8601852A SE 8601852 A SE8601852 A SE 8601852A SE 460193 B SE460193 B SE 460193B
- Authority
- SE
- Sweden
- Prior art keywords
- phenyl
- hydroxy
- group
- oxy
- pyran
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 methylthio , methylsulfinyl Chemical group 0.000 claims description 159
- 150000001875 compounds Chemical class 0.000 claims description 121
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000000460 chlorine Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 229910052801 chlorine Chemical group 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- KPSZWAJWFMFMFF-UHFFFAOYSA-N hept-5-enoic acid Chemical compound CC=CCCCC(O)=O KPSZWAJWFMFMFF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims 3
- 125000004414 alkyl thio group Chemical group 0.000 claims 3
- 125000004429 atom Chemical group 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 94
- 239000000243 solution Substances 0.000 description 53
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 47
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 35
- 239000003480 eluent Substances 0.000 description 32
- 239000002904 solvent Substances 0.000 description 28
- 238000004587 chromatography analysis Methods 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 21
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000377 silicon dioxide Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000004458 analytical method Methods 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- UQDAEORWFCPQCU-UHFFFAOYSA-N acetic acid;oxolane;hydrate Chemical compound O.CC(O)=O.C1CCOC1 UQDAEORWFCPQCU-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229910052754 neon Inorganic materials 0.000 description 4
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910000365 copper sulfate Inorganic materials 0.000 description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 2
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- CVPWYDXAVJCNAG-UHFFFAOYSA-N n-(4-hydroxyphenyl)benzamide Chemical compound C1=CC(O)=CC=C1NC(=O)C1=CC=CC=C1 CVPWYDXAVJCNAG-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 2
- 102220254284 rs755928199 Human genes 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- YURNCBVQZBJDAJ-UHFFFAOYSA-N 2-heptenoic acid Chemical compound CCCCC=CC(O)=O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NKVJKVMGJABKHV-UHFFFAOYSA-N 3-carboxypropyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCC(=O)O)C1=CC=CC=C1 NKVJKVMGJABKHV-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 101000794560 Arbacia punctulata Calmodulin-beta Proteins 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
460 193 cytoprotektion och är därför av intresse för behandling av magsår. 460 193 cytoprotection and is therefore of interest for the treatment of gastric ulcers.
Uppfinningen tillhandahåller sålunda föreningar med den allmänna formeln l __='1cu2)nxír:u;;>mc<12+21 --n ”"%. ål) I (Zlllli C: -4 vari n är l eller 2; m är 2 - 5 och X är cis eller trans -CH=CH- eller -CH2-CH2-; eller m är l - 4 och X är -CH=C=CH-; Rl är (a) fenyl (eventuellt substituerad med Cl_4alkyl, Cl_4alkoxi, Cl_4alkanoyl, metyltio, metylsulfinyl, metylsulfonyl, halogen (t.ex. klor eller brom), -CO2R2 (vari R2 är en väteatom eller Cl_4alkyl eller fenyl), -NHCOR2 (vari R2 har ovan an- given betydelse eller är en fenylgrupp eventuellt substitue- rad med nydroxyl, cu3com1- eller Qcomn, -coNR3R4 (vari R3 och R4 kan vara lika eller olika och vardera betecknar en väteatom eller en Cl_4alky1grupp), -NHCONH2, -CH2CH(CONH2)NHCOCH3 eller -CH2CH(CONH2)NHCO~<:::>) eller (b) 2-naftyl; RD R? / y är __ CH? ._IU\__ C ._ flAr / \ RS m1 vari R5, R6 och R7 vardera är en väteatom eller en metylgrupp 47/ w 460 193 och minst är en väteatom; och Ar är en fenylgrupp (eventuellt substituerad med en eller tvâ Cl_4alkyl, Cl_4 Cl Cl_4alkylsulfonyl, halogen eller trifluormetylgrupper); och de fysiologiska acceptabla salterna därav. alkoxi, _4alkyltio, Cl_4alkylsulfinyl, Föreliggande strukturformler innefattar enantiomererna av var och en av ifrågavarande föreningar liksom blandningar av enantiomererna innefattande racemat.The invention thus provides compounds of the general formula l __ = '1cu2) nxír: u ;;> mc <12 + 21 --n ""%. Ål) I (Zlllli C: -4 wherein n is 1 or 2; m is 2-5 and X is cis or trans -CH = CH- or -CH 2 -CH 2 -, or m is 1-4 and X is -CH = C = CH-, R 1 is (a) phenyl (optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, methylthio, methylsulfinyl, methylsulfonyl, halogen (eg chlorine or bromine), -CO 2 R 2 (wherein R 2 is a hydrogen atom or C 1-4 alkyl or phenyl), -NHCOR 2 (wherein R 2 is as defined above or is a phenyl group optionally substituted with neydroxyl, cu3com1- or Qcomn, -coNR3R4 (wherein R3 and R4 may be the same or different and each represents a hydrogen atom or a C1-4alkyl group), -NHCONH2, -CH2CH (CONH2) NHCOCH3 or -CH2CH (CONH2) NHCO or (b) 2-naphthyl; RD R? / y is __ CH? ._IU \ __ C ._ fl Ar / \ RS m1 wherein R5, R6 and R7 are each a hydrogen atom or a methyl group 47 and at least one hydrogen atom, and Ar is a phenyl group (optionally substituted with one or more two C 1-4 alkyl, C 1-4 C 1-4 alkylsulfonyl, halogen or trifluoromethyl groups); and the physiologically acceptable salts thereof. The present structural formulas include the enantiomers of each of the compounds as well as mixtures of the enantiomers including racemates.
I allmänhet föredrages de föreningar med formel (1) i vilka kolatomen, som bär gruppen -(CH2)nX(CH2)mCO2Rl och/eller kolatomen i gruppen Y, som bär -OH-gruppen (speciellt den förra),är i R-konfiguration och blandningar innehållande sådana isomerer .In general, those compounds of formula (1) in which the carbon atom bearing the group - (CH2) nX (CH2) mCO2R1 and / or the carbon atom in the group Y bearing the -OH group (especially the former) are in R- configuration and mixtures containing such isomers.
Alkylgrupperna omnämnda ovan i definitionen av föreningarna med formel (1) kan vara raka eller grenade.The alkyl groups mentioned above in the definition of the compounds of formula (1) may be straight or branched.
När Rl i föreningarna med formel (l) är fenyl substituerad med en grupp -CO2H kan föreningarna bilda salt med baser.When R 1 in the compounds of formula (1) is phenyl substituted by a group -CO 2 H, the compounds may form salt with bases.
Exempel på lämpliga salter är alkalimetall (t.ex. natrium- och kalium)-salter.Examples of suitable salts are alkali metal (eg sodium and potassium) salts.
I föreningar vari X är -CH=CH- eller -CH2CH2- är m företrä- desvis 3 när n är 1 och m är företrädesvis 2 eller 4 när n är 2. När X är -CH=C=CH- är m företrädesvis 2 och n är l och 1 eller 3 när n är 2.In compounds wherein X is -CH = CH- or -CH 2 CH 2 -, m is preferably 3 when n is 1 and m is preferably 2 or 4 when n is 2. When X is -CH = C = CH-, m is preferably 2 and n is 1 and 1 or 3 when n is 2.
När X är -CH=CH- är den företrädesvis cis -CH=CH-.When X is -CH = CH- it is preferably cis -CH = CH-.
När Rl är en substituerad fenylgrupp kan den exempelvis vara fenyl substituerad i meta, orto eller, särskilt, para- position med en klor- eller bromatom eller en metyl-, etyl-, propyl-, n-butyl-, t-butyl-, metoxi-, etoxi-, propoxi-, butoxi-, acetyl-, propionyl-, metyltio-, metylsulfinyl-, '460 193 metylsulfonyl-, -COZH-, -COZCH3-, -CO CH CH3-, 2 2 -C02-<::3>-, -NHCHO-, -NHCOCH3-, bensoylamino-, (acetyl- amino)bensoylamino-, (hydroxi)bensoylamino-, -CONHZ-, -CONHCHB , -CON (CH3) 2-, -CONHCH2CH3- , -CONH (CH2CH3) 2- , -NHcoNH2-, -cH2cH(coNn2)NHcocH3 eller CHZCHæoNHQNHCOQ grupp- Särskilt användbara substituenter,som kan vara närvarande på en substituerad fenylgrupp Rl innefattar Cl_4alkoxi, alkanoyl, metyltio, metylsulfonyl, -CO2R2, -NHCOR2, Cl"4 3 4 2 3 4 -CONR R (vari R , R och R formel (l)), -NHCONH2 eller -CH2CH(CONH2)NHCOCH3 grupper.When R 1 is a substituted phenyl group it may be, for example, phenyl substituted in the meta, ortho or, in particular, para position with a chlorine or bromine atom or a methyl, ethyl, propyl, n-butyl, t-butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, methylthio, methylsulfinyl, methylsulfonyl, -COZH-, -COZCH3-, -CO CH CH3-, 2 2 -CO2- < :: 3> -, -NHCHO-, -NHCOCH3-, benzoylamino-, (acetylamino) benzoylamino-, (hydroxy) benzoylamino-, -CONHZ-, -CONHCHB, -CON (CH3) 2-, -CONHCH2CH3-, Particularly useful substituents, which may be present on a substituted phenyl group R 1, include C 1-4 alkoxy, alkanoyl, methylC 2, N 2 CO 2, Cl "4 3 4 2 3 4 -CONR R (wherein R, R and R are formula (1)), -NHCONH2 or -CH2CH (CONH2) NHCOCH3 groups.
Särskilt användbara substituenter av denna typ innefattar har samma betydelse som i metoxi, acetyl, metyltio, metylsulfonyl, -COZCH3, -NHCOCH3, bensoylamino, (p-acetylamino)bensoylamino, (p-hydroxi)- bensoylamino, -CONH2, -CON(CH3) 9, -NHCONHZ eller -CHzCH (CONHZ) NHCOCH3 .Particularly useful substituents of this type include have the same meaning as in methoxy, acetyl, methylthio, methylsulfonyl, -COZCH 3, -NHCOCH 3, benzoylamino, (p-acetylamino) benzoylamino, (p-hydroxy) -benzoylamino, -CONH 2, -CON (CH 3 ) 9, -NHCONH 2 or -CH 2 CH (CONH 2) NHCOCH 3.
Gruppen Rl är företrädesvis en substituerad fenylgrupp där substituenten kan vara i meta-, orto- eller särskilt para-position eller är en 2-naftylgrupp.The group R1 is preferably a substituted phenyl group where the substituent may be in the meta, ortho or especially para position or is a 2-naphthyl group.
Föreningar vari Rl är en fenylgrupp substituerad (speciellt i para~ställning) med en metoxi-, acetyl-, -COZCH3-, -NHCOCH3-, bensoylamino-, -CONH2-, -C0N(CH3)2- eller -CH2CH(CONH2)NHC0CH3-grupp eller Rl är en 2-naftylgrupp är sär ski lt användbara .Compounds in which R1 is a phenyl group substituted (especially in para) with a methoxy-, acetyl-, -COZCH3-, -NHCOCH3-, benzoylamino-, -CONH2-, -CON (CH3) 2- or -CH2CH (CONH2) NHCOCH3 group or R1 is a 2-naphthyl group are particularly useful.
I gruppen Y är R6 och R7 företrädesvis väteatomer. Före- 6 ningar vari RS är H eller -CH3 och R och R7 är väteatomer föredras även.In the group Y, R 6 and R 7 are preferably hydrogen atoms. Compounds wherein R 5 is H or -CH 3 and R and R 7 are hydrogen atoms are also preferred.
När Ar fenylgruppen är substituerad kan substituenten vara i meta-, orto- eller paraposition och kan exempelvis vara metyl, etyl, propyl, butyl, metoxi, etoxi, propoxi, butoxi, 460 193 metyltio, metylsulfinyl, metylsulfonyl, fluor, klor, brom eller trifluormetyl. Företrädesvis är endast en enkel sub- stituent närvarande, speciellt i para-ställning. I allmänhet är Ar företrädesvis fenyl eller fenyl substituerad med halogen, speciellt fluor eller klor.When the Ar phenyl group is substituted, the substituent may be in the meta, ortho or para position and may be, for example, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methylthio, methylsulfinyl, methylsulfonyl, fluorine, chlorine, bromine or trifluoromethyl. Preferably only a single substituent is present, especially in the para-position. In general, Ar is preferably phenyl or phenyl substituted with halogen, especially fluorine or chlorine.
De ovan angivna preferenserna gäller både separata och i kombination med en eller flera av de övrigt angivna prefe- renSeIna.The above preferences apply both separately and in combination with one or more of the other stated preferences.
En föredragen grupp av föreningar enligt uppfinningen har således formeln (1) vari: X är -CH=CH- eller -CH2CH2- och n är l och m är 3 eller n är 2 och m är 2 eller 4, eller X är -CH=C=CH- och n är l och m är 2 eller n är 2 och m är l eller 3; Rl är en fenylgrupp substituerad (företrädesvis i para- ställning) med en metoxi-, acetyl-, -COZCH3-, -NHCOCH3-, bensoylamino-, -CONH2-, -CON(CH3)2- eller -CHZCH(CONH2)NHCOCH3-grupp eller Rl är en 2-naftylgrupp; R5 är en väteatom eller en metylgrupp; R6 och R7 är väteatomer; och Ar är fenyl eller fenyl substituerad med fluor eller klor.Thus, a preferred group of compounds of the invention has the formula (1) wherein: X is -CH = CH- or -CH 2 CH 2 - and n is 1 and m is 3 or n is 2 and m is 2 or 4, or X is -CH = C = CH- and n is 1 and m is 2 or n is 2 and m is 1 or 3; R 1 is a phenyl group substituted (preferably in the para-position) with a methoxy, acetyl, -COZCH 3 -, -NHCOCH 3 -, benzoylamino-, -CONH 2 -, -CON (CH 3) 2 - or -CH 2 CH (CONH 2) NHCOCH 3 - group or R 1 is a 2-naphthyl group; R 5 is a hydrogen atom or a methyl group; R 6 and R 7 are hydrogen atoms; and Ar is phenyl or phenyl substituted with fluorine or chlorine.
Föreningar av denna typ vari kolatomen, som bär -(CH2)nX(CH2)nCO2Rl-gruppen är i R-konfiguration föredras I särskilt. Speciellt föredragna föreningar av denna typ är 1 är en íenylgrupp substituerad (företrädesvis i de vari R para-position) med-bensoylamino eller -CONH2, speciellt den förra.Compounds of this type in which the carbon atom bearing the - (CH 2) n X (CH 2) n CO 2 R 1 group is in the R configuration are particularly preferred. Particularly preferred compounds of this type are 1 is an phenyl group substituted (preferably in those in which R is para-position) with -benzoylamino or -CONH 2, especially the former.
En särskilt föredragen grupp av föreningar enligt uppfin- ningen är följande: 460 193 /13-/lv-(§),2f5(§*),3 2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat; /lg-/lu (gpzfg(y),3m//-(-)-4-(acety1amin<>)fenyl 7-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)~5-oxocyklopentyl/*5- heptenoat; /lg-/lu.(§),2(3(§*),3K //-(-)-4-(bensoylamino)fenyl 7-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5- heptenoat; /lg-/lN.(§,§*),2[B(ß*),3oi//-(+)-4-/2-(acetylamino)-3-amino- 3-oxopropyl/fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)- 5-oxocyklopentyl/-5-heptenoat; /lB-/lvi (å) ,2§ (_l=§*) ,3b!//-(fl-Ll-(aminokarbonyl)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /lg-/lä {§),2jB(§*),3a[//-(-)-3-(bensoylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi~3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /lg-/la (g) ,2 p, (y) ,3o¿//-(-)-4-(N,N-d1mety1am1nokarbony1)- fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxo- cyklopentyl/-5-heptenoat; /lE-/l BL (å) ,2 f.) (§*) ,3 0L//"(~) metyl 4-//7-/3-hydroxi-2- (2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-l-oxo-5- heptenyl/oši/bensoat; /lg-/lu_(§),2]å(§*),3u;//-2-naftalenyl 7-/3-hydroxi-2-(2- hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat; /lg-/lg,(§),2[B,3 oxí-2-(2-hydroxi-2-metyl-3-fenoxipropoxi)-5~oxocyklopentyl/- 5-heptenoat; /lg-/loL(Å),2[5,3d.//-4-metoxifenyl 7-/2-/3-(4-fluorfenoxi)- 2-hydrøxipropoxi/-3-hydroxi-5-oxocyklopentyl/-5-heptenoat; /lg-/loc (g) ,2 [1>(§*) , 3 <>L //-(-) -4fl (bensoylamino) fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/~ 4-heptcnoat; /lg-/lol,2(5(§*),3(i//-(-)-4~(bcnsoylamino)fenyl 3-hydroxi- 2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopcntanhoptanoat och /lg-/lu (E) .2 [s (33)) ,3 a //-(-)wwaminokarbonynfenyl 7-/3- hydroxi-2-(2~hydroxi-3~fenoxipropoxi)-5-oxøcyklopentyl/-5- 460 195 heptenoat.An especially preferred group of compounds of the invention are the following: 460 193 / 13- / lv- (§), 2f5 (§ *), 3 2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5 -heptenoate; [.alpha.] D @ 20 (gpzfg (y), 3m // - (-) - 4- (acetylamine)> phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] * 5-heptenoate; /lg-/lu.(§)2(3(§*).3K // - (-) - 4- (benzoylamino) phenyl 7- / 3-hydroxy-2- (2-hydroxy -3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate; /lg-/1N.(§,§ *), 2 [B (ß *), 3oi // - (+) - 4- / 2- ( acetylamino) -3-amino-3-oxopropyl / phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; [1B-] § (_1 = § *), 3b [// - (fl-L1- (aminocarbonyl) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; / lg- / lä {§), 2jB (§ *), 3a [// - (-) - 3- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5 -oxocyclopentyl / 5-heptenoate; [.alpha.] D @ 20 (g), 2 .mu.l (γ), 30 .mu.l - (-) - 4- (N, N-dimethylaminocarbonyl) phenyl 7- [3-hydroxy] -2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate; / 1E- / 1 BL (α), 2 f.) (§ *), 30L // "(~ ) methyl 4- [7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -1-oxo-5-heptenyl] oxy / benzoate; / lg- / lu_ (§) , 2] å (§ *), 3u; // - 2-naphthalenyl 7- / 3-hy hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate; [.alpha.] D @ 20, (§), 2 [B, 3-oxy-2- (2-hydroxy-2-methyl-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; /lg-/loL(Å),2[5,3d.//-4-methoxyphenyl 7- [2- [3- (4-fluorophenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclopentyl] -5 -heptenoate; / lg- / loc (g), 2 [1> (§ *), 3 <> L // - (-) -4fl (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3- phenoxypropoxy) -5-oxocyclopentyl [4-heptocnate; [1- (5 (§ *)), 3 (1H - (-) - 4 - (benzoylamino) phenyl) 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentanehoptanoate and [.alpha.] DEG-.mu.l (E) .2 [s (33)), 3 [alpha] - (-) - Waminocarbonynphenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] - 5- 460 195 heptenoate.
En särskilt användbar grupp av denna typ är: /lß-/l°4(Ä),2/3(§*),30(//-(-)~4-acetylfenyl 7-/3~hydroxi- 2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat; /lg-/IM (Q),2/B(R*),3o(//~(-)-4-(acetylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-hcptenoat; /lg-/lg;(å),2/5(§*),3d.//“(-)~4-(bensoylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /lg-/lßá(§),2/3(§*),3(K//'(-)-4-(aminokarbonyl)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /13-/lw!(§),2/%(§*),3@ 7-/3-hydroxi~2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /13-/104(§),2[$(§*)¿3X//-(-)-4-(N,N-dimetylaminokarbonyl)- fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklo- pentyl/-5-heptenoat; /lg-/l,&(š),2[5(§*),3|M//-(-) metyl 4-//7-/3-hydroxi-2- (2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-l-oxo-5- heptenyl/oxi/bensoat; /lg-/ln!(§),2l3(§*),3:X//-2-naftalenyl 7-/3~hydroxi-2-(2- hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat; /l§~/lg (§),2{5,3 M//-4-metoxifenyl 7-/2-/3-(4-fluorfenoxi)- 2-hydroxipropoxi/-3-hydroxi-5-oxocyklopentyl/-5-heptenoat; /lg-/l~<(§),2{B(§*),3oi//-(-)-4-(bensoylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 4~heptenoat, och /lß-/l O! ,2 ß (§_*) ,30( H-(fl-fll-(bensoylamino)fenyl 3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyk1opentan- hcptanoat. 460 195 En ytterligare viktig grupp av föreningar enligt uppfinningen som har speciellt användbara fysiko-kemiska egenskaper, sem gör dem mycket lämpliga för farmaceutíska beredningar, är: /ig-(lu (_23) ,z/>, (y) ,3o< /f-(fl-ßl-acetylfenyi v-/a-hyaroxi- 2-(2-hydroxi~3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat; /lg-/lsL(§),2[5(§*),3(X//-(-)-4-(acetylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-heptenoat; /lg-/lßc(§),2/B(§*),3 K//-(_)-4-(bensoylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- S-heptenoat; /13-/1 ot (å) , 2 [g (_P¿*) ,30( //- (-)-4-/4- (acetylamino)bensoylamino/- fenyl 7-/3-hydroxi-2- (2-hydroxi-B-fenoxipropoxi) -5-oxo- cyklopentyl/-S-heptenoat; /l_R-/l M (å) , 2 [5 (_I§*) , 3 (X //- (-) -4-(aminokarbonyl) fenyl 7-/3-hydroxi-2- (2-hydroxi-3-fenoxipropoxi) -â-oxocyklopentylJ- S-heptenoat; /lg-/l OL (§,§*) , 2 ß (§_*) ,3 Ok //- (+) -4-/2- (acetylamino) -3-amino- B-oxopropyl/fenyl 7-/3-hydroxi-2- ( Z-hydroxi-S-fenoxipropoxi) - S-oxocyklopentyll-S-heptenoat; /lg-/l ß (å) , 2 QL (§*) ,3 vi //" (_) -3-(bensoylamino) fenyl 7-/3-hydroxi-2- (2-hydroxi-3-fenoxipropoxi) -5-oxocyklopentyl/- S-heptenoat; /lß-/l (X (å) ,2 (5 (§*) , 3 OL//- ("') metyl 4-//7-/3-hydroxi-2- (2- hydroxi-3-fenoxipropoxi) -5-oxocyklopentyl/-l-oxo-S-heptenyl/- oxi/bensoat; /lß-/l ßL (å) , 2 (g, (§*) , 3 oL//-2- (bensoylamino) fenyl 7-/3-hydroxi-2- (2-hydroxi~B-fenoxipropoxi) -S-oxocyklopentylß- S-heptenoat; /lß-/l nL (å) .2 [5 (§*) ,3 oi //~2-naftalenyl 7-/3-hydroxi-2-(2- hydroxi-B-fenoxipropoxi) -S-oxocyklopentyl/-5-heptenoat; /lë-/l OC (å) , 2 [g , 3 (i //-4- (metylsulfonyl) fenyl 7-/3-hydroxi- 2~/ 2-hyfdroxi-3-/4 - (metyltio) fenoxi /propoxi/-S-oxocyklo- pentyl/-S-heptenoat; 460 195 /lš-/l aL (å) ,2{3 (EH ,3 <1 //-(-)-4-(bensoylamino) fenyl 7-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 4-heptenoat; /lg-/loL(§),2{5(§*),3(X//-(-)-4-(bensoylamino)fenyl 9-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-7- nonenoat, och /lg-/lM.,2ß (§*),3y //-(-)-4-(bensoylamino)fenyl 3-hydroxi- 2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentanheptanoat.A particularly useful group of this type is: / lß- / l ° 4 (Ä), 2/3 (§ *), 30 (// - (-) ~ 4-acetylphenyl 7- / 3 ~ hydroxy-2- ( 2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate; 1g- / 1M (Q), 2 / B (R *), 30 (// ~ (-) - 4- (acetylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hptenoate; /lg-/lg ;(å),2/5(§*),3d.// ((-) - 4- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; [1-9] (§), 2 / 3 (§ *), 3 (K // '(-) - 4- (aminocarbonyl) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; [13-] [(§), 2 /% (§ *), 3 @ 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; / 13 - / 104 (§), 2 [$ (§ *) ¿3X // - (-) - 4- (N, N-dimethylaminocarbonyl) - phenyl 7- [3-hydroxy-2- (2-hydroxy-3- phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate; / lg- / 1, & (š), 2 [5 (§ *), 3 | M // - (-) methyl 4 - // 7- / 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -1-oxo-5-heptenyl / oxy / benzoate; / lg- / ln1 (§), 213 (§ *), 3 : X // - 2-naphthalenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) - 5-oxocyclopentyl / -5-heptenoate; [§], 2 {5,3 M // - 4-methoxyphenyl 7- [2- [3- (4-fluorophenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclopentyl] - 5-heptenoate; [1- (§)), 3 {B (§ *), 3oi // - (-) - 4- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) ) -5-oxocyclopentyl / -4-heptenoate, and / lß- / l O! , 2 ß (§_ *), 30 (H- (fl-fl 1- (benzoylamino) phenyl 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentane hptanoate. 460 195 Another important group of compounds of the invention which have particularly useful physicochemical properties which make them very suitable for pharmaceutical preparations are: / ig- (lu (_23), z />, (y), 30o </ f- (fl- ßl -acetylphenyl- [α-hyaroxy- 2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; /g- / lsL (§), 2 [5 (§ *), 3 (X // - (-) - 4- (acetylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate; 1g- / lßc (§), 2 / B (§ *), 3K // - (_) - 4- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -S-heptenoate ; / 13- / 1 ot (å), 2 [g (_P¿ *), 30 (// - (-) - 4- / 4- (acetylamino) benzoylamino] -phenyl 7- [3-hydroxy-2- (2-hydroxy-β-phenoxypropoxy) -5-oxocyclopentyl / -S-heptenoate; 1_R- / 1 M (α), 2 [5 (_I§ *), 3 (X // - (-) - 4- (aminocarbonyl) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -α-oxocyclopentyl] -S-heptenoate; / lg- / 1 OL (§, § *) , 2 ß (§_ *), 3 Ok // - (+) -4- [2- (acetylamino) -3-amino-β-oxopropyl] phenyl 7- [3-hydroxy-2- (Z-hydroxy- S-phenoxypropoxy) -S-oxocyclopentyl-S-heptenoate; [.alpha.] DEG-3β-hydroxy-2- (2-hydroxy-3-phenoxy-propoxy) -5-oxocyclopentyl / - S-heptenoate; / lß- / 1 (X (å), 2 (5 (§ *), 3 OL // - ("') methyl 4- // 7- / 3-hydroxy- 2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -1-oxo-S-heptenyl / oxy / benzoate; / lß- / l ßL (å), 2 (g, (§ *), 3 oL // 2- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-β-phenoxypropoxy) -S-oxocyclopentyl] -S-heptenoate; / lß- / l nL (å) .2 [5 (§ *), 3 [alpha] -2-naphthalenyl 7- [3-hydroxy-2- (2-hydroxy-β-phenoxypropoxy) -S-oxocyclopentyl] -5-heptenoate; , 2 [g, 3- (1 - - 4- (methylsulfonyl) phenyl 7- [3-hydroxy-2- [2-hydroxy-3- [4- (methylthio) phenoxy] propoxy] -5-oxocyclopentyl] -S-heptenoate; 460 195 / lš- / l aL (å), 2 {3 (EH, 3 <1 // - (-) - 4- (benzoylamino) phenyl 7- / 3-hydroxy-2- (2 -Hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl [4-heptenoate] [1- [10 (§), 2 {5 (§ *), 3 (X // - (-) - 4- (benzoylamino) phenyl 9- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -7-nonenoate, and /lg-/1M.,2ß (§ *), 3y // - (-) - 4- (benzoylamino) phenyl 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentane heptanoate.
En särskilt föredragen förening enligt uppfinningen är: /lg-/104(Ä),2[5(§*),3CÅ//'(“)~4-(bensoylamino)fenyl 7-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5- heptenoat.An especially preferred compound according to the invention is: /lg- / 104 (Ä), 2 [5 (§ *), 3CÅ // '(“) ~ 4- (benzoylamino) phenyl 7- / 3-hydroxy-2- (2 -hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate.
Föreningar med formel (l) inhiberar magsyrasekretion såsom exempelvis visas genom deras förmåga att inhibera histamin- inducerad sekretoriskt respons i perfuserad råttmage enligt metoden av Ghosh M. N och Schild i Br. J. Pharmacol., 1958, lå, 54 modifierad av Parsons M. E., Ph. D. Thesis, University of London, 1969.Compounds of formula (I) inhibit gastric acid secretion as shown, for example, by their ability to inhibit histamine-induced secretory response in perfused rat stomach according to the method of Ghosh M. N and Schild in Br. J. Pharmacol., 1958, lay, 54 modified by Parsons M. E., Ph. D. Thesis, University of London, 1969.
Föreningarna ger även gastrointestinal cytoprotektion såsom exempelvis visas genom deras förmåga att inhibera etanol- inducerade skador på medveten råtta enligt metoden av Robert et al i Gastroenterology, 1979, Zl, 433, modifierad genom användningen av 5 mg/kg/s.c. indometacin innan admi- nistrationen av testföreningen.The compounds also provide gastrointestinal cytoprotection as demonstrated, for example, by their ability to inhibit ethanol-induced damage to conscious rats according to the method of Robert et al in Gastroenterology, 1979, Z1, 433, modified by the use of 5 mg / kg / s.c. indomethacin before administration of the test compound.
Föreningarna är således av intresse för prevention och/eller behandling av magsår. De kan även användas för behandling av andra tillstånd som uppkommer genom hypersekretion av magsyra. De kan även beredas på konventionellt sätt med en eller flera farmaceutiska bärare, exempelvis för oral, bukal, parenteral eller rektal administration.The associations are thus of interest for the prevention and / or treatment of gastric ulcers. They can also be used to treat other conditions that arise from hypersecretion of stomach acid. They may also be formulated in conventional manner with one or more pharmaceutical carriers, for example for oral, buccal, parenteral or rectal administration.
Föreningarna kan beredas för oral administration genom exem- pelvis tabletter, kapslar, pulver, solntioner eller sirap 460 195 10 framställda på konventionellt sätt med acceptabla excipienter.The compounds may be formulated for oral administration by, for example, tablets, capsules, powders, solvents or syrups prepared in conventional manner with acceptable excipients.
Föreningarna kan beredas för parenteral administration genom bolusinjektion eller kontinuerlig infusion. Beredningar för injektion kan tillhandahållas i enhetsdosform i ampuller eller i multidosbehâllare med ett tillsatt konserveringsmedel.The compounds may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be supplied in unit dosage form in ampoules or in multi-dose containers with an added preservative.
För bukal administration kan föreningarna beredas som tab- letter eller trokisker på konventionellt sätt; och för Iektal administration kan kompositioner såsom supposito- rier eller retensionslavemang, exempelvis innehållande kon- ventionella suppositoriebaser såsom kakaosmör eller andra I .q _. glyceriaer, anvandas.For buccal administration, the compounds may be formulated as tablets or troches in a conventional manner; and for ectal administration, compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other I. glyceria, are used.
Föreningarna administreras företrädesvis oralt, exempelvis i en mängd av 0,5 till 300 /ug/kg kroppsvikt, l till 4 gånger dagligen. För parenteral administration kan före- ningarna administreras i mängder om 0,01 till 10 /ug/kg kroppsvikt, l till 4 gånger dagligen. Den exakta dosen beror naturligtvis på åldern och tillståndet hos patienten.The compounds are preferably administered orally, for example in an amount of 0.5 to 300 .mu.g / kg of body weight, 1 to 4 times daily. For parenteral administration, the compounds may be administered in amounts of 0.01 to 10 .mu.g / kg of body weight, 1 to 4 times daily. The exact dose, of course, depends on the age and condition of the patient.
Lämpliga metoder för framställning av föreningarna enligt uppfinningen beskrives nedan vari de olika grupperna och symbolerna är som ovan angivet om icke annat anges. (a) Föreningar med formel (l) kan framställas genom depro~ tektering av en motsvarande förening vari ringhydroxigruppen och hydroxigruppen i Y är skyddade.Suitable methods for preparing the compounds of the invention are described below wherein the various groups and symbols are as indicated above unless otherwise indicated. (a) Compounds of formula (1) may be prepared by deprotection of a corresponding compound wherein the ring hydroxy group and the hydroxy group in Y are protected.
De skyddade föreningarna har sålunda formel (2) i/'X CíCH2)r1X(Û|{_f_-§mCÛ2Rx^ 460 193 11 vari R8 är en lämplig hydroxylskyddande grupp (t.ex. tetra- hydropyran-2-yl, tetrahydrofuran-2-yl, etoxietyl, tri(ko1- väte)silyl eller arylmetyl) och Y' definieras som en grupp Re RV __çH_,___c__\c_oAf 5/\ 8 R UR De två R8-grupperna i föreningarna med formel (2) är lämp- ligen samma men kan vara olika om så önskas.The protected compounds thus have formula (2) wherein R 8 is a suitable hydroxyl protecting group (eg tetrahydropyran-2-yl, tetrahydrofuran-2-yl). 2-yl, ethoxyethyl, tri (hydrocarbon) silyl or arylmethyl) and Y 'are defined as a group Re RV __çH _, ___ c __ \ c_oAf 5 / \ 8 R UR The two R8 groups in the compounds of formula (2) are suitable - exactly the same but can be different if desired.
När R8 är tri(kolväte)silyl kan kolvätesubstituenterna vara lika eller olika, t.ex. Cl_6alkyl, C2_6alkenyl, C3_7- cykloalkyl, C7_20aralkyl och C6_20arylgrupper. Sådana grupper innefattar metyl, etyl, n-propyl, isopropyl, n-butyl, iso- butyl, t-butyl, allyl, fenyl och bensyl. Föredragna kolväte- grupper är Cl_4alkyl, t.ex. metyl och t-butyl. Trimetylsilyl och t-butyldimetylsilylgrupper föredras särskilt.When R8 is tri (hydrocarbon) silyl, the hydrocarbon substituents may be the same or different, e.g. C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 7-20 aralkyl and C 6-20 aryl groups. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl, phenyl and benzyl. Preferred hydrocarbon groups are C 1-4 alkyl, e.g. methyl and t-butyl. Trimethylsilyl and t-butyldimethylsilyl groups are especially preferred.
När R8 är en arylmetylgrupp kan den innehålla upp till 20 kolatomer, t.ex. bensyl, difenylmetyl eller trifenylmetyl.When R 8 is an arylmethyl group it may contain up to 20 carbon atoms, e.g. benzyl, diphenylmethyl or triphenylmethyl.
Sättet som användes för att deprotektera den skyddade hydroxylgruppen beror på naturen hos R8 men i allmänhet kan syrahydrolys eller reduktion användas.The method used to deprotect the protected hydroxyl group depends on the nature of R8 but in general acid hydrolysis or reduction can be used.
När således R8 är en tetrahydropyran-2-yl, tetrahydrofuran- 2-yl eller etoxietylgrupp kan deprotekteringen ske med en syra. Lämpliga syror innefattar oorganiska syror såsom klorvätesyra och organiska syror såsom ättiksyra eller tri- fluorättiksyra. Lämpliga lösningsmedel innefattar etrar (t.ex. dietyleter, dioxan och tetrahydrofuran), halogenerade kolväten (t.ex. diklormetan, kolväten (t.ex. toluen), dipo- lära aprotiska lösningsmedel (t.ex. aceton, acetonitril, dimetylsulfoxid och dimctylformamid) och alkoholer (t.ex. metanol, etanol och etylenglykol). När så önskas kan lös- ningsmedlet användas i kombination med vatten. Reaktionen kan ske vid vilken som helst lämplig temperatur såsom från 460 193 12 o till 5o° c, t.ex. 40 till 5o° c.Thus, when R 8 is a tetrahydropyran-2-yl, tetrahydrofuran-2-yl or ethoxyethyl group, the deprotection can take place with an acid. Suitable acids include inorganic acids such as hydrochloric acid and organic acids such as acetic acid or trifluoroacetic acid. Suitable solvents include ethers (eg diethyl ether, dioxane and tetrahydrofuran), halogenated hydrocarbons (eg dichloromethane, hydrocarbons (eg toluene), dipolar aprotic solvents (eg acetone, acetonitrile, dimethylsulfoxide and dimethylformamide) and alcohols (eg methanol, ethanol and ethylene glycol), if desired, the solvent can be used in combination with water, the reaction can take place at any suitable temperature such as from 460 193 12 o to 5o ° c, t eg 40 to 50 ° C.
En tri{;olväte)silylgrupp kan exempelvis avlägsnas genom syra- hydrolys, t.ex. utspädd mineralsyra eller trifluorättiksyra eller genom behandling med fluorjoner (t.ex. från en kvaternär ammoniumfluorid såsom tetra-n-butyl-ammoniumfluorid), eller genom behandling med vattenhaltigtfluorväte. Arylmetyl- grupper kan avlägsnas genom reduktion, t.ex. genom hydrogeno- lys, t.ex. med en ädelmetallkatalysator såsom platina eller palladium, eller genom behandling med en Lewis-syra (t.ex. bortrifluorid-eterat) i närvaro av en tiol (t.ex. etantiol) i ett lämpligt lösningsmedel såsom diklormctan vid t.ex. rumstemperatur.A tri (; hydrogen) silyl group can be removed, for example, by acid hydrolysis, e.g. dilute mineral acid or trifluoroacetic acid or by treatment with fluorine ions (eg from a quaternary ammonium fluoride such as tetra-n-butylammonium fluoride), or by treatment with aqueous fluorine. Arylmethyl groups can be removed by reduction, e.g. by hydrogenolysis, e.g. with a noble metal catalyst such as platinum or palladium, or by treatment with a Lewis acid (eg boron trifluoride etherate) in the presence of a thiol (eg ethanethiol) in a suitable solvent such as dichloromethane at e.g. room temperature.
Föreningarna med formel (2) kan framställas genom oxidation av en förening med formel (3) \(cH2)nx(cH2)mco2R1 Ü) med exempelvis pyridiniumklorokromat i närvaro av en buffert (t.ex. natriumacetat) i ett lämpligt lösningsmedel (t.ex. diklormetan) vid lämplig temperatur (t.ex. -l0° C till rums- temperatur). Alternativt kan oxidationen ske med dimetyl- sulfoxid, aktiverad med N,N'-dicyklohexylkarbodiimid i när- varo av pyridiniumtrifluoracetat i ett lösningsmedel såsom diklormetan vid t.ex. -100 C till rumstemperatur. Andra konventionella oxidativa metoder kan även användas, exempel- vis Jones reagens.The compounds of formula (2) may be prepared by oxidation of a compound of formula (3) ((cH2) nx (cH2) mco2R1 Ü) with, for example, pyridinium chlorochromate in the presence of a buffer (eg sodium acetate) in a suitable solvent (t (eg dichloromethane) at a suitable temperature (eg -10 ° C to room temperature). Alternatively, the oxidation can take place with dimethyl sulfoxide, activated with N, N'-dicyclohexylcarbodiimide in the presence of pyridinium trifluoroacetate in a solvent such as dichloromethane at e.g. -100 C to room temperature. Other conventional oxidative methods can also be used, for example Jones reagent.
Intermediärföreningar med formel (3) kan framställas enligt de metoder som allmänt beskrivits i det europeiska patentet 160 495.Intermediate compounds of formula (3) may be prepared according to the methods generally described in European Patent 160,495.
Man bör inse att deprotekteringsmetodcn (a) i allmänhet app- 460 193 13 liceras tillsammans med bildningen genom oxidation av cyklo- pentylringoxogruppen. Således kan föreningarna med formel (l) i allmänhet framställas genom oxidering av en motsvarande förening med formel (3).It should be appreciated that the deprotection method (a) is generally applied in conjunction with the formation by oxidation of the cyclopentyl ring oxo group. Thus, the compounds of formula (1) can generally be prepared by oxidizing a corresponding compound of formula (3).
Bildningen av ringoxogruppen kan emellertid även ske innan införandet av den önskade Rl gruppen genom förestring (t.ex. enligt metoden (b) nedan) och den skyddande gruppen därefter avlägsnas. (b) Föreningar med formel (l) kan även framställas genom förestring av motsvarande karboxylsyror, t.ex. föreningarna vari Rl är en väteatom enligt konventionella metoder.However, the formation of the ring oxo group can also take place before the introduction of the desired R1 group by esterification (eg according to method (b) below) and the protecting group is subsequently removed. (b) Compounds of formula (1) may also be prepared by esterification of the corresponding carboxylic acids, e.g. the compounds wherein R 1 is a hydrogen atom according to conventional methods.
Exempelvis kan en förening med formel (l) framställas genom överföring av motsvarande karboxylsyra i ett aktiverat derivat (t.ex. en motsvarande blandad anhydrid) bildad exempelvis genom omsättning med ett alkylkloroformiat (t.ex. isobutylkloroformiat) eller en syraklorid (t.ex. pivaloyl- klorid) i närvaro av en lämplig bas (t.ex. trietylamin eller pyridin). Det aktiverade derivatet kan därefter omsät- tas med en ändamålsenlig förening RIOH vilka antingen är kända föreningar eller kan framställas enligt metoder analoga till de som användes för framställning av kända föreningar.For example, a compound of formula (1) may be prepared by converting the corresponding carboxylic acid into an activated derivative (eg a corresponding mixed anhydride) formed for example by reaction with an alkyl chloroformate (eg isobutyl chloroformate) or an acid chloride (e.g. pivaloyl chloride) in the presence of a suitable base (eg triethylamine or pyridine). The activated derivative can then be reacted with an appropriate compound R10H which are either known compounds or can be prepared according to methods analogous to those used for the preparation of known compounds.
Lämpliga lösningsmedel innefattar dipolära aprotiska lös- ningsmedel (t.ex. aceton, acetonitril och dimetylformamid) och halogenerade kolväten (t.ex. diklormetan). Omsättningen kan genomföras vid vilken som helst lämplig temperatur, t.ex. från 00 C till rumstemperatur.Suitable solvents include dipolar aprotic solvents (eg acetone, acetonitrile and dimethylformamide) and halogenated hydrocarbons (eg dichloromethane). The reaction can be carried out at any suitable temperature, e.g. from 00 C to room temperature.
Samma grupp av föreningar med formel (l) kan även framställas genom att först motsvarande karboxylsyra omsättes med di- cyklohexylkarbodiimid i närvaro av 4-dimetylamínopyridin och därefter behandling av produkten med en fenol Rl0H.The same group of compounds of formula (I) can also be prepared by first reacting the corresponding carboxylic acid with dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine and then treating the product with a phenol R10H.
Denna reaktion sker lämpligen vid ändamålsenlig temperatur (t.ex. OO C till rumstemperatur) i ett lösningsmedel såsom eter eller diklormetan. 460 195 14 Karboxylsyrorna som erfordras som utgångsmaterial för denna reaktion kan framställas enligt de metoder som allmänt beskrivits i det europeiska patentet l60 495. (c) Föreningar med formel (l) vari X är en ~CH2-CH2-grupp kan framställas genom reduktion av en motsvarande förening vari X är en cis- eller trans-CH=CH-grupp eller en acetylen- grupp. Lämpliga metoder för reduktion innefattar väte i närvaro av en katalysator, t.ex. palladium på en bärare (t.ex. kol). Lämpliga lösningsmedel innefattar etylacetat, etanol och metanol. (d) Föreningar med formel (l) vari X är en -CH=CH-grupp kan framställas genom selektiv reduktion av en motsvarande förening vari X är en acetylengrupp. Lämpliga metoder för reduktion innefattar väte i närvaro av en katalysator, t.ex. palladium på en bärare (t.ex. CaCO3 eller BaSO4) och för- giftad med exempelvis bly eller kinolin. Lämpliga lösnings- medel innefattar etylacetat och metanol. Denna omsättning är särskilt lämplig för framställningen av föreningar vari X är cis-CH=CH-.This reaction is conveniently carried out at an appropriate temperature (eg 0 ° C to room temperature) in a solvent such as ether or dichloromethane. The carboxylic acids required as starting materials for this reaction can be prepared according to the methods generally described in European Patent 160,495. (C) Compounds of formula (I) wherein X is a -CH 2 -CH 2 group can be prepared by reduction of a corresponding compound wherein X is a cis or trans-CH = CH group or an acetylene group. Suitable methods for reduction include hydrogen in the presence of a catalyst, e.g. palladium on a support (eg carbon). Suitable solvents include ethyl acetate, ethanol and methanol. (d) Compounds of formula (1) wherein X is a -CH = CH group can be prepared by selective reduction of a corresponding compound wherein X is an acetylene group. Suitable methods for reduction include hydrogen in the presence of a catalyst, e.g. palladium on a support (eg CaCO3 or BaSO4) and poisoned with eg lead or quinoline. Suitable solvents include ethyl acetate and methanol. This reaction is particularly suitable for the preparation of compounds wherein X is cis-CH = CH-.
De acetylener som erfordras som utgångsmaterial kan framstäl- las på motsvarande acetylensyror genom förestring med an- vändning av ovan beskrivna metoder. Acetylensyraintermediä- rerna kan framställas enligt de metoder som i allmänhet be- skrivits i det europeiska patentet 160 495. (e) Föreningar med formel (l) vari X är en trans-CH=CH- grupp kan framställas genom isomerisering av en motsvarande förening vari X är en cis-CH=CH-grupp.The acetylenes required as starting materials can be prepared on the corresponding acetylenic acids by esterification using the methods described above. The acetylenic acid intermediates can be prepared according to the methods generally described in European Patent 160,495. (E) Compounds of formula (1) wherein X is a trans-CH = CH group can be prepared by isomerizing a corresponding compound wherein X is a cis-CH = CH group.
Isomeriscringen kan exempelvis ske genom behandling av mot- svarande cisförening med toluen-p-sulfinsyra i dioxan (t.ex. vid återlopp) eller azobisisobutyronitril och tio- fenol med användning av exempelvis ett kolvätclösningsmcdel (t.ex. bensen) vid vilken som helst lämplig temperatur upp 460 193 15 till återloppstemperatur.The isomerisation can be effected, for example, by treating the corresponding cis compound with toluene-p-sulfinic acid in dioxane (eg at reflux) or azobisisobutyronitrile and thiophenol using, for example, a hydrocarbon solvent (eg benzene) at any suitable temperature up to 460 193 15 to reflux temperature.
Förfarandena enligt metoderna (b - e) kan även appliceras på föreningar med formlerna (2) och (3) och produkterna efteråt överföras i föreningar med formel (1) enligt de ovan be- skrivna metoderna.The processes according to methods (b - e) can also be applied to compounds of formulas (2) and (3) and the products subsequently transferred to compounds of formula (1) according to the methods described above.
När en specifik enantiomer med formel (l) erfordras bör utgångsmaterial med den önskade stereokemiska konfiguratio- nen användas i de ovan angivna förfarandena. Sådana utgångs- material kan framställas exempelvis genom användning av de metoder som beskrives i det europeiska patentet 160 495 från en enantiomer intermediär såsom beskrivits i det europeiska patentet 74 856.When a specific enantiomer of formula (1) is required, starting materials of the desired stereochemical configuration should be used in the procedures set forth above. Such starting materials can be prepared, for example, using the methods described in European Patent 160,495 from an enantiomeric intermediate as described in European Patent 74,856.
Följande exempel åskådliggör uppfinningen.The following examples illustrate the invention.
Temperaturerna är i OC.The temperatures are in OC.
"Torkad" hänför sig till torkning med vattenfri MgSO4."Dried" refers to drying with anhydrous MgSO 4.
T.l.c. - tunnskiktskromatografi på silika. Kromatografin genomfördes på silikagel.T.l.c. thin layer chromatography on silica. The chromatography was performed on silica gel.
Följande förkortningar användes: ER-eter; EA-etylacetat; PE~petroleumeter (kokpunkt 60 - 800 om icke annat anges); DIBAL-diisobutylaluminiumhydrid; THF-tetrahydrofuran; CH2Cl2-diklormetan; CHCI3-kloroform; CHBr3-bromoform; DMF-dimetylformamid; DMSO-dimetylsulfoxid; EtOH-etanol; MeOH-metanol; CH3CN-acetonitril; Et3N-triety]- amin; N.T.P. - normalt tryck och temperatur.The following abbreviations were used: ER ether; EA-ethyl acetate; PE petroleum ether (boiling point 60 - 800 unless otherwise specified); DIBAL diisobutylaluminum hydride; THF-tetrahydrofuran; CH 2 Cl 2 -dichloromethane; CHCl 3 chloroform; CHBr3 bromoform; DMF-dimethylformamide; DMSO dimethyl sulfoxide; EtOH-ethanol; MeOH-methanol; CH 3 CN-acetonitrile; Et 3 N-triethyl] -amine; N.T.P. normal pressure and temperature.
Intcrmediär l /lS-/ o<(Z) ,2_/3 (2S*) ,30f 5 vi //-7-/5-hydroxi-Z-/B-fenoxi-Z- /(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetrahydro~2H- pyran-2-X1)oxi/cyklopentyl/-5-heptensyra 460 195 16 Intermediär 2 /lS-/lOL (Z) '2 (ä ,3 d. .5 Oß//-(+) metyl 7-/5-hydroxi-2-/2~metyl-3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi)propoxi/-3-/(tetra- hydro-Zë-pyran-2-yl)oxi/cyklopentyl/-5-heptenoat Intermediär 3 (a) /l§-/ld-(Z),2í5,3d.,5U_//-(+)-metyl 7-/2-/3-(4-fluor- fenoxi)-2-/(tetrahydro-2H-pyran-2-yl)oxi/prQpoxi/-5-hydroxi- 3-/(tetrahydro-ZÉ-pyran-2-yl)oxi/cyklopentyl/-5-hegtenoat (b) /1s-/s<_z_) ,2 9,3 apso N-(H-metyl v-/z-/s-(z-klor- fenoxi)-2~/(tetrahydro-ZH-pyran-2-yl)oxi/propoxi/-5-hydroxi 3-/(tetrahydro-2H-pvran-2-yl)oxi/çyklopentyl/-5-heptenoat (c) /lå-/1.ü(š),2(5,3Üs,5U-//-(+)-metyl 7-/5-hydroxi-2- /3-/4"(metylti0)fenOXi/-2~/(tetrahydro-Zëfpyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-ZH-pyran-2-yl)oxi/cyklopentyl/-5- heptenoat n šntermediär 4 /3aR-/3a mL , 4 uk ( 2R*) , 5 (b , 6a Cl/ß-hexahydro-Ll-/3-fenoxi-2- /(tetrahydro-2H-pyran-2-yl)oxi/propoxi/~5-/(tctrahydro-2H- pyran-2-yl)oxi/-2H-cyklopenta/b/furan-2-ol Intermediär 5 /lR-/lw.,5ob,6c¿,8R*(R*)//-8-(2-hydroxi-3-fenoxipropoxi)-6- (fenylmetoxi)-2-oxabicyklo/3.2.1/oktan-3-on Intermediär 6 /lS-/lßi (_Zi) ,2 ß (2_S_*) ,3 V~,5d~ //-(+)-metyl 9-/5-hydroxi-2- /3-fenoxi-2~/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3- /(tetrahydro-2H-Qyran~2-yl)oxi/cyklopentyl/-7-nonenoat Intermediärerna l - 6 framställes såsom beskrivits i det europeiska patentet 160 495. 460 193 17 Intermediär 7 Metyl 4-/(tetrahydro-2H-pyran-2-yl)oxi/bensoat En lösning av metyl 4-hydroxibensoat (10 g) i EA (60 ml) innehållande mättande eterhaltig HCl (3,5 ml) behandlades med dihydropyran (12 ml) och lösningen fick stâ vid rumstem- peratur i 24 timmar. En ytterligare mängd dihydropyran (12 ml) och eterhaltig HCl (3,5 ml) tillsattes och lösningen lämnades i 17 timmar. Lösningen indunstades och resten upp- löstes i ER (100 ml) och tvättades med 2 N NaOH-lösning (2 x 50 ml), saltlake (50 ml) och torkades därefter. Indunst- ning gav en rest, som vid rening genom kromatografi med an- vändning av 3:97 ER-toluen som elueringsmedel gav titel- föreningen som en vit fast substans (l0,2 g) smältpunkt ss - s2°. lneëmsåeëië 4-/Itetrahydro-2H-pyran-2-yl)oxi)bensoesyra En suspension av intermediär 7 (l0,0 g) i MeOH (200 ml) och 5 N NaOH-lösning (30 ml) omrördes vid rumstemperatur i 24 timmar. Lösningen indunstades till ungefär 50 ml och späddes med vatten (100 ml). Blandningen filtrerades genom hyflo och filtratet tvättades med ER (2 x 30 ml) och surgjordes genom droppvis tillsats av 5 N saltsyra. Den erhållna fäll- ningen avfiltrerades och gav titelföreningen som en vit fast substans (s,zs g), smäitpunkt 138 - 139°.Intermediate 1 / 1S- / o <(Z), 2/3 (2S *), 30f 5 vi // - 7- / 5-hydroxy-Z- / B-phenoxy-Z- / (tetrahydro-2H-pyran- 2-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-X1) oxy] cyclopentyl] -5-heptenoic acid 460 195 16 Intermediate 2 / 1S- / 1OL (Z) '2 (ä, 3 d. 5 Oß // - (+) methyl 7- [5-hydroxy-2- [2-methyl-3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy) propoxy] -3 - / (tetrahydro-Z-pyran-2-yl) oxy / cyclopentyl / -5-heptenoate Intermediate 3 (a) /l§-/ld-(Z),2í5,3d.,5U_//-(+ ) -methyl 7- [2- [3- (4-fluoro-phenoxy) -2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -5-hydroxy-3 - [(tetrahydro-Z pyran-2-yl) oxy / cyclopentyl / -5-hegtenoate (b) / 1s / s <_z_), 2 9,3 apso N- (H-methyl v- / z- / s- (z-chloro- phenoxy) -2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy / -5-hydroxy 3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate (c) /lå-/1.ü(š),2(5,3Üs,5U-//-(+)-methyl 7- / 5-hydroxy-2- / 3- / 4 "(methylti0) phenOXi / -2 ~ [(tetrahydro-Zepyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate n intermediate 4 / 3aR- / 3a mL, 4 μk (2R *), 5 (b, 6a Cl / ß-hexahydro- L1- [3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -5 - [(tetrahydro-2H-pyran-2-yl) oxy] -2H-cyclopenta [b] furan -2-ol Intermediate 5 /lR-/lw.,5ob,6c¿,8R*(R*)//-8-(2-hydroxy-3-phenoxypropoxy)-6- (phenylmethoxy) -2-oxabicyclo / 3.2 .1 / octan-3-one Intermediate 6 / lS- / lßi (_Zi), 2 ß (2_S_ *), 3 V ~, 5d ~ // - (+) - methyl 9- / 5-hydroxy-2- / 3-Phenoxy-2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -7-nonenoate Intermediates 1-6 are prepared as described in European patent 160 495. 460 193 17 Intermediate 7 Methyl 4 - / (tetrahydro-2H-pyran-2-yl) oxy / benzoate A solution of methyl 4-hydroxybenzoate (10 g) in EA (60 ml) containing saturating ethereal HCl (3.5 ml) was treated with dihydropyran (12 ml) and the solution was allowed to stand at room temperature for 24 hours. An additional amount of dihydropyran (12 ml) and ethereal HCl (3.5 ml) were added and the solution was left for 17 hours. The solution was evaporated and the residue was dissolved in ER (100 mL) and washed with 2 N NaOH solution (2 x 50 mL), brine (50 mL) and then dried. Evaporation gave a residue which on purification by chromatography using 3:97 ER-toluene as eluent gave the title compound as a white solid (10.2 g) mp ss - s2 °. A suspension of intermediate 7 (10.0 g) in MeOH (200 ml) and 5 N NaOH solution (30 ml) was stirred at room temperature for 24 hours. . The solution was evaporated to about 50 ml and diluted with water (100 ml). The mixture was filtered through hyflo and the filtrate was washed with ER (2 x 30 ml) and acidified by dropwise addition of 5 N hydrochloric acid. The resulting precipitate was filtered off to give the title compound as a white solid (s, zs g), mp 138-139 °.
Intermediär 9 N-(4-hydroxifenyl)-4-/(tetrahydro-2H-pyran-2-yl)oxi/bensamid En lösning av intermediär 8 (8,1 g) i torr THF (200 ml) vid OO behandlades med Et3N (6,0 ml) och därefter pivaloylklorid (5,4 ml) och blandningen omrördes vid Oo i 30 minuter. En lösning av 4-aminofenol (3,0 g) i DMF (30 ml) tillsattes och blandningen omrördes i 17 timmar vid rumstemperatur och 460 193 18 i 1,5 timmar vid 800. Blandningen filtrerades, filtratet indunstades och resten upplöstes i ER (200 ml). När denna hälldes i vatten (200 ml) erhölls en fällning som avfiltre- rades och kristalliserades ur EA-MeOH och gav titelföre- ningen som en vit fast substans (5,6 g), smältpunkt l73-1740.Intermediate 9 N- (4-hydroxyphenyl) -4 - [(tetrahydro-2H-pyran-2-yl) oxy] benzamide A solution of intermediate 8 (8.1 g) in dry THF (200 mL) at 0 ° C was treated with Et 3 N (6.0 ml) and then pivaloyl chloride (5.4 ml) and the mixture was stirred at 0 ° C for 30 minutes. A solution of 4-aminophenol (3.0 g) in DMF (30 ml) was added and the mixture was stirred for 17 hours at room temperature and 460 193 18 for 1.5 hours at 800. The mixture was filtered, the filtrate was evaporated and the residue was dissolved in ER ( 200 ml). When this was poured into water (200 ml), a precipitate was obtained which was filtered off and crystallized from EA-MeOH to give the title compound as a white solid (5.6 g), m.p.
Intermediär 10 (a) /lS-/la (Z) ,2ß (2S*) ,3 ot ,5 0í//-(+)-4-acetylfenyl 7-/5-hydroxi-2-/3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5- hegtenoat En lösning av intermediär l (0,45 g) i torr CH3CN (15 ml) vid -100 behandlades med Et3N (0,2 ml) följt av isobutyl- kloroformiat (0,l4 ml). Efter omröring i 45 minuter till- sattes p-hydroxiacetofenon (0,23 g). Omröringen fortsatte i 2 timmar vid -10 till 00 och därefter späddes blandningen med vatten och extraherades med ER (3 x 50 ml). De kombine- rade extrakten tvättades med lO-procentig kopparsulfatlös- ning (75 ml), vatten (l0 ml) och torkades därefter. In- dunstning gav en rest, som vid rening genom kromatografi med användning av 2:1 ER-PE (40 - 600) som elueringsmedel gav titelföreningen som en klistersubstans (0,43 g).Intermediate 10 (a) / 1S- / la (Z), 2β (2S *), 3 .mu.l, 5 .mu.l // - (+) - 4-acetylphenyl 7- [5-hydroxy-2- [3-phenoxy-2] - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-hegtenoate A solution of intermediate 1 (0.45 g) in dry CH 3 CN (15 mL) at -100 was treated with Et 3 N (0.2 mL) followed by isobutyl chloroformate (0.4 mL). After stirring for 45 minutes, p-hydroxyacetophenone (0.23 g) was added. Stirring was continued for 2 hours at -10 to 00 and then the mixture was diluted with water and extracted with ER (3 x 50 ml). The combined extracts were washed with 10% copper sulfate solution (75 ml), water (10 ml) and then dried. Evaporation gave a residue which on purification by chromatography using 2: 1 ER-PE (40-600) as eluent gave the title compound as an adhesive (0.43 g).
I.r. (cHBr3) 3550, 1753, 1678 cm'l, /az/zš + 19,e° (neon).I.r. (cHBr3) 3550, 1753, 1678 cm -1, / az / zš + 19, e ° (neon).
Följande föreningar framställdes på samma sätt från inter- mediär l och ändamålsenlig fenol: (b) /lS-/loL (Z) ,2 ß(2S*) ,3 o(_,50L//-(+)-4-(acctylamino)fenyl 7-/5-hydroxi-2-73-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi7cyklopentyl/-5- hegtenoat _ 1.:. (cnßr3) ssso, 3425, 1750, 1690 cm“l f /ol/zš + 7,9° (meon) 460 193 19 (C) /lS-/l|m(Z),2 ß(2S*),3 d,5|x//-(+)~4-/(aminokarbonyl)- amino/fenyl 7-/5~hydroxi-2-/3-fenoxi-2-/(tetrahydro-2H-pyran- ;:yl)oxi/propoxi/-3-/(tetrahydro-ZH-pyran-2-yl)oxi/cyklo- Eentyl/-5-hegtenoat 1.r. (cHBr3) 3510, 3410, 1748, 1682 cm'1, / 042% + 1s,4° (neon) (d) /lS-/l.&(Z),2[3(2S*),3 &,501//-(+)-4-(bensoylamino)fenyl 7-/5-hydroxi-2:/3-feno;i-2-/(tetrahydro~2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi7cyklopentyl/-5- hegtenoat _ Pivaloylklorid (0,l8 g) sattes till en lösning av intermediär 1 (0,7 g) och Et3N (0,3s g) 1 torr Dnr (5 ml) vid 0°. Efter 10 minuter tillsattes en lösning av 4-(bensoylamino)fenol (O,53 g) i DMF (2 ml) och omröring fortsatte i 6 timmar vid Oo och 18 timmar vid rumstemperatur. Reaktionsblandningen späddes med EA (150 ml) och tvättades i tur och ordning med vatten (2 x 50 ml), 10-procentig kopparsulfatlösning (2 x 50 ml), vatten (50 ml) och saltlake (50 ml). Dettorkade organiska extraktet indunstades och gav en rest som renades genom kromatografi på Et3N-deaktiverad silika med användning av l:l cyklohexan-EA som elueringsmedel. Titelföreningen erhölls som en klistersubstans (O,55 q). 1.r. (cHBr3), 3520, 3425, 1750, 1673 cm"l, /gl/2% + 2o° (cHc13) Följande föreningar framställdes på samma sätt som interme- diär l0d från intermediär 1 och ändamålsenlig fenol: (e) /lÉ-/lQL (å) ,2'(b(2§_*) ,3 u,50L//-(+)-4-/4-(aCetylaminOJ- bensoylamino/fenyl 7-/5-hydroxi-2-/3-fenoxi-2-/(tetrahydro- 2H-pyran-2-yl)oxi/propoxi/-3-/(tetrahydro-ZH-pyran-2-yl)- oši/cyklopentyl/-5-heptenoat _ :.r. (cHBr3) 3560, 3520, 3425, 1745, 1690, 1670 cm'l /g¿/¿g + 20,6° (cHc13) 460 195 20 (f) /lS-/lßé (Z) ,2{$ (2S*) ,3o< ,5vi//-(+)-4-(aminokarbonyl)- fenyl 7:/5-Qyd;oxi-2-/š-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)- oxi/propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cy§lopentyl/- 5-hegtenoat _ I.r. (CHBIB) 3520, 3400, 1755, 1672 cm_l, /Of/23 + 200 (CHCl3) (q) /1s-/1°L,2_rs(2S*)50,501//-<+>-ï1-/z- amino) -3ïamino-š-gxopropyl7fenyl 7-/5-hydroxi-2-/3-fenoxi-2- / (tetrahydro-ZH-pyran-Z-yl) oxi/propoxi/-3-/ (tetrahydro-ZH- pyran-2-yl) oxi7cyklopentyl/-5-heptenoat _ I.r. (CHBI3) 3500, 3400, 1745, 1690, 1660 cm_l, 20 o /ok/ D + 24 (CHCl3) (h) /1s-/10L(z),2!5(2s*),3«.,50.//-(+)-3-(bens0y1amin0)- fenyl 72/5-hydçoxi-z-/š-fenoxi-Z-/(tetrahydro-ZH-pyran-Z- yl) oxi/propoxi/-3-/ (tetrahydro-ZH-pyran-Z-yl) oxi7cyklc- gentyl/-S-hegtenoat _ 1.r. (cHBr3) 3700 - 3100. 1755, 1e77_cm"1, 20 o /nL/ D + 27 (CHCl3) (i) /lS-/lßl (Z) ,2 ß (2S*) ,3 04 ,5 0L//-4- (ILN-dimetylamino- karbonylïfenyl 1-7-/5-hyäroxi-2-/3-fenoxi-2-/(tetrahydro-ZH- pyran-Z-yl) oxi/propoxi/-3-/ (tetrahydro-2H-pyran-2-yl) oxi/ï cyklopentyl/-S-heptenoat _ 1.r. (cnBr3) 3530, 1750, 1740, 1626 cm"1 (j) /lS-/l BL (Z) , 2 [5(2S*) , 3 vL , 50k // metyl 4-//7-/5-hydroxi- 2-/3-fenSxi-2-/ïtetrahycïro-ZH-pyran- Z-vl ) oxi/gopoxi/-B- / (tetrahydro-2H-pyran-2-y 1) oši/cyklopentyl/-l-oxo-S- heptenXl/oxi/bênsoat I.r. (cnBr3) 3590, 3520, 1750, 1715 cm"1. 460 193 21 (k) /1s-/°<(z),2{¿ (2§*),3 oL,5oc//-<+>-4-///4-/(tetrahyaro- 2H-pyran:2-yl)Exi/fenyl/karbonyl/amino/fenyl 7-/5-hydroxi- 2:/3-fen0Xi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3- /(tetrahydro-2H-Qyran-2-yl)oši/cyklopentyl/~5-heptenoat från intermediär l och 9 I.r. (CHBIB) 3580, 3420, 1748, 1668 cm-1 20 /OL/ D + 21° (cHc13) (1) /lS-/lot (Z) ,2 ß(2S*) ,3 (X.,50(.//~2-(bensoylaminmfenyl 7-/5-hydroxi-2-/3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2~yl)oxi/cyklopentyl/-5- lzavfiefßeê: I.r. (CHBr3) 3520, 3440, 1728, 1688, 1516 cm_l (m) /1s-/1oL(z),2[5(2s*),3ousøí/ßz-naftalenyl 7-/5- hydroxi-2-/3-fe;§xi-2-/?tetrahydro-2H-pyran-2-yl)oxi/- propoxi/~3-/(tetrahydro-ZH-pyran-2-y1)oxi/cyklopentyl/-5- hcgtenoat _ Lr. (cmar3) 3530, 1750 cnfl (n) /l_S_-/l oL (Z) ,2 ß ,3 oL,5 vt H-Ll-(bensoylamino) fenyl 7-/5-hydroxi-2-72-metyl-3-fenoxi-2-/(tetrahydro-2ë:pyran-2- yl)oxi/propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopenty1/- 5-hegtenoat, från intermediär 12:.The following compounds were prepared in the same manner from intermediate 1 and appropriate phenol: (b) / 1S- / loL (Z), 2 ß (2S *), 3 o (_, 50L // - (+) - 4- ( acylamino) phenyl 7- [5-hydroxy-2-73-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy7cyclopentyl / -5- hegtenoate _ 1.:. (cnßr3) ssso, 3425, 1750, 1690 cm “lf / ol / zš + 7.9 ° (meon) 460 193 19 (C) / lS- / l | m ( Z), 2 ß (2S *), 3 d, 5 μx // - (+) ~ 4 - [(aminocarbonyl) amino] phenyl 7- [5-hydroxy-2- [3-phenoxy-2-] (tetrahydro-2H-pyran-1-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cycloethyl-5-hegtenoate 1.r. (cHBr 3) 3510, 3410 , 1748, 1682 cm'1, / 042% + 1s, 4 ° (neon) (d) /lS-/l.&(Z),2[3(2S*),3 &, 501 // - (+ ) -4- (benzoylamino) phenyl 7- [5-hydroxy-2: β-pheno-2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro- 2H-Pyran-2-yl) oxy7cyclopentyl / -5-hegtenoate Pivaloyl chloride (0.8 g) was added to a solution of intermediate 1 (0.7 g) and Et 3 N (0.3 g) 1 dry Dnr (5 ml) After 0 minutes, a solution of 4- (benzoylamino) phenol (0, 53 g) in DMF (2 ml) and stirring was continued for 6 hours at 0 ° C and 18 hours at room temperature. The reaction mixture was diluted with EA (150 mL) and washed successively with water (2 x 50 mL), 10% copper sulfate solution (2 x 50 mL), water (50 mL) and brine (50 mL). The dried organic extract was evaporated to give a residue which was purified by chromatography on Et 3 N-deactivated silica using 1: 1 cyclohexane-EA as eluent. The title compound was obtained as an adhesive (0.5 g). 1.r. (cHBr3), 3520, 3425, 1750, 1673 cm -1 / g / 2% + 20 ° (cHc13) The following compounds were prepared in the same manner as intermediate 10d from intermediate 1 and appropriate phenol: (e) / lÉ- / lQL (å), 2 '(b (2§_ *), 3 u, 50L // - (+) - 4- / 4- (αCetylaminOJ- benzoylamino / phenyl 7- / 5-hydroxy-2- / 3 -phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -osyl] cyclopentyl] -5-heptenoate. (cHBr3) 3560, 3520, 3425, 1745, 1690, 1670 cm -1 / g¿ / ¿g + 20.6 ° (cHc13) 460 195 20 (f) / lS- / lßé (Z), 2 {$ ( 2S *), 3o <, 5vi // - (+) - 4- (aminocarbonyl) -phenyl 7: [5-C]; oxy-2- [6-phenoxy-2 - [(tetrahydro-2H-pyran-2- yl) - oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-hegtenoate Ir (CHBIB) 3520, 3400, 1755, 1672 cm -1, / Of / 23 + 200 (CHCl3) (q) / 1s- / 1 ° L, 2_rs (2S *) 50,501 // - <+> - ï1- / z-amino) -3ïamino-š-gxopropyl7phenyl 7- / 5-hydroxy-2 N-3-phenoxy-2- [(tetrahydro-ZH-pyran-Z-yl) oxy] propoxy] -3- [(tetrahydro-ZH-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate-Ir (CHBI3) 3500, 3400, 1745, 1690, 1660 cm_l, 20 o / ok / D + 24 (CHCl3) (h) /1s-/10L(z),2!5(2s*),3 «.,50.//-(+)-3-(bens0y1amin0)- phenyl 72 / 5- Hydroxy-z- [β-phenoxy-Z - [(tetrahydro-ZH-pyran-Z-yl) oxy] propoxy] -3- [(tetrahydro-ZH-pyran-Z-yl) oxy] -cycyl-gentyl] -S-hegtenoate _ 1.r. (cHBr3) 3700 - 3100. 1755, 1e77_cm "1, 20 o / nL / D + 27 (CHCl3) (i) / lS- / lßl (Z), 2 ß (2S *), 3 04, 5 0L // -4- (ILN-dimethylaminocarbonylphenyl 1-7- [5-hydroxy-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro- 2H-pyran-2-yl) oxy [cyclopentyl] -S-heptenoate - 1.r. (cnBr3) 3530, 1750, 1740, 1626 cm -1 (j) / 1S- / 1 BL (Z), 2 [ 5 (2S *), 3 μL, 50k // methyl 4- // 7- [5-hydroxy-2- [3-phenoxy-2- [tetrahyciro-ZH-pyran-Z-yl) oxy] gopoxy / -B - / (tetrahydro-2H-pyran-2-yl) oxy / cyclopentyl / -1-oxo-S-heptenX1 / oxy / benzoate Ir (cnBr3) 3590, 3520, 1750, 1715 cm "1. 460 193 21 (k) / 1s- / ° <(z), 2 {¿(2§ *), 3 oL, 5oc // - <+> - 4 - /// 4 - [(tetrahydro-2H-pyran: 2-yl) Exi] phenyl / carbonyl / amino / phenyl 7- [5-hydroxy-2: β-phenoxy-2 - [(tetrahydro-2H- pyran-2-yl) oxy / propoxy / -3- [(tetrahydro-2H-Qyran-2-yl) oxy] cyclopentyl] -5-heptenoate from intermediate 1 and 9 Ir (CHBIB) 3580, 3420, 1748, 1668 cm -1 20 / OL / D + 21 ° (cHc13) (1) / 1S- / lot (Z), 2 ß (2S *), 3 (X., 50 (.// ~ 2- (benzoylamine) phenyl 7- / 5-hydroxy-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] - 5- lzav fi efßeê: Ir (CHBr3) 3520, 3440, 1728, 1688, 1516 cm_l (m) / 1s- / 1oL (z), 2 [5 (2s *), 3ousøí / ßz-naphthalenyl 7- / 5-hydroxy 2- [3-Fexi-2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5 - hcgtenoate _ Lr. (cmar3) 3530, 1750 cnfl (n) / l_S _- / l oL (Z), 2 ß, 3 oL, 5 vt H-Ll- (benzoylamino) phenyl 7- / 5-hydroxy-2- 72-methyl-3-phenoxy-2 - [(tetrahydro-2H: pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] - 5-hegtenoate, from intermediate 12 :.
Lr. (cam-B), 3520, 3430, 1750, 1675 mfl (0) /lå-/ld_(Z),211,3 íluorfenoxi)-2-/(tetrahydro-2H-pyran~2-yl)oxi/propoxi/-5- hydroxi-3-/(tetrahydro-2H-pyran~2-y1)oxi/cyklopentyl/-5- heptenoat, från intermediär l2b.Lr. (cam-B), 3520, 3430, 1750, 1675 mfl (0) / la- / ld_ (Z), 211.3 fluorophenoxy) -2 - [(tetrahydro-2H-pyran-2-yl) oxy / propoxy / -5-hydroxy-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 12b.
Lr. (cußrš) 3590, 3530, 1748 cm* 460 '(95 22 (p) /1s-/1°L(z),2;5,3«x,s0 - - l 7-/ 2-/3 - (B-klorfenoxi) -2-/ (tetrahydro-ZH-pyran-Z -yl) oxi/- propoxi/-S -hydroxi-3-/ (tetrahydro-ZH-pyran-2-yl) oxi /cyklo- Eentvl/-S-hegtenoat, från intermedišr l2c.Lr. (cußrš) 3590, 3530, 1748 cm * 460 '(95 22 (p) / 1s- / 1 ° L (z), 2; 5,3 «x, s0 - - l 7- / 2- / 3 - B-chlorophenoxy) -2- [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -S-hydroxy-3- [(tetrahydro-2H-pyran-2-yl) oxy] -cyclo-Eentyl] - S-hegtenoate, from intermedišr l2c.
I.r. (cHBr3) 3500, 3520, 1750 cm'l. (q) /lS-/l vL (Z), 2 få , 3 04 ,50C //-4- (metylsulfonyl) fenyl 7-/5-hydšoxi-2-73-/íl- (metyltio) fenoxi/-2-/ (tetrahydro-ZH- pyran-Z-yl) oxi/propoxi/-B-l (tetrahydro-ZH-pyran-Z-yl) oxå /- cyklopentyl/-S-heptenoat, från intermeäitaïr l2d . 1.r. (cHßr3) 3520, 1758 cm'1 (r) /lS-/l oL Jfl; (2S*) , 3 (X ,5 0C//-4- (aminokarbonyl) fenyl 7-/5~hyd;oxi-2-/3-fe;oxi-2-/ (tetrahydro-ZH-pyran-Z-yl) oxi/~ propoxi/-3-/ (tetrahydro-ZH-pyran-Z-yl)oxi7cyklopentyl/-4 , 5- hegtadienoat, från interm-ëdiär 12 e.I.r. (cHBr 3) 3500, 3520, 1750 cm -1. (q) / 1S- / l vL (Z), 2 fa, 3 04, 50C // - 4- (methylsulfonyl) phenyl 7- / 5-hydroxy-2-73- [[1- (methylthio) phenoxy] -2 - / (tetrahydro-ZH-pyran-Z-yl) oxy / propoxy / -B1 (tetrahydro-ZH-pyran-Z-yl) oxo [cyclopentyl] -S-heptenoate, from intermediate 12d. 1.r. (cHßr3) 3520, 1758 cm -1 (r) / lS- / l oL J fl; (2S *), 3 (X, 5 ° C // -4- (aminocarbonyl) phenyl 7- [5-hydroxy-2- [3-feoxy-2- [tetrahydro-ZH-pyran-Z- yl) oxy / propoxy / -3- [(tetrahydro-ZH-pyran-Z-yl) oxy] cyclopentyl] -4,5-hegtadienoate, from intermediate 12 e.
I.r. (CHBIB) 3520, 3405, 3600 - 3200, l960, 1758, l675 cm-l (s) /lS-/l Ok (Z) , 2 [5 (2S*) ,3 o! ,5 o( //-4- (bensoylamino) fenyl 7-/5-hydroxi-2-/3-fenoxi-2-/ (tetrahvdro-Zíí-pyran-Z-y l) oxi/- propoxi/-3-/ (tetrahydro-Zg-pvran-Z-vl) oxi/cvklopentvl/-fll- heptenoat, från intermediär 12 f.I.r. (CHBIB) 3520, 3405, 3600 - 3200, l960, 1758, l675 cm-1 (s) / lS- / l Ok (Z), 2 [5 (2S *), 3 o! , (5 - ((benzoylamino)) phenyl 7- [5-hydroxy-2- [3-phenoxy-2 -] (tetrahydro-Zi-pyran-Zyl) oxy] -propoxy] -3- / ( tetrahydro-Zg-pyran-Z-yl) oxy / cyclopentyl / -l-heptenoate, from intermediate 12 f.
I.r. (CHBr3) 3520, 3430, 1750, 1678 cm-l (t) /lS-/loL (Z) ,2 |fb(2S*) ,3 m,50(_//-4- (bensoylamino) fenvl 9-/S-hydšoxi-Z-73-fenoxš--2-/ (tetrahydro-ZH-pyran-Z-yl) oxi/- propoxi/-3-/ (tetrahydro-ZH-Qyran-Z-yl) oxi7cyklopentyl/-7- nonenoat, från intermediä; 12 g 1.:. (cHBr3) 3520, 3420, 1748, 1672 cm'1 460 193 23 Intermediär ll (a) /lš-/lué (å) ,2.ß (2R*) ,3 áL//-(-)-4-acetylfenyl 7-/5-oxo-2-/3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/- 3~/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5-heptenoat En omrörd lösning av intermediär 10 a (O,39 g) i torr CH2Cl2 (4 ml) och torr DMSO (0,4 ml) behandlades med dicyklohexyl- karbodiimid (0,5 g) följt av pyridiniumtrifluoracetat (0,l7 g). Efter 5 timmar vid rumstemperatur hälldes bland- ningen i vatten (50 ml) extraherades med ER (3 x 75 ml).I.r. (CHBr3) 3520, 3430, 1750, 1678 cm-1 (t) / 1S- / loL (Z), 2 μb (2S *), 3 m, 50 (_ // - 4- (benzoylamino) phenyl 9- [5-Hydroxy-Z-73-phenoxy-2- [(tetrahydro-ZH-pyran-Z-yl) oxy] -propoxy] -3- [(tetrahydro-ZH-Qyran-Z-yl) oxy] cyclopentyl] -7 - nonenoate, from intermediate; 12 g 1.:. (cHBr3) 3520, 3420, 1748, 1672 cm-1 460 193 23 Intermediate ll (a) / lš- / lué (å), 2.ß (2R *), 3 [alpha] - (-) - 4-acetylphenyl 7- [5-oxo-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [tetrahydro] -2H-pyran-2-yl) oxy / cyclopentyl / -5-heptenoate A stirred solution of intermediate 10 a (0.39 g) in dry CH 2 Cl 2 (4 mL) and dry DMSO (0.4 mL) was treated with dicyclohexyl. carbodiimide (0.5 g) followed by pyridinium trifluoroacetate (0.7 g) After 5 hours at room temperature, the mixture was poured into water (50 ml) and extracted with ER (3 x 75 ml).
Indunstning av de torkade extrakten gav en rest som renades genom kromatografi på syratvättad (pH 3,8) silika. Titel- föreningen erhölls som en färglös klistersubstans (0,27 g).Evaporation of the dried extracts gave a residue which was purified by chromatography on acid washed (pH 3.8) silica. The title compound was obtained as a colorless adhesive (0.27 g).
Lr. (CHBrB) men, 1743, 1680 mfl /oz/zšfl -13,7° (meon).Lr. (CHBrB) men, 1743, 1680 mfl / oz / zš 13 -13.7 ° (meon).
Följande förening framställdes på samma sätt: (b) /lä-/l N12),213(2R*),3:X1/-(+)-4-(fiCetYlamino)fenY1 7-/5-0X0~Z-/B-fgnoxi-Z-Ãtetrahydro-zë-pyran-z-yl) oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5- hegtenoat, från intermediär 10 b Lr. (essä) 3420, 1740, less emil /M/lgß + 16,70 (meon) (c) /lR-/la.(Z),2j3(2R*),3 fenyl 7-/5-oxo-2-/3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)- oxi/propoxi/~3-/(tetrahydro-2U-pyran~2-yl)oxi/gyklopenty1-5- hegtenoat En kall (Oo) omrörd suspension av intermediär 10 c (0,l5 g) och vattenfri natriumacctat (0,05 g) i CH2Cl2 (2 ml) behand- lades med pyridiniumklorokromat (O,l3 g). Blandningen_omrör- des vid OO i 30 minuter och vid rumstemperatur i l timme och renades därefter genom kromatografi på syratvättad (pH 3,8) silika med användning av EA som eluent. Titelföreningen er- hölls som en klistersubstans (0,09 g) T.l.c. EA Rf 0,3. 460 193 24 Följande föreningar framställdes på samma sätt: (d) /lš-/lbk (Z) ,2 ß (2R*) ,3 0L//-(-)-4-(bensoylaminmfenyl 7-/5-oxo-2~/3-fÄfioxi-2-/(tetrahydro-2§-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5- hegtenoat. från intermedíår 10 d 1 /x/Zg -11 I.r. (cHBr3) 3430, 1740, 1675 cm' ° (CHCI3) (e) /IÉ-/lOL (Z) ,2í5 (ZIF) ,3 vL//-(-)-4-/4-(acetylamino)- bensoylamino/-fenyl 7-/5-oxo-2-/3-fenoxi-2-/(tetrahydro-2H- pyran-2-yl)oxi/PrOP0Xi/“3~/(tetrahydro-ZH-pyran-Zfyl)oxi/- cyklopentyl/-5-heptenoat, från intermediär 10 e 1.:. (cHsr3) 3420, 1740, 1690, 1670 cm'l /cc/23 -s° (CHCl3) (f) /lR-/IOL (Z) ,2[5 (2R*) ,30(,//-(-)-4-(aminokarbonvl)fcnyl 7-/5*0X0-2-/3-fen0Xi~2~/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5- heptenoat, från intermediär 10 f I.r. (CHBr ) 3525, 3405, l742, l675, 1599 Cm-l 20 o /m¿/ D -16,3 (CHCl3) (9) /lR-/1-KÅ2,S*),2/3(2R*):3& //-(-)-4-/2-(acetylamino)- 3-amino-3-oxopršpçl/feåy1 -0-/5-oxo~2-/3-fenoxi-2-/(tetra- hydro-2§~pyran-2-yl)oxi/Qropoxi-3-/(tetrahydro-2H-pyran-2- yl)oxi/cykloQentyl/-5-heptenoat, från intermediå; 10 g I.r. (CHBr3) 3505, 3400, 1740, 1690, 1665 Cm_l 20 Ü _o /ø(/ D -5,4 (CHCl3) (h) /lR-/l°4(Z),2_ß(2R*),3UL//-(-)-3-(bcnsoylamino)fcny1 7-/5-oxo:2-/3-fcnoxí-2-7ktctrahydro-2H-pyran-2-yl)oxi/T propoxi/-3-/(tetrahydro-2§:pyran-2-ylíßxi/cyklopentyl/-5- heptenoat, från intermediär 10 h 1 20 0 I.r. (CHBI3) 3430, 1742, 1680, 1526 cm- /C(/ D -7 (CHCl3) 460 193 25 (1) /lR-/lu.(å),;J3(2å*),3<1//-4-(N.N-dimetylaminokarbony}) fenyl 7-/5-oxo-2-/3-fencxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5- heptenoat, från intermediär 10 i 1.r. 1740, 1622 cm'1 (j) /1R-/1« (z),z¿3(2R*),34 fenoxi~2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetra- hydro-2H~pyran-2-yl)oxi/cyklopentyl/-l-oxo-5-heptenyl/oxi/- bensoat, från intermediär 10 j 1.r. (cHBr3) 1745, 1720 cm'l <1) /1R-/1a.(z),2;3(25*),3a //-(-)-4~///4-/(tetrahyaro- 2H-pyran:2-yl)oši/fenyl/karbonyl/amino/fenyl 7-/5-oxo-2-/3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi-3-/(tetra- hydro~2E-pyran-2:yl)øxi/cyklopentyl/-5-heptenoat, från intermediär 10 k I.r. (caBr3) 3435, 1745, 1720, 1672 cm"l /on/23 -s,9° (cHc13) ll 1) (lR-/l0L(Z),2!3(2R*),3¿(//-2-(bensoylamino)fenyl 7-/5-oxo-3-/3-fe;oxi-2-/Ttetrahydro-2H-pyran-2-yl)oxi/~ propoxi/-3-/(tetrahydro-2H-pyran-2-ylïoxi/cyklopengyl/-5- hegtenoat, från intermediš; 10 l I.r. (cHBr3) 3440, 1760, 1740, 1678 cm"l ll m) /lR-/l0L(Z),2/3(2R*),3(X//-2-naftalenyl 7-/5-oxo-2- /3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/gropoxi/-3- /(tetrahydro~2H~pyran-2-yl)oxi/cyklopentyl/-5-heptenoat, från intermediär 10 m I.r. (CHBr3) 1745 cmïl 460 195 26 ll n) /lR-/ld.(Z),2¿3,3nä//-4-(bensoylamino)fenyl 7-/2-/2-me:yl-3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-5-oxo-3-/(tetrahydro-2§-pyran-2-yl)oxi/cyklopentyl/- 5-hegtenoat, från intermediär 10 n I.r. (cHBr3) 3430, 1740, 1672 cm'l 11 0) /1R-/lg (z),215,3 fluorfenoxi)-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/~5- oxo-3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5-heptenoat från intermediär lO o.The following compound was prepared in the same manner: (b) / lä- / l N12), 213 (2R *), 3: X1 / - (+) - 4- (fi CetYlamino) phenY1 7- / 5-0X0 ~ Z- / B -phenoxy-Z-tetrahydro-z-pyran-z-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-hegtenoate, from intermediate 10 b Lr. (essä) 3420, 1740, less emil / M / lgß + 16,70 (meon) (c) /lR-/la.(Z),2j3(2R*),3 phenyl 7- / 5-oxo-2- 3-Phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) -oxy-propoxy] -3- [(tetrahydro-2H-pyran-2-yl) -oxy-gyclopentyl] -5-hegtenoate A cold (Oo ) Stirred suspension of intermediate 10 c (0.1 g) and anhydrous sodium acetate (0.05 g) in CH 2 Cl 2 (2 ml) were treated with pyridinium chlorochromate (0.1 g). The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour and then purified by chromatography on acid washed (pH 3.8) silica using EA as eluent. The title compound was obtained as an adhesive (0.09 g) T.l.c. EA Rf 0.3. 460 193 24 The following compounds were prepared in the same manner: (d) / lš- / lbk (Z), 2 ß (2R *), 30L // - (-) - 4- (benzoylamine-phenyl-7/5-oxo-2 N-3-Phenoxy-2 - [(tetrahydro-2§-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-hegtenoate. from intermediate 10 d 1 / x / Zg -11 Ir (cHBr3) 3430, 1740, 1675 cm -1 (CHCl3) (e) / IÉ- / lOL (Z), 2í5 (ZIF), 3 vL // - (- ) -4- [4- (acetylamino) -benzoylamino] -phenyl 7- [5-oxo-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] PrOPOXi / / (tetrahydro-ZH-pyran-Z-phyl) oxy / cyclopentyl / -5-heptenoate, from intermediate 10 e 1.: (cHsr3) 3420, 1740, 1690, 1670 cm -1 / cc / 23 -s ° (CHCl3 ) (f) / 1R- / IOL (Z), 2 [5 (2R *), 30 (, // - (-) - 4- (aminocarbonyl) phenyl 7- / 5 * 0XO-2- / 3-phenOXi (2-[(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 10 CHBr) 3525, 3405, l742, l675, 1599 Cm-l 20 o / m¿ / D -16.3 (CHCl3) (9) / lR- / 1-KÅ2, S *), 2/3 (2R *) : 3 H / - (-) - 4- [2- (acetylamino) -3-amino-3-oxopropyl] phenyl] -O- [5-oxo-2- [3-phenoxy-2] - [(tetrahydro-2-pyran-2-yl) oxy] -ropoxy-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cycloquentyl] -5-heptenoate, from intermediates; 10 g I.r. (CHBr3) 3505, 3400, 1740, 1690, 1665 Cm_l 20 Ü _o / ø (/ D -5.4 (CHCl3) (h) / lR- / l ° 4 (Z), 2_ß (2R *), 3UL / N - (-) - 3- (binsoylamino) phenyl 7- [5-oxo: 2- [3-phenoxy-2-7-octrahydro-2H-pyran-2-yl) oxy] -P propoxy / -3 - [(tetrahydro- § 2: pyran-2-yl / oxy / cyclopentyl / -5-heptenoate, from intermediate 10 h 1 20 Ir (CHBI3) 3430, 1742, 1680, 1526 cm-1 / C (/ D -7 (CHCl3) 460 193 25 ( 1) /lR-/lu.(å),;J3(2å*),3<1//-4-(NN-dimethylaminocarbony}) phenyl 7- [5-oxo-2- / 3-phenoxy-2- / (tetrahydro-2H-pyran-2-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 10 in 1.r. 1740 , 1622 cm -1 (j) / 1R- / 1 «(z), z z3 (2R *), 34 phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy / -3- / (tetrahydro-2H-pyran-2-yl) oxy / cyclopentyl / -1-oxo-5-heptenyl / oxy / benzoate, from intermediate 10 μl (cHBr 3) 1745, 1720 cm -1 1) /1R-/1a.(z)2;3(25*)3a // - (-) - 4 ~ /// 4 - / (tetrahyaro- 2H-pyran: 2-yl) osi / phenyl carbonyl / amino / phenyl 7- [5-oxo-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy-3 - [(tetrahydro-2E-pyran-2-yl) 2: yl) oxy / cyclopent yl / -5-heptenoate, from intermediate 10 k I.r. (caBr3) 3435, 1745, 1720, 1672 cm -1 l / on / 23 -s, 9 ° (cHc13) ll 1) (1R- / 10L (Z), 2,3 (2R *), 3¿ (// -2- (benzoylamino) phenyl 7- [5-oxo-3- [3-phenoxy-2- [tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- [(tetrahydro-2H- pyran-2-yloxy / cyclopengyl / -5-hegtenoate, from intermediates; 10 l Ir (cHBr 3) 3440, 1760, 1740, 1678 cm -1 (11l) / 1R- / 10L (Z), 2/3 (2R * ), 3 (X // - 2-naphthalenyl 7- [5-oxo-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] gropoxy] -3- [(tetrahydro- 2H-pyran-2-yl) oxy / cyclopentyl / -5-heptenoate, from intermediate 10 m Ir (CHBr 3) 1745 cm -1 460 195 26 ll n) /lR-/ld.(Z),2¿3,3nä// -4- (benzoylamino) phenyl 7- [2- [2-methyl-3-phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -5-oxo-3- (tetrahydro-2§-pyran-2-yl) oxy / cyclopentyl / 5-hegtenoate, from intermediate 10 n Ir (cHBr 3) 3430, 1740, 1672 cm -1 110) / 1R- / lg (z), 215 1,3-fluorophenoxy) -2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -5-oxo-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate from intermediate 10 o.
I.r. (cHBr3) 1744 cm'l Följande föreningar framställdes på samma sätt som inter- mediär ll a. ll p) /lR-/lßL(Z),2!$,3 K//-4-(metyltio)fenyl 7~/2-/3-(3- klorfenoxi)-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-5-oxo- 3-/(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5-heptenoat från intermediär 10 p. 1.:. (cHßr3) 1742 cm'l (q) /lR-/ld.(Z)L2ß ¿3ñ.//-4-(metylsulfonyl)fenyl 7-/2-/3- /4-(metyltio)fenoxi/-2-/(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-5-oxo-3-/(tetrahydro-ZH-pyran-2~yl)oxi/cyklopentyl/- 5-heptenoat, från intermediär 10 q. 1.r. (cHBr3) 1740 cm"1 Följande föreningar framställdes på samma sätt som inter- mediär ll c. (r) /läf/lM,2!3(2R*),3ø&//~4-(aminokarbonyl)fenyl 7-/5- oxo-2-/3-fenoxi-2-/?tctrahydro~2H-pyran-2-yl)oxi/proQgxi/- 3-/(tetrahydro-ZH-pyran-2-yl)oxi/cyklopcntyl/-4,5-hepta- dienoat, från intermediär 10 r l.r. (CHBI3) 3520, 3410, 1962, 1742, 1676 Cm-1 460 195 27 (S) /lR~/lu-(Z),2[3(2R*),3d'//-4-(bensoylamino)fenyl 7-/5-0XO:2-/3-f;fiOXi-2-7(tetrahydro-2H-pyran-2-yl)oxi/- propoxi/-3-/(tctrahydro-2H-pyran-2-ylïoxi/cyklopentyl/-4- hegtenoat, från intermedišr 10 s 1.:. (cHBr3) 3430, 1742, 1675 cm"l (t) /lR-/lSX (Z) ,2 fi, (2R*) ,3 oL//-4~(bensoylamino) fenyl 9-/5-oxo-2-/3'f@n°Xí'2"/(tetrahydro-2H-pyran-2-yl)oxi/~ propoxi/-3-/(tetrahydro-2H-pyran-2-yl)0xi/Cyklopentyl/-7- nonenoat, från intermediär 10 t. 1.r. I.r. (cHBr 3) 1744 cm -1 The following compounds were prepared in the same manner as intermediate ll a. ll p) / lR- / lßL (Z), 2! $, 3 K // - 4- (methylthio) phenyl 7 ~ / 2- [3- (3-chlorophenoxy) -2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -5-oxo-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl / -5-heptenoate from intermediate 10 p. 1.:. (cHßr3) 1742 cm -1 (q) /lR-/ld.(Z)L2ß ¿3ñ .//- 4- (methylsulfonyl) phenyl 7- / 2- / 3- / 4- (methylthio) phenoxy / -2 - [(tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -5-oxo-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoate, from intermediate 10 q 1.r. (cHBr 3) 1740 cm -1 The following compounds were prepared in the same manner as intermediate 11 c. (r) / läf / lM, 2; 3 (2R *), 3ø & // ~ 4- (aminocarbonyl) phenyl 7- / 5 oxo-2- [3-phenoxy-2- (tetrahydro-2H-pyran-2-yl) oxy] propoxy) -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4, 5-heptadienoate, from intermediate 10 r 1r (CHBI3) 3520, 3410, 1962, 1742, 1676 Cm-1 460 195 27 (S) / 1R ~ / lu- (Z), 2 [3 (2R *), 3d '// 4- (benzoylamino) phenyl 7- [5-oxo: 2- [3-oxy-2-7 (tetrahydro-2H-pyran-2-yl) oxy] -propoxy] -3- / (tetrahydro-2H-pyran-2-yloxy / cyclopentyl / -4-hegtenoate, from intermediate 10 s 1.: (cHBr 3) 3430, 1742, 1675 cm -1 (t) / 1R- / 1SX (Z), 2 fi, (2R *), 3oL // - 4- (benzoylamino) phenyl 9- [5-oxo-2- [3'f @ n ° Xi'2 "/ (tetrahydro-2H-pyran-2-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] Cyclopentyl] -7-nonenoate, from intermediate 10 h.
Intermediär 12 (a) /15-/11x(§),2¿3,3 1,5fx//-7-/5-hydr0x1-2-/2-mety1-3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetra- hydro-ZH-pyran-2-yl)oxi/cyklopentyl/-5-heptensyra En lösning av intermediär 2 (0,98 g) i MeOH (15 ml) behand- lades med 5 N NaOH-lösning (6 ml). Efter 30 minuter hälldes blandningen i vatten (100 ml) och extraherades med ER (150 nl).Intermediate 12 (a) / 15- / 11x (§), 2,3,3 1,5fx // - 7- / 5-hydroxy1-2- / 2-methyl-3-phenoxy-2 - / (tetrahydro-2H -pyran-2-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoic acid A solution of intermediate 2 (0.98 g) in MeOH ( 15 ml) was treated with 5 N NaOH solution (6 ml). After 30 minutes, the mixture was poured into water (100 ml) and extracted with ER (150 nl).
Vattenlösningen surgjordes med en mättad NH4Cl-lösning (150 ml) och extraherades därefter med EA (4 x 50 ml). De kombinerade extrakten torkades och indunstades och gav titclförcningen som en klistersubstans (O,88 g). 1.r. (cHBr3) 3510, 3400 - 2500, 1730, 1708 cm'l.The aqueous solution was acidified with a saturated NH 4 Cl solution (150 mL) and then extracted with EA (4 x 50 mL). The combined extracts were dried and evaporated to give the title compound as an adhesive (0.8 g). 1.r. (cHBr3) 3510, 3400 - 2500, 1730, 1708 cm -1.
Följande föreningar framställdes på samma sätt: (b) /lS/loL (Z) ,2)ß , 3 oL , 5 0(//-7-/2-/3- (Ål-fluorfenoxi) -2- /(tetrahydro-2H-Byran-Z-X1)oxi/propoxi/~5-hydroxi-3-/(tetra- hydro-2H-pyran-2-yl)oxi/cyklopentyl/-5-heptensyra, från intermediär 3 a. 1.:. 460 193 28 (c) /is/lu (z) ,2,g, ,3 x ,50¿ //~7-/2-/3-(B-klorfenoxi) ~2- /(tetrabydro-EH-pyran-2-yl)oxi/propoxi/-5-hydroxi-3-/(tetra- nydro-ZH-pyran:2-yl)oxi/cyklopentyl/-5-heptensyra, från f intermediär 3 b I.r.) (cmar3) 3590, 3510, 3700 - 2400, 1730, 1705 om* (d) /lS-/lüf(Z),2/§,3M.,5K.//-7-/5-hydr0xi-2-/3-/4-(mety1- tio)-fenoxi/-2-/(tetrahydro-2H~pyran-2-yl)oxi/propoxi/-3- /(tetrahydro-2H-pyran-2-yl)oxi/cyklopentyl/-5-heptensyra, från intermediär 3 c.The following compounds were prepared in the same manner: (b) / 1S / 10L (Z), 2) ß, 3oL, 50 (// - 7- / 2- / 3- (Al-fluorophenoxy) -2- / (tetrahydro -2H-Byran-Z-X1) oxy / propoxy / -5-hydroxy-3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -5-heptenoic acid, from intermediate 3 a. 1. 460 193 28 (c) / is / lu (z), 2, g,, 3x, 50¿ // ~ 7- / 2- / 3- (B-chlorophenoxy) ~ 2- / (tetrabydro-EH -pyran-2-yl) oxy / propoxy / -5-hydroxy-3 - [(tetrahydro-ZH-pyran: 2-yl) oxy] cyclopentyl] -5-heptenoic acid, from intermediate 3 b Ir) (cm 3 ) 3590, 3510, 3700 - 2400, 1730, 1705 om * (d) /lS-/lüf(Z),2/§,3M.,5K.//-7-/5-hydr0xi-2-/3- [4- (methylthio) -phenoxy] -2- [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] - 5-heptenoic acid, from intermediate 3 c.
I.r. (CHBr3) 3520, 3600 - 2500, 1730, 1708 cm_l (e) /1s-/1 x, 2 ß (zsn , 3 a ,s or //-7-/s-hyar0><1-2-/s-fenoxi- 2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3*/(tetrahydro- 2H-pyran-2~yl)oxi/cyklopentyl/-4,5-heptadiensyra, från intermediär 15 I.r. (cHBrB) 3500, 1920, 1730 cm* (f) /l_S_-/l0L (å) ,2 ß (2:5_*) ,3 oL ,50L //-7-/5-hydroxi-2-/3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetra- hydro-2H-pyran~2-yl)oxi/cyklopentyl/-4-heptensyra (3-karboxipropyl)trifenylfosfoniumbromid (1,ll g) och ka- lium tert-butoxid (O,58 g) i torr THF (10 ml) omrördes vid rumstemperatur i 45 minuter. En lösning av intermediär 19 (0,58 g) i torr THF (10 ml) tillsattes och omrörningen vid rumstemperatur fortsatte i 1 timme. En ytterligare identisk mängd förbildad ylid sattes till reaktionsblandningen och omröringen fortsatte i 1,5 timmar. Vatten (20 ml) tillsattes och blandningen tvättades med ER (3 x 50 ml). De organiska tvättvätskorna återcxtraherades med 8-procentig NaHCO3-1ös- 3 ning (2 x 20 ml). De kombinerade vattenhaltiga cxtrakten behandlades med mättad NH4C1 (30 ml) och produkten extrahe- rades med ER (3 x 50 ml). Extrakten tvättades med saltlake w (15 ml), torkades och koncentrerades i vakuum och gav titel- 460 193 29 föreningen som en olja (0,55 g).I.r. (CHBr3) 3520, 3600 - 2500, 1730, 1708 cm_l (e) / 1s- / 1 x, 2 ß (zsn, 3 a, s or // - 7- / s-hyar0> <1-2- / s -phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy / -3 * / (tetrahydro-2H-pyran-2-yl) oxy / cyclopentyl / -4,5-heptadienoic acid, from intermediate 15 Ir (cHBrB) 3500, 1920, 1730 cm -1 (f) / l_S _- / l0L (å), 2 ß (2: 5_ *), 3 oL, 50L // - 7- / 5-hydroxy-2- / 3 phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4-heptenoic acid (3-carboxypropyl ) triphenylphosphonium bromide (1.1 g) and potassium tert-butoxide (0.58 g) in dry THF (10 ml) were stirred at room temperature for 45 minutes A solution of intermediate 19 (0.58 g) in dry THF ( 10 ml) was added and stirring at room temperature was continued for 1 hour An additional identical amount of preformed ylide was added to the reaction mixture and stirring was continued for 1.5 hours Water (20 ml) was added and the mixture was washed with ER (3 x 50 ml). The organic washings were re-extracted with 8% NaHCO 3 solution (2 x 20 mL). The combined aqueous extracts were treated with saturated NH 4 Cl (30 mL) and the product was extracted with ER (3 x 50 mL). The extracts were washed with brine w (15 ml), dried and concentrated in vacuo to give the title compound as an oil (0.55 g).
I.r. (CHBI3) 3500, 3600 ~ 2300, 1728, 1710 Cm_l.I.r. (CHBI3) 3500, 3600 ~ 2300, 1728, 1710 Cm_l.
Följande förening framställdes på samma sätt som intermediär l2 a: (g) /lå-/lgL(Z),2/3(2S*),3N,5,cX//-7-/5-hydroxi-2-/3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetra- hydro-ZH-pyran-2:yl)oxi/cyklopentyl/-7-nonensyra, från intermediär 6 I.r. (CHBr3) 3510, 3000 ~ 2500, 1730, 1710 cm_l.The following compound was prepared in the same manner as intermediate 12a: (g) / low- / IgL (Z), 2/3 (2S *), 3N, 5, cX // - 7- / 5-hydroxy-2- / 3 phenoxy-2 - [(tetrahydro-2H-pyran-2-yl) oxy] propoxy] -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -7-nonenoic acid, from intermediate 6 Ir (CHBr3) 3510, 3000 ~ 2500, 1730, 1710 cm -1.
Intermediär l3 /lS-/lß¿,2j3(2S*),3m ,5 M//-metyl 6-hydroxi-7-/5-hydroxi-2- /3-fenoxi-2-/(tetrahydro-ZH-pyran-2-yl)oxi/propoxi/-3- /(tetrahydro-2H~pyran~2-yl)oxi/cyklopentyl/-4-heptynoat n-butyllitium (1,6 M i hexan, 61,5 ml) sattes till en lösning av diisopropylamin (l3,8 ml) och hexametylfosforamid (l7,5 ml) i ER (140 mi) vid o° under kväve. Lösningen kylaes till -700 och en lösning av 4-pentynsyra (4,87 g) i THF (50 ml) tillsattes. Blandningen fick därefter värmas till rumstem- peratur och efter l timme tillsattes en lösning av interme- diär 4 (3,5 g) i ER (60 ml). Efter 18 timmar tillsattes en lösning av oxalsyradihydrat (14 g) i vatten (200 ml) och den organiska fasen avskildes. Vattenfasen extraherades med EA (200 ml) och de kombinerade organiska faserna torkades och indunstades. Resten upplöstes i DMF (30 ml) behandlades med metyljodid (12 ml) och kaliumfluorid (8 g). Efter 3 timmar späddes lösningen med EA (200 ml) och tvättades med vatten (3 x 200 ml) och saltlake (200 ml). De vattenhaltiga tvättfl vätskorna återextraherades med EA (200 ml) och de kombinerade organiska faserna torkades och indunstades. Resten renades genom kromatografí med användning av 4:1 ökande till 2:1 ER-EA som elueringsmedal och gav titelföreningen som en olja 460 193 30 (2,9 Q) I.r. lntermediär 14 /lR-/ls¿,2 ß(2R*),3 ä,5|//-metyl 6-acetyloxi-7-/5-acetyloxi- 2-/3-fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3- /(tetrahydro-ZH-pyran-2-yl)oxi/cyklopentyl/-4-heptynoat Trietylamin (8,2 ml), ättiksyraanhydrid (6,7 ml) och 4-di- metylaminopyridin (70 mg) sattes till en omrörd lösning av intermediär 13 (2,8 g) i CH2C12 (60 ml). Efter 2 timmar av- lägsnades lösningsmedlet och kromatografi av resten med an- vändning av 4:1 ER-PE (40 - 600) som elueringsmedel gav titelföreningen som en olja (3,1 g).Intermediate 13 [mu] [[alpha] - [.alpha.]. @ 2,3 (2S *), 3m, 5 [mu] M-methyl 6-hydroxy-7- [5-hydroxy-2- [3-phenoxy-2 - [(tetrahydro-2H-pyran) -2-yl) oxy / propoxy / -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4-heptynoate n-butyllithium (1.6 M in hexane, 61.5 ml) was added a solution of diisopropylamine (13.8 ml) and hexamethylphosphoramide (13.5 ml) in ER (140 ml) at 0 ° under nitrogen. The solution was cooled to -700 and a solution of 4-pentanoic acid (4.87 g) in THF (50 ml) was added. The mixture was then allowed to warm to room temperature and after 1 hour a solution of intermediate 4 (3.5 g) in ER (60 ml) was added. After 18 hours, a solution of oxalic acid dihydrate (14 g) in water (200 ml) was added and the organic phase was separated. The aqueous phase was extracted with EA (200 ml) and the combined organic phases were dried and evaporated. The residue was dissolved in DMF (30 ml) treated with methyl iodide (12 ml) and potassium fluoride (8 g). After 3 hours, the solution was diluted with EA (200 mL) and washed with water (3 x 200 mL) and brine (200 mL). The aqueous washings were re-extracted with EA (200 ml) and the combined organic phases were dried and evaporated. The residue was purified by chromatography using 4: 1 increasing to 2: 1 ER-EA as eluent to give the title compound as an oil 460 193 (2.9 Q) I.r. Intermediate 14 / 1R- / 1s, 2β (2R *), 3α, 5β-methyl 6-acetyloxy-7- [5-acetyloxy-2- [3-phenoxy-2 - [(tetrahydro-2H) -pyran-2-yl) oxy / propoxy / -3- [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4-heptynoate Triethylamine (8.2 ml), acetic anhydride (6.7 ml) and 4-Dimethylaminopyridine (70 mg) was added to a stirred solution of intermediate 13 (2.8 g) in CH 2 Cl 2 (60 mL). After 2 hours, the solvent and chromatography of the residue using 4: 1 ER-PE (40-600) as eluent gave the title compound as an oil (3.1 g).
I.r. (CHBrB) 1728 cnfl Intermediär 15 /lR-/lM.,2jš(2R*),3 $q5[(//-metyl 7-/5-acety1oxi-2-/3- fenoxi-2-/(tetrahydro-2H-pyran-2-yl)oxi/propoxi/-3-/(tetra- hydro-2H-pyran-2-yl)oxi/cyklopentyl/-4,5-heptadienoat Metyllitium (1,6 M i ER, 44,5 ml) sattes till en omrörd sus- pension av koppar(I)jodid (6,8 g) i ER (120 ml) vid -100 under kväve. När tillsatsen var fullständig erhölls en klar lösning som därefter kyldes till -780 och en lösning av inter- mediär 14 (0,85 g) i ER (50 ml) vid -780 tillsattes. Efter 1,5 timmar tillsattes mättad NH4Cl~lösning (200 ml) och blandningen omrördes vid rumstemperatur i 1 timme. De or- ganiska faserna tvättades med mättad saltlake (200 ml) och vattenfasen extraherades med ER (200 ml). De torkade orga- niska extrakten indunstades och resten renades genom kroma- = tografi med användning av 3:1 ER~PE (40 - 600) som elue- ringsmedel och gav titelföreningen som en olja (1,2 g). u- :.r. 460 195 31 Intermediär 16 /lR-/l0°,5 MV6 (fenylmetoxi)-2-oxabicyklo/3,2,l/oktan-3-ol DIBAL (lM i hexan, 10 ml) sattes till en kall (-780) omrörd lösning av intermediär 5 (2,7 g) i CH2Cl2 (50 ml). Efter 2 timmar tillsattes en ytterligare mängd DIBAL (6,7 ml) och omröringen fortsatte i 2,5 timmar. MeOH (20 ml) tillsattes droppvis,efter 15 minuter vid rumstemperatur tillsattes eter (60 ml). Den erhållna blandningen filtrerades genom hyflo och filtratet indunstades och gav titelföreningen som en klistersubstans (2,6 g). 1.r. (cnBr3) 3580, 2720, 1718 cm'1 Intermediär 17 /lS-/l 01- , 2/3 (S*) , 3 Oll , 5 ot/ß-B-hydroxi-Z* (Z-hydroxi-Érfenoxi- propoxi)-5-(fenylmetoxi)cyklopentanpropanal Till en kall (OO) lösning av kalium-tert-butoxid (2,9 g) i THF (40 ml) under N2 tillsattes (metoximetyl)trifenylfosfo- niumklorid (8,84 g). Efter 5 minuter tillsattes en lösning av intermediär 16 (2,6 g) i THR (25 ml) och blandningen om- rördes vid OO i 30 minuter. En mättad lösning av NH4Cl (50 ml) tillsattes och blandningen extraherades med ER (3 x 60 ml). De kombinerade extrakten torkades och indunstades och gav en olja (9,1 q).I.r. (CHBrB) 1728 cnfl Intermediate 15 /lR-/1M.,2jš(2R*)3 $ q5 [(// - methyl 7- / 5-acetyloxy-2- / 3-phenoxy-2 - / (tetrahydro-2H -pyran-2-yl) oxy / propoxy / -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentyl] -4,5-heptadienoate Methyllithium (1.6 M in ER, 44.5 ml) was added to a stirred suspension of copper (I) iodide (6.8 g) in ER (120 ml) at -100 under nitrogen, when the addition was complete a clear solution was obtained which was then cooled to -780 and a solution of intermediate 14 (0.85 g) in ER (50 ml) was added at -780. After 1.5 hours saturated NH 4 Cl solution (200 ml) was added and the mixture was stirred at room temperature for 1 hour. was washed with saturated brine (200 ml) and the aqueous phase was extracted with ER (200 ml), the dried organic extracts were evaporated and the residue was purified by chromatography using 3: 1 ER-PE (40-600) as eluent. and the title compound as an oil (1.2 g). Intermediate 16 / 1R 3-o 1 DIBAL (1M in hexane, 10 mL) was added to a cold (-780) stirred solution of intermediate 5 (2.7 g) in CH 2 Cl 2 (50 mL). After 2 hours, an additional amount of DIBAL (6.7 ml) was added and stirring was continued for 2.5 hours. MeOH (20 ml) was added dropwise, after 15 minutes at room temperature ether (60 ml) was added. The resulting mixture was filtered through hyflo and the filtrate was evaporated to give the title compound as an adhesive (2.6 g). 1.r. (cnBr3) 3580, 2720, 1718 cm -1 Intermediate 17 / lS- / l 01-, 2/3 (S *), 3 Oll, 5 ot / ß-B-hydroxy-Z * (Z-hydroxy-Erfenoxy- propoxy) -5- (phenylmethoxy) cyclopentanepropanal To a cold (OO) solution of potassium tert-butoxide (2.9 g) in THF (40 ml) under N 2 was added (methoxymethyl) triphenylphosphonium chloride (8.84 g). After 5 minutes, a solution of intermediate 16 (2.6 g) in THR (25 mL) was added and the mixture was stirred at 0 ° C for 30 minutes. A saturated solution of NH 4 Cl (50 mL) was added and the mixture was extracted with ER (3 x 60 mL). The combined extracts were dried and evaporated to give an oil (9.1 g).
Den orena produkten omrördes i l:l 0,25 N svavelsyra-aceton (80 ml) i 48 timmar vid rumstemperatur. Det organiska lös~ ningsmedlet indunstades därefter i vakuum och den vatten- haltiga återstoden extraherades med EA (3 x 50 ml). De kombinerade organiska faserna tvättades med mättad saltlake (30 ml) torkades och indunstades. Resten renades genom kro- matografi med användning ER som elueringsmedel och gav titelföreningen sem en olja (1,5 g). 460 193 32 1.r. (cnBr3) 3580, 3460, 272o, 1718 cm'1.The crude product was stirred in 1: 1 0.25 N sulfuric acid acetone (80 ml) for 48 hours at room temperature. The organic solvent was then evaporated in vacuo and the aqueous residue was extracted with EA (3 x 50 ml). The combined organic phases were washed with saturated brine (30 ml), dried and evaporated. The residue was purified by chromatography using ER as eluent to give the title compound as an oil (1.5 g). 460 193 32 1.r. (cnBr3) 3580, 3460, 272o, 1718 cm-1.
Intermediär 18 /lS-/loL ,2 ß (2S*) ,3 oc, 5 vi l/-Z-/B-fenoxi-Z-l (tetrahydro-ZH- pyran-2-yl)oxi/propoxi/-5-(fenylmetoxi)-3-/(tetrahydro-2H- pyran-2-yl)oxi/cyklopentapropanal Dihydropyran (0,95 ml) och pyridiniumtoluen-p-sulfonat (0,1 g) sattes till en omrörd lösning av intermediär 17 (l,44 g) i cnzclz (4o m1) vid o°. Efter omröring 1 20 rimmar vid rums- temperatur tvättades blandningen med vatten (2 x 10 ml), 8-procentig NaHCO3 (2 X l0 ml) och saltlake (2 x 10 ml). Lös- ningsmedlet indunstades och resten renades genom kromato- grafi med användning av l:l ER-PE (40 - 600) som eluerings- medel och gav titelföreningen som en klístersubstans (1,9 g). 1.5. (cHBr3) 2720, 1720 cm'l Intermediär 19 /4aR-/4a GL , 5 oL (2R*) , öß , 7a oL //-oktahydro-5-/3-fenoxi-2-/ (tetra- hydro-2H-pyran-2-yl)oxi/propoxi/-6-/(tetrahydro-2H-pyran- 2-yl)oxi/cyklopenta/b/pyran-2-ol En lösning av intermediär 18 (0,94 g) i EA (50 ml) hydroge- nerades över förreducerad 10-procentig palladium på träkol (0,97 g) vid N.T.P. i 22 timmar. Katalysatorn och lösnings- medlet avlägsnades och den kvarvarande oljan (0,75 g) rcnades genom kromatografi med användning av 3:l ER~PE (40 - 600) som elueringsmedel och gav titelföreningen som en olja (0,49 g) 1.r. (cHBr3) 3570 cm"1 I följande exempel framställdes föreningarna på samma sätt som föreningen enligt exempel l, där försöksdetaljerna inte gesQ 460 193 33 Exemgel l /lR-/la.(å)-2,6(R*),3 (2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat En lösning av intermediär lla (0,24 g) i 20:lO:3 ättiksyra- vatten-THF (2,5 ml) upphettades till 400 i 4 timmar. Lös- ningsmedlet avlägsnades i vakuum och resten renades genom kromatografi på syratvättad (pH 3,8) silika med användning av 75:l ER-MeOH som elueringsmedel och gav titelföreningen som en vit fast substans (O,l4 g) smältpunkt 55 - 56,50.Intermediate 18 / 1S- / 10L, 2β (2S *), 3β, 5μl / Z- / B-phenoxy-Z1 (tetrahydro-ZH-pyran-2-yl) oxy / propoxy / -5- ( phenylmethoxy) -3 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopentapropanal Dihydropyran (0.95 ml) and pyridinium toluene p-sulfonate (0.1 g) were added to a stirred solution of intermediate 17 (1, 44 g) in cnzclz (40 ml) at 0 °. After stirring for 20 hours at room temperature, the mixture was washed with water (2 x 10 ml), 8% NaHCO 3 (2 x 10 ml) and brine (2 x 10 ml). The solvent was evaporated and the residue was purified by chromatography using 1: 1 ER-PE (40-600) as eluent to give the title compound as a sticker (1.9 g). 1.5. (cHBr 3) 2720, 1720 cm -1 Intermediate 19 / 4aR- / 4a GL, 5oL (2R *), δ, 7aoL // - octahydro-5- [3-phenoxy-2- / (tetrahydro-2H -pyran-2-yl) oxy / propoxy / -6 - [(tetrahydro-2H-pyran-2-yl) oxy] cyclopenta [b] pyran-2-ol A solution of intermediate 18 (0.94 g) in EA (50 ml) was hydrogenated over pre-reduced 10% palladium on charcoal (0.97 g) at NTP for 22 hours. The catalyst and solvent were removed and the residual oil (0.75 g) was calculated by chromatography using 3: 1 ER-PE (40 - 600) as eluent to give the title compound as an oil (0.49 g). . (cHBr3) 3570 cm -1 In the following examples, the compounds were prepared in the same manner as the compound of Example 1, where the test details are not given Exemplary gel l /lR-/la.(å)-2,6(R*).3 ( 2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate A solution of intermediate 11a (0.24 g) in 20: 10: 3 acetic acid-water-THF (2.5 ml) was heated to 400 in 4 The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using 75: 1 ER-MeOH as eluent to give the title compound as a white solid (0.1 g) m.p. 56.50.
Kristallisation ur metylacetat-PE gav en vit fast substans, smältpunkt 64 - es° /øfl/zš” -1a,1° (meon).Crystallization from methyl acetate-PE gave a white solid, mp 64 - es ° / ø fl / zš ”-1a, 1 ° (meon).
Analys funnet: C 68,02, H 6,63 C29H34O8 erfordrar C 68,22, H 6,7l % ßxemgel 2 /lR-/lN_(Z),2[5(R*),3LK//-(-)-4-(acetylamino)fenyl 7-/3- hydroxi-2-(2-hydroxi-3-íenoxipropoxi)-5-oxocyklopentyl/-5- hegtenoat En lösning av intermediär ll b (0,3 g) i 20:lO:3 ättiksyra- vatten-THF (3 ml) upphettades vid 40 - 430 i 4 timmar. Lös- ningsmedlet avlägsnades i vakuum och återstoden renades genom kromatografi på syratvättad (pH 3,8) silika med an- vändning av EA som elueringsmedel och gav titelföreningen som en vit fast substans (0,l2 g), smältpunkt 60 - 630.Analysis found: C 68.02, H 6.63 C 29 H 34 O 8 requires C 68.22, H 6.71%% gel 2 / 1R- / 1N_ (Z), 2 [5 (R *), 3LK // - (-) -4- (acetylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hegtenoate A solution of intermediate II b (0.3 g) in 20: 10 : 3 acetic acid-water-THF (3 ml) was heated at 40-430 for 4 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using EA as eluent to give the title compound as a white solid (0.2 g), mp 60-630.
Kristallisation ur t-butylmetyleter gav en vit fast substans, smaltpunkt 74,5 - 7s° /u /zgß -19,4° (meon) Analys funnet: C 65,86, H 6,71, N 2,66 C 6 C H NO erfordrar 6 ,27, H 6,71, N 2,57 % 29 35 8 460 193 34 Exempel 3 /lR-/l°<(Z),2[3(R*),3ç(//-4-/(aminokarbonyl)amino/fenyl 7-73-hydroši-å-(šlhydroxi-3-fenoxipropoxi)-5-oxocyklo- Eentyl/-5~heptenoat. (0,04 g) från íntermediär ll c (0,09 g) renad med användning av 20:l EA~MeOh som elueringsmedel.Crystallization from t-butyl methyl ether gave a white solid, mp 74.5-7s ° / h / zgß -19.4 ° (meon) Analysis found: C 65.86, H 6.71, N 2.66 C 6 CH NO requires 6.27, H 6.71, N 2.57% 29 35 8 460 193 34 Example 3 / 1R- / 1 ° <(Z), 2 [3 (R *), 3ç (// - 4- (aminocarbonyl) amino / phenyl 7-73-hydroxy-α- (β-hydroxy-3-phenoxypropoxy) -5-oxocycloethyl-5-heptenoate (0.04 g) from intermediate III c (0.09 g) purified using 20: 1 EA ~ MeOh as eluent.
T.l.c. 20:l EA~MeOH Rf 0,25. I.r. (CHBr3) 3570, 3500, 3400, 1740, 1680 cnfl.T.l.c. 20: 1 EA ~ MeOH Rf 0.25. I.r. (CHBr3) 3570, 3500, 3400, 1740, 1680 cnfl.
Exemgel 4 /lR-/la (Z)-2[3(R*),3 hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5~ hegtenoat En lösning av intermediär ll d (O,24 g) i 20:l0:3 ättiksyra~ vatten-THF (3 ml) upphettades vid 40 - 420 i 3 timmar. Lös- ningsmedlet avlägsnades i vakuum och återstoden renades genom kromatografi på syratvättad (pH 3,8) silika med an- vändning av 7:3 EA-cyklohcxan som elueringsmedel och gav efter sönderdelning med ER titelföreningen som ett vitt pulver (o,ov g) , smält-punkt 125 - 127° /x/zg -29,3° (cncl3) Analys funnet: C 69,4, H 6,4, N 2,3 C34H37NO8 C 69,5, H 6,4, N 2,4 % gxempel 5 /lR-/loL(Z),2/3(R*),30\//-(-)-4-/4-(acetylamino)bensoy1- _ _ , ._ amino/fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5- oxocyklopentyl/-5-hegtenoat En lösning av intermediär ll e (0,24 g) i 20:l0:3 ättiksyra- vatten-THF (3 ml) upphettades vid 40 - 420 i 4 timmar. Lös- ningsmedlet avlägsnades i vakuum och gav en fast återstod, som renades genom kromatografi på syratvättad (pH 3,8) silika med användning av EA som elueringsmedel och gav efter sön- derdelning med ER titelšöreningen som ett vitt pulver (0,06 g), 460 193 35 ° (neon) smältpunkt 150 - 154° /cx/23 -10 Analys funnet: C 66,7, H 6,3, N 4,5 C36H4oN2O9 erfordrar C 67,1, H 6,3, N 4,4 % Exemgel 6 /lR-/loL(Z),2[g(R*),3 _: vw f _ hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5- hegtenoat En lösning av intermediär ll f (0,44 g) i 20:l0:3 ättiksyra- vatten-THF (5 ml) upphettades vid 409 i 3 timmar. Lösnings- medlet avlägsnades i vakuum och resten renades genom kroma- tografi på syratvättad (pH 3,8) silika med användning av 95:5 EA-EtOH som elueringsmedel. Sönderdelning med ER följt av kristallisation ur EA-PE gav titelföreningen som en vit fast substans (0,l4 g), smältpunkt 104 - 1059 /°¿ /zg -13,2° (ston) _ Analys funnet: C 65,65 H 6,7 N 2,7 C28H33NO8 erfordrar C 65,7 H 6,5 N 2,7 % Exemgel 7 /lR-/loL(Z;S*),2[}(R*)pšdj/-(+)-4-/2-(acetylamino)-3-amino- 3-oxoprogyl/fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxiproooxi)- 5-oxocyklopentyl/-5-heptenoat En lösning av intermediär ll g (0,37 g) i 20:lO:3 ättiksyra- vatten-THF (6 ml) upphettades vid 400 i 3 timmar. Lösnings- medlet avlägsnades i vakuum och en portion av återstoden (O,l9 g) renades genom kromatografi på syratvättad (pH 3,8) silika med användning av 9:1 CH2Cl2-EtOH som elueringsmeflel.Example gel 4 / 1R- [1a (Z) -2 [3 (R *), 3 hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hegtenoate A solution of intermediate II d (O) 24 g) in 20: 10: 3 acetic acid-water-THF (3 ml) was heated at 40-420 for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using 7: 3 EA-cyclohxane as eluent to give, after decomposition with ER, the title compound as a white powder (o, g) , melting point 125 - 127 ° / x / zg -29.3 ° (cncl3) Analysis found: C 69.4, H 6.4, N 2.3 C 34 H 37 NO 8 C 69.5, H 6.4, N 2 , 4% Example 5 / 1R- / loL (Z), 2/3 (R *), 30 \ // - (-) - 4- / 4- (acetylamino) benzoyl] -amino / phenyl 7 Β-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-hegtenoate A solution of intermediate II e (0.24 g) in 20: 10: 3 acetic acid-water-THF ( 3 ml) was heated at 40 - 420 for 4 hours. The solvent was removed in vacuo to give a solid residue which was purified by chromatography on acid washed (pH 3.8) silica using EA as eluent to give the title compound as a white powder (0.06 g) after decomposition with ER , 460 193 35 ° (neon) melting point 150 - 154 ° / cx / 23 -10 Analysis found: C 66.7, H 6.3, N 4.5 C 36 H 40 N 2 O 9 requires C 67.1, H 6.3, N 4 , 4% Exemgel 6 / 1R- / 10L (Z), 2 [g (R *), 3:: vf hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hegtenoate A solution of intermediate 11f (0.44 g) in 20: 10: 3 acetic acid-water THF (5 ml) was heated at 409 for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using 95: 5 EA-EtOH as eluent. Decomposition with ER followed by crystallization from EA-PE gave the title compound as a white solid (0.14 g), m.p. 104 DEG-1059 DEG / 13 DEG-13.2 DEG (stone). Analysis found: C 65.65 H 6.7 N 2.7 C 28 H 33 NO 8 requires C 65.7 H 6.5 N 2.7% Exemgel 7 / 1R- / loL (Z; S *), 2 [} (R *) pjdj / - (+) - 4- [2- (acetylamino) -3-amino-3-oxoprogyl / phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxyprooxy) -5-oxocyclopentyl] -5-heptenoate A solution of intermediate II g (0.37 g) in 20: 10: 3 acetic acid-water-THF (6 ml) was heated at 400 for 3 hours. The solvent was removed in vacuo and a portion of the residue (0.9 g) was purified by chromatography on acid washed (pH 3.8) silica using 9: 1 CH 2 Cl 2 -Eth as eluent.
Sönderdelning med ER följt av kristallisation ur EA-PE gav titelföreningen som en vit fast substans (0,04 g), smält- punkt 1050 /oá/zg + 3,50 (Eon), 1.r. (Nujol) 1740, 1720, 1660, 1645 om* ' 460 193 36 Exemgel 8 /lR-/lbL (Z) ,2ß (R*) ,3 ví//-(-)-3-(bensoylamino)fenyl 7-/3- hydroxí-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5- hegtenoat En lösning av intermediär ll h (0,35 g) i 20:l0:3 ättiksyra- vatten-THF (5 ml) upphettades vid 40 - 420 2,5 timmar. Lös- ningsmedlet avlägsnades i vakuum och återstoden renades på kromatografi på syratvättad (pH 3,8) silika med användning av 3:1 EA~cyklohexan som elueringsmedel och gav efter sönder- delning med ER titelföreningen som ett vitt pulver (O,l6 g), smältpunxt 89 - 91° /fx/zfi ~2s,7° (cnc13) Analys funnet C 69,3 H 6,4 N 2,2 C34H37NO8 C 69,5 H 6,4 N 2,4 % Exemgel 9 /lR-/l«_(Z),2{g(R*),3(i//-(-)-4-(N,N-dimetylaminokarbonyi)- fenyl 7-/3-hydro§i-2-(2-hydroxi-3-fcnoxipropoxi)-5-oxocyklo- Eentyl/-5-heptenoat, (0,08 g) från intermediär ll i (0,24 g) renad med användning av EA som eluent. I.r. (CHBr3) 3580, 3420, 1745, 1624 auf] /oí/zg -z9° (cnc13) Analys funnet: C 66,53, H 7,04, N 2,53 C30H37NO8 erfordrar C 66,77, H 6,91, N 2,60 % Excmgel 10 /lR“/1%.(Z)f2[§(R*),3W.//'(-) metyl 4-//7-/3-hydroxi-2-(2- hydroxi-2-fenoxiproooxi)5-oxocyklopentyl/-l-oxo-5-heptenyl/~ oxi/bensoat En lösning av intermediär ll i (0,19 g) i 20:l0:3 ättiksyra- vatten-THF (10 ml) upphettades vid 400 i 3 timmar. Lösnings- medlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med användning 460 193 37 av ER som elueringsmedel gav titelföreningen som en vit fast o substans (0,1 g), smä1tpunkt 45 - 470, /“_/23 -33 (cHc13) Analys funnet: C 66,25 H 6,63 C29H34O9 erfordrar C 66,15 H 6,51 % Exemgel ll /1R-/10L(Z) ,2 ß (R*) ,3 v( //-(-)-4-/4-(hydrox1)bensoylamino/fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/- 5-hegtenoat En lösning av av intermediär ll k (0,57 g) i 20:lO:3 ättik- syra-vatten-THF (10 ml) upphettades vid 400 i 3,5 timmar.Decomposition with ER followed by crystallization from EA-PE gave the title compound as a white solid (0.04 g), mp 1050 / oá / zg + 3.50 (Eon), 1.r. (Nujol) 1740, 1720, 1660, 1645 om * '460 193 36 Exemgel 8 / lR- / lbL (Z), 2ß (R *), 3 ví // - (-) - 3- (benzoylamino) phenyl 7- 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-hegtenoate A solution of intermediate 11 h (0.35 g) in 20: 10: 3 acetic acid-water THF (5 ml) was heated at 40-420 2.5 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid washed (pH 3.8) silica using 3: 1 EA-cyclohexane as eluent to give, after decomposition with ER, the title compound as a white powder (0.6 g) , melting point 89 - 91 ° / fx / z fi ~ 2s, 7 ° (cnc13) Analysis found C 69.3 H 6.4 N 2.2 C34H37NO8 C 69.5 H 6.4 N 2.4% Example gel 9 / 1R (1) (Z), 2 {g (R *), 3 (i // - (-) - 4- (N, N-dimethylaminocarbonyl) -phenyl 7- [3-hydroxy-2- ( 2-hydroxy-3-phenoxypropoxy) -5-oxocycloethylene--5-heptenoate, (0.08 g) from intermediate II in (0.24 g) purified using EA as eluent, Ir (CHBr 3) 3580, 3420, 1745, 1624 auf] / oi / zg -z9 ° (cnc13) Analysis found: C 66.53, H 7.04, N 2.53 C 30 H 37 NO 8 requires C 66.77, H 6.91, N 2.60 % Excmgel 10 /lR „/1%.(Z)f2[§(R*)3W.//'(-) methyl 4 - // 7- / 3-hydroxy-2- (2- hydroxy-2- phenoxyprooxy) 5-oxocyclopentyl / -1-oxo-5-heptenyl / oxy / benzoate A solution of intermediate 11 in (0.19 g) in 20: 10: 3 acetic acid-water-THF (10 ml) was heated at 400 in 3 hours The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 460 193 37 of ER as eluent to give the title compound as a white solid (0.1 g), mp 45-70 ° C. / 23 -33 (cHc13) Analysis found: C 66.25 H 6.63 C29H34O9 requires C 66.15 H 6.51% Example gel 11 / 1R- / 10L (Z), 2 ß (R *), 3 v (// - (-) - 4- [4- (hydroxy) benzoylamino] phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -5-hegtenoate A solution of intermediate 11 k (0.57 g) in 20: 10: 3 acetic acid-water-THF (10 ml) was heated at 400 for 3.5 hours.
Lösningsmedlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med an- vändning av 4:l EA-PE som elueringsmedel och gav efter sön- derdelning med ER ett vitt pulver (0,22 g). Kristallisation ur EA-PE gav titelföreningen som en vit fast substans .The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 4: 1 EA-PE as eluent to give, after decomposition with ER, a white powder (0.22 g) . Crystallization from EA-PE gave the title compound as a white solid.
Analys funnet C 67,35 H 6,1 N 2,2 C34H37NO9 erfordrar C 67,65 H 6,2 N 2,3 % fixemgel 12 /1R-/lu_(Z),2/5(R*),3 M//-2-(bensoylamíno)fenyl 7-/3-hydroxi- 2-:Z-hydroxi-å-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat (0,029 q) från intermediär ll 1 (0,05O g) renad med använd- ning av 2.1 EA-cyklohexan som elueringsmedel. T.1.c. 2:1 EA- cyklonexan Rf o,z, 1.:. (enar ) 3580, 3440, 1742, 1675 Cm"l. 3 Exemgel 13 /IR-/lßí(Z),2f¶lR*),3«Å//-2~naftalenyl 7-/3-hvdroxi-2-(2- fl~ _, I _ hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5-heptenoat En lösning av intermediär ll m (0,44 g) i 20:10:3 ättiksyra~ 460 193 38 vatten-THF (12 ml) upphettades vid 40 - 420 i 3 timmar. Lös- ningsmedlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med användning av 3:1 ER-EA som elueringsmedel och gav efter sönderdelning med ER titelföreningen som ett vitt pulver (0,l5 g), smält- 21 punkt 11 - 73° /@¿/ 3 -35° (cHc13) Analys funnet C 71,79 H 6,60 C3lH34O7 erfordrar C 7l,79 H 6,61 % Exempel l4 /lR-/lo¿(Z),2'S,30L//-(-)~4-(bensoylamino)fenyl 7-/3-hydroxi- 2-:Z-hydroxí-å-metyl-3-fenoxipropoxi)-5-oxocyklopentyl/-5- heptenoat, (0,06 g) från intermediär ll n (0,ll g) renad med användning av ER som elueringsmedel. I.r. (CHBr3) 3580, 3420, 1742, 1672 cm"l /oc/2% -7° (neon) Analys funnet: C 69,42 H 6,85 N 2,21 C35H39NO8 erfordrar C 69,87 H 6,53 N 2,3 % Bxemgel 15 /lR-/l¶L(Z),2!5,3:L//-4-metoxifenyl 7-/2-/3-(4-fluorofenoxi)- 2-nydroxišfopoxi/-3-hydroxi-5-oxocyklopentyl/-5-heptenoat, (0,06 g) från intermediär ll o (0,09 g) renad med användning av 97:3 ER-MeOh som elueringsmedel. I.r. (CHBr3) 3580, 3450, 1745 cm"l.Analysis found C 67.35 H 6.1 N 2.2 C 34 H 37 NO 9 requires C 67.65 H 6.2 N 2.3% xemgel 12 / 1R- / lu_ (Z), 2/5 (R *), 3 M // - 2- (benzoylamino) phenyl 7- [3-hydroxy-2-: 2-hydroxy-α-phenoxypropoxy) -5-oxocyclopentyl] -5-heptenoate (0.029 q) from intermediate 11 (0.05O g) purified using 2.1 EA-cyclohexane as eluent. T.1.c. 2: 1 EA-cyclonexane Rf o, z, 1.:. (enar) 3580, 3440, 1742, 1675 Cm "l. 3 Exemgel 13 / IR- / lßí (Z), 2f¶lR *), 3« Å // - 2-naphthalenyl 7- / 3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate A solution of intermediate 11 m (0.44 g) in 20: 10: 3 acetic acid ~ 460 193 38 water THF (12 ml) was heated at 40-420 for 3 hours, the solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 3: 1 ER-EA as eluent to give after decomposition with the ER title compound as a white powder (0.85 g), melting point 21 - 73 ° / @ 3/35 -35 ° (cHc13) Analysis found C 71.79 H 6.60 C 31 H 34 O 7 requires C 71.79 H 6.61% Example 14 / 1R- / 10 (Z), 2'S, 30L // - (-) - 4- (benzoylamino) phenyl 7- [3-hydroxy- 2-: Z-hydroxy-α-methyl- 3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate, (0.06 g) from intermediate 11 n (0.1 g) purified using ER as eluent Ir (CHBr 3) 3580, 3420, 1742, 1672 cm l / oc / 2% -7 ° (neon) Analysis found: C 69.42 H 6.85 N 2.21 C 35 H 39 NO 8 requires C 6 9.87 H 6.53 N 2.3% Bxemgel 15 / 1R- / 1L (Z), 2,3,3: L // - 4-methoxyphenyl 7- [2- / 3- (4-fluorophenoxy) ) - 2-Nydroxyphosphoxy / -3-hydroxy-5-oxocyclopentyl / -5-heptenoate, (0.06 g) from intermediate 10 (0.09 g) purified using 97: 3 ER-MeOh as eluent. I.r. (CHBr3) 3580, 3450, 1745 cm -1.
Analys funnet: C 64,75 H 6,59 C28H33FO8 erfordrar C 65,10 H 6,44 % Excmgcl 16 /lR-/lN_(Z),215,3(X//-4-(metyltio)fenyl 7-/2-/3-(4-klorfen- oxl)-2-hydroxipropoxi/-3~hydroxi-5-oxocyklopentyl/-5-heptenoat, (0,1 g) från intermediär ll P (O,l6 9) rcnad med användning av 98:2 ER-MQOH som elueringsmedcl. I.r. (CHBr3) 3580, 3440, 460 193 39 1 1742 cm" , T.1.c. 9s=2 .ER-meon Rf 0,25.Analysis found: C 64.75 H 6.59 C 28 H 33 FO 8 requires C 65.10 H 6.44% Excmgcl 16 / 1R- / 1N_ (Z), 215.3 (X // - 4- (methylthio) phenyl 7- / 2- [3- (4-chlorophenoxy) -2-hydroxypropoxy] -3-hydroxy-5-oxocyclopentyl] -5-heptenoate, (0.1 g) from intermediate 11 P (0.69)) using of 98: 2 ER-MQOH as eluent med. Ir (CHBr 3) 3580, 3440, 460 193 39 1 1742 cm -1, T.1.c. 9s = 2 .ER-meon Rf 0.25.
Exempel l7 /1R-/1@< /2~hydroxi-3-/4-(metyltio)fenoxi/propoxi/-5-oxocyklopentyl/~ 5-hegtenoat En lösning av intermediär ll q (0,l4 g) i 20:l0:3 ättiksyra- vatten-THF (3 ml) upphettades vid 40 - 420 i 3 timmar. Lös- ningsmedlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med användning av 75:25 ökande till 90:10 EA-ER som elueringsmedel och gav titelföreningen som en vit fast substans (0,09 g), smält- punkt 73 - 76° Lr. (cnsr3) 3580, 3440, 1742 mfl. fixempel 18 /lR-(ld.,2f§(R*),3 A/-(-)-4-(aminokarbonyl)fenyl 7-/3-hydroxi- 2-12-hydroxi-5-fenoxipropoxi)-5-oxocyklopentyl/-4,5-heota- dienoat, (O,l9 g) från intermediär ll r (0,35 g) renad med användning av 3:2 EA-CH3CN som elueringsmedel. T.l.c. 3:2 EA-CH3CN Rf 0,3, I.r. (CHBr3) 3580, 3520, 3400, 1960, 1740, 1672 cnfl, /OL/zg -21,o° (cnc13).Example 17 / 1R- / 1® </ 2-hydroxy-3- / 4- (methylthio) phenoxy / propoxy / -5-oxocyclopentyl / -5-hegtenoate A solution of intermediate 11 q (0.4 g) in 20: 10: 3 acetic acid-water-THF (3 ml) was heated at 40-420 for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 75:25 increasing to 90:10 EA-ER as eluent to give the title compound as a white solid (0.09 g), melting point 73 - 76 ° Lr. (cnsr3) 3580, 3440, 1742 mfl. Example 18 / 1R-(ld.,2f§(R*)3 A / - (-) - 4- (aminocarbonyl) phenyl 7- [3-hydroxy-2-12-hydroxy-5-phenoxypropoxy) -5- oxocyclopentyl / -4,5-heothadienoate, (0.9 g) from intermediate 11r (0.35 g) purified using 3: 2 EA-CH 3 CN as eluent. T.l.c. 3: 2 EA-CH 3 CN Rf 0.3, I.r. (CHBr3) 3580, 3520, 3400, 1960, 1740, 1672 cnfl, / OL / zg -21, o ° (cnc13).
Exemgel 19 /lR-/11(Z),2/3(R*),30L//-(-)-4-(bensoylamino)fenyl 7-/3- hydroxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-4- hegtenoat En lösning av intermediär 11 s (0,l7 9) i 20:10:3 ättiksyra- vatten-THF (10 ml) upphettades vid 400 i 2 timmar. Lösnings- medlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med användning av 2:1 EA~cyk1ohexan som elueringsmedel och gav titelföre- ningen som en vit fast substans (0,11 g), smältpunkt 85-880. yr. (cnar3) 3580, 3430, 1745, 1675, /ouzg - 270 460 193 40 ßxemgel 20 /lR-/lV- (Z) ,2 ß (R*) ,3 OC//-(-) -4-(bensoylamino) fenyl 9-/3- hydroxi-2-(2-hydroxi~3-fenoxípropoxi)-5-oxocyklopentyl/-7- nonenoat En lösning av intermediär ll t (0,55 g) i 20:lO:3 ättiksyra- vatten-THF (15 ml) upphettades vid 400 i 4 timmar. Lösnings- medlet avlägsnades i vakuum och återstoden renades genom kromatografi på syra-tvättad (pH 3,8) silika med användning av 7:3 EA-cyklohexan som elueringsmedel och gav efter sönder- delning med ER titelföreningen som en vit fast substans (o,24 g), smäitpunkt 121 - 12z° ßa:/23 -34° (CHC13) Analys funnet C 70,23 H 6,66 N 2,17 C36H4lNO8 erfordrar C 70,22 H 6,71 N 2,27 % Exemgel 2l /lR-/loL,2 5(R*),3 (2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentanheptanoat En lösning av föreningen enligt exempel 4 (0,1 g) i EA (35 ml) hydrogenerades över för-reducerad lO-procentig palla- dium på träkol (0,03 g) vid N.T.P. i 40 minuter och därefter avlägsnades lösningsmedlet och katalysator. Titelföreningen erhölls som en vit fast substans (0,07 g), smältpunkt 127 - 13o° /oc/zg -29,3° (CHC13) lxJ ~ F* UI Analys funnet: C 69,38 H 6,69 N \ N08 erfordrar C 69,25 H 6,67 fl Ix) s u) G) oo H39 C34 šåàfllläå? /lR-/lCX (E) , 2 ß (R*) ,3 àL//-(-)-4-(aminokarbonyl) fenyl 7-/3- hy roxi-2-(2-hydroxi-3-fenoxipropoxi)-5-oxocyklopentyl/-5- heptenoat En lösning av föreningen enligt exempel 6 (0,l5 Q) tiofenol 460 193 41 (0,46 ml) och azobisisobutyronitril (0,1 g) i CHZCN (3 ml) och benscn (3 ml) omrördes vid âterlopp i 6,5 timmar. Rening genom kromatografi (X2) på syra-tvättad (pH 3,8) silika med användning av 9:1 EA-CH3CN som elueringsmedel gav titel- föreningen som en klistersubstans (0,l3 g). 1.r. (cHBr3) ssao, 3515, 3400, 1742, 1672 cm"l, 2 /O¿/ g -3o° (cHc13) Analys funnet: C 66,12 H 6,8 N 2,52 C28H33NO8 erfordrar C 65,74 H 6,5 N 2,74 % Exemgel 23 jlR-/lßL(Z),2(3(§*),30(//-(-)-4-(bensoylamino)fenyl 7-/3-hydroxi-2-(2-hydroxi-3-fenoxipropoxi)5-oxocyklopentyl/- §-hegtenoat Pivaloylklorid (0,0l ml) sattes till en lösning av interme- aiär 1 (o,o3 g) och Et3N (o,o1 mi) 1 torr DMF (1 mi) via o°.Example gel 19 / 1R- / 11 (Z), 2/3 (R *), 30L // - (-) - 4- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) ) -5-Oxocyclopentyl / -4-hegtenoate A solution of intermediate 11 s (0.199) in 20: 10: 3 acetic acid-water-THF (10 ml) was heated at 400 for 2 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 2: 1 EA-cyclohexane as eluent to give the title compound as a white solid (0.11 g). mp 85-880. dizzy. (cnar3) 3580, 3430, 1745, 1675, / ouzg - 270 460 193 40 ßxemgel 20 / lR- / lV- (Z), 2 ß (R *), 3 OC // - (-) -4- (benzoylamino ) phenyl 9- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl] -7-nonenoate A solution of intermediate 11 t (0.55 g) in 20: 10: 3 acetic acid water -THF (15 ml) was heated at 400 for 4 hours. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH 3.8) silica using 7: 3 EA-cyclohexane as eluent to give, after decomposition with ER, the title compound as a white solid (o, 24 g), melting point 121 - 12z ° ßa: / 23 -34 ° (CHCl 3) Analysis found C 70.23 H 6.66 N 2.17 C 36 H 41 NO 8 requires C 70.22 H 6.71 N 2.27% Example gel 21 1R- / 10L, 25 (R *), 3- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentaneheptanoate A solution of the compound of Example 4 (0.1 g) in EA (35 ml) was hydrogenated over reduced 10% palladium on charcoal (0.03 g) at NTP for 40 minutes and then the solvent and catalyst were removed. The title compound was obtained as a white solid (0.07 g), m.p. 127 DEG-130 DEG C./2 DEG-29.3 DEG (CHCl3) 1xJ-F * UI Analysis found: C 69.38 H 6.69 N requires C 69.25 H 6.67 fl Ix) su) G) oo H39 C34 šåàfllläå? 1R- / 1CX (E), 2β (R *), 3αL // - (-) - 4- (aminocarbonyl) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) -5-oxocyclopentyl / -5-heptenoate A solution of the compound of Example 6 (0.15 Q) thiophenol 460 193 41 (0.46 ml) and azobisisobutyronitrile (0.1 g) in CH 2 CN (3 ml) and benzene (3 ml) was stirred at reflux for 6.5 hours. Purification by chromatography (X2) on acid-washed (pH 3.8) silica using 9: 1 EA-CH 3 CN as eluent gave the title compound as an adhesive (0.3 g). 1.r. (cHBr3) ssao, 3515, 3400, 1742, 1672 cm -1 1.2 / 0 ° / g -3o ° (cHc13) Analysis found: C 66.12 H 6.8 N 2.52 C 28 H 33 NO 8 requires C 65.74 H 6.5 N 2.74% Exemgel 23 μlR- / lßL (Z), 2 (3 (§ *), 30 (// - (-) - 4- (benzoylamino) phenyl 7- [3-hydroxy-2- (2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl / §-hegtenoate Pivaloyl chloride (0,01 ml) was added to a solution of intermediate 1 (0,3 g) and Et 3 N (0,1 ml) 1 dry DMF (1 ml) via o °.
Efter 10 minuter tillsattes en lösning av 4-(bensoylamino)- fenol (0,l7 g) och Et3N (0,0l ml) i DMF (l ml) och omrö- ringen fortsatte i 2 timmar vid Oo och 3,5 timmar vid rums- temperatur. Reaktionsblandningen späddes med EA (30 ml) och tvättades i tur och ordning med vatten (10 ml), 10- procentig kopparsulfatlösning (15 ml), vatten (10 ml) och saltlake (l5 ml). Det torkade organiska extraktet indunsta- des och gav en rest, som renades genom kromatografi på syra- tvättad (pH3,8) silika med användning av 1:1 cyklohexan-EA som elueringsmedel. Titelföreningen erhölls som en vit fast substans (0,05 g). l I.r. (CHBr3), 3580, 3430, 1745, 1675 cm- , T.l.c. l:l cyklo- hexan-EA Rf 0,15 Nedan anges exempel på farmaceutiska beredningar med använd- ning av föreningarna enligt uppfinningen. I exemplen användes uttrycket "aktiv beståndsdel" för en förening enligt uppfin- ningen såsom en förening beskriven i de föregående exemplen, uxempelvis föreningen enligt exempel 4. -460 193 42 l. Tabletter Dessa framställdes genom direkt kompression mg/tablett aktiv beståndsdel 0,015 till 0,2 magnesiumstearat, BP 1,5 mikrokristallin cellulosa, USP 150,0 till kompressionsvikt Den aktiva beståndsdelen blandades med ungefär 10 % av den mikrokristallina cellulosan och blandades därefter med kvar- varande mikrokristallin cellulosa och magnesiumstearat.After 10 minutes, a solution of 4- (benzoylamino) -phenol (0.1 g) and Et 3 N (0.01 ml) in DMF (1 ml) was added and stirring was continued for 2 hours at 0 ° C and 3.5 hours at room temperature. The reaction mixture was diluted with EA (30 mL) and washed successively with water (10 mL), 10% copper sulfate solution (15 mL), water (10 mL) and brine (15 mL). The dried organic extract was evaporated to give a residue, which was purified by chromatography on acid-washed (pH 3.8) silica using 1: 1 cyclohexane-EA as eluent. The title compound was obtained as a white solid (0.05 g). l I.r. (CHBr 3), 3580, 3430, 1745, 1675 cm -1, T.l.c. 1: 1 cyclohexane-EA Rf 0.15 The following are examples of pharmaceutical preparations using the compounds of the invention. In the examples, the term "active ingredient" is used for a compound of the invention as a compound described in the preceding examples, for example the compound of Example 4. -460 193 42 l. Tablets These were prepared by direct compression mg / tablet active ingredient 0.015 to 0 , 2 magnesium stearate, BP 1.5 microcrystalline cellulose, USP 150.0 to compression weight The active ingredient was mixed with about 10% of the microcrystalline cellulose and then mixed with the remaining microcrystalline cellulose and magnesium stearate.
Denna blandning sampressas med användning av 6 mm diameter stansar till tabletter på en lämplig maskin.This mixture is compressed using 6 mm diameter punches into tablets on a suitable machine.
Tabletterna kan filmbeläggas med lämpliga filmbildandc mate- rial, t.ex. metylcellulosa eller hydroxipropylmetylcellulosa med användning av standardteknik. 2. Kagslar :ng/tablett aktiv beståndsdel 0,015 till 0,2 magnesiumstearat, BP l,0 *stärkelse 1500 100,0 till fyllvikt * En form av direkt komprimerbar stärkelse.The tablets may be film coated with suitable film-forming materials, e.g. methylcellulose or hydroxypropylmethylcellulose using standard techniques. 2. Kagslar: ng / tablet active ingredient 0.015 to 0.2 magnesium stearate, BP 1.0 * starch 1500 100.0 to fill weight * A form of directly compressible starch.
Den aktiva bestândsdelen förblandas med en viss mängd av stärkelse 1500 varefter denna förblandning blandas med kvar- varande stärkelse 1500 och magnesiumstearat. Denna blandning fylles därefter i hårdgelatinkapselskal storlek nr 2 med användning av lämpliga maskiner. i)The active ingredient is premixed with a certain amount of starch 1500, after which this premix is mixed with the remaining starch 1500 and magnesium stearate. This mixture is then filled into size 2 hard gelatin capsule shells using suitable machines. in)
Claims (11)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858510277A GB8510277D0 (en) | 1985-04-23 | 1985-04-23 | Carbocyclic compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8601852D0 SE8601852D0 (en) | 1986-04-22 |
| SE8601852L SE8601852L (en) | 1986-10-24 |
| SE460193B true SE460193B (en) | 1989-09-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8601852A SE460193B (en) | 1985-04-23 | 1986-04-22 | 13-OXAPROSTAGLANDINES OF PGE TYPE, SET TO MANUFACTURING THESE AND A PHARMACEUTICAL COMPOSITION |
Country Status (29)
| Country | Link |
|---|---|
| JP (1) | JPS61249951A (en) |
| KR (1) | KR860008132A (en) |
| CN (1) | CN1011783B (en) |
| AT (1) | AT395421B (en) |
| AU (1) | AU593797B2 (en) |
| BE (1) | BE904656A (en) |
| CA (1) | CA1275094A (en) |
| CH (1) | CH667265A5 (en) |
| DE (1) | DE3613573A1 (en) |
| DK (1) | DK183986A (en) |
| ES (3) | ES8802137A1 (en) |
| FI (1) | FI85368C (en) |
| FR (1) | FR2580632B1 (en) |
| GB (2) | GB8510277D0 (en) |
| GR (1) | GR861060B (en) |
| HK (1) | HK51691A (en) |
| HU (1) | HU199411B (en) |
| IL (1) | IL78552A (en) |
| IT (1) | IT1190277B (en) |
| LU (1) | LU86404A1 (en) |
| MY (1) | MY100829A (en) |
| NL (1) | NL8601025A (en) |
| NO (1) | NO165069C (en) |
| NZ (1) | NZ215910A (en) |
| PH (1) | PH23597A (en) |
| PT (1) | PT82440B (en) |
| SE (1) | SE460193B (en) |
| SG (1) | SG92990G (en) |
| ZA (1) | ZA863006B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB8625322D0 (en) * | 1986-10-22 | 1986-11-26 | Glaxo Group Ltd | Chemical compounds |
| EP0265247B1 (en) * | 1986-10-22 | 1990-08-08 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| GB8625325D0 (en) * | 1986-10-22 | 1986-11-26 | Glaxo Group Ltd | Chemical compounds |
| GB8625326D0 (en) * | 1986-10-22 | 1986-11-26 | Glaxo Group Ltd | Medicaments |
| GB8625321D0 (en) * | 1986-10-22 | 1986-11-26 | Glaxo Group Ltd | Chemical compounds |
| JP2696933B2 (en) * | 1987-06-16 | 1998-01-14 | 日産化学工業株式会社 | Substituted cyclic ketones and substituted cyclic enones and methods for their preparation |
| US5227505A (en) * | 1987-06-16 | 1993-07-13 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
| US5254708A (en) * | 1987-06-16 | 1993-10-19 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
| US5231208A (en) * | 1987-06-16 | 1993-07-27 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
| GB8822141D0 (en) * | 1988-09-21 | 1988-10-26 | Glaxo Group Ltd | Chemical compounds |
| WO1999032441A1 (en) * | 1997-12-22 | 1999-07-01 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
| EP2422814A1 (en) | 2003-07-25 | 2012-02-29 | Ono Pharmaceutical Co., Ltd. | Remedy for cartilage-related diseases |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2082176B (en) * | 1980-08-12 | 1984-07-11 | Sanofi Sa | Heteroprostaglandin derivatives and processes for preparing them |
| NZ197729A (en) * | 1980-08-12 | 1985-03-20 | Sanofi Sa | 13-oxaprostanoic acid derivatives and pharmaceutical compositions |
| GB8410396D0 (en) * | 1984-04-24 | 1984-05-31 | Glaxo Group Ltd | Carbocyclic compounds |
-
1985
- 1985-04-23 GB GB858510277A patent/GB8510277D0/en active Pending
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1986
- 1986-04-21 IL IL78552A patent/IL78552A/en not_active IP Right Cessation
- 1986-04-22 NZ NZ215910A patent/NZ215910A/en unknown
- 1986-04-22 FI FI861687A patent/FI85368C/en not_active IP Right Cessation
- 1986-04-22 GB GB08609821A patent/GB2174702B/en not_active Expired
- 1986-04-22 ZA ZA863006A patent/ZA863006B/en unknown
- 1986-04-22 FR FR868605781A patent/FR2580632B1/en not_active Expired
- 1986-04-22 GR GR861060A patent/GR861060B/en unknown
- 1986-04-22 DK DK183986A patent/DK183986A/en not_active Application Discontinuation
- 1986-04-22 BE BE0/216578A patent/BE904656A/en not_active IP Right Cessation
- 1986-04-22 IT IT47919/86A patent/IT1190277B/en active
- 1986-04-22 CA CA000507274A patent/CA1275094A/en not_active Expired - Fee Related
- 1986-04-22 CN CN86102778A patent/CN1011783B/en not_active Expired
- 1986-04-22 ES ES554238A patent/ES8802137A1/en not_active Expired
- 1986-04-22 NO NO861584A patent/NO165069C/en unknown
- 1986-04-22 PH PH33693A patent/PH23597A/en unknown
- 1986-04-22 AT AT0106986A patent/AT395421B/en not_active IP Right Cessation
- 1986-04-22 AU AU56461/86A patent/AU593797B2/en not_active Ceased
- 1986-04-22 LU LU86404A patent/LU86404A1/en unknown
- 1986-04-22 PT PT82440A patent/PT82440B/en not_active IP Right Cessation
- 1986-04-22 NL NL8601025A patent/NL8601025A/en not_active Application Discontinuation
- 1986-04-22 CH CH1622/86A patent/CH667265A5/en not_active IP Right Cessation
- 1986-04-22 KR KR1019860003086A patent/KR860008132A/en not_active Application Discontinuation
- 1986-04-22 SE SE8601852A patent/SE460193B/en not_active IP Right Cessation
- 1986-04-22 DE DE19863613573 patent/DE3613573A1/en not_active Withdrawn
- 1986-04-23 JP JP61092446A patent/JPS61249951A/en active Pending
- 1986-10-03 HU HU864173A patent/HU199411B/en not_active IP Right Cessation
- 1986-12-30 MY MYPI86000259A patent/MY100829A/en unknown
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1987
- 1987-08-12 ES ES557659A patent/ES8900044A1/en not_active Expired
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1988
- 1988-04-12 ES ES557828A patent/ES9000022A1/en not_active Expired - Fee Related
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1990
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1991
- 1991-07-04 HK HK516/91A patent/HK51691A/en unknown
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