GB2174702A - Cyclopentyl ethes and their preparation and pharmaceutical formulation - Google Patents
Cyclopentyl ethes and their preparation and pharmaceutical formulation Download PDFInfo
- Publication number
- GB2174702A GB2174702A GB08609821A GB8609821A GB2174702A GB 2174702 A GB2174702 A GB 2174702A GB 08609821 A GB08609821 A GB 08609821A GB 8609821 A GB8609821 A GB 8609821A GB 2174702 A GB2174702 A GB 2174702A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alpha
- hydroxy
- phenyl
- heptenoate
- phenoxypropoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 title description 36
- -1 3-phenoxy-2-hydroxypropyl Chemical group 0.000 claims abstract description 145
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 65
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- SSUFGFDSOZQATQ-UHFFFAOYSA-N 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]hept-5-enoic acid Chemical compound C=1C=CC=CC=1OCC(O)COC1C(O)CC(=O)C1CC=CCCCC(O)=O SSUFGFDSOZQATQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 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
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 230000027119 gastric acid secretion Effects 0.000 abstract description 4
- 230000002496 gastric effect Effects 0.000 abstract description 4
- 208000025865 Ulcer Diseases 0.000 abstract description 3
- 231100000397 ulcer Toxicity 0.000 abstract description 3
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 124
- 239000000543 intermediate Substances 0.000 description 91
- 239000000243 solution Substances 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 239000003480 eluent Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 28
- 238000004587 chromatography analysis Methods 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000377 silicon dioxide Substances 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-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 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- 238000001665 trituration Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000012267 brine Substances 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
- 230000009467 reduction Effects 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 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
- 238000002425 crystallisation Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 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
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001721 carbon Chemical group 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
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 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
- 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
- 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
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 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
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- UWAOHFMOWBQIJH-UHFFFAOYSA-N 3-cyclopentylpropanal Chemical compound O=CCCC1CCCC1 UWAOHFMOWBQIJH-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
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- KKESHWHAHJPLSR-UHFFFAOYSA-N C=1C=CC=CC=1OCC(O)COC1C(O)CC(=O)C1CC=CCCCC(=O)OC1=CC=CC=C1 Chemical compound C=1C=CC=CC=1OCC(O)COC1C(O)CC(=O)C1CC=CCCCC(=O)OC1=CC=CC=C1 KKESHWHAHJPLSR-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 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
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- BOTLEXFFFSMRLQ-UHFFFAOYSA-N cyclopentyloxycyclopentane Chemical class C1CCCC1OC1CCCC1 BOTLEXFFFSMRLQ-UHFFFAOYSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 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
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 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
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 238000007911 parenteral administration Methods 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003166 prostaglandin E2 derivatives Chemical class 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
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000000126 substance Substances 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
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- BIXOMCMIEGNURI-UHFFFAOYSA-N 2-(oxan-2-yloxy)cyclopenta[b]furan-2-ol Chemical compound O1C(CCCC1)OC1(C=C2C(O1)=CC=C2)O BIXOMCMIEGNURI-UHFFFAOYSA-N 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
- 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
- GIDLWOPUFGMILA-UHFFFAOYSA-N 4-(oxan-2-yloxy)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1OCCCC1 GIDLWOPUFGMILA-UHFFFAOYSA-N 0.000 description 1
- OOKSYCBCCXZJHD-UHFFFAOYSA-N 7-(2-heptoxy-3-hydroxy-5-oxocyclopentyl)heptanoic acid Chemical compound CCCCCCCOC1C(O)CC(=O)C1CCCCCCC(O)=O OOKSYCBCCXZJHD-UHFFFAOYSA-N 0.000 description 1
- SXPOUQILTINREE-UHFFFAOYSA-N 7-[3-(oxan-2-yloxy)-2-[2-(oxan-2-yloxy)-3-phenoxypropoxy]-5-oxocyclopentyl]hept-5-enoic acid Chemical compound C1CCCOC1OC1CC(=O)C(CC=CCCCC(=O)O)C1OCC(OC1OCCCC1)COC1=CC=CC=C1 SXPOUQILTINREE-UHFFFAOYSA-N 0.000 description 1
- 101100534780 Arabidopsis thaliana SWI3D gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 241000183024 Populus tremula Species 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000003182 bronchodilatating effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 1
- KDMICHPWNLJREW-UHFFFAOYSA-N methyl 4-(oxan-2-yloxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1OCCCC1 KDMICHPWNLJREW-UHFFFAOYSA-N 0.000 description 1
- NPKFOESRHBKQGX-UHFFFAOYSA-N methyl 4-[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]hept-5-enoyloxy]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC(=O)CCCC=CCC1C(=O)CC(O)C1OCC(O)COC1=CC=CC=C1 NPKFOESRHBKQGX-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- MLBYLEUJXUBIJJ-UHFFFAOYSA-N pent-4-ynoic acid Chemical compound OC(=O)CCC#C MLBYLEUJXUBIJJ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RFKOOMCUROAVJQ-UHFFFAOYSA-N phenyl 7-[5-hydroxy-3-(oxan-2-yloxy)-2-[2-(oxan-2-yloxy)-3-phenoxypropoxy]cyclopentyl]hept-5-enoate Chemical compound OC1CC(C(C1CC=CCCCC(=O)OC1=CC=CC=C1)OCC(COC1=CC=CC=C1)OC1OCCCC1)OC1OCCCC1 RFKOOMCUROAVJQ-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- LBZIXWRZFXPLJU-UHFFFAOYSA-N propan-2-one;sulfuric acid Chemical compound CC(C)=O.OS(O)(=O)=O LBZIXWRZFXPLJU-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- ZBQCPWMIGVSOGB-UHFFFAOYSA-N trans-Non-7-ensaeure Natural products CC=CCCCCCC(O)=O ZBQCPWMIGVSOGB-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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
Abstract
Compounds are described of formula (I> <IMAGE> in which n is 1 or 2; m is 2-5 and x is -CH=CH- or -CH2-CH2-; or m is 1-4 and x is -CH=C=CH-; R<1> is phenyl, substituted phenyl or naphthyl; Y substituted or unsubstituted 3-phenoxy-2-hydroxypropyl. These compounds inhibit gastric acid secretion and provide gastrointestinal cytoprotection, and may be formulated for use in the treatment of ulcers.
Description
SPECIFICATION
Cyclopentyl ethers and their preparation and pharmaceutical formulation
Prostaglandin E2 is a naturally occurring substance which has many physiological actions. For example, it inhibits gastric acid secretion and provides gastrointestinal cytoprotection, lowers blood pressure, stimulates and relaxes smooth muscle, inhibits platelet aggregation and inhibits lipolysis.
Synthetic PGE2 analogues offer the possibility of different potency, longer duration of activity and increased selectivity of action and are therefore of considerable interest.
Many different PGE2 analogues have been suggested in the past for use in medicine but in only one instance have 13-oxa compounds been proposed in this respect. Thus, British Patent
Specification 20821 76A describes a group of compounds which includes 2-(heptyloxy)-3-hydroxy-5-oxo-cyclopentaneheptanoic acid and a 15-hydroxy derivative thereof. These compounds are stated to inhibit blood platelet aggregation and have bronchodilatory activity, and are proposed for use as antithrombotic or antiasthmatic agents.
We have now found a new group of cyclopentyl ethers that have PGE2-type activity. Compounds in this class have a particularly useful profile of biological action. In particular they have shown high potency and extended duration of action as regards the inhibition of gastric acid secretion and gastrointestinal cytoprotection and are therefore of interest in the treatment of ulcers.
The invention thus provides compounds of the general formula (1)
wherein
n is 1 or 2;
m is 2-5 and X is cis or trans -CH=CH- or -CH2-CH2-; or m is 1-4 and X is -CH=C=CH-; Rl is (a) phenyl [optionally substituted by C14 alkyl, C14 alkoxy, C1-4 alkanoyl, methylthio, methylsulphinyi, methylsulphonyl, halogen (e.g. chlorine or bromine), -CO2R2 [where R2 is a hydrogen atom or C14 alkyl or phenyl], -NHCOR2 [where R2 is as defined above or is a phenyl group optionally substituted by hydroxyl, CH3CONH- or
-CONR3R4 [where R3 and R4 may be the same or different and are each a hydrogen atom or C14 alkyl group], -NHCONH2, -CH2CH(CONH2)NHCOCH3, or
or (b) 2-naphthyl;;
Y is
where R5, R6 and R7 is each a hydrogen atom or a methyl group and at least one is a hydrogen atom; and
Ar is a phenyl group (optionally substituted by one or two C14 alkyl, C14 alkoxy, C1 4alkoxy, C1-4 alkylthio, C14 alkylsulphinyl, C1-4 alkylsulphonyl, halogen or trifluoromethyl groups); and the physiologically acceptable salts thereof.
The structural formula herein are to be understood to include the enantiomers of each of the compounds concerned as well as mixtures of the enantiomers including racemates.
In general, the compounds of formula (1) in which the carbon atom carrying the group -(CH2)nX(CH2)mCO2R' and/or the carbon atom in the group Y carrying the -OH group (particularly the former) are in the R-configuration and mixtures containing such isomers are preferred.
The alkyl groups referred to above in the definition of the compounds of formula (1) may be straight or branched.
When R1 in the compounds of formula (1) is phenyl substituted by a group -CO2H the compounds are capable of salt formation with bases. Examples of suitable salts are alkali metal (e.g. sodium and potassium) salts.
In compounds where X is -CH=CH- or -CH2CH2-, 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.
When X is -CH=CH- it is preferably cis -CH=CH-.
When R1 is a substituted phenyl group it may be, for example, phenyl substituted in the meta, ortho or, in particular, para positions by a chlorine or bromine atom or a methyl, ethyl propyl, nbutyl, t-butyl, methoxy, ethoxy, propoxy, butoxy, acetyl, propionyl, methylthio, methylsulphinyl, methylsulphonyl, -CO2H, -CO2CH3, -CO2CH2CH3,
-NHCHO, -NHCOCH3, benzoylamino, (acetylamino)benzoylamino, (hydroxy)benzoylamino, -CONH2, -CONHCH3 CON(CHs)2, -CONHCH3CH3, -CONH(CH2CH3)2, -NHCONH2, -CH2CH(CONH2)NHCOCH3 or
group.
Particularly useful substituents which may be present on a substituted phenyl group R1 include C14 alkoxy, C14 alkanoyl, methylthio, methylsulphonyl, -CO2R2, -NHCOR2, -CONR3R4 [where R2,
R3 and R4 are as defined for formula (I)], -NHCONH2 or -CH2CH(CONH2)NHCOCH3 groups. Espe cialiy useful substituents of this type include methoxy, acetyl, methylthio, methylsulphonyl, -CO2CH3, -NHCOCH3, benzoylamino, (p-acetylamino)benzoylamino, (p-hydroxy)benzoylamino, -CONH2, -CON(CH3)2, -NHCONH2 or CH2CH(CONH2)NHCOCHa.
The group R1 is preferably a substituted phenyl group where the substituent may be in the meta, ortho or, in particular, para positions, or is a 2-naphthyl group.
Compounds in which R1 is a phenyl group substituted (particularly in the para-position) by a methoxy, acetyl, -CO2CH3, -NHCOCH3-, benzoylamino, -CONH2, -CON(CH3)2 or -CH2CH(CONH2)NHCOCH3 group, or R1 is a 2-naphthyl group, are particularly useful.
In the group Y, R6 and R7 are preferably hydrogen atoms. Compounds in which R5 is H or -CH3 and R6 and R7 are hydrogen atoms are also preferred.
When the Ar phenyl group is substituted, the substituent may be in the meta, ortho or para positions and may be for example methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, metylthio, methylsulphinyl, methylsulphonyl, fluoro, chloro, bromo or trifluoromethyl. Preferably, only a single substituent is present, particularly at the para-position. In general, Ar is preferably phenyl or phenyl substituted by halogen, particularly fluoro or chloro.
The preferences indicated above apply both separately and in combination with one or more of the other stated preferences.
A preferred group of compounds of the invention thus has the formula (1) in which:
X is -CH=CH- or -CH2CH2- 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;
R1 is a phenyl group substituted (preferably in the para-position) by a methoxy, acetyl, -CO2CH3 -NHCOCH3, benzoylamino, -CONH2, -CON(CH3)2 or -CH2CH(CONH2)NHCOCH3 group or
R1 is a 2-naphthyl group;
R5 is a hydrogen atom or a methyl group;
R6 and R7 are hydrogen atoms; and
Ar is phenyl or phenyl substituted by fluoro or chloro.
Compounds of this type in which the carbon atom carrying the -(CH2)nX(CH2)mCO2R1 group is in the R- configuration are particularly preferred. Especially preferred compounds of this type are those in which R1 is a phenyl group substituted (preferably in the para-position) by benzoylamino or -CONH2, particularly the former.
A particularly useful group of compounds according to the invention are the following: [ 1 R-[ 1 a(Z) ,2ss(R*) ,3a]l-(- )4-Acetylphenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oXo- cyclopentyl]-5-heptenoate;
[1 R-[ 1 a(Z),2fl(R),3a]]-( - )-4-(Acetylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate;
[ 1 R-[ 1 α(Z),2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate; [1R-[1a(Z,S*),2ss(R*),3α]]-(+)-4-[2-(Acetylamino)-3-amino-3-oxopropyl]phenyl 7-[3-hydroxy-2-(2hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;;
[1 R-[ 1 a(Z),2P(R"),3a]l-(- )-(Aminocarbonyl) phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)- 5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-(Benzoaminophenyl 7-[3-hydroxy-2-[2-hydroxy-3-phenoxypropoxy)-5 oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-(N,N-Dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phe noxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 α(Z),2ss(R*),3α]]-(-) Methyl 4-[[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oXocyclo- pentyl]- 1 -oxo-5-heptenyljoxy]benzoate;; [1 R-[ 1 a(Z),2ss(R*),3a]]-2-Naphthalenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oXocyclo- pentyl]-5-heptenoate; [1R-[1α(Z),2ss,3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-2-methyl-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss,3α]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-hydroxypropoxy]-3-hydroxy-5 oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-4-heptenoate; [1R-[1α,2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate; and [1R-[1α(E),2ss(R*),3α]]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypro poxy)-5-oxocyclopentyl]-5-heptenoate.
As especially useful group of compounds of this type are: [1R-[1α(E),2ss(R*),3α]]-(-)-4-Acetylphenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxo cyclopentyl]-5-heptenoate; [1R-[1α(E),2ss(R*),3α]]-(-)-4-(Acetylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl]-5-heptenoate; [ 1 R-[ 1 a(Z),2P(R"),3 a]l-(- )-4-(Benzoylamino) phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate; [1R-[1α(E),2ss(R*),3α]]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(E),2ss(R*),3α]]-(-)-3-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl]-5-heptenoate;; [1 R-[ 1 a(Z),2fi(),3a]]-( - )-4-(N,N-Dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)- Methyl 4-[[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclo pentyl]- 1 -oxo-5-heptenyl]oxyjbenzoate; [ 1 R-[ 1 α(Z),2ss,(R*),3α]]-2-Naphthalenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss,3α]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-hydroxypropoxy]-3-hydroxy-5oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl]-4-heptenoate; and [1R-[1α,2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate.
A further important group of compounds according to the invention that have especially useful physico-chemical properties which make them very suitable for pharmaceutical formulation are: [1R-[1α(Z),2ss(R*),3α]]-(-)-4-Acetylphenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Acetylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 a(Z),2fi(F?) ,3a]]-( - )-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Acetylamino)benzoylamino]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;; [1 R-[ 1 a(Z),2fl(i?),3a]]-( - )-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z,S*),2ss(R*),3α]]-(+)-4-[2-(Acetylamino)-3-amino-3-oxo-propyl]phenyl 7-[3-hydroxy-2-(2hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-3-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 α(Z),2ss(R*),3α]]-(-) Methyl 4-[[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oXocyclo- pentyl]- 1 -oxo-5-heptenyl]oxy]benzoate; [1R-[1a(Z),2ss(R*),3α;]]-2-(Benzoamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5oxocyclopentyl]-5-heptenoate;
[ 1 R-[ 1 a(Z),2P(R"),3 a]l-2-Na phthalenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclo
pentyl]-5-heptenoate;
[ 1 R-[ 1 a(2),2fi,3aj]-(- )-4-(Methylsulphonyl)phenyl 7-[3-hydroxy-2-[2-hydroxy-3-[4-(methylthio)phe- noxy]propoxy]-5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 a(Z),2P(R),3a]l-(-)-4-(Benzoylamino)phen 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 a(Z),2ss(R*),3a]]-()-4-(Benzoylamino)phenyl 9-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-7-nonenoate; and [1 R-[ 1 a,2P(R"),3a]l-(-)-4-(Benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate.
A particularly preferred compound according to the invention is: [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)
5-oxocyclopentyl]-5-heptenoate.
Compounds of formula (1) inhibit gastric acid secretion, as determined for example by their ability to inhibit histamine-induced secretory responses in the rat perfused stomach, following the method of Ghosh M.N. and Schild in Br.J.Pharmacol., 1958, 13, 54 as modified by Parsons
M.E., Ph.D Thesis, University of London, 1969.
The compounds also provide gastrointestinal cytoprotection, as determined for example by their ability to inhibit ethanol-induced lesions in the conscious rat, following the method of
Robert et al in Gastroenterology, 1979, 77, 433, modified by the use of 5mg/kg/s.c. indomethacin prior to the administration of the test compound.
The compounds are thus of interest in the prevention and/or treatment of ulcers. They may also be used in the treatment of other conditions which arise from the hypersecretion of gastric acid. They may be formulated in conventional manner with one or more pharmaceutical carriers, for example for oral, buccal, parenteral or rectal administration.
The compounds may be formulated for oral administration as, for example, tablets, capsules, powders, solutions or syrups prepared by conventional means with acceptable excipents.
The compounds may be formulated for parenteral administration by bolus injections or continuous infusion. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers, with an added preservative.
For buccal administration, the compounds may be formulated as tablets or lozenges in conventional manner; and for rectal administration compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glyceride, can be used.
The compounds are preferably administered orally, for example in amounts of 0.5 to 300 ,ug/kg body weight, 1 to 4 times daily. For parenteral administration, the compounds may be administered in amounts of 0.01 to 10,ltg/kg body weight, 1 to 4 times daily. The precise dose will of course depend on the age and condition of the patient.
Suitable methods for preparing the compounds of the invention are described below, the various groups and symbols being as defined above except where otherwise indicated.
(a) Compounds of formula (1) may be prepared by deprotection of a corresponding compound in which the ring hydroxy group and the hydroxy group in Y are protected.
The protected compounds are thus of formula (2)
in which R8 is a suitable hydroxyl protecting group [e.g. tetrahydropyran-2-yl, tetrahydrofuran-2yl, ethoxyethyl, tri(hydrocarbyl)silyl or arylmethyl] and Y' is defined as a group
The two R8 groups in the compounds of formula (2) are conveniently the same, but they may be different if desired.
Where R8 is tri(hydrocarbyl)silyl the hydrocarbyl substituents may be the same or different e.g.
C16 alkyl, C26 alkenyl, C37 cycloalkyl, C7 20 aralkyl and C6 20 aryl groups. Such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, allyl, phenyl and benzyl. Preferred hydrocarbyl groups are C14 alkyl, e.g. methyl and t-butyl. Trimethylsilyl and t-butyldimethylsilyl groups are particularly preferred.
When R8 is an arylmethyl group it may contain up to 20 carbon atoms, e.g. benzyl, diphenylmethyl or triphenylmethyl.
The method used to deprotect the protected hydroxyl group will depend on the nature of R8 but in general acid hydrolysis or reduction may be used.
Thus, for example when R8 is a tetrahydropyran-2-yl, tetrahydrofuran-2-yl or ethoxyethyl group deprotection may be carried out 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 (e.g. diethyl ether, dioxan and tetrahydrofuran) halogenated hydrocarbons (e.g.
dichloromethane, hydrocarbons (e.g. toluene), dipolar aprotic solvents (e.g. acetone, acetonitrile, dimethylsulphoxide and dimethylformamide) and alcohols (e.g. methanol, ethanol and ethylene glycol). Where desired the solvents may be used in combination with water. The reaction may be carried out at any suitable temperature, such as from 0 to 50"C, e.g. 40 to 50"C.
A tri(hydrocarbyl)silyl group may for example be removed by acid hydrolysis, e.g. with dilute mineral acid or trifluoroacetic acid or by treatment with fluoride ions (e.g. from a quaternary ammonium fluoride such as tetra-n-butyl ammonium fluoride), or by treatment with aqueous hydrogen fluoride. Arylmethyl groups may 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 (e.g. boron trifluoride-etherate) in the presence of a thiol (e.g. ethanethiol) in a suitable solvent such as dichloromethane at e.g. room temperaure.
Compounds of formula (2) may be prepared by oxidation of a compound of formula (3)
with for example pyridinium chlorochromate in the presence of a buffer (e.g. sodium acetate) in a suitable solvent (e.g. dichloromethane) at an appropriate temperature (e.g. - 100C to room temperature). Alternatively, the oxidation may be carried out with dimethylsulphoxide, activated by N,N'-dicyclohexylcarbodiimide, in the presence of pyridinium trifluoroacetate in a solvent such as dichloromethane at e.g. - 100C to room temperature. Other conventional oxidative methods can also be used, for example Jones reagent.
Intermediate compounds of formula (3) may be prepared by the methods generally described in European Patent Specification 160495.
It will be appreciated that the deprotection method (a) is usually applied in connection with the formation by oxidation of the cyclopentyl ring oxo group. Thus, the compounds of formula (1) may generally be prepared by oxidising a corresponding compound of formula (3).
The formation of the ring oxo group may however be effected prior to the introduction of the desired R1 group by esterification (e.g. by method (b) below) and the protecting groups removed thereafter.
(b) Compounds of formula (1) may also be prepared by esterifying the corresponding carboxylic acids, i.e. the compounds in which R1 is a hydrogen atom, by conventional methods.
Thus for example a compound of formula (1) may be prepared by conversion of the corresponding carboxylic acid into an activated derivative (e.g. a corresponding mixed anhydride) formed for example by reaction with an alkyl chloroformate (e.g. isobutyl chloroformate) or an acid chloride (e.g. pivaloyl chloride) in the presence of a suitable base (e.g. triethylamine or pyridine). The activated derivative can then be reacted with an appropriate compound R'OH, which are either known compounds or may be prepared by methods analogous to those used for the preparation of known compounds. Suitable solvents include dipolar aprotic solvents (e.g.
acetone, acetonitrile and dimethylformamide) and halogenated hydrocarbons (e.g. dichloromethane). The reaction may be carried out at any suitable temperature e.g. from 0 C to room temperature.
The same group of compounds of formula (1) may 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 R'OH. This reaction is conveniently per formed at an appropriate temperature (e.g. 0 C to room temperature) in a solvent such as ether or dichloromethane.
The carboxylic acids required as starting materials for this reaction may be prepared by the methods generally described in European Patent Specification 160495.
(c) Compounds of formula (1) in which X is a -CH2-CH2- group may be prepared by reduction of a corresponding compound in which X is a cis or trans -CH=CH- group or an acetylene group. Suitable methods of reduction include hydrogen in the presence of a catalyst, e.g.
palladium, on a support (e.g. carbon). Suitable solvents include ethyl acetate, ethanol and methanol.
(d) Compounds of formula (1) in which X is a -CH=CH- group may be prepared by selective reduction of a corresponding compound in which X is an acetylene group. Suitable methods of reduction include hydrogen in the presence of a catalyst, e.g. palladium on a support (e.g. CaCO3 or BaSO4) and poisoned for example by lead or quinoline. Suitable solvents include ethyl acetate and methanol. This reaction is particularly suitable for the preparation of compounds in which X is cis -CH=CH-.
The acetylenes required as starting materials may be prepared from the corresponding acetylenic acids by esterification using the methods described above. The acetyienic acid intermediates may be prepared by the methods generally described in European Patent Specification 160495.
(e) Compounds of formula (1) in which X is a trans -CH=CH- group may be prepared by isomerisation of a corresponding compound in which X is a cis -CH=CH- group.
The isomerisation may for example be effected by treating the corresponding cis compound with toluene-p-sulphinic acid in dioxan (e.g. at reflux), or azobisisobutyronitrile and thiophenol, using for example a hydroarbon solvent (e.g. benzene) at any suitable temperature up to reflux.
The processes in methods (b-e) may also be applied to compounds of formula (2) and (3) and the products subsequently converted into compounds of formula (1) by the methods described above.
When a specific enantiomer of formula (1) is required, starting materials having the desired stereochemical configuration should be used in the above processes. Such starting materials may be prepared for example using the methods described in European Patent Specification 160495 from an enantiomeric intermediate as described in European Patent Specification 74856.
The following examples illustrate the invention.
Temperatures are in C 'Dried' refers to drying with anhydrous MgSO4. T.l.c.-Thin layer Chromatography on silica.
Chromatography was carried out on silica gel.
The following abbreviations are used:
ER-ether; EA-ethyl acetate; PE-petroleum ether (b.p. 60-80 unless otherwise stated); DIBALdiisobutylaluminium hydride; THF-tetrahydrofuran; CH2Cl2-dichloromethane; CHCI3-chloroform; CHBr3-brnmoform; DMF-dimethylformamide; DMSO-dimethylsulphoxide; EtOH-ethanol; MeOHmethanol; CH3CN-acetonitrile; Et3N-triethylamine; N.T.P.-normal temperature and pressure.
Intermediate 1 [1 S-[ 1 a(Z), 2fi(2S*), 3a5a]j- 7-[5-Hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yI) oxy]propoxy]-3- [(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoic acid
Intermediate 2 [1 S-[ 1 a(Z), 2fi, 3a, Safl-(+) Methyl 7-[5-hydroxy-2-[2-me thyl-3-phenoxy-2-[(tetrah ydro-2H-p yran-2- yl)oxy]propoxy]-3-[(tetrahydro-2H-p yran-2-yl) oxy]cyclopentyl]-5-hep tenoa te Intermediate 3
(a) [1S-[1α(Z),2ss,3α,5α]]-(+)-Methyl 7-[2-[3-(4-fluorophenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
(b) [ S-[ 1α(Z),2ss,3α,5α ;]]-(+)-Methyl 7-[2-[3-(3-chlorophenoxy)-2-[(te trahydro-2H-p yran-2-yl)oxy]- propoxy]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
(c) [1S-[1α(Z),2ss,3α,5α]]-(+)-Methyl 7-[5-Hydroxy-2-[3-[4-(methylthio)phenoxy]-2-[(tetrahydro-2H pyran-2-yI)oxy]propoxy]-3-[(te trahydro-2H-pyran-2-yI) oxy]cyclopen tyl]-5-heptenoate Intermediate 4 [3aR-[3aα,4α(2R*),5ss,5α]]-Hexahydro-4-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5 [(tetrahydro-2H-pyran-2-yl)oxy]-2H-cyclo penta[b]furan-2-ol Intermediate 5 [1R-[1α,5α,6α,8R*(R*)]]-8-(2-Hydroxy-3-phenoxypropoxy)-6-(phenylmethoxy)-2-oxabicyclo[3.2.1]oc- tan-3-one
Intermediate 6 [1S-[1α(Z),2ss(2S*),3α;,5α]]-(+)-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 were prepared as described in European Patent Specification No 160495.
Intermediate 7
Methyl 4-[(tetrahydro-2H-pyran-2-yl)oxy]benzoate
A solution of methyl 4-hydroxybenzoate (10g) in EA (60ml) containing saturated ethereal HCl
(3.5 ml) was treated with dihydropyran (12ml) and the solution was allowed to stand at room temperature for 24h. A further quantity of dihydropyran (12ml) and ethereal HCI (3.5ml) was added and the solution was left for 17h. The solvent was evaporated and the residue was dissolved in ER (100ml) and washed with 2N NaOH solution (2X50ml), brine (50ml) and then dried. Evaporation gave a residue which on purification by chromatography using 3:97 ER-tolu- ene as eluant gave the title compound as a white solid (10.2g), m.p. 58-62".
Intermediate 8 4-[(Tetrahydro-2H-pyran-2-yl)oxy]benzoic acid
A suspension of Intermediate 7 (10.0g) in MeOH (200ml) and 5N NaOH solution (30ml) was atirred at room temperature for 24h. The solution was evaporated to about 50ml and diluted with water (100ml). The mixture was filtered through hyflo and the filtrate was washed with ER (2X30ml) and acidified by the dropwise addition of 5N hydrochloric acid. The resulting precipitate was filtered off to give the title compound as a white solid (8.259), m.p. 138-399 .
Intermediate 9 4-(4-Hydroxyphenyl)-4-[(tetrahydro-2H-pyran-2-yl)oxy]benzamide
A solution of Intermediate 8 (8.1g) in dry THF (200ml) at 0 was treated with Et2N (6.0ml) and then pivaaloyl chloride (5.4ml) and the mixture was stirred at 0 for 30 min. A solution of 4aminophenol (3.0g) in DMF (30ml) was added and the mixture was stirred for 17h at room temperature and for 1.5h at 80 . The mixture was filtered, the filtrate was evaporated and the residue dissolved in ER (200ml). Pouring into water (200ml) gave a precipitate which was filtered off and crystallised from EA-MeOH to give the title compound as a white solid (5.6g), m.p.
173-174".
Intermediate 10 (a) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Acetylamino)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
A solution of Intermediate 1 (0.459) in dry CH3CN (15ml) at - 100 was treated with Et,N (0.2ml) followed by isobutyl chloroformate (0.14ml). After stirring for 45 min. p-hydroxyacetophenone (0.239) was added. Stirring was continued for 2h at 100 to 0O and then the mixture was diluted with water and extracted with ER (3X50ml). The combined extracts were washed with
10% copper sulphate solution (75ml), water (10ml) and then dried.Evaporation gave a residue which on purification by chromatography using 2:1 ER-PE (40-60 ) as eluent gave the title compound as a gum (0.439).
l.r. (CHB3) 3550, 1753, 1678cm-1, [α]D22+19.6 (MeOH)
The following compounds were prepared in a similar manner from Intermediate 1 and the appropriate phenol: (b) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Acetylamino)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3580, 3425, 1750, 1690cm-1, [α]D22+7.9 (MeOH) (c) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Aminocarbonyl)amino]phenyl-7-[5-hydroxy-2-[3-phenoxy-2- [(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3510, 3410, 1748, 1682cm-1, [α;]D22+15.4 (MeOH) (d) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Benzoylamino)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
Pivaloyl chloride (0.18g) was added to a solution of Intermediate 1 (0.7g) and Et3N (0.38g) in dry DMF (5ml) at 0 . After 10 min a solution of 4-(benzoylamino)phenol (0.53g) in DMF (2ml) was added and stirring continued for 6h at 0 and 18h at room temperature. The reaction mixture was diluted with EA (150 ml) and washed consecutively with water water (2X50ml), 10% copper sulphate solution (2X50ml), water (50ml) and brine (50ml). The dried organic extract was evaporated to give a residue which was purified by chromatography on Et3N-deactivated silica using 1:1 cyclohexane-EA as eluent.The title compound was obtained as a gum (0.55g).
l.r. (CHBr3) 3520, 3425, 1750, 1673 cm-1, [α]D20 + (CHCL3)
The following compounds were prepared in a similar manner to Intermediate 10d from Intermediate 1 and the appropriate phenol: (e) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Acetylamino)benzoylamino]phenyl 7-[5-hydroxy-2-[3-phenoxy2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3580, 3520, 3425, 1745, 1690, 1670cm-1, [α]D20+20.6 (CHCl3) (f) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-(Aminocarbonyl)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3520, 3400, 1755, 1672cm-1, [α;]D20+20 (CHCl3) (g) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-4-[2-(Acetylamino)-3-amino-3-oxopropyl]phenyl 7-[5-hydroxy- 2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3500, 3400, 1745, 1690, 1660cm-1, [α]D20+24 (CHCl3) (h) [1S-[1α(Z),2ss(2S*),3α,5α]]-(+)-3-(Benzoylamino)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3700-3100, 1755, 1677cm-1, [α]D20+27 (CHCl3) (i) [1S-[1α(Z),2ss(2S*),3α,5α;]]-(+)-4-(N,N-Dimethylaminocarbonyl) phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate l.r. (CHBr3) 3530, 1750, 1740, 1626cm (i) I I Sj 7 a(Z), 2ss(2S*),3α,5α]] Methyl 4-[[7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)ox- y]propoxy]-3-[(tetrnhydro-2H-pyrnn-2-yl)oxy]prnpoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentylj-
1 -oxo-5-heptenyl]oxy]benzoate l.r. (CHBr3) 3590, 3520, 1750, 1715cm (k) [1S-[1α(Z),2ss(2S*),3α,5α;]]-(+)-4-[[[4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl]carbonyl]amino]phenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from Intermediates 1 and 9
I.r. (CHBn) 3580, 3420, 1748, 1668cm ', [α]D20+21 (CHCl3) (l) [1S-[1α(Z),2ss(2S*),3α,5α]]-2-(Benzoylamino)phenyl 7-[5-hydroxy-2-[(tetrahydro-2Hpyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy ]cyclopentyl]-5-heptanoate l.r. (CHBr3) 3520, 3440, 1728, 1688, 1516cm (m) [1S-[1α(Z),2ss(2S*),3α,5α;]]-2-Naphthalenyl 7-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate l.r. (CHBr3) 3530, 1750cm 1 (n) [1S-[1α(Z),2ss,3α,5α]]-4-(Benzoylamino)phenyl 7-[5-hydroxy-2-[2-methyl-3-phenoxy-2-[(tetrahy dro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from
Intermediate 1 2a I.r. (CHBr3) 3520, 3430, 1750, 1675cm (o) [1S-[1α(Z),2ss,3α,5α]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 12b. I.r. (CHBr3) 3590, 3530, 1748cm a (p) [1S-[1α(Z),2ss,3α,5α]]-4-(Methilthio)phenyl 7-[2-[3-(3-chlorophenoxy)-2-[(tetrahydro-2H-pyran-2yl)oxy]propoxy]-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 12c. I.r. (CHBr3) 3580, 3520, 1750cm (q) [1S-[1α(Z),2ss,3α,5α]]-4-(Methylsulphonyl)phenyl 7-(5-hydroxy-2-[3-[4-(methylthio)phenoxy]-2 [(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate.
from Intermediate 12d. I.r. (CHBr3) 3520, 1758cm (r) [1S-[1α,2ss(2S*),3α,5α]]-4-((Aminocarbonyl)phenyl 7-[5-hydroxy-2-[(tetrahydro-2Hpyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-4,5-heptadienoate, from Intermediate 12e. I.r. (CHBr3) 3520, 3405, 3600-3200, 1960, 1758, 1675cm-1 (s) [1S-[1α(Z),2ss(2S*),3α,5α]]-4-(Benzoamino)phenyl 7-[5-hydroxy-2-[3-phenoxy-2-(tetrahydro-2Hpyran-2-yl)oxy]propoxy]-3-[(tertahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 12f. I.r. (CHBr3) 3520, 3430, 1750, 1578cm-1 (t) [1S-[1α(Z),2ss(2S*),3α,5α,]]-4-(Benzoamino)phenyl 9-[5-hydroxy-2-[3-phenoxy-2-[(tetrahydro-2Hpyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-7-noneoate, from Intermediate 12g.I.r. (CHBr3) 3520, 3420, 1748, 1672cm Intermediate 11 (a) [1R-[1α(Z),2ss(2R"),3α,]]-(-)-Acetylphenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate
A stirred solution of Intermediate 10a (0.39g) in dry CH2CI2 (4ml) and dry DMSO (0.4ml) was treated with dicyclohexylcarbodiimide (0.5g) followed by pyridinium trifluoroacetate (0.17g). After 5h at room temperature the mixture was poured into water (50ml) and extracted with ER (3X 75ml). Evaporation of the dried extracts gave a residue which was purified by chromatography on acid-washed (pH3.8) silica. The title compound was obtained as a colourless gum (0.27g).
l.r. (CHBr3) 1760, 1743, 1680cm-1, [α]D222-13.7 (MeOH)
The following compound was prepared in a similar manner: (b) [1R-[1α(Z),2ss(2R*),3α,]]-(+)-4-(Acetylamino)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10b l.r. (CHBr3) 3420, 1740, 1685cm 1, [α]D186+16.7 (MeOH) (c) [1R-[1α(Z),2ss(2R*),3α;,]]-4-[(Aminocarbonyl)amino]phenyl 7-[5 oxo-2-[3-phenoxy-2-[(tetrahydro 2H-p yran-2-y13 oxy]propoxy]-3-(tetrah ydro-2H-p yran-2-yl)oxy]cyclopen tyl]-5-heptenoate A cold (0 ), stirred suspension of Intermediate 10c (0.15g) and anhydrous sodium acetate (0.05g) in CH2CI2 (2ml) was treated with pyridinium chlorochromate (0.13g). The mixture was stirred at 0 for 30 min. and at room temperature for 1h and then purified by chromatography on acid-washed (pH3.8) silica using EA as eluent. The title compound was obtained as a gum (0.09g). T.l.c. EA Rf 0.3.
The following compounds were prepared in a similar manner: (d) [1R-[1α(Z),2ss(2R*),3α,]]-(-)-(Benzoylamino)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H pyran-2-yl) oxy]propoxy]-3-[(te trahydro-i-l-p yran-2-yl) oxy]cyclopen tyl]-5-hep tenoa te, from I nterme- diate 10d l.r. (CHBr3) 3430, 1740, 1675cm 1, [α]D20-11 (CHCl3) (e) [1R-[1α(Z),2ss(2R*),3α,]]-(-)-4-[4-(Acetylamino)benzoylamino]phenyl 7-[5-oxo-2-[3-phenoxy-2 [(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10e l.r. (CHBr3) 3420, 1740, 1690, 1670cm , [α]D20 - 50 (CHCl3) (f) [1R-[1α(Z),2ss(2R*),3α;,]]-(-)-4-(Aminocarbonyl)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2Hpyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoate, from Intermediate 10f l.r. (CHBr3) 3525, 3405, 1742, 1675, 1599cm 1, [α]D20-16.3 (CHCl3) (g) [1R11a(Z,S*),2ss(2R*),3a,]]-()-4-[2-(Acetylamino)-3-amino-3-oxopropyl]phenyl 7-[5-oxo-2-[3phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5heptenoate, from Intermediate 10g.
l.r. (CHBr3) 3505, 3400, 1740, 1690, 1665 cm-1, [α]D20-3.4 (CHCl3) (h) [1R-[1α(Z),2ss(2R*),3α,]]-(-)-3-(Benzoylamino)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H pyran-a- yl)oxy]propoxy]-3-[(te trah ydro-2H-pyran-2-yl)oxy]cyclopen tyl]-5-hep tenoa te, from Interme- diate 10h. I.r. (CHBr3) 3430, 1742, 1680, 1526cm ', [α]D20 - 70 (CHCI3) (i) [1 R-[ 1 a(Z),2fi(2R*), 3a,ll-4-(N, N-Dimethylaminocarbonyl) phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10i.I.r. (CHBr3) 1740, 1622cm 1 (j) [1R-[1α(Z),2ss(2R*),3α,]] Methyl 4-[[7-[5-oxo-2-[3-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 10j. I.r. (CHBr3) 1745, 1720cm 1 (k) [1R-[1α(Z),2ss(2R*),3α,]]-(-)-4-[[[4-(Tetrahydro-2H-pyran-2-yl)oxy]phenyl]carbonyl]amino]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 10k I.r. (CHBr3) 3435, 1745, 1720, 1672cm [α]D20 - 8.9 (CHCl3) 11l) [1R-[1α(Z),2ss(2R*),3α;,]]-2-(Benzoamino)phenyl 7-[5-oxo-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentenyl]-5-heptenoate, from Intermediate 101 I.r. (CHBr3) 3440, 1760, 1740,1678cm~' 11 m) [1R-[1α(Z),2ss(2R*),3α,]]-2-Naphthalenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10m l.r. (CHBr3) 1745cm-1 11n) [1R-[1α(Z),2ss,3α,]]-4-(Benzoylamino)phenyl 7-[2-[2-methyl-3-phenoxy-2-[(tetrahydro-2H-pyran2-yl)oxy]propoxy]-5-oxo-3-[(tetahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermedidiate 1 On l.r. (CHBr3) 3430, 1740, 1672cm-1 11o) [1R-[1α(Z),2ss,3α;,]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-oxo-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10o. I.r. (CHBr3) 1744cm '
The following compounds were prepared in a similar manner to Intermediate 1 1a:- 11p) [1R-[1α(Z),2ss,3α,]]-4-(Methylthio)phenyl 7-[2-[3-(3-chlorophenoxy)-2-(tetrahydro-2H-pyran-2yl)oxy]propoxy]-5-oxo-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10p. l.r. (CHBr3) 1742cm-1.
(q) [1R-[1α(Z),2ss,3α,]]-4-(Methylsulphonyl)phenyl 7-[2-[3-[4-(methylthio)phenoxy]-2-[(tetrahydro-2H-pyran2-yl)oxy]propoxy]-5-oxo-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptanoate, from Intermediate 10q. I.r. (CHBr3) 1740cm 1
The following compounds were prepared in a similar manner to Intermediate 1 1c::- (r) [1R-[1α,2ss,(2R*),3α,]]-4-(Aminosulphonyl)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-4,5-heptadienoate, from Inate 10r l.r. (CHBr3) 3520, 3410, 1962, 1742, 1676cm (s) [1R-[1α(Z),2ss(2R*),3α,]]-4-(Benzoylamino)phenyl 7-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran 2-yl)oxy]propoxy]-3-[(tetrahydro-2H-p yran-2-yl)oxy]cyclopentyl]-4-heptenoate. from Intermediate 10s l.r. (CHBr3) 3430, 1742, 1675cm 1 (t) [1R-[1α(Z),2ss(2R*),α;,]]-4-(Benzoylamino)phenyl 9-[5-oxo-2-[3-phenoxy-2-[(tetrahydro-2H-pyran2-yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran]cyclopentyl]-7-nonenoate, from Inermediate 10t.1.r. (CHBr3) 3430, 1742, 1678cm
Intermediate 12 (a) [1s-[1α(Z),2ss,5α]]-7-[5-Hydroxy-2-[2-methyl-3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]pro- poxy]-3-[(tetrahydro-2H-pyran-2-yloxy-2-yl)oxy]cyclopentyl]-5heptenoic acid
A solution of Intermediate 2 (0.989) in MeOH (15ml) was treated with 5N NaOH solution (6ml).
After 30 min the mixture was poured into water (100ml) and extracted with ER (150ml). The aqueous solution was acidified with a saturated NH4CI solution (150ml) and then extracted with
EA (4X50ml). The combined extracts were dried and evaporated to give the title compound as a gum (0.889). I.r. (CHBr3) 3510, 3400-2500, 1730, 1708cm 1
The following compounds were prepared in a similar manner: (b) [1S[1α(Z),2ss,3α,5α,]]-7-[2-[3-(4-Fluorophenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hy- droxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoic acid, from Intermediate 3a. I. r.
(CHBr3) 3510, 3400-2400, 1730, 1708cm 1 (c) [1S[1α(Z),2ss,3α,5α,]]-7-[2-[3-(3-Chlorophenoxy)-2-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy]-5-hy- droxy-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoic acid, from Intermediate 3b l.r.
(CHBr3) 3590, 3510, 3700-2400, 1730, 1705 cm-1 (d)[l S-[ 1 a(Z), 2"', 3a, Sa,]]- 7-[5-Hydroxy-2-[3-[4-(methy!thio)phenoxy]-2-[(tetrahydro-2H-p yran-2-yI)- oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-5-heptenoic acid, from Intermediate 3c. l.r. (CHBr3) 3520, 2600-2500, 1730, 1708 cm-1 (e) [1Sl1a(Z),2ss(2S#;),3a,5a,]]-7-[5-Hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]pro- poxyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-4,5-heptanoic acid, from Intermediate 15
I.r. (CHBr3) 3500, 1920, 1730cm-1 (f) [1Sl1a(Z),2ss(2S*),3a,5a,]]-7-[5-Hydroxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-yl)oxy]pro- poxy]-3-[(tetrahydro-2H-p yran-2-yl)oxy]cyclopentyl]-4-heptenoic acid (3-Carboxypropyl)triphenylphosphonium bromide (1.11 g) and potassium tert-butoxide (0.589) in dry THF (10ml) were stirred at ambient temperature for 45 min. A solution of the Intermediate 19 (0.58g) in dry THF (10ml) was added and stirring at ambient temperature was continued for 1h. A further identical quantity of preformed ylide was added to the reaction mixture and stirring was continued for 1.5h.Water (20ml) was added and the mixture was washed with ER (3X50ml). The organic washings were back extracted with 8% NaHCO2 solution (2X20ml). The combined aqueous extracts were treated with saturated NH4CI (30ml) and the product was extracted with ER (3X50ml). The extracts were washed with brine (15ml), dried and concentrated in vacuo to yield the title compound as an oil (0.55g).
I.r. (CHBr3) 3500, 3600-2300, 1728, 1710cm '
The following compound was prepared in a similar manner to
Intermediate 12a: (9) TI Sf 1 a (Z), 2fi(2S ,), 3a, Sa,]]- 7-[5-Hydroxy-2-[3-phenoxV-2-[(tetrahydro-2H-p yran-2-yI)oxV]pro- poxy]-3-[(tetrahydro-2H-p yran-2-yl) oxy]cyclopentyl]- 7-nonenoic acid, from Intermediate 6
I.r. (CHBr3) 3510, 3000-2500, 1730, 1710cm
Intermediate 13 [1S-[1α,2ss(2S*),3α,5α;]]-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-hertynoate n-Butyl lithium (1.6M in hexane, 61.5ml) was added to a solution of diisopropylamine (13.8ml) and hexamethylphosphoramide (17.5ml) in ER (140ml) at 0 under nitrogen. The solution was cooled to 70 and a solution of 4-pentynoic acid (4.879) in THF (50ml) added. The mixture was then allowed to warm to room temperature, and after 1 h, a solution of Intermediate 4 (3.59) in ER (60ml) was added. After 18h, a solution of oxalic acid dihydrate (149) in water (200ml) was added and the organic phase separated.The aqueous phase was extracted with EA (200ml) and the combined organic phases dried and evaporated. The residue was dissolved in
DMF (30ml) and treated with methyl iodide (12ml) and potassium fluoride (89). After 3h the solution was diluted with EA (200ml) and washed with water (3X200ml) and brine (200ml). The aqueous washings were back-extracted with EA (200ml) and the combined organic phases 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 (2.99).
I.r. (CHBr3) 3580, 3500, 1728cm 1
Intermediate 14 [1R-[1α,2ss(2R*),3α,5α]]-Methyl 6-acetyloxy-7-[5-acetyloxy-2-[3-phenoxy-2-[(tetrahydro-2H-pyran-2yl)oxy]propoxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-4-heptynoate
Triethylamine (8.2ml), acetic anhydride (6.7ml) and 4-dimethylamino pyridine (70mg) were added to a stirred solution of Intermediate 13 (2.89) in CH2CI2 (60ml). After 2h the solvent was removed and chromatography of the residue using 4:1 ER-PE (40-60 C) as eluent gave the title compound as an oil (3.19).I.r. (CHBr3) 1728cm
Intermediate 15 [1 R-[ 1 a, 2fi(2R *), 3a, 5a]]-MethVI 7-[5-acetyloxy-2-[3-phenoxy-21(tetrahydro-2H-pyran-2-yl)oxy]pro- poxy]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]-4,5-heptadienoate
Methyl lithium (1.6M in ER, 44.5ml) was added to a stirred suspension of cuprous iodide (6.89) in ER (120ml) at -10 under nitrogen. When the addition was complete, a clear solution was obtained which was then cooled to -78 and a solution of the Intermediate 14 (0.859) in ER
(50ml) at -78 was added.After 1.5h, saturated NH4CI solution (200ml) was added and the mixture stirred at room temperature for 1 h. The organic phases was washed with saturated brine (200ml) and the aqueous phase extracted with ER (200ml). The dried organic extracts were evaporated and the residue purified by chromatography using 3:1 ER-PE (40-60 ) as eluent to give the title compound as an oil (1.2g).I.r. (CHBr3) 1960, 1728cm
Intermediate 16 [1R-[1α,5α,6α,8R*(R*)]]-8-(2-Hydroxy-3-phenoxypropoxy)-6-(phenylmethoxy)-2-oxybicyclo[3.2.1]oc- tan-3-ol
DIBAL (1M in hexane, 10ml) was added to a cold (-78"), stirred solution of Intermediate 5 (2.79) in CH2CI2 (50ml). After 2h a further quantity of DIBAL (6.7ml) was added and stirring continued for 2.5h. MeOH (20ml) was added dropwise and after 15 min at room temperature ether (60ml) was added.The resultant mixture was filtered through hyflo and the filtrate evaporated to give the title compound as a gum (2.6g). I.r. (CHBr3) 3580, 2720, 1718cm-'
Intermediate 17 [1S-[1α,2ss(S*),3α,5α]]-3-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-(phenylmethoxy)cyclopenta- nepropanal
To a cold (0 ) solution of potassium tert-butoxide (2.99) in THF (40ml), under N2, was added (methoxymethyl)triphenylphosphonium chloride (8.849). After 5 min a solution of Intermediate 16 (2.69) in THF (25ml) was added and the mixture stirred at 0 for 30 min. A saturated solution of NH4CI (50ml) was added and the mixture was extracted with ER (3X60ml). The combined extracts were dried and evaporated to yield an oil (9.1g).
The crude product was stirred in 1:1 0.25N sulphuric acid-acetone (80ml) for 48h at ambient temperature. The organic solvent was then removed in vacuo and the aqueous residue extracted with EA (3X50ml). The combined organic phases were washed with saturated brine (30ml), dried and evaporated. The residue was purified by chromatography using ER as eluent to give the title compound as an oil (1.5g).
I.r. (CHBr3) 3580, 3460, 2720, 1718cm 1.
Intermediate 18 [1S-[1α,2ss(S*),3α,5α]]-2-[3-Phenoxy-2-[(tetrahydro-2H-pyran-2-yl)pxy]propoxy]-5-(phenylmethoxy)3-[(tetrahydro-2H-pyran-2-ylpoxy]cyclopentanepropanal Dihydropyran (0.95ml) and pyridinium toluene-p-sulphonate (O.lg) were added to a stirred solution of Intermediate 17 (1.449) in CH2CI2 (40ml) at 0 . After stirring for 20h at room temperature the mixture was washed with water (2X10ml), 8% NaHCO2 (2X10ml) and brine (2X10ml). The solvent was evaporated and the residue purified by chromatography using 1:1 ER-PE (40-60 ) as eluent to yield the title compound as a gum (1.9g).I.r. (CHBr3) 2720, 1720cm
Intermediate 19 [4aR-[4aa,5a(2R#J,6ss,7aa]]-Octahydro-5-[3-phenoxy-2-[(tetrahydro-2H-pyran-2-ylpoxy]propoxy]-6- tetrah ydro-2H-pyran-2-ylloxy]cyclopenra[b]p yran-2-ol A solution of Intermediate 18 (0.949) in EA (50ml) was hydrogenated over pre-reduced 10% palladium on charcoal (0.979) at N.l.P. for 22h. The catalyst and solvent were removed and the residual oil (0.759) purified by chromatography using 3:1 ER-PE (40-60 ) as eluent to give the title compound as an oil (0.499).
I.r. (CHBr3) 3570cm t In the following examples, where the experimental details are not given, the compounds were prepared in a similar manner to the compound of Example 1.
Example 1 [1R-[1α(Z),2ss(R*),3α]]-(-)-4-Acetylphenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 1 lea (0.249) in 20:10:3 acetic acid-water-THF (2.5ml) was heated at 40 for 4h. The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH3.8) silica using 75:1 ER-MeOH as eluent to give the title compound as a white solid (0.149), m.p. 55-56.5 . Crystallisation from methyl acetate-PE gave a white solid, m.p.
64-65 ,[α]D224 - 18.1 (MeOH)
Analysis Found: C,68.02; H,6.63.
C29H3409 requires C,68.22; H,6.71%.
Example 2 [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Acetylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5 oxocyclopentyl]-5-heptenoate A solution of Intermediate 1 lib (0.3g) in 20:10:3 acetic acid-water-THF (3ml) was heated at 40-43 for 4h. The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using EA as eluent to give the title compound as a white solid (0.129), m.p. 60-63 . Crystallisation from t-butylmethylether gave a white solid, m.p. 74.5-75 .
[α]D209 - 19.4 (MeOH)
Analysis Found: C,65.86; H,6.71; N,2.66.
C29H35NO8 requires C,66.27; H,6.71; N,2.57%.
Example 3 [1R-[1α(Z),2ss(R*),3α]]-4-[(Aminocarbonyl)amino]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypro- poxy)-5-oxocyclopentyl]-5-heptenoate, (0.049) from Intermediate 11c (0.009g) purified using 20:1
EA-MeOH as eluent. T.l.c. 20:1 EA-MeOH Rf 0.25. I.r. (CHBr3) 3570, 3500, 3400, 1740, 1680cm '
Example 4 [1R-[1α(Z),2ss(R"),3α]]-(-)-4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5 oxocyclopentyl]-5-heptenoate A solution of Intermediate 11 d (0.24g) in 20:10:3 acetic acid-water-THF (3ml) was heated at 40-42 for 3H.The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using 7:3 EA-cyclohexane as eluent to give after trituration with
ER the title compound as a white powder (0.07g), m.p. 125-127 . [α]D20-29.3 (CHCl3)
Analysis Found: C,69.4; H,6.4; N,2.3.
C24H27NO8 C,69.5; H,6.4; N,2.4%.
Example 5 [1 R-[ 1 a(Z),2fi(R*),3a]]-(-)-4-[4-(A cetylamino)benzoylamino]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phe- noxypropoxy)-5-oxocyclopentyl]-5-heptanoate
A solution of Intermediate 11 e (0.249) in 20:10:3 acetic acid-water-THF (3ml) was heated at 40-42 for 4h. The solvent was removed in vacuo to give residue which was purified by chromatography on acid-washed (pH3.8) silica using EA as eluent to give trituration with ER thi titla compound as a white powder (0.06g), m.p. 150-154 , [α]D20 - 10 (MeOH)
Analysis Found: C,66.7; H,6.3; N,4.5.
C26H40N2O,, requires C,67.1; H,6.3; N,4.4%.
Example 6 [1R-[1α(Z),2ss(R"),3α]]-(-)-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate
A solution od Intermediate 11h (0.35g) in 20:10:3 acetic adid-water-THF (5ml) was heated at 40 for 3h. The solvent was removed in vacuo and the residue purified by chromatography on acidwashed (pH3.8) silica using 95:5 EA-EtOH as eluent. Trituration with ER followed by crystallisation from EA-PE gave the title compound as a white solid (0.14g), m.p. 104-105 , [α]D20 - 13.2 (EtOH)
Analysis Found: C,65.65; H,6.7; N,2.7.
C28H33N08 requires C,65.7; H,6.5; N,2.7%.
Example 7 [1R-[1α(Z,S*),2ss(R*),3α]]-(+)-4-[2-(Acetylamino)-3-oxopropyl]phenyl 7-[3-hydroxy-2-(2-hy droxy-3-phenoxypropoxy)-5-oxocyclopentyq-5-heptenoate A solution of Intermediate llg (0.379) in 20:10:3 acetic acid-water-THF (6ml) was heated at 40 for 3h. The solvent was removed in vacuo and a portion of the residue (0.1 9g) was purified by chromatography on acid-washed (pH3.8) silica gel using 9:1 CH2CI2-EtOH as eluent.Trituration with ER followed by crystallisation from EA-PE gave the title compound as a white solid (0.049), m.p. 105 [a]D +3.5o (EtOH), I.r. (Nujol) 1740, 1720, 1660, 1645cm
Example 8 [1R.[1α(Z),2ss(R"),3α]]-(-)-3-(Benzoylamino)phenyl 7-(3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5 oxocyclopentyl]-5-heptenoate A solution of intermediate 1 1h (0.35g) in 20:10:3 acetic acid-water-THF (5ml) was heated at 40-42 for 2,5 h.The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using 3:1 EA-cyclohexane as eluent to give after trituration with
ER the title compound as a white powder (0.16g), m.p. 89-91 , [α]D20-25.7 (CHCl3) Analysis Found: C,69.3; H,6.4; N,2.2.
C34H37N08 C,69.5; H,6.4; N,2.4%.
Example 9 [1R-[1α(Z),2ss(R"),3α]]-4-(N,N-Dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptanoate, (0.08g) from intermediate 11i (0.24g) purified using EA element EA as eluent. l.r. (CHBr3) 3580, 3420, 1745, 1624 cm, [α]D20-29 (CHCl3) Analysis Found: C,66.53; H,7.04; N,2.53.
C20H22N08 requires C,66.77; H,6.91; N,2.60%.
Example 10 [1R-[1α(Z),2ss(R*),3α]]-(-) Methyl 4-[[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl-1-oxo-5-hepteny]oxy]benzoate
A solution of Intermediate 1 li (0.19g) in 20:10:3 acetic acid-water-THF (10ml) was heated at 40 for 3h. The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using ER as eluent to give the title compound as a white solid (0.1g), m.p. 45-47 , [α]D20-33 (CHCl3)
Analysis Found: C,66.25; H,6.63.
C2,,H24O9 requires C,66.15; H,6.51%
Example 11 [1R-[1α(Z),2ss(R*)a]]-(-)-4-[4-(Hydroxy)benzoylamino]phenyl 7-[3-hydroxy-3-phenox ypropoxy)a-oxocyclopentyl]-5-heptenoate A solution of Intermediate 11k (O.57g) in 20:10:3 acetic acid-water-THF (10ml) was heated at 40 for 3.5h. The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH3.8) silica using 4:1 EA-PE as eluent to give after trituration with ER a white powder (0.22g). Cristallisation from EA-PE gave the title compound as a white solid
(0.18g), m.p. 108-110 C [α]D20 - 13.9 (EtOH) Analysis Found: C,67.35; H,6.1; N,2.2.
C34H37NOg requires C,67.65; H,6.2; N,2.3%.
Example 12 [1R-[1α(Z),2ss(R*),3a]]-(2)-(Benzoylamino]phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxpropoxy)-5-ox
ocyclopentyl-5-heptenoate, (.029g) from Intermediate 11l (0.050g) purified using 2:1 EA-cyclohexane as eluent. T.l.c. 2:1 EA-cyclohexane Rf 0.2. l.r. (CHBr3) 3580, 3440, 1742, 1675cm
Example 13 [1R-[1α(Z),2ss(R*),3α]]-2-Naphthalenyl 7-[3-hydroxy-2-(2-phenoxpropoxy)-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 11m (0.44g) in 20: 10:3 acetic acid-water-THF (12ml) was heated at 40-42 for 3h.The solvent was removed in vacuo and the residue was purified by chromatography on acid-washed (pH3.8) silica using 3:1 ER-EA as eluent to give after trituration with ER the title compound as a white powder (0.15g), m.p. 71-73 [α]D20 - 35 (CHCl3)
Analysis Found: C,69.42;H,6.85;N,2.21.
C31H3407 requires C,71.79; H,6.61%.
Example 14 [1R-[1α(Z),2ss,3α]]-2-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate, (0.06g) from Intermediete 11n (0.11g) purified using ER as eluent.
l.r. (CHBr3) 3580, 3420, 1742, 1672cm , [α]D20 - 7 (MeOH)
Analysis Found: C,69.42; H,6.85; N,2.21.
C35H39NO8 requires C,69.87; H,6.53; N,2.3%.
Example 15 [1R-[1α(Z),2ss,3α]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-hydroxypropoxy]-3-hydroxy-5-oxocyclopentyl]-5-heptenoate, (0.06g) from Intermediate 110 (0.09g) purified using 97:3 ER-MeOH as eluent. l.r. (CHBr3) 3580, 3450, 1745cm
Analysis Found: C,64.75; H,6.59.
C28H33FO3 requires C,65.10; H,6.44%.
Example 16 [1R-[1α(Z),2ss,3α]]-4-[4-(Methylthio)phenyl 7-[2-[3-(4-chlorophenoxy)-2-hydroxypropoxy]-3-hydroxy-5-ox ocyclopentyl]-5-heptenoate, 0.1g) from Intermediate 11p (0.16g) purified using 98:2 ER-MeOH as eluent. I.r. (CHBr3) 3580, 3440, 1742cm 1, T.l.c. 98:2 ER-MeOH Rf 0.25
Example 17 [1R-[1α(Z),2ss,3α]]-4-(Methylsulphonyl)phenyl 7-[3-hydroxy-2-[2-hydroxy-3-[4-(methylthio)phenoxy]propoxy]-5-oxocyclopentyl]-5-heptenoate
A solution of Intermediate 11q (0.14g) in 20: 10:3 acetic acid-water-THF (3ml) was heated at 40-42 for 3h. The solvent was removed in vacuo an dthe residue was purified by chromatography on acid-washed (pH3.8) silica using 75:25 increasing to 90:10 EA-ER as eluent to give the title compound as a white solid (0.09g), m.p. 73-76
I.r. (CHBr3) 3580, 3440, 1742cm 1
Example 18 [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5oxocyclopentyl]-4,5-heptadienoate, (0.19g) from Intermediate 11r (0.35g) purified using 3:2 EA
CH3CN as eluent.T.l.c. 3:2 EA-CH3CN Rf 0.3, l.r. (CHBr3) 3580, 3520, 3400, 1960, 1740, 1672cm 1, [α]D20 -21 CHCl3)
Example 19 [1R-[1α(Z),2ss(R*),3α]]-(-)-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-3-phenoxypropoxy)-5 oxocyclopentyl]-4-heptenoate
A solution of Intermediate 11s (0.179) in 20:10:3 acetic acid-water-THF (10ml) was heated at 40 for 2h.The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using 2:1 EA-cyclohexane as eluent to give the title compound as a solid (0.11g), m.p. 85-88
I.r. (CHBr3) 3580, 3430, 1745, 1675, [a]200 -27' (CHCl3)
Example 20 [1R-[1α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 9-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5 oxocyclopentyl]-7-nonenoate A solution of Intermediate 1 1t (O.55g) in 20:10:3 acetic acid-water-THF (15ml) was heated at 40 for 4h.The solvent was removed in vacuo and the residue purified by chromatography on acid-washed (pH 3.8) silica using 7:3 EA:cyclohexane as eluent to give after trituration with ER the title compound as a white soild (0.24g), m.p. 121-122 [α]D20 -34 (CHCl3)
Analysis Found: C,70.23; H,6.66; N,2.17.
C36H4'NO8 requires C,70.22; H,6.71; N,2.27%.
Example 21 [1R-[1α,2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate
A solution of the compound of Example 4 (0.1 g) in EA (35ml) was hydrogenated over prereduced 10% palladium on charcoal (0.03g) at N.T.P. for 40 min and then the solvent and catalyst were removed. The title compound was obtained as a white solid (0.079), m.p.
127-130 , [α]D20 -29.3 (CHCl3)
Analysis Found: C,69.38; H,6.69; N,2.15.
C34H39NO8 requires C,69.25; H,6.67; N,2.38%.
Example 22 [1R-[1α(E),2ss(R*),3α]]-(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy) 6-oxocyclopentyl]-5-heptenoate A solution of the compound of Example 6 (0. 1 5g), thiophenol (0.46ml) and azobisisobutyronitrile (0.1g) in CH2CN (3ml) and benzene (3ml) was stirred at reflux for 6.5h. Purification by chromatography (X2) on acid-washed (pH3.8) silica using 9:1 EA-CH3CN as eluent gave the title compound as a gum (0.139).
I.r. (CHBr3) 3580, 3515, 3400, 1742, 1672cm 1, [a]020 -30' (CHCl3) Analysis Found: C,66.12; H,6.8; N,2.52.
C28H33NO8 requires C,65.74; H,6.5; N,2.74%.
Example 23 [1R-[1α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5oxocyclopentyl]-5-heptenoate
Pivaloyl chloride (0.01ml) was added to a solution of Intermediate 1 (0.039) and Et3N (0.01ml) in dry DMF (1ml) at 0 . After 10 min a solution of 4-(benzoylamino)phenol (0.17g) and Et3N (0.01ml) in DMF (1ml) was added and stirring continued for 2h at 0 and 3.5h at room temperature. The reaction mixture was diluted with EA (30ml) and washed consecutively with water (10ml), 10% copper sulphate solution (15ml), water (10ml) and brine (15ml). The dried organic extract was evaporated to give a residue which was purified by chromatography on acidwashed (pH3.8) silica using 1:1 cyclohexane-EA as eluent.The title compound was obtained as a white solid (0.05g).
l.r. (CHBr3) 3580, 3430, 1745, 1675cm 1, T.l.c. 1:1 Cycxlohexane-EA Rf 0.15
The following are examples of pharmacuetical formulations using compounds of the invention. In the examples, the term "active ingredient" is used to denote a compound of the invention, such as a compound described in the preceding examples, for example the compound of Example 4.
1. Tablets
These may be 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 is blended with about 10% of the microcrystalline cellulose then blended with the remaining microcrystalline cellulose and magnesium stearate. The blend is then compressed using 6mm diameter punches into tablets on a suitable machine.
The tablets may be film coated with suitable film forming materials e.g. methyl cellulose or hydroxypropyl methylcellulose using standard -techniques.
2. Capsules
mg/tablet
Active ingredient 0.015 to 0.2
Magnesium stearate, BP 1.0 4Starch 1500 100.0
to fill weight A form of directly compressible starch.
The active ingredient is preblended with some of the Starch 1500 then this preblend is mixed with the remaining Starch 1500 and magnesium stearate. The mix is then filled into size No 2 hard gelatin capsule shells using suitable machinery.
Claims (15)
1. Compounds of the general formula (I)
wherein
n is 1 or 2;
m is 2-5 and X is cis or trans -CH=CH- or -CH2CH2-; or m is 1-4 and X is -CH=C=CH-; Rl is (a) phenyl [optionally substitued by C1-4 alkyl, C1-4 alkoxy, C1-4 alkanoxy, methylthio, methylsulphinyl, methylsulphonyl, halogen, -CO2R [where R is a hydrogen atom or C1-4 alkylor phenyl], -NHCOR2 [where R2 is as defined above or is a phenyl group optionally substituted by hydroxyl,
CH3CONH- or benzoylamino], -CONR R4[where R and R4 may be the same or different and are each a hydrogen atom or C1-4 alkyl group], -NHCONH2, -CH2CH(CONH2)NHCOCH3, or
(b) 2-naphthyl;;
Y is
where R5, R6 and R7 are each a hydrogen atom or a methyl group and at least one is a hydrogen atom, and
Ar is a phenyl group (optionally substituted by one or two C14 alkyl, C14 alkoxy, C14 alkythio, C14 alkylsulphinyl, C14 alkylsulphonyl, halogen or trifluoromethyl groups)
and the salts of compounds in which R2 is a hydrogen atom.
2. Compounds as claimed in claim 1 in which X is -CH=CH- or -CH2-CH2- and m is 3 when n is 1 and m is 2 or 4 when n is 2; or X is -CH=C=CH- and m is 2 when n is 1 and m is 1 or 3 when n is 2.
3. Compounds as claimed in claim 1 or claim 2 in which R1 is phenyl substituted by a C14 alkoxy, C14 alkanoyl, methylthio, methylsulphonyl, -CO2R2, -NHCOR2, -CONR3R4, -NHCONH2 or -CH2CH(CONH2)NHCOCH3 group or R1 is a 2-naphthyl group.
4. Compounds as claimed in claim 1 or claim 2 in which R1 is phenyl substituted by a methoxy, acetyl, -CO2CH3, -NHCOCH2, benzoylamino, -CONH2, -CON(CH3)2 or -CH2CH(CONH2)NHCOCH3 group, or R1 is a 2-naphthyl group.
5. Compounds as claimed in any preceding claim in which R5, R6 and R7 are hydrogen atoms and Ar is phenyl or phenyl substituted by fluoro or chloro.
6. Compounds as claimed in claim 1 in which:
X is -CH=CH- or -CH2CH2- 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;
R1 is a phenyl group substituted by a methoxy, acetyl, -CO2CH3, -NHCOCH3, benzoylamino, -CONH2, -CON(CH3)2 or -CH2CH(CONH2)NHCOCH3 group or R' is a 2-naphthyl group;
R5 is a hydrogen atom or a methyl group;
R6 and R7 are hydrogen atoms; and
Ar is a phenyl or phenyl substituted by fluoro or chloro.
7. Compounds as claimed in any preceding claim in which the carbon atom carrying the group -(CHJnX(CH2)mCO2RI is in the R-configuration.
8. A compound as claimed in claim 1 said compound being:
[1 R-[ 1 α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate .
9. A compound as claimed in claim 1, said compound being: [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(Acetylphenyl) 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate;
[1 R-[ 1 α(Z),2ss(R*),3α]]-(-)-4-[4-(Acetylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 [1R-[1α(Z),2ss(R*),3α]]-( + )-4-[2-(Acetylamino)-3-amino-3-oxopropyl]phenyl 7-[3-hydroxy-2-(2hydroxy-3-phenoxypropoxy-5-oxocyclopentyl)]-5-heptenioate;
[1 R-[ 1 a(Z) ,2ss(R*) ,3a]]-(- )-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypro poxy)-5-oxocyciopentyl]-5-heptenoate;; [1 R-[ 1 a(Z),2P(R"),3a]l-( - )3-(Benzoylami no)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5- oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-(N,N-Dimethylaminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3 phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 α(Z),2ss(R*),3α]]-(-)- Methyl 4-[[7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oXocyclo- pentyl]- 1 -oxo-5-heptenyl]oxy]benzoate; [1R-[1α(Z),2ss(R*),3α]]-2-Naphthalenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α;]]-(-)-4-[4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-4-Methoxyphenyl 7-[2-[3-(4-fluorophenoxy)-2-hydroxypropoxy]-hydroxy-5oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)5-oxocyclopentyl]-4-heptenoate;
[1 R-[ 1 α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentaneheptanoate; or
[1 R-[1 a(E) ,2ss(R*) 3α]]--(-)-4-(Aminocarbonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate.
10. A compound as claimed in claim 1, said compound being: [1R-[1α(Z),2ss(R*),3α]]-(-)-4-[4-(Acetylamino)benzoylamino]phenyl 7-[3-hydroxy-2-(2-hydroxy-3 phenoxypropoxy)-5-oxocyclopentyl]-5-heptenoate; [1 R-[ 1 a(Z),2ss(R*),3a]]-2-(Benzoylamino)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5oxocyclopentyl]-5-heptenoate; [1R-[1α(Z),2ss(R*),3α]]-4-(Methylsulphonyl)phenyl 7-[3-hydroxy-2-(2-hydroxy-3-(4-methylthio)phenoxy ]propoxy]-5-oxocyclopentyl]-5-heptenoate; or [1R-[1α(Z),2ss(R*),3α]]-(-)-4-[4-(Benzoylamino)phenyl 9-[3-hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5oxocyclopentyl]-7-nonenoate.
11. A pharmaceutical composition comprising a compound as claimed in any preceding claim together with one or more pharmaceutical carriers.
12. A composition as claimed in claim 11 in the form of a tablet.
13. A composition as claimed in claim 11 in the form of a tablet containing the compound of claim 8 as active ingredient.
14. A composition as claimed in claim 11 in the form of a tablet containing 0.015 to 0.2 mg of the compound of claim 8.
15. A process for the preparation of a compound as claimed in claim 1 which comprises: (a) deprotecting a corresponding compound in which the ring hydroxy group and the hydroxy group in Y are protected; (b) esterifying a corresponding compound in which R' is a hydrogen atom; (c) in the preparation of a compound in which X is -CH2-CH2-, reducing a corresponding compound in which X is -CH=CH- or an acetylene group; (d) in the preparation of a compound in which X is -CH=CH-, selectively reducing the corresponding compound in which X is an acetylene group; or (e) in the preparation of a compound in which X is trans -CH=CH-, isomerising the corresponding compound in which X is cis -CH=CH-.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MYPI86000259A MY100829A (en) | 1985-04-23 | 1986-12-30 | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
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 |
|---|---|
| GB8609821D0 GB8609821D0 (en) | 1986-05-29 |
| GB2174702A true GB2174702A (en) | 1986-11-12 |
| GB2174702B GB2174702B (en) | 1988-06-15 |
Family
ID=10578043
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858510277A Pending GB8510277D0 (en) | 1984-04-23 | 1985-04-23 | Carbocyclic compounds |
| GB08609821A Expired GB2174702B (en) | 1985-04-23 | 1986-04-22 | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB858510277A Pending GB8510277D0 (en) | 1984-04-23 | 1985-04-23 | Carbocyclic compounds |
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) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0268388A1 (en) * | 1986-10-22 | 1988-05-25 | Glaxo Group Limited | Anti-inflammatory compositions |
| US4847369A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| US4847370A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| US4847255A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their use in medicine |
| US4851523A (en) * | 1986-10-22 | 1989-07-25 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| EP0361772A2 (en) * | 1988-09-21 | 1990-04-04 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5227505A (en) * | 1987-06-16 | 1993-07-13 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
| 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 |
| 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 |
| WO1999032441A1 (en) * | 1997-12-22 | 1999-07-01 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
| WO2005009468A1 (en) | 2003-07-25 | 2005-02-03 | Ono Pharmaceutical Co., Ltd. | Remedy for cartilage-related diseases |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0160495A2 (en) * | 1984-04-24 | 1985-11-06 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ197729A (en) * | 1980-08-12 | 1985-03-20 | Sanofi Sa | 13-oxaprostanoic acid derivatives and pharmaceutical compositions |
| GB2082176B (en) * | 1980-08-12 | 1984-07-11 | Sanofi Sa | Heteroprostaglandin derivatives and processes for preparing them |
-
1985
- 1985-04-23 GB GB858510277A patent/GB8510277D0/en active Pending
-
1986
- 1986-04-21 IL IL78552A patent/IL78552A/en not_active IP Right Cessation
- 1986-04-22 DE DE19863613573 patent/DE3613573A1/en not_active Withdrawn
- 1986-04-22 AT AT0106986A patent/AT395421B/en not_active IP Right Cessation
- 1986-04-22 CN CN86102778A patent/CN1011783B/en not_active Expired
- 1986-04-22 NZ NZ215910A patent/NZ215910A/en unknown
- 1986-04-22 IT IT47919/86A patent/IT1190277B/en active
- 1986-04-22 GB GB08609821A patent/GB2174702B/en not_active Expired
- 1986-04-22 PT PT82440A patent/PT82440B/en not_active IP Right Cessation
- 1986-04-22 KR KR1019860003086A patent/KR860008132A/en not_active Application Discontinuation
- 1986-04-22 NO NO861584A patent/NO165069C/en unknown
- 1986-04-22 SE SE8601852A patent/SE460193B/en not_active IP Right Cessation
- 1986-04-22 ZA ZA863006A patent/ZA863006B/en unknown
- 1986-04-22 CA CA000507274A patent/CA1275094A/en not_active Expired - Fee Related
- 1986-04-22 ES ES554238A patent/ES8802137A1/en not_active Expired
- 1986-04-22 FI FI861687A patent/FI85368C/en not_active IP Right Cessation
- 1986-04-22 CH CH1622/86A patent/CH667265A5/en not_active IP Right Cessation
- 1986-04-22 GR GR861060A patent/GR861060B/en unknown
- 1986-04-22 NL NL8601025A patent/NL8601025A/en not_active Application Discontinuation
- 1986-04-22 PH PH33693A patent/PH23597A/en unknown
- 1986-04-22 LU LU86404A patent/LU86404A1/en unknown
- 1986-04-22 FR FR868605781A patent/FR2580632B1/en not_active Expired
- 1986-04-22 BE BE0/216578A patent/BE904656A/en not_active IP Right Cessation
- 1986-04-22 AU AU56461/86A patent/AU593797B2/en not_active Ceased
- 1986-04-22 DK DK183986A patent/DK183986A/en not_active Application Discontinuation
- 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
-
1987
- 1987-08-12 ES ES557659A patent/ES8900044A1/en not_active Expired
-
1988
- 1988-04-12 ES ES557828A patent/ES9000022A1/en not_active Expired - Fee Related
-
1990
- 1990-11-15 SG SG929/90A patent/SG92990G/en unknown
-
1991
- 1991-07-04 HK HK516/91A patent/HK51691A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0160495A2 (en) * | 1984-04-24 | 1985-11-06 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0268388A1 (en) * | 1986-10-22 | 1988-05-25 | Glaxo Group Limited | Anti-inflammatory compositions |
| US4847369A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| US4847370A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| US4847255A (en) * | 1986-10-22 | 1989-07-11 | Glaxo Group Limited | Cyclopentyl ethers and their use in medicine |
| US4851523A (en) * | 1986-10-22 | 1989-07-25 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| US4855293A (en) * | 1986-10-22 | 1989-08-08 | Glaxo Group Limited | Anti-inflammatory compositions comprising a systemic non-steroidal anti-inflammatory drug and a cyclopentyl ether |
| EP0361772A2 (en) * | 1988-09-21 | 1990-04-04 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
| EP0361772A3 (en) * | 1988-09-21 | 1990-08-29 | Glaxo Group Limited | Cyclopentyl ethers and their preparation and pharmaceutical formulation |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930422 |