GB1582853A - Prostane derivatives - Google Patents
Prostane derivatives Download PDFInfo
- Publication number
- GB1582853A GB1582853A GB25231/77A GB2523177A GB1582853A GB 1582853 A GB1582853 A GB 1582853A GB 25231/77 A GB25231/77 A GB 25231/77A GB 2523177 A GB2523177 A GB 2523177A GB 1582853 A GB1582853 A GB 1582853A
- Authority
- GB
- United Kingdom
- Prior art keywords
- radical
- derivative
- formula
- carboxy
- alkyl
- 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.)
- Expired
Links
- UKVVPDHLUHAJNZ-PMACEKPBSA-N prostane Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC UKVVPDHLUHAJNZ-PMACEKPBSA-N 0.000 title claims description 36
- -1 alkyloxycarbonyl radical Chemical class 0.000 claims description 118
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 35
- 150000003254 radicals Chemical class 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 18
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 4
- POKRQUNDSGAZIA-OALUTQOASA-N 7-[(1r,2s)-2-octylcyclopentyl]hepta-2,4-dienoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCC=CC=CC(O)=O POKRQUNDSGAZIA-OALUTQOASA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001350 alkyl halides Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 4
- 125000005699 methyleneoxy group Chemical group [H]C([H])([*:1])O[*:2] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000008174 sterile solution Substances 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 3
- BFKVXNPJXXJUGQ-UHFFFAOYSA-N [CH2]CCCC Chemical compound [CH2]CCCC BFKVXNPJXXJUGQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 125000004965 chloroalkyl group Chemical group 0.000 claims description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- DNPWNTOGNWAMRB-GXOGWTJNSA-N (1R,2S)-1-[(4E)-hepta-4,6-dienyl]-2-octylcyclopentane Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCC\C=C\C=C DNPWNTOGNWAMRB-GXOGWTJNSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims description 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000013618 particulate matter Substances 0.000 claims description 2
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 claims description 2
- OLRJXMHANKMLTD-UHFFFAOYSA-N silyl Chemical compound [SiH3] OLRJXMHANKMLTD-UHFFFAOYSA-N 0.000 claims description 2
- 235000019980 sodium acid phosphate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000007858 starting material Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 5
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 150000003138 primary alcohols Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- CSCPPACGZOOCGX-WFGJKAKNSA-N deuterated acetone Substances [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 3
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- SNRDFPUMRHPUCQ-UHFFFAOYSA-N CS(=O)C[Na] Chemical compound CS(=O)C[Na] SNRDFPUMRHPUCQ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 241001465754 Metazoa Species 0.000 description 2
- 241000786363 Rhampholeon spectrum Species 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001351 alkyl iodides Chemical class 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- LMKPHJYTFHAGHK-UHFFFAOYSA-N cyclodrine Chemical compound C1CCCC1(O)C(C(=O)OCCN(CC)CC)C1=CC=CC=C1 LMKPHJYTFHAGHK-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000130 luteolytic agent Substances 0.000 description 2
- 230000003529 luteolytic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 description 2
- KRMKFDBVYFUPAC-PMACEKPBSA-N (1r,2s)-1-hept-3-enyl-2-octylcyclopentane Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCC=CCCC KRMKFDBVYFUPAC-PMACEKPBSA-N 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-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
- WZXLHTGRNRKWOY-UHFFFAOYSA-N 2-cyclopentyloxyoxane Chemical compound C1CCCC1OC1OCCCC1 WZXLHTGRNRKWOY-UHFFFAOYSA-N 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
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- VJGGHXVGBSZVMZ-QIZQQNKQSA-N Cloprostenol Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(Cl)=C1 VJGGHXVGBSZVMZ-QIZQQNKQSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000743114 Homo sapiens WASH complex subunit 4 Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 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
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
- 101800000989 Oxytocin Proteins 0.000 description 1
- 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 102100038143 WASH complex subunit 4 Human genes 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- WZEMSIKSCALWJZ-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO.CCO WZEMSIKSCALWJZ-UHFFFAOYSA-N 0.000 description 1
- YXMVRBZGTJFMLH-UHFFFAOYSA-N butylsilane Chemical compound CCCC[SiH3] YXMVRBZGTJFMLH-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004407 chorionic gonadotrophin Drugs 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 229960004409 cloprostenol Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-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
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000012173 estrus Effects 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- WWSWYXNVCBLWNZ-QIZQQNKQSA-N fluprostenol Chemical compound C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)OC1=CC=CC(C(F)(F)F)=C1 WWSWYXNVCBLWNZ-QIZQQNKQSA-N 0.000 description 1
- 229950009951 fluprostenol Drugs 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- SDMCZCALYDCRBH-UHFFFAOYSA-N methoxymethyl(triphenyl)phosphanium Chemical class C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SDMCZCALYDCRBH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000035935 pregnancy Effects 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
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229960004509 serum gonadotrophin Drugs 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical class Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(54) PROSTANE DERIVATIVES
(71) We, IMPERIAL CHEMICAL INDUSTRIES LIMITED, Imperial
Chemical House, Millbank, London SWIP 3JF, a British Company, do hereby
Jeclare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel prostane derivatives, and in particular it relates to novel 4-prostene derivatives possessing high luteolytic activity. The new compounds are therefore useful as contraceptives of for control of the oestrous cycle in animals. The compounds may also be useful for the induction of labour or the early termination of pregnancy, or as hypotensives, for the relief of bronchospasm or the inhibition of gastric acid. production.
According to the invention there is provided a prostane derivative of the formula:
wherein either
represents
and R1 is a carboxy radical, or a C2-r2 alkoxycarbonyl radical, or
represents
and R1 is a hydroxymethyl or C2~,2 alkoxymethyl radical, R2, R3 and R4, which may be the same or different, are each a hydrogen atom or a Alkyl radical, X is an ethylene or trans-vinylene radical, Y is a C,~5alkyleneoxy radical, wherein the oxygen atom is bonded to R5, R5 is a phenyl or naphthyl radical which is unsubstituted or is substituted by one or more substituents selected from halogen atoms, nitro radicals and Ct~salkyl, alkoxy and halogenoalkyl radicals, and n is 1 to 4, and for those compounds wherein R' is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof.
A suitable value for R' when it is a C2~,2alkoxycarbonyl radical is, for
example, a methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl or decyloxy- carbonyl radical, especially such a radical of 2 to 5 carbon atoms, and particularly a
methoxycarbonyl radical; and a suitable value for R' when it is a C2~12alkoxy- methyl radical is, for example, a methoxymethyl, ethoxymethyl, butoxymethyl or
decycloxymethyl radical, especially such a radical of 2 to 5 carbon atoms.
A suitable value for any of R2, R3 and R4 when it is a Alkyl radical is, for
example, a methyl, ethyl, propyl, butyl or pentyl radical, especially a methyl or
ethyl radical and particularly a methyl radical.
n is preferably I or 2.
A suitable value for Y is, for example, a methylenoxy, ethylenoxy,
trimethyleneoxy, ethylideneoxy, isopropylideneoxy [-C(CH3)20-], propyl
ideneoxy, I-methylpropylideneoxy [C(CH3)(C2H5).O] or l-ethylpropyl
ideneoxy [-C(C2H5)2.O-] radical, particularly a methyleneoxy or isopropyl
ideneoxy radical.
A suitable halogen substituent in R5, is, for example, a chlorine, fluorine,
bromine or iodine atom, especially a chlorine atom; a suitable Ct~5-alkyl or alkoxy
substituent in R5 is, for example, a methyl, ethyl, methoxy or ethoxgfadical, and a
suitable C15 halogenoalkyl substituent is, for example, a chloroalkyl or fluoroalkyl
radical, such as a trifluoromethyl radical. Preferred values for R5 contain not more than two substituents, and particular values are pehnyl, chlorophenyl, especially 3
chlorophenyl, and tritluoromethylpheny1, especially 4-trifluoromethylphenyl,
radicals.
A suitable pharmaceutically or veterinarily acceptable salt is, for example, an
ammonium, alkylammonium containing 1 to 4 Alkyl radicals, alkanol
ammonium containing 1 to 3 2-hydroxyethyl radicals, or alkali metal salt. for
example an ammonium, triethylammonium, ethanolammonium, diethanol
ammonium, sodium or potassium salt.
It will be observed that the novel prostane derivatives of the formula I
contain at least three asymmetrically substituted carbon atoms, namely -the two carbon atoms at which the side-chain are attached to the ring (the
relative stereochemistry at these two positions is fixed in formula I) and the
carbon atom of the group -CR5(0R6)- in the lower side-chain. In addition,
carbon atoms 2, 9 and 11 may also be asymmetrically substituted, so that it is clear
that the compounds of the invention may exist in racemic or in optically active
form. It is to be understood that'the useful bioligical properties of a racemic
compound, comprised of I and its mirror image, may be present to differing extents
in the optical isomers, and that this invention relates to racemates and to any
optically active form which shows the same useful properties, it being a matter of
common general knowledge how the optically active forms may be obtained, and
their bioligical properties determined. It is also to be understood that this invention
relates to both C-IS epimers, that is, epimers at the -CR3(0R4)- carbon atom in
the lower side chain.
A preferred group of prostane derivatives of the invention having high
luteolutic activity comprises compounds of the formula I wherein R' is a carboxy,
methoxycarbonyl, ethoxycarbonyl, hydroxymethyl or methoxymethyl radical, R2,
R3 and R4, which may be the same or different, are each a hydrogen atom or a
methyl radical,
represents
X is a trans-vinylene radical, Y is a methyleneoxy or idopropylideneoxy radical, n is 1, and R5 has the meaning stated above, particularly a phenyl radical, a halogenophenyl radical, for example a chlorophenyl radical, or a halogenoalkylphenyl radical, for example a trifluoromethylphenyl radical, and especially a phenyl, 3-chlorophenyl or 4-trifluoromethylphenyl radical. Preferred compounds in this group are methyl 16 - (4 - chlorophenoxy) - l9a,ll,l5a - trihydroxy - 17,18,19,20 - tetranor - 4 - cis,13 - trans - prostadienoate, 16 - (3 - chlorophenoxy) - 9ll,l5a - trihydroxy - 17,18,19,20 - tetranor - 4 - cis,13 - trans prostadienoic acid, and 16 - (3 - chlorophenoxy) - 17,18,19,20 - tetranor - 4 - cis,l3trans - prostadien - I,9ct ,15a - tetraol.
The novel prostane derivatives of the invention may be manufactured by methods known in themselves for the manufacture of chemically analogous compounds. Thus, the following processes are provided as a further feature of the invention, wherein R', R2, R3, R4, R5, n, X and Y have the meanings stated above, unless defined otherwise:- (a) for those compounds wherein
represents
and R3 is a hydrogen atom, the hydrolysis, for example with an acid, such as acetic acid, of a compound of the formula:
wherein R6 is a tetrahydropyran - 2 - yloxy radical and R7 is a tetrahydropyran 2 - yl radical or a Alkyl radical; (b) for those compounds wherein R' is an alkoxycarbonyl radical, the reaction of the corresponding prostane derivative of the formula I wherein R1 is a carboxy radical with a C11 diazoalkane, or of a salt thereof with a C,~" alkyl halide, for example an alkyl iodide or alkyl bromide; (c) for those compounds wherein R' is a hydroxymethyl radical and
represents
the reduction, for example with a complex metal hydride such as lithium aluminium hydride, of the corresponding prostane derivative of the formula I wherein R' is an alkoxycarbonyl radical; (d) for those compounds wherein
represents
and R3 is an alkyl radical, the oxidation, for example with chromium trioxide/pyridine complex, or Jones's reagent (chromic acid in acetone), of a compound of the formula:
wherein R3 is a Alkyl radical, R8 is a C212alkoxycarbonyl radical or a tri (C1~5-alkyl)silyloxycarbonyl radical, and R9 is a Alkyl or tri(C1-5-alkyl)silyl radical, or a tetrahydropyran - 2 - yl radical, whereatter It necessary the protecting silyl or tetrahydropyran - 2 - yl groups are hydrolysed by treating the product so obtained with an acid;
(e) for those compounds wherein R4 is an alkyl radical, the reaction of the cor
responding prostane derivative of the formula I wherein R4 is a hydrogen atom
with an alkyl halide, for example an alkyl iodide, in the presence of one molecular
proportion of a strong base, for example sodium hydride; (f) for those compounds wherein
represents
and R3 is a Alkyl radical, the hydrolysis, with an acid, of a silyl derivative of the formula:-
wherein R10 is a tri(C1-5alkyl)silyloxy radical, R is a C1-5alkyl radical and R" is a tri(C,~5alkyl)silyloxycarbonyl, tri(C,~5alkyl)silyloxymethyl, C212alkoxycarbonyl or C212-alkoxymethyl radical; (g) for those compounds wherein
represents
R' is a carboxy or alkoxycarbonyl radical, and R4 is a hydrogen atom, the hydrolysis with alkali of a compound of the formual:-
wherein R2, R3, R5, X and Y have the meanings given above, R' is a carboxy or a C212alkoxycarbonyl radical, R12 is a hydrogen atom, when R3 is an alkyl radical, or a carboxylic acyl radical such as a acetyl, benzoyl orp-phenylbenzoyl radical, when
R3 is a hydrogen atom, and R'3 is a carboxylic acyl radical such as an acetyl, benzoyl or p-phenylbenzoyl radical; (h) for those compounds wherein R' is a carboxy radical, and
represents
the reaction of a lactol of the formula:
with a triphenylphosphonium salt of the formula Ph3P.(CH2)n+,CHR2.COOH.Z- wherein Z- is an anion, for example bromide, in the presence of a strong base.
(i) for those compounds wherein R' is a carboxy radical, the hvdrolvsis of a corresponding compound of the formula I wherein R1 is an alkoxycarbonyl radical.
A starting material of the formula II may be obtained by reacting the known lactol VII with methyltriphenylphosphonium bromide in the presence of a strong base to give the allyl derivative VIII, which is treated with 2,3 - dihydropyran to give the tris(tetrahydropyran - 2 - yl) derivative IX. IX is reacted with borane in the presence of alkaline hydrogen peroxide to give the primary alcohol X, the primary alcohol X is oxidesed with Collins' reagent to the aldehyde XI is subjected to a Wittig reaction with a triphenylphosphonium bromide derivative, PH3P+.(CH2)n+,CHR2COOH.Br-, in the presence of a strong base to give the required starting material of the formula II, wherein X is a trans-vinylene radical
and R7 is a tetrahydropyran - 2 - yl radical.
Starting materials of the formula II wherein X is an ethylene radical may be prepared by a sequence of reactions similar to that described above, but starting from the corresponding known saturated lactol in place of the unsaturated lactol
VII.
The starting material of the formula III may be obtained by selective silylation
of the corresponding prostane derivative of the invention wherein
represents
with, for example, tri(C,~5alkyl)silyl
amide, such as diethylamino-dimethyl-t.butylsilane.
The starting material of the formula IV may be obtained from the corresponding compound of the formula I wherein
represents
and R3 is a hydrogen atom, by selective oxidation with one equivalent of Jones' reagent to give a ketone XII, which is treated with an excess of a silylating agent, for example a tri(C,~5alkyl)silylamide, to protect the C-9 and C-I 1 hydroxy radicals, and the carboxy radical if present, giving the silyl derivative XIII. The silyl derivative XIII is then treated with a C15 alkylmagnesium halide to give the required starting material IV.
The starting material of the formula V may be obtained by treating the known acetal XIV with an acid chloride, R'3CI, in pyridine to give the protected acetal XV, which is reacted with borane and alkaline hydrogen peroxide to give the alcohol
XVI. The alcohol XVI is oxidised. to the aldehyde XVIIwith Collin's reagent, and the aldehyde XVII is reacted with a phosphonium salt, Ph3P(CH2)2CHR1R2, in the presence of a base to give the olefin XVIII, which is hydrolysed selectively, for example with concentrated hydrochloric acid and 2% v/v of isopropanol in chloroform, to the hydroxy-aldehyde XIX. The hydroxy-aldehyde XIX is treated with a phosphonate reagent, (CH3O)2PO.CH2CO.YR5, to give an enone XX, and the enone XX is reduced with a Meerwein-Ponndorf reagent to the diol XXI, which is epimerized by reaction with diethyl azodicarboxylate, triphenylphosphine and a carboxylic acid, R130H, to a starting material V, (R12 = R13 = carboxylic acyl,
X = trans-vinylene).
Starting materials of the formula V wherein R3 is an alkyl radical may be obtained by reacting the enone XX with dihydropyran to give a tetrahydropyranyl ether or with a silylating agent to give a silyl ether XXII, which is treated with a Grignard reagent R3MgBr to give an enol XXIII, the protecting tetrahydropyranyl or trialkylsilyl group is hydrolysed, and the diol XXIV is epimerized in the reaction described above to give a starting material V (R12 = hydrogen, R'3 = carboxylic 'acyl, X = trans-vinylene).
V V (R12 = R'3 = carboxylic acyl, X = trans-vinylene) THP = tetrahydropyran - 2 - yl
Corresponding starting materials V wherein X is an ethylene radical may be obtained in a completely analogous manner, but carrying out the reduction of the enone XX with sodium borohydride instead of with a Meerwein-Ponndorf reducing agent.
V V (R12 = H, R'3 = carboxylic acyl, X = trans-vinylene) R = tetrahydropyran - 2 - yl or trialkylsilyl.
The starting material of the formula VI may be obtained from known bis(tetrahydropyranyl) derivatives XXV, by reaction thereof with a (methoxymethyl)triphenylphosphonium salt in the presence of a strong base to give an olefin
XXVI, which on treatment at pH 2 with hydrochloric acid/potassium chloride buffer in methanol gives a compound XXVIt. Further treatment of the compound
XXVII at pH I with hydrochloric acid/potassium chloride buffer in tetrahydrofuran removes the protecting methyl group to give the required lactol starting material VI.
It is to be understood, of course, that an optically active prostane derivative of the invention may be obtained either by resolving the corresponding racemate, or by resolving a suitable starting material or other intermediate in the preparative reaction sequence.
As stated above, the prostane derivatives of the invention possess luteolytic properties, and in particular they are more active as luteolytic agents and less active as smooth muscle stimulants than the naturally occurring prostaglandins.
Thus, for example, methyl 16 - (4 - chlorophenoxy) - 9a ,15a - trihydroxy 17,18,19,20 - tetranor - 4 - cis,l3 - trans - prostadienoate is approximately 100 times as active as natural prostaglandin F2a as a luteolytic agent in hamsters (subcutaneous dosing) but possesses only approximately one twentieth of the smooth muscle stimulant activity.
When a prostane derivative of the invention is to be used for the induction of labour, it is used in the same way as it is known to use the naturally occurring prostaglandin E2, that is by administering a sterile substantially aqueous solution containing from 0.01 to 10yg./ml., preferably 0.01 to I Mg./ml. of the compound, by intravenous infusion, or by transcervical extra-amniotic or intra-amniotic infusion until labour commences. Also, for this purpose, the prostane derivatives of the invention may be used in combination or concurrently, with a uterine stimulant, for example oxytocin, in the same way as it is known to use the natural prostaglandin in combination, or concurrently, with oxytoxin for the induction of labour.
Certain of the compounds, including those wherein R' is a phydroxymethyl radical, are particularly effective when dosed orally. When a prostane derivative of the invention is to be used for control of the oestrus cycle in animals, for example cattle or horses, it is used in the same way as it is known to use the prostaglandin derivatives known as cloprostenol and fluprostenol for this purpose. The compounds may be used for this purpose in combination, or concurrently, with a gonadotrophin, for example pregnant mare serum gonadotrophin (PMSG) or human chorionic gonadotrophin (HCG) to hasten the onset of the next cycle.
Thus, according to a further feature of the invention there is provided a pharmaceutical or veterinary composition comprising a prostane derivative of the formula I together with a pharmaceutically or veterinarily acceptable diluent or carrier.
The composition may be in a form suitable for oral administration, for example tablets or capsules, in a form suitable for inhalation, for example an aerosol or a solution suitable for spraying, in a form suitable for infusion, for example sterile, substantially aqueous, or oily, solutions or suspensions, or in the form of a suppository or pessary, suitable for anal or vaginal use.
The compositions of the invention may be prepared by conventional means, and may contain conventional excipients.
The composition is preferably in the form of a tablet, capsule or a substantially aqueous, sterile solution, and a particular preferred composition is a substantially aqueous, sterile solution containing from 25 to 150,ag./ml., preferably from 25 to 75 ,ug./ml.
The invention is illustrated, but not limited by the following Examples.
Throughout the Examples, RF values refer to silica gel plates supplied commercially by Merck (trademark) of Darmstadt, and the spots were visualised either by fluorescence under ultravoilet radiation, by exposure to iodine vapour, or by spraying the plates with a solution of ceric ammonium nitrate in sulphuric acid and heating. Organic solutions were dried with anhydrous magnesium sulphate.
Example 1.
To a solution of 16 - (3 - chlorophenoxy) - 9a,l l,l5a - tris(tetra- hydropyran - 2 - yloxy) - 17,18,19,20 - tetranor - 4 - cis,13 - trans - prostadienoic
acid (78 mg.) on dry methanol (1.2 ml.) was added toluene-p-sulphonic acid (116 ,it.
of a 1% w/v solution in tetrahydrofuran) and the mixture was stirred at room
temperature for 16 hours. Pyridine (3 drops) was added and the solvents were
evaporated. The residue was extracted with diethyl ether (40 ml.) and washed
successively with saturated sodium bicarbonate solution and brine. Evaporation of the solvent gave methyl 16 - (3 - chlorophenoxy) - 9a,l l,l5a - trihydroxy - 17,18,19,20 - tetranor - 4 - cis,l3 - trans - prostadienoate. Purification by thin
layer chromatography on silica gel plates using 3% v/v acetic acid in ethyl acetate
as the developing solvent gave the pure compound, RF=0.2. The n.m.r. spectrum
in deuterated acetone showed the following characteristic bands (8 values): 6.85-7.3, multiplet, 4 aromatic protons 5.16.05, multiplet, 4 aromatic protons 3.9--4.5, multiplet, 5H,
3.62, singlet, 3H, methyl ester.
The mass spectrum of the tris(timethylsilyl) derivative showed (M-CH3)+ = 639.2761 (calculated for C33H52ClO ,Si3 = 639.2756).
The tris(tetrahydropyranyl ether) used as starting material may be obtained as follows:
Finely powdered methylunphenylphosphonium bromide (536 mg.) was dried under vacuum for I hour and then dissolved in dimethyl sulphoxide (1.5 ml.), and the solution was cooled to room temperature. To this solution was added 0.625 ml.
of a 2M solution of methanesulphinylmethyl sodium in dimethyl sulphoxide, followed by a solution of 4,B - [4 - (3 - chlorophenoxy) - 3a - (tetrahydropyran - 2 - yloxy) - I - trans - butenyll - 2,3,3at, 6ap - tetrahydro - 2 - hydroxy - 5p (tetrahydropyran - 2 - yloxy)cyclopenteno[b] - furan (254 mg.) in a mixture of dimethyl sulphoxide (2.5 ml.) and toluene (1 ml.). The solution was stirred for 2 hours, and the solvent was evaporated under reduced pressure. The residue was shaken with water (I ml.) and diethyl ether (5 ml.), and the aqueous phase was separated and re-extracted with diethyl ether (6 x 2 ml.). The combined ether extracts were washed with saturated brine and dried, and the solvent was evaporated. The residue was chromatographed on silica gel (80 g.), and elution with 50% v/v ethyl acetate in toluene gave the allyl derivative, 2a - allyl - 3P - [4 - (3 chlorophenoxy) - 3a - (tetrahydropyran - 2 - yloxy) - I - trans - butenyl] - 4p (tetrahydropyran - 2 - yloxy)cyclopentan - I a - ol R = 0.5 (50% v/v ethyl acetate in toluene).
To a solution of the allyl derivative (212 mg.) in methylene chloride (4.2 ml.) under an atmosphere of nitrogen was added successively redistilled 2,3dihydropyran (192 cl.) and a solution of anhydrous toluene - p - sulphonic acid in tetrahydrofuran (84 y1. of a 1% w/v solution). After 10 minutes, pyridine (1 drop) was added, followed by ethyl acetate (20 ml.). The solution was washed successively with saturated sodium bicarbonate solution and brine, and was dried, and evaporation of the solvents gave the tris(tetrahydropyranyl ether). 2a - allyl 3p - [4 - (3 - chlorophenoxy) - 3a - (tetrahydropyran - 2 - yloxy) - I - trans - butenyl] - 1a,5A - bis(tetrahydropyran - 2 - yloxy) - cyclopentane, RF = 0.6 (25% v/v ethyl acetate in toluene).
To a solution of the tris(tetrahydropyranyl ether), (59 mg.), in dry tetrahydrofuran (2 ml.) under an atmosphere of argon at OOC. was added 80,us. of a I M solution of borane in tetrahydrofuran. After 3 hours, water (0.16 ml.), IN sodium
hydroxide (0.16 ml.) and 30% w/v hydrogen peroxide (0.4 ml.) were added successively, and the mixture was stirred at 0 C. for 30 minutes. The reaction
mixture was diluted with water (10 ml.) and extracted with methylene chloride (4 x 25 ml.). The organic extracts were washed successively with dilute sodium sulphite solution, sodium bicarbonate solution and brine, and were then dried, and the solvents were evaporated to give the primary alcohol, 3 -(2p - [4 - (3 - chlorophenoxy) - 3a - (tetrahydropyran - 2 - yloxy) - I - trans - butenyl] - 3,Sa his- (tetrahydropyran - 2 - yloxy)cyclopent - lce - yllpropanol, RF=0.3 (50% v/v ethyl
acetate in toluene).
A solution of the primary alcohol (119 mg.) in methylene dichloride (2 ml.) was added to a stirred 0.5M solution of Collins' reagent (3.1 ml.). After 15 minutes at room temperature, the mixture was poured onto a column of "Florisil" (trade mark) magnesium silicate (14 g.), and eluted with 20% v/v ethyl acetate in methylene dichloride to give the aldehyde, 3 - 12,B - [4 - (3 - chlorophenoxy) 3a - (tetrahydropyran - 2 - yloxy) - I - trans - butenyl] - 3,5a - bis(tetrahydropyran - 2 - yloxy)cyclopent - Ia - yllpropionaldehyde, RF=0.6 (50% v/v ethyl acetate in toluene).
Finely powdered (3 - carboxypropyl)triphenylphosphonium bromide (320 mg.) was heated to 1000C. under vacuum for 1 hour. The evacuated vessel was filled with an atmosphere of dry nitrogen, the solid was dissolved in dimethyl sulphoxide (3 ml.) and the solution was cooled to room temperature. To this solution was added 0.75 ml. of a 2M solution of methanesulphinylmethyl sodium in dimethyl sulphoxide, followed by a solution of the aldehyde described above (112 mg.) in a mixture of dimethyl sulphoxide (5 ml.) and toluene (2 ml.) The solution was stirred for 3 hours, and the solvent was evaporated under reduced pressure at a temperature below 40"C. The residue was shaken with water (2 ml.)
and extracted with water (5 x 10 ml.) and the extracts were discarded. The aqueous solution was acidified to pH 3--4 with 2N aqueous oxalic acid, and extracted with a mixture of equal parts of ether and petroleum ether (b.p. 40-60 C., 5 x 6 ml.). The extracts were combined, washed with saturated brine and dried, and evaporation of the solvents gave the acid, 16 - (3 - chXorophenoxy) - 9a,ll,l5a - tris(tetrahydropyran - 2 - yloxy) - 17,18,19,20 - tetranor - 4 - cis, 13 - trans - prostadienoic acid, RF = 0.5 (50% v/v ethyl acetate in toluene).
Example 2.
To a solution of methyl 16 - (3 - chlorophenoxy) - 9α,11 ,15α - trihydroxy 17,18,19,20 - tetranor - 4 - cis,13 - trans - prostadienoate (32 mg.) in diethyl ether (I ml.) and tetrahydrofuran (1 ml.) was added lithium aluminium hydride (28 mg.).
The mixture was stirred at room temperature for 10 minutes, the excess of hydride was destroyed by the addition of water (0.5 ml.), and the mixture was extracted with methylene chloride. The extracts were dried, and the solvent was evaporated to give 16 - (3 - chlorophenoxy)- 17,18,19,20 - tetranor - 4- cis,l3 - trans prostadien - 1,9a ,15a - tetranol, RF = 0.3 (5% v/v methanol in ethyl acetate).
The n.m.r. spectrum in deuterated acetone showed the following characteristic bands (8 values): 6.8-7.4, broad multiplet, 4H, aromatic protons 5.3.05, broad multiplet, 4H, olefinic protons 3.24.5, broad multiplet, 7H,
+ 4 exchangeable protons.
The mass spectrum of the tetra(trimethylsilyl) derivative showed M+ = 698.3425
(calculated for C33H5aClO"Si4 = 697.29991).
Example 3.
To a solution of methyl 16 - (3 - chlorophenoxy) - 9a,l lp,15a - trihydroxy
17,18,19,20 - tetranor - 4 - cis,l3 - trans - prostadienoate (12 mg.) on a mixture of methanol (1.37 ml.) and water (0.273) was added.0.273 ml. of a 1M solution of potassium hydroxide in methanol. The mixture was stirred at room temperature for
18 hours, acidified to pH 4.5 with aqueous oxalic acid, and diluted with ethyl.
acetate (40 ml.) The mixture was washed with brine, the organic phase was separated, dried, and tulle solvent was evaporated to give 16 - (3 - chlorophenoxy) - 9a,11ss,15a - trihydroxy - 17,18,19,20 - tetranor - 4 - cis,13 - trans prostadienoic acid, RF = 0.3 (5% v/v acetic acid in ethyl acetate). The n.m.r.
spectrum in deuterated acetone showed the following characteristic bands ( values): 6.85-7.3, broad multiplet, 4H, aromatic protons
5.2-6.0, broad multiplet, 4H, olefinic protons 3.94.5, broad multiplet, 5H, -CH-O- + 4-exchangeable protons.
The mass spectrum of the tris(trimethylsilyl) derivative showed (M-CH3
B.P. The solution was made up to volume with water for injection, and the pH was checked to be between 6.7 and 7.7 The solution was filtered to remove particulate matter, sterilised by filtration, and filled into pre-sterilised neutral glass ampoules under aseptic conditions.
The prostadienoic acid derivative may, of course, be replaced by an equivalent amount of another prostane derivative of the invention
Example 5.
The process described in Example 4 was repeated, omitting the sodium phosphate B.P. and sodium acid phosphate B.P., to give ampoules containing a sterile aqueous solution of 16 -(3 - chlorophenoxy) - 9a,I l,I5a - trihydroxy 17,18,19,20 - pentanor - 4 - cis,l3 - trans - prostadienoic acid, which are used in the manner described in Example 4.
The prostadienoic acid derivative may be replace by an equivalent amount of another prostanoic acid derivative of the invention, the give other sterile solutions.
WHAT WE CLAIM IS-: 1. A prostane derivative of the formula:
wherein either
represents
and R' is a carboxy radical, or a C2~12 alkyloxycarbonyl radical, or
represents
and R1 is a hydroxymethyl or C2~,2 alkoxymethyl radical, R2, R3 and R4, which may be the same or different, are each a hydrogen atom or a Alkyl radical, X is an ethylene or trans-vinylene radical, Y is a C,~salkyleneoxy radical, wherein the oxygen atom is bonded to R5, R5 is a phenyl or naphthyl radical which is unsubstituted or is substituted by one or more substituents selected from halogen atoms, nitro radicals and C,~salkyl, alkoxy and halogenoalkyl radicals, and n is I to 4, and for those compounds wherein R' is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof.
2. A prostane derivative as claimed in claim 1 wherein R' is a carboxy, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, decycloxycarbonyl, methoxymethyl, ethoxymethyl, butoxymethyl or decyloxymethyl radical,
R2, R3 and R4 are each a hydrogen atom or a methyl, ethyl, propyl, butyl or pentyl radical, n is I or 2, X has the meaning stated in claim 1, Y is a methyleneoxy, ethyleneoxy, trimethyleneoxy, ethylideneoxy, isopropylideneoxy, propylideneoxy, l-methylpropylideneoxy or l-ethylpropylideneoxy radical, and R5 is a phenyl or naphthyl radical which is unsubstituted or is substituted by one or more substituents selected from chlorine, bromine, iodine and fluorine atoms, a methyl, ethyl, methoxy, ethoxy, chloroalkyl and fluoroalkyl radicals, and for those compounds wherein R' is a carboxy radical, the ammonium, alkylammonium containing I to 4 Alkyl radicals, alkanolammonium containing I to 3 2hydroxyethyl radicals and alkali metal salts thereof.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (13)
1. A prostane derivative of the formula:
wherein either
represents
and R' is a carboxy radical, or a C2~12 alkyloxycarbonyl radical, or
represents
and R1 is a hydroxymethyl or C2~,2 alkoxymethyl radical, R2, R3 and R4, which may be the same or different, are each a hydrogen atom or a Alkyl radical, X is an ethylene or trans-vinylene radical, Y is a C,~salkyleneoxy radical, wherein the oxygen atom is bonded to R5, R5 is a phenyl or naphthyl radical which is unsubstituted or is substituted by one or more substituents selected from halogen atoms, nitro radicals and C,~salkyl, alkoxy and halogenoalkyl radicals, and n is I to 4, and for those compounds wherein R' is a carboxy radical, the pharmaceutically or veterinarily acceptable salts thereof.
2. A prostane derivative as claimed in claim 1 wherein R' is a carboxy, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, decycloxycarbonyl, methoxymethyl, ethoxymethyl, butoxymethyl or decyloxymethyl radical,
R2, R3 and R4 are each a hydrogen atom or a methyl, ethyl, propyl, butyl or pentyl radical, n is I or 2, X has the meaning stated in claim 1, Y is a methyleneoxy, ethyleneoxy, trimethyleneoxy, ethylideneoxy, isopropylideneoxy, propylideneoxy, l-methylpropylideneoxy or l-ethylpropylideneoxy radical, and R5 is a phenyl or naphthyl radical which is unsubstituted or is substituted by one or more substituents selected from chlorine, bromine, iodine and fluorine atoms, a methyl, ethyl, methoxy, ethoxy, chloroalkyl and fluoroalkyl radicals, and for those compounds wherein R' is a carboxy radical, the ammonium, alkylammonium containing I to 4 Alkyl radicals, alkanolammonium containing I to 3 2hydroxyethyl radicals and alkali metal salts thereof.
3. A prostane derivative as claimed in claim I or 2 wherein R' is a carboxy,
hydroxymethyl or methoxycarbonyl radical, R2, R3 and R4 are each a hydrogen atom or a methyl radical, X has the meaning stated in claim 1, n is I or 2, Y is a methyleneoxy or isopropylideneoxy radical, and R5 is a phenyl or a chlorophenyl or trifluoromethylphenyl radical containing not more than two substituents.
4. A prostane derivative as claimed in claim 3 wherein R5 is a 3-chlorophenyl or 4-trifluoromethylphenyl radical.
5. A prostane derivative as claimed in claim I wherein R' is a carboxy, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl or methoxymethyl radical, R2,
R3 and R4, which may be the same or different, are each a hydrogen atom or a methyl radical,
represents
X is a trans-vinylene radical, Y is a methyleneoxy or idopropylideneoxy radical, n is
1, and R5 is a phenyl, 3-chlorophenyl or 4-trifluoromethylphenyl radical.
6. A prostane derivative as claimed in claim I which is methyl 16 - (4 - chloro
phenyoxy) - 9a ,15a - trihydroxy - 17,18,19,20 - tetranor - 4 - cis,13 - trans prostadienoate, 16 -(3 - chlorophenoxy) -9a,lI,I5a trihydroxy - 17,18',19,20 tetranor - 4 - cis,l3 - trans - prostadienoic acid, or 16 - (3 - chlorophenoxy)
17,18,19,20 - tetranor - 4 - cis,l3 trans - prostadien - l,9a,ll'l5a - tetraol.
7. A prostane derivative as claimed in any one of claimsl to 6 which is in
racemic form.
8. A prostane derivative as claimed in any one of claims I to 6 which is in an
optically active and luteolytically effective form.
9. A process for the manufacture of a prostane derivative as claimed in claim I
which comprises:- (a) for those compounds wherein
represents
and R3 is a hydrogen atom, the hydrolysis of a compound of the formula:
wherein Re is a tetrahydropyran - 2 - yloxy radical and R7 is a tetrahydropyran 2 - yl radical or a C1aIkyl radical; (b) for those compounds wherein R' is an alkoxycarbonyl radical, the reaction of the corresponding prostane derivative of the formula I wherein R1 is a carboxy radical with a C,~" diazoalkane, or of a salt thereof with a C,~" alkyl halide; (c) for those compounds wherein R' is a hydroxymethyl radical and
represents
the reduction of the corresponding prostane derivative of the formula I wherein R is an alkoxycarbonyl radical; (d) for those compounds wherein
represents
and R3 is an alkyl radical, the oxidation of a compound of the formula:
wherein R3 is a C1-5alkyl radical, R8 is a C2-12alkoxycarbonyl radical or a tri (C, 5-alkyl)silyloxycarbonyl radical, and R9 is a Alkyl or tri(C1-5-alkyl)silyl radical, or a tetrahydropyran - 2 - yl radical, whereafter if necessary the protecting silyl or tetrahydropyran - 2 - yl groups are hydrolysed by treating the product so obtained with an acid; (e) for those compounds wherein R4 is an alkyl radical, the reaction of the corresponding prostane derivative of the formula I wherein R4 is a hydrogen atom with an alkyl halide in the presence of one molecular proportion of a strong base; (f) for those compounds wherein
represents
and R3 is a C1-5alkyl radical, the hydrolysis, with an acid, of a silyl derivative of the formula:
wherein R10 is a tri(C1-5-alkyl)silyloxy radical, R3 is a C1-5alkyl radical and R is a tri(C1-5alkyl)silyloxycarbonyl, tri(C1-5alkyl)silyloxymethyl, C212alkoxycarbonyl or C212alkoxymethyl radical; (g) for those compounds wherein
represents'
R' is a carboxy or alkoxycarbonyl radical, and R4 is a hydrogen atom, the hydrolysis with alkali of a compound of the formula
wherein R' is a carboxy or a C212aIkoxycarbonyl radical, R12 is a hydrogen atom, when R3 is an alkyl radical, or a carboxylic acyl radical when R3 is a hydrogen atom, and R13 is a carboxylic acyl radical; (h) for those compounds wherein R' is a carboxy radical, and
represents
the reaction of a lactol of the formula:
with a triphenylphosphonium salt of the formula Ph3P.(CH2)n+,CHR2.COOH.Z-, wherein Z is an anion in the presence of a strong base; or (i) for those compounds wherein R' is a carboxy radical, the hydrolysis of a corresponding compound
of the formula I wherein R1 is an alkoxycarbonyl radical; and wherein R', R2, R3,
R4, R5, n, X and Y, unless otherwise defined, have the meanings stated in claim 1.
10. A pharmaceutical or veterinary composition comprising a prostane
derivative as claimed in claim I together with a pharmaceutically or veterinarily
acceptable diluent or carrier.
II. A prostane derivative as claimed in claim I substantially as hereinbefore
described in any one of Examples I to 3.
12. A process as claimed in claim 9 substantially as hereinbefore described in
any one of Examples 1 to 3.
13. A pharmaceutical or veterinary composition as claimed in Claim 10
substantially as hereinbefore described in Example 4. or 5.
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB25231/77A GB1582853A (en) | 1977-06-16 | 1977-06-16 | Prostane derivatives |
CA304,147A CA1088929A (en) | 1977-06-16 | 1978-05-26 | Prostane derivatives |
ZA00783071A ZA783071B (en) | 1977-06-16 | 1978-05-29 | Prostane derivatives |
NZ187399A NZ187399A (en) | 1977-06-16 | 1978-05-29 | Prostane derivatives pharmaceutical and veterinary compositions |
AU36815/78A AU520150B2 (en) | 1977-06-16 | 1978-06-02 | Prostane derivatives |
FR7818005A FR2394515A1 (en) | 1977-06-16 | 1978-06-15 | NEW PROSTANE DERIVATIVES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM |
DE19782826462 DE2826462A1 (en) | 1977-06-16 | 1978-06-16 | PROSTANDERIVATIVES, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL AND VETERINARY COMPOSITIONS CONTAINING THE SAME |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB25231/77A GB1582853A (en) | 1977-06-16 | 1977-06-16 | Prostane derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1582853A true GB1582853A (en) | 1981-01-14 |
Family
ID=10224331
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB25231/77A Expired GB1582853A (en) | 1977-06-16 | 1977-06-16 | Prostane derivatives |
Country Status (7)
Country | Link |
---|---|
AU (1) | AU520150B2 (en) |
CA (1) | CA1088929A (en) |
DE (1) | DE2826462A1 (en) |
FR (1) | FR2394515A1 (en) |
GB (1) | GB1582853A (en) |
NZ (1) | NZ187399A (en) |
ZA (1) | ZA783071B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7109371B2 (en) | 2004-01-05 | 2006-09-19 | Johnson Matthey Public Limited Company | Prostaglandin synthesis |
JP2007517780A (en) * | 2003-12-19 | 2007-07-05 | ジョンソン、マッセイ、パブリック、リミテッド、カンパニー | Prostaglandin synthesis |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1516414A (en) * | 1975-08-22 | 1978-07-05 | Ici Ltd | Prostane derivatives |
ZA771725B (en) * | 1976-04-21 | 1978-02-22 | Upjohn Co | Ayal prostaglandin analogs |
-
1977
- 1977-06-16 GB GB25231/77A patent/GB1582853A/en not_active Expired
-
1978
- 1978-05-26 CA CA304,147A patent/CA1088929A/en not_active Expired
- 1978-05-29 ZA ZA00783071A patent/ZA783071B/en unknown
- 1978-05-29 NZ NZ187399A patent/NZ187399A/en unknown
- 1978-06-02 AU AU36815/78A patent/AU520150B2/en not_active Expired
- 1978-06-15 FR FR7818005A patent/FR2394515A1/en active Granted
- 1978-06-16 DE DE19782826462 patent/DE2826462A1/en not_active Withdrawn
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007517780A (en) * | 2003-12-19 | 2007-07-05 | ジョンソン、マッセイ、パブリック、リミテッド、カンパニー | Prostaglandin synthesis |
JP2011201883A (en) * | 2003-12-19 | 2011-10-13 | Johnson Matthey Plc | Prostaglandin synthesis |
US7109371B2 (en) | 2004-01-05 | 2006-09-19 | Johnson Matthey Public Limited Company | Prostaglandin synthesis |
US7141706B2 (en) | 2004-01-05 | 2006-11-28 | Johnson Matthey Public Limited Company | Protected and unprotected triols for prostaglandin synthesis |
US7161042B2 (en) | 2004-01-05 | 2007-01-09 | Johnson Matthey Public Limited Company | Protected diols for prostaglandin synthesis |
Also Published As
Publication number | Publication date |
---|---|
AU520150B2 (en) | 1982-01-14 |
FR2394515A1 (en) | 1979-01-12 |
DE2826462A1 (en) | 1979-01-04 |
ZA783071B (en) | 1979-05-30 |
AU3681578A (en) | 1979-12-06 |
FR2394515B1 (en) | 1984-01-06 |
NZ187399A (en) | 1980-04-28 |
CA1088929A (en) | 1980-11-04 |
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