DK143498B - OXAPROSTAGLANDIN COMPOUNDS OF E2 OR F2AL FARACET FOR USE AS FERTILITY CONTROLS - Google Patents
OXAPROSTAGLANDIN COMPOUNDS OF E2 OR F2AL FARACET FOR USE AS FERTILITY CONTROLS Download PDFInfo
- Publication number
- DK143498B DK143498B DK303973AA DK303973A DK143498B DK 143498 B DK143498 B DK 143498B DK 303973A A DK303973A A DK 303973AA DK 303973 A DK303973 A DK 303973A DK 143498 B DK143498 B DK 143498B
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- DK
- Denmark
- Prior art keywords
- oxa
- solution
- trans
- hydroxy
- mmol
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title description 14
- 230000035558 fertility Effects 0.000 title description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- -1 unsaturated C2Q fatty acids Chemical class 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 229960000583 acetic acid Drugs 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- 239000012299 nitrogen atmosphere Substances 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 229960002986 dinoprostone Drugs 0.000 description 20
- 230000000694 effects Effects 0.000 description 18
- 150000003180 prostaglandins Chemical class 0.000 description 18
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 230000009102 absorption Effects 0.000 description 14
- 238000010521 absorption reaction Methods 0.000 description 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 14
- 239000002245 particle Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 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 12
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000003033 spasmogenic effect Effects 0.000 description 8
- 210000004291 uterus Anatomy 0.000 description 8
- 206010000210 abortion Diseases 0.000 description 7
- 231100000176 abortion Toxicity 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 210000003405 ileum Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000001766 physiological effect Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 210000002460 smooth muscle Anatomy 0.000 description 6
- 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 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229940124630 bronchodilator Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 241000700199 Cavia porcellus Species 0.000 description 4
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 239000010779 crude oil Substances 0.000 description 4
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000002211 ultraviolet spectrum Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical group 0.000 description 3
- 239000003929 acidic solution Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008241 heterogeneous mixture Substances 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- GATUGNVDXMYTJX-UHFFFAOYSA-N methyl 4-phenylbenzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C1=CC=CC=C1 GATUGNVDXMYTJX-UHFFFAOYSA-N 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000001476 sodium potassium tartrate Substances 0.000 description 3
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 3
- NKAAEMMYHLFEFN-ZVGUSBNCSA-M sodium;(2r,3r)-2,3,4-trihydroxy-4-oxobutanoate Chemical class [Na+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O NKAAEMMYHLFEFN-ZVGUSBNCSA-M 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- KUGRPPRAQNPSQD-UHFFFAOYSA-N OOOOO Chemical compound OOOOO KUGRPPRAQNPSQD-UHFFFAOYSA-N 0.000 description 2
- DTAFLBZLAZYRDX-UHFFFAOYSA-N OOOOOO Chemical compound OOOOOO DTAFLBZLAZYRDX-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- VHDGWXQBVWAMJA-UHFFFAOYSA-N methyl 4-methoxybutanoate Chemical compound COCCCC(=O)OC VHDGWXQBVWAMJA-UHFFFAOYSA-N 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001519 tissue Anatomy 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
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- MZMOPYFNDDILMI-UHFFFAOYSA-N 1-dimethoxyphosphoryl-5-methoxypentan-2-one Chemical compound COCCCC(=O)CP(=O)(OC)OC MZMOPYFNDDILMI-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical group O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 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
- 241000282465 Canis Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- JLNTWVDSQRNWFU-UHFFFAOYSA-N OOOOOOO Chemical compound OOOOOOO JLNTWVDSQRNWFU-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 125000003180 beta-lactone group Chemical group 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- BHXIWUJLHYHGSJ-UHFFFAOYSA-N ethyl 3-ethoxypropanoate Chemical compound CCOCCC(=O)OCC BHXIWUJLHYHGSJ-UHFFFAOYSA-N 0.000 description 1
- NQYKGEPHDRUFJL-UHFFFAOYSA-N ethyl 4-ethoxybutanoate Chemical compound CCOCCCC(=O)OCC NQYKGEPHDRUFJL-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000035884 vasodepression Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07—ORGANIC CHEMISTRY
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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Description
(19) DANMARK(19) DENMARK
(12) FREMLÆGGELSESSKRIFT dij 1431)-98 B(12) PRESENTATION Dij (1431) -98 B
DIREKTORATET FOR PATENT- OO VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT-OO TRADE MARKET
(21) Ansøgning nr. 5059/75 (51) lnt.CI.3 C 07 C 177/00 (22) Indleveringsdag 1· jun. 1975 A 61 |( 31/557 (24) Løbedag 1· jun. 1975 (41) Aim. tilgængelig 5· dec. 1975 (44) Fremlagt 51 · aug. 1981 (86) International ansøgning nr. -(86) International indleveringedag -(85) Videreførelsesdag -(62) Stamansøgning nr. -(21) Application no. 5059/75 (51) lnt.CI.3 C 07 C 177/00 (22) Filing day 1 · jun. 1975 A 61 | (31/557 (24) Running Day 1 · Jun 1975 (41) Aim Available 5 · Dec 1975 (44) Submitted 51 · Aug 1981 (86) International Application No - (86) International Filing Day - (85) Continuation Day - (62) Stock Application No. -
(30) Prioritet 2. jun. 1972, 259215* US 50. apr. 1975, 555644, US(30) Priority Jun 2 1972, 259215 * US 50 Apr 1975, 555644, US
(71) Ansøger PFIZER INC., New York, US.(71) Applicant PFIZER INC., New York, US.
(72) Opfinder Michael Rose Johnson, US: Hans-Jurgen Ernst Hess, US.(72) Inventor Michael Rose Johnson, US: Hans-Jurgen Ernst Hess, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Boutard.(74) Associate Engineer Hofman-Bang & Boutard.
(54) Oxaprostaglandin-forhindelser af E2- eller F2alfa-rækken til an= vendeise som fertilitetskontrol« midler.(54) Oxaprostaglandin inhibitions of the E2 or F2alfa series for use as fertility control agents.
Opfindelsen angår hidtil ukendte oxaprostaglandin-forhindelser af E2- eller F2a-rækken til anvendelse som fertilitetskontrolmidler. Disse forbindelser er analoge til de naturligt forekommende pros-taglandiner og er ejendommelige ved, at de har den i kravets kendetegnende del angivne formel I.This invention relates to novel oxaprostaglandin compounds of the E2 or F2a series for use as fertility control agents. These compounds are analogous to the naturally occurring process taglandins and are peculiar in that they have the formula I specified in the characterizing part of the claim.
DD
o ^ Prostaglandineme er umættede C2Q-fedtsyrer, som udviser forskel- O lige fysiologiske virkninger. For eksempel er prostaglandineme af £ af E- og A-rækken kraftige vasodilatorer (Bergstrom, et al.,The prostaglandins are unsaturated C₂Q fatty acids which exhibit different physiological effects. For example, the prostaglandins of β of the E and A series are potent vasodilators (Bergstrom, et al.,
Acta Physiol. Scan. 64:552-55, 1965 og Bergstrom, et al., t 3 2 143498Acta Physiol. Scan. 64: 552-55, 1965 and Bergstrom, et al., T 3 2 143498
Life Sci. 6:449-455, 1967) og sænker det systemiske arterieblodtryk (vasodepression) ved intravenøs indgivning (Weeks and King, Federation Froc. 23:327, 1964; Bergstrom, et al., 1965, op. cit.; Carlson, et al., Acta. Med. Scand. 183:423-430, 1968; og Carlson, et al., Acta Physiol. Scand. 75:161-169, 1969).Life Sci. 6: 449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King, Federation Froc. 23: 327, 1964; Bergstrom, et al., 1965, op. Cit; Carlson, et al. , Acta. Med. Scand. 183: 423-430, 1968; and Carlson, et al., Acta Physiol. Scand. 75: 161-169, 1969).
En anden velkendt fysiologisk virkning af PGE-^ og PGE2 er som bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969)·Another well-known physiological effect of PGE- and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4: 723-726, 1969).
Endnu en vigtig fysiologisk rolle spiller de naturlige prosta-glandiner i forbindelse med forplantningscyklussen. PGEg vides at have evne til at fremkalde veer (Karim, et al., J. Obstet Gynaec. Brit. Cwlth. 77:200-210, 1970), at fremkalde terapeutisk abort (Bygdeman, et al., Contraception, 4, 293 (1971)) og at være anvendelig til kontrol af fertilitet (Karim, Contraception, 3, 173 (1971)). Der er opnået patenter på flere prostaglandiner af E- og F-rækken som vefremkaldere hos pattedyr (belgisk patent nr.Another important physiological role of the natural prostaglandins plays in the reproductive cycle. PGEg is known to have the ability to induce labor (Karim, et al., J. Obstet Gynaec. Brit. Cwlth. 77: 200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971)) and to be useful for controlling fertility (Karim, Contraception, 3, 173 (1971)). Patents have been obtained on several prostaglandins of the E and F series as mammalian web developers (Belgian patent no.
754 158 og vesttysk patent nr. 2 034 641) og på FGF^, F£ og F^ til kontrol af forplantningscyklussen (sydafrikansk patent nr. 69/6089).754 158 and West German Patent No. 2 034 641) and on FGF ^, F £ and F ^ for control of the reproductive cycle (South African Patent No. 69/6089).
Andre kendte fysiologiske aktiviteter for PGE^ er ved inhiberin-gen af mavesyresekretion (Shaw og Ramwell, i Worcester Symp. on Prostaglandins, New York, Wiley, 1968, s. 55-64) og også af blod-pladeaggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).Other known physiological activities for PGE1 are through the inhibition of gastric acid secretion (Shaw and Ramwell, in Worcester Symp. On Prostaglandins, New York, Wiley, 1968, pp. 55-64) and also of platelet aggregation (Emmons, et al. , Brit. Med. J. 2: 468-472, 1967).
Det vides nu, at sådanne fysiologiske virkninger in vivo kun vil blive fremkaldt i et kort tidsrum efter indgivningen af en prostaglandin. En væsentlig mængde vidnesbyrd angiver, at grunden til dette hurtige ophør af aktivitet er, at de naturlige prostaglandiner hurtigt og effektivt deaktiveres metabolisk ved β-oxidation af carboxylsyresidekæden og ved oxidation af 15a-hydroxygruppen (Anggard, et al., Acta. Physiol. Scand., 81, 396 (1971) og deri givne henvisninger).It is now known that such physiological effects in vivo will only be induced for a short time after the administration of a prostaglandin. A substantial amount of testimony indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are rapidly and efficiently metabolically deactivated by β-oxidation of the carboxylic acid side chain and by oxidation of the 15α-hydroxy group (Anggard, et al., Acta. Physiol. Scand , 81, 396 (1971) and references cited therein).
Det blev selvfølgelig betragtet som ønskeligt at tilvejebringe analoge til prostaglandinerne, som ville have ækvivalente fysiologiske aktiviteter med de naturlige forbindelser, men hos hvilke virkningens selektivitet og aktivitetens varighed ville være forøget. Forøget virkningsselektivitet kunne forventes at afhjælpe de alvorlige bivirkninger, især gastrointestinale bivirkninger, som hyppigt iagttages efter systemisk indgivning af de 3 143498 naturlige prostaglandiner (se Lancet, 536, 1971).Of course, it was considered desirable to provide analogs to the prostaglandins, which would have equivalent physiological activities with the natural compounds, but at which the selectivity and duration of activity would be increased. Increased efficacy selectivity could be expected to alleviate the serious side effects, especially gastrointestinal side effects, which are frequently observed after systemic administration of the natural prostaglandins (see Lancet, 536, 1971).
De hidtil ukendte forbindelser ifølge opfindelsen er u-trisnor-prostaglandiner, som i 17-stillingen har to hydrogenatomer og én substituent med formlen (CH2)n~0“ ’ hvori n er 0 eller 1, og m er 0, 1 eller 2. Disse forbindelser tilfredsstiller på enestående måde de ovennævnte krav, dvs. de har aktivitetsprofiler, som kan sammenlignes med de naturlige prostaglandiners, selv om de er mere vævsselektive i deres virkning og udviser længere varighed af aktiviteten end de naturlige prostaglandiner.The novel compounds of the invention are u-trisnor-prostaglandins, which at the 17-position have two hydrogen atoms and one substituent of formula (CH 2) n ~ 0 '' where n is 0 or 1 and m is 0, 1 or 2. These compounds uniquely satisfy the above requirements, viz. they have activity profiles comparable to those of natural prostaglandins, although they are more tissue selective in their action and exhibit longer duration of activity than natural prostaglandins.
Særligt foretrukne, hidtil ukendte prostaglandiner ifølge opfindelsen, er: 9-oxo-lla,15a-dihydroxy-19-oxa-cis-5-trans-13-prostadiensyre; 9-oxo-lla,15a-dihydroxy-19-oxa-cis-5-trans-13- uu-homopro stadiensyre; 9-oxo-lla,15a-dihydroxy-18-oxa-cis-5-trans-13-prostadiensyre; 9a,11a,15a-trihydroxy-19-oxa-cis-5-trans-13-prostadiensyre; 9a, 11a, 15a-trihydroxy-19-oxa-cis-5-trans-13-«>-homoprostadiensyre; 9a,lla,15a-trihydroxy-18-oxa-cis-5-trans-13-prostadiensyre.Particularly preferred, novel prostaglandins of the invention are: 9-oxo-11α, 15α-dihydroxy-19-oxa-cis-5-trans-13-prostadioic acid; 9-oxo-11a, 15a-dihydroxy-19-oxa-cis-5-trans-13-uu-homoprostatic acid; 9-oxo-lla, 15a-dihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid; 9a, 11a, 15a-trihydroxy-19-oxa-cis-5-trans-13-prostadienoic acid; 9a, 11a, 15a-trihydroxy-19-oxa-cis-5-trans-13 -> - homoprostadienic acid; 9a, lla, 15a-trihydroxy-18-oxa-cis-5-trans-13-prostadienoic acid.
Fremstillingen af de hidtil ukendte oxaprostaglandin-forbindelser ifølge opfindelsen kan belyses ved det følgende reaktionsskema, 1 2 hvori R betyder hydrogen, 2-tetrahydropyranyl eller -CO-R , hvor R betyder alkyl med 1-5 carbonatomer, phenyl eller p-bi- phenyl, THP betyder 2-tetrahydropyranyl, og n og m har den i kravet angivne betydning.The preparation of the novel oxaprostaglandin compounds of the invention can be elucidated by the following reaction scheme, wherein R is hydrogen, 2-tetrahydropyranyl or -CO-R, where R is alkyl of 1-5 carbon atoms, phenyl or p-biphenyl , THP means 2-tetrahydropyranyl, and n and m have the meaning set forth in the claim.
4 1434984 143498
REAKTIONSSKEMASCHEME
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VI VIIVI VII
5 143498 tt°H “ A) -» J-C (CH2)n-rO- J-VVA/^^V0· {P° (CHg^CHj THP0 \ (CH2)nCH5 OIHP 0®^H-A (A) - »J-C (CH2) n-rO-J-VVA / ^^ V0 · {P ° (CHg ^ CHj THP0 \ (CH2) nCH5 OIHP 0® ^
vin IXwine IX
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Oxapro staglandln F2a eller E^Oxapro staglandln F2a or E ^
Som vist i reaktionsskemaet bringes aldehydet I til at reagere med det hidtil ukendte reagens II til dannelse af ketonen III. Reaktanterne anvendes i væsentligt ækvimolære forhold, og reaktionen udføres fortrinsvis i ca. 30 minutter.As shown in the reaction scheme, the aldehyde I is reacted with the novel reagent II to form the ketone III. The reactants are used in substantially equimolar ratios, and the reaction is preferably carried out for approx. 30 minutes.
Ketonen III behandles med 1,2-dimethoxyethan og zinkborhydrid i ca. 1 time til dannelse af alkoholerne IV og V, som derpå adskilles, f.eks. ved anvendelse af søjlekromatografi med ether som elueringsmiddel.The ketone III is treated with 1,2-dimethoxyethane and zinc borohydride for approx. 1 hour to form the alcohols IV and V which are then separated, e.g. using column chromatography with ether as the eluent.
V —* VI involverer behandling med vandfrit kaliumcarbonat i ca.V - * VI involves treatment with anhydrous potassium carbonate for approx.
1 time efterfulgt af saltsyre og ekstraktion, f.eks. med ethyl-acetat, og endelig koncentrering, VI —* VII kræver behandling med 2,3-dihydropyran og p-toluen-sulfonsyre i ca. 15 minutter i en nitrogenatmosfære og efterfølgende kombination med ether, vaskning med f.eks. natriumhydrogen-carbonatopløsning og derpå med saltvand og endelig koncentrering.1 hour followed by hydrochloric acid and extraction, e.g. with ethyl acetate, and finally concentration, VI - * VII requires treatment with 2,3-dihydropyran and p-toluene sulfonic acid for approx. 15 minutes in a nitrogen atmosphere and subsequent combination with ether, washing with e.g. sodium bicarbonate solution and then with brine and final concentration.
VII —> VIII udføres ved reaktion i ca. 1 time med diisobutyl-aluminiumhydrid i n-hexan afkølet til -78° C i en nitrogenatmosfære. Blandingen blandes derpå med ether, vaskes, tørres og koncentreres.VII -> VIII is carried out by reaction for approx. 1 hour with diisobutyl aluminum hydride in n-hexane cooled to -78 ° C in a nitrogen atmosphere. The mixture is then mixed with ether, washed, dried and concentrated.
VIII —» IX udføres ve4 reaktion med (4-carboxy-b-butyl)-triphenylphosphoniumbromid og methylsulfinylmethid i dimethylsulf-oxid ved stuetemperatur i mindst 2 timer. Blandingen gøres derpå sur med f.eks. vandig saltsyre og ekstraheres derefter med ethyl-acetat og koncentreres ved inddampning.VIII - IX is reacted with (4-carboxy-b-butyl) -triphenylphosphonium bromide and methylsulfinylmethide in dimethylsulfoxide at room temperature for at least 2 hours. The mixture is then acidified with e.g. aqueous hydrochloric acid and then extracted with ethyl acetate and concentrated by evaporation.
6 143498 IX —» oxaprostaglandin F2a involverer hydrolyse med vandig eddikesyre, koncentrering og rensning ved søjlekromatografi.Oxaprostaglandin F2a involves hydrolysis with aqueous acetic acid, concentration and purification by column chromatography.
IX —> oxaprostaglanding E2 kræver behandling med Jones' reagens i ca. 20 minutter ved -10° C til dannelse af et andet mellemprodukt før syrebehandlingen og rensningen som ovenfor.IX -> oxaprostagland E2 requires treatment with Jones' reagent for approx. 20 minutes at -10 ° C to form another intermediate prior to the acid treatment and purification as above.
Det hidtil ukendte reagens II fremstilles ved at bringe et passende phosphonat, såsom dimethyl-methyl-phosphonat, i et reaktionsinert opløsningsmiddel, såsom tetrahydrofuran, og i en nitrogenatmosfære i kontakt med en organolithiumforbindelse, såsom n-butyllithium. Derpå tilsættes en tilsvarende alkoxyester, såsom methyl-4-methoxybutyrat, og produktet renses ved ekstraktion i methylenchlorid og koncentreres.The novel reagent II is prepared by contacting an appropriate phosphonate such as dimethyl methyl phosphonate in a reaction inert solvent such as tetrahydrofuran and in a nitrogen atmosphere with an organolithium compound such as n-butyllithium. Then, a corresponding alkoxy ester such as methyl 4-methoxybutyrate is added and the product is purified by extraction in methylene chloride and concentrated.
Fra den angivne litteratur er de naturlige prostaglandiner kendt for at udøve et spektrum af fysiologiske aktiviteter. Ved talrige in vivo og in vitro prøvninger er det påvist, at de her omhandlede oxaprostaglandin-analoge har de samme fysiologiske aktiviteter som udøves af de naturlige prostaglandiner. Disse prøvninger inkluderer blandt andet en prøvning for virkning på isoleret glat muskel fra marsvin-ileum og rotte-uterus, en prøvning for virkning på histamininduceret broncho spasme hos marsvin, en prøvning for virkninger på hunde-blodtryk, en prøvning for fremkaldelse af diarré hos mus og en prøvning for fremkaldelse af abort hos tidligt gravide rotter.From the literature cited, the natural prostaglandins are known to exert a spectrum of physiological activities. Numerous in vivo and in vitro tests have shown that the oxaprostaglandin analogs in question have the same physiological activities as the natural prostaglandins. These tests include a test for effect on isolated smooth muscle from guinea pig ileum and rat uterus, a test for efficacy on histamine-induced broncho-spasm in guinea pigs, a test for effects on canine blood pressure, a test for inducing diarrhea in mice. and a test for inducing abortion in prematurely pregnant rats.
Resultaterne af disse forskellige fysiologiske prøvninger er anført i tabel I nedenfor. Det vil bemærkes, at disse oxa-prostaglandin-analoge ikke blot har en fertilitetskontrolvirkning, som kvantitativt kan sammenlignes med de naturlige prostaglandiners, men at de også har fordelen af vævsselektivitet, især 19-oxa-prostaglandin E2.The results of these different physiological tests are given in Table I below. It will be noted that these oxa-prostaglandin analogs not only have a fertility control effect that is quantitatively comparable to those of natural prostaglandins, but that they also have the benefit of tissue selectivity, especially 19-oxa-prostaglandin E2.
På basis af den iagttagne forskel ved rotte-uterus- og marsvinil eum-pr øvning erne med 19-oxa-prostaglandin E2 ville man forvente at have en reduktion af de ubehagelige gastrointestinale bivirkninger, som mødtes, når 11 aturlig PGEg anvendtes som abortfremkalder (Lancet, 536, 1971)· Denne vigtige fordel er blevet rigeligt bekræftet af, at 19-oxa-prostaglandin E2 nu har vist sig at være kun 10 % så effektiv som naturlig PGE2 til fremkaldelse af diarré hos mus in vivo, medens den er lige så effektiv som naturlig PGE2 til fremkaldelse af abort hos den tidligt gravide rotte.On the basis of the observed difference in rat uterus and guinea pig eum-per exercise with 19-oxa-prostaglandin E2, one would expect to have a reduction in the unpleasant gastrointestinal side effects encountered when 11 abrupt PGEg was used as an abortion inducer (Lancet , 536, 1971) · This important advantage has been abundantly confirmed by the fact that 19-oxa-prostaglandin E2 has now been found to be only 10% as effective as natural PGE2 in inducing diarrhea in mice, while equally effective as natural PGE2 for inducing abortion in the prematurely pregnant rat.
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De fysiologiske reaktioner iagttaget ved disse prøvninger er nyttige til bestemmelse af anvendeligheden af prøvestoffet til behandling af forskellige naturlige og pathologiske tilstande.The physiological responses observed in these tests are useful in determining the utility of the test substance in treating various natural and pathological conditions.
De følgende yderligere prøvninger, hvorved en række oxaprostag-landin-forbindelser ifølge opfindelsen er sammenlignet med naturlig PGE2 og PGF2a, viser at forbindelserne ifølge opfindelsen har selektive aktiviteter, der gør dem nyttige som midler til fertilitetskontrol. PGE2 og PGF2a markedsføres i dag til human brug som midler til fremkaldelse af aborter i tredie måned. De anvendte prøvninger er følgende: Ål. Spasmogen virkning på isoleret marsvineuterus, angivet som relativ styrke (PGE2/PGF2a = 100): en prøvning for ferti litet skontrol-aktivitet.The following further tests comparing a number of oxaprostaglandin compounds of the invention with natural PGE2 and PGF2a show that the compounds of the invention have selective activities which make them useful as fertility control agents. Today, PGE2 and PGF2a are marketed for human use as a means of developing abortions in the third month. The tests used are as follows: Eel. Spasmogenic effect on isolated guinea pig uterus, expressed as relative potency (PGE2 / PGF2a = 100): a test for fertility control activity.
A2. Spasmogen virkning på isoleret rotteuterus, angivet som relativ styrke (PGE2/FGF2a = 100): en prøvning for fertili-tetskontrol-aktivitet.A2. Spasmogenic effect on isolated rat uterus, expressed as relative potency (PGE2 / FGF2a = 100): a test for fertility control activity.
B. Spasmogen virkning på isoleret marsvineileum, angivet som relativ styrke (PGE2/FGF2a = 100): en prøvning for diarré, en almindelig gastrointenstinal bivirkning af prostaglan-diner.B. Spasmogenic effect on isolated guinea pig ileum, expressed as relative potency (PGE2 / FGF2a = 100): a test for diarrhea, a common gastrointestinal side effect of prostaglandin diner.
C. Tilnærmet % beskyttelse af marsvin mod en toxisk aerosoldosis af histamin ved aerosolindgivning af midlet i æk-vimolær dosis til 100yug/ml PGE2 (PGE2 = 85%) : en prøvning for bronchodilator-aktivitet.C. Approximate% protection of guinea pigs against a toxic dose of histamine by aerosol administration of the agent in equimolar dose to 100 µg / ml PGE 2 (PGE 2 = 85%): a test for bronchodilator activity.
D. Tærskelværdi (i yug/kg i. v.) for depressorvirkning på blodtrykket hos anæstetiserede hunde (PGE2 = 0,1): en prøvning for antihypertensiv aktivitet.D. Threshold (in yug / kg in v.) For depressant effect on the blood pressure of anesthetized dogs (PGE2 = 0.1): a test for antihypertensive activity.
Resultaterne er anført i den følgende table II: 143498 9The results are given in the following Table II: 143498 9
TABEL_IITABEL_II
Forbindelse Eks.nr. Smp. Al A2 B C DConnection Ex. Mp. All A2 B C D
---1-—--1- 18- oxa-PGE2 4 olie ' 11 3,3 3 1,0 19- oxa-PGE2 1 55-56° C 10-20 10 1 19 1,0 19-oxa-FGF2a 2 olie 15 10 2,5 19-oxa-vVhomo-PGE2 3 58° C 33 10 38 0,4 19-oxa-u-homo-FGf,2oc 3 olie 10 3--- 1 -—-- 1- 18-oxa-PGE 2 4 oil 11 3.3 3 1.0 19-oxa-PGE 2 1 55-56 ° C 10-20 10 1 19 1.0 19-oxa FGF2a 2 oil 15 10 2.5 19-oxa-vHomo-PGE2 3 58 ° C 33 10 38 0.4 19-oxa-u-homo-FGf, 2oc 3 oil 10 3
Det ses af tabel II, (1) at 18-oxa-PGE2, fremstillet i eksempel 4, er et mere selektivt middel til fertilitetskontrol end PGE2 på grund af dens 3 gange så store selektivitet af spasmogen bivirkning på uterus-fremfor ileumglatmusklen og dens reducerede bronchodilator- og hypotensive aktivitet; (2) at 19-oxa-PGE2, fremstillet i eksempel 1, er et mere selektivt middel til fertilitetskontrol end PGE2 på grund af dens 10 - 20 gange så store selektivitet af spasmogen virkning på uterus- fremfor ileumglatmuskel og dens reducerede bronchodilator-og hypotensive aktivitet; (3) at 19-oxa-PGF2a, fremstillet i eksempel 2, er et mere selektivt middel til fertilitetskontrol end PGF2a på grund af dens mere end 4 gange så store selektivitet af spasmogen virkning på uterus- fremfor ileumglatmuskel; (4) at 19-oxa-u)-homo-PGE2, fremstillet i eksempel 3» er et mere selektivt middel til fertilitetskontrol end PGE2 på grund af dens 3 gange så store selektivitet af spasmogen virkning på uterus- fremfor ileumglatmuskel og den reducerede bronchodilator- og hypotensive aktivitet; og (5) at 19-oxa-u-homo-PGF2a, fremstillet i eksempel 3, er et mere selektivt middel til fertilitetskontrol end PGF2a på grund af den 3 gange så store selektivitet af spasmogen virkning på uterus- fremfor ileumglatmuskel.It can be seen from Table II, (1) that 18-oxa-PGE2, prepared in Example 4, is a more selective means of fertility control than PGE2 because of its 3x selectivity of spasmogenic side effect on the uterus rather than the ileum smooth muscle and its reduced bronchodilator and hypotensive activity; (2) that 19-oxa-PGE2, prepared in Example 1, is a more selective agent for fertility control than PGE2 because of its 10-20 times greater selectivity of spasmogenic effect on uterus rather than ileum smooth muscle and its reduced bronchodilator and hypotensive activity; (3) that 19-oxa-PGF2a, prepared in Example 2, is a more selective agent for fertility control than PGF2a because of its more than 4 times greater selectivity of spasmogenic effect on uterus rather than ileum smooth muscle; (4) that 19-oxa-u) -homo-PGE2 prepared in Example 3 is a more selective agent for fertility control than PGE2 because of its 3x selectivity of spasmogenic effect on uterus rather than ileum smooth muscle and reduced bronchodilator - and hypotensive activity; and (5) that 19-oxa-u-homo-PGF2a, prepared in Example 3, is a more selective agent for fertility control than PGF2a because of the 3-fold selectivity of spasmogenic effect on uterine rather than ileum smooth muscle.
De hidtil ukendte oxaprostaglandin-forbindelser ifølge opfindelsen har mere selektive aktivitetsprofiler end de tilsvarende naturligt forekommende prostaglandiner og udviser i mange tilfælde en længere virkningsvarighed. Hvis der for eksempel ønskes 143498 10 en intravaginal behandling til abortfremkaldelse, er et egnet medium en tampon imprægneret med 19-oxa-l"-homo-'-pro staglandin-®2α eller lactose-tabletter med det samme middel. Ved sådanne behandlinger ville en egnet dosis være omkring 100 mg, idet der anvendes 1 eller 2 doser.The novel oxaprostaglandin compounds of the invention have more selective activity profiles than the corresponding naturally occurring prostaglandins and in many cases exhibit a longer duration of action. For example, if an intravaginal treatment for abortion induction is desired, a suitable medium is a tampon impregnated with 19-oxa-1 "-homo-"-pro staglandin-2α or lactose tablets with the same agent. a suitable dose should be about 100 mg, using 1 or 2 doses.
I tilfælde, hvor en midtvejsabort er nødvendig, ville et effektivt middel være en fysiologisk saltopløsning af 19-oxa-PGE2 indgivet som en intravenøs infusion. En egnet dosering kunne være fra omkring 5 til omkring 100 pg/min., indgivet i et tidsrum på fra omkring 2 til omkring 10 timer.In cases where a mid-term abortion is needed, an effective agent would be a physiological saline solution of 19-oxa-PGE2 administered as an intravenous infusion. A suitable dosage could be from about 5 to about 100 pg / min, administered for a period of from about 2 to about 10 hours.
De hidtil ukendte oxaprostaglandinforbindelser ifølge opfindelsen kan anvendes i en lang række farmaceutiske præparater, som indeholder forbindelsen eller et farmaceutisk acceptabelt salt deraf, og de kan indgives på samme måde som naturlige prostaglandiner ad en række forskellige veje, såsom intravenøst, oralt og topisk, herunder som aerosol, intravaginalt og intranasalt. Farmaceutisk acceptable salte inkluderer salxe af farmaceutisk acceptable baser, såsom alkali- og jordalkalimetalbaser, ammoniak og aminer.The novel oxaprostaglandin compounds of the invention can be used in a wide variety of pharmaceutical compositions containing the compound or a pharmaceutically acceptable salt thereof, and may be administered in the same way as natural prostaglandins by a variety of routes, such as intravenously, orally and topically, including as aerosol, intravaginally and intranasally. Pharmaceutically acceptable salts include salts of pharmaceutically acceptable bases such as alkali and alkaline earth metal bases, ammonia and amines.
Til fremstilling af enhver af de ovennævnte doseringsformer eller enhver af de talrige andre mulige former kan anvendes forskellige reaktionsinerte fortyndingsmidler, excipienter eller bærere. Sådanne stoffer inkluderer for eksempel vand, ethanol, gelatiner, lactose, stivelser, magnesiumstearat, talcum, vegetabilske olier, benzylalkoholer, gummier, polyalkylenglycoler, vaseline, cholesterol og andre kendte bærere for lægemidler. Om ønsket kan disse farmaceutiske midler indeholde hjælpestoffer, såsom konserveringsmidler, befugtningsmidler, stabiliseringsmidler eller andre terapeutiske midler, såsom antibiotica.To prepare any of the above dosage forms or any of the numerous other possible forms, various reaction-inert diluents, excipients or carriers may be used. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, vaseline, cholesterol and other known carriers for drugs. If desired, these pharmaceutical agents may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.
De følgende eksempler tjener til nærmere at belyse fremstillingen af oxaprostaglandin-forbindelseme ifølge opfindelsen.The following examples serve to illustrate the preparation of the oxaprostaglandin compounds of the invention.
n 143498 EKSEMPEL_1 A. En opløsning af 12,4 g (100 nmol) dimethylmethylphosphonat i 125 ml tørt tetrahydrofuran blev afkølet til -78° C i en tør nitrogenatmosfære. Til den omrørte phosphonatopløsning sattes 45 ml 2,37 M n-butyllithium i hexanopløsning dråbevis i løbet af 30 minutter med en sådan hastighed, at reaktionstemperaturen aldrig steg over -65° C. Efter yderligere 5 minutters omrøring ved -78° C tilsattes dråbevis 6,6 g (50,0 mmol) methyl-4-methoxybutyrat [fremstillet ifølge R. Huisgen og J. Reinertshafter, Am., 575, 197 (1952)] med en hastighed, som holdt reaktionstemperaturen på under -70° C (10 minutter). Efter 3 timer ved -78° C fik reaktionsblandingen lov at opvarmes til omgivelsernes temperatur og blev neutraliseret med 6 ml eddikesyre og rotationsinddampet til en hvid gel. Det gelatinøse materiale blev optaget i 25 ml vand, den vandige fase ekstraheret tre gange med hver gang 100 ml methyl-enchlorid, og de kombinerede organiske ekstrakter blev tørret over magnesiumsulfat og koncentreret (vandstrålepumpe) til en rå remanens og destilleret, kp. 141 - 145° C/l,7 - 0,6 mmHg, hvorved der blev opnået 7,6 g (68 %) dimethyl-2-oxo-6-oxaheptylphos-phonat.EXAMPLE_1 A. A solution of 12.4 g (100 nmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 45 ml of 2.37 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 6 was added. 6 g (50.0 mmol) of methyl 4-methoxybutyrate [prepared according to R. Huisgen and J. Reinertshafter, Am., 575, 197 (1952)] at a rate which kept the reaction temperature below -70 ° C (10 minutes). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature and neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase extracted three times with 100 ml of methylene chloride each time, and the combined organic extracts dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled, b.p. 141 - 145 ° C / 1.7 - 0.6 mmHg to give 7.6 g (68%) of dimethyl 2-oxo-6-oxaheptylphosphonate.
Gasfasechromatografi (der anvendtes en 127 x 6 mm kolonne indeholdende 10 % SE 30 på "Chromosorb1® P", partikelstørrelse 0,149-0,177 mm, ved 105° C) angav en renhed på > 99,9 %. NMR-spek-tret (CDCl^) viste: 0Gas phase chromatography (using a 127 x 6 mm column containing 10% SE 30 on "Chromosorb1® P", particle size 0.149-0.177 mm, at 105 ° C) indicated a purity of> 99.9%. The NMR spectrum (CDCl3) showed: 0
En dublet centreret ved 3,78 <5 (J = 11,5 Hz, 6H) for (CH^0)2-P-; en triplet centreret ved 3,37 6 (2H) for CHj-0-CH2-CH2-; en singlet ved 3,28 i (3H) for CH,-0-CHo-, -> d 0 0 en dublet centreret ved 3,14 4 (J = 23 Hz, 2H) for -C-CH5-P-; 0 * en triplet centreret ved 2,71 4 (2H) for -CH2-CH2-C- og en en multiplet 1,57 - 2,10 δ (2H) for -CH2-CH2-CH2.A doublet centered at 3.78 <5 (J = 11.5 Hz, 6H) for (CH2 O) 2 -P-; a triplet centered at 3.37 δ (2H) for CH₂-O-CH₂-CH₂-; a singlet at 3.28 in (3H) for CH, -O-CHO-, -> d 0 0, a doublet centered at 3.14 4 (J = 23 Hz, 2H) for -C-CH5-P-; 0 * a triplet centered at 2.71 4 (2H) for -CH2-CH2-C- and a multiple 1.57 - 2.10 δ (2H) for -CH2-CH2-CH2.
B. Det under A fremstillede dimethyl-2-oxo-6-oxaheptylphosphonat (1,68 g, 7,5 mmol) i 125 ml vandfri ether blev behandlet med 2,5 ml (5,9 mmol) 2,37 M n-butyllithium i n-hexan i en tør nitrogenatmosfære ved stuetemperatur. Efter 5 minutters omrøring tilsat- 22 143498 tes yderligere 225 ml vandfri ether efterfulgt af 1,75 g (5,0 mmol) 2-[3a-p-phenylbenzoyloxy-5oc-hydroxy-^-formylcyclopentan-Ια-yl]eddikesyr e-Z^-lacton i én portion. Efter 30 minutter blev reaktionsblandingen omsat med 2,5 ni iseddike, fortyndet med 200 ml vandfri ether, vasket to gange med 200 ml 10 % saltsyre, en gang med 200 ml mættet vandig natriumhydrogencarbonatopløsning, en gang med 100 ml vand, tørret over vandfrit magnesiumsulfat og inddampet, hvorved der blev opnået 1,972 g (88 %) 2-[3a-p-phenyl-benzoyloxy-5a-hydroxy-2p-(3-oxo-7-oxa-trans-l-octen-l-yl)cyclo-pent-la-yljeddikesyre-^lacton som en olie.B. The dimethyl 2-oxo-6-oxaheptyl phosphonate (1.68 g, 7.5 mmol) prepared in A in 125 mL of anhydrous ether was treated with 2.5 mL (5.9 mmol) of 2.37 M n butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature. After 5 minutes of stirring, an additional 225 ml of anhydrous ether was added followed by 1.75 g (5.0 mmol) of 2- [3a-p-phenylbenzoyloxy-5oc-hydroxy-β-formylcyclopentan-Ια-yl] acetic acid eZ -lactone in one serving. After 30 minutes, the reaction mixture was reacted with 2.5 µl glacial acetic acid, diluted with 200 ml of anhydrous ether, washed twice with 200 ml of 10% hydrochloric acid, once with 200 ml of saturated aqueous sodium bicarbonate solution, once with 100 ml of water, dried over anhydrous magnesium sulfate. and evaporated to give 1.972 g (88%) of 2- [3α-β-phenyl-benzoyloxy-5α-hydroxy-2β- (3-oxo-7-oxa-trans-1-octen-1-yl) cyclo -pent-la-ylacetic acid- ^ lactone as an oil.
Produktets infrarøde spektrum (CHCl^) udviste absorptionsbånd ved 1770 cm”^· (stærk), 1717 cm-1 (stærk), 1675 cm~^ (middel) og 1630 cm-^ (middel), som kan tilskrives carbonylgrupperne. Det ultra-violette spektrum havde en = 274 nm og en = 21 380 (ethanolopløsning). NMR-spektret (CDCl^) udviste en multiplet ved 7,23 - 8,18 S (9H) for p-biphenylgruppen, en dublet af dubletter centreret ved 6,71 6 (IH, J = 7,16 Hz) og en dublet centreret ved 6,27 6 (IH, J = 16 Hz) for de alkeniske protoner, en triplet ved 3,30 i> (2H) for -C^-C^-O-CH^, en singlet ved 3,21 & (3H) for -C^-O-CH^, og multipletter ved 4,90 - 5,50 £ (2H), 2,21 - 3,07 S (8H) og 1,58 - 2,06 6 (2H) for resten af protonerne.The infrared spectrum (CHCl 3) of the product exhibited absorption bands at 1770 cm -1 (strong), 1717 cm -1 (strong), 1675 cm -1 (medium) and 1630 cm -1 (medium) attributable to the carbonyl groups. The ultraviolet spectrum had a = 274 nm and a = 21,380 (ethanol solution). The NMR spectrum (CDCl3) showed a multiplet at 7.23 - 8.18 S (9H) for the p-biphenyl group, a duplicate of duplicates centered at 6.71 δ (1H, J = 7.16 Hz) and a duplicate centered at 6.27 δ (1H, J = 16 Hz) for the alkenic protons, a triplet at 3.30 i> (2H) for -C ^-C ^-O-CH₂, a singlet at 3.21 (3H) for -C ^-O-CH₂, and multiples at 4.90 - 5.50 ((2H), 2.21 - 3.07 S (8H) and 1.58 - 2.06 δ (2H) ) for the rest of the protons.
C. Til en opløsning af 1972 mg (4,4 mmol) 23α-p-phenylbenzoyloxy-5«~hydroxy-2|i - ( 3-oxo-7-oxa-trans-l-octen-l-yl) cyclopent-iq -yl}-eddikesyre-^-lacton, fremstillet under B, i 15 ml tørt 1,2-dimethoxyethan i en tør nitrogenatmosfære ved omgivelsernes temperatur sattes dråbevis 4,0 ml af en 0,5 M zinkborhydridopløsning. Efter omrøring ved stuetemperatur i 1 time blev reaktionsblandingen afkølet til 0° C, og der tilsattes dråbevis en mættet na-triumhydrogentartratopløsning, indtil hydrogenudviklingen ophørte. Reaktionsblandingen omrørtes i 5 minutter, ved hvilket tidspunkt der tilsattes 250 ml tørt methylenchlorid. Efter tørring over magnesiumsulfat og koncentrering (vandstrålepumpe) blev det resulterende halvfaste stof renset ved søjlekromatografi på silica-gel (Baker '’Analyzed" Reagent, partikelstørrelse 0,074 - 0,250 13 , U$498 mm) under anvendelse af ether som eluerlngsmiddel♦ Efter eluering af de mindre polære urenheder elueredes fraktioner indeholdende 450 mg 2-[3a-p-phenylbenzoyloxy-5oc-hydroxy-2p-(3oc-hydroxy-7-oxa-trans-l-octen-l-yl)cyclopent-la-yl]eddikesyre-,T^lacton, 294 mg 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2p-(3p-hydroxy-7-oxa-trans- 1- octen-l-yl)cyclopent-la-yl]eddikesyre-^-lacton og 486 mg af de to blandet.C. To a solution of 1972 mg (4.4 mmol) of 23α-p-phenylbenzoyloxy-5β-hydroxy-2β - (3-oxo-7-oxa-trans-1-octen-1-yl) cyclopentane L-acetone, prepared under B, in 15 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 4.0 ml of a 0.5 M zinc borohydride solution. After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 ° C and a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, at which time 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker '' Analyzed Reagent, particle size 0.074 - 0.250 13, U $ 498 mm) using ether as eluent. minor polar impurities eluted fractions containing 450 mg of 2- [3a-p-phenylbenzoyloxy-5oc-hydroxy-2β- (3oc-hydroxy-7-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetic acid Lactone, 294 mg of 2- [3α-β-phenylbenzoyloxy-5α-hydroxy-2β- (3β-hydroxy-7-oxa-trans-1-octen-1-yl) cyclopent-1α-yl] acetic acid -lactone and 486 mg of the two mixed.
Det infrarøde spektrum (CHCl·*) af den første af disse to forbin- > —1 delser havde stærke carbonylabsorptioner ved 1770 og 1715 cm .The infrared spectrum (CHCl3) of the first of these two compounds had strong carbonyl absorptions at 1770 and 1715 cm.
D. En heterogen blanding af 450 mg (1,0 mmol) 2-£3#.-p-phenylbenzoyl-oxy-5eo-hydroxy-2P- (3x,-hydroxy-7-oxa-trans-l-octen-l-yl) cyclopent- 1 -yl]eddikesyre-Clacton, fremstillet under C, 4,5 ml absolut methanol og 140 mg fint pulveriseret vandfrit kaliumcarbo-nat blev omrørt ved stuetemperatur i 1 time og derpå afkølet til 0° C. Til den afkølede opløsning sattes 2,0 ml (2,0 mmol) 1,QN vandig saltsyre. Efter omrøring ved 0° i yderligere 10 minutter tilsattes 5 ml vand under samtidig dannelse af methyl-p-phenyl-benzoat, som blev opsamlet ved filtrering. Filtratet blev mættet med fast natriumchlorid, ekstraheret med ethylacetat (4 x 10 ml), de kombinerede organiske ekstrakter vasket med mættet natrium-hydrogencarbonat (10 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 204 mg (76 9é) viskøs, olieagtig 2- [3α,5α-dihydroxy-2β-(3α-hydroxy-7-oxa-trans~l-octen-l-yl)-cy clopent-la-yl ] eddike syr e-Z^-lac t on.D. A heterogeneous mixture of 450 mg (1.0 mmol) of 2β-β-p-phenylbenzoyl-oxy-5eo-hydroxy-2β- (3x, -hydroxy-7-oxa-trans-1-octene-1 -yl) cyclopent-1-yl] acetic acid Clactone, prepared under C, 4.5 ml of absolute methanol and 140 mg of finely powdered anhydrous potassium carbonate was stirred at room temperature for 1 hour and then cooled to 0 ° C. solution was added 2.0 ml (2.0 mmol) of 1, QN aqueous hydrochloric acid. After stirring at 0 ° for an additional 10 minutes, 5 ml of water was added while forming methyl p-phenyl benzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts washed with saturated sodium hydrogen carbonate (10 ml), dried over magnesium sulfate and concentrated to give 204 mg (76 g) viscous, oily 2- [3α, 5α-dihydroxy-2β- (3α-hydroxy-7-oxa-trans-1-octen-1-yl) -cyclopent-la-yl] acetic acid eZ ^ -lac t on.
Det infrarøde spektrum (CHC1,) udviste en stærk absorption ved — 1 > Ί 1770 cm for lactoncarbonylet og middel absorption ved 960 cm for trans-dobbeltbindingen.The infrared spectrum (CHCl 3) exhibited strong absorption at - 1> Ί 1770 cm for the lactone carbonyl and mean absorption at 960 cm for the trans double bond.
E. Til en opløsning af 192 mg (0,71 mmol) 2-£3«u5&-dihydroxy-2(S-(3oe.-hydroxy-7-oxa-trans-l-octen-yl)cyclopent-Lt-yl3eddikesyre-)f^lacton, fremstillet under D, i 5 ml vandfrit methylenchlorid og 1 ml 2,3-dihydropyran ved 0° C i en tør nitrogenatmosfære sattes 5 mg p-toluensulfonsyre-monohydrat. Efter omrøring i 15 minutter blev reaktionsblandingen kombineret med 100 ml ether, etheropløsningen vasket med mættet natriumhydrogencarbonat (1 x 15 ml), derpå med mættet saltvand (l x 15 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 310 mg (100 %) 2-[5cc-hydroxy-3oc(tetrahydropyran-2-yloxy)-2p-(3a-[tetra-hydropyran-2-yloxy]-7-oxa-trans-l-octen-l-yl)cyclopent-l<x-yl]-eddikesyre-J^lacton.E. To a solution of 192 mg (0.71 mmol) of 2- [3- [dihydroxy-2 (S- (3e.-hydroxy-7-oxa-trans-1-octen-yl) cyclopent-Lt-yl] acetic acid -) Phylactone, prepared under D, in 5 ml of anhydrous methylene chloride and 1 ml of 2,3-dihydropyran at 0 ° C in a dry nitrogen atmosphere was added 5 mg of p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml), then with saturated brine (1 x 15 ml), dried over magnesium sulfate and concentrated to give 310 mg (100%). ) 2- [5cc-hydroxy-3oc (tetrahydropyran-2-yloxy) -2β- (3a- [tetrahydropyran-2-yloxy] -7-oxa-trans-1-octen-1-yl) cyclopent-1 x-yl] -acetic acid lactone J ^.
14 143498 NMR-spektret (CDCl^) udviste en multiplet ved 5,30 - 5,62 S (2H) for de alkeniske protoner, en singlet ved 3,34 S (3H) for methyletherprotonerne, og multipletter ved 4,36 - 5,18 i (4H), 3,22 - 4,24 ί (9H) og 1,18 - 2,92 £ (20H) for de resterende protoner.The NMR spectrum (CDCl 3) showed a multiplet at 5.30 - 5.62 S (2H) for the alkenic protons, a singlet at 3.34 S (3H) for the methyl ether protons, and multiples at 4.36-5 , 18 in (4H), 3.22 - 4.24 ί (9H) and 1.18 - 2.92 £ (20H) for the remaining protons.
F. En opløsning af 310 mg (0,71 mmol) 2-£5*--hydroxy-3cL-(tetra-hydropyran-2-yloxy)-2β-(3a- [tetrahydropyran-2-yloxy ]-7-oxa-trans- 1- octen-l-yl) cyclopent-l«.-yl}eddikesyre-^lacton, fremstillet under E, i 5 ml tørt toluen blev afkølet til -78° C i en tør nitrogenatmosfære. Til denne afkølede opløsning sattes 1,5 ml 20 % diisobutylaluminiumhydrid i n-hexan dråbevis med en sådan hastighed, at den indre temperatur aldrig steg over -65° C (15 minutter). Efter yderligere 45 minutters omrøring ved -78° C tilsattes vandigt methanol, indtil gasudviklingen ophørte, og reaktionsblandingen fik lov at opvarme til stuetemperatur. Reaktionsblandingen blev kombineret med 100 ml ether, vasket med 50 % natriumkaliumtartratopløsning (4 x 20 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 290 mg (93 %) 2- [ 5oc-hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3α- [ t etrahydr o-pyran-2-yloxy]-7-oxa-trans-l-octen-l-yl)cyclopent-l-yl Jacetal-dehyd- ^hemiacetal.F. A solution of 310 mg (0.71 mmol) of 2- [5 * - hydroxy-3cL- (tetrahydropyran-2-yloxy) -2β- (3a- [tetrahydropyran-2-yloxy] -7-oxa) -trans-1-octen-1-yl) cyclopent-1β-yl} acetic acid β-lactone, prepared under E, in 5 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 1.5 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After a further 45 minutes of stirring at -78 ° C, aqueous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml), dried over magnesium sulfate and concentrated to give 290 mg (93%) of 2- [5oc-hydroxy-3α (tetrahydropyran-2 yloxy) -2β- (3α- [t-ethrahydr o-pyran-2-yloxy] -7-oxa-trans-1-octen-1-yl) cyclopent-1-yl Jacetal dehydrohemiacetal.
G. Til en opløsning af 870 mg (2,0 mmol) (4-oarboxy-n-butyl)-triphenylphosphoniumbromid i en tør nitrogenatmosfære i 5,0 ml tørt dimethylsulfoxid sattes 2,0 ml (4,4 mmol) af en 2,2 M opløsning af natriummethylsulfonylmethid i dimethylsulfoxid. Til denne røde ylidopløsning sattes dråbevis en opløsning af 290 mg (0,66 mmol) 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2β-(3α-[tetrahydropyran-2-yloxy]-7-oxa-trans-l-octen-l-yl)cyclopent-l^-yljacetaldehyd-if-hemiacetal, fremstillet tinder F, i 3,0 ml tørt dimethylsulfoxid i løbet af 20 minutter. Efter yderligere 2 timers omrøring ved stuetemperatur hældtes reaktionsblandingen ud i vand. Den basiske vandige opløsning blev vasket to gange med ethylacetat (20 ml) og gjort sur til pH ca. 3 med 10 % vandig saltsyre. Den sure opløsning blev ekstraheret med ethylacetat (3 x 20 ml), og de kombinerede organiske ekstrakter vasket 1 gang med vand (10 ml), tørret over magnesiumsulfat og inddampet til en fast remanens, der vejede 784 mg. Denne faste remanens blev udrevet med ethylacetat og filtreret. Filtratet blev renset ved søjlechromatografi på silica-gel (Baker "Analyzed” 143498 15G. To a solution of 870 mg (2.0 mmol) (4-oarboxy-n-butyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 5.0 ml of dry dimethyl sulfoxide was added 2.0 ml (4.4 mmol) of a 2 , 2 M solution of sodium methylsulfonylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 290 mg (0.66 mmol) of 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy] -7-oxa) -trans-1-octen-1-yl) cyclopent-1β-ylacetaldehyde-if-hemiacetal, prepared from tinder F, in 3.0 ml of dry dimethyl sulfoxide over 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture was poured into water. The basic aqueous solution was washed twice with ethyl acetate (20 ml) and acidified to pH ca. 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml) and the combined organic extracts washed once with water (10 ml), dried over magnesium sulfate and evaporated to give a solid residue weighing 784 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed").
Reagent, partikelstørrelse 0,074 - 0,250 mm) under anvendelse af ethylacetat som elueringsmiddel. Efter fjernelse af urenheder med høj Rf blev der opsamlet 225 mg (66 %) 9a-hydroxy-llcc,15oc-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadien-syre.Reagent, particle size 0.074 - 0.250 mm) using ethyl acetate as eluant. After removal of high Rf impurities, 225 mg (66%) of 9α-hydroxy-11cc, 15oc-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadienic acid were collected.
NMR-spektret (CDCl^) udviste en multiplet (variabel) ved 5,85 - 6,38 b (2H) for -OH-protonerne, en multiplet ved 5,27 - 5,68 b (4H) for de alkeniske protoner, en multiplet ved 4,52-4,84 i (2H) for acetal-protonerne, en singlet ved 3,34 & (3H) for methylether-protonerne, og multipletter ved 3,25 - 4,35 b (9H) og 1,20 - 2,72 i (28H) for de resterende protoner.The NMR spectrum (CDCl3) showed a multiplet (variable) at 5.85 - 6.38 b (2H) for the -OH protons, a multiplet at 5.27 - 5.68 b (4H) for the alkenic protons, a multiplet at 4.52-4.84 in (2H) for the acetal protons, a singlet at 3.34 & (3H) for the methyl ether protons, and multiples at 3.25 - 4.35 b (9H) and 1 , 20 - 2.72 in (28H) for the remaining protons.
H. Til en opløsning af 190 mg (0,356 mmol) 9a-hydroxy-ll«.,15!,i--bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadiensyre, fremstillet under G, i 5 ml reagensrent acetone afkølet til -10° C under en nitrogenatmosfære sattes dråbevis 0,143 ml (0,356 mmol) Jones' reagens. Efter 20 minutter ved -10° C tilsattes 0,140 ml 2-propanol, og reaktionsblandingen omrørtes i yderligere 5 minutter, ved hvilket tidspunkt den blev kombineret med 40 ml ethylacetat, vasket med vand (3x5 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 174 mg 9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadiensyre.H. To a solution of 190 mg (0.356 mmol) of 9α-hydroxy-11 ', 15,11-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared under G, in 5 ml of reagent pure acetone cooled to -10 ° C under a nitrogen atmosphere was added dropwise 0.143 ml (0.356 mmol) of Jones' reagent. After 20 minutes at -10 ° C, 0.140 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, at which time it was combined with 40 ml of ethyl acetate, washed with water (3x5 ml), dried over magnesium sulfate and concentrated, 174 mg of 9-oxo-11a, 15a-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid were obtained.
I. En opløsning af 174 mg (0,334· mmol) 9-oxo-llii--15^--bis-tetrahydro-pyran-2-yloxy)-19-oxa-cis-5-trans-13~prostadiensyre, fremstillet under H, i 3,0 ml af en blanding af eddikesyre og vand i forholdet 65:35 blev omrørt under nitrogen ved 40° C i 5 timer og derpå koncentreret ved rotationsfordampning. Den resulterende rå o!/A\ bleV renset ved søjlechromatografi på silica-gel ("Mallinck-rodt^CC-4", partikelstørrelse 0,074 - 0,149 mm) under anvendelse af ethylacetat som elueringsmiddel. Efter eluering af mindre polære urenheder opsamledes det halvfaste stof 9-οχο-11α,15α-dihydroxy-19-oxa-cis-5-trans-13-prostadiensyre, som vejede 33 mg. Dette produkt er 19-oxa-prastaglandln E2, smp. 58 - 59° C (ethylacetat/ cyclohexan).I. A solution of 174 mg (0.334 mmol) of 9-oxo-III-15β-bis-tetrahydro-pyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared under H, in 3.0 ml of a 65:35 acetic acid-water mixture was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel ("Mallinck Root ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as eluant. After elution of minor polar impurities, the semisolid 9-οχο-11α, 15α-dihydroxy-19-oxa-cis-5-trans-13-prostadienic acid, which weighed 33 mg, was collected. This product is 19-oxa-prastaglandin E2, m.p. 58-59 ° C (ethyl acetate / cyclohexane).
16 14349816 143498
Analyse: beregnet: C 64,39 - Η 8,53-fundet: C 64,30 - H 8,28.Analysis: Calculated: C 64.39 - Η 8.53 Found: C 64.30 - H 8.28.
[a]p5 = -71,2 (C = 1,0, methanol).[α] δ = -71.2 (C = 1.0, methanol).
Produktets Infrarøde spektrum (CHCl^) udviste en stærk absorption ved 1715 cm-"1' for carbonylgrupperne og middel absorption ved 965 cm-1 for trans-dobbeltbindingen. Det ultraviolette spektrum i methanol med tilsat kaliumhydroxid udviste en λ = 278 nm og en e = nidx max 28 000.The infrared spectrum of the product (CHCl3) showed a strong absorption at 1715 cm -1 for the carbonyl groups and mean absorption at 965 cm -1 for the trans double bond. The ultraviolet spectrum in methanol with added potassium hydroxide exhibited an λ = 278 nm and an e. = nidx max 28 000.
EKSEMPEL_2EKSEMPEL_2
En opløsning af 52 mg (0,10 mmol) 9a-hydroxy-1115^-bis-(tetra-hydropyran-2-yloxy)-19-oxa-cis-5-trans-13-prostadiensyre, fremstillet i eksempel 1-G, i 3,0 ml af en blanding af iseddike og vand i forholdet 65:35 blev omrørt under nitrogen ved 40° C i 5 timer og derpå koncentreret ved rotationsfordampning. Den resulterende rå olie blev renset på silica-gel ("Mallinckrodt ^ CC-4", partikelstørrelse 0,074 - 0,149 mm) under anvendelse af ethyl-acetat og derpå methanol som opløsningsmidler. Efter eluering af mindre polære urenheder opsamledes den olieagtige 9oc,lla,15a-trihydroxy-cis-5-trans-13-prostadiensyre, der vejede 15 mg. Dette produkt er 19-oxaprostaglandin F2a‘ EKSEMPEL_3 A. En opløsning af 12,4 g (100 mmol) dimethylmethylphosphonat i 125 ml tørt tetrahydrofuran blev afkølet til -78° C i en tør nitrogenatmosfære. Til den omrørte phosphonatopløsning sattes 40 ml 2,67 M n-butyllithium i hexanopløsning dråbevis i løbet af 30 minutter med en sådan hastighed, at reaktionstemperaturen aldrig steg over -65° C. Efter yderligere 5 minutters omrøring ved -78° C tilsattes dråbevis 8,0 g (50,0 mmol) ethyl-4-ethoxybutyrat (fremstillet ifølge R. Huisgen og J. Reinertshafter, Ann., 575, 197 (1952)) med en hastighed, som holdt reaktionstemperaturen under -70° C (10 minutter). Efter 3 timer ved -78° C fik reaktionsblandingen lov at opvarmes til omgivelsernes temperatur, blev neutraliseret med 6 ml eddikesyre og rotationsinddampet til en hvid gel. Det gelatinøse materiale blev optaget i 25 ml vand, den vandige fase ekstraheret med 100 ml portioner af methylen-chlorid (tre gange), og de kombinerede organiske ekstrakter tør- 17 143498 ret over magnesiumsulfat og koncentreret (vandstrålepumpe) til en rå remanens og destilleret, kp. 130 - 132° C/0,1 mmHg, hvorved der blev opnået 7,4 g (62#) dimethyl-2-oxo-6-oxaoctylphosphonat.A solution of 52 mg (0.10 mmol) of 9α-hydroxy-1115β-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-prostadioic acid, prepared in Example 1-G , in 3.0 ml of a mixture of glacial acetic acid and water at a ratio of 65:35 was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified on silica gel ("Mallinckrodt ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate and then methanol as solvents. After eluting minor polar impurities, the oily 9oc, 11a, 15α-trihydroxy-cis-5-trans-13-prostadienic acid, weighing 15 mg, was collected. This product is 19-oxaprostaglandin F 2a EXAMPLE 3 A. A solution of 12.4 g (100 mmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 40 ml of 2.67 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 8 was added. 0 g (50.0 mmol) of ethyl 4-ethoxybutyrate (prepared according to R. Huisgen and J. Reinertshafter, Ann., 575, 197 (1952)) at a rate that kept the reaction temperature below -70 ° C (10 minutes) ). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase extracted with 100 ml portions of methylene chloride (three times), and the combined organic extracts dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled. , b.p. 130-132 ° C / 0.1 mmHg to give 7.4 g (62 #) of dimethyl 2-oxo-6-oxaoctyl phosphonate.
NMR-spektret (CDC1,) viste D 0 en dublet centreret ved 3,78 b (J = 11,5 Hz, 6H) for (CH^Ojg-P-, en triplet centreret ved 3,28 <h (2H) for CH^-O-CHg-, en kvartet ved 3,43 h (2H) for CH9-0-CH5-, —- 0 0 en dublet centreret ved 3,14 ^ (J = 23 Hz, 2H) -C-CH2-P-, en triplet centreret ved 2,71 & (2H) for -CHg-CHg-C-, en multiplet 1,57 - 2,20 & (2H) for -CH2-CH2-CH2 og en triplet centreret ved 1,15 b (3H) for CH-j-CHg-O-CH,,.The NMR spectrum (CDCl1) showed D0 a doublet centered at 3.78b (J = 11.5 Hz, 6H) for (CH₂O₂-β-, a triplet centered at 3.28 <h (2H) for CH 2 -O-CH 2 -, a quartet at 3.43 h (2H) for CH 9 -O-CH 5 -, -O 0 a doubled centered at 3.14 ^ (J = 23 Hz, 2H) -C-CH 2 -P-, a triplet centered at 2.71 & (2H) for -CHg-CHg-C-, a multiplet 1.57 - 2.20 & (2H) for -CH2-CH2-CH2 and a triplet centered at 1 , B (3H) for CH-j-CHg-O-CH ,,.
B. 2,5 g (10,7 mmol) dimethyl-2-oxo-6-oxaoctylphosphonat, fremstillet under A, i 175 ml vandfri ether blev behandlet med 5,0 ml (8,0 mmol) 1,6 M n-butyllithium i n-hexan i en tør nitrogen-atmosfære ved stuetemperatur. Efter 5 minutters omrøring tilsattes yderligere 350 ml vandfri ether efterfulgt af 2,5 g (7,2 mmol) 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2p-formylcyclopentan-la-yl]-eddikesyre-/^-lacton i en portion. Efter 30 minutter blev reaktionsblandingen omsat med 5,0 ml iseddike, fortyndet med 200 ml vandfri ether, vasket med 200 ml 10 % saltsyre (to gange), 200 ml mættet natriumhydrogencarbonatopløsning (én gang), 100 ml vand (én gang), tørret over magnesiumsulfat og inddampet, hvorved der blev opnået 3,591 g (109 %) rå 2-[3cc-p-phenylbenzoyloxy-5oc-hydroxy-2β-(3-oxo-7-oxa-trans-l-nonen-l-yl)cyclopent-la-yl]eddike syre-r-lac ton som en olie.B. 2.5 g (10.7 mmol) of dimethyl 2-oxo-6-oxaoctyl phosphonate prepared under A in 175 ml of anhydrous ether was treated with 5.0 ml (8.0 mmol) of 1.6 M n butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature. After 5 minutes of stirring, an additional 350 ml of anhydrous ether was added followed by 2.5 g (7.2 mmol) of 2- [3α-p-phenylbenzoyloxy-5α-hydroxy-2β-formylcyclopentan-1-yl] -acetic acid - β-lactone in one serving. After 30 minutes, the reaction mixture was reacted with 5.0 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed with 200 ml of 10% hydrochloric acid (twice), 200 ml of saturated sodium bicarbonate solution (once), 100 ml of water (once), dried. over magnesium sulfate and evaporated to give 3.591 g (109%) of crude 2- [3cc-p-phenylbenzoyloxy-5oc-hydroxy-2β- (3-oxo-7-oxa-trans-1-nonen-1-yl) cyclopent-la-yl] acetic acid-r-lac ton as an oil.
Produktets infrarøde spektrum (CHCl^) udviste absorptionsbånd ved I76O cm“^ (stærk), 1707 cm-^ (stærk), 1665 cm”·*· (middel) og 1620 cm-1 (middel), som kan tilskrives carbonylgrupperne. NMR-spektret (CDCl^) stemte overens med strukturen.The infrared spectrum (CHCl3) of the product exhibited absorption bands at 1776 cm -1 (strong), 1707 cm -1 (strong), 1665 cm -1 (medium) and 1620 cm -1 (medium) attributable to the carbonyl groups. The NMR spectrum (CDCl3) was consistent with the structure.
C. Til en opløsning af 3491 mg (7,6 mmol) rå 2-[3<c-p-phenylbenzo-yl-oxy-5&.-hydroxy-2j?> - ( 3 - o xo-7- oxa-trans - 1-nonen- 1-yl) cyclopent-!UL-yl]eddikesyre-i)^-lacton, fremstillet tinder B, i 30 ml tørt 18 143498 1,2-dimethoxyethan i en tør nitrogenatmosfære ved omgivelsernes temperatur sattes dråbevis 2,5 ml 0,5 M zinkborhydridopløsning.C. To a solution of 3491 mg (7.6 mmol) of crude 2- [3 <cp-phenylbenzoyl-oxy-5β-hydroxy-2β] - (3-oxo-7-oxa-trans-1 -nonone-1-yl) cyclopentyl-1-yl] -acetic acid-1-lactone, produced from tinder B, in 30 ml of dry 18 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 2.5 ml 0.5 M zinc borohydride solution.
Efter omrøring ved stuetemperatur i 1 time blev reaktionsblandingen afkølet til 0° C, og der tilsattes dråbevis en mættet natrium-hydrogentartratopløsning, indtil hydrogenudviklingen ophørte. Reaktionsblandingen blev omrørt i 5 'minutter, til hvilket tidspunkt der tilsattes 250 ml tørt methylenchlorid. Efter tørring over magnesiumsulfat og koncentrering (vandstrålepumpe) blev det resulterende halvfaste stof renset ved søjlechromatografi på silica-gel (Baker "Analyzed" Reagent, partikelstørrelse 0,074 -0,250 mm) under anvendelse af ether som elueringsmiddel. Efter eluering af mindre polære urenheder blev der elueret fraktioner indeholdende 705 mg 2-[5a-p-phenylbenzoyloxy-5cc-hydroxy-2p-(3a-hydroxy-7-oxa-trans-l-nonen-l-yl)cyclopent-la-yl]eddikesyre-/ilac-ton, en fraktion indeholdende 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2β-(3 P-hydroxy-7-oxa-trans-l-nonen-l-yl)cyclopent-la-yl]eddike-syre-^lacton og en fraktion af de to blandet.After stirring at room temperature for 1 hour, the reaction mixture was cooled to 0 ° C and a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 'minutes at which time 250 ml of dry methylene chloride was added. After drying over magnesium sulfate and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074-0.250 mm) using ether as eluant. After eluting minor polar impurities, fractions containing 705 mg of 2- [5a-p-phenylbenzoyloxy-5cc-hydroxy-2β- (3a-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopent-1a -yl] acetic acid / ilacone, a fraction containing 2- [3α-β-phenylbenzoyloxy-5α-hydroxy-2β- (3β-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopentyl la-yl] acetic acid-^ lactone and a fraction of the two mixed.
Det infrarøde spektrum (CHC1,) af den første forbindelse ovenfor 2 —1 havde stærke carbonylabsorptioner ved 1770 og 1705 cm . NMR-spektret (CDCl^) stemte overens med strukturen.The infrared spectrum (CHCl3) of the first compound above 2-1 had strong carbonyl absorptions at 1770 and 1705 cm. The NMR spectrum (CDCl3) was consistent with the structure.
D. En heterogen blanding af 703 mg (1,5 mmol) 2-£3^-p-phenylbenz-oyloxy- 5-<*--hydroxy-2fi - (3d-hydroxy-7-oxa-trans-l-nonen-l-yl) -cyclopent-l't-yl]]eddikesyre-Jjr-lacton, fremstillet under C, 7,0 ml absolut methanol og 207 mg fint pulveriseret vandfrit kaliumcarbonat blev omrørt ved stuetemperatur i 1 time og derpå afkølet til 0° C. Til den afkølede opløsning sattes 3,5 ml (3,0 mmol) 1,0 N vandig saltsyre. Efter omrøring ved 0° C i yderligere 10 minutter tilsattes 7 ml vand under samtidig dannelse af methyl-p-phenylbenzoat, som blev opsamlet ved filtrering. Filtratet blev mættet med fast natriumchlorid, ekstraheret med ethyl-acetat (4 x 10 ml), de kombinerede organiske ekstrakter blev vasket med mættet natriumhydrogencarbonat (10 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 350 mg (85,5 %) viskøs olieagtig 2-[3a,5oc-dihydroxy-2P-(3a-hydroxy-7-oxa-trans-l-nonen-l-yl) cyclopent-la-yl ] eddikesyre-/i-lacton.D. A heterogeneous mixture of 703 mg (1.5 mmol) of 2β-β-β-phenylbenz-oyloxy-5- (*) hydroxy-2β - (3d-hydroxy-7-oxa-trans-1-nonene) -l-yl) -cyclopent-1'-yl] -acetic acid Jjr-lactone, prepared under C, 7.0 ml of absolute methanol and 207 mg of finely powdered anhydrous potassium carbonate were stirred at room temperature for 1 hour and then cooled to 0 To the cooled solution was added 3.5 ml (3.0 mmol) of 1.0 N aqueous hydrochloric acid. After stirring at 0 ° C for a further 10 minutes, 7 ml of water was added while forming methyl p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml), the combined organic extracts washed with saturated sodium bicarbonate (10 ml), dried over magnesium sulfate and concentrated to give 350 mg (85.5%). ) viscous oily 2- [3α, 5oc-dihydroxy-2β- (3α-hydroxy-7-oxa-trans-1-nonen-1-yl) cyclopent-1α-yl] acetic acid / β-lactone.
Det infrarøde spektrum (CHCl^) udviste en stærk absorption ved 1170 cm-·*· for lactoncarbonylet og en middel absorption ved 965 cm-1 for trans-dobbeltbinding.The infrared spectrum (CHCl 3) exhibited strong absorption at 1170 cm -1 for the lactone carbonyl and a mean absorption at 965 cm -1 for trans double bond.
19 143498 E. Til en opløsning af 350 mg (1,28 mmol) 2-[3<t, 5<t-dihydroxy-2j2>-(3oL-hydroxy-7-oxa-trans-l-nonert»l-yl)oyelopent-la-yl]eddikesyre-'r-lacton, fremstillet vinder D, i 3,5 ml vandfrit methylenchlorid og 350 jil 2,3-dihydropyran ved 0° C i en tør nitrogenatmosfære sattes 3»5 mg p-toluensulfonsyre-monohydrat. Efter omrøring i 15 minutter blev reaktionsblandingen kombineret med 100 ml ether, etheropløsningen vasket med mættet natriumhydrogencarbonatopløsning (1 x 15 ml) og derpå med mættet saltvand (1 x 15 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 590 mg (>100 %) 2-[5α-Ι^η^-3α-(ΐβΐΓ3ΐητ(ΪΓορ3ΓΓηη-2^1οΧ5Γ)-2β- (3α-[tetrahydropyran-2-yloxy]7-oxa-trans-1-nonen-l-yl)cyclopent-Ια-yl]eddike syre-X^lacton.E. To a solution of 350 mg (1.28 mmol) of 2- [3 <t, 5 <t- dihydroxy-2,2 -> - (3oL-hydroxy-7-oxa-trans-1-non-1-yl) ) oyelopent-1-yl] acetic acid β-lactone, prepared winner D, in 3.5 ml of anhydrous methylene chloride and 350 µl of 2,3-dihydropyran at 0 ° C in a dry nitrogen atmosphere was added 3 5 mg of p-toluenesulfonic acid. monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml of ether, the ether solution washed with saturated sodium bicarbonate solution (1 x 15 ml) and then with saturated brine (1 x 15 ml), dried over magnesium sulfate and concentrated to give 590 mg (> 100%) 2- [5α-ΙΙη] -3α- (ΐβΐΓ3ΐητ (ΪΓορ3ΓΓηη-2 ^1οΧ5Γ) -2β- (3α- [tetrahydropyran-2-yloxy] 7-oxa-trans-1-nonen-1-yl) ) cyclopent-Ια-yl] acetic acid-X ^ lactone.
NMR-spektret (CDCl^) udviste en multiplet ved 5,30 - 5,65 i (2H) for de alkeniske protoner, en kvartet ved 3,50 S (2H) for ethyletherprotonerne, multipletter ved 4,35 - 5,18 h (4H), 3,22 - 4,24 S (8H) og 1,18 - 2,92 i (21H) og en triplet ved 1,20 S (3H).The NMR spectrum (CDCl3) showed a multiplet at 5.30 - 5.65 in (2H) for the alkenic protons, a quartet at 3.50 S (2H) for the ethyl ether protons, multiples at 4.35 - 5.18 h (4H), 3.22 - 4.24 S (8H) and 1.18 - 2.92 in (21H) and a triplet at 1.20 S (3H).
F. En opløsning af 575 mg (1,28 mmol) rå 2- [5a-hydroxy-3a-(tetrahydro-pyran-2-yloxy) - 2β-)( 3α- [tetishydropyran-2-yloxy]-7-oxa-trans-l-nonen-l-yl)cyclopent-yl]]eddikesyre-^-lacton, fremstillet under E, i 5,75 ml tørt toluen blev afkølet til -78° C i en tør nitrogenatmosfære. Til denne afkølede opløsning sattes 1,8 ml 20 % diisobutylaluminiumhydrid i n-hexan dråbevis med en sådan hastighed, at den indre temperatur aldrig steg over -65° C (15 minutter). Efter yderligere 1 times omrøring ved -78° C tilsattes vandigt methanol, indtil gasudviklingen ophørte, og reaktionsblandingen fik lov at opvarmes til stuetemperatur. Reaktionsblandingen blev kombineret med 50 ml ether, vasket med 50 % natriumkaliumtartratopløsning (4 x 10 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 458 mg (80 %) 2- [ 5a-hydroxy-3a- (tetrahydropyran-2-yloxy)-2β- (3α- [tetrahydro-pyran-2-yloxy]-7-oxa-trans-l-nonen-l-yl)cyclopent-l-yl]ac etal-dehyd-J^-hemiacetal.F. A solution of 575 mg (1.28 mmol) of crude 2- [5α-hydroxy-3α (tetrahydro-pyran-2-yloxy) -2β -) (3α- [tetishydropyran-2-yloxy] -7-oxa) -trans-1-nonen-1-yl) cyclopentyl-yl] -acetic acid - ^ - lactone, prepared under E, in 5.75 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 1.8 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never rose above -65 ° C (15 minutes). After an additional 1 hour stirring at -78 ° C, aqueous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 50 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 10 ml), dried over magnesium sulfate and concentrated to give 458 mg (80%) of 2- [5α-hydroxy-3α (tetrahydropyran-2 yloxy) -2β- (3α- [tetrahydro-pyran-2-yloxy] -7-oxa-trans-1-nonen-1-yl) cyclopent-1-yl] ac-ethyl-dehyde-J-hemiacetal.
20 143498 G. Til en opløsning af 1330 mg (3,0 mmol) (4-carboxy-n-butyl)-triphenylphosphoniumbromid i 6 ml tørt dimethylsulfoxid i en tør nitrogenatmosfære sattes 3,4 ml (6,8 mmol) af en 2,0 M opløsning af natriummethylsulfinylmethid i dimethylsulfoxid. Til denne røde ylid-opløsning sattes dråbevis en opløsning af 454 mg (1,0 mmol) rå 2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2β-(3α-[te-trahydropyran-2-yloxy]-7-oxa-trans-l-nonen-l-yl)cyclopent-la-yl]-acetaldehyd-tf'-hemiacetal, fremstillet tinder F, i 3,0 ml tørt dimethylsulfoxid i løbet af 20 minutter. Efter 2 timers omrøring ved stuetemperatur hældtes reaktionsblandingen ud i isvand. Den basiske vandige opløsning blev vasket to gange med ethylacetat (30 ml) og gjort sur til pH ca. 3 med 10 % vandig saltsyre.To a solution of 1330 mg (3.0 mmol) (4-carboxy-n-butyl)-triphenylphosphonium bromide in 6 ml of dry dimethyl sulfoxide in a dry nitrogen atmosphere was added 3.4 ml (6.8 mmol) of a 2 , 0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 454 mg (1.0 mmol) of crude 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy) ] -7-oxa-trans-1-nonen-1-yl) cyclopent-1a-yl] -acetaldehyde-tf'-hemiacetal, prepared from tinder F, in 3.0 ml of dry dimethyl sulfoxide over 20 minutes. After stirring for 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (30 ml) and acidified to pH ca. 3 with 10% aqueous hydrochloric acid.
Den sure opløsning blev ekstraheret med ethylacetat (4 x 25 ml), og de kombinerede organiske ekstrakter vasket en gang med vand (25 ml), tørret over magnesiumsulfat og inddampet til en fast remanens, der vejede 900 mg. Denne faste remanens blev udrevet med ethylacetat og filtreret. Filtratet blev renset ved søjle-chromatografi på silica-gel (Baker ’'Analyzed” Reagent, partikelstørrelse 0,074 - 0,250 mm) under anvendelse af ethylacetat som elueringsmiddel. Efter fjernelse af urenheder med høj Rf-værdi blev der opsamlet 290 mg (54 %) 9a-hydroxy-lla,15<x-bis-(tetra-hydropyran-2-yloxy)-19-oxa-cis-5-trans-13-m-homo-prostadiensyre.The acidic solution was extracted with ethyl acetate (4 x 25 ml) and the combined organic extracts washed once with water (25 ml), dried over magnesium sulfate and evaporated to a solid residue weighing 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker's Analyzed Reagent, particle size 0.074 - 0.250 mm) using ethyl acetate as eluant. After removal of high Rf impurities, 290 mg (54%) of 9α-hydroxy-11α, 15β-x-bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans 13-m-homo-prostadienoic acid.
NMR-spektret (CDCl^) udviste en multiplet (variabel) ved 6,2 - 6,6 b (2H) for -OH-protonerne, en multiplet ved 5,3 - 5,7 4 (4H) for de alkeniske protoner, en multiplet ved 4,6 - 4,9 & (2H) for acetalprotonerne, en kvartet ved 3,5 4 (2H) for ethyletherprotonerne, og multipletter ved 3,3 - 4,4 & (9H) og 1,0 - 2,6 b (31H) for de resterende protoner.The NMR spectrum (CDCl3) showed a multiple (variable) at 6.2 - 6.6 b (2H) for the -OH protons, a multiple at 5.3 - 5.7 4 (4H) for the alkenic protons, a multiplet at 4.6 - 4.9 & (2H) for the acetal protons, a quartet at 3.5 4 (2H) for the ethyl ether protons, and multiples at 3.3 - 4.4 & (9H) and 1.0 - 2 , 6 b (31H) for the remaining protons.
H. Til en opløsning af 290 mg (0,540 mmol) 9/£-hydroxy-ll*,15*--'bis-(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-w-homo-prosta-diensyre, fremstillet under G, i 5,4 ml reagensrent acetone afkølet til -10° C under nitrogen sattes dråbevis 0,226 ml (0,600 mmol) 2,67 M Jones' reagens. Efter 5 minutter ved -10° C tilsattes 0,230 ml 2-propanol, og reaktionsblandingen omrørtes i yderligere 5 minutter, til hvilket tidspunkt den blev kombineret med 21 143498 30 ml ethylacetat, vasket med vand (3 x 5 ml), tørret over magnesiumsulfat, koncentreret og chromatograferet på silica-gel (Baker, partikelstørrelse 0,074 - 0,250 mm, CH2C12 elueringsmiddel), hvorved der blev opnået 180 mg 9-oxo-lla,15a-bis-(tetrahydropyran- 2-yloxy)—19—oxa—cis—5—trans—13“fl*homo—prostadiensyre.H. To a solution of 290 mg (0.540 mmol) of 9β-hydroxy-11 *, 15 * - 'bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-w- homo-prostacetic acid, prepared under G, in 5.4 ml of reagent pure acetone cooled to -10 ° C under nitrogen was added dropwise 0.226 ml (0.600 mmol) 2.67 M Jones reagent. After 5 minutes at -10 ° C, 0.230 ml of 2-propanol was added and the reaction mixture was stirred for a further 5 minutes, at which time it was combined with 30 ml of ethyl acetate, washed with water (3 x 5 ml), dried over magnesium sulfate, concentrated and chromatographed on silica gel (Baker, particle size 0.074 - 0.250 mm, CH 2 Cl 2 eluant) to give 180 mg of 9-oxo-11a, 15a-bis- (tetrahydropyran-2-yloxy) -19-oxa-cis- 5-trans-13 "fl * homo-prostadienoic acid.
I. En opløsning af 129 mg (0,240 mmol) 9-οχο-ΙΙκ,15*-bis-(tetra-hydropyran-2-yloxy)-19-oxa-cis-5-trans-13-uJ-homo-prostadiensyre, fremstillet under H, i 3,0 ml af en blanding af iseddike og vand i forholdet 65:35 blev omrørt under nitrogen ved 40° C i 2,5 timer og derpå koncentreret ved rotationsfordampning. Den resulterende rå oli^blev renset ved søjlechromatografi på silica-gel ("Mallinckrodt©CC-4", partikelstørrelse 0,074 - 0,149 mm) under anvendelse af ethylacetat som elueringsmiddel. Efter eluering af mindre polære urenheder blev der opsamlet 9-oxo-lla, 15oc-dihydroxy-19-oxa-cis-5-trans-13-u>-homo-prostadiensyre, der vejede 40 mg (smp. 56 - 57° C). Dette produkt er 19-oxa-æ-homoprostaglan-din E2.I. A solution of 129 mg (0.240 mmol) of 9-οχο-κκ, 15 * -bis- (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-uJ-homo-prostadioic acid, prepared under H, in 3.0 ml of a mixture of glacial acetic acid and water at 65:35 ratio was stirred under nitrogen at 40 ° C for 2.5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified by column chromatography on silica gel ("Mallinckrodt © CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as eluant. After eluting minor polar impurities, 9-oxo-11a, 15oc-dihydroxy-19-oxa-cis-5-trans-13-u> -homo-prostadioic acid, weighing 40 mg (mp 56-57 ° C), was collected. ). This product is 19-oxa-æ-homoprostaglan-din E2.
Det ultraviolette spektrum i methanol med tilsat kaliumhydroxidopløsning udviste en \max = 278 nm og en emax = 25 700.The ultraviolet spectrum in methanol with potassium hydroxide solution added showed a max = 278 nm and an emax = 25 700.
Hvis der ønskes 19-oxa-w>-homoprostaglandin-F2^, følges den i eksempel 2 angivne procedure under anvendelse af produktet fremstillet under G ovenfor som udgangsmateriale.If 19-oxa-w? -Homoprostaglandin-F2 ^ is desired, the procedure set forth in Example 2 is followed using the product prepared under G above as the starting material.
EKSEMPEL_4 A. En opløsning af 12,4 g (100 mmol) dimethylmethylphosphonat i 125 ml tørt tetrahydrofuran blev afkølet til -78° C i en tør nitrogenatmosfære. Til den omrørte phosphonatopløsning sattes 40 ml 2,67 M n-butyllithium i hexanopløsning dråbevis i løbet af 30 minutter med en sådan hastighed, at reaktionstemperaturen aldrig steg over -65° C. Efter yderligere 5 minutters omrøring ved -78° C tilsattes dråbevis 7,6 g (50,0 mmol) ethyl-3-ethoxypropionat med en hastighed, der holdt reaktionstemperaturen under -70° C (10 minutter). Efter 3 timer ved -78° C fik reaktionsblandingen lov at opvarmes til omgivelsernes temperatur, blev neutraliseret med 6 ml eddikesyre og rotationsinddampet til en hvid gel. Det gelatinøse materiale blev optaget i 25 ml vand, den vandige fase 22 143698 ekstraheredes med 100 ml portioner ether (3 gange), de kombinerede organiske ekstrakter tørredes over magnesiumsulfat og koncentreredes (vandstrålepumpe) til en rå remanens og detilleredes, kp. 107 - 114° C/0,1 mmHg, hvorved der blev opnået 5,6 g (50 %) dimethyl-2-oxo-5-oxaheptylpho sphonat.EXAMPLE 4 A. A solution of 12.4 g (100 mmol) of dimethyl methyl phosphonate in 125 ml of dry tetrahydrofuran was cooled to -78 ° C in a dry nitrogen atmosphere. To the stirred phosphonate solution, 40 ml of 2.67 M n-butyllithium in hexane solution was added dropwise over 30 minutes at such a rate that the reaction temperature never rose above -65 ° C. After a further 5 minutes of stirring at -78 ° C, dropwise 7 was added. 6 g (50.0 mmol) of ethyl 3-ethoxypropionate at a rate that kept the reaction temperature below -70 ° C (10 minutes). After 3 hours at -78 ° C, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml of acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 25 ml of water, the aqueous phase 22 was extracted with 100 ml portions of ether (3 times), the combined organic extracts were dried over magnesium sulfate and concentrated (water jet pump) to a crude residue and distilled, b.p. 107 - 114 ° C / 0.1 mmHg to give 5.6 g (50%) of dimethyl 2-oxo-5-oxaheptylpho sphonate.
NMR-spektret (CDC1-) viste * 0 en dublet centreret ved 3»79 £ (J = 11 »5 Hz, 6h) for (CH^O^-P-, en triplet centreret ved 3 »28 6 (2H) for CH^-O-C^-C^- > en kvartet ved 3»43 6 (2H) for CH^-O-CH«-, —- ^ 0 0 en dublet centreret ved 3»14 i (J = 23 Hz, 2H) -C-CHg-P-, Π en triplet centreret ved 2,87 i (2H) for -CHg-C^-C- og en triplet ventreret ved 1,19 £ (3H) for CH^-CH^-O-CHg· B. 3,8 g (17,1 mmol) dimethyl-2-oxo-5-oxaheptylphosphonat, fremstillet under A, i 200 ml vandfri ether blev behandlet med 4,8 ml (12 mmol) 2,5 M n-butyllithium i n-hexan i en tør nitrogenatmosfære ved stuetemperatur. Efter 5 minutters omrøring tilsattes yderligere 400 ml vandfri ether efterfulgt af 4 g (11,4 mmol) 2-[3cc-p-phenylbenzoyloxy-5-a-hydroxy-2p-formylcyclopentan-la-yl]-eddikesyre-r-lacton i en portion. Efter 35 minutter blev reaktionsblandingen omsat med 5,0 ml iseddike, fortyndet med 200 ml vandfri ether, vasket med 200 ml 10 % saltsyre (2 gange), 200 ml mættet natriumhydrogencarbonatopløsning (1 gang), 100 ml vand (1 gang), tørret over magnesiumsulfat og inddampet, hvorved der blev opnået 4,057 (80 %) rå 2-[3a-p-phenylbenzoyloxy-5a-hydroxy-2P-(3-oxo-6-oxa-trans-l-octen-l-yl)cyclopent-la-yl]eddikesyre-Clacton som en olie.The NMR spectrum (CDCl3) showed * 0 a doublet centered at 3 »79 £ (J = 11» 5 Hz, 6h) for (CH₂O₂-β-, a triplet centered at 3 »28 6 (2H) for CH2 -OC2 -C2 -> a quartet at 3 »436 (2H) for CH2 -O-CH« -, --- ^ 0 0 a doublet centered at 3 »14 in ) -C-CHg-P-, Π a triplet centered at 2.87 in (2H) for -CHg-C -CHg · B. 3.8 g (17.1 mmol) of dimethyl 2-oxo-5-oxaheptyl phosphonate, prepared under A, in 200 ml of anhydrous ether was treated with 4.8 ml (12 mmol) of 2.5 M n -butyllithium in n-hexane in a dry nitrogen atmosphere at room temperature After 5 minutes of stirring, an additional 400 ml of anhydrous ether was added followed by 4 g (11.4 mmol) of 2- [3cc-p-phenylbenzoyloxy-5-a-hydroxy-2β- formylcyclopentan-1-yl] -acetic acid r-lactone in one portion After 35 minutes the reaction mixture was reacted with 5.0 ml of glacial acetic acid, diluted with 200 ml of anhydrous ether, washed with 200 ml of 10% hydrochloric acid (2 times), 200 ml saturated sodium bicarbonate solution (1 time), 10 0 ml of water (1 time), dried over magnesium sulfate and evaporated to give 4.057 (80%) of crude 2- [3a-p-phenylbenzoyloxy-5a-hydroxy-2β- (3-oxo-6-oxa-trans). 1-octen-1-yl) cyclopent-1-yl] acetic acid Clacton as an oil.
Produktets infrarøde spektrum (CHCl-j) udviste absorptionsbånd ved 1770 cm-"1' (stærk), 1707 cm-"*" (stærk), I67O cm-"1" (middel) og 1620 cm-i (middel), der kan tilskrives carbonylgrupperne. NMR-spektret (CDCl^) stemte overens med strukturen.The infrared spectrum (CHCl-j) exhibited absorption bands at 1770 cm -1 (strong), 1707 cm -1 (strong), 1767 cm -1 "(medium), and 1620 cm -1 can be attributed to the carbonyl groups.The NMR spectrum (CDCl3) was consistent with the structure.
C. Til en opløsning af 4100 mg (9,-2 mmol) rå 2-£3<J(-p-phenylbenzoyl-oxy-5<s( -hydroxy-2 β- (3-oxo-6-oxa-trans-l-octen-l-yl) cyclopent-Dc- 23 143498 ylQeddikesyre-fl-’-lacton, fremstillet under B, 30 ml tørt 1,2-dimet-hoxyethan i en tør nitrogenatmosfasre ved 0° C sattes dråbevis 4,5 ml af en 1,0 M zinkborhydridopløsning. Efter omrøring ved 0° C i en time tilsattes dråbevis en mættet natriumhydrogentartratopløsning, indtil hydrogenudviklingen ophørte. Reaktionsblandingen omrørtes i 5 minutter, til hvilket tidspunkt der tilsattes 200 ml tørt methylen-chlorid. Efter tørring over magnesiumsulfat og koncentrering (vandstrålepumpe) blev det resulterende halvfaste stof renset ved søjlechromatografi på silica-gel (Baker "Analyzed" Reagent, partikelstørrelse 0,074 - 0,250 mm) under anvendelse af ether/ethyl--acetat (5:l) som elueringsmiddel. Efter eluering af mindre polære urenheder elueredes fraktioner indeholdende 778 mg 2-[3oc-p-phenylbenzoyloxy-5a-hydroxy-2 β-(3oc-hydroxy-6-oxa-trans-l-octen- l-yl)cyclopent-la-yl]eddikesyre-3S^lacton (5), 2-[3<x-p-phenyl-benzoyloxy-5oc-hydroxy-^- (3 β-hydroxy-6-oxa-tΓans-l-oct en-l-yl) -cyclopent-loc-yl]eddikesyre-}f^lacton og 355 mg af de to blandet.C. To a solution of 4100 mg (9, -2 mmol) of crude 2- £ 3 <J (-p-phenylbenzoyl-oxy-5 <s (-hydroxy-2β- -l-octen-1-yl) cyclopent-Dc-23-acetic acid-β-l-lactone, prepared under B, 30 ml of dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at 0 ° C was added dropwise 4.5 After stirring at 0 ° C for one hour, a saturated sodium hydrogen tartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was stirred for 5 minutes, at which time 200 ml of dry methylene chloride was added. and concentration (water jet pump), the resulting semi-solid was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074 - 0.250 mm) using ether / ethyl acetate (5: 1) as eluent. minor polar impurities eluted fractions containing 778 mg of 2- [3oc-p-phenylbenzoyloxy-5α-hydroxy-2β- (3oc-hydroxy-6-oxa-trans-1-oc) tert-1-yl) cyclopent-1a-yl] acetic acid-3S-lactone (5), 2- [3β-phenyl-benzoyloxy-5oc-hydroxy-β - (3β-hydroxy-6-oxa-tanoic acid) 1-octene-1-yl) -cyclopent-loc-yl] -acetic acid} phylactone and 355 mg of the two mixed.
Det infrarøde spektrum (CHCl^) af den første af de ovennævnte fraktioner havde stærke carbonylabsorptioner ved 1775 og 1715 cm”·*·. NMR-spektret (CDCl^) stemte overens med strukturen.The infrared spectrum (CHCl3) of the first of the above fractions had strong carbonyl absorptions at 1775 and 1715 cm @ -1. The NMR spectrum (CDCl3) was consistent with the structure.
D. En heterogen blanding af lOOg mg (2,24 mmol) 2-[3ti,-p-phenyl-benzoyloxy-5a.-hydroxy-2 p-(3<t-hydroxy-6-oxa-trans-l-octen-l-yl) -cyclopent-l^-yl^eddikesyre-jf'-lacton, fremstillet under C, 10,0 ml absolut methanol og 310 mg fint pulveriseret, vandfrit kaliumcarbonat blev omrørt ved stuetemperatur i 1 time og derpå afkølet ved 0° C. Til den afkølede opløsning sattes 10 ml (10 mmol) 1,0 N saltsyre. Efter omrøring ved 0° C i yderligere 10 minutter tilsattes 10 ml vand under samtidig dannelse af methyl-p-phenylbenzoat, som blev opsamlet ved filtrering. Filtratet blev mættet med fast natriumchlorid, ekstraheret med ethylacetat (2 x 100 ml), de kombinerede organiske ekstrakter vasket med mættet natriumhydrogencarbonat (2 x 25 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 570 mg (94 %) viskøs, olieagtig 2-(3α,5α-dihydroxy-2β-(3α-hydroxy-6-oxa-trans- l-octen-l-yl)cyclopent-la-yl]eddikesyre-2i‘'-lacton.D. A heterogeneous mixture of 100 mg (2.24 mmol) of 2- [3t, -p-phenyl-benzoyloxy-5α-hydroxy-2β- (3 -l-yl) -cyclopent-11-yl-acetic acid-alpha-lactone, prepared under C, 10.0 ml of absolute methanol and 310 mg of finely powdered, anhydrous potassium carbonate was stirred at room temperature for 1 hour and then cooled at 0 ° C. To the cooled solution was added 10 ml (10 mmol) of 1.0 N hydrochloric acid. After stirring at 0 ° C for an additional 10 minutes, 10 ml of water was added while forming methyl p-phenylbenzoate, which was collected by filtration. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (2 x 100 ml), the combined organic extracts washed with saturated sodium bicarbonate (2 x 25 ml), dried over magnesium sulfate and concentrated to give 570 mg (94%) viscous, oily 2- (3α, 5α-dihydroxy-2β- (3α-hydroxy-6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetic acid-2β-lactone.
Det infrarøde spektrum (CHC1,) udviste en stærk absorption ved -1 _i 1770 cm for lactoncarbonylet og middel absorption ved 965 cm for trans-dobbeltbindingen.The infrared spectrum (CHCl 3) showed a strong absorption at -170 cmA for the lactone carbonyl and mean absorption at 965 cm for the trans double bond.
24 143498 E. Til en opløsning af 570 mg (2,11 mmol) 2-^3 £t,5^jrdihydroxy-2£-(3^-hydroxy-6-oxa-trans-l-octen..l-yl)cyclopent-la:-yl}eddikesyre-^-lacton, fremstillet under D, i 5,7 mg vandfrit methylen-chlorid og 570 μΐ 2,3-dihydropyran ved 0° i en tør nitrogen-atmosfære sattes 5,7 mg p-toluensulfonsyre-monohydrat. Efter omrøring i 15 minutter blev reaktionsblandingen kombineret med 200 ml ether, etheropløsningen vasket med mættet natriumhydrogen-carbonat (l x 25 ml) og derpå med mættet saltvand (1 x 25 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 925 mg (100 %) 2- [ 5a-hydroxy-3cc- (tetrahydropyran-2-yloxy) -2β-(3α-[tetrahydropyran-2-yloxy]-6-oxa-trans-l-octen-l-yl)cyclo-pent-la-yl]eddikesyre-Clacton.E. To a solution of 570 mg (2.11 mmol) of 2-3,3 t, 5 µg of dihydroxy-2 £ - (3 ) cyclopent-1a: -yl} acetic acid - ^ - lactone, prepared under D, in 5.7 mg of anhydrous methylene chloride and 570 μΐ of 2,3-dihydropyran at 0 ° in a dry nitrogen atmosphere was added 5.7 mg p -toluensulfonsyre monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 200 ml of ether, the ether solution washed with saturated sodium bicarbonate (1x25 ml) and then with saturated brine (1 x 25 ml), dried over magnesium sulfate and concentrated to give 925 mg ( 100%) 2- [5α-hydroxy-3β- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy] -6-oxa-trans-1-octen-1-yl) cyclopentene -la-yl] acetic acid Clacton.
NMR-spektret (CDClj) udviste en multiplet ved 5,30 - 5,70 S (2H) for de alkeniske protoner, en kvartet ved 3,40 S (2H) for ethyletherprotoneme, multipletter ved 4,35 - 5,18 & (4H), 3,18 - 4,32 £ (8H) og 1,18 - 2,92 4 (25H) og en triplet ved 1,10 & (3H).The NMR spectrum (CDCl3) showed a multiplet at 5.30 - 5.70 S (2H) for the alkenic protons, a quartet at 3.40 S (2H) for the ethyl ether protons, multiples at 4.35 - 5.18 & ( 4H), 3.18 - 4.32 pounds (8H) and 1.18 - 2.92 4 (25H) and a triplet at 1.10 & (3H).
F. En opløsning af 880 mg (2,01 mmol) rå 2-£5*_-hydroxy-3it-(tetra-hydropyran- 2-yloxy) -2(i- (3o_-rtetrahydropyran-2-yloxy3-6-oxa-trans- 1- octen-l-yl)cyclopent-l<x.-yl£eddikesyre-'CLlacton, fremstillet under E, i 8,8 ml tørt toluen blev afkølet til -78° C i en tør nitrogenatmosfære. Til denne afkølede opløsning sattes 3 ml 20 % diisobutylaluminiumhydrid i n-hexan dråbevis med en sådan hastighed, at den indre temperatur aldrig steg over -65° C (15 minutter). Efter yderligere 30 minutters omrøring ved -78° C tilsattes vandigt methanol, indtil gasudviklingen ophørte, og reaktionsblandingen fik lov at opvarmes til stuetemperatur. Reaktionsblandingen blev kombineret med 100 ml ether, vasket med 50 % natriumkaliumtartratopløsning (4 x 10 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 654 mg 2- [ 5oc-hydroxy-3a- (tetrahydropyran-2-yloxy) -2β- (3α- [ tetrahydro-pyran-2-yloxy]-6-oxa-trans-l-octen-l-yl)cyclopent-la-yl]acetal-dehyd-tf'-hemiacetal.F. A solution of 880 mg (2.01 mmol) of crude 2- 5'-hydroxy-3- (tetrahydropyran-2-yloxy) -2- (3- (3-tetrahydropyran-2-yloxy) -3- oxa-trans-1- octen-1-yl) cyclopent-1 (x.-yl) acetic acid-CLlactone, prepared under E, in 8.8 ml of dry toluene was cooled to -78 ° C in a dry nitrogen atmosphere. To this cooled solution, 3 ml of 20% diisobutyl aluminum hydride in n-hexane was added dropwise at such a rate that the internal temperature never increased above -65 ° C (15 minutes). After a further 30 minutes of stirring at -78 ° C, aqueous methanol was added until The reaction mixture was combined with 100 ml of ether, washed with 50% sodium potassium tartrate solution (4 x 10 ml), dried over magnesium sulfate and concentrated to give 654 mg of 2- [5oc-hydroxy]. -3α- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydro-pyran-2-yloxy] -6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetaldehyde tf'-hemiacetal.
25 U3498 G. Til en opløsning af 2600 mg (6,0 mmol) (4-carboxy-n-toutyl)-triphenylphosphoniumbromid i en tør nitrogenatmosfære i 6 ml tørt dimethylsulfoxid sattes 6,0 ml (12,0 mmol) af en 2,0 M opløsning af natriiimmethylsulfinylmethid i dimethylsulfoxid. Til denne røde ylid-opløsning sattes dråbevis en opløsning af 660 mg (1,5 mmol) rå 2-[ 5oc-hydroxy-3oc-(tetrahydropyran-2-yloxy)-2β-(3α-[te-trahydropyran-2-yloxy]-6-oxa-trans-l-octen-l-yl)cyclopent-la-yl]-acetaldehyd-r^-hemiacetal, fremstillet under F, i 5,0 ml tørt dimethylsulfoxid i løbet af 20 minutter. Efter yderligere 2 timers omrøring ved stuetemperatur hældtes reaktionsblandingen ud i isvand. Den basiske vandige opløsning blev vasket to gange med ethylacetat (100 ml) og gjort sur til pH ca. 3 med 10 % saltsyre. Den sure opløsning blev ekstraheret med ethylacetat (3 x 100 ml), og de kombinerede organiske ekstrakter vasket én gang med vand (25 ml), tørret over magnesiumsulfat og inddampet til en fast remanens. Denne faste remanens blev udrevet med ethylacetat og filtreret. Filtratet blev renset ved søjlechromatografi på silica-gel (Baker "Analyzed" Reagent, partikelstørrelse 0,074 -0,250 mm) under anvendelse af ethylacetat som elueringsmiddel.To a solution of 2600 mg (6.0 mmol) (4-carboxy-n-toutyl) -triphenylphosphonium bromide in a dry nitrogen atmosphere in 6 ml of dry dimethyl sulfoxide was added 6.0 ml (12.0 mmol) of a 2 , 0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 660 mg (1.5 mmol) of crude 2- [5oc-hydroxy-3oc- (tetrahydropyran-2-yloxy) -2β- (3α- [tetrahydropyran-2-yloxy) ] -6-oxa-trans-1-octen-1-yl) cyclopent-1a-yl] -acetaldehyde-R 2 -hemiacetal, prepared under F, in 5.0 ml of dry dimethyl sulfoxide over 20 minutes. After a further 2 hours of stirring at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (100 ml) and acidified to pH ca. 3 with 10% hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 100 ml) and the combined organic extracts washed once with water (25 ml), dried over magnesium sulfate and evaporated to give a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromatography on silica gel (Baker "Analyzed" Reagent, particle size 0.074 -0.250 mm) using ethyl acetate as eluant.
Efter fjernelse af urenheder med høj R^-værdi blev der opsamlet 550 mg (70 %) 9a-hydroxy-lla,15oc-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadiensyre.After removal of high R 2 value impurities, 550 mg (70%) of 9α-hydroxy-11α, 15oc-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid were collected. .
NMR-spektret (CDCl^) udviste en multiplet (variabel) ved 6,2 - 6,6 4 (2H) for -OH-protonerne, en multiplet ved 5*3 - 5,7 S (4H) for de alkeniske protoner, en multiplet ved 4,6-4,9 £ (2H) for acetalprotonerne, en kvartet ved 3,5 4 (2H) for ethylether-protonerne og multipletter ved 3,3 - 4,4 S (9H) og 1,0 - 2,6 4 (31H) for de resterende protoner.The NMR spectrum (CDCl3) showed a multiplet (variable) at 6.2 - 6.6 4 (2H) for the -OH protons, a multiple at 5 * 3 - 5.7 S (4H) for the alkenic protons, a multiplet at 4.6-4.9 pounds (2H) for the acetal protons, a quartet at 3.5 4 (2H) for the ethyl ether protons and multiples at 3.3-4.4 S (9H) and 1.0 2.6 4 (31H) for the remaining protons.
H. Til en opløsning af 400 mg (0,765 mmol) 9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadiensyre, fremstillet under G, i 8 ml reagensrent acetone afkølet til -10° C under nitrogen sattes dråbevis 0,338 ml (0,900 mmol) 2,67 M Jones’ reagens. Efter 5 minutter ved -10° C tilsattes 0,350 ml 2-propanol, og reaktionsblandingen omrørtes yderligere i 26 143498 5 minutter, til hvilket tidspunkt den blev kombineret med 60 ml ethylacetat, vasket med vand (3 x 5 ml), tørret over magnesiumsulfat og koncentreret, hvorved der blev opnået 280 mg 9-οχο-11α,15α-bis-(tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadien-syre.H. To a solution of 400 mg (0.765 mmol) of 9α-hydroxy-11α, 15α-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared under G, for 8 hours. ml of reagent pure acetone cooled to -10 ° C under nitrogen was added dropwise 0.338 ml (0.900 mmol) 2.67 M Jones' reagent. After 5 minutes at -10 ° C, 0.350 ml of 2-propanol was added and the reaction mixture was further stirred for 5 minutes, at which time it was combined with 60 ml of ethyl acetate, washed with water (3 x 5 ml), dried over magnesium sulfate and concentrated to give 280 mg of 9-ω-11α, 15α-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadienic acid.
I. En opløsning af 280 mg (0,240 mmol) 9-oxo-llø<, 15A.-bis-(tetrahy-dropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadiensyre, fremstillet under H, i 4,0 ml af en blanding af iseddike og vand i forholdet 65:35 omrørtes under nitrogen ved 40° C i 2,5 timer og blev derpå koncentreret ved rotationsfordampning. Den resulterende olie blev renset ved søjlechromatografi på silica-gel ("Mallinckrodi®CC-4", partikelstørrelse 0,074 - 0,149 mm) under anvendelse af ethylacetat som. elueringsmiddel. Efter eluering af mindre polære urenheder opsamledes den olieagtige 9-οχο-11α,15α-dihydroxy-18-oxa-cis-5-trans-13-prostadiensyre, som vejede 66 mg. Dette produkt er 18-oxaprostaglandin E2.I. A solution of 280 mg (0.240 mmol) of 9-oxo-lolo <15A-bis- (tetrahydro-dipyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared under H , in 4.0 ml of a mixture of glacial acetic acid and water at 65:35 ratio was stirred under nitrogen at 40 ° C for 2.5 hours and then concentrated by rotary evaporation. The resulting oil was purified by column chromatography on silica gel ("Mallinckrodi®CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate as. eluent. After elution of minor polar impurities, the oily 9-oο-11α, 15α-dihydroxy-18-oxa-cis-5-trans-13-prostadienic acid, which weighed 66 mg, was collected. This product is 18-oxaprostaglandin E2.
Det ultraviolette spektrum i methanol med tilsat kaliumhydroxidopløsning udviste en λ__„ = 278 nm og en ε = 23 800 - 25 600.The ultraviolet spectrum in methanol with added potassium hydroxide solution exhibited an λ = = 278 nm and a ε = 23 800 - 25 600.
tucUC ωαΛ EKSEMPEL 5tucUC ωαΛ EXAMPLE 5
En opløsning af 75 mg (0,10 mmol) 9tf-hydroxy-ll/v,15^-bis-(tetra-hydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadiensyre, fremstillet i eksempel 4-G, i 3,0 ml af en blanding af iseddikesyre og vand i forholdet 65:35 omrørtes under nitrogen ved 40° C i 5 timer og blev derpå koncentreret ved rotationsfordampning. Den resulterende rå olie blev renset på silica-gel ("Mallinckrodt^ CC-4", partikelstørrelse 0,074 - 0,149 mm) under anvendelse af ethylacetat og derpå methanol som elueringsmidler. Efter eluering af mindre polære urenheder opsamledes den olieagtige 9a,11a,15a-trihydroxy-18-oxa-cis-5-trans-13-prostaglandinsyre, som vejede 20 mg. Dette produkt er 18-oxaprostaglandin F2a.A solution of 75 mg (0.10 mmol) of 9β-hydroxy-11 / v, 15β-bis- (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadioic acid, prepared in Example 4-G, in 3.0 ml of a 65:35 acetic acid-water mixture was stirred under nitrogen at 40 ° C for 5 hours and then concentrated by rotary evaporation. The resulting crude oil was purified on silica gel ("Mallinckrodt ^ CC-4", particle size 0.074 - 0.149 mm) using ethyl acetate and then methanol as eluents. After eluting minor polar impurities, the oily 9a, 11a, 15a-trihydroxy-18-oxa-cis-5-trans-13-prostaglandic acid, which weighed 20 mg, was collected. This product is 18-oxaprostaglandin F2a.
EKSEMPEL_8EKSEMPEL_8
Til en opløsning af 35 mg 19-oxa-PGE2, fremstillet i eksempel 1, i 7 ml absolut methanol afkølet i is sattes en isafkølet opløsning af 105 mg natriumborhydrid i 12 ml absolut methanol. Opløsningen omrørtes under nitrogen i 20 minutter ved 0 - 5° C og derpå i 1,0 time ved stuetemperatur. Reaktionsblandingen blevTo a solution of 35 mg of 19-oxa-PGE 2, prepared in Example 1, in 7 ml of absolute methanol cooled in ice was added an ice-cooled solution of 105 mg of sodium borohydride in 12 ml of absolute methanol. The solution was stirred under nitrogen for 20 minutes at 0-5 ° C and then for 1.0 hour at room temperature. The reaction mixture was
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- 1973-05-28 SE SE7307521A patent/SE415756B/en unknown
- 1973-05-29 FI FI1735/73A patent/FI55995C/en active
- 1973-05-30 IN IN1265/CAL/73A patent/IN138739B/en unknown
- 1973-05-30 GB GB2306775A patent/GB1440603A/en not_active Expired
- 1973-05-30 GB GB2306575A patent/GB1440602A/en not_active Expired
- 1973-05-30 GB GB2584673A patent/GB1440601A/en not_active Expired
- 1973-06-01 IE IE881/73A patent/IE38568B1/en unknown
- 1973-06-01 DE DE2344838A patent/DE2344838C3/en not_active Expired
- 1973-06-01 CH CH797573A patent/CH590224A5/xx not_active IP Right Cessation
- 1973-06-01 CA CA173,035A patent/CA1095034A/en not_active Expired
- 1973-06-01 CH CH415576A patent/CH586716A5/xx not_active IP Right Cessation
- 1973-06-01 DE DE2327813A patent/DE2327813A1/en not_active Withdrawn
- 1973-06-01 DK DK303973A patent/DK143498C/en not_active IP Right Cessation
- 1973-06-01 CH CH415476A patent/CH589074A5/xx not_active IP Right Cessation
- 1973-06-02 JP JP6244973A patent/JPS5314062B2/ja not_active Expired
- 1973-06-04 YU YU01469/73A patent/YU36497B/en unknown
- 1973-06-04 PH PH14690A patent/PH11300A/en unknown
- 1973-06-04 DD DD171300A patent/DD109859A5/xx unknown
- 1973-06-04 LU LU67738A patent/LU67738A1/xx unknown
- 1973-06-04 DD DD182818A patent/DD124594A5/xx unknown
- 1973-06-04 NL NL7307740.A patent/NL162902C/en not_active IP Right Cessation
- 1973-06-04 AR AR248400A patent/AR199300A1/en active
-
1974
- 1974-01-29 AR AR252103A patent/AR203386A1/en active
- 1974-03-11 NO NO740849A patent/NO145438C/en unknown
-
1975
- 1975-04-07 PH PH17030A patent/PH12035A/en unknown
- 1975-04-07 PH PH17029A patent/PH11931A/en unknown
- 1975-09-16 ES ES441002A patent/ES441002A1/en not_active Expired
- 1975-09-16 ES ES441003A patent/ES441003A1/en not_active Expired
-
1976
- 1976-07-19 SE SE7608222A patent/SE7608222L/en unknown
- 1976-07-19 SE SE7608221A patent/SE418857B/en unknown
- 1976-07-19 SE SE7608223A patent/SE7608223L/en not_active Application Discontinuation
- 1976-09-08 JP JP51107651A patent/JPS5231054A/en active Granted
- 1976-09-08 JP JP51107650A patent/JPS5239629A/en active Pending
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PBP | Patent lapsed |