CH632493A5 - Process for preparing novel prostanoic acid derivatives - Google Patents
Process for preparing novel prostanoic acid derivatives Download PDFInfo
- Publication number
- CH632493A5 CH632493A5 CH664281A CH664281A CH632493A5 CH 632493 A5 CH632493 A5 CH 632493A5 CH 664281 A CH664281 A CH 664281A CH 664281 A CH664281 A CH 664281A CH 632493 A5 CH632493 A5 CH 632493A5
- Authority
- CH
- Switzerland
- Prior art keywords
- group
- hydroxy
- acid
- free
- oxo
- Prior art date
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- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- -1 hydroxymethylene group Chemical group 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 230000001882 diuretic effect Effects 0.000 claims description 2
- 210000001519 tissue Anatomy 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 208000001953 Hypotension Diseases 0.000 claims 1
- 208000004880 Polyuria Diseases 0.000 claims 1
- 229960002986 dinoprostone Drugs 0.000 claims 1
- 208000021822 hypotensive Diseases 0.000 claims 1
- 230000001077 hypotensive effect Effects 0.000 claims 1
- 210000004789 organ system Anatomy 0.000 claims 1
- 210000002460 smooth muscle Anatomy 0.000 claims 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 abstract description 9
- 150000003180 prostaglandins Chemical class 0.000 abstract description 9
- 230000029936 alkylation Effects 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- UKVVPDHLUHAJNZ-PMACEKPBSA-N prostane Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC UKVVPDHLUHAJNZ-PMACEKPBSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000012230 colorless oil Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 11
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 9
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-M ethanimidate Chemical compound CC([O-])=N DLFVBJFMPXGRIB-UHFFFAOYSA-M 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 150000004679 hydroxides Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical group OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- YVHAIVPPUIZFBA-UHFFFAOYSA-N Cyclopentylacetic acid Chemical compound OC(=O)CC1CCCC1 YVHAIVPPUIZFBA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 206010000210 abortion Diseases 0.000 description 2
- 231100000176 abortion Toxicity 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- FXKMTSIKHBYZSZ-UHFFFAOYSA-N 2-chloroethanesulfonic acid Chemical compound OS(=O)(=O)CCCl FXKMTSIKHBYZSZ-UHFFFAOYSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- VRDBIJCCXDEZJN-UHFFFAOYSA-N 2-piperidin-1-ylacetic acid Chemical group OC(=O)CN1CCCCC1 VRDBIJCCXDEZJN-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000005711 Benzoic acid Chemical group 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000012027 Collins reagent Substances 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical group CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- VIWZVFVJPXTXPA-UHFFFAOYSA-N N-(2-Carboxymethyl)-morpholine Chemical group OC(=O)CN1CCOCC1 VIWZVFVJPXTXPA-UHFFFAOYSA-N 0.000 description 1
- JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-UHFFFAOYSA-N 0.000 description 1
- ZSYNRWGRGQMHQK-VIZSFHNOSA-N N-acetyl-7-[(1R,2S)-2-[(3S)-3-hydroxy-3-methyloctyl]-5-oxocyclopentyl]heptanamide Chemical compound C(C)(=O)NC(CCCCCC[C@H]1C(CC[C@@H]1CC[C@@](CCCCC)(C)O)=O)=O ZSYNRWGRGQMHQK-VIZSFHNOSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BFKVXNPJXXJUGQ-UHFFFAOYSA-N [CH2]CCCC Chemical compound [CH2]CCCC BFKVXNPJXXJUGQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001559 benzoic acids Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- ZVKZVKWNVILEOS-UHFFFAOYSA-N bis(2-methylpropyl)sulfamic acid Chemical compound CC(C)CN(S(O)(=O)=O)CC(C)C ZVKZVKWNVILEOS-UHFFFAOYSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- YAIKGZQRXQYYJZ-UHFFFAOYSA-N cyclopentanesulfonic acid Chemical compound OS(=O)(=O)C1CCCC1 YAIKGZQRXQYYJZ-UHFFFAOYSA-N 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- DLTBAYKGXREKMW-UHFFFAOYSA-N cyclopropanesulfonic acid Chemical compound OS(=O)(=O)C1CC1 DLTBAYKGXREKMW-UHFFFAOYSA-N 0.000 description 1
- BAQKWXACUNEBOT-UHFFFAOYSA-N dibutylsulfamic acid Chemical compound CCCCN(S(O)(=O)=O)CCCC BAQKWXACUNEBOT-UHFFFAOYSA-N 0.000 description 1
- NXFNZLHFBJYCPG-UHFFFAOYSA-N diethylsulfamic acid Chemical compound CCN(CC)S(O)(=O)=O NXFNZLHFBJYCPG-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YGNOYUCUPMACDT-UHFFFAOYSA-N dimethylsulfamic acid Chemical compound CN(C)S(O)(=O)=O YGNOYUCUPMACDT-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003529 luteolytic effect Effects 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- GLGNSAPAWZUDRT-UHFFFAOYSA-N morpholine-4-sulfonic acid Chemical compound OS(=O)(=O)N1CCOCC1 GLGNSAPAWZUDRT-UHFFFAOYSA-N 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- HNDXKIMMSFCCFW-UHFFFAOYSA-N propane-2-sulphonic acid Chemical compound CC(C)S(O)(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical group OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc 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
- C07D307/93—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 condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
Abstract
Description
Die Erfindung betrifft die Herstellung neuer Prostanderivate der Formel The invention relates to the production of new prostate derivatives of the formula
■NHR. ■ NHR.
(I) (I)
W-D-E-R, W-D-E-R,
worin Rj einen Acylrest darstellt, where Rj represents an acyl radical,
A eine cis-CH=CH- oder -trans-CH=CH-Gruppe 25 bedeutet , A denotes a cis-CH = CH- or -trans-CH = CH group 25,
B eine -CH2-CH2-, trans-CH=CH-, -C=C- oder B is a -CH2-CH2-, trans-CH = CH-, -C = C- or
-CH-CH-Gruppe, -CH-CH group,
V V
CH, CH,
30 30th
wobei die Methylen-Gruppe a- oder ß-ständig sein kann, darstellt, where the methylene group can be a or β,
W eine freie, veresterte oder verätherte Hydroxymethylengruppe, eine freie oder ketalisierte Carbonyl- oder eine 35 freie, veresterte oder verätherte W is a free, esterified or etherified hydroxymethylene group, a free or ketalized carbonyl or a 35 free, esterified or etherified
ÇH3 ÇH3
■NHR. ■ NHR.
worin A eine cis-CH=CH- oder trans-CH=CH-Gruppe bedeutet und die restlichen Substituenten weiter oben definiert sind, herstellt und in der genannten Verbindung der Formel I die für A stehende CH=CH-Bindung zur -CH2-CH2-Bindung hydriert. in which A is a cis-CH = CH or trans-CH = CH group and the remaining substituents are defined above, and in the compound of formula I mentioned stands for the CH = CH bond to -CH2-CH2 -Hydrogenated bond.
Die Erfindung betrifft Verfahren zur Herstellung neuer Prostanderivate. The invention relates to methods for producing new prostate derivatives.
Es ist bekannt, dass die physiologischen Wirkungen der Prostaglandine sowohl im Säugetierorganismus als auch in vitro nur von kurzer Dauer sind, da sie rasch zu einer Vielzahl von pharmakologisch inaktiven Stoffwechselprodukten umgewandelt werden. Ausserdem ist es bekannt, dass die natürlichen Prostaglandine an sich keine biologische Spezifität besitzen, die für einen Arzneistoff notwendig ist. It is known that the physiological effects of prostaglandins, both in the mammalian organism and in vitro, are short-lived since they are rapidly converted to a variety of pharmacologically inactive metabolites. In addition, it is known that the natural prostaglandins do not have the biological specificity that is necessary for a drug.
Es war daher wünschenswert, Prostaglandinanaloga mit einem den natürlichen Prostaglandinen vergleichbaren Wirkungsspektrum zu entwickeln und Strukturveränderungen vorzunehmen, durch die die Dauer und Selektivität der Wirksamkeit gesteigert wird. It was therefore desirable to develop prostaglandin analogues with a spectrum of activity comparable to that of natural prostaglandins and to carry out structural changes which increase the duration and selectivity of the activity.
Es wurde nun gefunden, dass Prostaglandinsäureamid-Derivate überraschenderweise eine hervorragende Wirkungs-spezifität und eine längere Wirkungsdauer als natürliche Pro- It has now been found that prostaglandic acid amide derivatives surprisingly have an excellent activity specificity and a longer duration of activity than natural pro
(I) -C-Gruppe, wobei die OH-Gruppe a- oder ß-ständig sein (I) -C group, the OH group being a- or ß-permanent
40 OH 40 OH
kann, bedeutet, can means
D und E gemeinsam eine direkte Bindung oder D eine geradkettige oder verzweigte Alkylengruppe mit 45 1-5 C-Atomen oder eine -C=C-Gruppe, D and E together are a direct bond or D is a straight-chain or branched alkylene group with 45 1-5 C atoms or a -C = C group,
E ein Sauerstoff- oder Schwefelatom oder eine direkte Bindung bedeutet, E represents an oxygen or sulfur atom or a direct bond,
R3 eine Alkyl-, Cycloalkyl-, Aralkyl- gegebenenfalls substituierte Aryl-, Benzodioxol-2-yI- oder eine heterocyclische so Gruppe, R3 is an alkyl, cycloalkyl, aralkyl, optionally substituted aryl, benzodioxol-2-yI or a heterocyclic group,
Z eine freie oder ketalisierte Carbonylgruppe oder eine freie, verätherte oder veresterte Hydroxymethylengruppe und R2 ein Wasserstoffatom, eine geradkettige oder verzweigte Alkylgruppe mit 1-5 C-Atomen, eine -C=N-Gruppe, eine 55 Alkylthio- oder Alkanoylthio-Gruppe bedeuten, Z is a free or ketalized carbonyl group or a free, etherified or esterified hydroxymethylene group and R2 is a hydrogen atom, a straight-chain or branched alkyl group with 1-5 C atoms, a -C = N group, a 55 alkylthio or alkanoylthio group,
mit der Massgabe, dass, wenn Z eine Hydroxymethylengruppe ist, Rx nicht Wasserstoff bedeutet. with the proviso that when Z is a hydroxymethylene group, Rx is not hydrogen.
Dieser Disclaimer wurde zur Abgrenzung gegen das ältere 60 Recht FR 2 316 924 (Pfizer) eingeführt. This disclaimer was introduced to distinguish it from the older 60 law FR 2 316 924 (Pfizer).
Als Acylreste Rx kommen insbesondere organische Carbonsäuren und Sulfonsäuren mit 1-10 C-Atomen in Frage, die der aliphatischen, aromatischen, aromatisch-aliphatischen, cyclo-aliphatischen oder heterocyclischen Reihe angehören. 65 Diese Säuren können gesättigt, ungesättigt und/oder mehrbasisch und/oder in üblicher Weise substituiert sein. Als Beispiele für Substituenten seien Alkyl-, Hydroxy-, Alkoxy-, Oxo-oder Aminogruppen oder Halogenatome erwähnt. Suitable acyl radicals Rx are, in particular, organic carboxylic acids and sulfonic acids with 1-10 C atoms, which belong to the aliphatic, aromatic, aromatic-aliphatic, cyclo-aliphatic or heterocyclic series. 65 These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. Examples of substituents include alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms.
632493 632493
4 4th
Beispielsweise seien folgende Carbonsäuren genannt: Essigsäure, Propionsäure, Buttersäure, Isobuttersäure, Valerian-säure, Isovaleriansäure, Capronsäure, Önanthsäure, Capryl-säure, Trimethylessigsäure, Diäthylessigsäure, tert.-Butyl-essigsäure, Cyclopentylessigsäure, Cyclohexylessigsäure, Cyclopropancarbonsäure, Phenylessigsäure, Phenoxyessig-säure, Methoxyessigsäure, Mono-, Di- und Trichloressigsäure, Aminoessigsäure, Diäthylaminoessigsäure, Piperidinoessig-säure, Morpholinoessigsäure, Benzoesäure, mit Halogen-, Tri-fluormethyl-, Hydroxy- oder Carboxy-Gruppen substituierte Benzoesäuren, Furan-2-carbonsäure, Cyclopentylpropion-säure. Als besonders bevorzugte Acylreste werden solche mit bis zu 7 Kohlenstoffatomen betrachtet. For example, the following carboxylic acids are: acetic acid, propionic acid, butyric acid, isobutyric acid, Valerian acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, trimethylacetic acid, Diäthylessigsäure, tert-butyl-acetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, phenylacetic acid, phenoxyacetic acid , Methoxyacetic acid, mono-, di- and trichloroacetic acid, amino acetic acid, diethylamino acetic acid, piperidino acetic acid, morpholino acetic acid, benzoic acid, benzoic acids substituted with halogen, trifluoromethyl, hydroxy or carboxy groups, furan-2-carboxylic acid, cyclopentyl propion . Those with up to 7 carbon atoms are considered as particularly preferred acyl radicals.
Als Sulfonsäuren kommen beispielsweise Methansulfon-säure, Trifluormethansulfonsäure, Äthansulfonsäure, Isopro-pylsulfonsäure, ß-Chloräthansulfonsäure, Butansulfonsäure, Cyclopropansulfonsäure, Cyclopentansulfonsäure, Cyclo-hexansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, p-Chlorbenzolsulfonsäure, p-Methoxy-benzolsulfonsäure, N,N-Dimethylaminosulfonsäure, N,N-Diäthylaminosulfon-säure, N,N-Bis-(ß-Chloräthyl)-aminosulfonsäure, N,N-Diiso-butylaminosulfonsäure, N,N-Dibutylaminosulfonsäure, Pyrro-lidino-, Piperidino-, Piperazino-, N-Methylpiperazino-, Thio-pheno- und Morpholinosulfonsäure in Frage. Examples of suitable sulfonic acids are methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, isopropylsulfonic acid, β-chloroethanesulfonic acid, butanesulfonic acid, cyclopropanesulfonic acid, cyclopentanesulfonic acid, cyclo-hexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, n-chlorobenzenesulfonic acid, Dimethylaminosulfonic acid, N, N-diethylaminosulfonic acid, N, N-bis- (ß-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, piperazino-, N -Methylpiperazino-, thio-pheno- and morpholinosulfonic acid in question.
Als Alkylgruppen R2 kommen gerad- und verzweigtkettige Alkylreste mit 1-5 Kohlenstoffatomen in Betracht, wie beispielsweise der Methyl-, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl-, tert.-Butyl- und Pentylrest. Bevorzugt ist die Methyl- und Äthylgruppe. Suitable alkyl groups R2 are straight-chain and branched-chain alkyl radicals having 1-5 carbon atoms, such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl radical. The methyl and ethyl group is preferred.
Die Hydroxygruppen in W und in Z können funktionell abgewandelt sein, nämlich durch Verätherung oder Veresterung, wobei diese freien oder abgewandelten Hydroxygruppen in W und in Z a- oder ß-ständig sein können. The hydroxyl groups in W and in Z can be functionally modified, namely by etherification or esterification, and these free or modified hydroxyl groups in W and in Z can be a- or ß-permanent.
Als Äther- und Acylreste kommen die dem Fachmann bekannten Reste in Betracht. Bevorzugt sind leicht abspaltbare Ätherreste, wie beispielsweise der Tetrahydropyranyl-, Tetra-hydrofuranyl-, a-Äthoxyäthyl-, Trimethylsilyl-, Dimethyl-, tert.-Butyl-silyl- und Tri-p-benzyl-silylrest. Als Acylreste kommen die gleichen wie für Rj genannt in Frage; namentlich genannt seien beispielsweise Acetyl, Propionyl, Butyryl und Benzoyl. The radicals known to the person skilled in the art are suitable as ether and acyl radicals. Easily removable ether radicals, such as, for example, the tetrahydropyranyl, tetra-hydrofuranyl, α-ethoxyethyl, trimethylsilyl, dimethyl, tert-butyl-silyl and tri-p-benzyl-silyl radical, are preferred. The same acyl radicals as those mentioned for Rj come into question; Examples include acetyl, propionyl, butyryl and benzoyl.
Bedeutet W eine Carbonylgruppe, so kann diese nach den dem Fachmann bekannten Methoden funktionell abgewandelt sein, nämlich durch Ketalisierung. Besonders geeignet ist die Herstellung von cyclischen Ketalen, wie zum Beispiel mit Äthylenglykol, Propandiol-(l,3), 2,2-Dimethylpropandiol--(1,3), Cyclopentandiol-(l,2) oder Glycerin. If W is a carbonyl group, this can be functionally modified by the methods known to the person skilled in the art, namely by ketalization. The production of cyclic ketals, for example with ethylene glycol, propanediol- (1,3), 2,2-dimethylpropanediol- (1,3), cyclopentanediol- (1,2) or glycerol, is particularly suitable.
Als Alkylgruppen Rs kommen gerad- u. verzweigtkettige, gesättigte und ungesättigte Alkylreste, vorzugsweise gesättigte, mit 1-10, insbesondere 1-6 C-Atomen, in Frage, die gegebenenfalls durch gegebenenfalls substituiertes Aryl substituiert sein können. Beispielsweise genannt seien Methyl-, Äthyl-, Propyl-, Butyl-, Isobutyl-, tert.-Butyl-, Pentyl-, Hexyl-, As alkyl groups Rs come straight u. branched, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-6 C atoms, into question, which may be substituted by optionally substituted aryl. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
Heptyl-, Octyl-, Butenyl-, Isobutenyl-, Propenyl-, Pentenyl-, Benzyl- und p-Chlorbenzylgruppen. Heptyl, octyl, butenyl, isobutenyl, propenyl, pentenyl, benzyl and p-chlorobenzyl groups.
Die Cycloalkylgruppe R3 kann im Ring 4-10, vorzugsweise 5 und 6 Kohlenstoffatome enthalten. Die Ringe können durch Alkylgruppen mit 1-4 Kohlenstoffatomen substituiert sein. Beispielsweise seien genannt Cyclopentyl, Cyclohexyl, Me-thyl-cyclohexyl und Adamantyl. The cycloalkyl group R3 can contain 4-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methyl-cyclohexyl and adamantyl.
Als substituierte bzw. unsubstituierte Arylgruppen R3 kommen beispielsweise in Betracht: Phenyl, 1-Naphthyl und 2-Naphthyl, die jeweils substituiert sein können durch 1-3 Halogenatome, eine Phenylgruppe, 1-3 Alkylgruppen mit jeweils 1-4 C-Atomen, eine Chlormethyl-, Fluormethyl-, Tri-fluormethyl-, Carboxyl-, Alkoxy- oder Hydroxygruppe. Bevorzugt ist die Substitution in 3- und 4-Stellung am Phenyl- Examples of suitable substituted or unsubstituted aryl groups R3 are: phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, one phenyl group, 1-3 alkyl groups, each with 1-4 C atoms, one Chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, alkoxy or hydroxy group. The substitution in the 3- and 4-positions on the phenyl is preferred.
ring zum Beispiel durch Fluor, Chlor, Alkoxy oder Trifluor-methyl oder in 4-Stellung durch Hydroxy. ring, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position by hydroxy.
Als heterocyclische Gruppen R3 kommen 5- und 6glied-rige Heterocyclen in Frage, die wenigstens 1-Heteroatom, vorzugsweise Stickstoff, Sauerstoff oder Schwefel enthalten. Beispielsweise seien genannt 2-Furyl, 2-Thienyl, 2-Pyridyl, 3-Pyridyl, 4-Pyridyl u.a. Suitable heterocyclic groups R3 are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and others.
Das erfindungsgemässe Verfahren zur Herstellung der neuen Verbindungen ist dadurch gekennzeichnet, dass man ein Lactol der Formel The process according to the invention for the preparation of the new compounds is characterized in that a lactol of the formula
OH OH
worin B, W, D, E, R2 und R3 die oben angegebene Bedeutung haben, mit einem Wittig-Reagenz der Formel wherein B, W, D, E, R2 and R3 have the meaning given above, with a Wittig reagent of the formula
O O
Ph3P=CH-(CH2)3-C^ (V) Ph3P = CH- (CH2) 3-C ^ (V)
N-Rx (-) N-Rx (-)
worin wherein
Ph eine Phenylgruppe bedeutet und Rj die oben angegebene Bedeutung hat, Ph represents a phenyl group and Rj has the meaning given above,
umsetzt. implements.
Ein weiteres erfindungsgemässes Verfahren bezieht sich auf die Herstellung von neuen Verbindungen der Formel Another method according to the invention relates to the preparation of new compounds of the formula
W-D-E-R W-D-E-R
worin A' eine -CH2-CH2-Gruppe bedeutet und die restlichen Substituenten weiter oben definiert sind. wherein A 'represents a -CH2-CH2 group and the remaining substituents are defined above.
Die neuen Verbindungen der Formel IA werden erfindungsgemäss erhalten, indem man zuerst, wie beschrieben, According to the invention, the new compounds of the formula IA are obtained by first, as described,
eine Verbindung der Formel I herstellt und dann in dieser die sich in 5,6-Stellung befindliche Doppelbindung hydriert. produces a compound of formula I and then hydrogenates the double bond in the 5,6-position.
In erfindungsgemäss erhaltenen Verbindungen kann eine vorhandene 9-Hydroxygruppe nach intermediärem Schutz der 15-Hydroxygruppe zur Carbonylgruppe oxydiert werden. Ebenfalls kann man in erhaltenen Verbindungen geschützte Hydroxygruppen W und Z freisetzen und vorhandene -CH=CH- Bindungen (B) zu -CH2-CH2- Bindungen hydrieren. In compounds obtained according to the invention, an existing 9-hydroxy group can be oxidized to the carbonyl group after intermediate protection of the 15-hydroxy group. It is also possible to release protected hydroxyl groups W and Z in the compounds obtained and to hydrogenate existing —CH = CH bonds (B) to give —CH2-CH2 bonds.
Falls die erfindungsgemäss erhaltene Verbindung als Ra-zemat anfällt, kann man die Epimeren trennen. If the compound obtained according to the invention is obtained as a racemate, the epimers can be separated.
Die erfindungsgemässe Umsetzung der Lactole der Formel IV mit dem Wittig-Reagenz der Formel V, das man aus dem entsprechenden Phosphoniumbromid mit Methansulfinyl-methylnatrium oder Kalium-tert.-butylat in Dimethylsulfoxid herstellen kann, wird gewöhnlich bei Temperaturen von 0°C The inventive reaction of the lactols of formula IV with the Wittig reagent of formula V, which can be prepared from the corresponding phosphonium bromide with methanesulfinyl-methyl sodium or potassium tert-butoxide in dimethyl sulfoxide, is usually carried out at temperatures of 0 ° C.
5 5
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40 40
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bis 100°C, vorzugsweise bei 20°C bis 80°C, in einem aproti-schen Lösungsmittel, vorzugsweise Dimethylsulfoxid oder Di-methylformamid, vorgenommen. up to 100 ° C, preferably at 20 ° C to 80 ° C, in an aprotic solvent, preferably dimethyl sulfoxide or dimethylformamide.
Die bevorzugte Oxydation anwesender Hydroxygruppen kann nach an sich bekannten Methoden mit den üblichen 5 Oxydationsmitteln vorgenommen werden. Beispielsweise kann die Oxydation der 9-Hydroxygruppe zum 9-Keton unter intermediärem Schutz der 15-Hydroxygruppe durch Silylierung [Chem. Comm. (1972), 1120] mit Jones-Reagenz (J. Chem. Soc. 1953, 2555) erfolgen. Man arbeitet gewöhnlich mit 10 The preferred oxidation of the hydroxyl groups present can be carried out according to methods known per se with the usual 5 oxidizing agents. For example, the oxidation of the 9-hydroxy group to the 9-ketone with intermediate protection of the 15-hydroxy group by silylation [Chem. Comm. (1972), 1120] with Jones reagent (J. Chem. Soc. 1953, 2555). You usually work with 10
einem Überschuss des Oxydationsmittels in einem inerten Lösungsmittel, wie Aceton, bei Temperaturen zwischen 30°C und —50°C, vorzugsweise bei etwa —20°C. Die Reaktion ist allgemein nach etwa 5 bis 30 Minuten beendet. an excess of the oxidizing agent in an inert solvent such as acetone at temperatures between 30 ° C and -50 ° C, preferably at about -20 ° C. The reaction is generally complete in about 5 to 30 minutes.
Die Ketalisierung der 9- oder 15-Carbonylgruppen kann in an sich bekannter Weise erfolgen. Beispielsweise wird mit Äthylenglykol in Gegenwart eines sauren Katalysators unter Wasserabscheidung erhitzt. Als saure Katalysatoren sind p-Toluolsulfonsäure und Perchlorsäure besonders geeignet. The 9- or 15-carbonyl groups can be ketalized in a manner known per se. For example, heating with ethylene glycol in the presence of an acidic catalyst with water separation. P-Toluenesulfonic acid and perchloric acid are particularly suitable as acidic catalysts.
Sollen im Primärprodukt enthaltene C=C-Doppelbindun-gen reduziert werden, kann die Hydrierung nach an sich bekannten Methoden erfolgen. If C = C double bonds contained in the primary product are to be reduced, the hydrogenation can be carried out according to methods known per se.
Die Hydrierung der 5,6-Doppelbindung wird insbesondere in an sich bekannter Weise bei tiefen Temperaturen, vorzugsweise bei etwa — 20°C, in einer Wasserstoffatmosphärein Gegenwart eines Edelmetallkatalysators durchgeführt. Als Katalysator ist z.B. 10% Palladium auf Kohle geeignet. The hydrogenation of the 5,6-double bond is carried out in particular in a manner known per se at low temperatures, preferably at about -20 ° C, in a hydrogen atmosphere in the presence of a noble metal catalyst. The catalyst is e.g. 10% palladium on carbon suitable.
Wird sowohl die 5,6- als auch die 13,14-Doppelbindung hydriert, so arbeitet man im allgemeinen bei höherer Temperatur vorzugsweise bei etwa 20°C. If both the 5,6- and the 13,14-double bond are hydrogenated, it is generally preferred to work at about 20 ° C. at a higher temperature.
Die Freisetzung der funktionell abgewandelten Hydroxygruppen, nämlich der Ester- bzw. Äthergruppen, kann nach bekannten Methoden erfolgen. Beispielsweise wird die Abspaltung von Hydroxyschutzgruppen, wie beispielsweise des Tetrahydropyranylrestes, in einer wässrigen Lösung einer organischen Säure, wie zum Beispiel Oxalsäure, Essigsäure, Propionsäure u.a., oder in einer wässrigen Lösung einer anorganischen Säure, wie zum Beispiel Salzsäure, durchgeführt. Zur Verbesserung der Löslichkeit wird zweckmässigerweise ein mit Wasser mischbares inertes organisches Lösungsmittel zugesetzt. Geeignete organische Lösungsmittel sind zum Beispiel Alkohole, wie Methanol und Äthanol, und Äther, wie Dimethoxyäthan, Dioxan und Tetrahydrofuran. Tetrahydro-furan wird bevorzugt angewendet. Die Abspaltung wird vorzugsweise bei Temperaturen zwischen 20°C und 80°C durchgeführt. The functionally modified hydroxyl groups, namely the ester or ether groups, can be released by known methods. For example, cleavage of hydroxy protecting groups such as the tetrahydropyranyl group is carried out in an aqueous solution of an organic acid such as oxalic acid, acetic acid, propionic acid and the like, or in an aqueous solution of an inorganic acid such as hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is expediently added. Suitable organic solvents are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydro-furan is preferred. The cleavage is preferably carried out at temperatures between 20 ° C and 80 ° C.
Eine bevorzugte Verseifung der Acylgruppen erfolgt beispielsweise mit Alkali- oder Erdalkali-carbonaten oder -hy-droxyden in einem Alkohol oder in der wässrigen Lösung eines Alkohols. Als Alkohole kommen insbesondere aliphatische Alkohole in Betracht, wie zum Beispiel Methanol, Äthanol, Butano! usw., vorzugsweise Methanol. Als Alkalicarbo-nate und -hydroxyde seien Kalium- und Natriumsalze genannt, bevorzugt sind die Kaliumsalze. Als Erdalkalicarbo-nate und -hydroxyde sind beispielsweise geeignet Calcium- 55 carbonat, Calciumhydroxyd und Bariumcarbonat. Die Umsetzung erfolgt im allgemeinen bei — 10°C bis +70°C, vorzugsweise bei +25°C. A preferred saponification of the acyl groups takes place, for example, with alkali or alkaline earth carbonates or hydroxides in an alcohol or in the aqueous solution of an alcohol. Aliphatic alcohols, such as, for example, methanol, ethanol, butano, are particularly suitable as alcohols! etc., preferably methanol. Potassium and sodium salts may be mentioned as alkali metal carbonates and hydroxides; the potassium salts are preferred. Suitable alkaline earth metal carbonates and hydroxides are, for example, calcium carbonate, calcium hydroxide and barium carbonate. The reaction is generally carried out at from -10 ° C. to + 70 ° C., preferably at + 25 ° C.
Das im erfindungsgemässen Verfahren als Ausgangsver-bindung eingesetzte Lactol der Formel IV kann hergestellt werden, indem man einen Aldehyd der Formel The lactol of the formula IV used as the starting compound in the process according to the invention can be prepared by adding an aldehyde of the formula
(VIII) (VIII)
[E. J. Corey et al. J. Org. Chem. 39, 256 (1974)] mit einem 15 Phosphoran oder Phosphonat in einer Wittig-Reaktion zu einer a,ß-ungesättigten Carbonylverbindung IX, worin B, D, E und Rs die oben angegebene Bedeutung aufweisen, umsetzt, deren Doppelbindung in 13,14-Stellung (PG-Numerierung) gewünschtenfalls hydriert werden kann. [E. J. Corey et al. J. Org. Chem. 39, 256 (1974)] with a phosphorane or phosphonate in a Wittig reaction to give an α, β-unsaturated carbonyl compound IX, in which B, D, E and Rs have the meaning given above, whose double bond in the 13.14 position (PG numbering) can, if desired, be hydrogenated.
20 20th
(IX) (IX)
-E-R, -HE,
35 Nach einer Reduktion der 15-Ketogruppe, bevorzugt mit Zinkborhydrid oder durch Umsetzung mit Alkylmagnesium-bromid oder Alkyllithium, erhält man gewöhnlich die epime-ren 15a- und 15ß-Alkohole (PG-Numerierung), die gewünschtenfalls getrennt werden können, und in die man ge-40 gebenenfalls Hydroxyschutzgruppe am 15-C-Atom einführt. Beispielsweise erhält man mit Dihydropyran eine Verbindung der Formel 35 After a reduction of the 15-keto group, preferably with zinc borohydride or by reaction with alkyl magnesium bromide or alkyl lithium, the epimeric 15a and 15ß alcohols (PG numbering) are usually obtained, which can be separated if desired, and into which one optionally introduces a hydroxyl protecting group on the 15 C atom. For example, a compound of the formula is obtained with dihydropyran
(X) (X)
\W-D-E-R. \ W-D-E-R.
Das so erhaltene Lacton kann mit Diisobutylaluminium-hydrid zum Lactol der Formel IV reduziert werden. The lactone obtained in this way can be reduced to the lactol of the formula IV using diisobutylaluminum hydride.
Die neuen, erfindungsgemäss herstellbaren Prostansäure-amide der Formel I sind wertvolle Pharmaka, da sie bei 50 ähnlichem Wirkungsspektrum eine wesentlich verbesserte (höhere Spezifität) und vor allem wesentlich längere Wirkung aufweisen als die entsprechenden natürlichen Prostaglandine. Im Vergleich zu PGE- und PGA-Derivaten zeichnen sich die neuen 11-Desoxyprostaglandine durch grössere Stabilität aus. 65 Einige der neuen Verbindungen haben eine starke antifertile Wirksamkeit. Zur Auslösung von Aborten sind wesentlich geringere Mengen der neuen Prostansäureamide im Vergleich zu den natürlichen Prostaglandinen erforderlich. The new prostanoic acid amides of the formula I which can be prepared according to the invention are valuable pharmaceuticals because, with a similar spectrum of activity, they have a significantly improved (higher specificity) and, above all, a substantially longer activity than the corresponding natural prostaglandins. Compared to PGE and PGA derivatives, the new 11-deoxyprostaglandins are characterized by greater stability. 65 Some of the new compounds have strong antifertile activity. Much smaller amounts of the new prostanoic acid amides are required to trigger abortions compared to the natural prostaglandins.
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6 6
Bei der Registrierung der isotonischen Uteruskontraktion an der narkotisierten Ratte und am isolierten Ratten- oder Meerschweinchenuterus zeigt sich, dass die erfindungsgemäss erhaltenen Substanzen wesentlich wirksamer sind und ihre Wirkungen länger anhalten als bei den natürlichen Prostaglandinen. When registering the isotonic uterine contraction on the anesthetized rat and on the isolated rat or guinea pig uterus, it is found that the substances obtained according to the invention are considerably more effective and their effects last longer than with natural prostaglandins.
Einige der neuen Prostansäureamide sind geeignet, nach einmaliger intrauteriner oder vaginaler Applikation eine Menstruation zu induzieren oder eine Schwangerschaft zu unterbrechen. Ein Teil der Verbindungen wirkt luteolytisch und eignet sich zur Synchronisation des Sexualzyklus bei weiblichen Säugetieren wie Affen, Pferden, Rindern, Schweinen usw. Some of the new prostanoic acid amides are suitable for inducing menstruation or interrupting pregnancy after a single intrauterine or vaginal application. Some of the compounds have a luteolytic effect and are suitable for synchronizing the sexual cycle in female mammals such as monkeys, horses, cattle, pigs, etc.
Die gute Gewebsspezifität der erfindungsgemäss herstellbaren antifertil wirksamen bzw. blutdrucksenkenden Substan-zei zeigt sich bei der Untersuchung an anderen glattmuskulären Organen, wie beispielsweise am Meerschweinchen-Ileum oder an der isolierten Kaninchen-Trachea, wo eine wesentlich geringere Stimulierung zu beobachten ist als durch die natürlichen Prostaglandine. The good tissue specificity of the antifertile active substance or antihypertensive substance that can be produced according to the invention is shown in the examination on other smooth muscular organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where a significantly lower stimulation is to be observed than by natural ones Prostaglandins.
Manche der erfindungsgemäss hergestellten Wirkstoffe zeigen an der isolierten Kaninchen-Trachea in vitro sogar eine bronchodilatatorische Wirkung und hemmen stark die Magensäuresekretion. Die blutdrucksenkend und diuretisch wirksamen Verbindungen wirken zusätzlich regulierend bei Herzrhythmusstörungen. Some of the active substances produced according to the invention even show a bronchodilator effect on the isolated rabbit trachea in vitro and strongly inhibit gastric acid secretion. The antihypertensive and diuretic compounds also regulate cardiac arrhythmias.
Für die medizinische Anwendung können die neuen Wirkstoffe in eine für die Inhalation, für orale, parenterale oder lokale (zum Beispiel vaginale) Applikation geeignete Form überführt werden. For medical use, the new active ingredients can be converted into a form suitable for inhalation, for oral, parenteral or local (for example vaginal) application.
Zur Inhalation werden zweckmässigerweise Aerosollösungen hergestellt. Aerosol solutions are expediently prepared for inhalation.
Für die orale Applikation sind beispielsweise Tabletten, Dragées oder Kapseln geeignet. For oral administration, for example, tablets, dragées or capsules are suitable.
Für die parenterale Verabreichung werden bevorzugt sterile, injizierbare, wässrige oder ölige Lösungen benutzt. Sterile, injectable, aqueous or oily solutions are preferably used for parenteral administration.
Für die vaginale Applikation sind z.B. Zäpfchen geeignet und üblich. For vaginal application e.g. Suppositories suitable and common.
Die erfindungsgemäss erhaltenen Wirkstoffe können in Verbindung mit den in der Galenik bekannten und üblichen Hilfsstoffen, z.B. zur Herstellung von Präparaten zur Auslösung eines Abortes, zur Zyklussteuerung, zur Einleitung einer Geburt oder zur Behandlung der Hypertonie dienen. The active compounds obtained according to the invention can be used in conjunction with the auxiliaries known and customary in galenics, e.g. for the preparation of preparations for inducing an abortion, for cycle control, for induction of birth or for the treatment of hypertension.
Kieselgel. Mit Methylenchlorid/Isopropanol (9+1) erhält man 320 mg der Titelverbindung als farbloses Öl. Silica gel. With methylene chloride / isopropanol (9 + 1), 320 mg of the title compound are obtained as a colorless oil.
IR (CHCI3): 3600, 3400, 2930, 2860, 1735, 1705, 1270, 972/cm. IR (CHCI3): 3600, 3400, 2930, 2860, 1735, 1705, 1270, 972 / cm.
5 5
Beispiel 3 Example 3
1 l-Desoxy-16,16-dimethyl-Prostaglandin-Ez-methylsulfonamid 1 l-deoxy-16,16-dimethyl-prostaglandin-Ez-methylsulfonamide
250 mg ll-Desoxy-l6,16-dimethyl-prostaglandin-E2-me-10 thylsulfonamid-15-tetrahydropyran-2-yl-äther rührt man 5 Stunden bei 45°C mit 10 ml einer Mischung aus Eisessig/ Wasser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an Kieselgel. Mit Methylenchlorid/Isopropanol (9 + 1) erhält 15 man 173 mg der Titelverbindung als farbloses Öl. 250 mg ll-deoxy-16,16-dimethyl-prostaglandin-E2-me-10 thylsulfonamid-15-tetrahydropyran-2-yl ether are stirred for 5 hours at 45 ° C with 10 ml of a mixture of glacial acetic acid / water / tetrahydrofuran ( 65/35/10), evaporated in vacuo and the residue purified by column chromatography on silica gel. With methylene chloride / isopropanol (9 + 1), 15 mg of the title compound are obtained as a colorless oil.
IR (CHC13): 3590, 3400, 2940, 2863, 1735, 1720, 1340, 975/cm. IR (CHC13): 3590, 3400, 2940, 2863, 1735, 1720, 1340, 975 / cm.
Beispiel 4 Example 4
20 (5Z,13E)-(15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20--tetranor-prostadiensäure-acetylamid 20 (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16-phenoxy-17,18,19,20 - tetranor-prostadienoic acid acetylamide
In Analogie zu Beispiel 2 erhält man aus 270 mg des entsprechenden 15-Tetrahydropyranyläthers mit 11 ml einer Mi-25 schung aus Eisessig/Wasser/Tetrahydrofuran (65/35/10) 190 mg der Titelverbindung als farbloses Öl. In analogy to Example 2, 190 mg of the corresponding 15-tetrahydropyranyl ether with 11 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) gives 190 mg of the title compound as a colorless oil.
IR (CHCI3): 3590, 3400, 1735, 1705, 1600, 975/cm. IR (CHCI3): 3590, 3400, 1735, 1705, 1600, 975 / cm.
30 30th
Beispiel 5 Example 5
ll-Desoxy-I6-methyl-prostaglandin-E2-ctcetylamid ll-deoxy-I6-methyl-prostaglandin-E2-ctcetylamide
390 mg ll-Desoxy-16-methyl-prostaglandin-E2-acetyl-amid-15-tetrahydropyran-2-yl-äther rührt man 16 Stunden bei Raumtemperatur mit 15 ml einer Mischung aus Eisessig/Was-35 ser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an Kieselgel. Mit Methylenchlorid/Isopropanol (9+1) erhält man 290 mg der Titelverbindung als farbloses Öl. 390 mg of II-deoxy-16-methyl-prostaglandin-E2-acetyl-amide-15-tetrahydropyran-2-yl ether are stirred for 16 hours at room temperature with 15 ml of a mixture of glacial acetic acid / water 35 / tetrahydrofuran (65 / 35/10), evaporates in vacuo and purifies the residue by column chromatography on silica gel. With methylene chloride / isopropanol (9 + 1), 290 mg of the title compound are obtained as a colorless oil.
IR (CHClg): 3650, 3400, 2935, 2860, 1735, 1705, 972/ IR (CHClg): 3650, 3400, 2935, 2860, 1735, 1705, 972 /
40 cm' 40 cm '
Beispiel 1 example 1
(5Z,13E)-( 15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20--tetranor-prostadiensäure-methylsulfonamid (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16-phenoxy-17,18,19,20 - tetranor-prostadienoic acid methylsulfonamide
300 mg (5Z,13E)-(15R)-9-oxo-15-(tetrahydropyran-2-yl--oxy)-16-phenoxy-17,18,19,20-tetranor-prostadiensäure-me-thylsulfonamid rührt man 5 Stunden bei 40°C mit 12 ml einer Mischung aus Eisessig/Wasser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an Kieselgel. Mit Methylenchlorid/ Isopropanol (9+1) erhält man 210 mg der Titelverbindung als farbloses Öl. 300 mg (5Z, 13E) - (15R) -9-oxo-15- (tetrahydropyran-2-yl - oxy) -16-phenoxy-17,18,19,20-tetranor-prostadienoic acid-methylsulfonamide are stirred 5 hours at 40 ° C with 12 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and the residue is purified by column chromatography on silica gel. With methylene chloride / isopropanol (9 + 1), 210 mg of the title compound are obtained as a colorless oil.
IR (CHClg): 3590, 3400,2940, 2860, 1736, 1720, 1600, 1340, 972/cm. IR (CHClg): 3590, 3400, 2940, 2860, 1736, 1720, 1600, 1340, 972 / cm.
Beispiel 2 Example 2
1 l-Desoxy-16,16-dimethyl-Prostaglandin-Ez-acetylamid 1 l-deoxy-16,16-dimethyl-prostaglandin-Ez-acetylamide
450 mg 1 l-Desoxy-16,16-dimethyl-prostaglandin-E2-ace-tylamid-15-tetrahydropyran-2-yl-äther rührt man 16 Stunden bei Raumtemperatur mit 16 ml einer Mischung aus Eisessig/ Wasser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an 450 mg of 1 l-deoxy-16,16-dimethyl-prostaglandin-E2-ace-tylamide-15-tetrahydropyran-2-yl ether are stirred for 16 hours at room temperature with 16 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65 / 35/10), evaporated in vacuo and the residue purified by column chromatography
Beispiel 6 Example 6
ll-Desoxy-16-methyl-Prostaglandin-E2-methylsulfonamid ll-deoxy-16-methyl-prostaglandin-E2-methylsulfonamide
45 320 mg ll-Desoxy-16-methyl-prostaglandin-E2-methyl-sulfonamid-15-tetrahydropyran-2-yläther rührt man 5 Stunden bei 45°C mit 13 ml einer Mischung aus Eisessig/Wasser/Te-trahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an Kiesel-50 gel. Mit Methylenchlorid/Isopropanol (9+1) erhält man 240 mg der Titelverbindung als farbloses Öl. 45 320 mg ll-deoxy-16-methyl-prostaglandin-E2-methyl-sulfonamide-15-tetrahydropyran-2-yl ether are stirred for 5 hours at 45 ° C with 13 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65 / 35/10), evaporated in vacuo and the residue is purified by column chromatography on silica gel 50. With methylene chloride / isopropanol (9 + 1), 240 mg of the title compound are obtained as a colorless oil.
IR (CHCI3): 3600, 3400, 2940, 2860, 1735, 1720, 1340, 972/cm. IR (CHCI3): 3600, 3400, 2940, 2860, 1735, 1720, 1340, 972 / cm.
55 Beispiel 7 55 Example 7
(5Z,13E)-(9S,15S)-9,15-Dihydroxy-17-phenyl-18,19,20--trinor-prostadiensäure-methylsulfonamid (5Z, 13E) - (9S, 15S) -9,15-dihydroxy-17-phenyl-18,19,20 - trinor-prostadienoic acid methylsulfonamide
Zu einer Lösung von 2,6 g [4-(MethansulfonyIamino-60 carbonyl)-buty]]-triphenyl-phosphoniumbromid in 10 ml trok-kenem Dimethylsulfoxid tropft man bei 15°C 10 ml einer Lösung von Methansulfinylmethylnatrium in DMSO (Herstellung: Man löst 0,5 g 50%ige Natriumhydridsuspension in 10 ml DMSO während einer Stunde bei 70°C) und rührt 15 65 Minuten bei Raumtemperatur. Zur roten Ylenlösung tropft man eine Lösung von 355 mg (3RS,3aR,4R,6aS,3'S)-4-[(E)--3-Hydroxy-5-phenyl-l-pentenyl]-2-hydroxy-perhydrocyclo-penta[b]-furan in 7 ml DMSO und rührt 4 Stunden bei 45°C. 10 ml of a solution of methanesulfinylmethyl sodium in DMSO are dripped into a solution of 2.6 g of [4- (methanesulfonylamino-60 carbonyl) -buty]] triphenylphosphonium bromide in 10 ml of dry dimethyl sulfoxide at 15.degree. C. (Preparation: Man dissolves 0.5 g of 50% sodium hydride suspension in 10 ml of DMSO for one hour at 70 ° C) and stirred for 15 65 minutes at room temperature. A solution of 355 mg (3RS, 3aR, 4R, 6aS, 3'S) -4 - [(E) - 3-hydroxy-5-phenyl-1-pentenyl] -2-hydroxy-perhydrocyclopenta is added dropwise to the red ylene solution [b] -furan in 7 ml DMSO and stirred for 4 hours at 45 ° C.
7 7
632493 632493
Das Reaktionsgemisch wird auf Eiswasser gegossen, mit 10%-iger Zitronensäurelösung auf pH 4-5 angesäuert und viermal mit je 50 ml eines Gemisches aus Äther/Pentan (1 +1) extrahiert. Die organische Phase wird mit Sole geschüttelt, über Magnesiumsulfat getrocknet und im Vakuum eingedampft. Nach Chromatographie des Rückstandes an Kieselgel erhält man mit Methylenchlorid/Isopropanol (8+2) 310 mg der Titelverbindung als farbloses Öl. The reaction mixture is poured onto ice water, acidified to pH 4-5 with 10% citric acid solution and extracted four times with 50 ml of a mixture of ether / pentane (1 +1). The organic phase is shaken with brine, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel, 310 mg of the title compound are obtained as a colorless oil with methylene chloride / isopropanol (8 + 2).
IR (CHClj): 3600, 3400, 2940, 1720, 1600, 1585, 1345, 972/cm. IR (CHClj): 3600, 3400, 2940, 1720, 1600, 1585, 1345, 972 / cm.
Das Ausgangsmaterial für die obige Verbindung wird wie folgt hergestellt: The starting material for the above compound is made as follows:
a) (lS,5R,6R)-6-[(E)-3-oxo-5-phenyl-l-pentenyl]-2-oxa-bi-cyclo-[3.3.0]-octan-3-on a) (IS, 5R, 6R) -6 - [(E) -3-oxo-5-phenyl-1-pentenyl] -2-oxa-bi-cyclo [3.3.0] octan-3-one
Aus 1,3 g (lS,5R,6S)-6-Formyl-2-oxa-bicyclo-[3.3.0]--octan-3-on und 2,8 g Dimethyl-2-oxo-4-phenylbutylphosphat erhält man 1,35 g der Titelverbindung als farbloses Öl. Obtained from 1.3 g of (IS, 5R, 6S) -6-formyl-2-oxa-bicyclo [3.3.0] octan-3-one and 2.8 g of dimethyl-2-oxo-4-phenylbutyl phosphate 1.35 g of the title compound as a colorless oil.
IR (CHCI3): 1770, 1695, 1670, 1655, 1600, 1585, 972/cm. IR (CHCI3): 1770, 1695, 1670, 1655, 1600, 1585, 972 / cm.
b) (lS,5R,6R,3'S)-6-[(E)-3-Hydroxy-5-phenyl-l-pentenyl]-2--oxa-bicyclo-[ 3.3.0 ]-octan-3-on b) (IS, 5R, 6R, 3'S) -6 - [(E) -3-hydroxy-5-phenyl-1-pentenyl] -2 - oxa-bicyclo [3.3.0] octan-3-one
Aus 1,2 g des nach Beispiel 7 a) erhaltenen Ketons stellt man 410 mg der Titelverbindung als farbloses Öl. 410 mg of the title compound are prepared as a colorless oil from 1.2 g of the ketone obtained according to Example 7 a).
IR (CHC13): 3600, 1770, 1600, 1585, 972/cm. IR (CHC13): 3600, 1770, 1600, 1585, 972 / cm.
c) (2RS,3aR,4R,6aS,3'S)-4-[(E)-3-Hydroxy-5-phenyl-l-pen-tenyl]-2-hydroxy-perhydrocyclopenta[b]-furan c) (2RS, 3aR, 4R, 6aS, 3'S) -4 - [(E) -3-Hydroxy-5-phenyl-l-pentenyl] -2-hydroxy-perhydrocyclopenta [b] furan
Zu einer auf — 65°C gekühlten Lösung von 400 mg der nach Beispiel 7 b) hergestellten Verbindung in 15 ml trockenem Toluol tropft man unter Argon 4 ml einer 20% igen Lösung von Diisobutylaluminiumhydrid in Toluol, rührt 30 Minuten bei — 65°C und beendet die Reaktion durch tropfenweise Zugabe von Isopropanol. Man versetzt mit 1,5 ml Wasser, lässt auf Raumtemperatur erwärmen, rührt 30 Minuten, filtriert und dampft im Vakuum ein. Dabei erhält man 390 mg der Titelverbindung als farbloses Öl. 4 ml of a 20% solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 400 mg of the compound prepared according to Example 7 b) in 15 ml of dry toluene, cooled to -65 ° C., and the mixture is stirred at -65 ° C. for 30 minutes and terminate the reaction by dropwise addition of isopropanol. 1.5 ml of water are added, the mixture is allowed to warm to room temperature, stirred for 30 minutes, filtered and evaporated in vacuo. This gives 390 mg of the title compound as a colorless oil.
IR: 3600, 1600, 1585, 972/cm. IR: 3600, 1600, 1585, 972 / cm.
Beispiel 9 Example 9
ll-Desoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-E2--acetylamid ll-deoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-E2 - acetylamide
5 355 mg ll-Desoxy-13,14-dihydro-16,16-dimethyl-prosta-glandin-E2-acetylamid-15-tetrahydropyran-2-yläther rührt man 4 Stunden bei 50°C mit 12 ml einer Mischung aus Eisessig/ Wasser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie 10 an Kieselgel. Mit Methylenchlorid/Isopropanol (9 + 1) erhält man 280 mg der Titelverbindung als farbloses Öl. 5 355 mg of II-deoxy-13,14-dihydro-16,16-dimethyl-prosta-glandin-E2-acetylamide-15-tetrahydropyran-2-yl ether are stirred for 4 hours at 50 ° C. with 12 ml of a mixture of glacial acetic acid / Water / tetrahydrofuran (65/35/10), evaporated in vacuo and the residue purified by column chromatography 10 on silica gel. With methylene chloride / isopropanol (9 + 1), 280 mg of the title compound are obtained as a colorless oil.
IR (CHCI3): 3600, 3400, 1735, 1705, 1270/cm. IR (CHCI3): 3600, 3400, 1735, 1705, 1270 / cm.
15 15
Beispiel 8 Example 8
(5Z,I3E)-( 15S)-15-Hydroxy-9-oxo-17 -phenyl-18,19,20-trinor--prostadiensäure-methylsulfonamid (5Z, I3E) - (15S) -15-hydroxy-9-oxo-17-phenyl-18,19,20-trinor - prostadienoic acid methylsulfonamide
Zu einer Lösung von 100 mg des nach Beispiel 7 hergestellten Sulfonamids in 4 ml absolutem Aceton gibt man bei —45°C 1,2 ml N,N-Diäthyltrimethylsilylamin und rührt 6 Stunden bei —40°C. Anschliessend verdünnt man mit 40 ml Äther, den man vorher auf — 70°C abgekühlt hat, schüttelt einmal mit 5 ml eisgekühlter Natriumbicarbonatlösung und zweimal mit je 5 ml Sole, trocknet mit Natriumsulfat und dampft im Vakuum ein. Den auf diese Art erhaltenen 15-(Tri-methylsilyläther) löst man in 15 ml absolutem Methylenchlorid und versetzt bei +5°C mit einer Lösung von 700 mg Collins-Reagenz (Herstellung: siehe Org. Synthesis Vol. 52, 5), rührt 10 Minuten, verdünnt mit 50 ml Äther, filtriert und dampft im Vakuum ein. Zur Abspaltung der Silylätherschutz-gruppe rührt man den Rückstand mit einer Mischung aus 9 ml Methanol, 0,9 ml Wasser und 0,45 ml Eisessig 45 Minuten bei Raumtemperatur. Anschliessend verdünnt man mit 50 ml Äther, schüttelt mit gesättigter Natriumbicarbonatlösung zweimal mit je 10 ml Sole, trocknet über Magnesiumsulfat und dampft im Vakuum ein. Nach Reinigung durch präparative Schichtchromatographie (Methylenchlorid/Methanol 9 + 1 als Laufmittel) an Kieselgelplatten erhält man 33 mg der Titelverbindung als schwach gelb gefärbtes Öl. 1.2 ml of N, N-diethyltrimethylsilylamine are added to a solution of 100 mg of the sulfonamide prepared according to Example 7 in 4 ml of absolute acetone at −45 ° C. and the mixture is stirred at −40 ° C. for 6 hours. The mixture is then diluted with 40 ml of ether, which has previously been cooled to -70 ° C., shaken once with 5 ml of ice-cooled sodium bicarbonate solution and twice with 5 ml of brine, dried with sodium sulfate and evaporated in vacuo. The 15- (tri-methylsilyl ether) obtained in this way is dissolved in 15 ml of absolute methylene chloride and mixed with a solution of 700 mg of Collins reagent (preparation: see Org. Synthesis Vol. 52, 5) at + 5 ° C., stirred 10 minutes, diluted with 50 ml ether, filtered and evaporated in vacuo. To split off the silyl ether protection group, the residue is stirred with a mixture of 9 ml of methanol, 0.9 ml of water and 0.45 ml of glacial acetic acid at room temperature for 45 minutes. The mixture is then diluted with 50 ml of ether, shaken twice with saturated sodium bicarbonate solution, each with 10 ml of brine, dried over magnesium sulfate and evaporated in vacuo. After purification by preparative layer chromatography (methylene chloride / methanol 9 + 1 as eluent) on silica gel plates, 33 mg of the title compound are obtained as a pale yellow oil.
IR (CHC13): 3600, 3400, 1735, 1720, 1600, 1585, 975/ IR (CHC13): 3600, 3400, 1735, 1720, 1600, 1585, 975 /
cm. cm.
Beispiel 10 Example 10
(5Z,13E)-(9S,15R)-9,15-Dihydroxy-16-phenoxy-17,18,19,20--tetranor-prostadiensäure-methylsulfonamid (5Z, 13E) - (9S, 15R) -9,15-dihydroxy-16-phenoxy-17,18,19,20 - tetranor-prostadienoic acid methylsulfonamide
20 200 mg einer entsprechend geschützten Verbindung rührt man 5 Stunden bei 45°C mit 8 ml einer Mischung aus Eis-essig/Wasser/Tetrahydrofuran (65/35/10), dampft im Vakuum ein und reinigt den Rückstand durch Säulenchromatographie an Kieselgel. Mit Chloroform/Methanol (9 +1) erhält 25 man 140 mg der Titelverbindung als farbloses Öl. 20 200 mg of a correspondingly protected compound is stirred for 5 hours at 45 ° C. with 8 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10), evaporated in vacuo and the residue is purified by column chromatography on silica gel. With chloroform / methanol (9 +1), 25 mg of the title compound are obtained as a colorless oil.
IR (CHClj): 3600, 3400, 2940, 1720, 1600, 1340, 975/ IR (CHClj): 3600, 3400, 2940, 1720, 1600, 1340, 975 /
cm. cm.
Beispiel 11 Example 11
30 In Analogie zu den Beispielen 1, 2, 7, 8, 9 und 10 lassen sich die folgenden Prostaglandine herstellen: (5Z,13E)-(15R)-15-Hydroxy-9-Oxo-16-(4-chlorphenoxy)-17, 18,19,20-tetranor-prostadiensäure-methylsulfonamid (5Z, 13E)-( 15R)-15-Hydroxy-9-oxo-16-(3-chlorphenoxy)-35 -17,18,19,20-tetranor-prostadiensäure-methylsulfonamid (5Z, 13E)-(15R)-15-Hydroxy-9-oxo-16-(4-f luorphenoxy)--17,18,19,20-tetranor-prostadiensäure-methylsulfonamid (5Z,13E)-(15R)-15-Hydroxy-9-oxo-16-(3-trifIuormethyl-phenoxy)-17,18,19,20-tetranor-prostadiensäure-methy lsulfon-40 amid 30 The following prostaglandins can be prepared analogously to Examples 1, 2, 7, 8, 9 and 10: (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16- (4-chlorophenoxy) - 17, 18,19,20-tetranor-prostadienoic acid methylsulfonamide (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16- (3-chlorophenoxy) -35 -17,18,19,20-tetranor -prostadienoic acid-methylsulfonamide (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16- (4-f luorphenoxy) - 17,18,19,20-tetranor-prostadienoic acid-methylsulfonamide (5Z, 13E) - (15R) -15-Hydroxy-9-oxo-16- (3-trifluoromethyl-phenoxy) -17,18,19,20-tetranor-prostadienoic acid methyl sulfone-40 amide
(5Z,13E)-(9S,15R)-9,15-Dihydroxy-16-(4-Chlorphenoxy)--17,18,19,20-tetranor-prostadiensäure-methylsulfonamid (5Z)-( 15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetra-nor-prostensäure-methylsulfonamid 45 11-Desoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-E2--methylsulfonamid (5Z, 13E) - (9S, 15R) -9,15-dihydroxy-16- (4-chlorophenoxy) - 17,18,19,20-tetranor-prostadienoic acid methylsulfonamide (5Z) - (15R) -15- Hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetra-nor-prostenic acid-methylsulfonamide 45 11-deoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-E2 - methylsulfonamide
11-Desoxy-l 3,14-dihydro-16-methyl-prostagIandin-E2-methyl-sulfonamid 11-deoxy-l 3,14-dihydro-16-methyl-prostagiandin-E2-methyl-sulfonamide
11 -Desoxy-13,14-dihydro-16-methyl-prostaglandin-E2-acety 1-50 amid 11-Deoxy-13,14-dihydro-16-methyl-prostaglandin-E2-acety 1-50 amide
(5Z)-(15S)-15-Hydroxy-15-methyl-9-oxo-prostensäure-methyl-sulfonamid (5Z) - (15S) -15-Hydroxy-15-methyl-9-oxo-prostensäure-methyl-sulfonamide
(5Z)-( 15S)-15-Hydroxy-15-methyl-9-oxo-prostensäure-acetyl-amid (5Z) - (15S) -15-Hydroxy-15-methyl-9-oxo-prostonic acid-acetyl-amide
55 11 -Desoxy-13,14-dihydro-prostaglandin-E2-methylsulfonamid ll-Desoxy-13,14-dihydro-prostaglandin-E2-acetylamid (5Z, 13E)-( 15S)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20--tetranor-prostadiensäure-methylsulfonamid (5Z, 13E)-( 15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20-60 -tetranor-prostadiensäure-phenylsulfonamid 55 11 -Desoxy-13,14-dihydro-prostaglandin-E2-methylsulfonamide II-deoxy-13,14-dihydro-prostaglandin-E2-acetylamide (5Z, 13E) - (15S) -15-hydroxy-9-oxo-16 -phenoxy-17,18,19,20 - tetranor-prostadienoic acid-methylsulfonamide (5Z, 13E) - (15R) -15-hydroxy-9-oxo-16-phenoxy-17,18,19,20-60 -tetranor -prostadien acid-phenylsulfonamide
1 l-Desoxy-16,16-dimethyl-prostaglandin-E2-phenylsulfonamid 1 l-Desoxy-16,16-dimethyl-prostaglandin-E2-benzoylamid (5Z, 13E)-( 11R, 15R)-15-Hydroxy-11 -methy 1-9-oxo-16-phenoxy- 17,18,19,20-tetranor-prostadiensäure-methylsulf onamid 65 11-Desoxy-l 1 a-16,16-trimethyl-prostaglandin-E2-methyI-sulfonamid 1 l-deoxy-16,16-dimethyl-prostaglandin-E2-phenylsulfonamide 1 l-deoxy-16,16-dimethyl-prostaglandin-E2-benzoylamide (5Z, 13E) - (11R, 15R) -15-hydroxy-11 - methyl 1-9-oxo-16-phenoxy-17,18,19,20-tetranor-prostadienoic acid-methylsulfonamide 65 11-deoxy-l 1 a-16,16-trimethyl-prostaglandin-E2-methyl-sulfonamide
11-Desoxy-l la,16-dimethyl-prostaglandin-E2-methylsulfon-amid. 11-deoxy-l la, 16-dimethyl-prostaglandin-E2-methylsulfone-amide.
632493 632493
8 8th
Beispiel 12 Example 12
(13E)-(15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20--tetranor-prostensäure-methylsulfonamid (13E) - (15R) -15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20 - tetranor-prostensic acid methylsulfonamide
Man schüttelt eine Lösung von 220 mg der nach Beispiel 1 hergestellten Verbindung in 20 ml Essigester mit 20 mg Palladium (10%ig auf Kohle) unter einer Wasserstoffatmosphäre bei — 25°C und verfolgt den Verlauf der Hydrierung dünn-schichtchromatographisch. Nach 1,5 Stunden spült man mit Stickstoff, filtriert und dampft im Vakuum ein. Nach Chromatographie an Kieselgel mit Methylenchlorid/Isopropanol (9+1) erhält man 163 mg der Titelverbindung als farbloses Öl. A solution of 220 mg of the compound prepared according to Example 1 in 20 ml of ethyl acetate with 20 mg of palladium (10% on carbon) is shaken under a hydrogen atmosphere at - 25 ° C. and the course of the hydrogenation is followed by thin-layer chromatography. After 1.5 hours, the mixture is flushed with nitrogen, filtered and evaporated in vacuo. After chromatography on silica gel with methylene chloride / isopropanol (9 + 1), 163 mg of the title compound are obtained as a colorless oil.
IR (CHC13): 3595, 3400, 2940, 2860, 1735, 1720, 1600, 1340, 972/cm. IR (CHC13): 3595, 3400, 2940, 2860, 1735, 1720, 1600, 1340, 972 / cm.
Beispiel 13 Example 13
( 13E)-( 15S)-15-Hydroxy-l 5-methyl-9-oxo-prostensäure- (13E) - (15S) -15-Hydroxy-l 5-methyl-9-oxo-prostic acid-
-acetylamid acetylamide
In Analogie zu Beispiel 12 erhält man aus 160 mg der nach Beispiel 17 hergestellten Verbindung 105 mg der Titelverbindung als farbloses Öl. In analogy to Example 12, 105 mg of the title compound is obtained as a colorless oil from 160 mg of the compound prepared according to Example 17.
IR (CHCI3): 3600, 3400, 1735, 1705, 972/cm. IR (CHCI3): 3600, 3400, 1735, 1705, 972 / cm.
Beispiel 14 Example 14
11 -Desoxy-16,16-dimethyl-prostaglcmdin-E ^acetylamid 11-Deoxy-16,16-dimethyl-prostaglcmdin-E ^ acetylamide
In Analogie zu Beispiel 12 erhält man aus 150 mg der nach Beispiel 6 hergestellten Verbindung 125 mg der Titelverbindung als farbloses Öl. Analogously to Example 12, from 150 mg of the compound prepared according to Example 6, 125 mg of the title compound are obtained as a colorless oil.
IR (CHClj): 3600,3400, 2935, 2860, 1735, 1705, 1270, 972/cm. IR (CHClj): 3600.3400, 2935, 2860, 1735, 1705, 1270, 972 / cm.
Beispiel 15 Example 15
11-Desoxy-l 6-methyl-prostaglandin-E^acetylamid 11-deoxy-1 6-methyl-prostaglandin-E ^ acetylamide
In Analogie zu Beispiel 12 erhält man aus 110 mg der nach Beispiel 9 hergestellten Verbindung 85 mg der Titelverbindung als farbloses öl. Analogously to Example 12, 85 mg of the title compound are obtained as a colorless oil from 110 mg of the compound prepared according to Example 9.
IR (CHCI3): 3600, 3400, 2925, 2860, 1735, 1705, 972/ IR (CHCI3): 3600, 3400, 2925, 2860, 1735, 1705, 972 /
cm. cm.
Beispiel 16 Example 16
In Analogie zu Beispiel 12 können aus den entsprechenden Prostadiensäureamiden die folgenden Prostensäureamide hergestellt werden: In analogy to Example 12, the following prostatic acid amides can be prepared from the corresponding prostadic acid amides:
(13E)-(15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20--tetranor-prostensäure-acetylamid (13E) - (15R) -15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20 - tetranor-prostic acid acetylamide
( 13 E)-( 15S)-15-Hydroxy-15-methyl-9-oxo-prostensäure-me-thylsulfonamid (13E) - (15S) -15-Hydroxy-15-methyl-9-oxo-prostenic acid-methylsulfonamide
11 -Desoxy-16,16-dimethyl-prostaglandin-Ej-methylsulf onamid 11-Deoxy-16,16-dimethyl-prostaglandin-Ej-methylsulfonamide
11-Desoxy-l 6-methyl-prostaglandin-Ei-methylsulfonamid 11-deoxy-l 6-methyl-prostaglandin-egg-methylsulfonamide
11-Desoxy-l la-methyl-prostaglandin-Ermethylsulfonamid 11-deoxy-l la-methyl-prostaglandin-ermethylsulfonamide
(13E)-(11R, 15RS)-1 l,15-Dimethyl-15-hydroxy-9-oxo-prosten- (13E) - (11R, 15RS) -1 l, 15-dimethyl-15-hydroxy-9-oxo-prosten-
säure-methylsulfonamid acid methylsulfonamide
11-Desoxy-prostaglandin-Ej-methylsulfonamid 11-deoxy-prostaglandin-Ej-methylsulfonamide
( 13S)-( 15S)-15-Hydroxy-9-oxo-l 7-phenyl-18,19,20-trinor- (13S) - (15S) -15-hydroxy-9-oxo-l 7-phenyl-18,19,20-trinor-
-prostensäure-methylsulfonamid -prostenic acid-methylsulfonamide
11-Desoxy-l la-methyl-prostaglandin-E1-acetylamid 11-deoxy-l la-methyl-prostaglandin-E1-acetylamide
(13E)-(11R,15RS)-1 l,15-Dimethyl-15-hydroxy-9-oxo-prosten- (13E) - (11R, 15RS) -1 l, 15-dimethyl-15-hydroxy-9-oxo-prosten-
säure-acetylamid acid acetylamide
11 -Desoxy-prostaglandin-Ej-acetylamid 11-Deoxy-prostaglandin-Ej-acetylamide
( 13E)-(9S, 15R)-9,15-Dihydroxy-16-phenoxy-17,18,19,20- (13E) - (9S, 15R) -9.15-dihydroxy-16-phenoxy-17.18, 19.20-
-tetranor-prostensäure-methylsulfonamid. -tetranor-prostic acid-methylsulfonamide.
Beispiel 17 Example 17
(15R)-15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranor--prostansäure-methylsulfonamid (15R) -15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranor - prostanoic acid methylsulfonamide
Man schüttelt eine Lösung von 150 mg der nach Beispiel 1 hergestellten Verbindung in 15 ml Essigester mit 15 mg Palladium (10%ig auf Kohle) 1 Stunde unter einer Wasserstoffatmosphäre bei Raumtemperatur. Nach Filtration erhält man durch Chromatographie des Eindampfrückstandes an Kieselgel mit Chloroform/Isopropanol (9 + 1) 95 mg der Titelverbindung als farbloses Öl. A solution of 150 mg of the compound prepared according to Example 1 in 15 ml of ethyl acetate with 15 mg of palladium (10% on carbon) is shaken for 1 hour under a hydrogen atmosphere at room temperature. After filtration, chromatography of the evaporation residue on silica gel with chloroform / isopropanol (9 + 1) gives 95 mg of the title compound as a colorless oil.
IR (CHClg): 3600, 3400,2940, 2860, 1735, 1720,1600, 1340/cm. IR (CHClg): 3600, 3400, 2940, 2860, 1735, 1720, 1600, 1340 / cm.
Das NMR-Spektrum zeigt keine olefinischen Protonen. The NMR spectrum shows no olefinic protons.
Beispiel 18 Example 18
( 15S)-15-Hydroxy-l 5-methyl-9-oxo-prostansäure-acetylamid (15S) -15-Hydroxy-l 5-methyl-9-oxo-prostanoic acid acetylamide
In Analogie zu Beispiel 17 erhält man aus 130 mg einer entsprechenden Verbindung 89 mg der Titelverbindung als farbloses Öl. Analogously to Example 17, 89 mg of the title compound is obtained as a colorless oil from 130 mg of a corresponding compound.
IR (CHCI3): 3600, 3400, 1735, 1705/cm. IR (CHCI3): 3600, 3400, 1735, 1705 / cm.
Beispiel 19 Example 19
1 l-Desoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-Ej--acetylamid 1 l-deoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-Ej - acetylamide
In Analogie zu Beispiel 17 erhält man aus 115 mg der nach Beispiel 6 hergestellten Verbindung 88 mg der Titelverbindung als farbloses Öl. Analogously to Example 17, 88 mg of the title compound are obtained as a colorless oil from 115 mg of the compound prepared according to Example 6.
IR (CHCI3): 3600, 3400, 1735, 1705, 1270/cm. IR (CHCI3): 3600, 3400, 1735, 1705, 1270 / cm.
Beispiel 20 Example 20
1 l-Desoxy-13,14-dihy dro-16-methyl-prostaglandin-Ef -acetylamid 1 l-deoxy-13,14-dihy dro-16-methyl-prostaglandin-Ef -acetylamide
In Analogie zu Beispiel 17 erhält man aus 95 mg der nach Beispiel 9 hergestellten Verbindung 62 mg der Titelverbindung als farbloses Öl. Analogously to Example 17, from 95 mg of the compound prepared according to Example 9, 62 mg of the title compound are obtained as a colorless oil.
IR (CHCI3): 3600, 3400, 2930, 2860, 1735, 1705/cm. IR (CHCI3): 3600, 3400, 2930, 2860, 1735, 1705 / cm.
Beispiel 21 Example 21
In Analogie zu Beispiel 17 können aus den entsprechenden Prostadiensäureamiden die folgenden Prostansäureamide hergestellt werden: In analogy to Example 17, the following prostanoic acid amides can be prepared from the corresponding prostanic acid amides:
( 15R)-15-Hy droxy-9-oxo-16-phenoxy-17,18,19,20-tetranor--prostansäure-acetylamid (15R) -15-Hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranor - prostanoic acid acetylamide
(15S)-15-Hydroxy-15-methyl-9-oxo-prostansäure-acetylamid 11-Desoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-Ei--methylsulfonamid (15S) -15-Hydroxy-15-methyl-9-oxo-prostanoic acid-acetylamide 11-deoxy-13,14-dihydro-16,16-dimethyl-prostaglandin-egg-methylsulfonamide
1 l-Desoxy-13,14-dihydro-16-methyl-prostaglandin-Ej-methyl-sulfonamid 1 l-deoxy-13,14-dihydro-16-methyl-prostaglandin-Ej-methyl-sulfonamide
11-Desoxy-13,14-dihydro-11 a-methyl-prostaglandin-E^me-thylsulfonamid 11-deoxy-13,14-dihydro-11 a-methyl-prostaglandin-E-methyl-sulfonamide
(llR,15RS)-ll,15-Dimethyl-15-hydroxy-9-oxo-prostansäure--methylsulfonamid ll-Desoxo-13,14-dihydro-prostaglandin-E1-methylsulfonamid 11-Desoxy-13,14-dihydro-1 la-methyl-prostaglandin-Eracetyl-amid (llR, 15RS) -ll, 15-dimethyl-15-hydroxy-9-oxo-prostanoic acid - methylsulfonamide ll-deoxo-13,14-dihydro-prostaglandin-E1-methylsulfonamide 11-deoxy-13,14-dihydro-1 la-methyl-prostaglandin-eracetyl-amide
(llR,15RS)-ll,15-DimethyI-15-hydroxy-9-oxo-prostansäure--acetylamid (llR, 15RS) -ll, 15-dimethyI-15-hydroxy-9-oxo-prostanoic acid - acetylamide
1 l-Desoxy-13,14-dihydro-prostaglandin-Ej-acetylamid. 1 l-deoxy-13,14-dihydro-prostaglandin-Ej-acetylamide.
5 5
10 10th
15 15
20 20th
25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
60 60
65 65
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762629834 DE2629834A1 (en) | 1976-06-30 | 1976-06-30 | NEW PROSTANIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH632493A5 true CH632493A5 (en) | 1982-10-15 |
Family
ID=5982096
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH794777A CH632492A5 (en) | 1976-06-30 | 1977-06-28 | Process for preparing novel prostanoic acid derivatives |
| CH664281A CH632493A5 (en) | 1976-06-30 | 1981-10-16 | Process for preparing novel prostanoic acid derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH794777A CH632492A5 (en) | 1976-06-30 | 1977-06-28 | Process for preparing novel prostanoic acid derivatives |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS537648A (en) |
| BE (1) | BE856326A (en) |
| CH (2) | CH632492A5 (en) |
| DE (1) | DE2629834A1 (en) |
| DK (1) | DK292777A (en) |
| FR (1) | FR2356636A1 (en) |
| GB (1) | GB1588157A (en) |
| IE (1) | IE45606B1 (en) |
| IT (1) | IT1114813B (en) |
| LU (1) | LU77648A1 (en) |
| NL (1) | NL7706588A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0022443B1 (en) * | 1979-07-17 | 1984-09-26 | Pfizer Inc. | N-alkanesulfonyl 16,16-dimethyl-17-oxaprostaglandin carboxamides |
| JPS6033429B2 (en) * | 1980-04-28 | 1985-08-02 | 小野薬品工業株式会社 | Prostaglandin-like compounds |
| US4292445A (en) * | 1980-04-28 | 1981-09-29 | The Upjohn Company | Amide and sulfonamide derivatives of 2-decarboxy-2-aminomethyl-PG-type compounds |
| JPS6127087A (en) * | 1984-07-16 | 1986-02-06 | 株式会社東芝 | Induction heating cooking device |
| US5385945A (en) * | 1992-10-21 | 1995-01-31 | Allergan, Inc. | 7-(5-substituted cyclopentyl) and (5-substituted cyclopentenyl) heptyl alcohols, heptylamines and heptanoic acid amides, and method of lowering intraocular pressure in the eye of a mammal by administration of these novel compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1440361A (en) | 1972-07-24 | 1976-06-23 | American Cyanamid Co | 11-deoxyprostaglandins of the e and f series and the preparation thereof |
| IE43462B1 (en) * | 1975-06-23 | 1981-03-11 | Pfizer | Substituted tetranorprostaglandins |
-
1976
- 1976-06-30 DE DE19762629834 patent/DE2629834A1/en not_active Withdrawn
-
1977
- 1977-06-15 NL NL7706588A patent/NL7706588A/en not_active Application Discontinuation
- 1977-06-27 IE IE1305/77A patent/IE45606B1/en unknown
- 1977-06-28 LU LU77648A patent/LU77648A1/xx unknown
- 1977-06-28 IT IT7725122A patent/IT1114813B/en active
- 1977-06-28 CH CH794777A patent/CH632492A5/en not_active IP Right Cessation
- 1977-06-29 GB GB27188/77A patent/GB1588157A/en not_active Expired
- 1977-06-30 DK DK292777A patent/DK292777A/en not_active Application Discontinuation
- 1977-06-30 BE BE178963A patent/BE856326A/en not_active IP Right Cessation
- 1977-06-30 FR FR7720092A patent/FR2356636A1/en active Granted
- 1977-06-30 JP JP7845177A patent/JPS537648A/en active Pending
-
1981
- 1981-10-16 CH CH664281A patent/CH632493A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| LU77648A1 (en) | 1977-10-10 |
| DK292777A (en) | 1977-12-31 |
| IT1114813B (en) | 1986-01-27 |
| IE45606B1 (en) | 1982-10-06 |
| FR2356636B1 (en) | 1980-04-25 |
| DE2629834A1 (en) | 1978-01-12 |
| NL7706588A (en) | 1978-01-03 |
| GB1588157A (en) | 1981-04-15 |
| FR2356636A1 (en) | 1978-01-27 |
| BE856326A (en) | 1977-12-30 |
| IE45606L (en) | 1977-12-30 |
| CH632492A5 (en) | 1982-10-15 |
| JPS537648A (en) | 1978-01-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |