DE2616304A1 - Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activities - Google Patents
Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activitiesInfo
- Publication number
- DE2616304A1 DE2616304A1 DE19762616304 DE2616304A DE2616304A1 DE 2616304 A1 DE2616304 A1 DE 2616304A1 DE 19762616304 DE19762616304 DE 19762616304 DE 2616304 A DE2616304 A DE 2616304A DE 2616304 A1 DE2616304 A1 DE 2616304A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- general formula
- acid
- compounds
- prostadien
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 230000002045 lasting effect Effects 0.000 title abstract 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 7
- 150000002148 esters Chemical class 0.000 title 1
- -1 benzodioxol-2-yl Chemical group 0.000 claims abstract description 128
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
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- 239000002253 acid Substances 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
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- 239000000543 intermediate Substances 0.000 claims abstract description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 16
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- 238000002360 preparation method Methods 0.000 claims description 8
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- 238000012986 modification Methods 0.000 claims description 4
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- 125000000468 ketone group Chemical group 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
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- 238000006243 chemical reaction Methods 0.000 description 13
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- 239000012230 colorless oil Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
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- 230000003647 oxidation Effects 0.000 description 9
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 150000003180 prostaglandins Chemical class 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
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- 239000012442 inert solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 239000003810 Jones reagent Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical class CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
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- 230000009467 reduction Effects 0.000 description 4
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- 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
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 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
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- IWYVYUZADLIDEY-UHFFFAOYSA-N 4-methoxybenzenesulfonic acid Chemical compound COC1=CC=C(S(O)(=O)=O)C=C1 IWYVYUZADLIDEY-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
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- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
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- 208000002991 Ring chromosome 4 syndrome Diseases 0.000 description 1
- 238000006932 Simmons-Smith cyclopropanation reaction Methods 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 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
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 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
- 235000010233 benzoic acid Nutrition 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
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- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 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
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 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
- 239000002775 capsule Substances 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical compound NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
- UYDJAHJCGZTTHB-UHFFFAOYSA-N cyclopentane-1,1-diol Chemical compound OC1(O)CCCC1 UYDJAHJCGZTTHB-UHFFFAOYSA-N 0.000 description 1
- YAIKGZQRXQYYJZ-UHFFFAOYSA-N cyclopentanesulfonic acid Chemical compound OS(=O)(=O)C1CCCC1 YAIKGZQRXQYYJZ-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-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
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 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 compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 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 class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 150000005165 hydroxybenzoic acids Chemical class 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- NONOKGVFTBWRLD-UHFFFAOYSA-N isocyanatosulfanylimino(oxo)methane Chemical compound O=C=NSN=C=O NONOKGVFTBWRLD-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000029860 luteolysis Effects 0.000 description 1
- 230000005906 menstruation Effects 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
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
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- GLGNSAPAWZUDRT-UHFFFAOYSA-N morpholine-4-sulfonic acid Chemical class OS(=O)(=O)N1CCOCC1 GLGNSAPAWZUDRT-UHFFFAOYSA-N 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000510 noble metal Inorganic materials 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
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 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
- PJDMFGSFLLCCAO-UHFFFAOYSA-N prostaglandin-F2alpha methyl ester Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(=O)OC PJDMFGSFLLCCAO-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- BUXTXUBQAKIQKS-UHFFFAOYSA-N sulfuryl diisocyanate Chemical compound O=C=NS(=O)(=O)N=C=O BUXTXUBQAKIQKS-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- UTXPCJHKADAFBB-UHFFFAOYSA-N tribenzyl(chloro)silane Chemical compound C=1C=CC=CC=1C[Si](CC=1C=CC=CC=1)(Cl)CC1=CC=CC=C1 UTXPCJHKADAFBB-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 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
- 230000001836 utereotrophic effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- 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
- C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Neue Prostansäurederivate undNew prostanoic acid derivatives and
Verfahren zu ihrer Iterstellung Im llauptpatent .............................. (Patentanmeldung P 25 23 676.4) erden Prostanderivate der allgemeinen Formel I beschrieben worin P einen über das C-Atom 1 verknüpften beliebig substituierten Prostanrest darstellt, R1 einen Säurerest einer organischen Carbon- oder Sulfonsäure mit 1 - 15 C-Atomen oder einer anorganischen Säure, R2 und R3 Wasserstoffatome oder Alkylgruppen mit 1 - 4 C-Atomen bedeuten.Process for their creation In the main patent .............................. (patent application P 25 23 676.4) prostane derivatives of the general formula I are described where P is an arbitrarily substituted prostane radical linked via the carbon atom 1, R1 is an acid radical of an organic carboxylic or sulfonic acid with 1-15 carbon atoms or an inorganic acid, R2 and R3 denote hydrogen atoms or alkyl groups with 1-4 carbon atoms .
Diese Verbindungen zeigen überraschenderweise eine hervorragende Wirkungsspezifität und eine längere Wirkungsdauer als natürliche Prostaglandine. So wird beispielsweise bei sehr guter uterotroper Wirkung keine Stimulation der Darm-und Gefäßmuskulatur hervorgerufen.These compounds surprisingly show an excellent specificity of action and a longer duration of action as natural prostaglandins. So For example, if the uterotrophic effect is very good, there will be no stimulation of the intestinal and gastrointestinal tract Vascular muscles caused.
In Weiterentwicklung des Hauptpatentes ............................In further development of the main patent ............................
(Patentamneldung P 25 23 676.4) wurde nun gefunden, daß Verbindungen der allgemeinen Formel Ia, in denen R1 eine darstellt, mindestens ebenso gute selektive Wirkungen besitzen.(Patent application P 25 23 676.4) it has now been found that compounds of the general formula Ia in which R1 is a represents, have at least as good selective effects.
Die vorliegende Erfindung betrifft demnach Prostanderivate der allgemeinen Formel Ia worin R1 eine bedeutet, wobei U ein Sauerstoff- oder Schwefelatom und R6 einen gegebenenfalls substituierten Alkyl-, Cycloalkyl- oder Arylrest oder einen Säurerest darstellt, und gemäß dem Hauptpatent ........................The present invention accordingly relates to prostane derivatives of the general formula Ia where R1 is a denotes, where U represents an oxygen or sulfur atom and R6 represents an optionally substituted alkyl, cycloalkyl or aryl radical or an acid radical, and according to the main patent .................... ....
(Patentanmeldung P 25 23 676.4) P einen über das C-Atom-1 verknüpften beliebig substituierten Prostanrest darstellt und R2 und R3 Wasserstoffatome oder Alkylgruppen mit 1 - 4 C-Atomen bedeuten. (Patent application P 25 23 676.4) P one linked via the C atom-1 represents any substituted prostane radical and R2 and R3 hydrogen atoms or alkyl groups with 1 to 4 carbon atoms.
Der Prostanrest P kann in beliebiger Weise substituiert sein. Bevorzugt sind Prostanreste P, wie sie in natürlich vorkommenden und künstlich hergestellten Prostaglandinen auftreten.The prostane residue P can be substituted in any way. Preferred are prostate residues P, as found in naturally occurring and artificially produced Prostaglandins occur.
Als mögliche funktionelle Gruppen oder Substituenten des Prostanrestes P seien beispielsweise genannt: Alkylgruppen mit 1 - 4 C-Atomen in 2-,3-,13-,15-,16-,17-, 11- und/oder 15-Stellung, Arylgruppen, vorzugsweise Phenyl, in 17-Stellung, Alkylengruppen, vorzugsweise Methylen, in 10,11- und/oder 13,14-Stellung, Hydroxyl- oder funktionell abgewandelte Hydroxylgruppen in 9-,11- und/oder 15-Stellung, Oxogruppen in 9-,11- und/oder 15-Stellung, Doppelbindungen in 5,6-, 10,11-,13,14- und/oder 17,18-Stellung, Dreifachbindungen in 13,14-, 16,17- und/oder 4,5-Stellung, Ketale in 15-Stellung, Halogenatome in 10-,14-,16- und/oder 17-Stellung.As possible functional groups or substituents of the prostane residue Examples of P are: alkyl groups with 1 - 4 carbon atoms in 2-, 3-, 13-, 15-, 16-, 17-, 11- and / or 15-position, aryl groups, preferably phenyl, in the 17-position, alkylene groups, preferably methylene, in the 10,11- and / or 13,14-position, hydroxyl or functional modified hydroxyl groups in 9-, 11- and / or 15-position, oxo groups in 9-, 11- and / or 15-position, double bonds in 5,6-, 10,11-, 13,14- and / or 17,18-position, Triple bonds in the 13.14, 16.17 and / or 4.5 positions, ketals in the 15 position, Halogen atoms in the 10-, 14-, 16- and / or 17-position.
Bevorzugte Prostanderivate der vorliegenden Erfindung sind Verbindungen der allgemeinen Formel IIa worin R11 R2 und R3 die oben angegebene Bedeutung haben, A eine -CH2-CH2- oder cis- CH=CH- oder trans-CH=CH-Gruppe bedeutet, B eine -CH2-CH2- oder trans-CH=CH-Gruppe oder eine oder eine wobei die Methylen-Gruppe α- oder ß-ständig sein kann, darstellt, W eine freie oder funktionell abgewandelte Hydroxymethylengruppe, eine freie oder funktionell abgewandelte Carbonyl-oder eine wobei die OH-Gruppe a- oder ß-ständig und funktionell abgewandelt sein kann, bedeutet, D und E gemeinsam eine direkte Bindung oder D eine geradkettige oder verzweigte Alkylengruppe mit 1 - 5 C-Atomen oder eine E ein Sauerstoff- oder Schwefel atom oder eine direkte Bindung bedeutet, R4 eine Alkylgruppe, eine Cycloalkylgruppe, eine gegebenenfalls substituierte Arylgruppe, eine Benzodioxol-2-yl-Gruppe, eine heterocyclische Gruppe, Z eine Carbonyl- oder eine freie oder funktionell abgewandelte Hydroxymethylengruppe, steht, wobei die Hethylengruppe a- oder ß-ständig sein kann, für steht, wenn Z eine Hydroxymethylengruppe bedeutet oder oder -CH=CH- steht, wenn Z eine Carbonylgruppe darstellt, wobei der Rest R5 eine Alkyl- oder eine freie oder funktionell abgewandelte Hydroxygruppe bedeutet Unter einer soll ein substituierter Carbamoyl oder Thiocarbamoylrest verstanden werden. Die Carbamidsäure oder Thiocarbamidsäure kann am Stickstoffatom substituiert sein durch einen Alkyl-, Cycloalkyl-, Aryl- oder Säurerest.Preferred prostane derivatives of the present invention are compounds of the general formula IIa wherein R11, R2 and R3 have the meaning given above, A is a -CH2-CH2- or cis-CH = CH- or trans-CH = CH- group, B is a -CH2-CH2- or trans-CH = CH- group or one or one where the methylene group can be in the α or β position, W represents a free or functionally modified hydroxymethylene group, a free or functionally modified carbonyl group or a where the OH group can be α or β and functionally modified, D and E together denotes a direct bond or D a straight-chain or branched alkylene group with 1-5 carbon atoms or a E is an oxygen or sulfur atom or a direct bond, R4 is an alkyl group, a cycloalkyl group, an optionally substituted aryl group, a benzodioxol-2-yl group, a heterocyclic group, Z is a carbonyl or a free or functionally modified hydroxymethylene group, stands, where the ethylene group can be α or ß position, for stands when Z is a hydroxymethylene group or or -CH = CH- if Z is a carbonyl group, where the radical R5 is an alkyl or a free or functionally modified hydroxyl group a substituted carbamoyl or thiocarbamoyl radical should be understood. The carbamic acid or thiocarbamic acid can be substituted on the nitrogen atom by an alkyl, cycloalkyl, aryl or acid radical.
Als Alkylgruppen It6 sind gerade oder verzweigte Alkylgruppen mit 1 - 10 C-Atomen zu betrachten, wie beispielsweise Methyl, Äthyl, Propyl, Isobutyl, Butyl, Pentyl, Heptyl, Hexyl, Decyl.As alkyl groups It6 are straight or branched alkyl groups 1 - 10 carbon atoms to be considered, such as methyl, ethyl, propyl, isobutyl, Butyl, pentyl, heptyl, hexyl, decyl.
Die Alkylgruppen.R6 können gegebenenfalls 1 bis mehrfach substituiert sein durch Halogenatome, Alkoxygruppen, gegebenenfalls substituierte Arylgruppen, Dialkylamine und Trialkylammonium.The Alkylgruppen.R6 can optionally be substituted one to several times be by halogen atoms, alkoxy groups, optionally substituted aryl groups, Dialkylamines and trialkylammonium.
Als Substituenten seien beispielsweise genannt Fluor-, Chlor- oder Bromatome, Phenyl, Dimethylamin, Diäthylamin, Methoxy, Äthoxy.Examples of substituents that may be mentioned are fluorine, chlorine or Bromine atoms, phenyl, dimethylamine, diethylamine, methoxy, ethoxy.
Als bevorzugte Alkylgruppen R6 ist Methyl, Äthyl, Propyl, Isobutyl, Butyl, Trichlormethyl, Trifluormethyl zu nennen.Preferred alkyl groups R6 are methyl, ethyl, propyl, isobutyl, Mention butyl, trichloromethyl, trifluoromethyl.
Cycloalkylgruppen R6 sind Reste mit 4 - 8 C-Atomen, wie beispielsweise Cyclobutyl, Cyclopentyl, Cyclohexyl, vorzugsweise Cyclopropyl.Cycloalkyl groups R6 are radicals with 4-8 carbon atoms, such as, for example Cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.
Als Arylgruppen kommen sowohl substituierte wie auch unsubstituierte Arylgruppen und Heteroarylgruppen in Betracht, wie beispielsweise 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-, Trifluormethyl-oder Alkoxygruppe und Thienyl, Furyl, Pyridyl. Bevorzugt ist die Substitution in 3- und 4-Stellung am Phenylring, zum Beispiel durch Fluor, Chlor, Alkoxy oder Trifluormethyl.Both substituted and unsubstituted groups can be used as aryl groups Aryl groups and heteroaryl groups such as phenyl, 1-naphthyl and 2-naphthyl, each of which may be substituted by. 1 - 3 halogen atoms, a phenyl group, 1 - 3 alkyl groups each with 1 - 4 carbon atoms, a chloromethyl, Fluoromethyl, trifluoromethyl or alkoxy group and thienyl, furyl, pyridyl. Preferred is the substitution in the 3- and 4-position on the phenyl ring, for example by fluorine, chlorine, Alkoxy or trifluoromethyl.
Als Säurereste kommen organische Carbonsäuren und Sulfonsäuren mit 1 - 15 C-Atomen in Frage, die der aliphatischen, aromatischen, aromatisch-aliphatischen, cyclo-aliphatischen oder heterocyklischen Reihe angehören. Diese Säuren können gesättigt, ungesättigt und/oder mehrbasisch und/oder in üblicher Weise substituiert sein. Als Beispiele für Substituenten seien Alkyl-, Hydroxy-, Alkoxy-1 Oxo- oder Aminogruppen oder Halogenatome erwähnt. Organic carboxylic acids and sulfonic acids come along as acid residues 1 - 15 carbon atoms in question, those of the aliphatic, aromatic, aromatic-aliphatic, belong to cyclo-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and / or polybasic and / or substituted in the usual way. as Examples of substituents are alkyl, hydroxy, alkoxy-1 oxo or amino groups or halogen atoms mentioned.
Beispielsweise seien folgende Carbonsäuren genannt: Essigsäure, Propionsäure, Buttersäure, Isobuttersäure, Valeriansäure, Isovaleriansäure, Capronsäure, Önanthsäure, Caprylsäure, Trimethylessigsäure, Diäthylessigsäure, tert.-Butylessigsäure, Cyclopentylessigsäure, Cyclohexylessigsäure, Phenylessigsäure, Phenoxyessigsäure, Methoxyessigsäure, ono-, Di- und Trichloressigsäure, Aminoessigsäure, Diäthylaminoessigsäure, Piperidinoessigsäure, Morpholinoessigsäure, Benzoesäure, mit Halogen-, Trifluormethyl-, Alkoxy-1 Hydroxy- oder Oarboxy-Gruppen substituierte Benzoesäuren, Furan-2-carbonsäure, Cyclopentylpropionsäure. Als besonders bevorzugte Acylreste werden solche mit bis zu 6 Kohlenstoffatomen betrachtet. The following carboxylic acids may be mentioned as examples: acetic acid, propionic acid, Butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, Caprylic acid, trimethyl acetic acid, diethyl acetic acid, tert.-butyl acetic acid, cyclopentyl acetic acid, Cyclohexylacetic acid, phenoxyacetic acid, phenoxyacetic acid, methoxyacetic acid, ono-, Di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, Morpholinoacetic acid, benzoic acid, with halogen, trifluoromethyl, alkoxy-1 hydroxy benzoic acids, furan-2-carboxylic acid, cyclopentylpropionic acid, substituted by carboxy groups. Particularly preferred acyl radicals are those with up to 6 carbon atoms considered.
Als Sulfonsäuren kommen beispielsweise Methansulfonsäure, Äthansulfonsäure, Isopropylsulfonsäure, ß-Chloräthansulfonsäure 1 Butansulfonsäure, Cyclopentansulfonsäure, Cyclohexansulfonsäure, Benzolsulfonsäure, p-Toluolsulfonsäure, p-Chlorbenzolsulfonsäure1 p-Methoxy-benzolsulfonsäure, N,N-Dimethylaminosulfonsäure, N,N-Diäthylaminosulfonsäure, N,N-Bis-(ß-Chloräthyl)-aminosulfonsäure, N,N-Diisobutylaminosulfonsäure, N,N-Dibutylaminosulfonsäure, Pyrrolidino-, Piperidino-, Piperazino-, N-Methylpiperazino-, Thiopheno- und Morpholinosulfonsäure in Frage.As sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, Isopropylsulphonic acid, ß-chloroethanesulphonic acid 1 butanesulphonic acid, cyclopentanesulphonic acid, Cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid 1 p-methoxy-benzenesulphonic acid, N, N-dimethylaminosulphonic acid, N, N-diethylaminosulphonic acid, N, N-bis (ß-chloroethyl) -aminosulfonic acid, N, N-diisobutylaminosulfonic acid, N, N-dibutylaminosulfonic acid, Pyrrolidino, piperidino, piperazino, N-methylpiperazino, thiopheno and morpholino sulfonic acids in question.
Als Alkylgruppen R2 und R kommen gerad- und verzweigtkettige .3 Alkylreste mit 1 - 4 Kohlenstoffatomen in Betracht wie beispielsweise der Methyl,, Äthyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl- und tert. Butyl-Rest. Bevorzugt ist die Methyl- und Äthylgruppe.The alkyl groups R2 and R are straight-chain and branched-chain .3 alkyl radicals with 1 - 4 carbon atoms such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl and tert. Butyl residue. Preferred is the methyl and ethyl group.
Die Hydroxygruppen 25 und in W und in Z können funktionell abgewandelt sein beispielsweise durch Verätherung oder Veresterung, wobei die freie oder abgewandelten Ilydroxygruppen in W und in Z a- oder ß-ständig sein können.The hydroxyl groups 25 and in W and in Z can be functionally modified be for example by etherification or esterification, the free or modified Ilydroxygruppen in W and in Z can be a- or ß-position.
Als Äther- und Acylreste kommen die dem Fachmann bekannten Reste in Betracht. Bevorzugt sind leicht abspaltbare Atherreste wie beispielsweise der Tetrahydropyranyl-, Tetrahydrofuranyl-, er-Äthoxyäthyl-, Trimethylsilyl-, Dimethyl- tert.The radicals known to the person skilled in the art are used as ether and acyl radicals Consideration. Easily split off atomic residues such as tetrahydropyranyl, Tetrahydrofuranyl, er-ethoxyethyl, trimethylsilyl, dimethyl tert.
butyl-silyl- und Tri-p--benzyl-silylrest Als Acylreste kommen die gleichen wie für R1 genannt in Frage; namentlich genannt seien beispielsweise Acetyl, Propionyl, Butyryl, Benzoyl.butyl-silyl and tri-p-benzyl-silyl radicals as acyl radicals come the same as mentioned for R1 in question; may be mentioned by name, for example Acetyl, propionyl, butyryl, benzoyl.
Bedeutet W eine Carbonylgruppe, so kann diese nach den dem Fachmann bekannten Methoden funktionell abgewandelt sein wie beispielsweise durch Ketalisierung. Besonders geeignet ist die Herstellung von cyclischen Ketalen mit 1 - 3 C-Atomen im Ring, wie zum Beispiel mit Äthylenglykol, Propandiol-(1,3), 2,2-Dimethylpropandiol-(1,3), Cyclopentandiol-(1,2) oder Glycerin.If W is a carbonyl group, this can be according to the one skilled in the art known methods can be functionally modified, for example by ketalization. The preparation of cyclic ketals with 1-3 carbon atoms is particularly suitable in the ring, such as with ethylene glycol, propanediol (1,3), 2,2-dimethylpropanediol (1,3), Cyclopentanediol (1,2) or glycerine.
Als Alkylgruppe R4 kommen gerad- und 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-, Athyl-, Propyl-, Butyl-, Isobutyl-, tert. Butyl-, Pentyl-, Hexyl-, Heptyl-, Octyl-, Butenyl-, Isobutenyl-, Propenyl-, Pentenyl-, Benzyl- und p-Chlorbenzyl.As the alkyl group R4, there are straight- and branched-chain, saturated ones and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1 - 6 carbon atoms, in question, optionally substituted by optionally substituted aryl can be substituted. Examples include methyl, ethyl, propyl, Butyl, isobutyl, tert. Butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, Propenyl, pentenyl, benzyl and p-chlorobenzyl.
Die Cycloalkylgruppe R4 kann im Ring-4 - 10, vorzugsweise 5 und 6 Kohlenstoffatome enthalten. Die Ringe können durch Alkylgruppen mit 1 - 4 Kohlenstoffatomen substituiert sein.The cycloalkyl group R4 in ring-4-10, preferably 5 and 6 Contain carbon atoms. The rings can be formed by alkyl groups with 1 to 4 carbon atoms be substituted.
Beispielsweise seien genannt Cyclopentyl-, Cyclohexyl, Methyl-cyclohexyl und Adamantyl.Cyclopentyl-, cyclohexyl and methyl-cyclohexyl may be mentioned as examples and adamantyl.
Als substituierte bzw. unsubstituierte Arylgruppen R4 kommen beispielsweise in Betracht: Phenyl, 1-Naphthyl und 2-Naphthyl, die jeweils substituiert sein können durch 1 - 3 Ilalogenatome, eine Phenylgruppe, 1 - 3 Alkylgruppen mit jeweils 1 - 4 C-Atomen, eine Chlormethyl-, Fluormethyl-, Trifluormethyl-, Carboxyl-, Alkoxy- oder Hydroxygruppe.Examples of substituted or unsubstituted aryl groups R4 are into consideration: phenyl, 1-naphthyl and 2-naphthyl, each of which can be substituted by 1 - 3 halogen atoms, a phenyl group, 1 - 3 alkyl groups each with 1 - 4 carbon atoms, one chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, alkoxy or hydroxy group.
Bevorzugt ist die. Substitution in 3- und 4-Stellung am Phenylring zum Beispiel durch Fluor, Chlor, Alkoxy oder Trifluormethyl oder in 4-Stellung durch Hydroxy.Is preferred. Substitution in 3- and 4-positions on the phenyl ring for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4-position Hydroxy.
Als Alkylrest R kommen niedere Alkylreste mit 1 - 2 5 C-A-tomen in Betracht, vorzugsweise der Methylrest.Lower alkyl radicals with 1 - 2 5 carbon atoms can be used as the alkyl radical R Consider, preferably the methyl radical.
Als heterocyklische Gruppen R4 kommen 5- und 6-gliedrige Heterocyclen in Frage, die wenigstens 1-Heteroatom, vorzugsweise Stickstoff, Sauerstoff oder Schwefel enthalten.The heterocyclic groups R4 are 5- and 6-membered heterocycles in question, the at least 1-heteroatom, preferably nitrogen, oxygen or Contain sulfur.
Beispielsweise seien genannt 2-F4ryl, 2-Thienyl, 2-Pyridyl, 3-Pyridyl-, 4-Pyridyl u.a.Examples include 2-F4ryl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl et al.
Die Erfindung betrifft die Abänderung des Verfahrens gemäß Hauptpatent ................ (Patentanmeldung P 25 23 676.4) zur Herstellung der neuen Prostanderivate der allgemeinen Formel Ia aus Verbindungen der allgemeinen Formel III worin P, R2 und R die oben angegebene Bedeutung haben, und 5 freie Hydroxygruppen gegebenenfalls intermediär geschützt sind, dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel III mit Verbindungen der allgemeinen Formel V U = C = N - R6 V, worin U und R6 die oben angegebene Bedeutung haben1 umsetzt und gegebenenfalls anschließend geschützte Hydroxygruppen freisetzt und/oder freie Hydroxygruppen oxydiert oder verestert und/oder freie Ketogruppen ketalisiert oder reduziert und/oder Doppelbindungen hydriert oder methyleniert und/oder durch Wasserabspaltung in 10,11-Stellung eine Doppelbindung einführt und gegebenenfalls die Epimeren trennt.The invention relates to the modification of the process according to the main patent ................ (patent application P 25 23 676.4) for the preparation of the new prostane derivatives of the general formula Ia from compounds of the general formula III wherein P, R2 and R have the meaning given above, and 5 free hydroxyl groups are optionally protected intermediately, characterized in that compounds of the general formula III with compounds of the general formula VU = C = N - R6 V, in which U and R6 are the The meaning given above has converted 1 and, if appropriate, subsequently releases protected hydroxyl groups and / or oxidizes or esterifies free hydroxyl groups and / or ketalizes or reduces free keto groups and / or hydrogenates or methylenates double bonds and / or introduces a double bond by splitting off water in the 10,11-position and, if necessary separates the epimers.
Als bevorzugte Ausgangsprodukte sind geeignet Verbindungen der Formel IV worin 22 R3, A, Z, X, Y, B, W, D, E und R4 die oben angegebene Bedeutung haben.Compounds of the formula IV are suitable as preferred starting materials in which R3, A, Z, X, Y, B, W, D, E and R4 have the meanings given above.
Die Umsetzung der Alkohole der allgemeinen Formeln III und IV erfolgt in Abänderung des Verfahrens gemäß dem Hauptpatent .................... (Patentanmeldung P 25 23 676.4) in an sich bekannter Weise. Zum Beispiel kann man einen Alkohol der allgemeinen Formeln III oder IV mit einem Isocyanat oder Thioisocyanat der allgemeinen Formel V U = C = N - R6 V, worin U und R6 die oben angegebene Bedeutung haben, gegebenenfalls unter Zusatz eines tertiären Amins, wie zum Beispiel Triäthylamin oder Pyridin zur Reaktion bringen. Die Umsetzung kann ohne Lösungsmittel oder in einem inerten Lösungsmittel, vorzugsweise Aceton, Acetonitril, Dimethylacetamid, Methylenchlorid, Tetrahydrofuran, Äther, Benzol, Toluol, DMSO bei Temperaturen über oder unter Raumtemperatur, zum Beispiel zwischen -80°C bis 1000C, vorzugsweise bei 0 - 300C, vorgenommen werden.The alcohols of the general formulas III and IV are reacted in modification of the process according to the main patent .................... (patent application P 25 23 676.4) in a manner known per se. For example you can have an alcohol the general formulas III or IV with an isocyanate or thioisocyanate of the general Formula V U = C = N - R6 V, in which U and R6 have the meaning given above, optionally with the addition of a tertiary amine, such as triethylamine or pyridine for Bring reaction. The reaction can be carried out without a solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, methylene chloride, tetrahydrofuran, Ether, benzene, toluene, DMSO at temperatures above or below room temperature, for Example between -80 ° C to 1000C, preferably at 0-300C.
Enthält das Ausgangsprodulft neben der 1-ständigen 011-Gruppe noch zusätzliche OII-Gruppen im Prostanrest, so werden diese OH-Gruppen nach dem erfindungsgemäßen Verfahren auch zur Reaktion gebracht. Werden letztlich Endprodukte gewünacht, deren zusätzliche Ilydroxylgruppen im Prostanrest als freie Hydroxylgruppen vorliegen, geht man zweckmäßigerweise von Ausgangsprodukten aus, in denen diese durch vorzugsweise leicht abspaltbare Ätherreste intermediär geschützt sind. Werden als Ausgangsprodukt Verbindungen.eingesetzt, die im Prostanrest funktionell abgewandelte OH-Gruppen, beispielsweise durch Atherbildung, haben1 so können im Endprodukt, nach Freisetzung der funktionell abgewandelten OEI-Gruppen, diese verestert werden, wobei man verschiedene Acylgruppen im Endprodukt einführen kann.In addition to the 1-unit 011 group, the output module also contains additional OII groups in the prostane residue, then these OH groups according to the invention Process also brought to reaction. If end products are ultimately desired, their additional Ilydroxylgruppen are present in the prostane residue as free hydroxyl groups, one expediently starts from starting products in which these preferably go through easily split off ether residues are intermediately protected. Are used as a starting product Compounds used that contain functionally modified OH groups in the prostane residue, for example through ether formation, have1 so can in the end product, after release of the functionally modified OEI groups, these are esterified, whereby one different Can introduce acyl groups in the final product.
Die Freisetzung der funktionell abgewandelten Hydroxygruppen erfolgt nach bekannten Methoden. Beispielsweise wird die Abspaltung von Hydroxyschutzgruppen, wie beispielsweise des Tetrahydropyranylrestes, in einer wäßrigen Lösung einer organischen Säure, wie zum Beispiel 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. Tetrahydrofuran wird bevorzugt angewendet. Die Abspaltung wird vorzugsweise bei Temperaturen zwischen 200C und 300C durchgeführt.The functionally modified hydroxyl groups are released according to known methods. For example, the elimination of hydroxyl protective groups, such as the tetrahydropyranyl radical, in an aqueous solution of an organic Acid, such as acetic acid, propionic acid, etc. or in an aqueous solution an inorganic acid such as hydrochloric acid carried out. To improve the solubility, a water-miscible one is expediently used inert organic solvent added. Suitable organic solvents are for example alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, Dioxane and tetrahydrofuran. Tetrahydrofuran is preferred. The split is preferably carried out at temperatures between 200C and 300C.
Die Ketalisierung erfolgt in an sich bekannter Weise. Beispielsweise wird mit Äthylenglykol in Gegenwart eines sauren Katalysators unter Wasserabscheidung erhitzt. Als saure Katalysatoren sind p-Toluolsulfonsäure und Perchlorsäure besonders geeignet.The ketalization takes place in a manner known per se. For example is with ethylene glycol in the presence of an acidic catalyst with water separation heated. Particularly acidic catalysts are p-toluenesulfonic acid and perchloric acid suitable.
Die Oxydation anwesender Hydroxygruppen wird nach an sich bekannten Methoden mit den üblichen Oxydationsmitteln vorgenommen. Beispielsweise kann die Oxydation der 9-IIydroxygruppe zum Keton mit Jones-Reagenz (J. Chem. Soc. 1953, 2555) erfolgen. Man arbeitet mit einem Überschuß des Oxydationsmittels n einem geeigneten Verdünnungsmittel, wie Aceton bei Temperaturen zwischen OOC und -50°C, vorzugsweise bei -200C, Die Realction ist allgemein nach.5 bis 30 Minuten beendet. Vorzugsweise erfolgt die Oxydation nach intermediärem Schutz der 11- und 15-Ilydroxygruppe, zum Beispiel durch Silylierung (Chem. Comm. (1972), 1120). Die Silylierung wird beispielsweise mit N,N-Diäthyltrimethylsilylamin in Aceton bei -700C bis +20°C, vorzugsweise bei 4000 C bis OOC, vorgenommen. Als weitere Oxydationsmittel sind Silbercarbonat auf "Celite" oder Collins-Reagenz geeignet (Tetrahedron Letters 1968, 3363).The oxidation of hydroxyl groups present is carried out according to known Methods made with the usual oxidizing agents. For example, the Oxidation of the 9-II-hydroxy group to the ketone with Jones reagent (J. Chem. Soc. 1953, 2555). One works with an excess of the oxidizing agent in a suitable one Diluents such as acetone at temperatures between OOC and -50 ° C, preferably at -200C, the Realction is generally over after 5 to 30 minutes. Preferably the oxidation takes place after the intermediate Protection of the 11- and 15-Ilydroxygruppe, for example by silylation (Chem. Comm. (1972), 1120). The silylation will for example with N, N-diethyltrimethylsilylamine in acetone at -700C to + 20 ° C, preferably at 4000 C to OOC. As further oxidizing agents are Silver carbonate suitable for "Celite" or Collins reagent (Tetrahedron Letters 1968, 3363).
Die regioselektive Oxydation von 9,11-Dihydroxyverbindungen, die in 15-Stellung keine oxydierbare Hydroxygruppe enthalten, wird nach den dem Fachmann bekannten Methoden vorgenommen. The regioselective oxidation of 9,11-dihydroxy compounds which contain no oxidizable hydroxyl group in the 15-position, according to the expert known methods.
Zur Oxydation der 11a-Hydroxygruppe verwendet man vorzugsweise Jones-Reagenz oder Collins-Reagenz, während die regioselektive Oxydation der 9a-Hydroxygruppe mit Fetizon-Reagenz (Tetrahedron 29, 2867 (1973)), Silbercarbonat oder Platin/ Sauerstoff (Adv. in Carbohydrate Chem. 17, 169 (1962)) erfolgt. Die Oxydation mit Jones-Reagenz wird bei -400C bis +200C, vorzugsweise bei -30°C bis -100C oder mit Collins-Reagenz bei -20°C bis 300C, vorzugsweise bei OOC bis 200C, in einem gegen das Oxydationsmittel inerten Lösungsmittel durchgeführt. Als Lösungsmittel können Methylenchlorid, Chloroform, Äthylenchlorid, Pyridin u.a., vorzugsweise Jedoch Methylenchlorid, verwendet werden. Jones reagent is preferably used to oxidize the 11a-hydroxy group or Collins reagent, during the regioselective oxidation of the 9a-hydroxy group with Fetizon reagent (Tetrahedron 29, 2867 (1973)), silver carbonate or platinum / oxygen (Adv. In Carbohydrate Chem. 17, 169 (1962)). Oxidation with Jones reagent is at -400C to + 200C, preferably at -30 ° C to -100C or with Collins reagent at -20 ° C to 300C, preferably at 0OC to 200C, in one against the oxidizing agent inert solvent carried out. Methylene chloride, chloroform, Ethylene chloride, pyridine, etc., but preferably methylene chloride can be used.
Als Lösungsmittel für die Oxydation mit Fetizon-Reagenz, Silbercarbonat oder Platin mit Sauerstoff können Benzol, Toluol1 Xylol, Essigester, Aceton1 Tetrahydrofuran, Diäthyläther und Dioxan und andere inerte Lösungsmittel verwendet werden. Die Reaktionstemperaturen liegen zwischen 200C und 11000 bei der Silbercarbonat- oder Fetizon-Oxydation, vorzugsweise bei der Siedetemperatur des Lösungsmittels. Bei der Oxydation mit Platin/Sauerstoff werden Temperäturen von vorzugsweise 200C - 500C angewandt.As a solvent for the oxidation with Fetizon reagent, silver carbonate or platinum with oxygen, benzene, Toluene1 xylene, ethyl acetate, Acetone1 tetrahydrofuran, diethyl ether and dioxane and other inert solvents be used. The reaction temperatures are between 200C and 11000 at the Silver carbonate or fetizone oxidation, preferably at the boiling point of the Solvent. During the oxidation with platinum / oxygen temperatures of preferably 200C - 500C applied.
Die Reduktion der 9-Ketogruppe wird mit üblichen Reduktionsmitteln durchgeführt, zum Beispiel wird mit Natriumborhydrid, Lithium-tri-tert.-butoxy-aluminiumhydrid, Zinkborhydrid, Aluminiumisopropylat in Gegenwart eines Alkohols, oder Kalium-tri-sek. -butyl-borhydrid reduziert, vorzugsweise mit Natriumborhydrid bei Temperaturen zwischen -50°C und 0 0 +50001 vorzugsweise bei 0 0 bis 20 0, durchgeführt. Als Lösungsmittel für diese Reaktion kommen je nach verwendetem Reduktionsmittel in Frage Methanol, Äthanol, i-Propanol, Diäthyläther, Dioxan, Tetrahydrofuran. Bei der Reduktion mit Natriumborhydrid wird vorzugsweise Methanol, Äthanol oder Isopropanol verwendet. Das entstehende a- und ß-OH-Epimerengemisch kann in üblicher Weise durch Säulen- oder Schichtchromatographie getrennt werden.The reduction of the 9-keto group is carried out with conventional reducing agents carried out, for example with sodium borohydride, lithium tri-tert.-butoxy-aluminum hydride, Zinc borohydride, aluminum isopropylate in the presence of an alcohol, or potassium tri-sec. -butyl borohydride reduced, preferably with sodium borohydride at temperatures between -50 ° C and 0 0 +50001 preferably at 0 0 to 20 0 carried out. As a solvent Depending on the reducing agent used, methanol can be used for this reaction, Ethanol, i-propanol, diethyl ether, dioxane, tetrahydrofuran. When reducing with Sodium borohydride is preferably used with methanol, ethanol or isopropanol. The resulting a- and ß-OH epimer mixture can in the usual way by column or layer chromatography.
Sollen im Primärprodukt enthaltene C=C-Doppelbindungen gewünschtenfalls reduziert werden, erfolgt die Hydrierung nach an sich bekannten Methoden.Should C = C double bonds contained in the primary product, if desired are reduced, the hydrogenation is carried out by methods known per se.
Die Hydrierung der 5,6-Doppelbindung wird in an sich bekannter Weise bei tiefen Temperaturen, vorzugsweise bei -20°C, in einer Wasserstoffatmosphäre in Gegenwart eines Edelmetallkatalysators durchgeführt. Als Katalysator ist zum Beispiel 10 % Palladium auf Kohle geeignet.The hydrogenation of the 5,6 double bond is carried out in a manner known per se at low temperatures, preferably at -20 ° C, in a hydrogen atmosphere in the presence of a Noble metal catalyst carried out. As a catalyst for example 10% palladium on carbon is suitable.
Wird sowohl die 5,6- als auch die-13,14-Doppelbindung hydriert, so arbeitet man bei höherer Temperatur vorzugsweise bei 200C.If both the 5,6 and the -13,14 double bond are hydrogenated, then one works at a higher temperature, preferably at 200C.
Die Dehydratisierung der 9-Oxoverbindung, bei welcher die 11-IIydroxygruppe und ein Wasserstoffatom aus der 10-Stellung abgespalten werden zu einem Prostaglandin-A-Derivat, kann unter Bedingungen, wie sie dem Fachmann allgemein bekannt sind, durchgeführt werden. Im allgemeinen erfolgt die Dehydratisierung in einer Lösung einer organischen Säure, wie Essigsäure, oder einer anorganischen Säure, wie Salzsäure, bei Temperaturen zwischen 200C und 000C. Nach etwa 2 bis 17 Stunden ist die Reaktion beendet.The dehydration of the 9-oxo compound in which the 11-II-hydroxy group and a hydrogen atom is split off from the 10-position to form a prostaglandin A derivative, can be carried out under conditions that are generally known to the person skilled in the art will. In general, the dehydration takes place in a solution of an organic Acid such as acetic acid or an inorganic acid such as hydrochloric acid at temperatures between 200C and 000C. The reaction has ended after about 2 to 17 hours.
Die Methylenierung der 10,11- und/oder 13,14-Doppelbindung erfolgt bei den 9-Oxo- oder 15-Oxoverbindungen nach an sich bekannten Methoden. Beispielsweise seien genannt die Umsetzung mit Diazokohlenwasserstoffen, gegebenenfalls in Gegenwart von Metallsalzen, die Umsetzung mit Dimethylsulfoxoniummethylid und die Umsetzung nach Simmons-Smith mit Zink und Methylendihalogeniden.The methylenation of the 10,11 and / or 13,14 double bond takes place in the case of the 9-oxo or 15-oxo compounds by methods known per se. For example may be mentioned the reaction with diazo hydrocarbons, if appropriate in the presence of metal salts, the reaction with Dimethylsulfoxoniummethylid and the implementation according to Simmons-Smith with zinc and methylene dihalides.
Eine bevorzugte Ausführungsform besteht darin, daß man die obengenannten Verbindungen mit Diazokohlenwasserstoffen, wie beispielsweise Diazomethan, Diazoäthan, Diazopropan, vorkugsweise mit Diazomethan, umsetzt. Die Reaktion wird beispielsweise in Gegenwart von Metallsalzcn bei Temperaturen zwischen 200C und -l000C, vorzugsweise bei OOC, in einem inerten Lösungsmittel, wie zum Beispiel Diäthyläther; Tetrallydrofuran, Glyme, Diglyme, Dioxan, vorzugsweise in Diäthyläther, durchgeführt. Als Metallsalze können Fkupferchlorid, Kupferacetat, Palladium-II-acetat, Palladium-II-chlorid, vorzugsweise Palladium-II-acetat, verwendet werden.A preferred embodiment is that one of the above Compounds with diazo hydrocarbons, such as diazomethane, diazoethane, Diazopropane, preferably with diazomethane. The reaction is for example in the presence of metal salts at temperatures between 200C and -10000C, preferably at OOC, in an inert solvent such as Diethyl ether; Tetrallydrofuran, glyme, diglyme, dioxane, preferably in diethyl ether, carried out. As metal salts, copper chloride, copper acetate, palladium-II-acetate, Palladium (II) chloride, preferably palladium (II) acetate, can be used.
Die Trennung der Epimeren erfolg nach den dem Fachmann bekannten Methoden, wie beispielsweise durch Säulen- oder Schichtchromatographie oder durch fraktionierte Kristallisation.The epimers are separated according to the methods known to the person skilled in the art, such as by column or layer chromatography or by fractionated Crystallization.
Die Herstellung von Verbindungen der allgemeinen Formeln III bzw. IV mit fl2 und R3 in der Bedeutung von Wasserstoff erfolgt nach den üblichen Methoden, beispielsweise dadurch1 daß man ein entsprechendes Prostansäurederivat zu eine primären Alkohol reduziert. Bevorzugt ist die Reduktion von Prostansäureestern mit Litlliumaluminiumhydrid.The preparation of compounds of the general formulas III or IV with fl2 and R3 meaning hydrogen is carried out according to the usual methods, for example, by converting a corresponding prostanoic acid derivative into a primary one Alcohol reduced. The reduction of prostanoic acid esters with lithium aluminum hydride is preferred.
Die Herstellung von neuen Verbindungen der allgemeinen Formeln III bzw. IV, worin R2 eine Alkylgruppe und ein Wasserstoffatom bedeutet, erfolgt üblicherweise zum Beispiel durch Reduktion eines Prostansäurederivates zum Aldehyd. Die Reduktion wird bevorzugt an Prostansäureestern mit Diisobutylaluminiumhydrid bei -700C bis -40°C C in einem inerten Lösungsmittel, wie beispielsweise Toluol, vorgenommen. Die anschließende Umsetzung des Aldehyds mit Alkyllithium liefert bei OOC in einem inerten Lösungsmittel, vorzugsweise in Äther-und Tetrahydrofurangemischen, die sekundären Alkohole der Verbindungen der allgemeinen Formeln III und IV.The preparation of new compounds of the general formulas III or IV, in which R2 is an alkyl group and a hydrogen atom, is usually carried out for example by reducing a prostanoic acid derivative to the Aldehyde. The reduction is preferred on prostanoic acid esters with diisobutylaluminum hydride at -700C to -40 ° C in an inert solvent such as toluene, performed. The subsequent reaction of the aldehyde with alkyllithium provides OOC in an inert solvent, preferably in ether and tetrahydrofuran mixtures, the secondary alcohols of the compounds of the general formulas III and IV.
Die Herstellung von neuen Verbindungen der allgemeinen Formeln III und IV, worin R2 und R3 eine Alkylgruppe bedeuten, erfolgt nach den üblichen Methoden, beispielsweise durch Umsetzung eines Prostansäureesters mit Alkyllithium bei Temperaturen zwischen -100C bis +100C, vorzugsweise bei OOC in einem inerten Lösungsmittel wie beispielsweise Äther und Tetrahydrofurangemischen unter Ausbildung der tertiären Alkohole der allgemeinen Formeln III und IV.The preparation of new compounds of the general formulas III and IV, in which R2 and R3 are an alkyl group, is carried out according to the usual methods, for example by reacting a prostanoic acid ester with alkyl lithium at temperatures between -100C to + 100C, preferably at OOC in an inert solvent such as for example, ether and tetrahydrofuran mixtures with the formation of the tertiary Alcohols of the general formulas III and IV.
Werden im Endprodukt freie OII-Gruppen gewünscht, so ist es zweckmäßig, vor der Reduktion zu den C1-Alkoholen die gegebenenfalls anwesenden freien Hydroxyl- oder frei-en Oxogruppen intermediär zu schützen, beispielsweise durch Verätherung bzw. Ketalisierung.If free OII groups are desired in the end product, it is advisable to before the reduction to the C1 alcohols any free hydroxyl or to protect free oxo groups intermediately, for example by etherification or ketalization.
Mit ililfe des erfindungsgemäßen Verfahrens lassen sich beispielsweise auch die folgenden Verbindungen herstellen: (5Z,13E)-(8R,9S,11R,15S)-1-(N-Acetylcarbamoyloxy)-5,13 prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Acetylcarbamoyloxy)-11,15-dihydroxy-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S)-1-(N-Acetylcarbamoyloxy)-15-hydroxy-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9R,11R,12R,15S)-1-(N-Phenylcarbamoyloxy)-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Phenylcarbamoyloxy)-11,15-dihydroxy-5,13-prostadien-9-on (5Z,13E)-(aR,12S,15S)-1-(N-Phenylcarballloyloxy)-15-hydroxy-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Methyl-thiocarbamoyl-oxy)-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Methyl-thiocarbamayloxy)-11,15-dihydroxy-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S)-1-(N-Methyl-thiocarbamoyloxy)-15-hydroxy 5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Methylcarbamoyloxy)-15-methyl-5, 1 3-prostadien-9, 11, 15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Methylcarbamoyloxy)-11,15-dihydroxy-15-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S)-1-(N-Metylcarbamoyloxy)-15-hydroxy-15-methyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-1-(N-Metylcarbamoyloxy)-16-methyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S,16RS)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy-16-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S,16RS)-1-(N-Metylcarbamoyloxy)-15-hydroxy-16-methyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-16,16-dimethyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy- 16, 1 6-ditnethyl-5, 1 3-prostadien-9-on (5Z,13E)-(t3R,12S,15R)-l-(N-Methylcarbamoyloxy)-15-hydroxy-16, 1 6-dimethyl-5, 10, 1 3-prostatrien- 9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-16-phenoxy-17,18,19-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-16-(3-trifluormethylphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy-16-(3-trifluormethylphenoxy)-17,18,19,20-tetranor-5,1 3-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Metylcarbamoyloxy)-17-phenyl-18,19,20-trinor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Metylcarbamoyloxy)-11,15-dihydroxy- 1 7-phenyl- 18, 1 9, 20-trinor-5, 1 3-prostadien-9-on (5Z,13E)-(8R,11R,12R,15S)-1-(N-Metylcarbamoyloxy)-15-hydroxy-1 1 -methyl-51 1 3-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-[(N-Metylcarbamoyloxy)-carbamayloxy]-15-methyl-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-15-methyl-5,13-prostadien-9-on (5Z-13E)-(8R,12S,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-15-hydroxy-15-methyl-5,10,13-prostatrien-9-on (5Z-13E)-(8R,9S,11R,12R,15S,16RS)-1-[(N-Methansulfonyl)-carbamoyloxy]-16-methyl-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15S,16RS)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-methyl-5,13-prostadien-9-on (5Z-13E)-(8R,12S,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-15-hydroxy-16-methyl-5,10,13-prostatrien-9-on (5Z-13E)-(8R,9S,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16,16-dimethyl-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16,16-dimethyl-11,15-dihydroxy-5,13-prostadien-9-on (5Z-13E)-(8R,12S,15R)-1-[(N-Methansulfonyl)-carbamyloxy]-15-hydroxy-16,16,-dimethyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16- ( 3-trifluormethyiphenoxy) 17,181 191 20-tetranor-5, 1 3-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-(3-trifluormethylphenyl)-17,18,19,20-tetranor-5, 1 3-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-16-(4-chlorphenol)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-16-(4-fluorphenoxy)-17,18,19,20-tetranor-5,13-prostadion-9,11,15-triol (5Z-13E)-(8R,11R,12R,15R)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-16-(4-fluorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-17-phenyl-18,19,20-trinor-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13-prostadien-9-on (5Z-13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dimethyl-15-hydroxy-5,13-prostadien-9-on (5Z-13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-15-hydroxy-11-methyl-5,13-prostadien-9-on (5Z-13E)-(8R,9S,11R,12R,15S)-1-[(N-Acetyl-carbamoyloxy]-15-methyl-5,13-prostadien-9,11,15-triol (5Z-13E)-(8R,11R,12R,15S)-1-[(N-Acetylcarbamoyloxy)-11,15-dihydroxy-15-methyl-5,13-prostadien-9-on (5Z-13E)-(8R,12S,15S)-1-[(N-Acetylcarbamoyloxy)-15-hydroxy-15-methyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-1-(N-Acetyl-carbamoyloxy)-16-methyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S,16RS)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy-16-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,12R,15S,16RS)-1-(N-Acetyl-carbamoyloxy)-15-hydroxy-16-methyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-16,16-dimethyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15R)-1-(N-Acetyl-carbamoyloxy)-15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-16-pheoxy-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-16-(3-trifluormethylphenoxy)-17,18,19,20-tetranor,5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-11,15 dihydroxy- 16- ( -I;ri£luoreletlzylphelloxy - 1 7, 18,1 9, 20-tetranor-5, 1 3-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-17-phenyl-18,19,20-trinor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-15-hydroxy-11-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-15-methyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Acetyl-carbamoyloxy)-11,15-dihydroxy- 1 5-methyl-5, 1 3-prostadien-9-on (5Z 1 3E ) - (811, 125, 155) -1 -(N-Phenylcarbamoyloxy) -1 5-hydroxy-15-methyl-5,10,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-1-(N-phenyl-carbamoyloxy)-16-methyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,9S,11R,12R,15S,16RS)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-16-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S,16RS)-1-(N-phenylcarbamoyloxy)-15-hydroxy-16-methyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-16,16-dimethyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15R)-1-(N-phenylcarbamoyloxy)-15-hydroxy-16,16-dimethyl-5,10,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-16-phenoxy-17,18,19,20,tetranor-5,13-prostadien-9,11,15,triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-16-(3-trifluormethylphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-16-(3-trifluormethyslphenoxy)-17,18,19,20-teranor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-16-(4-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadien-9-on (5Z,13E)-(8R,11R,12R,15S)-1-(N-phenylcarbamoyloxy)-11,15-dihydroxy-17,phenyl-18,19,20-trinor-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-phenylcarbamoyloxy)-17-phenyl-18,19,20-trinor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-phenylcarbamoyloxy)-15-hydroxy-11-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-methyl-thiocarbamoyloxy)-15-methyl-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15S)-1-(N-methyl-thiocarbamoyloxy)-11,15-dihydroxy-15-methyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15S)-1-(N-methyl-thiocarbamoyloxy)-15-hydroxy-15-methyl-5,10,13-prostadien-9-on (5Z,13E)-(8R,11R,12R,15S,16RS)-1-(N-methyl-thiocarbamoyloxy)-11,1 5-dihydroxy-1 6-methyl-5, 1 3-prostadien-9-on (5Z,13E)-(8R,12S,15S,16RS)-1-(N-methyl-thiocarbamoyloxy)-15-hydroxy-16-tnethyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,11R,12R,15R)-1-(N-methyl-thiocarbamoyloxy)-11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-on (5Z,13E)-(8R,12S,15R)-1-(N-methyl-thiocarbamoyloxy)-15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-on (5Z,13E)-(8R,9S,11R,12R,15R)-1-(N-methyl-thiocarbamoyloxy)-16-phenoxy-17,18,19,20-tetranor-5,13-prostadien-9,11,15-triol (5Z,13E)-(8R,11R,12R,15R)-1-(N-methyl-thiocarbamoyloxy)-16-phenoxy-11,15-dihydroxy-17,18,19,20-tertanor-5,13-prostadien-9-on (13E)-(8R,12S,15S,16RS)-1-(N-methylcarbamoyloxy)-15-hydroxy-16-methyl-10,13-prostadien-9-on (8R,12S,15S,16RS)-1-(N-methylcarbamoyloxy)-15-hydroxy-16-methyl-1 0-prosten-9-on (1 3E)-(811, S,15S,16RS)-1-/tN-methansulfonyl)-carbamoyloxy7-15-hydroxy-16-methyl-10, 13-prostadien-9-on (8R,12S,15S,16RS)-1-[(N-methylsulfonyl)-carbamoyloxy]-15-hydroxy-16-methyl-10-prosten-9-on (13E)-(8R,12S,15S,16RS)-1-(N-Acetylcarbamoyloxy)-15-hydroxy-16-methyl-10,13-porostadien-9-on (8R,12S,15S,16RS)-1-(N-Acetylcarbamoyloxy)-15-hydrdoxy-16-methyl- 1 O-prosten-9-on (13E)-(8R,12S,15R)-1-(N-methylcarbamoyloxy)-16,16-dimethyl-15-hydroxy-10,13-prostadien-9-on (8R,12S,15R)-1-(N-methylcarbamoyloxy)-16,16-dimethyl-15 hydroxy- 1 O-prosten-9-on (13E)-(8R,12S,15R)-1-[(N-methansulfonyl)-carbamoyloxy]-16,16 dimethyl-15-hydroxy-10,13-prostadien-9-on (8R,12S,15R)-1-[(N-methansulfonyl)-carbamoyloxy]-16,16-dimethyl-15-hydroxy-10-prosten-9-on (10E)-(8R,12S,15R)-1-(N-Acetylcarbamoyloxy)-16,16-dimethyl-15-hydroxy-10,13-prostadien-9-on (81t-,12S,15R) - 1 - (N-Acetylcarbamoyloxy) -16, 16 6-dimethyl -15-hydroxy-1 0-prosten-9-on (5Z,13E)-(8R,11R,12R,15S)-1-(N-phenylcarbamoyloxy3-15-hydroxy-11,15-dimethyl-5,13-prostadien-9-on (5Z,13E)-(8R,11R,12R,15S)-1-(N-Acetylcarbamoyloxy)-15-hydroxy-11,15-dimetyl-5,13-prostadien-9-on (5Z,13E)-(8R,11R,12R,15S)-1-(N-Methylcarbamoyloxy)-15-hydroxy-11,15-dimethyl-5,13-prostadien-9-on (13E)-(8R,11R,12R,15S)-1-(N-Methylcarbamoyloxy)-15-hydroxy-11,15-dimethyl-13-prosten-9-on Die neuen Prostanderivate der allgemeinen Formeln Ia und Ila sind wertvolle Pharmaka, da sie bei ähnlichem lfirkungsspektrum eine wesentlich stärkere und vor allem wesentlich längere Wirkung aufweisen als die entsprechenden natürlichen Prostaglandine.With the aid of the method according to the invention, for example also make the following compounds: (5Z, 13E) - (8R, 9S, 11R, 15S) -1- (N-acetylcarbamoyloxy) -5.13 prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetylcarbamoyloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-acetylcarbamoyloxy) -15-hydroxy-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (aR, 12S, 15S) -1- (N-phenylcarballloyloxy) -15-hydroxy-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyl-oxy) -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methyl-thiocarbamayloxy) -11,15-dihydroxy-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy 5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-methyl-5, 1 3-prostadien-9, 11, 15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13- prostadien-9-on (5Z, 13E) - (8R, 12S, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-methylcarbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16, 1 6-diethyl-5, 1 3-prostadien-9-one (5Z, 13E) - (t3R, 12S, 15R) -l- (N-methylcarbamoyloxy) -15-hydroxy-16, 1 6-dimethyl-5, 10, 1 3-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16-phenoxy-17.18 , 19-tetranor-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy-16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methylcarbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor -5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11,15- triplet (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-Metylcarbamoyloxy) -11,15-dihydroxy- 1 7-phenyl- 18, 1 9, 20-trinor-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-1 1-methyl-51 1 3-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methylcarbamoyloxy) -carbamayloxy] -15-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S, 16RS) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-11,15-dihydroxy-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15R) -1 - [(N-methanesulfonyl) -carbamyloxy] -15-hydroxy-16,16, -dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (3-trifluoromethylphenoxy) 17,181 191 20-tetranor-5, 1 3-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11, 15-dihydroxy-16- (3-trifluoromethylphenyl) -17,18,19,20-tetranor-5, 1 3-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (4-chlorophenol) -17.18, 19,20-tetranor-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (3-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (3-chlorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16- (4-fluorophenoxy) -17,18,19,20-tetranor-5, 13-prostadione-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-16- (4-fluorophenoxy) -17,18,19,20- tetranor-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -17-phenyl-18,19,20-trinor-5,13-prostadiene-9, 11.15-triplet (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13- prostadien-9-on (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dimethyl-15-hydroxy-5,13-prostadien-9-one (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-acetyl-carbamoyloxy] -15-methyl-5,13-prostadiene-9,11,15-triol (5Z-13E) - (8R, 11R, 12R, 15S) -1 - [(N-acetylcarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z-13E) - (8R, 12S, 15S) -1 - [(N-acetylcarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12R, 15S, 16RS) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16-pheoxy-17,18,19,20-tetranor-5,13-prostadiene-9, 11.15-triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13- prostadien-9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor, 5,13- prostadiene 9,11,15 triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11.15 dihydroxy-16- (-I; ri £ luoreletlzylphelloxy - 17, 18, 19, 20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor-5,13- prostadiene 9,11,15 triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor- 5.13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11, 15-triplet (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-17-phenyl-18,19,20-trinor-5,13- prostadien-9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -15-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-acetyl-carbamoyloxy) -11,15-dihydroxy-1 5-methyl-5, 1 3-prostadien-9-one (5Z 1 3E) - (811, 125, 155) -1 - (N-phenylcarbamoyloxy) -1 5-hydroxy-15-methyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-phenyl-carbamoyloxy) -16-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 9S, 11R, 12R, 15S, 16RS) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-phenylcarbamoyloxy) -15-hydroxy-16-methyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16,16-dimethyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-phenylcarbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16-phenoxy-17,18,19,20, tetranor-5,13-prostadiene-9,11, 15, triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene- 9-on (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16- (3-trifluoromethylphenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16- (3-trifluoromethyslphenoxy) -17,18,19,20-teranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -16- (4-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadiene- 9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-16- (4-chlorophenoxy) -17,18,19,20-tetranor-5, 13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -11,15-dihydroxy-17, phenyl-18,19,20-trinor-5,13-prostadiene-9- on (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -17-phenyl-18,19,20-trinor-5,13-prostadiene-9,11,15- triplet (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy) -15-hydroxy-11-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-methyl-5,13-prostadiene-9,11,15-triol (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methyl-thiocarbamoyloxy) -11,15-dihydroxy-15-methyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-15-methyl-5,10,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S, 16RS) -1- (N-methyl-thiocarbamoyloxy) -11.1 5-dihydroxy-1 6-methyl-5, 1 3-prostadien-9-one (5Z, 13E) - (8R, 12S, 15S, 16RS) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-16 -tethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -11,15-dihydroxy-16,16-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 12S, 15R) -1- (N-methyl-thiocarbamoyloxy) -15-hydroxy-16,16-dimethyl-5,10,13-prostatrien-9-one (5Z, 13E) - (8R, 9S, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -16-phenoxy-17,18,19,20-tetranor-5,13-prostadiene-9, 11.15-triplet (5Z, 13E) - (8R, 11R, 12R, 15R) -1- (N-methyl-thiocarbamoyloxy) -16-phenoxy-11,15-dihydroxy-17,18,19,20-tertanor-5,13- prostadien-9-on (13E) - (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-10,13-prostadien-9-one (8R, 12S, 15S, 16RS) -1- (N-methylcarbamoyloxy) -15-hydroxy-16-methyl-10-prosten-9-one (1 3E) - (811, S, 15S, 16RS) -1- / tN-methanesulfonyl) -carbamoyloxy7-15-hydroxy-16-methyl-10, 13-prostadien-9-one (8R, 12S, 15S, 16RS) -1 - [(N-methylsulfonyl) -carbamoyloxy] -15-hydroxy-16-methyl-10-prosten-9-one (13E) - (8R, 12S, 15S, 16RS) -1- (N-acetylcarbamoyloxy) -15-hydroxy-16-methyl-10,13-porostadien-9-one (8R, 12S, 15S, 16RS) -1- (N-acetylcarbamoyloxy) -15-hydroxy-16-methyl-1 O-prosten-9-one (13E) - (8R, 12S, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-15-hydroxy-10,13-prostadien-9-one (8R, 12S, 15R) -1- (N-methylcarbamoyloxy) -16,16-dimethyl-15 hydroxy-1 O-prosten-9-one (13E) - (8R, 12S, 15R) -1 - [(N-methanesulfonyl) -carbamoyloxy] -16,16 dimethyl-15-hydroxy-10,13-prostadien-9-one (8R, 12S, 15R) -1 - [(N-methanesulfonyl) carbamoyloxy] -16,16-dimethyl-15-hydroxy-10-prosten-9-one (10E) - (8R, 12S, 15R) -1- (N-acetylcarbamoyloxy) -16,16-dimethyl-15-hydroxy-10,13-prostadien-9-one (81t-, 12S, 15R) -1 - (N-acetylcarbamoyloxy) -16, 16 6-dimethyl -15-hydroxy-10-prosten-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-phenylcarbamoyloxy3-15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-acetylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-5,13-prostadien-9-one (13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-11,15-dimethyl-13-prosten-9-one the new prostane derivatives of the general formulas Ia and Ila are valuable pharmaceuticals, because they have a much stronger and, above all, essential, with a similar range of effects have a longer effect than the corresponding natural prostaglandins.
Die neuen Prostaglandin-Analoga vom E:-, D- und F-Typ wirken sehr stark luteolytisch, d.h. zur Auslösung einer Luteolyse benötigt man wesentlich geringere Dosierungen als bei den entsprechenden natürlichen Prostaglandinen.The new prostaglandin analogs of the E: -, D- and F-type are very effective strongly luteolytic, i.e. to trigger a luteolysis one needs significantly less Dosages than with the corresponding natural prostaglandins.
Auch zur Auslösung von Aborten sind wesentlich geringere Mengen der neuen Prostaglandin-Analoga im Vergleich zu den natürlichen Prostaglandinen erforderlich.Much smaller amounts of the are also used to trigger abortions new prostaglandin analogs are required compared to the natural prostaglandins.
Bei der Registrierung der isotonischen Uteruskontraktion an der narkotisierten Ratte und am isolierten Rattenuterus zeigt sich, daß die erfindungsgemäßen Substanzen wesentlich wirlcsamer sind und ihre Wirkungen länger anhalten als bei den natürlichen Prostaglandinen.When registering the isotonic uterine contraction on the anesthetized The rat and the isolated rat uterus shows that the substances according to the invention are much more effective and their effects last longer than natural ones Prostaglandins.
Die neuen Prostanderivate sind geeignet, nach einmaliger intrauteriner Applikation Pine Menstruation zu induzieren oder eine Schwangerschaft zu unterbrechen. Dabei ist als therapeutischer Fortschritt anzusehen, daß - neben der überraschend guten Dissoziation antifertiler Eigenschaften -auch Effekte auf andere Organsysteme nahezu vollständig verhindert werden. Sie eignen sich ferner zur Synchronisation des Sexualzylilus bei weiblichen Säugetieren wie Affen, Kaninchen1 Rindern, Schweinen usw.The new prostane derivatives are suitable after a single intrauterine Application Pine to induce menstruation or to interrupt pregnancy. It is to be regarded as a therapeutic progress that - in addition to the surprising good dissociation of anti-fertile properties - also effects on other organ systems can be almost completely prevented. They are also suitable for synchronization of the sexual cylilus in female mammals such as monkeys, rabbits1 cattle, pigs etc.
Die gute Wirkungsdissoziation der erfindungsgemäßen Substanzen zeigt sich bei der Untersudhung an asndere glarttmuskulären Organen, wie beispielsweise am Meerschweinchen-Ileum oder an der isolierten Kaninchen-Trachen, wo eine wossentlich geringere Stimulierung zu beobachten ist als durch die natürichen Prostagladine.The good dissociation of action of the substances according to the invention is shown when examining other smooth muscle organs, such as on the guinea pig ileum or on the isolated rabbit trachea, where one is known Less stimulation can be observed than with the natural prostagladins.
Die erifndungsgemäßen Wirkstoffe der PG E-Reihe zeigen an der isolierten Kaninchen-Trachea in vitro bronchodilatatorische Wirkung und hemmen stark die Magensäuresekretion und wirken regulierend bei Herzhythmusstörungen. Die neuen Verbindungen der PG A- und PG E-Reihe senken ferner den Blutdruck und wirken dieretisch.The active ingredients of the PG E series according to the invention show on the isolated Rabbit trachea in vitro bronchodilator effects and strongly inhibit gastric acid secretion and have a regulating effect on cardiac arrhythmias. The new connections of the PG A- and PG E series also lower blood pressure and are dieretic.
Die erfindungsgemäßen Wirkstoffe der F-Reihe wirken weniger was für ihre therapeut als natürliches Prostaglandin F2a, was für therapeutishcen Anwendung von großen Vorteil ist. Für die medizinische Anwendung können die Wirkstoffe Applikation die Inhalation, für orale oder parenterale Applikation geeignete Form überführt werden. Zur Inhalation werden zweckmäßigerweise Aerosol- oder Spraylösungen hergestellt.The active ingredients of the F-series according to the invention have less of an effect Your therapist as a natural prostaglandin F2a, what a therapeutic application is of great benefit. For medical use, the active ingredients can be Application the inhalation, transferred form suitable for oral or parenteral administration will. Aerosol or spray solutions are expediently prepared for inhalation.
Für die orale Applikation sind beispielsweise Tabletten, Dragees oder Kapseln geeignet.For oral administration, for example, tablets, coated tablets or Suitable for capsules.
Für die parenterale Verabreichung werden sterile, injizierbare, wäßrige oder ölige Löswigen benutzt.For parenteral administration, sterile, injectable, aqueous or oily solvents used.
Die Erfindung betrifft damit auch Arzneimittel auf Basis der Verbindungen der allgemein( 1 Formeln 1 und II und der üblichen HilSs- und Trägerstoffe.The invention thus also relates to medicaments based on the compounds the general (1 formulas 1 and II and the usual auxiliaries and carriers.
Die erfindungsgemäßen Wirkstoffe sollen in Verbindung mit den in der Galenik bekannten und üblichen Hilstofen, zum Beispiel zur Herstellung von Präparaten zur Auslösung eines Abortes, zur Zyklussteuerung oder zur Einleitung einer Geburt dienen. Für diesen Zweck können sterile, wäßrige Lösungen, die 0,01 - 10 pg/ml der aktiven Verbindung enthalten, als intravenöse Infusion angewendet werden. Zur Herstellung wäßriger isotonischer Lösungen sind die Verbindungen der allgemeinen Formeln I und II besonders geeignet. Zur Steigerung der Löslichkeit können Alkohole, wie Äthanol, Äthylenglykol und Propylenglykol, hinzugefügt werden.The active ingredients according to the invention should be used in conjunction with the Galenik known and usual Hilstofen, for example for the production of preparations to trigger an abortion, to control the cycle or to initiate a birth to serve. For this purpose, sterile, aqueous solutions containing 0.01-10 pg / ml of the active compound should be administered as an intravenous infusion. For the production Aqueous isotonic solutions are the compounds of the general formulas I and II particularly suitable. To increase the solubility, alcohols such as ethanol, Ethylene glycol and propylene glycol, can be added.
B e i s p i e l 1 (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Methylcarbamoyl-oxy)-5,13-nrostadien- ,11,15-triol Zu einer Lösung von 300 mg des nach Beispiel 1 b) erhaltenen 1-Alkohols in 5 ml absolutem Tetrahydrofuran fügte man nacheinander 1,2 ml Methylisocyanat und 3 Tropfen Triäthylamin, ließ über Nacht bei Raumtemperatur stehen, dampfte im Vakuum zur Trockne und reinigte den Rückstand durch Filtrieren über Kieselgel mit Äther/Pentan (1:1). Man erhielt 305 mg des entsprechenden Urethans als farbloses 01.Example 1 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyl-oxy) -5,13-nrostadiene- , 11,15-triol To a solution of 300 mg of the 1-alcohol obtained according to Example 1 b) 1.2 ml of methyl isocyanate were added successively in 5 ml of absolute tetrahydrofuran and 3 drops of triethylamine, left to stand overnight at room temperature, evaporated in the Vacuum to dryness and the residue was purified by filtering through silica gel Ether / pentane (1: 1). 305 mg of the corresponding urethane were obtained as colorless 01.
IR (CHCl3): 3470, 2943, 1700, 1650, 1020, 975 /cm Man rührte 250 mg (5Z,13E)-(8R,9S,11R,12R,15S)-1-(N-Methyl carbamoyloxy)-11,15-bis(Tetrahydropyran-2-yloxy)-9-tribenzylsilyloxy-5,15-prostadien in 15 ml einer Mischung aus Eisessig/ Wasser/Tetrahydrofuran (65/35/10) 5 Stunden bei 500C, dampfte im Vakuum ein und reinigte den Rückstand durch Chromatographie an Kieselgel mit Äther/Dioxan (7+3). Man erhielt 105 mg der Titelverbindung als farbloses Öl.IR (CHCl3): 3470, 2943, 1700, 1650, 1020, 975 / cm Stir 250 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methyl carbamoyloxy) -11,15-bis (tetrahydropyran-2-yloxy) -9-tribenzylsilyloxy-5,15-prostadiene in 15 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) for 5 hours at 50 ° C., evaporated in vacuo and the residue was purified by chromatography on silica gel with ether / dioxane (7 + 3). 105 mg of the title compound were obtained as colorless oil.
IR (CHCl3): 3605, 3470, 2935, 1700, 1650, 1512, 1080, 972, 947 /cm NMR (CDCl3): # 5,3 - 5,6 m, 4H olefin. Protonen 3,8 - 4,3 m, 5H carbinol. Protonen und -CH2-CH2-O 2,85 d, 7Hz ) ) -NH-CH3 2,78 d, 7Hz ) 0,88 t, 7Hz 3H, -CH2-CH3 Das Ausgangsmaterial für die obige Reaktion wurde folgendermaßen hergestellt: 1 a) 1,00 g Prostaglandin F2α-methylester -11,15-bis-(tetr2« hydropyranyl)äther (erhalten aus der entsprechenden Säure, siehe J. Amer.Chem. Soc. 91, 5675 (1969), mit Diazomethan) gelöst in 25 ml Pyridin versetzte man mit 1,40 g Tribenzylsilylchlorid und rührte 5 Stunden bei 500C unter Argon. Nach Abdestillieren des Lösungsmittels im Vakuum chromatographierte man den öligen Rückstand an Kieselgel mit Äther/Pentan-Gemischen. Dabei erhielt man 2,05 g des entsprechenden 9-Tribenzylsilyläthers als farbloses Öl.IR (CHCl3): 3605, 3470, 2935, 1700, 1650, 1512, 1080, 972, 947 / cm NMR (CDCl3): # 5.3-5.6m, 4H olefin. Protons 3.8-4.3 m, 5H carbinol. Protons and -CH2-CH2-O 2.85 d, 7Hz)) -NH-CH3 2.78 d, 7Hz) 0.88 t, 7Hz 3H, -CH2-CH3 That Starting material for the above reaction was prepared as follows: 1 a) 1.00 g prostaglandin F2α-methyl ester -11,15-bis- (tetr2 «hydropyranyl) ether (obtained from the corresponding acid, see J. Amer. Chem. Soc. 91, 5675 (1969), with diazomethane) dissolved in 25 ml of pyridine, 1.40 g of tribenzylsilyl chloride were added and the mixture was stirred 5 hours at 500C under argon. After distilling off the solvent in vacuo the oily residue was chromatographed on silica gel with ether / pentane mixtures. This gave 2.05 g of the corresponding 9-tribenzylsilyl ether as colorless Oil.
1 b) 2,05 g des Silyläthers in 80 ml absolutem Äther versetzt man bei Raumtemperatur protionsweise mit 0,5 g Lithiumaluminiumhydrid, rührte 2 Stunden bei 20°C, zer störte den Reagenzüberschuß mit t Essigester, fügte 1,2 ml Wasser zu, rührte 1 Stunde bei 200C, filtrierte und dampfte im Vakuum ein. Man erhielt 1,95 g des dünnschichtchromatographisch völlig einheitlichen (5Z, 13E)-(8R,9S,11R,12R,15S)-11,15,Bis-(tetrahydropyran-2-yloxy)-9 tribenzylsilyloxy-5,13-prostadien-1-ol.1 b) 2.05 g of the silyl ether in 80 ml of absolute ether are added at room temperature in portions with 0.5 g of lithium aluminum hydride, stirred for 2 hours at 20 ° C, destroyed the excess reagent with t ethyl acetate, added 1.2 ml of water to, stirred for 1 hour at 200C, filtered and evaporated in vacuo. One received 1.95 g of (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -11.15, bis (tetrahydropyran-2-yloxy) -9, which is completely uniform by thin layer chromatography tribenzylsilyloxy-5,13-prostadien-1-ol.
Das 111-Spektrum (in Chloroform) zeigte keine Carbonylschwingung mehr. The 111 spectrum (in chloroform) showed no carbonyl vibration more.
B e i s p i e l 2 (5Z,13E)-(8R,11R,12R,15S)-1-(N-Methylcarbamoyl-oxy)-11,15-dihydroxy-5,13-prostadien-9-on Man rührte 300 mg (5Z,13E)-(8R,11R,12R,15S)-1-(N-Methylcarbamoyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-5,13-prostadien-9-on mit 9 ml einer Mischung aus Eisessig/Wasser/Tetrahydrofuran (65/35/10) 6 Stunden bei 4000, dampfte anschließend im Vakuum zur Trockne. Nach Reinigung des Rückstandes durch Chroniatographie an Kieselgel (Äther/Essigester 7+3) erhielt man 145 mg der Titelverbindung als farbloses Öl.For example 2 (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyl-oxy) -11,15-dihydroxy-5,13-prostadien-9-one 300 mg of (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadiene-9- were stirred on with 9 ml of a mixture of glacial acetic acid / water / tetrahydrofuran (65/35/10) for 6 hours at 4000, then evaporated to dryness in vacuo. After purifying the residue Chroniatography on silica gel (ether / ethyl acetate 7 + 3) gave 145 mg of the Title compound as a colorless oil.
IR (CHCl3): 3605, 3470, 2940, 1735, 1700, 1650, 1512, 1085, 972, 948 /cm Das Ausgangsmaterial für die obige Reaktion wurde folgendermaßen hergestellt: 2 a) Eine Lösung von 370 mg des nach Beispiel 1 hergestellten Urethans und 110 mg Tetrabutylammoniumfluorid in 30 ml Tetrahydrofuran rührte man 2 Stunden bei OOC, verdünnte mit Wasser, extrahierte mit Äther, schüttelte den organischen Extrakt mit Sole, trocknete über Magnesiumsulfat und dampfte im Vakuum zur Trockne. Nach Filtration über Kieselgel mit Äther erhielt man 205 mg (5Z,13E)-(8R,9S, 11R,12R,15S)-1-(N-Methylcarbamoyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-5,13-prostadien-9-ol als farbloses Öl.IR (CHCl3): 3605, 3470, 2940, 1735, 1700, 1650, 1512, 1085, 972, 948 / cm The starting material for the above reaction was prepared as follows: 2 a) A solution of 370 mg of the urethane prepared according to Example 1 and 110 mg Tetrabutylammonium fluoride in 30 ml of tetrahydrofuran was stirred for 2 hours at OOC, diluted with water, extracted with ether, shaken the organic extract with brine, dried over magnesium sulfate and evaporated to dryness in vacuo. To Filtration through silica gel with ether gave 205 mg of (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5 , 13-prostadien-9-ol as a colorless oil.
2 b) zu einer Lösung von 290 mg der vorstehend erhaltenen 9-Hydroxyverbindung in 8 ml Aceton tropfte man bei -20°C 0,25 ml Jones-Reagenz und rührte 25 Minuten bei -200C, zerstörte den Reagenzüberschuß dadurch Zugabe von Isopropanol, verdünnte mit Äther und schüttelte mit Sole neutral. Nach Trocknen über Magnesiumsulfat und Eindampfen erhielt man 265 mg (5Z,13E)-(8R,11R,12R, 15S)-1-(N-Methylcarbamoyloxy)-11,15-bis-(tetrahydropyran-2-yloxy)-5,13-prostadie-9-on als farbloses Öl.2 b) to a solution of 290 mg of the 9-hydroxy compound obtained above 0.25 ml of Jones reagent was added dropwise to 8 ml of acetone at -20 ° C. and the mixture was stirred for 25 minutes at -200C, the excess reagent destroyed by adding isopropanol, diluted with ether and shaken neutral with brine. After drying over magnesium sulfate and Evaporation gave 265 mg (5Z, 13E) - (8R, 11R, 12R, 15S) -1- (N-methylcarbamoyloxy) -11,15-bis- (tetrahydropyran-2-yloxy) -5,13-prostadie-9 -on as a colorless oil.
IR (CHCl3): 3470, 2945, 1735, 1700, 1650, 1080, 972, 948 /cm B e i s p i e l 3 (5Z,13E)-(8R,12S,15S)-1-(N-Methylcarbamoyloxy)-15-hydroxy-5,10,13-prostatrien-9-on Man rührte 250 mg des nach Beispiel 2 hergestellten PGE-Derivates in 16 ml 90 %iger Essigsäure 16 Stunden bei 60°C, dampfte im Vakuum ein.und reinigte den Rückstand durch präparative Schichtchromatographie (Kieselgel, Äther). Man erhielt 165 mg der Titelverbindung als farbloses Öl. IR (CHCl3): 3470, 2945, 1735, 1700, 1650, 1080, 972, 948 / cm B e i s p i e l 3 (5Z, 13E) - (8R, 12S, 15S) -1- (N-methylcarbamoyloxy) -15-hydroxy-5,10,13-prostatrien-9-one 250 mg of the PGE derivative prepared according to Example 2 were stirred in 16 ml of 90% strength Acetic acid 16 hours at 60 ° C, evaporated in vacuo and purified the residue by preparative layer chromatography (silica gel, ether). 165 mg were obtained the title compound as a colorless oil.
IR (CHCl3): 3600, 3500 (breit), 2940, 1700, 1602, 978 /cm.IR (CHCl3): 3600, 3500 (broad), 2940, 1700, 1602, 978 / cm.
B e i s p i e l 4 (5Z,13E)-(8R,9S,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-5,13-prostadien-9,11,15-triol Zu einer Lösung von 405 mg des nach Beispiel 1 b erhaltenen l-Alkohols in 10 ml absolutem Toluol fügte man bei OOC 145 mg Met11allsulfonylisocyanat und rührte 1 Stunde bei 20 - 2500, versetzte mit Wasser, schüttelte mit Äther aus, wusch den Extrakt mit Sole, trocknete über Magnesiumsulfat und dampfte im Vakuum ein. Nach Filtration des Rückstandes über Kieselgel mit Methylenchlorid erhielt man 390 mg (5Z,13E)-(8R,9S, 11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-bis-(tetrahydropyran-2-yloxy)-9-tribenzyloxy-5,13-prostadien als farbloses Öl.For example 4 (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -5,13-prostadiene-9,11,15-triol To a solution of 405 mg of the 1-alcohol obtained according to Example 1b in 10 ml 145 mg of metal sulfonyl isocyanate were added to absolute toluene at OOC and the mixture was stirred Hour at 20 - 2500, mixed with water, shaken out with ether, washed the Extract with brine, dried over magnesium sulfate and evaporated in vacuo. To Filtration of the residue through silica gel with methylene chloride gave 390 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-bis (tetrahydropyran-2-yloxy) -9-tribenzyloxy-5, 13-prostadia as a colorless oil.
Aus 300 mg erhält man in Analogie zu Beispiel 1 120 mg der Titelverbindung als farbloses Öl.In analogy to Example 1, 120 mg of the title compound are obtained from 300 mg as a colorless oil.
IR (CHCl3): 3600, 3380, 1720, 1400, 1346, 1020, 975 /cm.IR (CHCl3): 3600, 3380, 1720, 1400, 1346, 1020, 975 / cm.
13 e i s p i. R 1 5 (5Z,13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-dihydroxy-5,13-prostadien-9-on In Analogie zu Beispiel 2 erhielt man aus 250 mg (5Z,13E) (8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-bis-(tetrahydropyran-2-yloxy)-5, 13-prostadien-9-on 112 mg der Titelverbindung als farbloses Öl.13 e i s p i. R 15 (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-dihydroxy-5,13-prostadien-9-one In analogy to Example 2, from 250 mg (5Z, 13E) (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) carbamoyloxy] -11,15-bis (tetrahydropyran-2-yloxy) -5, 13-prostadien-9-one 112 mg of the title compound as a colorless oil.
IR (CHCl3): 3600, 3400, 2940, 1735 (Schulter), 1720, 1400, 1345, 1020, 976 /cm Das Ausgangsmaterial für die obige Umsetzung wurde wie folgt hergestellt: 5 a) In Analogie zu Beispiel 2 a) erhielt man aus 400 mg der in Beispiel 4 hergestellten 9-Tribenzylsilyloxy-Verbindung und 120 mg Tetrabutylammoniumfluorid 210 mg (5Z,l3E)-(8R,9S,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy]-11,15-bis-(tetrahydropyran-2-yloxy)-5,13-prostadien-9-ol als farbloses Öl.IR (CHCl3): 3600, 3400, 2940, 1735 (shoulder), 1720, 1400, 1345, 1020, 976 / cm The starting material for the above reaction was prepared as follows: 5 a) In analogy to Example 2 a), 400 mg of that prepared in Example 4 were obtained 9-tribenzylsilyloxy compound and 120 mg tetrabutylammonium fluoride 210 mg (5Z, 13E) - (8R, 9S, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy] -11,15-bis- (tetrahydropyran- 2-yloxy) -5,13-prostadien-9-ol as a colorless oil.
5 b) In Analogie zu Beispiel 2 b) erhielt man aus 210 mg der vorstehend hergestellten Verbindung und 0,2 ml Jones-Reagenz 170 mg (5Z,13E)-(8R,11R,12R,15S)-1-[(N-Methansulfonyl)-carbamoyloxy7-11,15-bis-(1;etrahydropyran-2-yloxy)-5,13-prostadien-9-on als farbloses Öl.5 b) In analogy to Example 2 b), 210 mg of the above were obtained prepared compound and 0.2 ml Jones reagent 170 mg (5Z, 13E) - (8R, 11R, 12R, 15S) -1 - [(N-methanesulfonyl) -carbamoyloxy7-11,15-bis- (1; etrahydropyran- 2-yloxy) -5,13-prostadien-9-one as a colorless oil.
B e i s p i e l 6 (5Z,13E)-(8R,12S,15S)-1-[(N-Methansulfonyl)-carbamoyl-oxy] 15-hydroxy-5,10,13-prostatrien-9-on Man rührte 200 mg des nach Beispiel 5 hergestellten PGE-Derivats in 12 ml 90 %iger Essigsäure 16 Stunden bei 600C, dampfte im Vakuum ein und reinigte den Rückstand durch präparative Schichtchromatographie (Kieselgel, Methylenchlorid/I sopropanol 9+1). Man erhielt 105 mg der Titelverbindung als farbloses Öl.Example 6 (5Z, 13E) - (8R, 12S, 15S) -1 - [(N-methanesulfonyl) -carbamoyl-oxy] 15-hydroxy-5,10,13-prostatrien-9-one 200 mg of that prepared according to Example 5 were stirred PGE derivative in 12 ml of 90% acetic acid for 16 hours at 60 ° C., evaporated in vacuo and purified the residue by preparative layer chromatography (silica gel, Methylene chloride / isopropanol 9 + 1). 105 mg of the title compound were obtained as colorless Oil.
IR (CHCl3): 3600, 3500, 2944, 1710, 1603, 978 /cmIR (CHCl3): 3600, 3500, 2944, 1710, 1603, 978 / cm
Claims (1)
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19762616304 DE2616304A1 (en) | 1976-04-12 | 1976-04-12 | Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activities |
NL7605381A NL7605381A (en) | 1975-05-26 | 1976-05-20 | METHOD FOR PREPARING PROSTANE DERIVES AND METHOD FOR PREPARING A MEDICINAL PRODUCT WITH PROSTAGLANDIN ACTION. |
CH640376A CH623036A5 (en) | 1975-05-26 | 1976-05-21 | |
AT373376A AT359657B (en) | 1975-05-26 | 1976-05-21 | METHOD FOR PRODUCING NEW PROSTANE DERIVATIVES |
LU75011A LU75011A1 (en) | 1975-05-26 | 1976-05-24 | |
IE1084/76A IE44255B1 (en) | 1975-05-26 | 1976-05-24 | Esters of prostan-1-ol derivatives, process for their manufacture and preparations containing them |
AU14225/76A AU510695B2 (en) | 1975-05-26 | 1976-05-24 | Prostane derivatives |
HU76SCHE566A HU177906B (en) | 1975-05-26 | 1976-05-25 | Process for preparing new prostane derivatives |
GB21622/76A GB1553710A (en) | 1975-05-26 | 1976-05-25 | Esters of prostan-1-ol derivatives process for their manufacture and preparations containing them |
US05/689,849 US4105792A (en) | 1975-05-26 | 1976-05-25 | Prostane dervatives |
SE7605925A SE7605925L (en) | 1975-05-26 | 1976-05-25 | NEW PROSTANCE DERIVATIVES AND WAY TO PRODUCE THE SAME |
DK229476A DK229476A (en) | 1975-05-26 | 1976-05-25 | PROSTAND DERIVATIVES AND PROCEDURES FOR THE MANUFACTURE OF IT |
JP51061035A JPS51143643A (en) | 1975-05-26 | 1976-05-26 | New prostane derivatives* process for manufacture thereof and medicines containing said compounds |
CA253,389A CA1091226A (en) | 1975-05-26 | 1976-05-26 | Prostane derivatives and process for their manufacture |
FR7615918A FR2312240A1 (en) | 1975-05-26 | 1976-05-26 | PROSTANE DERIVATIVES AND MEDICINAL PRODUCTS CONTAINING IT |
US05/882,687 US4256745A (en) | 1975-05-26 | 1978-03-02 | New prostane derivatives and process for their preparation |
US05/883,428 US4159343A (en) | 1975-05-26 | 1978-03-03 | Prostane derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE19762616304 DE2616304A1 (en) | 1976-04-12 | 1976-04-12 | Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activities |
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DE2616304A1 true DE2616304A1 (en) | 1977-11-03 |
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DE19762616304 Withdrawn DE2616304A1 (en) | 1975-05-26 | 1976-04-12 | Esters of 1-hydroxy prostaglandins - with stronger, more selective and longer lasting activities |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US7906552B2 (en) | 2004-08-10 | 2011-03-15 | Allergan, Inc. | Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
-
1976
- 1976-04-12 DE DE19762616304 patent/DE2616304A1/en not_active Withdrawn
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US7906552B2 (en) | 2004-08-10 | 2011-03-15 | Allergan, Inc. | Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US8168680B2 (en) | 2004-08-10 | 2012-05-01 | Allergan, Inc. | Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
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