DE2362280A1 - 21-SULFINYL STEROIDS OF THE DELTA HOCH 4PREGNAN SERIES, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents
21-SULFINYL STEROIDS OF THE DELTA HOCH 4PREGNAN SERIES, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDSInfo
- Publication number
- DE2362280A1 DE2362280A1 DE2362280A DE2362280A DE2362280A1 DE 2362280 A1 DE2362280 A1 DE 2362280A1 DE 2362280 A DE2362280 A DE 2362280A DE 2362280 A DE2362280 A DE 2362280A DE 2362280 A1 DE2362280 A1 DE 2362280A1
- Authority
- DE
- Germany
- Prior art keywords
- dione
- diene
- fluoro
- acetal
- cycl
- 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.)
- Ceased
Links
- 150000001875 compounds Chemical class 0.000 title claims description 37
- 238000000034 method Methods 0.000 title claims description 26
- 230000008569 process Effects 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 4
- 229940126601 medicinal product Drugs 0.000 title 1
- -1 alkyl radical Chemical class 0.000 claims description 64
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- KSRHWBLHVZJTKV-UHFFFAOYSA-N iodobenzene dichloride Chemical compound ClI(Cl)C1=CC=CC=C1 KSRHWBLHVZJTKV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 372
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 100
- 150000001241 acetals Chemical class 0.000 description 97
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 28
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 24
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 150000003431 steroids Chemical class 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- QIEPWCSVQYUPIY-LEKSSAKUSA-N Delta(1)-progesterone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 QIEPWCSVQYUPIY-LEKSSAKUSA-N 0.000 description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003461 sulfonyl halides Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XRHGYUZYPHTUJZ-UHFFFAOYSA-M 4-chlorobenzoate Chemical compound [O-]C(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-M 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000000292 calcium oxide Substances 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- 101150100121 gna1 gene Proteins 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 125000004718 n-hexylthio group Chemical group C(CCCCC)S* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- NUDKKGSOPWMRIK-LWKDCUQFSA-N (8R,9S,10S,13R)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12-decahydro-1H-cyclopenta[a]phenanthrene Chemical compound C=CC1=CC=C2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C NUDKKGSOPWMRIK-LWKDCUQFSA-N 0.000 description 1
- CPUKWYXYHPOQJH-RDQPJNLGSA-N (8r,9s,10s,13s,14s)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15-dodecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(=CC4)C=C)[C@@H]4[C@@H]3CCC21 CPUKWYXYHPOQJH-RDQPJNLGSA-N 0.000 description 1
- UZCQLCJQCCJUFL-GSPFLADASA-N (9R,10S,13R)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,9,11,12-octahydro-1H-cyclopenta[a]phenanthrene Chemical class C=CC1=CC=C2C3=CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C UZCQLCJQCCJUFL-GSPFLADASA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- CVBUKMMMRLOKQR-UHFFFAOYSA-N 1-phenylbutane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CC=CC=C1 CVBUKMMMRLOKQR-UHFFFAOYSA-N 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- KTUNYMABCQRLQC-KPONLSSESA-N 2-[(8S,9S,10R,13S,14S,17S)-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-17-yl]ethane-1,1,1,2-tetrol Chemical compound OC(C(O)(O)O)[C@H]1CC[C@H]2[C@@H]3CCC4=CCC=C[C@]4(C)[C@H]3CC[C@]12C KTUNYMABCQRLQC-KPONLSSESA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 101100456896 Drosophila melanogaster metl gene Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 201000009053 Neurodermatitis Diseases 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- DFGFSNJQZDZDNF-UHFFFAOYSA-N cyclohexanone;hexan-2-one Chemical compound CCCCC(C)=O.O=C1CCCCC1 DFGFSNJQZDZDNF-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-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
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000006107 n-hexyl sulfinyl group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- LPNBBFKOUUSUDB-UHFFFAOYSA-M p-toluate Chemical compound CC1=CC=C(C([O-])=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-M 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 description 1
- YYZZFSZNGFVMKC-UHFFFAOYSA-M potassium;4-methylthiobenzate Chemical compound [K+].CC1=CC=C(C([S-])=O)C=C1 YYZZFSZNGFVMKC-UHFFFAOYSA-M 0.000 description 1
- DGVCCCXMVDDDBJ-UHFFFAOYSA-N potassium;ethanol;ethanolate Chemical compound [K+].CCO.CC[O-] DGVCCCXMVDDDBJ-UHFFFAOYSA-N 0.000 description 1
- LKFCPWBGBPJDRC-UHFFFAOYSA-M potassium;thiobenzate Chemical compound [K+].[O-]C(=S)C1=CC=CC=C1 LKFCPWBGBPJDRC-UHFFFAOYSA-M 0.000 description 1
- JWMFYGXQPXQEEM-WZBAXQLOSA-N pregnane Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- GWLDWFHTQHBVSF-UHFFFAOYSA-M sodium;hexanethioate Chemical compound [Na+].CCCCCC([O-])=S GWLDWFHTQHBVSF-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
11 -21-Sulfinylsteroide derZ\ -Pregnanreihe, Verfahren zu'ihrer Herstellung und diese Verbindungen enthaltende. Arzneimittel " 11 -21-Sulfinylsteroide the Z \ -Pregnanreihe, method zu'ihrer preparation and compositions containing these compounds. Medicines "
Priorität': 15. Dezember 1972,.V.St.A.,. Nr. 315 701 .Priority ': December 15, 1972, .V.St.A.,. No. 315 701.
Die Erfindung betrifft 21-Sulfinylsteroide der der allgemeinen Formel IThe invention relates to 21-sulfinyl steroids of the general formula I.
Δ*.Δ *.
PregnanreihePregnan series
(D(D
in der R1 einen Alkylrest mit 1 bis 6 Kohlenstoffatomen, einen. Cycloalkylrest mit 3 bis 7 Kohlenstoffatomen, einen monocyclischen Aryl- oder Aralkylrest, R2 ein Wasserstoffatoin, einen Al-'kylrest mit 1 bis 6 Kohlenstoffatomen oder eine Hydroxylgruppe !und Rv ein Wasserstoffatom, einen Alkylrest mit 1 Ms β Kohlen- "in which R 1 is an alkyl radical having 1 to 6 carbon atoms, a. Cycloalkyl radical with 3 to 7 carbon atoms, a monocyclic aryl or aralkyl radical, R 2 a hydrogen atom, an Al-alkyl radical with 1 to 6 carbon atoms or a hydroxyl group! And Rv a hydrogen atom, an alkyl radical with 1 Ms β carbon "
l_s-tof fat omen, eine Methylen- oder Hydroxylgruppe'bedeutet» oder _Jl_s-tof fat omen, a methylene or hydroxyl group 'means' or _J
■' .. -401825/11■ '.. -401825/11
Rp und R, zusammen eine cyclisierte Dioxologruppe der allgemei-• nen FormelRp and R, together a cyclized dioxo group of the general formula
-O-O
-0 "" x R,
5-0 "" x R,
5
oder eine cyclisierte Oxazolgruppe der allgemeinen Formelor a cyclized oxazole group of the general formula
darstellen, wobei R^ und Rp- gleich oder verschieden sind und Wasserstoffatome, Alkylreste mit 1 bis 6 Kohlenstoffatomen oder ' monocyclische Arylreste bedeuten oder R^ und R,- zusammen einen Cycloalkylrest mit J> bis 7 Kohlenstoffatomen bilden und Rg einen Alkylrest mit 1 bis 6 Kohlenstoffatomen darstellt, X^ 'eine Hydroxylgruppe oder ein Halogenatom, X2 ein Wasserstoff- oder Halogenatom und X- ein Wasserstoff- oder Halogenatom oder einen Alkylrest mit 1 bis 6 Kohlenstoffatomen bedeutet.represent, where R ^ and Rp- are the same or different and hydrogen atoms, alkyl radicals with 1 to 6 carbon atoms or 'mean monocyclic aryl radicals or R ^ and R, - together form a cycloalkyl radical with J> to 7 carbon atoms and Rg is an alkyl radical with 1 to Represents 6 carbon atoms, X ^ 'represents a hydroxyl group or a halogen atom, X 2 represents a hydrogen or halogen atom and X- represents a hydrogen or halogen atom or an alkyl radical having 1 to 6 carbon atoms.
Die gestrichelten Linien in den Ringen A, B und D bedeuten die gegebenenfalls anwesende Doppelbindung.The dashed lines in rings A, B and D indicate any double bond that may be present.
Als Alkylreste kommen unverzv/eigte oder verzweigte Reste mit 1 bis 6 Kohlenstoffatomen, wie die Methyl-, Äthyl-, Propyl-, Isopropyl-, η-Butyl-, sek.-Butyl-, tert.-Butyl-, Amyl- und Hexylgruppen in Frage. Der Ausdruck Cycloalkylrest bedeutet einen einwertigen gesättigten alicyclisehen Ring mit 3 bis 7 Kohlenstoffatomen, wie die Cyclopropyl-, Cycle butyl-, Cyclopentyl-, Cyclohexyl- und Cycloheptylgruppe.. Der Ausdruck'Arylrest'bedeutet einen monocyclisehen carbocyclischen aromatischen Rest, derThe alkyl radicals are straight or branched radicals with 1 up to 6 carbon atoms, such as the methyl, ethyl, propyl, isopropyl, η-butyl, sec-butyl, tert-butyl, amyl and hexyl groups in question. The term cycloalkyl means a monovalent saturated alicyclic ring with 3 to 7 carbon atoms, such as the cyclopropyl, cycle butyl, cyclopentyl, cyclohexyl and cycloheptyl group .. The term 'acryl radical' means a monocyclic carbocyclic aromatic radical which
409825/1140409825/1140
gegebenenfalls durch Halogenatome, Alkoxyreste mit 1 bis 6 Kohlenstoffatomen oder Alkylreste mit 1 bis 6 Kohlenstoffatomen substituiert ist. Spezielle Beispiele für diese Arylreste sind die Phenyl-, Methoxyphenyl-, Äthoxyphenyl-, Tolyl-, iithylphenyl-, Propylphenyl-, Fluorphenyl- und Chlorphenylgruppe. Der Ausdruck "Aralkylrest" bedeutet einen Alkylrest mit 1 bis 6 Kohlenstoffatomen, der durch einen Arylrest der vorgenannten Art substituiert ist. Spezielle Beispiele sind die Benzyl- und PhenatlTylgruppe. Als Halogenatome kommen Fluor-,. Chlor-, Brom- und Jodatome in. Frage. Chlor- und Bromatome sind bevorzugt.·optionally by halogen atoms, alkoxy radicals with 1 to 6 carbon atoms or alkyl radicals with 1 to 6 carbon atoms is substituted. Specific examples of these aryl radicals are the phenyl, methoxyphenyl, ethoxyphenyl, tolyl, iithylphenyl, Propylphenyl, fluorophenyl and chlorophenyl groups. The expression “Aralkyl radical” means an alkyl radical having 1 to 6 carbon atoms which is substituted by an aryl radical of the aforementioned type is. Specific examples are the benzyl and phenat / tyl groups. As halogen atoms come fluorine ,. Chlorine, bromine and iodine atoms in question. Chlorine and bromine atoms are preferred.
Die 2.1-SuIfinylsteroide der allgemeinen Formel I gehören zur A -Pregnenreihe, einschließlich der Pregnadien-,. Pregnatrien- und Pregnatetraenreihe. _ ' The 2.1-sulfinyl steroids of the general formula I belong to the A -Pregnen series, including the pregnadiene. Pregnatrien and pregnatetraen series. _ '
Zur Herstellung der Verbindungen der allgemeinen Formel I können Zwischenprodukte der allgemeinen Formeln II bis VI verwendet werden: · .For the preparation of the compounds of general formula I can Intermediate products of the general formulas II to VI are used: ·.
ι— S-R,- S-R,
r—S-Hr-S-H
(II)(II)
40982S-/114040982S- / 1140
(IV)(IV)
(VI)(VI)
20 Spezielle Ausgangsverbindungen zur Herstellung der Verbindungen der allgemeinen Formel I sind Verbindungen der allgemeinen Formel VII und VIII:20 Special starting compounds for making the connections of the general formula I are compounds of the general formula VII and VIII:
409825/1140409825/1140
ι OHι OH
undand
Steroide dieser Art sind z.B. aus der US-PS 3 048 581 und der
GB-PS 869 5
einen Cycloalkyl-, J^ryl- oder Arallcylrest-.Steroids of this type are disclosed, for example, in US Pat. No. 3,048,581 and British Pat. No. 869,5
a cycloalkyl, j ^ ryl or arallcyl radical.
bekannt. R7 bedeutet einsn niederen Alkylrest oderknown. R 7 denotes a lower alkyl radical or
- Die Erfindung betrifft auch ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, das dadurch gekermzeichnet ist, daß man ein 21-Mercaptosteroid der allgemeinen Formel II - r- S-R,- The invention also relates to a process for the preparation of the compounds of the general formula I, which is characterized in that a 21-mercaptosteroid of the general formula II - r - SR,
(H)(H)
in der R1, R2, R,, X1, X2 und X, die vorstehende Bedeutung haben, mit einem Oxidationsmittel behandelt. Als Oxidationsmittel kommen solche Verbindungen in Frage, die selektiv das Schv/efelatom in der 21-Stellung zum entsprechenden SuIfoxid in Gegenwart Lvon Hydroxyl- und Ketogruppen und/oder Kohlenstoff-Kohlenstoff~ _,in which R 1 , R 2 , R 1 , X 1, X 2 and X, as defined above, are treated with an oxidizing agent. Suitable oxidizing agents are those compounds in question which selectively SChv / efelatom in the 21-position to give the corresponding SuIfoxid in the presence of L of hydroxyl and keto groups and / or carbon-carbon ~ _,
409825/1140409825/1140
Doppelbindungen oxidieren. Spezielle Beispiele für die im . . findungsgemäßen Verfahren verwendbaren Oxidationsmittel sind Jodosobenzoldiacetat, N-Bromsuccinimid, N-Chlorsucciniraid, Jodbenzoldichlorid oder Natriummetaperjodat, Als Oxidationsmittel wird Natriurnmetaperjodat bevorzugt.Oxidize double bonds. Specific examples of the im. . Oxidizing agents which can be used in the process according to the invention are iodosobenzene diacetate, N-bromosuccinimide, N-chlorosuccinimide, iodobenzene dichloride or sodium metaperiodate. Sodium metaperiodate is preferred as the oxidizing agent.
Die Oxidationsreaktipn wird in einem Lösungsmittel durchgeführt, das gegenüber den Reaktionsteilnehmern inert ist und sowohl das Ausgangssteroid als auch das Oxidationsmittel zumindest in gev;issem Ausmaß löst. Bei Verwendung von Natriummeta^perjodat als Oxidationsmittel v/erden vorzugsweise niedere aliphatische Alkohole, wie Methanol, als Lösungsmittel verwendet. Die Umsetzung des 21-Mercaptosteroids mit dem Oxidationsmittel wird im allge-. meinen bei Temperaturen von etwa -50 bis +800C, vorzugsweise bei -15 bis +400G,während eines Zeitraums von etwa 12 Stunden bis zu 7 Tagen, vorzugsweise während 1 bis 4 Tagen, durchgeführt. Die gebildete Verbindung der allgemeinen Formel I wird in an sich bekannter Weise isoliert. Beispielsweise wird das Reaktionsgemisch in Wasser eingegossen, sofern ein wassermischbares LösungsThe oxidation reaction is carried out in a solvent which is inert to the reactants and which dissolves both the starting steroid and the oxidizing agent at least to a certain extent. When using sodium meta ^ periodate as the oxidizing agent, lower aliphatic alcohols, such as methanol, are preferably used as the solvent. The reaction of the 21-mercaptosteroid with the oxidizing agent is generally. mean at temperatures from about -50 to +80 0 C, preferably from -1 5 to +40 0 G, carried out for a period of about 12 hours to 7 days, preferably for 1 to 4 days. The compound of general formula I formed is isolated in a manner known per se. For example, the reaction mixture is poured into water, provided that it is a water-miscible solution
undand
mittel verwendet wurde ,/die ausgefällte Verbindung wird abfiltriert und getrocknet.medium was used / the precipitated compound is filtered off and dried.
Die 21-Mercaptosteroide sind neue Verbindungen, die z.B. durch Umsetzen von Alkalimetall salzen von Mercaptanen (MSR^ , wobei --H-ein Alkalimetallkation, vorzugsweise ein Natrium- oder Kaliumkation, bedeutet, mit Steroiden der allgemeinen Formel V hergestellt werden:The 21-mercaptosteroids are new compounds, e.g. Reaction of alkali metal salts from mercaptans (MSR ^, where --H- a Alkali metal cation, preferably a sodium or potassium cation, means prepared with steroids of the general formula V. will:
409826/11-40.409826 / 11-40.
236228Ö236228Ö
(V)(V)
r—S-Rr-S-R
(ID(ID
Ein weiteres Verfahren zur Herstellung der 21-Mercaptosteroide-' der allgemeinen Formel II besteht in der Umsetzung--eines Alkali •raetallsalzes eines Mercaptans (MSR^) rait Steroiden der .allgemei nen Formel VI: ■ ■ . ., ι .Another method of making the 21-mercaptosteroids- ' of the general formula II consists in the reaction - an alkali • metallic salt of a mercaptan (MSR ^) rait steroids of the .general nen formula VI: ■ ■. ., ι.
(VI)(VI)
(II)(II)
Anstelle der 2.1-Jodverbindungen können auch andere 21-Halogenverbindungen verwendet werden. Die 21-Jodverbindungen werden je-. doch bevorzugt eingesetzt. ' ' .Instead of the 2.1-iodine compounds, other 21-halogen compounds can also be used be used. The 21-iodine compounds are each-. but preferably used. ''.
40962S7114Ö40962S7114Ö
Die Umwandlung der Steroide der allgemeinen Formel V oder VI in die 21-Mercaptosteroide der allgemeinen Formel II wird vorzugsweise in einem inerten, polaren Lösungsmittel, wie Methanol, Acetonitril oder Dimethylformamid, bei Temperaturen von 0 bis 10O0C, vorzugsweise 30 bis. 6O0C,während eines Zeitraums von 12 Stunden bis 7 Tagen, vorzugsweise 1 bis 3 Tagen, durchgeführt. Das Ausgangssteroid wird, mit 1 bis 6, vorzugsweise. 1 bis J5 Holäquivalenten des Alkalimercäptids umgesetzt. Nach beendeter Umsetzung wird das Reaktionsgemisch gegebenenfalls neutralisiert,. in Wasser eingegossen und das ausgefällte" 21-Mercaptosteroid. der allgemeinen Formel II abfiltriert und getrocknet.The conversion of the steroids of the general formula V or VI into the 21-mercaptosteroids of the general formula II is preferably carried out in an inert, polar solvent, such as methanol, acetonitrile or dimethylformamide, at temperatures from 0 to 10O 0 C, preferably 30 to. 6O 0 C, carried out over a period of 12 hours to 7 days, preferably 1 to 3 days. The starting steroid is, with 1 to 6, preferably. 1 to J5 hol equivalents of the Alkalimercäptids implemented. After the reaction has ended, the reaction mixture is optionally neutralized. poured into water and the precipitated "21-mercaptosteroid. of the general formula II filtered off and dried.
Ein weiteres Verfahren zur Herstellung der 21-Mercaptosteroide der allgemeinen Formel II besteht in der selektiven Alkylierung der entsprechenden 21-Mercaptosteroide der allgemeinen Formel III:Another method of making the 21-mercaptosteroids of the general formula II consists in the selective alkylation of the corresponding 21-mercaptosteroids of the general formula III:
r-S-H
- OrSH
- O
Basebase
Alkylierungsmit
tel.Alkylation with
tel.
Das Alkylierungsmittel kann durch die allgemeine Formel R^X^ wie-·The alkylating agent can be represented by the general formula R ^ X ^ as- ·
. ■■" ο ο dergegeben werden, in der X/ die Gruppe o J R H. ■■ "ο ο given in the X / the group o J R H
H 7' -"-^-01VH 7 '- "- ^ - 01 V
oder ein Halogenatom bedeutet» Das 21-Msrcaptosteroid der allgemeinen .Formel III wird mit einem geringen Überschuß einer Base,_jor a halogen atom means »The 21-msrcaptosteroid of the general .Formula III is with a slight excess of a base, _j
409825/1140 .409825/1140.
wie Natriumhydrid, in einem inerten polaren Lösungsmittel, wie 1-,2-Dime"thoxyäthan,während eines Zeitraums von etwa 15 Minuten bis 24 Stunden, vorzugsweise während 1 bis 3 Stunden,bei Temperaturen von O bis 8O°C, vorzugsweise von 30 bis 500C,umgesetzt. Anschließend wird das Reaktionsgemisch mit einem geringen Überschuß des entsprechenden .Alkylierungsmittels R1X^ versetzt. Die Reaktionszeit beträgt etwa 30 Minuten bis 48 Stunden, vorzugsweise 3 bis 24 Stunden,bei Temperaturen von 50 bis 100°C, vorzugsweise von 25 bis 800C. Nach dem Verdampfen des Lösungsmittels hinterbleibt das 21-Mercaptosteroid der allgemeinen Formel II.such as sodium hydride, in an inert polar solvent such as 1-, 2-Dime "thoxyethane, for a period of about 15 minutes to 24 hours, preferably for 1 to 3 hours, at temperatures of 0 to 80 ° C, preferably from 30 to 50 0 C, is reacted. Subsequently, the reaction mixture is treated with a slight excess of the corresponding .Alkylierungsmittels R 1 X ^. the reaction time is about 30 minutes to 48 hours, preferably 3 to 24 hours, at temperatures from 50 to 100 ° C, preferably from 25 to 80 ° C. After the solvent has evaporated, the 21-mercaptosteroid of the general formula II remains.
-. Die 21-Sulfonate der allgemeinen Formel V können durch Umsetzen - der entsprechenden 21-Hydroxysteroide der allgemeinen Formel VII mit etwa 1 Moläquivalent eines Sulfonylhalogenids der allgemeinen Formel O-. The 21-sulfonates of the general formula V can by reacting - the corresponding 21-hydroxysteroids of the general formula VII with about 1 molar equivalent of a sulfonyl halide of the general formula O
Il
R--S-YIl
R - SY
7S 7 p
hergestellt werden, in der Y ein Chlor- oder Bromatom bedeutet. Die Umsetzung wird in einem inerten wasserfreien Lösungsmittel . ' in Gegenwart eines Säureacceptors, z.B. eines tertiären Amins, wie Triäthylamin}oder einer heterocyclischen Base, wie Pyridin, durchgeführt. Die Umsetzung verläuft nach folgendem Reaktions-in which Y is a chlorine or bromine atom. The reaction is carried out in an inert anhydrous solvent. 'in the presence of an acid acceptor, for example a tertiary amine such as triethylamine } or a heterocyclic base such as pyridine. The implementation takes place according to the following reaction
schema:
25scheme:
25th
409825/1U0409825 / 1U0
(V)(V)
Wie vorstehend erläutert, kann das 21~Hydroxysteroid der allgemeinen Formel VII mit dem SuIfonylhalogenid in einem inerten wasserfreien Lösungsmittel umgesetzt werden. Die Umsetzung kann je-doch auch in"einem flüssigen tertiären Amin oder einer heterocyclischen Base als Lösungsmittel und Halogenwasserstoffacceptor durchgeführt werden. Die Reaktionszeit kann einige Stunden bis zu mehrere Tage, vorzugsweise 12 bis 24 Stunden,betragen» Die Umsetzung kann bei Temperaturen von -80 bis +40 C;vorzugsweise von -50 bis +100C,durchgeführt werden. Nach beendeter Umsetzung wird das Reaktionsgemisch in kaltes Wasser eingegossen und das Steroid der- allgemeinen Formel V abfiltriert und getrocknet. As explained above, the 21-hydroxysteroid of the general formula VII can be reacted with the sulfonyl halide in an inert anhydrous solvent. The reaction can, however, also be carried out in a liquid tertiary amine or a heterocyclic base as solvent and hydrogen halide acceptor. The reaction time can be from a few hours to several days, preferably from 12 to 24 hours preferably from -50 performed to +10 0 C. After completion of the reaction, the reaction mixture is poured into cold water and the steroid DER general formula V filtered off and dried; +40 C..
Die 21-Jodsteroide der allgemeinen Formel VI können in an sich bekannter Weise hergestellt werden; vgl. J. Am. Chem. Soc, Bd. 80 (1958), S. 250 und Ed. 81 (1959), S. 439 sowie JVOrg. Chem., Bd. 25 (1960), S. 1966.The 21-iodine steroids of the general formula VI can in itself are produced in a known manner; see J. Am. Chem. Soc, Vol. 80 (1958), p. 250 and Ed. 81 (1959), p. 439 and JVOrg. Chem., 25, 1966 (1960).
409825/1140409825/1140
Ein allgemeines Verfahren zur Herstellung von 21-Jodsteroiden der allgemeinen Formel VI geht von einem entsprechenden Steroid der allgemeinen Formel VIII aus: ' '. ■ " \ A general process for the preparation of 21-iodine steroids of the general formula VI is based on a corresponding steroid of the general formula VIII: ''. ■ "\
(VIII)(VIII)
Dieses Steroid wird mit einem Gemisch von Calciumoxid, Jod und einem freie Radikale liefernden Initiator^ vorzugsweise Azoisobuttersäuredinitrilj in·einem geeigneten Lösungsmittelsystem, wie einem Gemisch aus Tetrahydrofuran und "Methanol .,nach, folgendem R.eaktions schema umgesetzt: ' . ' .This steroid is made with a mixture of calcium oxide, and iodine a free radical initiator ^ preferably azoisobutyric acid dinitrile in a suitable solvent system, such as a mixture of tetrahydrofuran and "methanol., according to the following Reaction scheme implemented: '. '.
J2,CaOJ 2 , CaO
Initiatorinitiator
.- ·■■ ■-."■ ;■= '■■-- ~ ■ ■■■ ...(Vi) S :-■; S.- · ■■ ■ -. "■; ■ = '■■ - ~ ■ ■■■ ... (Vi) S: - ■; S
Nach einer Reaktionszeit von etv.-a 30 Minuten bis 24 Stunden, vorzugsweise von etwa 1 bis 4 Stunden,bei Temperaturen von -30 bis -i-50°C, vor"zugsv.'oise +10 bis +3O0C5wird das ReaktionsgemischAfter a reaction time of etv.-a 30 minutes to 24 hours, preferably from about 1 to 4 hours, at temperatures from -30 to -i-50 ° C, prior to "zugsv.'oise +10 to + 3O 0 C 5 is the reaction mixture
409825/1140,409825/1140,
mit einem geeigneten organischen Lösungsmittel,. wie Methylen- · -. chlorid, verdünnt und mit einer wäßrigen Lösung einer Verbindung gewaschen, die überschüssiges Jod reduziert, wie Natriumthiosulfat. Sodann wird äas organische Lösungsmittel abdestilliert. Es hinterbleibt das ^T-Jödste'T'oid der allgemeinen Formel VI.■ .with a suitable organic solvent. like methylene · -. chloride, diluted and with an aqueous solution of a compound washed that reduces excess iodine, such as sodium thiosulfate. The organic solvent is then distilled off. It What remains is the ^ T-Jödste'T'oid of the general formula VI. ■.
Ein -weiteres Verfahren zur Herstellung von 2t-Jodsteroiden der allgemeinen Formel VI besteht in der Umsetzung eines 21-SuIfonatsteroids der allgemeinen Formel V mit einem Alkalimetallgodid, vorzugsweise Natrium- oder Kaliumiodid, in einem polaren, inerten Lösungsmittel, wie Aceton oder einem niederen Alkohol nach folgendem Reaktionsschema:Another process for the production of 2t iodine steroids of the general formula VI consists in the implementation of a 21-sulfonate steroid of the general formula V with an alkali metal iodide, preferably sodium or potassium iodide, in a polar, inert solvents such as acetone or a lower alcohol according to the following reaction scheme:
AlkalijοdidAlkali iodide
(V)(V)
Die Reaktionszeit kann 'etwa 30 Minuten bis, 48 Stunden, vorzugsweise 1 bis 24 Stunden? bei Temperaturen von -20 M1S1 +1OQ0O, :r vorzugsweise von +10 bis +eO^Cvbetragen.; Sodann wird -das .Lösungsmittel abdestillle^t, 'der· Rückstand- -mit.= "asser verrührt, und das 21-Jodsteroid abfiltriert und getrocknet; - .: ... ... . : The reaction time can be about 30 minutes to 48 hours, preferably 1 to 24 hours ? at temperatures of -20 M 1 S 1 + 10Q 0 O ,: r is preferably from +10 to + eO ^ Cv .; Then - the "solvent" is distilled off, the "residue" - stirred with. = "Water, and the 21-iodine steroid is filtered off and dried; - .: ... .... :
9025/11409025/1140
. - 13 -. - 13 -
Es stehen mehrere Verfahren zur Herstellung der 21-Mercapto-. steroide der allgemeinen Formel III zur Verfügung. Bei einem Verfahren wird ein 21-Acylthiosteroid der allgemeinen Formel IV mit etwa 1 bis 5, vorzugsweise 1,1 bis 3 Moläquivalenten eines Alkalimetallsalzes, vorzugsweise einem Natrium- oder Kaliumsalzeines niederen Alkohols, z.B. mit Natriummethoxid, oder einem ■Alkalimetallcarbonat, wie Kaliumcarbonat, in einem feuchten, inerten polaren Lösungsmittel, .z.B. dem entsprechenden Alkohol, wie Methanol, oder Dimethylsulfoxid, nach folgendem Reaktionsschema umgesetzt:There are several methods of making the 21-mercapto. steroids of the general formula III are available. In one method, a 21-acylthiosteroid of the general formula IV with about 1 to 5, preferably 1.1 to 3 molar equivalents of one Alkali metal salt, preferably a sodium or potassium salt lower alcohol, e.g. with sodium methoxide, or a ■ Alkali metal carbonate, such as potassium carbonate, in a moist, inert polar solvents, e.g. the corresponding alcohol, such as methanol, or dimethyl sulfoxide, according to the following reaction scheme implemented:
(III)(III)
Die Reaktionszeit beträgt"etwa 1 Stunde bis 5 Tage, vorzugsweise 6 Stunden bis 2 Tage,bei Temperaturen von -10 bis +800C, vorzugsweise von +20 bis +5O0C. Nach beendeter Umsetzung wird das Reaktionsgemisch mit einer niederen aliphatischen Carbonsäure, wie Essigsäure, in einer der verwendeten Base entsprechenden Menge behandelt und in Wasser eingegossen. Das Produkt wird abfiltriert und getrocknet. ■ The reaction time is "for about 1 hour to 5 days, preferably 6 hours to 2 days, at temperatures from -10 to +80 0 C, preferably from +20 to + 5O 0 C. After the reaction, the reaction mixture with a lower aliphatic carboxylic acid , such as acetic acid, treated in an amount corresponding to the base used and poured into water. The product is filtered off and dried
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Ein Alternatiwerfahren zur Herstellung der 21-Mercaptosteroide ·. der allgemeinen Formel III besteht in der Umsetzung eines 21-substituierten Steroids der allgemeinen Formel V oder VI? wobei in den Steroiden der allgemeinen Formel VI anstelle des Jodatoms auch ein anderes Halogenatom stehen kann, mit einem Alkalimetallhydrogensulfid, vorzugsweise Natrium- oder Kaliumhydrogensulfid, in einem polaren Lösungsmittel, wie Dimethylformamid oder einem niederen Alkohol, wie Äthanol:An alternative process for the preparation of the 21-mercaptosteroids. of the general formula III consists in the implementation of a 21-substituted steroid of the general formula V or VI ? where in the steroids of the general formula VI there can also be another halogen atom instead of the iodine atom, with an alkali metal hydrogen sulfide, preferably sodium or potassium hydrogen sulfide, in a polar solvent such as dimethylformamide or a lower alcohol such as ethanol:
MSHMSH
R-,R-,
MSHMSH
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Die Reaktionszeit beträgt % etwa 15 Minuten bis 4 Tage,- vorzugsweise 30 Minuten bis 2 Tage, bei Temperaturen von 25 bis2000C, vorzugsweise von: 60 bis 1500C. Nach beendeter Umsetzung, wird das Realrfcionsgemiscn-stark eingeengt, abgekühlt, mit einem Äquiva-The reaction time is% about 15 minutes to 4 days, - preferably 30 minutes to 2 days, at temperatures of 25 to 200 0 C, preferably from: 60 to 150 0 C. After the reaction, the Realrfcionsgemiscn-stark is concentrated, cooled, diluted with an equiva-
5- lent einer starken Säure, wie Salzsäure, neutralisiert, in das 5-fache Volumen Wasser eingegossen und das ausgefällte 21-Mer- captostero.ld abfiltriert und getrocknet. „ . \ ■'" '■■" 5- lent of a strong acid, such as hydrochloric acid, neutralized, poured into 5 times the volume of water and the precipitated 21-mercaptostero.ld filtered off and dried. ". \ ■ '"'■■"
mercapto
Die 21-Acyl / steroide der allgemeinen Formel IV können durchmercapto
The 21-acyl / steroids of the general formula IV can by
IQ Umsetzen eines Steroids der allgemeinen Formel V. oder VI (wobei das Jodatom in der 21-Stellung des Steroids der allgemeinen Formel VI auch' durch ein anderes Halogenatom ersetzt seih kann) mit etwa Ί bis 5, -vorzugsweise 1 bis 3 Moläquivalenten eines..Alkalimetallsalzes, vorzugsweise des Kaliiomsalzes einer Thio'carboris'aure der allgemeinen Formel R^-C-S-M in einem inerten,polaren Lösungsmittel, wie Aceton oder Dimethylformamid, hergestellt werden. IQ Implementation of a steroid of the general formula V. or VI (where the iodine atom in the 21-position of the steroid of the general formula VI can also be replaced by another halogen atom) with about Ί to 5, preferably 1 to 3 molar equivalents of an alkali metal salt, preferably the potassium salt of a thio'carboric acid of the general formula R ^ -C-S-M in an inert, polar solvent such as acetone or dimethylformamide.
2020th
(V)(V)
/H/H
Die Reaktionszeit beträgt etwa 1 Stunde bis 4 Tage* vorzugsweise 3 Stunden bis 2 Tage,bei Temperaturen von Ö bis 10O0C, vor-■ zugsweise von 30 bis 7O?C. Nach beendeter Umsetzung wird das Lösungsmittel abdestilliert, der Rückstand mit Wasser verrührt und das Produkt abfiltriert und getrocknet. tThe reaction time is about 1 hour to 4 days * preferably 3 hours to 2 days, at temperatures from east to 10O 0 C, ■ pre- preferably from 30 to 7O? C. When the reaction has ended, the solvent is distilled off, the residue is stirred with water and the product is filtered off and dried. t
Nachstehend sind schematisch die vorstehend erläuterten Verfahren zur Herstellung der neuen Verbindungen der Erfindung wiedergegeben. In dem Reaktionsschema bedeutet K den RestThe following are schematically the processes explained above for the preparation of the new compounds of the invention. In the reaction scheme, K means the remainder
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)Η) Η
O Il S—R,O Il S — R,
T.T.
S-R,S-R,
U-oU-o
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Die Verbindungen der allgemeinen Formel I sind viertvolle Arz-• neistoffe mit glucocorticoider und antiphlogistischer Wirkung. Sie können daher zur Behandlung von rheumatoider Arthritis in . gleicherweise wie z.B. Hydrocortison eingesetzt" werden. Die Dosis hängt von der Aktivität des jeweils verwendeten Steroids"ab. Die Verbindungen der Erfindung können ferner lokal- zur Behänd-""υ lung von Hauterkrankungen, wie Dermatitis, Sonnenbrand, Neurodermatitis, Ekzemen und anogenitalem Pruritus verwendet werden.The compounds of the general formula I are four full medicinal substances with glucocorticoid and anti-inflammatory effects. They can therefore be used to treat rheumatoid arthritis in. in the same way as hydrocortisone, for example. The dose depends on the activity of the steroid used in each case. The compounds of the invention may also local to Behänd- "" υ development of skin disorders such as dermatitis, sunburn, neurodermatitis, anogenital pruritus and eczema are used.
Bei oraler Verabfolgung können die Verbindungen der allgemeinen Formel I in einer Dosis von. 0,1 bis 200 mg/70 kg Körpergewicht',11 vorzugsweise von 0,3 bis 100 mg/70 kg Körpergewicht verwendet' * Werden. Bei lokaler Anwendung können die Verbindungen der allgemeinen Formel I in einer Menge von 0,01 bis 5,0 Gewichtsprozent,When administered orally, the compounds of general formula I can be used in a dose of. 0.1 to 200 mg / 70 kg body weight ', 11 preferably from 0.3 to 100 mg / 70 kg body weight' * are used. When applied locally, the compounds of general formula I can be used in an amount of 0.01 to 5.0 percent by weight,
.15 vorzugsweise 0,05 bis 2,0 Gewichtsprozent, in einer herkömmlichen Creme oder Lotion verwendet werden..15 preferably 0.05 to 2.0 percent by weight, in a conventional one Cream or lotion can be used.
Die Beispiele erläutern die Erfindung. Sämtliche Umsetzungen in den Beispielen wurden unter einer Inertgasatmosphäre, wie Argon, bei Raumtemperatur und unter Verwendung wasserfreier Lösungsmittel durchgeführt, sofern nichts anderes angegeben ist. Reaktionsgemische, die erhitzt wurden, wurden zur Aufarbeitung auf Raumtemperatur abgekühlt. 9-Halogensteroide bedeuten die 9a-Halogen-The examples illustrate the invention. All implementations in The examples were performed under an inert gas atmosphere such as argon at room temperature and using anhydrous solvents carried out unless otherwise stated. Reaction mixtures, which were heated were cooled to room temperature for work-up. 9-halogen steroids mean the 9a-halogen
steroide. .steroids. .
..
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■·■.-.■..■ B e:i-:-.s.p i e 1 Ir . 9-Fluor-i1 β, 16-χ, 1 7, 21:-tetrahvdroxyprep;na-1, 4-die,n-3.20-dion-21 - p-toluolsulforiat,. cycl. 16,17-Acetal mit Aceton •Eine^Losung von 2,9 g 9-:Fluor-11 β ,..16a'., 17,21-tetrahydroxypregna-1,4-dien-3,20^dion cycl·. ' 1.6,-17-Acetal mit Aceton mit .30 ml vias- . serfreiem Pyridin wird "bei -56 C mit einerO C kalten Lösung von 1*8 g p-Toluolsulfonylchlorid ;in .18 ml wasserfreiem Methylen-.ι chlorideversetzt. Das Reaktionsgemisch wird 2 Stijnden bei -300C ■lind anschließend 96 Stunden .bei -50C gerührt. Hierauf wird das Reaktionsgemisch in Chloroform eingegossen und nacheinander mit Wasser,.verdünnter Salzsäure, verdünnter wäßriger Natriumcarbonatlösung und ¥asser·gewaschen. Die Chloroformlösung wird über Natriumsulfat.getrocknet und eingedampft. Es hinterbleibt die. . ■ rohe Ti-telverbindung·. Nach dem. Verrühren mit Wasser wird das Produkt abfiltriert, getrocknet, und aus.einem Gemisch von.Aceton und Hexan umkristallisiert.' F. -.248 bis 2490C ."■"·.■ · ■ .-. ■ .. ■ B e: i -: -. Sp ie 1 Ir . 9-fluoro-i1 β, 16-χ, 17, 21: -tetrahydroxyprep; na-1, 4-die, n-3.20-dione-21- p-toluene sulforate ,. cycl. 16,17-acetal with acetone • A ^ solution of 2.9 g of 9-: fluorine-11 β, .. 16a '., 17,21-tetrahydroxypregna-1,4-diene-3,20 ^ dione cycl ·. '1.6, -17-acetal with acetone with .30 ml vias-. serfreiem pyridine is "at -56 C with einerO C cold solution of 1 * 8 g of p-toluenesulfonyl chloride;. in .18 ml of anhydrous methylene chloride .ι ever sets The reaction mixture is 2 Stijnden at -30 0 C ■ lind then 96 hours .for stirred -5 0 C. Then the reaction mixture is poured into chloroform and washed successively with water, .verdünnter hydrochloric acid, dilute aqueous sodium carbonate solution and ¥ ater ·. the chloroform solution is and evaporated on Natriumsulfat.getrocknet. It remains behind the.. ■ crude Ti After being stirred with water, the product is filtered off, dried and recrystallized from a mixture of acetone and hexane. F. -.248 to 249 0 C. "■" ·.
■. λ .·-.·■- :-;- -■■■·■= . · B e ■£ s-p i; e 1 e. 2. bis 1.8 / Gemäß Beispiel -1, .jedoch -unter Verwendung der. in Spalte 1 genanntenrSt eroi.de "werden. die: in Spalte 2 auf geführten Ster-oid- • tosylate erhalten»· .;,,·. ,.. ■■.--.■ · .. ; ■. λ. · -. · ■ -: - ; - - ■■■ · ■ =. · B e ■ £ sp i; e 1 e. 2. to 1.8 / According to example -1, but using the. in column 1 mentionedrSt eroi.de ". the : Steroid- • tosylates listed in column 2 received» ·.; ,, ·., .. ■■ .--. ■ · .. ;
Beisp:. :.- λ ·, c spalte 1 ■...-, - Spalte TI .^z- Example: : .- λ ·, c column 1 ■ ...-, - column TI . ^ z-
•2 : ^9-Fluör^-1;ß>-1:6a-, 17-,21- ;.- 9-Fluor-11 β„46α, 17,21--,.• 2: ^ 9-fluorine ^ -1 ; β> -1: 6a-, 17-, 21-; .- 9-fluoro-11 β "46α, 17,21-- ,.
tetrahydrox3'pregna-4- . . tetraKydroxypregna-4-en-tetrahydrox3'pregna-4-. . tetraKydroxypregna-4-en-
en-3,20-dion, cycl. 3,20-dion-21-p-toluolsplfona:t,en-3,20-dione, cycl. 3,20-dione-21-p-toluenesplfona : t,
16,17-Acetal mit Aceton cycl. 16,17-Acetal mit Aceton.16,17-acetal with acetone cycl. 16,17 acetal with acetone.
3 9-Fluor~11ß,1-6a,17,21- 9-Fluor-11ß, 16«, 17,21-tetra-3 9-fluoro-11β, 1-6a, 17,21- 9-fluoro-11β, 16 ", 17,21-tetra-
tetrahyd roxypr egna-1,4- hydroxjrpregna-1,4-dien-3,20-tetrahyd roxypr egna-1,4- hydroxjrpregna-1,4-diene-3,20-
dien-3,20-dion,cycl. dion-21-p.-toluolsulfonat,diene-3,20-dione, cycl. dione-21-p-toluenesulfonate,
16,17-Acetal mit Aceto- cycl; 16,17-Acetal rait Ace-16,17-acetal with acetocycl; 16,17-acetal rait ace-
phenon (ß-Methyl) tophenon (β-Methyl) - ' -phenon (ß-methyl) tophenon (β-methyl) - '-
Beisp. ' Spalte I Ex. ' Column I
9-Fluor~11ß,i6a,17,21- tetrahydroxypregna-1, 4~ dien-3,20-dion, cy-cl. 16,17-Acetal mit. Acetaldehyd (α-Methyl)9-fluoro ~ 11β, 16a, 17,21-tetrahydroxypregna-1, 4 ~ diene-3,20-dione, cy-cl. 16,17 acetal with. acetaldehyde (α-methyl)
5 9-Fluor-11-ß-,1-6a, 17,21-5 9-fluoro-11-ß-, 1-6a, 17.21-
tetrahydroxypregna-1,4-dien~3,20-dion, cycl. 16,17-Acetal mit Cyclohexanon tetrahydroxypregna-1,4-diene ~ 3,20-dione, cycl. 16,17 acetal with cyclohexanone
11ß,17,21-Trihydroxy-6, •16-dimethyl-1,4,6,15-pregnatetraen-35.20-dion. 11β, 17,21-trihydroxy-6, • 16-dimethyl-1,4,6,15-pregnatetraen-35,20-dione.
9-F1UOI--118,17,21-trihydroxy-16a-methylpregna-1,4-dien-3,20-dion 9-F1UOI - 118,17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione
9-Fluor-11ß,17,21-trihy-9-fluoro-11ß, 17,21-trihy-
droxy-iöa-methylpregna-. 1,4-dien-3,20-diondroxy-iöa-methylpregna-. 1,4-diene-3,20-dione
6a,9-Difluor-11ß,17a,21-6a, 9-difluoro-11ß, 17a, 21-
trihydroxy-16o; -methj'-l pregna-1,4-dlen-3,20-dion trihydroxy-16o; -methj'-l pregna-1,4-dlen-3,20-dione
6a,9-Difluor-11ß,i6a,17,6a, 9-difluoro-11ß, i6a, 17,
21-tetrahydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal'mit Aceton21-tetrahydroxypregna-1,4-diene-3,20-dione, cycl. 16,17-acetal 'with acetone
6a-^luor-11ß,21-dihydroxy-16oc-raethylpregna-1,4-dien-3,20-dion 6a- ^ luor-11ß, 21-dihydroxy-16oc-raethylpregna-1,4-diene-3,20-dione
gjiß-Dichlor-öß-fluor-16α,17,21-trihydroxypregna-'l ,4-dien-3,20-dion, cycl. 16,17-Acetal mit Acetongjiß-dichloro-öß-fluor-16α, 17,21-trihydroxypregna-'l , 4-diene-3,20-dione, cycl. 16,17 acetal with acetone
11ß,16α,17,21-Tetrahydroxypregna-1 ,4-dien-3j 20-dj.on, cycl. 16,17-Acetal rait Aceton.11β, 16α, 17,21-tetrahydroxypregna-1 , 4-dien-3j 20-dj.on, cycl. 16,17 acetal with acetone.
Spalte II ' Column II '
9-Fluor-11 β,16α,17,21-tetrahydroxypregna-1 , 4-dienj"3,20.-dion-21-p-toluolsulfonat, cycl. 16,17-Acetal· mit Acetaldehyd (ά-Methyl)9-fluoro-11β, 16α, 17,21-tetrahydroxypregna-1 , 4-dienj "3,20.-dione-21-p-toluenesulfonate, cycl. 16,17-acetal with acetaldehyde (ά-methyl)
9-Fluor-11ß,16α,17,21-tetrahydro xyp re gna-1 ,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17-Acetal mit Cyclohexanon ■9-fluoro-11β, 16α, 17,21-tetrahydro xyp re gna-1, 4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16,17 acetal with cyclohexanone ■
11 β,17,21-Trihydroxy-6,16-dimethyl-1,4,6,15-pregnate-' traen~3,20-dion-21-p-toluolsulf onat . ■11 β, 17,21-trihydroxy-6,16-dimethyl-1,4,6,15-pregnate- ' traen ~ 3,20-dione-21-p-toluenesulf onat. ■
9-Fluor-11 β,17,21-trihydroxy-16a-methylpregna-1,4-dien-3,20-dion~21-p-toluolsulfonat 9-fluoro-11β, 17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,17,21-trihydroxy-16a-methylpregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 9-fluoro-11ß, 17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
6a,9-Difluor-11 β,17a,21-trihydroxy-16a-raethylpre gna-1., 4-dien-3,20-dion-21-p-toluolsulfonat .6a, 9-difluoro-11β, 17a, 21-trihydroxy-16a-raethylpre gna-1., 4-diene-3,20-dione-21-p-toluenesulfonate .
6a,9-Difluor-11ß,16a,17,21-tetrahydroxypregna-1,4-dien» 3,20-dion-21-p-toluolsulfonat, cycl.. 16,17-Acetal mit' Aceton6a, 9-difluoro-11ß, 16a, 17,21-tetrahydroxypregna-1,4-diene » 3,20-dione-21-p-toluenesulfonate, cycl .. 16,17-acetal with 'acetone
6a-Fluor-11 β,21-dihydroxy-16a-methylpregna-1,4-dien-3,20-dion-21-p-toluolsulfo-. nat6a-fluoro-11β, 21-dihydroxy-16a-methylpregna-1,4-diene-3,20-dione-21-p-toluenesulfo-. nat
9,11ß-Dichlor-6ß-fluor-16α, 17,21-trihydroxypregna-1,4-dien-3,20-dion-21-p-toluolsulf onat, cycl. 16,17-Acetal mit Aceton9,11ß-dichloro-6ß-fluoro-16α, 17,21-trihydroxypregna-1,4-diene-3,20-dione-21-p-toluenesulf onate, cycl. 16,17 acetal with acetone
11 β,16α,17,21-Tetrahydroxypregna-1 ,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17-Acetal mit Aceton.11 β, 16α, 17,21-tetrahydroxypregna-1 , 4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16,17 acetal with acetone.
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Beisp. ' Spalte I Spalte II Example ' Column I Column II
11ß,17,21-Trihydroxy-16- 11ß,17,21-Trihydroxy-16-memethyl enpregna-1,4- thylen-pregna-1,4-dien~3,.20-dien-3,20-dion diön-21-p-toluolsulfonat11 [beta], 17,21-trihydroxy-16-11 [beta], 17,21-trihydroxy-16-memethyl enpregna-1,4-ethylene-pregna-1,4-diene ~ 3, .20-diene-3,20-dione diön-21-p-toluenesulfonate
9-Fluor-11ß,21-dihydroxy- 9-Fluor-11ß,21-dihydroxy-16a, I6a,17-dimethylpregna-1,4- 17-dimethylpregna-i,4-dien-9-fluoro-11ß, 21-dihydroxy-9-fluoro-11ß, 21-dihydroxy-16a, I6a, 17-dimethylpregna-1,4-17-dimethylpregna-i, 4-diene
dien-3,20-dion. 3,20-dion-21-p-toluolsulfo-diene-3,20-dione. 3,20-dione-21-p-toluenesulfo-
. nat.. nat.
9-Fluor-1Tß,17,21-trihy- 9-Fluor-11ß,17,21-trihydroxydroxy-16-methylenpregna-16-methylenpregna-1 .,4-dien- · 1,4-dien-3,20-dion 3,20-dion-21 -p--fcoiuolsul-f o-9-fluoro-1Tβ, 17,21-trihy-9-fluoro-11β, 17,21-trihydroxydroxy-16-methylenepregna-16-methylenepregna-1 ., 4-diene- 1,4-diene-3,20-dione 3,20-dione-21 -p - fcoiuolsul-f o-
nat.nat.
9-Fluor-11ß,21-dihydroxy- 9-Fluor-11ß,21-dihydroxy-2'-2'-raethylpregna-1,4-dieno methylpregna-1,4-dieno/i7o:,9-fluoro-11β, 21-dihydroxy-9-fluoro-11β, 21-dihydroxy-2'-2'-raethylpregna-1,4-dieno methylpregna-1,4-dieno / i7o :,
/Ϊ7α,ΐ6α-4/οχ3ζο1-3.,20- I6a-d/-oxazol-3,20-dion-21-/Ϊ7α,ΐ6α-4/οχ3ζο1-3.,20- I6a-d / -oxazole-3,20-dione-21-
dion p-toluolsulfonatdione p-toluenesulfonate
9-Fluor-11ß,i6a,17,21- " 9-Fluor-11ß,16a,17,21-tetratetrahydroxjrpregna-i ,4- hydroxypregna~1,4-dien-3,20-dien-3,20-dion-i6-acetat. dion-i6-acetat-21-p-toluolsulf onat.9-fluoro-11β, 16a, 17,21- "9-fluoro-11β, 16a, 17,21-tetratetrahydroxjrpregna-i , 4- hydroxypregna ~ 1,4-diene-3,20-diene-3,20-dione-i6-acetate. dione-16-acetate-21-p-toluenesulfonate.
Beispiele 19 und 20Examples 19 and 20
Gemäß Beispiel 1, jedoch unter Verwendung der in Spalte I auf-• geführten Sulfonylhalogenide werden die in Spalte II aufgeführten Steroidsulfonate erhalten. · ·As in Example 1, but using the information listed in column I led sulfonyl halides, the steroid sulfonates listed in column II are obtained. · ·
Beisp. Spalte I . Spalte II . Example column I. Column II .
. 19 Methansulf önylToromid~ 9-Fluor-11.ßt 16a, 17,21-tetra-. 19 methanesulfonyl toromid ~ 9-fluoro-11.ß t 16a, 17,21-tetra-
hydroxj'pregna-i, 4-dien-3,20-hydroxj'pregna-i, 4-diene-3.20-
. ■ dion-21-methansulfonat, cycl.. ■ dione-21-methanesulfonate, cycl.
16,17-Acetal mit Aceton16,17 acetal with acetone
■ Cyclopentylsulfonyl- 9-Fluqr-11ß,16α,17,21-tetrachlorid ' hydroxypregna-1,4-dien-3,2C-■ Cyclopentylsulfonyl-9-Fluqr-11β, 16α, 17,21-tetrachloride 'hydroxypregna-1,4-diene-3,2C-
dion-21-cyclopentylsulfonat, cycl. 16,17-Acetal mit Aceton-, ·dione-21-cyclopentylsulfonate, cycl. 16,17-acetal with acetone, ·
..Beispiel 21 "..Example 21 "
9-Fluor-11 ß, 16a, 17-trihydroxy~21 -(methylthio)-pregna-i,4-dler--
- 3,20-dion, cycl. 16,17-Acetal mit Aceton
Eine Lösung von 5,0 g 9-Fluor-11ß,i6a,17,21-tetrahydroxy-preg- _j 9-fluoro-11 ß, 16a, 17-trihydroxy ~ 21 - (methylthio) -pregna-i, 4 - dler-- - 3,20-dione, cycl. 16,17 acetal with acetone
A solution of 5.0 g of 9-fluoro-11β, 16a, 17,21-tetrahydroxy-preg- _j
409825/1140409825/1140
na-1,4-dien-3,20-dion-21-p-toluolsulfonat cycl. 16,17-Acetal mit Aceton und 2,1 g Natriummethylmercaptid in 150 ml wasserfreiem Methanol v/ird 60 Stunden bei -Raumtemperatur unter Argon als Schutzgas unter Rückfluß gekocht. Sodann v/ird das Reaktionsgemisch mit 3,0 ml Eisessig angesäuert, mit 75 ml V/asser verdünnt und stark eingeengt. Das ausgefällte Rohprodukt wird abfiltriert, mit Wasser gewaschen und getrocknet. Nach Umkristallisation aus einem Gemisch von Aceton und Petroläther schmilzt die TitelverMndung bei 268 bis 269°C.Na-1,4-diene-3,20-dione-21-p-toluenesulfonate cycl. 16,17 acetal with acetone and 2.1 g of sodium methyl mercaptide in 150 ml of anhydrous methanol for 60 hours at room temperature under argon boiled under reflux as a protective gas. The reaction mixture is then v / ied acidified with 3.0 ml glacial acetic acid, diluted with 75 ml v / ater and severely narrowed. The precipitated crude product is filtered off, washed with water and dried. After recrystallization from a mixture of acetone and petroleum ether, the title compound melts at 268 to 269 ° C.
Beispiele 22 bis 38Examples 22 to 38
Gemäß Beispiel 21, jedoch unter Verwendung der in Spalte I .auf- " . geführten Steroidtosylate, werden die in Spalte II aufgeführtenAccording to Example 21, but using the in column I .auf- " . Listed steroid tosylates are those listed in Column II
21-Methylthiosteroide erhalten. t21-methylthiosteroids obtained. t
■J5 Beisp. Spalte I Spalte II ■ J5 Example Column I Column II
9-Fluor-11ß,-i6a,17,21- 9-Fluor-11ß, I6a,17-trihydrotetrahydroxy-pregna-4-enxy-21-(methylthio)-pregna-4-3,20-dion-21-p~toluolsulen~3,20-dion, cycl. 16,17-fonat, cycl. 16,17-Acetal Acetal mit Aceton.9-fluoro-11β, -i6a, 17,21- 9-fluoro-11β, 16a, 17-trihydrotetrahydroxy-pregna-4-enxy-21- (methylthio) -pregna-4-3,20-dione-21-p ~ toluene ~ 3,20-dione, cycl. 16,17-phonate, cycl. 16,17-acetal acetal with acetone.
mit Acetonwith acetone
9-Fluor-11ß,16a,17,21-te- 9-Fluor-11ß, 1 Sa,17-trihydroxy trahydroxypregna-1,4-dien- 21 - (methylthio) -pregna-1,4- ,·"9-fluoro-11ß, 16a, 17,21-te- 9-fluoro-11ß, 1 Sa, 17-trihydroxy trahydroxypregna-1,4-diene-21 - (methylthio) -pregna-1,4-, · "
3,20-dion-21-p-toluolsul- dien-3,2Ö-dion, cycl. 16,17-fonat, cycl. 16,17-Acetal Acetal mit'Acetophenon mit Acetophenon (ß-Methyl) (ß-Methyl) 9-Fluor-11ß,i6a,17,21-te- 9-Fluor-11ß,i6a,17-trihy(Irotrahydroxypregna-1,4-dienxy-21-(methylthio)-pregna-3,20-dion-21-p-toluolsul-1,4-dien-3,20-dion, cycl.3,20-dione-21-p-toluenesul- diene-3,2Ö-dione, cycl. 16.17-fonat, cycl. 16,17-acetal acetal with acetophenone with acetophenone (ß-methyl) (ß-methyl) 9-fluoro-11ß, 16a, 17,21-te- 9-fluoro-11ß, 16a, 17-trihy (irotrahydroxypregna-1,4-dienxy-21- (methylthio) -pregna-3,20-dione-21- p-toluenesul-1,4-diene-3,20-dione, cycl.
■ fonat, cycl. 16,17-Acetal 16,17-Acetal mit Acetaldehyd mit Acetaldehyd (α-Methyl) (α-Methyl)■ fonat, cycl. 16,17-acetal 16,17-acetal with acetaldehyde with acetaldehyde (α-methyl) (α-methyl)
25 9-Fluor-11ß,i6a,17,21-te- 9-Fluor-11ß,i6a,17-trihydroxy-25 9-fluoro-11ß, 16a, 17,21-te- 9-fluoro-11ß, 16a, 17-trihydroxy-
trahydroxypregna-1,4-dien- 21-(methylthio)-pregna-1,4-trahydroxypregna-1,4-diene- 21- (methylthio) -pregna-1,4-
■3,20-dion-21-p-toluolsul- dien-3,20~dion, cycl.■ 3,20-dione-21-p-toluenesul- diene-3,20 ~ dione, cycl.
fonat, cycl. 16,17-Acetal 16,17-Acetal mit Cyclohexanon mit Cyclohexanonfonat, cycl. 16,17 acetal 16,17 acetal with cyclohexanone with cyclohexanone
409325/1UÖ409325 / 1UÖ
Beisp. . Spalte I ' Ex . Column I '
■ 26 11ß,17-,21-Trihydroxy-t6,-i6-dimethyl-1,4,6,15-pregnatetraen-3,20-dion->21~p-. toluolsulfonat■ 26 11β, 17-, 21-trihydroxy-t6, -i6-dimethyl-1,4,6,15-pregnatetraen-3,20-dione-> 21 ~ p-. toluenesulfonate
·■ · 27 9-Fluor-11ß',17,21-trihydroxy~1 öß-methylp-regna-· ■ · 27 9-fluoro-11β ', 17,21-trihydroxy ~ 1 öß-methylp-regna-
1,4-dien-3,20-dion-21-p- · toluol sulfon'at , ' \1,4-diene-3,20-dione-21-p- toluene sulfon'ate, '\
• 28- 9-Fluor-11ß, 1-7^21-trihy-• 28- 9-fluoro-11ß, 1-7 ^ 21-trihy-
droxy-i6a-methylpregna-, ■ 1,4-dien-.3,.20-dion-21-p~ , toluolsulfonatdroxy-16a-methylpregna-, ■ 1,4-diene-.3, .20-dione-21-p ~, toluenesulfonate
.29 6α, 9-Difluor-11ß,17α,21- . 1Ö trihydroxy-16a~methylpregna-1.4-dien-3,20-dion-21-p-toluol sulfonat.29 6α, 9-difluoro-11β, 17α, 21-. 1Ö trihydroxy-16a ~ methylpregna-1,4-diene-3,20-dione-21-p-toluene sulfonate
' 30 6a, 9-Dif iuor-1.1 ß, 16a, 17,-21-tetrahydroxypregna-1,4-dien-3,20-dion-21-ptoluolsulfonat, cycl. 16,17-Acetal mit Aceton'30 6a, 9-dif iuor-1.1 ß, 16a, 17, -21-tetrahydroxypregna-1,4-diene-3,20-dione-21-ptoluenesulfonate, cycl. 16,17 acetal with acetone
31 6a-Fluor-11ß,21-dihydroxy-16a-metliyl-Oregna--1, ^-dien-3,20-dion-21-p-toluolsulfonat .. . ;31 6a-fluoro-11ß, 21-dihydroxy-16a-methyl-oregna - 1, ^ -diene-3,20-dione-21-p-toluenesulfonate ... ;
9,11ß-r)ichlor-6ß-fluor-16a,17,21-trihydroxypregna-1,4-dien-.3,20-dion- 9,11ß-r) ichlor-6ß-fluoro-16a, 17,21-trihydroxypregna-1,4-diene-.3,20-dione-
■ 21-p.-toluol sulfonat, cycl.■ 21-p-toluene sulfonate, cycl.
16,17-Acetal mit Aceton 2016,17 acetal with acetone 20th
11ß,16a,17,21-Tetrahydroxypregna-1,4-dien-3,20-. 11β, 16a, 17,21-tetrahydroxypregna-1,4-diene-3,20-.
■ dipn-21-p-toluolsulfona.t,■ dipn-21-p-toluolsulfona.t,
cycl. 16,17-Acetal„mit . Aceton · 'cycl. 16,17-acetal "with . Acetone '
11 β, ·17,: 21 - Trihydroxy-16-methylenpregna-1., 4-dien-11 β, 17:21 - trihydroxy-16-methylenpregna-1., 4-serve
' 3i20-dion-21-p-toluolsulf onat3 i 20-dione-21-p-toluenesulfonate
9-Fluor-11ß,21-dihydroxy-9-fluoro-11ß, 21-dihydroxy-
;16a,17-dimethylpregna-1,4-dieri-3,20-dipn-21-ptoluolsulfonat 16a, 17-dimethylpregna-1,4-dieri-3,20-dipn-21-p-toluenesulfonate
Spalte II · Column II
11ß,17-Dihydroxy-6,16-dimethyl-21-(methylthio)-1,4,6, 15-pregnatetraen-3 ,-20-dion.11β, 17-dihydroxy-6,16-dimethyl-21- (methylthio) -1,4,6, 15-pregnatetraen-3, -20-dione.
9-Fluor-11ß,-17-dihydroxy-16ßmethyl-21-^methylthio)-pregna-1,4-dien-3,20-dion. 9-fluoro-11β, -17-dihydroxy-16β-methyl-21- (1) methylthio) -pregna-1,4-diene-3,20-dione.
9-Fluor-11ß,17-dIhydrOxy-16a-methyl-21-(methylthio)-pregna-1,4~dien-3,20-dion 9-fluoro-11β, 17-dihydrOxy-16a-methyl-21- (methylthio) -pregna-1,4-diene-3,20-dione
6a, 9~Dif luor-11 ß, 17a-dihyclroxy-16a-methyl-21-(methylthio) -pregna-1,4-dien-3,-2Ö-dion 6a, 9 ~ dif luor-11 beta, 17-dihyclroxy-16a-methyl-21- (methylthio) - pregna-1,4-diene-3, -2Ö-dione
6a, 9-Dif luor-11 ß516a, 17-tri-. hydroxy-21-(methylthio)-pregna-1,4-di en- 3 ,.20-di on, eye 1.6a, 9-dif luor-11 ß 5 16a, 17-tri-. hydroxy-21- (methylthio) -pregna-1,4-di-en-3, .20-di on, eye 1.
16,17-Acetal mit Aceton16,17 acetal with acetone
6a-Fluor-11 ß-hydroxv-16a.-methyl-2i-(methylthio)-pregria-1,4-dien-3,20-dion 6a-fluoro-11β-hydroxv-16a.-methyl-2i- (methylthio) -pregria-1,4-diene-3,20-dione
9,11ß-Dichlor-6ß-fluor-16α, 17-dihy.droxy-21 - (methylthio) ■ pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit ; Aceton9,11ß-dichloro-6ß-fluoro-16α, 17-dihy.droxy-21 - (methylthio) ■ pregna-1,4-diene-3,20-dione, cycl. 16,17-acetal with; acetone
11ß,16a,17-Trihydroxy-21-(methylthio )-pregnö.-1,4-di'en-3,20-dion, cycl. 16,17-Acetal mit Aceton -11β, 16a, 17-trihydroxy-21- (methylthio) -pregno.-1,4-di'en-3,20-dione, cycl. 16,17-acetal with acetone -
11 ß, 17-Dihydroxy-16-^methylen-21-(methylthio)-pregna-1,4-dien-3,20-dion. 11β, 17-dihydroxy-16- ^ methylene-21- (methylthio) -pregna-1,4-diene-3,20-dione.
9-Fluor-1:1 ß-hydroxy-16α. 17-dimethyl-21 - (methylthio ).-pregna-1v4^dien-3,20-dion 9-fluoro-1: 1 β-hydroxy- 16α. 1 7-dimethyl-21 - (methylthio) .- pregna-1v4 ^ diene-3,20-dione
Beisp. Spalte I Ex . Column I.
9*Fluor-11ß,17,21~trihydro-XV-16-methylenpregna-1,4-dien-3,20-dion~21-p-toluolsulforiat 9 * fluoro-11β, 17,21 ~ trihydro-XV-16-methylenepregna-1,4-diene-3,20-dione ~ 21-p-toluene sulforate
' 9-Fluor-11ß,21-dihydroxy-'9-fluoro-11ß, 21-dihydroxy-
2'-methyl-pregna-1,4-dieno-2'-methyl-pregna-1,4-dieno-
/ϊ 7α,16ct-d/oxazol~3,20-dion-21-p-toluolsulfonat / ϊ 7α, 16ct-d / oxazole ~ 3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,i6a,17,21-tetrahydroxypregna-1,4-dien-3,20-dion-16-acetat-21 -p-toluolsulfonat 9-fluoro-11β, 16a, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione-16-acetate-21 -p-toluenesulfonate
Spalte IIColumn II
9-Fluor-11ß,17-dihydroxy-16-methylen-21-(methylthio)-pregna-1,4-dien-3,20-dipn 9-fluoro-11β, 17-dihydroxy-16-methylene-21- (methylthio) -pregna-1,4-diene-3,20-dipn
9-Fluor-i 1 ß-hydroxy-2'Ι - (methyl thio )-2'-methyl-pregna-1,4-dieno-/i7a,16a-d/-oxazol-3,20-dion 9-fluoro-i 1 ß-hydroxy-2'Ι - (methyl thio) -2'-methyl-pregna-1,4-dieno- / 17a, 16a-d / -oxazole-3,20-dione
9-Fluor-11ß,16a,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion 9-fluoro-11β, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione
Bei ,spiele 39 "bis 45For example, play 39 "to 45
Gemäß Beispiel 21, jedoch unter Verwendung der in Spalte I aufgeführten Mercaptide, werden die in Spalte II aufgeführten 21-Mercaptosteroide erhalten. . ' 'According to Example 21, but using those listed in column I. Mercaptides, will be those listed in Column II 21-mercaptosteroids obtained. . ''
Spalte II. Column II .
9-Fluor-21-(n-hexylthio)-11ß. 16a,17-trihydroxypregna-i Midien-3,20-dion, cj^cl. 16,17-Acetal mit Aceton9-fluoro-21- (n-hexylthio) -11β. 16a, 17-trihydroxypregna-i Midien-3,20-dione, cj ^ cl. 16,17 acetal with acetone
21-(Cyclopentylthio)-9-fluor-11ß »16a,17-trihydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton21- (Cyclopentylthio) -9-fluoro-11 [beta] »16a, 17-trihydroxypregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
21-(Benzylthio)-9-fluor-11ß,16a, . 17-trihydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton21- (benzylthio) -9-fluoro-11.beta., 1 6a. 17-trihydroxypregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9-Fluor-11ß,16a,17-trihydroxy-21-(phenylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21- (phenylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
mercaptidNa-cy el op enty 1-
mercaptid
4141
4242
Na-benzylmercaptidNa benzyl mercaptide
Na-thiophenolatNa thiophenolate
43 Na-p-chlorthiophenolat 21-(p-Chlorphenylthio)-9-fluor-43 Na-p-chlorothiophenolate 21- (p-chlorophenylthio) -9-fluoro-
11ß,16α,17-trihydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton11β, 16α, 17-trihydroxypregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
A09825/1U0A09825 / 1U0
Beisp. . - ■■■-■ " Spalte I ■ Spalte. II Ex . - ■■■ - ■ " Column I ■ Column. II
.44 ""■*. K-p-methoxythiophenolat 9a^Fluor-11ß,16ct, 17-trihydro-. . ■'.-'" / xy-2i-(p-methOXyphenylthIo)-.44 "" ■ *. K-p-methoxythiophenolate 9a ^ fluoro-11ß, 16ct, 17-trihydro-. . ■ '.-' "/ xy-2i- (p-methOXyphenylthIo) -
l4äil4äi
pg,j, cycl» 16,17-Acetal mit"'Acetonpg, j, cycl »16,17-acetal with" 'acetone
45 ' Na-p-methylthiophenolat gct-Flüor-Hß, Ιβα,ΐΤ^ xy-21.-(p-methy !phenyl thio)--pregna-1,4-dlen-3,20*di ön, cycl· 16,17-Acetal iiiit Aceton45 'Na-p-methylthiophenolate gct-Flüor-Hß, Ιβα, ΐΤ ^ xy-21 .- (p-methy! phenyl thio) - pregna-1,4-dlen-3.20 * di ön, cycl · 16,17-acetal iii with acetone
Beispiele 46 und 47Examples 46 and 47
-1,1 Qi3 6joc % t7-itrihydroxy^2i - (methylthio.)-^regna-i, 4-dien-3^Q-(JiOn, cycl.., 16,17-Acetal mit. Aceton
Gemäß Beispiel .21, jedoch unter Verwendung der in Spalte I auf
geführten 21-SuIf onylsteroide, wird die Titelverbindung herge-.
stellt.
Bei sp. Spalte I ι -1,1 Qi3 6joc % t7- i trihydroxy ^ 2i - (methylthio.) - ^ regna-i, 4-diene-3 ^ Q- (JiOn, cycl .., 16,17-acetal with. Acetone According to example. 21, but using the 21-sulfonyl steroids listed in column I, the title compound is prepared.
At sp. Column I ι
46 ·. 9-Fluor-riß)i6as17,21-tetrahydroxypregna-1,4-46 ·. 9-fluorine crack) i6as17,21-tetrahydroxypregna-1,4-
äieil-3,20-dion-2i-methansulfonat, cycl. '■ '. 16,17-Äcetar mit Acetonäieil-3,20-dione-2i-methanesulfonate, cycl. '■'. 16,17 aetar with acetone
47 9-Fluor-i 1ß, 16cc, 17,21-tetrahydroxypregna-i ,4-dien-3,2Ö-dion-21-cyclopentylsulfonat-cyclk 16,17^Acetal mit Aceton47 9-Fluoro-1ß, 16cc, 17,21-tetrahydroxypregna-1, 4-diene-3,2Ö-dione-21-cyclopentylsulfonate-cyclk 16.17 ^ acetal with acetone
B > e Ϊ s ρ i e 1 48 -B> e Ϊ s ρ i e 1 48 -
3,2D-dion,, cycl.» 16n 17-Acetal mit Aceton Gemäß Beispiel 2'1, jedoch unter Verwendung von 9-Fluor-11ß,16a,-17*-tr !hydroxy-21 - jödpreghä-1,4-dien-3»20-dion» cycl. IS, .17-Ace^. tal mit Aceton Wird die !Titelverbindung Erhalten. 3,2D-dione ,, cycl. » 16n 17-acetal with acetone As in Example 2'1, but using 9-fluoro-11ß, 16a, -17 * -tr! Hydroxy-21-jödpregha-1,4-diene-3 »20-dione» cycl. IS, .17-Ace ^. tal with acetone will get the! title compound.
409825/1140409825/1140
Γ - 26 - 23622&0 ■"'■ Γ - 26 - 23622 & 0 ■ "'■
Beispiel. 49 .Example. 49.
' 9-Fluor-11 β, 16->;, 17-trihydroxy-21 - (methylsulfinyl) -pregna-1,4- ' 9-Fluoro-11 β, 16 ->;, 17-trihydroxy-21 - (methylsulfinyl ) -pregna-1,4-
dien-3,20-dion, cycl. 16,17-Acetal mit Aceton ' Methode A; diene-3,20-dione, cycl. 16,17-acetal with acetone ' method A;
Eine Lösung von 2,0g 9-Fluor-11ß,16α,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion cycl. 16,17-Acetal mit-Aceton und 0,92 g Natriummetaperjodat in 400 ml Methanol wird 5 Tage bei 5°C gerührt. Nach dem 1. und 4. Tag wird eine v/eitere Menge von 0,92 g Natriummetaperjodat zugegeben. Nach beendeter Urasetzung wird das Lösungsmittel abdestilliert, das Rohprodukt in 400 ml Chloroform gelöst, mit Wasser gewaschen, getrocknet und ... an 20 g Florisil chromatographyert. 300 ml des Chloroformeluats werden verworfen. Anschließend v/ird die Chromatograph!ersäule mit 500 ml Äthylacetat und hierauf mit 400 ml Aceton eluiert, Die beiden Fraktionen werden vereinigt und zur Trockene eingedampft. Nach Umkristallisation aus einem Gemisch von Methylen-Chlorid und Petroläther schmilzt die Titelverbindung bei 234 bis 236°C.A solution of 2.0 g of 9-fluoro-11β, 16α, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione cycl. 16.17-acetal with acetone and 0.92 g of sodium metaperiodate in 400 ml of methanol is 5 days stirred at 5 ° C. After the 1st and 4th day, a larger amount of 0.92 g of sodium metaperiodate is added. After the end of the initialization the solvent is distilled off, the crude product in 400 ml of chloroform dissolved, washed with water, dried and ... chromatographed on 20 g of Florisil. 300 ml of the chloroform eluate are discarded. The chromatograph column is then v / o eluted with 500 ml of ethyl acetate and then with 400 ml of acetone, The two fractions are combined and evaporated to dryness. After recrystallization from a mixture of methylene chloride and petroleum ether melts the title compound at 234-236 ° C.
Methode B;Method B;
Eine Lösung von 4,64 g 9-Fluor-11ß,i6a,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion cycl. 16,17-Acetal mit Aceton in 800 ml Methanol wird bei 5°G unter Kühlung in einem Eiswasser-Salzbad anteilsweise mit 1,33 g N-Chlorsuccinimid in solcher Geschwindigkeit versetzt, daß die Innenteitiperatur des Reaktionsgemisches nicht über 100C ansteigt. Nach 2-tägigem Rühren bei 5°G v/ird das Lösungsmittel abdestilliert, der Rückstand in Chloroform gelöst und nacheinander mit kalter, verdünnter Natronlauge und ¥asser gewaschen. Hierauf wird die organische Phase getrocknet, ,A solution of 4.64 g of 9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione cycl. 16,17-acetal with acetone in 800 ml of methanol at 5 ° G, with cooling in an ice-salt bath in portions with 1.33 g of N-chlorosuccinimide at such a rate offset that the Innenteitiperatur of the reaction mixture does not rise above 10 0 C. After stirring for 2 days at 5 ° G v / ird the solvent is distilled off, the residue is dissolved in chloroform and washed successively with cold, dilute sodium hydroxide solution and water. The organic phase is then dried,
408825/1140408825/1140
filtriert und eingedampft. Es hinterbleibt die Titelverbindung.filtered and evaporated. The title compound remains.
Methode C: ' ' . - Method C: ''. -
Eine Lösung von 4,64 g 9-Fluor-11ß,i6a,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion cycl,. 16,17-Acetal mit; Aceton und 3,22 g Jodosobenzoldiäcetat in 100 ml Eisessig wird 4 Stunden unter Rückfluß erhitzt. Nach 16-stündigem Stehen bei Raumtemperatur wird das Reaktionsgemisch filtriert, nahe zum Siedepunkt erhitzt und mit 450 ml heißem Nasser verdünnt. Nach 15- bis 18-stündigem Stehen bei Raumtemperatur wird das Reaktionsgemisch auf etwa 200 ml eingedampft, auf Raumtemperatur ab-' gekühlt und die Titelverbindung abfiltriert. . "A solution of 4.64 g of 9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione cycl ,. 16,17-acetal with; Acetone and 3.22 g of iodosobenzene diacetate in 100 ml of glacial acetic acid are added for 4 hours heated to reflux. After standing for 16 hours at room temperature the reaction mixture is filtered, close to the boiling point heated and diluted with 450 ml of hot water. To The reaction mixture is left to stand for 15 to 18 hours at room temperature evaporated to about 200 ml, cooled to room temperature and the title compound filtered off. . "
Methode-D: .' 'Method-D:. ' '
Eine Lösung von 4,64 g 9-Fluor«11ß,i6a, ^- thio)-pregna-1,4-dien-3,20-dion cycl. 16,.17-Acetal. mit Aceton in 200 ml" lOvolumproζentigem wäßrigem Pyridin wird bei 20°C tropfenweise und unter Rühren mit einer Lösung von 2,75 g Jodbenzoldichlorid in wasserfreiem Pyridin versetzt'. Die Urasetzung wird nicht in direktem Sonnenlicht durchgeführt. Nach -10 Stunden wird das Reaktionsgemisch mit Chloroform verdünntA solution of 4.64 g of 9-fluorine «11ß, i6a, ^ - thio) -pregna-1,4-diene-3,20-dione cycl. 16, .17 acetal. with acetone in 200 ml of 10volumperentigem aqueous pyridine at 20 ° C dropwise and with stirring with a solution of 2.75 g Iodobenzene dichloride added to anhydrous pyridine '. The original setting is not performed in direct sunlight. To The reaction mixture is diluted with chloroform for 10 hours
': und nacheinander mit verdünnter Schwefelsäure und Wasser gev/a-ί . , ': and one after the other with dilute sulfuric acid and water gev / a- ί. ,
sehen. Nach dem Trocknen wird die organische Phase eingedampft.see. After drying, the organic phase is evaporated.
{ Es hinterbleibt die Titelverbindung. . ■ { The title compound remains. . ■
'25 ' -·■■-. .'25 '- · ■■ -. .
■ , ' B e i s ρ i e 1 e 50 bis 66■, 'B e i s ρ i e 1 e 50 to 66
■ Gemäß Beispiel 49, Methode A, jedoch, unter Verv/endung .der in Spalte Ί aufgeführten 21-Methylthiosteroide, viprden die in Spalte II aufgeführten 21-Methylsulfinyl^teroidperhalten»■ According to example 49, method A, however, using .der in Column Ί listed 21-methylthiosteroids, viprden those in column II listed 21-methylsulfinyl ^ teroidperhalten »
Bedsp. Spalte IBedsp. Column I.
9-Fluor-11ß,i6a,17-trihydroxy-21-(methylthio)-pregna-4-en-3j20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregna-4-en-3j20-dione, cycl. 16,17 acetal with acetone
51 9-Fluor,-11ß,i6a,17-tri-. hydroxy-21-(methylthio)-pregna-1^-dien^,20-dion, cycl. 16,17-Acetal mit Acetophenon (ß-Methyl)51 9-fluoro, -11β, 16a, 17-tri-. hydroxy-21- (methylthio) -pregna-1 ^ -diene ^, 20-dione, cycl. 16,17-acetal with acetophenone (ß-methyl)
9-Fluor-11ß,i6a,17-trihydroxy-21-(metl^lthio)-pregna-1,4-dien-3,20- 9-fluoro-11ß, 16a, 17-trihydroxy-21- (metl ^ lthio) -pregna-1,4-diene-3.20-
dion, cycl. 16,17-Acetal mit Acetaldehyd (α-Methyl)dione, cycl. 16,17 acetal with acetaldehyde (α-methyl)
9-Fluor-11ß,i6a,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Cyclohexanon9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with cyclohexanone
54 . 11ß-,17-Dihydroxy-6,i6-dimethyl-21-(methylthio)-1,4,6,15-pregnatetraen-3,20-dion 54. 11β-, 17-dihydroxy-6,16-dimethyl-21- (methylthio) -1,4,6,15-pregnatetraen-3,20-dione
9-Fluor-11 ß, 17-dilrydroxy-9-fluoro-11 ß, 17-dilrydroxy-
16ß-methyl-21-(methylthio) · pregna-1,4-dien-3,20-dion16ß-methyl-21- (methylthio) pregna-1,4-diene-3,20-dione
9-Fluor-11ß,17-dihydroxy-16a-methyl-21-(methyl thio)·9-fluoro-11β, 17-dihydroxy-16a-methyl-21- (methyl thio)
pregna-1,4-dien-3,20-tiionpregna-1,4-diene-3,20-tiion
6a,9-Difluor-11ß,17a-dihydroxy-16a-methyl-21-" (methylthio)-pregna-1,4-dien-3,20-dion 6a, 9-difluoro-11ß, 17a-dihydroxy-16a-methyl-21- " (methylthio) -pregna-1,4-diene-3,20-dione
.58 6a,9-Difluor-11ß,i6a,17-.58 6a, 9-difluoro-11ß, i6a, 17-
trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Acetontrihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-i6amethyl-21~(methylthio)-pregna-1,4-dien-3,20-dion Spalte II 6a-fluoro-11ß-hydroxy-16amethyl-21 ~ (methylthio) -pregna-1,4-diene-3,20-dione column II
9-Fluor-11ß,16a,17-trihydroxy-21-(methylsulfinyl)-pregna-4-en-3,20-dion, cycl. 16,17-Acetal mit Aceton.9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylsulfinyl) -pregna-4-en-3,20-dione, cycl. 16,17 acetal with acetone.
9~Fluor-11ß,16α,17-trihydroxy-21-(methylsulfinyl)-pregna-1 ,4-dien-3,20-dion, cycl. 16,17-Acetal mit. Acetophenon (ß-Methyl) ■ ■9 ~ fluoro-11β, 16α, 17-trihydroxy-21- (methylsulfinyl) -pregna-1 , 4-diene-3,20-dione, cycl. 16,17 acetal with. Acetophenone (β-methyl) ■ ■
9-Fluor-11ß,16α,17-trihydroxy-21-(methylsulfinyl)-pregna-1,4-dien-3j20-dion, cycl. 16,17-Acetal mit Acetaldehyd (α-Methyl)9-fluoro-11β, 16α, 17-trihydroxy-21- (methylsulfinyl) -pregna-1,4-diene-3j20-dione, cycl. 16,17-acetal with acetaldehyde (α-methyl)
9-Fluor-11ß,16a,17-trihydroxy-21-(methylsulfinyl)-pregna-1 ,4-di en-3, 20-dion, cycl. 16,17-Acetal mit Cyclohexanon9-fluoro-11β, 16a, 17-trihydroxy-21- (methylsulfinyl) -pregna-1 , 4-di-ene-3, 20-dione, cycl. 16,17 acetal with cyclohexanone
11 β,17-Dihydroxy-6,16-dimethyl-21-(methylsulfinyl)-1,4,6,15-pregnatetraen-3,20-dion 11 β, 17-dihydroxy-6,16-dimethyl-21- (methylsulfinyl) -1,4,6,15-pregnatetraen-3,20-dione
9-Fluor-11ß,17-dihydroxy-16ßmethyl-21-(methylsulfinyl)-pregna-1,4-dien-3,20-dion 9-fluoro-11β, 17-dihydroxy-16β-methyl-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
9-Fluor-11ß,17-dihydroxy-16amethyl-21-(methylsulfinyl)-pregna-1,4-dien-3»20-dion 9-fluoro-11β, 17-dihydroxy-16amethyl-21- (methylsulfinyl) -pregna-1,4-diene-3 »20-dione
6a,9-Difluor-11ß,17a-dihydroxy-16a-methyl-21-(methylsulfinyl)-pregna-1,4-dien-3,20-dion 6a, 9-difluoro-11ß, 17a-dihydroxy-16a-methyl-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
6a,9-Difluor-11ß,16a,17-trihydroxy-21-(methylsulfinyl)-pregna-1,4-dien-3,20-dion; cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-11β, 16a, 17-trihydroxy-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione; cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-16athyl-21-(methylsulfinyl)-pregna-1,4-dien-3,20-dion 6α-Fluoro-11β-hydroxy-16ethyl-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
4 0 9 8 2 5/1U4 0 9 8 2 5 / 1U
Beisp. Spalte IExample column I.
• 60 . 9,11ß-DiGhlor-6ß-fluor~ 16α,17-dihydroxy-21-(methylthio)-pregna-1, 4-dien-3,20-dion, .cycl. · 16,17-Acetal mit Aceton• 60. 9,11ß-DiGhlor-6ß-fluoro ~ 16α, 17-dihydroxy-21- (methylthio) -pregna-1, 4-diene-3,20-dione, .cycl. 16,17 acetal with acetone
61 11ß,i6a,17-Trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion, cycl. ' 16,17-Acetal mit Aceton61 11β, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
11 β, .^-Dihydroxy-iö-methylen-21 - (methylthio) -pregna-1, -4-dien-3', 20-dion11 β,. ^ - Dihydroxy-iö-methylene-21 - (methylthio) -pregna-1, -4-diene-3 ', 20-dione
9-Fluor-11ß-hydroxy-16a, 17-dimethyl-21-(methyl-9-fluoro-11ß-hydroxy-16a, 17-dimethyl-21- (methyl-
thio)-pregna-1,4-d-ien-3,20-dion thio) -pregna-1,4-d-ien-3,20-dione
' 64 9-Fluor-11ß,17-dihydroxy-16-methylen-21-(methylthio)-pregna-1,4-dien-3,20-dion 64 9-Fluoro-11β, 17-dihydroxy-16-methylene-21- (methylthio) -pregna-1,4-diene-3,20-dione
9-Fluor-11ß-hydroxy-2·- methyl-21-(methylthio)-9-fluoro-11ß-hydroxy-2 - methyl-21- (methylthio) -
pregna-1,4-dieno-/i7a, i6a-d/oxazol-:3,20-dionpregna-1,4-dieno- / i7a, i6a-d / oxazole-: 3,20-dione
9-Fluor-11 β,16α,17-trihydroxy-21-(methylthio)-pregna-1 ,'4-dien-3,20-dion Spalte II 9-fluoro-11β, 16α, 17-trihydroxy-21- (methylthio) -pregna-1, '4-diene-3,20-dione column II
9,11 ß-Dichlor-6ß-f luor-16·α ,-17-dihydroxy-21-(methylsülfinyl)-pregna-1 ,-4-dien-3,20-dlon, cycl. 16,17-Acetal mit Aceton9.11 β-dichloro-6β-fluoro-16 · α, -17-dihydroxy-21- (methylsulfinyl) -pregna-1 , -4-diene-3,20-dlon, cycl. 16,17 acetal with acetone
11ß, 16α, 17-Trihydrox-y-21 ~ (methylsulfinyl;-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton11β, 16α, 17-trihydrox-y-21- (methylsulfinyl; -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
11 ß, 17-Dihydro>:y-16«methylen-21-(methylsulfinyl)-pregna-. 1,4-dien-3,20-dion11β, 17-dihydro>: y-16 «methylene-21- (methylsulfinyl) -pregna-. 1,4-diene-3,20-dione
9-Fluor-11 ß-hydroxy-16a, 17·*- dimethyl-21-(methylsulfinyl)-pregna-1,4~dien--3,20-dion 9-fluoro-11 ß-hydroxy-16a, 17 * - dimethyl-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
9-Fluor-11ß,17-dihydroxy-16-methylen-21-(methylsulfinyl)-pregna-1,4-dien-3,20-dion 9-fluoro-11β, 17-dihydroxy-16-methylene-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
9-Fluor-1-1 ß-hydroxy-2· -metl^l» 21-(methylsulfinyl;-pregna-1, 4rdieno-/i 7a, 16a-öJ-oyL&zol-3,20-dion 9-fluoro-1-1β-hydroxy-2 · -metl ^ l »21- (methylsulfinyl; -pregna-1, 4rdieno- / i 7a, 16a-öJ-oyL & zol- 3,20-dione
9-Fluor-11ß,16a,17-trihydroxy-21-(methylsulfinyl)-pregna-1,4-dien-3,20~dion 9-fluoro-11β, 16a, 17-trihydroxy-21- (methylsulfinyl) -pregna-1,4-diene-3,20-dione
20 B e i. s ρ i e 1 e 67 Ms 7320 B e i. s ρ i e 1 e 67 Ms 73
Gemäß Beispiel 49, Methode A, jedoch unter Verwendung der in Spalte I aufgeführten 21-Mercaptosteroide, v/erden die in Spalte II aufgeführten 21-Sulfinylsteroide erhalten. Beisp. Spalte I Spalte IIAccording to Example 49, method A, but using the 21-mercaptosteroids listed in column I, the 21-sulfinyl steroids listed in column II are obtained. Example Column I Column II
25 67 9-Fluor-21-(n-hexylthio)- 9-Fluor-11ß,16«,17-trihydro-25 67 9-fluoro-21- (n-hexylthio) - 9-fluoro-11ß, 16 «, 17-trihydro-
11ß,16a,17-trihydroxy- xy-21-(n-hexylsulfinyl)-preg-11β, 16a, 17-trihydroxy-xy-21- (n-hexylsulfinyl) -preg-
pregna-1,4-dien-3,20-dion, na-1,4-dien-3,20-dion, eycl.pregna-1,4-diene-3,20-dione, na-1,4-diene-3,20-dione, eycl.
cycl. 16,17-Acetal mit 16,17-Acetal mit Aceton Aceton - .cycl. 16,17-acetal with 16,17-acetal with acetone Acetone -.
409825/1 UO409825/1 UO
Beisp. 68 Ex. 68
Spalte I Spalte II Gap e I Column II
6969
7070
7171
7272
7373
21-(Cyclopentylthio)-9- 9-Fluor-11ß, 16a,17-trihyf luor-11 ß, 16α, 17-trihydro- droxy-21 - (eyclopentylaulxypregna-1,4-dien»3,20-dion, f. inyl)-pregna-1,4-diencycl. 16,17-Acetal mit Aceton 3,20-dion, cycl. 16,17-Acetal mit Aceton21- (Cyclopentylthio) -9- 9-fluoro-11β, 16a, 17-trihyf luor-11 ß, 16α, 17-trihydroxy-21 - (eyclopentylaulxypregna-1,4-diene »3,20-dione, f. inyl) -pregna-1,4-diene cycl. 16,17-acetal with acetone 3,20-dione, cycl. 16,17 acetal with acetone
21-(Benzylthio)-9-fluor-11ß,16a,17-trihydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton21- (Benzylthio) -9-fluoro-11ß, 16a, 17-trihydroxypregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9-Fluor-11 β,16a,17-trihydroxy-21-(phenylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11 β, 16a, 17-trihydroxy-21- (phenylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
21-(p-Chlorphenylthio)-9-f luor-11ß,16α,17- trihydroxypregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton21- (p-chlorophenylthio) -9-fluoro-11ß, 16α, 17-trihydroxypregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9«-Fluor-11ß,16a,17-trihydroxy-21-(p-methoxyphenylthio;-pregna-1 , A-dien-3, 20-dion, cycl. 16,17-Acetal mit Aceton9 "-Fluoro-11β, 16a, 17-trihydroxy-21- (p-methoxyphenylthio; -pregna-1 , A-diene-3, 20-dione, cycl. 16,17 acetal with acetone
9a-Fluor-11ß,i6c£,17-trihydroxy-21~(p-methylphenylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton 9-Fluor-11ß,16a,17-trihydroxy-21 - (benzj^lsulf inyl) pregna-1,4-dien-3;20-dion, cycl. 16,17-Acetal mit Aceton -9a-fluoro-11β, 16c £, 17-trihydroxy-21- (p-methylphenylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17-acetal with acetone 9-fluoro-11ß, 16a, 17-trihydroxy-21 - (benzj ^ isulphynyl) pregna-1,4-diene-3 ; 20-dione, cycl. 16,17-acetal with acetone -
9-Fluor-11 β,16α,17-trihydroxy-21-(phenylsulfinyl)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11 β, 16α, 17-trihydroxy-21- (phenylsulfinyl) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9-Fluor-11 ß,16a,17-trihydroxy-21-(p-chlorphenylsulfinyl)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11 ß, 16a, 17-trihydroxy-21- (p-chlorophenylsulfinyl) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9a-F.luor-i 1 β, 16af, 17~trihydroxy-21-(p-methoxyphenylsulfinyl)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9a-F.luor-i 1 β, 16a f , 17 ~ trihydroxy-21- (p-methoxyphenylsulfinyl) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
9a-Fluor-11ß,16a,17-trihydroxy-21-(p-methylphenylsulfinyl)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton9a-fluoro-11beta, 16a, 17-trihydroxy-21- (p-methylphenylsulfinyl) -pregna-1,4-di ene-3,20-dione, cycl. 16,17 acetal with acetone
Beispiel 74Example 74
9-Fluor-11ß,16t,17-trihydroxy-21-mercaptopregna-i,4-dien-3,20-dion-21 -acetat, cycl. 16,17-Acetal mit_Aceton Eine Lösung von 10 g 9-Fluor-11ß,16a,17,21~tetrahydroxypregna-25 1,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17~Acetal'mit Aceton und 6,1 g Kaliumthioacetat in 500 ml Aceton v/ird 5 Stunden unter Rückfluß gekocht. Danach wird "das Reaktionsgemisch auf etwa 250 ml eingedampft, mit dem gleichen Volumen !"fässer versetzt und das ausgefällte Produkt abfiltricrt und getrocknet. 9-fluoro-11ß , 16t, 17-trihydroxy -21-mercaptop r egna-i, 4 -dien-3,20- dione- 21-acetate, cycl. 1 6,17-acetal mit_ Ace ton A solution of 10 g of 9-fluoro-11ß, 16a, 17,21-tetrahydroxypregna-25 1,4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16.17 Acetal with acetone and 6.1 g of potassium thioacetate in 500 ml of acetone are refluxed for 5 hours. Then "the reaction mixture is evaporated to about 250 ml, the same volume!" Barrels are added and the precipitated product is filtered off and dried.
4 0 9 8 2 5/1 UO4 0 9 8 2 5/1 UO
BAD ORiGtMAtBAD ORiGtMAt
1 Nach Umkristallisation aus einem Gemisch von "Aceton und Petroläther schmilzt die Titelverbindung bei 241 bis 242°C.1 After recrystallization from a mixture of "acetone and petroleum ether the title compound melts at 241 to 242 ° C.
Beispiele 75 bis 91Examples 75 to 91
5 Gemäß Beispiel 74, jedoch unter Verwendung der in Spalte I auf-5 As in Example 74, but using the information listed in column I
. in. in
geführten 21-p-Toluolsulfonate, werden die/Spalte II aufgeführten 21-Acetylthiosteroide erhalten. '■ · guided 21-p-toluenesulfonates, the / column II listed 21-acetylthiosteroids are obtained. '■ ·
Beisp. Spalte I Ex. Column I.
9-Fluor-11 ß,1ßo;, 17,21-teträhydroxypregn-4-en-3,20- dion-21-p-toluolsulfonat, 03^cI. 16,17-Acetal mit Aceton "-.-■■■9-fluoro-11 ß, 1ßo ;, 17,21-tetrahydroxypregn-4-en-3,20- dione-21-p-toluenesulfonate, 03 ^ cI. 16,17 acetal with Acetone "-.- ■■■
7676
7777
7878
7979
8080
8181
9-Fluor-11ß,16a,17,21-tetrahydroxypregna-1 ,4-dien-3,20-dion-2i-p"toluolsulfonat, cycl. 16,17-Acetalmit Acetophenon (G-Methyl)9-fluoro-11β, 16a, 17,21-tetrahydroxypregna-1 , 4-diene-3,20-dione-2i-p "toluenesulfonate, cycl. 16,17 acetal with Acetophenone (G-methyl)
9-Fluor-11ß,16a,17,21-tetrahydroxypregna-1,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17-'" Acetal mit Acetaldehyd (α-Methyl)9-fluoro-11ß, 16a, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16.17- '"acetal with acetaldehyde (α-methyl)
; V- Spalte II; V- column II
9-Fluor-11ß,16a, IT-trihydro-X3'-21-mercaptoprcgn-4-en~3,20-dion-21-acetat, cj^cl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, IT-trihydro-X3'-21-mercaptoprcgn-4-en ~ 3,20-dione-21-acetate, cj ^ cl. 16,17 acetal with acetone
9-Fluor-1Iß,16a,17-trIhydroxy-21-mercaptopregna-1,4-dien~3,20-diori-21~acetat, cycl. 16,17--Acetal "mit Acetophenon (ß>Methyl)9-fluoro-1Iß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene ~ 3,20-diori-21 ~ acetate, cycl. 16.17 - Acetal "with acetophenone (ß> methyl)
9-Fluor-11 ß, 16a, 17-trih3^droxy-21 -mercaptopregna-i ,A-dien-3,20-dion~21-acetat, cycl. 16,17-Acetal mit Acetaldehyd (α-Methyl) 9-fluoro-11 ß, 16a, 17-trih3 ^ droxy-21-mercaptopregna-i , a- diene-3,20-dione-21-acetate, cycl. 16,17-acetal with acetaldehyde (α-methyl)
9-Fluor-i1ß,16a,17,21- "■■ 9-Fluor-11ß, 16a, 17-trihydro-9-fluoro-11ß, 16a, 17.21- "■■ 9-fluoro-11ß, 16a, 17-trihydro-
tetrahydroxypregna-1,4- x.y-21-mercaptopregna-1,4-tetrahydroxypregna-1,4- x.y-21-mercaptopregna-1,4-
dien-3,20-dion-21-p-toluol- dien-3,2Ω-α.±οη-2Λ-&οζ±βΧ, diene-3,20-dione-21-p-toluene-3, 2Ω-α. ± οη-2Λ- & οζ ± βΧ,
sulfonat, cycl. I6,17-Ace- cycl. 16,17-Acetal mit C3/CI0-sulfonate, cycl. I6,17-acyclic. 16.17-acetal with C3 / CI0-
tal mit Cyclohexanon hexanontal with cyclohexanone hexanone
11ß,17,21-Trihydroxy-6,16- 11ß,17-Dihydrο xy~ 21-mercapto-11β, 17,21-trihydroxy-6,16-11β, 17-dihydrο xy ~ 21-mercapto-
dimethyl-1,4,6,15-pregna- 6,16-dimethyl-1.4,6,15-pregna-dimethyl-1,4,6,15-pregna- 6,16-dimethyl-1,4,6,15-pregna-
tetraen-3,20~dion-21-p- tetraen-3,20-dion-21-acetat
toluolsulfonat 'tetraene-3,20-dione-21-p-tetraene-3,20-dione-21-acetate
toluenesulfonate '
9-Fluor-11ß,17,21-trihy- 9-Fluor-11ß,17-dihydroxy-21-9-fluoro-11ß, 17,21-trihy- 9-fluoro-11ß, 17-dihydroxy-21-
droxy-i6ß-methylpregna-1,4- mercapto-16ß-methylpregna-droxy-16ß-methylpregna-1,4-mercapto-16ß-methylpregna-
dien-3,20-dion-21-p-tolu- 1,4-dien-3,20-dion-21-acetat olsulfonat · . - .diene-3,20-dione-21-p-tolu-1,4-diene-3,20-dione-21-acetate olsulfonate ·. -.
9-Fluor-11 ß, 17, 21-trihydro- 9-Flüor-11 ß, 17-dihydroö!iv'-21,-9-fluorine-11 ß, 17, 21-trihydro- 9-fluorine-11 ß, 17-dihydroö! Iv'-21, -
xy-16a-methylpregna-1,4- mercapto-I6a-methylprerna-xy-16a-methylpregna-1,4-mercapto-I6a-methylprerna-
dien-3,20-dion-2i-p-tolu- 1,4~dien-3,20-dion-21-acetat olsulfonat .-. ■diene-3,20-dione-2i-p-tolu-1,4-diene-3,20-dione-21-acetate olsulfonate .-. ■
409 825/ IUO409 825 / IUO
rtWiSlfiO OASrtWiSlfiO OAS
Beipp.Beipp.
Spalte IColumn I.
8282
8585
8686
8787
8888
8989
9090
9191
6α,9-Difluor-11 β,17α,21-tri·
hydroxy-16a-methylpregna-1,4-dien-3, 20-dion-21-p- .
toluolsulfonat6α, 9-difluoro-11β, 17α, 21-tri-hydroxy-16a-methylpregna-1,4-diene-3, 20-dione-21-p-.
toluenesulfonate
6a,9-Difluor-11ß,i6a,17,
21-tetrahydroxypregna-1,4-dien-3,2p-dion-21-p-toluolsulf
onat;, cycl. 16,17-Acetal
mit Aceton6a, 9-difluoro-11ß, i6a, 17,
21-tetrahydroxypregna-1,4-diene-3,2p-dione-21-p-toluenesulfonate; cycl. 16,17 acetal with acetone
6a-Fluor-1'1 β, 21 -dihydroxy-T6a-methyl-pregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 6a-fluoro-1'1 β, 21 -dihydroxy-T6a-methyl-pregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
9,11ß-Dichlor-6ß-fluor-16α, 17,21-trihydroxypregna-1,4-dien-3,20rdion-21-p-toluolsulf onat, cycl. 16,17-Acetal mit Aceton9,11ß-dichloro-6ss-fluoro-16α, 17,21-trihydroxypregna-1,4-diene-3,20-dione r 21-p-toluolsulf onate, cycl. 16,17 acetal with acetone
11 β, 16ct, 17,21 -Tetrahydroxypregna-1 ,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17-Acetal mit Aceton11 β, 16ct, 17.21 -Tetrahydroxypregna-1 , 4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16,17 acetal with acetone
11 β, 17,2.1 -Trihydroxy-16-methylen-pregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 11 β, 17,2.1 -trihydroxy-16-methylene-pregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
9-Pluor-11ß,21-dihydroxy-16α,17-dimethylpregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 9-fluorine-11β, 21-dihydroxy-16α, 17-dimethylpregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,17,21-trihydroxv-i6-methylenpregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 9-fluoro-11β, 17,21-trihydroxv-16-methylenepregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,21-dihydroxy-2'-methylpregna-1 ,.4-dieno-/I7a,i6a-d/oxazol-3,20-dion-21-p-toluolsulfonat 9-fluoro-11β, 21-dihydroxy-2'-methylpregna-1 , .4-dieno- / 17a, 16a-d / oxazole-3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,16a,17,21-tetrahydroxypregna-1,4-dien-3,20-dion-16-acetat-21-p-toluolsulfonat 9-fluoro-11β, 16a, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione-16-acetate-21-p-toluenesulfonate
Spalte IIColumn II
6a,9-Difluor-11ß,17a-dihydroxy-21 -mercapto-16a-m.ethylpregna-1,4-dien-35 20-dion-21-acetat 6a, 9-difluoro-11β, 17a-dihydroxy-21 -mercapto-16a-m.ethylpregna-1,4-diene-35 20-dione-21-acetate
6a,9-Difluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21- · acetat, cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21- · Acetate, cycl. 16,17 acetal with acetone
6a-Fluor-11 ß-hydroxy-21 -mercapto-1öa-methylpregna-1,4-dien-3,20-dion-21-acetat 6a-fluoro-11β-hydroxy-21-mercapto-10a-methylpregna-1,4-diene-3,20-dione-21-acetate
9,11ß-Dichlor-6ß-fluor-16α, 17-dihydroxy-21 -mercapt.0-pregna-1,4-dien-3,20-dion-21-acetat, cycl. 16,17-Acetal mit Aceton9,11ß-dichloro-6ß-fluoro-16α, 17-dihydroxy-21-mercapt.0-pregna-1,4-diene-3,20-dione-21-acetate, cycl. 16,17 acetal with acetone
11ß,16α,17-Trihydroxy-21 mercaptopregna-1,4-dien-3,20-dion-21-acetkt, cycl. 16,17-Acetal mit Aceton11β, 16α, 17-trihydroxy-21 mercaptopregna-1,4-diene-3,20-dione-21-acetate, cycl. 16,17 acetal with acetone
11ß,17-Dihydroxy-21-mercapto-16-methylenpregna-1,4-dien-3,20-dion-21-acetat 11β, 17-dihydroxy-21-mercapto-16-methylenepregna-1,4-diene-3,20-dione-21-acetate
9-Fluor-11ß-hydroxy-21-mercapto-16α,17-dimethylpreg~ na-1,4-dien-3,20-dion9-fluoro-11β-hydroxy-21-mercapto-16α, 17-dimethylpreg ~ na-1,4-diene-3,20-dione
9-Fluor-1.1ß,17-dihydroxy-21 mercapto-16-methylenpregna-1,4-dien-3,20-dion-21-acetat ■ - 9-fluoro-1.1ß, 17-dihydroxy-21 mercapto-16-methylenpregna-1,4-diene-3,20-dione-21-acetate ■ -
9-Fluor-11ß-hydroxy-21-mercapto-2 ^-methylpregha-1,4-dieno/i7α,1öa-dZ-oxazol-3,20-dion-21-acetat 9-fluoro-11β-hydroxy-21-mercapto-2 ^ -methylpregha-1,4-dieno / 17α, 10a-dZ-oxazole-3,20-dione-21-acetate
9-Fluor-11ß,16a,17-trihydroxy-21-mercaO'topregna-1,4-dien-3,20-dion-21-acetat 9-fluoro-11β, 16a, 17-trihydroxy-21-mercaO'topregna-1,4-diene-3,20-dione-21-acetate
409825/1140409825/1140
Beispiele 92 bis 96Examples 92 to 96
Gemäß Beispiel 74, jedoch unter Vervrendung der in Spalte I aufgeführten
Salze der Thiocarbonsäuren, werden die in Spalte II
aufgeführten 21-Acylthiosteroide erhalten.According to Example 74, but using the salts of the thiocarboxylic acids listed in column I, the in column II
21-acyl thiosteroids listed.
Beisp. Spalte I 92 . Na-thiohexanoat Example column I 92. Sodium thiohexanoate
93. Thiobenzoesäure-Kaliumsalz 93. Thiobenzoic acid potassium salt
94 p-Chlorthiobenzoesäure-Kaliumsalz 94 p-Chlorothiobenzoic acid potassium salt
95 p-Methoxythiobenzoesäure-Kaliurasalz 95 p-Methoxythiobenzoic Acid Potash Salt
96 p-Methylthiobenzoesäure-Kaliumsalz Spalte II96 p-methylthiobenzoic acid potassium salt Column II
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-»3,20-dion-21-hexanoat, cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene- »3,20-dione-21-hexanoate, cycl. 16,17 acetal with acetone
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-benzoat, cycl. 16,17-Ace~ tal mit Aceton · ■9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-benzoate, cycl. 16,17-Ace ~ tal with acetone · ■
9-F1UO1--11 ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-(p-chlorbenzoat), cycl. ' 16,17-Acetal mit Aceton9-F1UO1--11 ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21- (p-chlorobenzoate), cycl. 16,17 acetal with acetone
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-(p-methoxybenzoat), cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21- (p-methoxybenzoate), cycl. 16,17 acetal with acetone
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion~ 21-(p-methylbenzoat), cycl. 16,17-Acetal mit Aceton9-fluoro-11β, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione ~ 21- (p-methylbenzoate), cycl. 16,17 acetal with acetone
20 B e i.s ρ i e 1 9720 B e i.s ρ i e 1 97
Gemäß Beispiel 74, jedoch unter Verwendung von 9-Fluor-11ß,16a, 17-trihydroxy-21-jodpregna-1,4-dien-3,20-dion cycl. 16,17-Acetal mit Aceton, wird das 9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-.dion-21-acetat cycl. 16,17-Acetal mit Ace-According to Example 74, but using 9-fluoro-11β, 16a, 17-trihydroxy-21-iodpregna-1,4-diene-3,20-dione cycl. 16,17 acetal with acetone, the 9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-.dione-21-acetate cycl. 16,17-acetal with Ace-
ton erhalten.get sound.
4Q9826/1U04Q9826 / 1U0
Beispiel 98 9-Fluor-11 ß, 16·τ, 17-trihvdroxv-2i -mercantopregna-i, 4-dien-3, 20-dion, cycl. 16.17-Acetal mit Aceton Example 98 9-Fluoro-11 ß, 16 · τ, 17-trihvdroxv-2i - mercantopregna-i, 4-diene-3, 20- dione, cycl. 16 .1 7-acetal with acetone
• Methode A; • method A;
Eine Lösung von 4,0 g 9-Fluor-11ß,16a,17-trihydroxy--21-mercaptopregna-1,4-dien-3,20-dion-21-acetat cycl. 16,17-Acetal mit Aceton und 0,62 g Natriummethoxid in 115 ml wasserfreiem Methanol wird 4 Tage bei Raumtemperatur gerührt. Nach dem Ansäuern mit 3,3 ml Eisessig wird das Produkt abfiltriert, mit kaltem lasser gewaschen und getrocknet. Nach mehrmaliger Umkristallisation aus einem Gemisch von Dimethylformamid und Methanol schmilzt die Titelverbindung bei 315 bis 3160C.A solution of 4.0 g of 9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-acetate cycl. 16,17 acetal with acetone and 0.62 g of sodium methoxide in 115 ml of anhydrous methanol is stirred for 4 days at room temperature. After acidification with 3.3 ml of glacial acetic acid, the product is filtered off, washed with cold water and dried. After repeated recrystallization from a mixture of dimethylformamide and methanol, the title compound melts at 315-316 0 C.
Methode B bis F: " rMethod B to F: "r
• 15 Gemäß Methode A, jedoch unter Verwendung der in Spalte I aufgeführten
Basen und der in Spalte II aufgeführten Lösungsmittel wird die Titelverbindung hergestellt:
Methode I II• 15 According to method A, but using the bases listed in column I and the solvents listed in column II, the title compound is prepared:
Method e I II
B Natriumäthoxid ÄthanolB sodium ethoxide ethanol
C Kaliumäthoxid ÄthanolC potassium ethoxide ethanol
D Kalium-isopropoxid IsopropanolD potassium isopropoxide isopropanol
E Kaliumbicarbonat 5 % wäßriges MethanolE potassium bicarbonate 5 % aqueous methanol
F Kaliumcarbonat 5 % wäßriges MethanolF potassium carbonate 5 % aqueous methanol
Beispiele -99 bis 115 Gemäß Beispiel 98, jedoch unter Verwendung der in Spalte I aufgeführten 21-Acetyl thiosteroide, werden " d.i e in Spalte II auf geführten 21-Mercaptosteroide erhalten.Examples -99 to 115 As in Example 98, but using those listed in column I. 21-Acetyl thiosteroids are listed in column II 21-mercaptosteroids obtained.
40982.5/1 UO40982.5 / 1 UO
BAD ORiGfNALBAD ORiGfNAL
Beisp.Ex.
..
100100
101101
102102
103103
104104
105105
. 106. 106
107107
103103
Spalte IColumn I.
9-F-luoirr 11 ß, 16α, 17-trihydroxy-21-mercaptopregn-4-en-3,20-dion-21-acetat, ■ cycl. 16,17-Acetal mit Aceton9-F-luoirr 11 ß, 16α, 17-trihydroxy-21-mercaptopregn-4-en-3,20-dione-21-acetate, ■ cycl. 16,17 acetal with acetone
9-Fluor-11ß,16α,ί7-trihy- _ droxy-21-mercaptopregna- -1,4-d£en-3,20-dion-21-acetat, cycl. 16,17-Acetal mit Acetophenon (ß-Methyl)9-fluoro-11ß, 16α, ί7-trihy- _ droxy-21-mercaptopregna- -1,4-d £ en-3,20-dione-21-acetate, cycl. 16,17-acetal with acetophenone (ß-methyl)
9-Fluor-11ß,i6a,17~trihydroxy-21-mercaptopregna-? 1,4-dien-3,20-dion-21-acetat,· cycl. 16,17-Acetal mit Acetaldehyd-(α-Methyl)9-fluoro-11β, 16a, 17-trihydroxy-21-mercaptopregna-? 1,4-diene-3,20-dione-21-acetate, · cycl. 16,17 acetal with acetaldehyde (α-methyl)
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-acetat, cycl. 16,17-Acetal mit Cyclohexanon9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-acetate, cycl. 16,17 acetal with cyclohexanone
11ß,i7-Dihydroxy-21-mercapto-6,16-dimethyl~1,4,6, 15-pregnatetraeri-3t20rdion-21-acetat 11β, 17-dihydroxy-21-mercapto-6,16-dimethyl ~ 1,4,6, 15-pregnatetraeri-3t20rdione-21-acetate
9-Fluor-11 β, 17-dihydroxy-21-mercapto-16ß-methylpregna-1,4-dien-3,20-dion·=· 21-acetat .9-fluoro-11β, 17-dihydroxy-21-mercapto-16β-methylpregna-1,4-diene-3,20-dione = 21-acetate.
9-Fluor-11ß,17-dihydroxy-21-mercapto-16a-methylpregna-1.,4-dien-3,20-dion-21-acetat 9-fluoro-11ß, 17-dihydroxy-21-mercapto-16a-methylpregna-1., 4-diene-3,20-dione-21-acetate
6a,9-Difluor-11ß,17a-dihydrox3r-2t-mercapto-i 6α-methylpregna-1,4-dien-' 3,20-dion-21-acetat.6a, 9-difluoro-11ß, 17a-dihydrox3r-2t-mercapto-i 6α-methylpregna-1,4-diene- ' 3,20-dione-21-acetate.
6a,9-Difluor-'11ß,i6a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-acetat cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-'11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-acetate cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-21-mercapto-16a-methylpregna-1,4~dien-3,2O-dion-21-acetat 6a-fluoro-11ß-hydroxy-21-mercapto-16a-methylpregna-1,4-diene-3,2O-dione-21-acetate
Spalte II Column II
9-Fluor-11ß,16a ,Ί 7-trihydroxy-21-mercaptopregn-4-en-3,20-dion, cycl. 16,17-Acetal mit Aceton ' .9-fluoro-11ß, 16a, Ί 7-trihydroxy-21-mercaptopregn-4-en-3,20-dione, cycl. 16,17 acetal with acetone '.
9-Fluor-11 ß, 16α,, 17-trihydroxy-21-mereaptopregna-1,4-dien-3,2Ö-diön, cycl. 16,17-Acetal mit. Acetophenon (.ß-Methyl) 9-fluoro-11 ß, 16α ,, 17-trihydroxy-21-mereaptopregna-1,4-diene-3,2Ö-diön, cycl. 16,17 acetal with. Acetophenone (.ß-methyl)
9-Fluor-1.1 β, 16α, 17-tr.ihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl, 16,17-Acetal mit Acetaldehyd· ; (α-Methyl) 9-fluoro-1.1 β , 16α, 17-tr.ihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl, 16,17-acetal with acetaldehyde; (α-methyl)
9-Fluor-11 β,16α,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Cyclohexanon 9-fluoro-11β, 16α, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with cyclohexanone
11 β, 17-Dihydroxy-:21r-rnercapto-6,16-dimethyl-1,4,6,15^-pregnatetraen-i,20-dion 11 β, 17-dihydroxy-: 21 r -nercapto-6,16-dimethyl-1,4,6,15 ^ -pregnatetraen-i, 20-dione
9-Fluor-11 β,17-dihydroxy-21-mercapto-16ß-methylpregna-. 1,4-dien~3,20-dion9-fluoro-11β, 17-dihydroxy-21-mercapto-16β-methylpregna-. 1,4-diene ~ 3,20-dione
9-Fluor-11 β, 1;7-dihydroxy-21 mercapto-16a~methylpregna-■ 1,4-dien-3,. 20-dion9-fluoro-11 β, 1 ; 7-dihydroxy-21 mercapto-16a ~ methylpregna- ■ 1,4-diene-3,. 20-dione
6a, 9-Dif luor-11 β, .17a-dihydroxy-21-mercapto-16a-methylpregna-1,4-dien-3,20-dion 6a, 9-difluor-11β, .17a-dihydroxy-21-mercapto-16a-methylpregna-1,4-diene-3,20-dione
6a,9-Difluor-11 β,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton ." '6a, 9-difluoro-11 β, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone. "'
6a-Fluor-11ß-hydroxy-21-mercapto- 16a -methylpregna-1, 4-dien-3,20-dion ·6a-fluoro-11ß-hydroxy-21-mercapto-16a -methylpregna-1,4-diene-3,20-dione ·
409825/1140409825/1140
« 36 -«36 -
Beisp.
109 Ex.
109
110110
111111
112112
113113
114114
115115
Spalte IColumn I.
9,11ß-Dichlor-6ß-fluor-16α, 17-dihydroxy-21-mercapto-. pregna-1,4-dien-3,20-dion-21-acetat, cycl. 16,17-Acetal mit Aceton9,11ß-dichloro-6ß-fluoro-16α, 17-dihydroxy-21-mercapto-. pregna-1,4-diene-3,20-dione-21-acetate, cycl. 16,17 acetal with acetone
11 β,16α,17-Trihydroxy-21-mercaptopregna-1,4-dien-3,20~dion~21-acetat, cycl. 16,17-Acetal mit Aceton11 β, 16α, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20 ~ dione ~ 21-acetate, cycl. 16,17 acetal with acetone
11ß,17-Dihydroxy-21-mercapto-I 6-methylenpregna-1,4-dien-3,20-dion-21-acetat 11β, 17-dihydroxy-21-mercapto-I 6-methylenepregna-1,4-diene-3,20-dione-21-acetate
9-Fluor-11ß-hydroxy-21-mercapto-16a, 17-dimethylpregna-1,4-dien-3,20~dion-21-acetat 9-fluoro-11ß-hydroxy-21-mercapto-16a, 17-dimethylpregna-1,4-diene-3,20-dione-21-acetate
9-Fluor-11 β,17-dihydroxy-21 -rnercapto-16-methylenpregna-1,4-dien~3,20-dion-21-acetat 9-fluoro-11β, 17-dihydroxy-21 -rnercapto-16-methylenpregna-1,4-diene ~ 3,20-dione-21-acetate
9-Fluor-11ß-hydroxy-21-mercapto-2 '-methylpregna-1,4« dieno/ΐ 7a,16a-d/oxazol-3,20-dion-21-acetat 9-fluoro-11β-hydroxy-21-mercapto-2 '-methylpregna-1,4 " dieno / ΐ 7a, 16a-d / oxazole-3,20-dione-21-acetate
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-acetat 9-fluoro-11β, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-acetate
\ Spalte II \ Column II
9,11 ß-Dichlor-6ß-f luor-1.6a:, 17-dihydroxy-21-mercaptopregna-1 , 4-dien-3, 20-dio'n, cycl. 16,17-Acetal mit Aceton 9.11 ß-dichloro-6ß-fluorine-1.6a :, 17-dihydroxy-21-mercaptopregna-1, 4-diene-3, 20-dio'n, cycl. 16,17 acetal with acetone
11 ß, T6a, 17~Trihy.droxy-21 mercaptopregna-1,4-dien-3,20-dion cycl. 16,17-Acetal mit Aceton11 ß, T6a, 17 ~ Trihy.droxy-21 mercaptopregna-1,4-diene-3,20-dione cycl. 16,17 acetal with acetone
1113,17-Di}.i3rdroxy-21 -rnercapto-1 6~methylenOregna~1,4-dien-3,20-dion 1113,17-Di} .i3rdroxy-21 -rnercapto-1 6 ~ methylene oregna ~ 1,4-diene-3,20-dione
9-Fluor-11ß-hydroxy-21-mercapto-1 6a,17-dimethylpregna-1,4-dien~3,20-dion 9-fluoro-11β-hydroxy-21-mercapto-1 6a, 17-dimethylpregna-1,4-diene -3,20-dione
9-Fluor-11ß,17-dihydroxy-21 ■ mercapto-16-methylenpregna-1,4-dien-3,20-dion 9-fluoro-11β, 17-dihydroxy-21 ■ mercapto-16-methylenepregna-1,4-diene-3,20-dione
9-Fluor-11ß-hydroxy-21-mercapto-2'-methylpregna-1,4-dieno/i7a,1öa-d/oxazol-S,20-dion 9-fluoro-11β-hydroxy-21-mercapto-2'-methylpregna-1,4-dieno / 17a, 10a-d / oxazole-S, 20-dione
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion 9-fluoro-11β, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione
20 Bei s. piele1i6 Ms 120 20 At s. Piele1i6 Ms 120
9a-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton . Gemäß Beispiel 98, jedoch unter Verwendung der nachstehend aufgeführten Acylthipsteroide, wird die Titelverbindung erhalten. 9a-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone . According to Example 98, but using the acylthipsteroids listed below, the title compound is obtained.
Bei sp.At sp.
116116
117117
Spalte IColumn I.
9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion-21-hexanoat, cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione-21-hexanoate, cycl. 16,17 acetal with acetone
9-Fluor-11 ß, 16a, 17-trihydrox3^-21-mercaptopregna-1,4-dien-3,20-dion-21-benzoat, cycl. -16,17-Acetal mit Aceton _j9-fluoro-11 ß, 16a, 17-trihydrox3 ^ -21-mercaptopregna-1,4-diene-3,20-dione-21-benzoate, cycl. -16,17-acetal with acetone _j
409825/1U0409825 / 1U0
Beisp. Spalte IExample column I.
• 118 ^-Fluor-iißjio.ctj^-trihydroxy-SI-mercaptopregna-• ~1,4-dien-3,20-dioii-21-(p-chlorbenzOat), cycl. 16,'17-Acetal mit Aceton• 118 ^ -Fluor-iißjio.ctj ^ -trihydroxy-SI-mercaptopregna- • ~ 1,4-diene-3,20-dioii-21- (p-chlorobenzOate), cycl. 16, '17 acetal with acetone
119 9-Pluor-11ß,16α,17-trihydroxy-21-mercaptopregna-' ■ 1,4-dien-3,20-dion-21-(p-methoxyt)enzoat), cycl.119 9-Pluor-11ß, 16α, 17-trihydroxy-21-mercaptopregna- ' ■ 1,4-diene-3,20-dione-21- (p-methoxyt) enzoate), cycl.
16,17-Acetal mit Aceton16,17 acetal with acetone
120 9-Fluor-.11ß,16a,17-trihydroxy-21-raercaptopregna-1,4-dien-3,2O-dion-2T-(p~riiethylbenzoat;., cycl. 16,17-Acetal, mit Aceton ; 120 9-fluoro-11β, 16a, 17-trihydroxy-21-raercaptopregna-1,4-diene-3,2O-dione-2T- (pariethylbenzoate;., Cycl. 16,17-acetal, with acetone ;
B e i- s ρ ie I- 121 9-Fluor-11ß,16q,17-trihYdroxy-21-(methylthio)-pregna-1,4-dien-3.20-dion, cvcl. 16,17-Acetal mit Aceton " " Eine Lösung von 4,5 g 9-Fluor-11ß, 16a,^^17-trihydroxy-21-mercaptopregna-1,4-dienT3,20-dion cycl. 16,17-Acetal mit Aceton und 0,24 g Natriumhydrid in 300 ml 1,2-Dimethoxyäthan lirird 2 Stunden bei 500C gerührt. Sodann wird das Reaktionsgemisch tropfenweise mit 1,56 g M-ethyl jodid in 25 ml 1,2-Dimethoxyäthan versetzt. Das Gemisch wird 2 Tage bei 500C gerührt und sodann eingedampft. Das Rohprodukt wird aus einem Gemisch von Aceton und Petroläther umkristallisiert. · ■B e i- s ρ ie I- 121 9-fluoro-11ß, 16q, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3.20-dione, cvcl. 16,17-acetal with acetone "" A solution of 4.5 g of 9-fluoro-11β, 16a, ^^ 17-trihydroxy-21-mercaptopregna-1,4-diene T 3,20-dione cycl. 16,17-acetal with acetone and 0.24 g of sodium hydride in 300 ml of 1,2-dimethoxyethane lirird stirred for 2 hours at 50 0 C. 1.56 g of M-ethyl iodide in 25 ml of 1,2-dimethoxyethane are then added dropwise to the reaction mixture. The mixture is stirred for 2 days at 50 ° C. and then evaporated. The crude product is recrystallized from a mixture of acetone and petroleum ether. · ■
..
Beispiele 122 bis 138Examples 122-138
Gemäß Beispiel 121, jedoch unter Verwendung der in Spalte I aufgeführten 21-Mercaptosteroide, werden die in Spalte II aufgeführten 21-Methylthiösteroide erhalten.According to Example 121, but using those listed in column I. 21-mercaptosteroids, are those listed in column II Obtain 21-methylthio-steroids.
. .. .
409 8 25/1140409 8 25/1140
' 122 9-Fluor-11 β,16α,17-trihydroxy-21-mercaptopregn-4-en-3,20-dion, cycl. 16,17-Acetal mit Aceton'122 9-fluoro-11 β, 16α, 17-trihydroxy-21-mercaptopregn-4-en-3,20-dione, cycl. 16,17 acetal with acetone
.123 9-Fluor-11ß,16α,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Acetophenon (ß-Methyl).123 9-fluoro-11ß, 16α, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl. 16,17-acetal with acetophenone (ß-methyl)
9-Fluor-11β,16α,17-trihydroxy-21-mercaptopregna- 9-fluoro-11β, 16α, 17-trihydroxy-21-mercaptopregna-
1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Acetaldehyd (α-Methyl)1,4-diene-3,20-dione, cycl. 16,17-acetal with acetaldehyde (α-methyl)
9-Fluor-11ß,16α,17-trihydroxy-21-mercaptopregna- 9-fluoro-11ß, 16α, 17-trihydroxy-21-mercaptopregna-
1,4-dien-3,20-dion, cycl. : 16,17-Acetal mit Cyclohexanon 1,4-diene-3,20-dione, cycl. : 16,17-acetal with cyclohexanone
11ß,17-Dihydroxy-21-mercapto-6 , 1ö-dimethyl-i,4, 6,15-pregnatetraen-3,20-dion 11β, 17-dihydroxy-21-mercapto-6 , 1ö-dimethyl-i, 4, 6,15-pregnatetraen-3,20-dione
9-Fluor-11ß,17-dihydroxy-21-mercapto-16ß-methylpregna-1,4-dien-3,20-dion 9-fluoro-11β, 17-dihydroxy-21-mercapto-16β-methylpregna-1,4-diene-3,20-dione
9-Fluor-11ß,17-dihydroxy-21-mercapto-16a-methylpregna-1,4-dien-35 20-dion9-fluoro-11β, 17-dihydroxy-21-mercapto-16a-methylpregna-1,4-diene-3 5 20-dione
>0 129 6a, 9-Dif luor-11 ß, 17cc-dihydroxy-21 -mercapto-16a*- methylpregna-1,4-dien-3,20-dion > 0 129 6a, 9-difluor-11β, 17cc-dihydroxy-21 -mercapto-16a * - methylpregna-1,4-diene-3,20-dione
6a,9-Difluor-11ß,16a,17-trihydroxy-21-mercaptopregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-11ß, 16a, 17-trihydroxy-21-mercaptopregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-21-mercapto-16a-methylpregna-1,4-dien-3,20-dion 6a-fluoro-11β-hydroxy-21-mercapto-16a-methylpregna-1,4-diene-3,20-dione
9,11ß-Dichlor-6ß-iluor-9,11ß-dichloro-6ß-iluor-
16a,17-dihydroxy-21-mercaptopregna-1,4-dien-3,20-di on, cycl. 16,17-Acetal16a, 17-dihydroxy-21-mercaptopregna-1,4-diene-3,20-di on, cycl. 16,17 acetal
mit Acetonwith acetone
Spalte II Column II
9-Fluor-11ß,16a,17-trihydroxy-21-(methylthio)-pregn-4-en-3,20-dion, cycl. 16,17-Acetal mit Aceton9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregn-4-en-3,20-dione, cycl. 16,17 acetal with acetone
9-Fluor-11ß,16a,17-trihydro-χλγ-21 - (methylthio) -pregna-1,4-dien-3,20-dion, cycl, 16,17-Acetal mit Acetophenon (ß-Methyl)9-fluoro-11β, 16a, 17-trihydro-χλγ-21 - (methylthio) -pregna-1,4-diene-3,20-dione, cycl, 16,17-acetal with acetophenone (ß-methyl)
9-Fluor-11 ß, 1 '6a, 17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Acetaldehyd. (α-Methyl)9-fluoro-11 ß, 1 '6a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20-dione, cycl. 16,17 acetal with acetaldehyde. (α-methyl)
9-Fluor-11ß,16a,17-trihydroxy-21-(methylthio)-pregna-1,4-dien-3,20~dion, cycl. 16,17-Acetal mit Cyclohexanon9-fluoro-11ß, 16a, 17-trihydroxy-21- (methylthio) -pregna-1,4-diene-3,20 ~ dione, cycl. 16,17 acetal with cyclohexanone
11ß,17-Dihydroxy-6,16-dimethyl-21-(methylthitf)-i,4,6,15-pregnatetraen-3,20-dion 11β, 17-dihydroxy-6,16-dimethyl-21- (methylthitf) -i, 4,6,15-pregnatetraen-3,20-dione
9-Fluor-11 ß, 17- dihydroxy-16i3-methyl-21-(methylthio)-pregna-1 ,4-dien-3,20-dion9-fluoro-11β, 17-dihydroxy-16i3-methyl-21- (methylthio) -pregna-1 , 4-diene-3,20-dione
9-Fluor-11ß,17-dihydroxy-16amethyl-21-(methylthio)-pregna-1,4-dien-3,20-dion 9-fluoro-11β, 17-dihydroxy-16amethyl-21- (methylthio) -pregna-1,4-diene-3,20-dione
6a,9-Difluor-11ß,17a-dihydro-X3^-15a-methyl-21 - (methylthio) pregna-1,4-dien-3,20-dion 6a, 9-difluoro-11β, 17a-dihydro-X3 ^ -15a-methyl-21 - (methylthio) pregna-1,4-diene-3,20-dione
6a, 9-Dif luor-11 β, 16oc, 17- tri hydroxy~21-(methylthio)-pregna-1 ,4-dien-3.20-dion cycl. 16,17-Acetal mit Aceton 6a , 9-difluor-11 β, 16oc, 17-trihydroxy ~ 21- (methylthio) -pregna-1, 4-diene-3.20-dione cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-16amethyl-21-(methylthio)-pregna-1,4-dien-3,20-dion 6α-fluoro-11β-hydroxy-16amethyl-21- (methylthio) -pregna-1,4-diene-3,20-dione
9,11ß-Dichlor-6ß-fluor-16α, 17-clihydroxy-21 - (methylthio) pregna-1,4-dien-3,20-dion, cycl. 16,17 Acetal mit Aceton.9,11ß-dichloro-6ß-fluoro-16α, 17-clihydroxy-21 - (methylthio) pregna-1,4-diene-3,20-dione, cycl. 16.17 acetal with acetone.
409825/1140409825/1140
Beisp... Spalte I Example ... Column I
. 11 β,16α,· 17-Trihydroxy-21 mercaptopregna-1,4-dien-3, .20-dion, cycl. 16,17-Ä'cetäl mit Aceton ;. 11 β, 16α, 17-trihydroxy-21 mercaptopregna-1,4-diene-3, .20-dione, cycl. 16,17-Ä'cetäl with acetone;
■ 134 11 β,17-Dihydroxy-21-mer-. capto-16-methylenpregna-1, 4- dl en- 3,20- di on■ 134 11 β, 17-dihydroxy-21-mer-. capto-16-methylenpregna-1, 4- dl en- 3,20- di on
9-Fluor-11ß-hydroxy-21-mercapto-1βα.,17-dimethylpregna-1,4-dien-3,20-dion 9-fluoro-11β-hydroxy-21-mercapto- 1βα. , 17-dimethylpregna-1,4-diene-3,20-dione
- 136 g-Fluor-iiß^-dihydroxy-21 -merca-p to-16-methylenpregna-1,4-dien-3,20- - 136 g-Fluoro-IIβ ^ -dihydroxy-21 -merca-p to-16-methylenpregna-1,4-diene-3.20-
diondion
9-Fluor-11ß-hydroxy-21-mercapto-2r-methvipregna-1,4-dieno/i 7a, 16o;-d/-oxazol-3j20-dion 9-fluoro-11β-hydroxy-21-mercapto-2 r -methvipregna-1,4-dieno / i 7a, 16o; -d / -oxazole-3j20-dione
138· 9-Fluor-11ß,16a,17-trihydroxy-21-mercaptopregna-154-dien-3,20-dion 138 x 9-fluoro-11β, 16a, 17-trihydroxy-21-mercaptopregna-1 5 4-diene-3,20-dione
Spalte IIColumn II
11B9 16a,17-Tfihydroxy-21-(raethylthio )-pregnä-i , 4-dieil- 3,20-dion, cycl. 16,17-Acetal mit Aceton .11 B 9 16a, 17-Tfihydroxy-21- (raethylthio) -pregnä-i, 4-dieil-3,20-dione, cycl. 16,17 acetal with acetone.
11ß,17-Bihydroxy-16-methylen~ 21^(methylthio)-pregna-1j 4-dien-3»20-dion 11β, 17-bihydroxy-16-methylene ~ 21 ^ (methylthio) -pregna-1j 4-diene-3 »20-dione
9-Flüor-11ß-hydroxy-16a.17-dimethyl--21 - (methylthiο) -pregna-1 , 4-dien-^3,20-dion9-fluorine-11β-hydroxy-16a.1 7- dimethyl-21 - (methylthio) -pregna-1,4-diene- ^ 3,20-dione
9 -Fluor- ί 1 ß,, 17-dihydroxy-16-methylen-21-(methylthio)-uregria-1,4-dien-3,20Tdion 9 -Fluoro- ί 1 ß ,, 17-dihydroxy-16-methylene-21- (methylthio) -uregria-1,4-diene-3.20 T dione
9 -Fluor-11 ß-hydf 0x3?·- 21 -me thyl thiο)-2·-methylpregna-1,4-dieno/ϊ7a,16a-d/-öxazol-3,20-dion 9 -Fluor-11 ß-hydf 0x3? - 21-methyl thiο) -2 * -methylpregna-1,4-dieno / ϊ7a, 16a-d / -öxazol-3,20-dione
9-Fluor-11 ß, 16a. 17-tirihydroxy- -21-(methylthio)-pregna-1,4-dien-3,20-dion 9-fluoro-11β, 16a. 17-tirihydroxy- -21- (methylthio) -pregna-1,4-diene-3,20-dione
B: e i s ρ i e 1 ■ 139B: e i s ρ i e 1 ■ 139
' 9-Fluor-i 1 ß, 16g< 17-trihvdr.oxy-21 ~,iodpregna-4-en-3,20-dion, cycl. 16,17-Acetal. mit Aceton ; .' 9-Fluoro-1 ß, 16g <17-trihvdr.oxy-21 ~, iodpregna-4-en-3,20-dione, cycl. 16,17 acetal. with acetone ; .
20 Ein Gemisch aus 7,45 g 9-Fluor-11ß,16a,17-trihydroxypregna-1,4-dien-3,20~dion cycl. 16,17-Acetal mit Aceton, 9,90 g Calciuinoxid und 0,33 g AzoisoTDuttersäuredinitril in 200 ml eines Gemisches von Tetrahydrofuran und Methanol (1 : 1) v/ird unter starkem# Rühren tropf enweise mit einer Lösung von 6,6 g Jod. in 33 ml20 A mixture of 7.45 g of 9-fluoro-11ß, 16a, 17-trihydroxypregna-1,4-diene-3,20-dione cycl. 16,17-acetal with acetone, 9.90 g and 0.33 g Calciuinoxid AzoisoTDuttersäuredinitril in 200 ml of a mixture of tetrahydrofuran and methanol (1: 1) v / ill with vigorous stirring # dripping enweise with a solution of 6.6 g Iodine. in 33 ml
25 Tetrahydrofuran und 19 ml Methanol versetzt. Das Reaktionsgemisch v/ird 3 Stünden gerührt, sodann in Methylenchlorid eingegossen und filtriert. Das Filtrat wird mit 3prozentiger wäßriger Na- J ■ triumthiosulfatlösung und Wasser gewaschen und das Lösungsmittel bei einer Temperatur unterhalt) 40°C verdampft. Es hinter-25 tetrahydrofuran and 19 ml of methanol are added. The reaction mixture is stirred for 3 hours, then poured into methylene chloride and filtered. The filtrate is triumthiosulfatlösung with aqueous sodium 3prozentiger J ■ and washed water and the solvent at a temperature dependent) 40 ° C evaporated. It behind-
40982.S/1U040982.S / 1U0
bleibt die Titelverbindung.remains the title compound.
Beispiel 14Ο .Example 14Ο.
9-Fluor-11 β, 16g «-17-trihydroxv-21 -,jodpregna-1,4-dien-5,20-dion,9-fluoro-11 β, 16g «-17-trihydroxv-21 -, iodpregna-1,4-diene-5,20-dione,
• 5 cycl. 16,17-Acetal mit Aceton • 5 cycl. 16,17 acetal with acetone
Eine Lösung von 3,21 g 9-Fluor-11ß,16a,17,21-tetrahydroxypregna-•1,4-dieii-3,20-dion-21-p-toluolsulfonat cycl. 16,17-Acetal mit Aceton in 35 ml Aceton wird mit einer Lösung von 2,88 g Natriumiodid in 25 ml Aceton versetzt. Das Reaktionsgemisch wird 8 Stunden unter Rückfluß erhitzt, sodann auf etwa 8 ml eingedampft und abgekühlt. Hierauf werden 10 ml einer 0,1 η Natrium-■ thiosulfatlösung zugesetzt,, und das .Reaktionsgemisch wird auf O0C abgekühlt. Die auskristallisierte Titelverbindung wird ab- -filtriert und getrocknet. f A solution of 3.21 g of 9-fluoro-11ß, 16a, 17,21-tetrahydroxypregna- • 1,4-dieii-3,20-dione-21-p-toluenesulfonate cycl. 16,17 acetal with acetone in 35 ml acetone is mixed with a solution of 2.88 g sodium iodide in 25 ml acetone. The reaction mixture is refluxed for 8 hours, then evaporated to about 8 ml and cooled. 10 ml of a 0.1 η sodium thiosulfate solution are then added, and the reaction mixture is cooled to 0 ° C. The title compound which has crystallized out is filtered off and dried. f
Beispiele 141 bis 157Examples 141 to 157
Gemäß Beispiel 140, jedoch unter Verwendung der nachstehend in Spalte I aufgeführten Steroidtosylate, werden die in Spalte II aufgeführten 21-Jodsteroiäe erhalten. , "According to Example 140, but using the steroid tosylates listed below in column I, the in column II 21-Jodsteroiäe listed. , "
Beisp. . Spalte I Spalte II Ex . Column I Column II
141 9-Fluor-11ß,T6a,17/-21~tetra- 9-Fluor-11ß,i6af17-trihydrohydroxypregh-4-en-3,20-dionxy-21-oodpregn-4-en-3,20-21-p-toluolsulfonat, cycl.16, dion, cycl. 1.6,17-Acetal141 9-fluoro-11ß, T6a, 17 / -21 ~ tetra- 9-fluoro-11ß, 16a f 17-trihydroxypregh-4-en-3,20-dionxy-21-oodpregn-4-en-3,20- 21-p-toluenesulfonate, cycl. 16, dione, cycl. 1.6,17 acetal
17- Acetal mit Aceton. . mit Aceton17-acetal with acetone. . with acetone
142 9-Fluor-11ß,i6a,17-21-tetra- 9-Fluor-11ß,16«^17-trihy- · hydroxy-pregna-1,4-dien- droxy-21-jodpregna-1,4-3,20-dion-21-p-toluolsulfodien-3,20-dion, cycl.142 9-fluoro-11ß, 16a, 17-21-tetra- 9-fluoro-11ß, 16 «^ 17-trihy- · hydroxy-pregna-1,4-diene-droxy-21-iodpregna-1,4-3,20-dione-21-p-toluenesulfodiene-3,20-dione, cycl.
nat, cycl. 16,17-Acetal mit 16,17-Acetal mit Aceto-Acetophenon.(ß-Methyl) phenon (ß-Methyl)nat, cycl. 16,17-acetal with 16,17-acetal with aceto-acetophenone. (Ss-methyl) phenone (ß-methyl)
143 9-Fluor-11ß,16a,17f21-tetra- 9-Fluor-11ß,16a,17-trihyhydroxypregna-1,4-dien-3,20-droxy-21-jodpregna-1,4-dion-21-p-toluolsulfonat, . dien-3,20-dion, cycl. cycl.. 16,17-Acetal mit Acet- 16,17-Acetal mit Acetaldealdehyd (α-Methyl) hyd (α-Methyl)143 9-fluoro-11β, 16a, 17 f 21-tetra-9-fluoro-11β, 16a, 17-trihyhydroxypregna-1,4-diene-3,20-hydroxy-21-iodpregna-1,4-dione-21 -p-toluenesulfonate,. diene-3,20-dione, cycl. cycl .. 16,17-acetal with acet- 16,17-acetal with acetaldealdehyde (α-methyl) hyd (α-methyl)
409825/mO409825 / mO
Beisp,
144 Example,
144
145145
146146
147147
148148
149149
150150
Spalte IColumn I.
9-Fluor-11ß,16α,17,21-tetrahydroxy-pregna-1,4-dien-3,20-dion-21-p-toluolsulfonat, cycl. 16,17-Acetal mit Cyclohexanon9-fluoro-11β, 16α, 17,21-tetrahydroxy-pregna-1,4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16,17 acetal with cyclohexanone
1-1 β, 17,21 -Trihydroxy- 6,16-dimethyl-1,4,6,15-pregnatetraen-3,20-dion-21-ptoluolsulfonat 1-1 β, 17,21-trihydroxy-6,16-dimethyl-1,4,6,15-pregnatetraene-3,20-dione-21-ptoluenesulfonate
9-Fluor-11ß,17,21-trihydroxy- 1 6ß-methylpregna-1,4-dien-3,20-dion-21-p-toluolsulfonat 9-fluoro-11β, 17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-p-toluenesulfonate
6a, 9-Difluor-11ß,17,21 -trihydroxy-1 6a-methylpregna-1,4-dien-3,20-dion-2-1-p-. toluolsulfonat6a, 9-difluoro-11ß, 17,21-trihydroxy-1 6a-methylpregna-1,4-diene-3,20-dione-2-1-p-. toluenesulfonate
6a,9-Difluor-11ß,17a,21-trihydroxy-16a-methylpregna-1,4-dien-3,20-dion-21-ptoluolsulfonat 6a, 9-difluoro-11ß, 17a, 21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione-21-ptoluenesulfonate
6a, 9-Dif luor-11ß, 16a, 1,7, 21 tetrahydroxypregna-1,4-dien-3,20-dionr21-p-toluolsulfonat, cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-11ß, 16a, 1,7, 21 tetrahydroxypregna-1,4-diene-3,20-dione-21-p-toluenesulfonate, cycl. 16,17 acetal with acetone
6a-Fluor-11 β,21-dihydroxylöa-methylpregna-i^ --dien-3,20-dion-21-p-toluolsulfonat 6a-fluoro-11β, 21-dihydroxylöa-methylpregna-i ^ --diene-3,20-dione-21-p-toluenesulphonate
Spalte IIColumn II
9-Fluor-11 ß, 1 δα,. 17-trihydroxy-21 - jodpregna-1,4-dien-. 3,20-dion, cycl. 16,17-Acetal rait Cyclohexanon9-fluoro-11 ß, 1 δα ,. 17-trihydroxy-21 - iodpregna-1,4-diene-. 3,20-dione, cycl. 16,17 acetal with cyclohexanone
11 β,17-Dihydroxy-21-jod-6,16-dimethyl~1,4,6,15-pregnatetraen-3> 20-dion11 β, 17-dihydroxy-21-iodo-6,16-dimethyl ~ 1,4,6,15-pregnatetraen-3> 20-dione
9-B'luor-11 ß, Ί 7-dihydi-oxy-21 -jod-16ß-methylpregna-·· 1,4-dien-3,20-dion9-B'luor-11 ß, Ί 7-dihydi-oxy-21 -iodine-16ß-methylpregna- 1,4-diene-3,20-dione
6a,9-Difluor-11ß,17-dihydro· xy-21-jod-16a^raethylpregna-1,4-dien-3,20-dion ■6a, 9-difluoro-11ß, 17-dihydro xy-21-iodine-16a ^ raethylpregna-1,4-diene-3,20-dione ■
6a,9-Difluor-11ß,17a-dihydro· xy-21 -jod-16a-aiethylpregna-1,4-dien-3,'20-dion 6a, 9-difluoro-11ß, 17a-dihydro xy-21-iodo-16a-aiethylpregna-1,4-diene-3, '20 -dione
6a,9-Difluor-11ß,16a,17-trihydroxy-21-oodpregna-1,4·- dien-3,20-dion, cycl. 16,17-Acetal mit Aceton6a, 9-difluoro-11ß, 16a, 17-trihydroxy-21-oodpregna-1,4 · - diene-3,20-dione, cycl. 16,17 acetal with acetone
6a-Fluor-11ß-hydroxy-21-jod-16g-methylpregna-1,4--dien-3,20-diqn 6a-fluoro-11ß-hydroxy-21 - iodine-16g-methylpregna-1,4-diene-3,20-diqn
9,11ß-Dichlor-6ß-fluor-16a, 9,11ß-Dlchlor-6ß-fluor-16a, 1-7,21 -trihydroxypregna-1,4- 17-dihydroxy-21 - jodpregnadien-3,20-dion-21-p-toluolsul-1,4-dien-3,20-dion/ cycl. fonat, cycl. 16,17-Acetal 16,17-Acetal mit Aceton mit Aceton .9,11ß-dichloro-6ß-fluoro-16a, 9,11ß-dichloro-6ß-fluoro-16a, 1-7,21 -trihydroxypregna-1,4- 17-dihydroxy-21 - iodpregnadiene-3,20-dione-21-p-toluenesul-1,4-diene-3,20-dione / cycl. fonat, cycl. 16,17 acetal 16,17 acetal with acetone with acetone.
11β,16α,17,21-Tetrahydroxy-11β, 16α, 17,21-tetrahydroxy
153153
21-ρ-toluol sulf onat,- cycl. 16,17-Acetal mit Aceton21-ρ-toluene sulfonate, - cycl. 16,17 acetal with acetone
11 β,17,21-Trihydroxy-16-methylenpregna-1,4-dien-3,20-dion-2.1-p-toluolsulfonat. 11 β, 17,21-trihydroxy-16-methylenepregna-1,4-diene-3,20-dione-2.1-p-toluenesulfonate.
11ß,16α,17-Trihydroxy-21-jodpregna-1,4-dien-3,20-dion, cycl. 16,17-Acetal mit Aceton ,11β, 16α, 17-trihydroxy-21-iodpregna-1,4-diene-3,20-dione, cycl. 16,17-acetal with acetone,
11 β,17-Dihydroxy-21-jod-16-methylenpregna-1,4-dien-3,20-dion 11 β, 17-dihydroxy-21-iodo-16-methylenepregna-1,4-diene-3,20-dione
4 0.9825/14 0.9825 / 1
23622&023622 & 0
9-Fluor-11ß,21-dihydroxy-16α, 17-dimethylp.regna-1,4-di.en-3,20-dion-21 -p-toluolsulfonat 9-fluoro-11β, 21-dihydroxy-16α, 17-dimethylp.regna-1,4-di.en-3,20-dione-21 -p-toluenesulfonate
" 155 9-Fluor-11ß,17,21-trihydroxy-i6-methylenpregna-1,4-dien-3,.20-dion-21 -p-toluolsulfonat "155 9-Fluoro-11ß, 17,21-trihydroxy-16-methylenepregna-1,4-diene-3, .20-dione-21 -p-toluenesulfonate
9~Fluor-11ß,21-dihydroxy-2'-methylpregna-1,4-dieno-/I7a,i6a-d7oxazol-3,20-dion-21-p-toluolsulfonat 9 ~ Fluoro-11β, 21-dihydroxy-2'-methylpregna-1,4-dieno- / 17a, 16a-d7oxazole-3,20-dione-21-p-toluenesulfonate
9-Fluor-11ß,16a,17,21-tetrahydroxypregna-i,4-dien-3,20-diön-16-acetat-21-ptoluolsulfonat 9-fluoro-11β, 16a, 17,21-tetrahydroxypregna-i, 4-diene-3,20-diene-16-acetate-21-ptoluenesulfonate
Spalte IIColumn II
9-Fluor-11ß-hydroxy-21-jod-16σ,, 17-dimethylpregna-1,4-dien-3j20-dion 9-fluoro-11ß-hydroxy-21-iodo-16σ ,, 17-dimethylpregna-1,4-diene-3j20-dione
9-Fluor-11ß,17-dihydroxy-21 -- jod~16-methylenpregna-1,4-dien-3,20~dion 9-fluoro-11β, 17-dihydroxy-21 - iodine-16-methylenepregna-1,4-diene-3,20-dione
9-Fluor-11 ß-h3'droxy-2'l -ä 2' -methyl-pregnix-1,4-d.ieno /Ϊ7α, 16a~d7-oxa?;ol-3,20-di on '9-fluoro-11 ß-h3'droxy-2'l -ä 2'-methyl-pregnix-1,4-d.ieno / Ϊ7α, 16a ~ d7-oxa?; Ol-3,20-di on '
9-Fluor-11ß,16a,17-trihydroxy-21-jodpregna-1,4-dien-3,20-dion 9-fluoro-11β, 16a, 17-trihydroxy-21-iodpregna-1,4-diene-3,20-dione
Beispie'l 158 9-Fluor-11 β, 16ο:, 17-trihydroxy-21 -mercaptopregna-1,4-dien-3,20-Example 158 9-fluoro- 11 β, 16ο :, 17-trihydroxy-21 -mercaptopregna-1, 4 -diene-3, 20-
dion, cycl. 16,17-Acetal mit Aceton ' Methode A: dione, cycl. 16,17-acetal with acetone ' method A:
Eine Lösung von 5,9 g Natriuraäthoxid in 100 ml Dimethylformamid .wird mit wasserfreie'm Schwefelwasserstoff gesättigt. Sodann wird diese Lösung mit einer Lösung von 14,7 g 9-Fluor-11ß,16a,17,21-A solution of 5.9 g of sodium ethoxide in 100 ml of dimethylformamide .is saturated with anhydrous hydrogen sulfide. Then will this solution with a solution of 14.7 g of 9-fluoro-11ß, 16a, 17.21-
20 tetrahydroxypregna-1, 4-dien-3,20-dion-21-p-toluolsulfonat cycl. 16,17-Acetal mit Aceton in 50 ml Dimethylformamid versetzt. Nach 12-~stündigem Erhitzen auf 1000C wird das Reaktionsgemisch auf etwa 30 ml eingedampft, abgekühlt, mit 7,25 ml konzentrierter Salzsäure versetzt und in 90 ml i/asser eingegossen. Die Ti-20 tetrahydroxypregna-1, 4-diene-3,20-dione-21-p-toluenesulfonate cycl. 16,17-acetal was mixed with acetone in 50 ml of dimethylformamide. After heating to 100 ° C. for 12 hours, the reaction mixture is evaporated to about 30 ml, cooled, treated with 7.25 ml of concentrated hydrochloric acid and poured into 90 ml of i / water. The Ti
25 telverMndung wird abfiltriert und getrocknet.The compound is filtered off and dried.
409825/1U0409825 / 1U0
1 Methode--B:1 method - B:
Gemäß Methode A^ jedoch unter Verwendung von 9~Fluor-11ß,16a,17-trihydroxy-21-godpregna-i,4~dien-3,2Ö-dion cycl. i6,i7 mit Aceton, wird die Titelverbindung erhalten. 5 .■■■... . : - -According to method A ^ but using 9 ~ fluorine-11ß, 16a, 17-trihydroxy-21-godpregna-1, 4 ~ diene-3,2Ö-dione cycl. i6, i7 with acetone, the title compound is obtained. 5. ■■■ .... : - -
409-825/1 UO409-825 / 1 UO
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US00315701A US3803133A (en) | 1972-12-15 | 1972-12-15 | 21-sulfinyl steroids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2362280A1 true DE2362280A1 (en) | 1974-06-20 |
Family
ID=23225665
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2362280A Ceased DE2362280A1 (en) | 1972-12-15 | 1973-12-14 | 21-SULFINYL STEROIDS OF THE DELTA HOCH 4PREGNAN SERIES, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US3803133A (en) |
| CA (1) | CA1020546A (en) |
| DE (1) | DE2362280A1 (en) |
| FR (1) | FR2210410B1 (en) |
| GB (1) | GB1458517A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4098804A (en) * | 1973-05-30 | 1978-07-04 | Jouveinal S.A. | Esters of 21-thiol prednisone and prednisolone |
| FR2231374B1 (en) * | 1973-05-30 | 1976-10-22 | Jouveinal Sa | |
| US4177268A (en) * | 1973-05-30 | 1979-12-04 | Jouveinal S.A. | Method of alleviating inflammation by administration of dexamethasone derivatives |
| US4221917A (en) * | 1978-03-03 | 1980-09-09 | Phillips Petroleum Company | Production of esters from monoolefins and diolefins |
| FR2442856A1 (en) * | 1978-12-01 | 1980-06-27 | Sipsy | PROCESS FOR THE PREPARATION OF STEROIDS |
| US5420120A (en) * | 1993-12-17 | 1995-05-30 | Alcon Laboratories, Inc. | Anti-inflammatory glucocorticoid compounds for topical ophthalmic use |
-
1972
- 1972-12-15 US US00315701A patent/US3803133A/en not_active Expired - Lifetime
-
1973
- 1973-12-07 CA CA187,699A patent/CA1020546A/en not_active Expired
- 1973-12-11 GB GB5739173A patent/GB1458517A/en not_active Expired
- 1973-12-14 DE DE2362280A patent/DE2362280A1/en not_active Ceased
- 1973-12-17 FR FR7345076A patent/FR2210410B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| US3803133A (en) | 1974-04-09 |
| GB1458517A (en) | 1976-12-15 |
| CA1020546A (en) | 1977-11-08 |
| FR2210410B1 (en) | 1977-01-28 |
| FR2210410A1 (en) | 1974-07-12 |
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