GB1564144A - D-homosteroids - Google Patents
D-homosteroids Download PDFInfo
- Publication number
- GB1564144A GB1564144A GB46765/76A GB4676576A GB1564144A GB 1564144 A GB1564144 A GB 1564144A GB 46765/76 A GB46765/76 A GB 46765/76A GB 4676576 A GB4676576 A GB 4676576A GB 1564144 A GB1564144 A GB 1564144A
- Authority
- GB
- United Kingdom
- Prior art keywords
- group
- 17ass
- hydroxy
- dien
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000000795 D-homosteroids Chemical class 0.000 title claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- -1 tetrahydropyran - 2 - yloxy Chemical group 0.000 claims description 39
- 238000002844 melting Methods 0.000 claims description 34
- 230000008018 melting Effects 0.000 claims description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000004043 oxo group Chemical group O=* 0.000 claims description 18
- 239000002244 precipitate Substances 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 17
- 229910002027 silica gel Inorganic materials 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- HNDHDMOSWUAEAW-UHFFFAOYSA-N (8alpha,9beta,10alpha,13alpha,14beta)-Androsta-4,6-dien-3-one Natural products O=C1CCC2(C)C3CCC(C)(C=CC4)C4C3CCC2=C1 HNDHDMOSWUAEAW-UHFFFAOYSA-N 0.000 claims description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000001704 evaporation Methods 0.000 claims description 7
- 230000008020 evaporation Effects 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229960001124 trientine Drugs 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- HFVMLYAGWXSTQI-QYXZOKGRSA-N 5alpha-androst-16-en-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CC[C@H]21 HFVMLYAGWXSTQI-QYXZOKGRSA-N 0.000 claims description 4
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 4
- 150000002902 organometallic compounds Chemical class 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- NYYWEOCMCXIVQT-OJEXMJBDSA-N (8S,9S,10R,13R,14S)-10,13-dimethyl-4,5,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C[C@@]12C=CC[C@H]1[C@@H]1CCC3CC(C=C[C@]3(C)[C@H]1CC2)=O NYYWEOCMCXIVQT-OJEXMJBDSA-N 0.000 claims description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- GHDIHPNJQVDFBL-UHFFFAOYSA-N methoxycyclohexane Chemical compound COC1CCCCC1 GHDIHPNJQVDFBL-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000002419 homosteroids Chemical class 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000004411 aluminium Substances 0.000 description 6
- 229910052782 aluminium Inorganic materials 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910000091 aluminium hydride Inorganic materials 0.000 description 4
- 150000002081 enamines Chemical class 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 3
- 230000001548 androgenic effect Effects 0.000 description 3
- HNDHDMOSWUAEAW-VMXHOPILSA-N androstadienone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CCC2=C1 HNDHDMOSWUAEAW-VMXHOPILSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- BLXSFCHWMBESKV-UHFFFAOYSA-N 1-iodopentane Chemical compound CCCCCI BLXSFCHWMBESKV-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002084 enol ethers Chemical class 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 229940093476 ethylene glycol Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000000366 juvenile effect Effects 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229940008015 lithium carbonate Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 150000007659 semicarbazones Chemical class 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- FOJWFSASQRGXET-VMXHOPILSA-N (8S,9S,10R,13R,14S)-10,13-dimethyl-2,7,8,9,11,12,14,15-octahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1=CCC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CC=C21 FOJWFSASQRGXET-VMXHOPILSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000186063 Arthrobacter Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-BKFZFHPZSA-N Calcium-45 Chemical compound [45Ca] OYPRJOBELJOOCE-BKFZFHPZSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000186660 Lactobacillus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000193386 Lysinibacillus sphaericus Species 0.000 description 1
- 241000490027 Raukaua simplex Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- LVAMVZXECCXUGI-UHFFFAOYSA-N acetic acid;thallium Chemical compound [Tl].CC(O)=O LVAMVZXECCXUGI-UHFFFAOYSA-N 0.000 description 1
- 101150099544 acyP gene Proteins 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction 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
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007269 dehydrobromination reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 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
- 230000003054 hormonal effect Effects 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CXHHAWACKSPTFF-UHFFFAOYSA-N iodomethylcyclohexane Chemical compound ICC1CCCCC1 CXHHAWACKSPTFF-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- LTRVAZKHJRYLRJ-UHFFFAOYSA-N lithium;butan-1-olate Chemical compound [Li+].CCCC[O-] LTRVAZKHJRYLRJ-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical group [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 1
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960003484 testosterone enanthate Drugs 0.000 description 1
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
(54) NOVEL D-HOMOSTEROIDS
(71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a
Swiss Company of 12X184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
The present invention relates to novel Dhomosteroids. More particularly, the invention is concerned with novel D-homosteroids, a process for the manufacture thereof and pharmaceutical preparations containing same.
The novel D-homosteroids provided by the present invention have the following general formula
wherein the broken lines in the A-ring denote
optional carbon-carbon bonds; R' represents
a hydrogen atom or a methyl group; R3 repre
sents an oxo group or, when the A-ring is
unsaturated, an oxo, (n-H, ss-OH) or ss-O-acyl) group; the 5-hydrogen atom (when
present) has the .arconfiguration; R7 represents
a hydrogen atom or a methyl group; R'7ass represents a hydrogen atom or a C1--Clo alkyl, benzyl, cyclohexyl-methyl, acyl, tetra
hydropyranyl or cycloalkenyl group; and Rl7ad represents a hydrogen atom or a lower
alkyl, ethynyl, vinyl or propadienyl group.
As used in this specification, the term "acyP denotes acyl groups derived from organic acids; for example, from alkanecarb
oxylic acids containing up to 11 carbon atoms
(especially from lower alkanecarboxylic acids
containing up to 7 carbon atoms) such as acetic acid, propionic acid, caproic acid, valeric
acid, oenanthic acid or undecylenic acid; or from oxalic acid, succinic acid or citric acid, or from aromatic carboxylic acids such as benzoic acid, phenylacetic acid or phenoxyacetic acid, or from heterocvclic carboxylic acids such as nicotinic acid, or from cycloaliphatic carboxylic acids such as cyclopentylpropionic acid.
The lower alkyl groups contemplated herein contain up to 7 carbon atoms and can be straight-chain or branched-chain. Examples of such lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl and isomers of the latter. The preferred lower alkyl groups are methyl and ethyl. An alkyl group denoted by can can contain up to 10 carbon atoms. Ex- amples of such alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and decyl.
Cycloalkenyl groups preferably contain from 5 to 8 carbon atoms. Examples of such groups are cyclopent - 1 - enyl cyclohex - 1- enyl.
A preferred group of D - homosteroids of
formula I comprises those in which R1 repre
sents a hydrogen atom, R3 represents an oxo group and the A-ring contains a double-bond.
In addition, those D - homosteroids of formula
I in which Rl7aa represents a hydrogen atom or a methyl or ethyl group and Rl7a: represents a hydrogen atom or a lower alkanoyl group are preferred. Examples of D - homosteroids of formula I are: 17ass - (3 - Cyclopentyl - propionyloxy)
homoandrosta - 4,16 - dien - 3 - one, 17ap - nicotinoyloxy - D - homoandrosta- 4,16 - dien - 3 - one, 17ap - propionyloxy - D - homoandrosta- 1,4,16 - trien - 3 - one, 17alb - hydroxy - 7a - methyl - D - homo- androsta - 1,4,16 - trien - 3 - one, la,7a - dimethyl - 17ap - hydroxy - D - homo
androsta - 4,16 - dien - 3 - one, 17aj3 - hydroxy - 7a - methyl - D - homo
androsta - 4,16 - dien - 3 - one, 17a, - hydroxy - 7a - methyl - D - homo androst - 16 - en - 3 - one, 17ass - hydroxy - 7a - methyl - D - homo - 5a
androsta - 1,16 - dien - 3 - one, 17 - hydroxy - 1 - methyl - D - homo - androsta - 1,16 - dien - 3 - one, 1α,17aα - dimethyl 17aα; - hydroxy
homoandrosta - 4,16 - dien - 3 - one, 317a - dihydroxy - 17aa - methyl
homo - 5a - androsta - 1,16 - diene, 17ap - hydroxy - 17a1z- methyl - D - homo- 5a - androsta - 1,16 - dien - 3 - one, 17ass - hydroxy - la,l7 - dimethyl
homo - - androst - 16 - en - 3 - one, 17ass - hydroxy - 17aα - ethyl - D - homo 5ez - androst - 16 - en - 3 - one, 17aα - ethyl - 17 - hydroxy - - methyl
D - homo - 5α - androst - 16 - en - 3
one, 17ap - hydroxy - la - methyl - D - homo - 5a
androst - 16 - en - 3 - one,
17ass - hydroxy - - 7a,17a - dimethyl
homoandrosta - 4,16 - dien - 3 - one,
17ass - pentyloxy - D - homoandrosta - 4,16 dien - 3 - one, 17ass - n - decyloxy - D - homoandrosta
4,16 - dien - 3 - one, 17ap - benzyloxy - D - homoandrosta - 4,16 dien - 3 - one, 17ass - cyclohexylmethoxy -D - homoandrosta 4,16-dien-3-one,and 17ass - undecanoyloxy - D - homoandrosta- 4,16 - dien - 3 - one.
According to the process provided by the present invention, the D-homosteroids of formula I hereinbefore are manufactured by
(a) oxidising the 3-hydroxy or 3-hydroxy
A5 grouping in a D-homosteroid of the general formula
wherein Rl, R17ass and Rl72 have the significance given earlier and the broken line in the 5,6position denotes an optional carbon-carbon bond, to the 3-keto or 3-keto-#4 grouping, or
(b) reacting a D - homosteroid of the general formula
wherein
R, R3 and the broken lines in the A-ring
have the significance given earlier, with an organometallic compound yielding a Rl7aa group, a 3-keto group being intermediately protected, or
(c) reacting a D - homosteroid of the general formula
wherein Rl, R17aα and R17ass have the significance
given earlier, with a methyl Grignard compound in the presence of copper-I chloride, or
(d) reacting a D - homosteroid of the general formula
wherein Rl'aa and R'7, have the significance given
earlier and the broken line in the 5,6
position denotes an optional carbon
carbon bond, with a methyl Grignard compound in the presence of copper-I chloride and subsequently rearranging a #5 double bond in the reaction product into the 4,5-position by acid treatment, or
(e) acylating the hydroxy group(s) in a
D-homosteroid of formula I in which at least one hydroxy group is present in the 3-position or 17-position, or
(f) subjecting a D-homosteroid of the general formula
wherein
R3 and the broken lines in the A-ring have
the significance given earlier and 2
represents an oxo or (OR17ass, Rl7aa group,
to reduction of the 17a-keto group to the hydr
oxy group (with intermediate protection of a
3-keto group) when Z represents an oxo group,
or to reduction of the 3-keto group and a 17a-keto group which may be present to the
hydroxy group when R3 represents an oxo
group and the A-ring is monounsaturated, or
(g) subjecting a D-homosteroid of formula
I which is saturated or monounsaturated in the
A-ring and in which R3 represents an oxo
group to dehydrogenation in the 1-2-position
and/or 4,5-position, or
(h) converting the 17ap-hydroxy group in a D-homosteroid of formula I in which R7 represents a hydrogen atom and R', R3, R?.
R' a'l and the broken lines in the A-ring have the significance given earlier into a cycloalkenyl, tetrahydropyranyl, C1Cl,, alkyl, benzyl or cyclohexylmethyl ether, or
(i) subjecting a D-homesteroid of formula
I in which Rl7ass represents an acyl, tetrahydropyranyl or cycloalkenyl group and R', R3, R7, Rt7aa and the brokenu lines in the A-ring have the significance given earlier to saponification of a 17ass-acyloxy group and a 3-acyloxy group which may be present or to cleavage of a 17aP-tetrahydropyranyl or cycloalkenyl ether, or
(j) hydrogenating the ethynyl group in a
D-homosteroid of the general formula
wherein R, R3, R?, Rl7ass and the broken lines in
the A-ring have the significance given
earlier,
to the vinyl group.
The oxidation according to process embodiment (a) can be carried out in a manner which is known per se according to the Oppenauer procedure (e.g. using aluminium isopropylate or terLbutylate) or by means of oxidising agents such as chromium trioxide (e.g. Jones' reagent) or according to the Pfitzner-Moffatt procedure using dimethylsulphoxide/dicyclo- hexyicarbodiimide (the initially obtained A5- 3-ketone requiring subsequent isomerisation to the A4-3-ketone) or by means of dimethyl sulphoxide/pyridine/sulphur trioxide.
The reaction of a D-homosteroid of formula
III with an organometallic compound according to process embodiment (b) can also be carried out in a manner which is known per Se. The organometallic compound can be a
Grignard compound (e.g. ethynylmagnesium bromide, methylmagnesium bromide or vinylmagnesium bromide) or an alkali metal organic compound such as sodium potassium or
vinyl lithium. A 3-keto group which is simultaneously present can be intermediately pro
tected, for example as a ketal, enol ether, enamine or semicarbazone.
The 7-methylation of a D-homosteroid of formula IV and the l-methylation of a homosteroid of formula V according to process embodiments (c) and (d) can also be carried out in a manner known per se by reaction with a methyl Grignard compound.
When, in embodiment (d), a lzmethylzs compound is initially obtained, the a5 double bond can be rearranged into the 4,5-position by treatment with ethanolic sulphuric acid whilst warming.
The acylation of a free hydroxy group in the 3-position or 17a/-position in a D-homosteroid of formula I can be carried out by treatment with a reactive acid derivative (e.g.
an acid halide or acid anhydride) in the presence of a base (e.g. pyridine or collidine).
The reduction of a 3-keto or 17a-keto group according to process embodiment (f)
can be carried out in a manner known per se using a complex metal hydride; for example, a di(lower alkoxy)aluminium hydride such as diisobutoxyaluminium hydride, a tri(lower
alkoxy)aluminium such as triisopropoxyalum
inium, lithium aluminium hydride, sodium
aluminium hydride, sodium borohydride, tri
methoxylithium aluminium hydride or tri
butoxylithium aluminium hydride. Suitable
solvents for this reduction are hydrocarbons
(e.g. cyclohexane, benzene or toluene) or ethers
(e.g. diethyl ether or tetrahydrofuran). Where
a 17a-keto group is to be reduced alone in
the presence of a 3-keto group, the 3-keto
group is intermediately protected. A 3-keto
group can be protected in the presence of a
4,5-double bond in the form of an enamine
or enol ether.A non-conjugated 3-keto group
can be protected as a metal. The introduction
and splitting off of these protecting groups
can be carried out according to known pro
cedures.
A 1,2-dehydrogenation according to process
embodiment (g) can be carried out in a manner
known per se using a dehydrogenating agent
such as selenium dioxide, 2,3-dichloro-5,6-di
cyanobenzoquinone, thallium triacetate or lead
tetraacetate. The 1,2-dehydrogenation can also
be carried out microbiologically; for example,
using Schizo-itycetes, in particular those of the
genus Arthrobacter (e.g. R. Simplex ATCC -6946), Bacillus (e.g. B. Ientus ATCC 13805
and B. sphaericus ATCC 7055), Pseudomonar (e.g. P. aeruginosa IFO 3505), Flavobacterium
(e.g. flavenscens IFO 3058), Lactobacillus (e.g.
L. Brevis IFO 3345) and Nocarbia (e.g. N.
opaca ATCC 4276).
Double bonds can be simultaneously in the 1,2^ and 4,5-positions by bromination to give
a 2,4 - dibromo - 3 - ketone and dehydro
bromination of the latter using lithium carbon
ate and lithium bromide in dimethylform
amide. A 4,5-double bond can also be intro
duced by brominating a 3-ketosteroid, which
is saturated in the A-ring, in glacial acetic
acid to give a 2la;4-dibromo derivative, reduc
ing said derivative with chromium-II chloride
to give a 4tbromo compound and then de
hydrobrominating said 4a-bromo compound,
via the semicarbazone, by treatment with
succinic acid to give a A4-3-ketone.
The etherification of a 17aljt-hydroxy group
according to process embodiment (h) can be
carried out, for example, by treatment with dihvdropyran in order to manufacture a tetrahydropyranyl ether or by treatment with a cycloalkanone ketal in the presence of a catalytic amount of acid (e.g. p-toluene-sulphonic acid) in order to maufacture a cYcloallrenvl ether. For the manufacture of a 17aRCt--Co alkyl, benzyl or cyclo-hexylmethyl ether, it is expedient to intermediately protect a 3-keto group. The protection of a 3-keto group is preferably accomplished by ketalisation (e.g.
with ethyleneglvcol in the presence of a catalytic amount of acid such as p-toluene-sulphonic acid). The etherification of the 17ass- hydroxy group can be carried out by conversion into an alkali metal salt e.g. the sodium salt) with a strong base (e.g. sodium hydride) followed by reaction with a C1-C10 alkyl, benzvl or cyclohexylmethyl halide such as pentyl iodide, benzyl chloride or cyclohexylmethyl iodide in a solvent such as dimethylsulphoxide or benzene.
The saponification of 17ald-acyloxy and 3acyloxy groups or the cleavage of 17ass-ether groups according to process embodiment (i) can be carried out in a manner known per se.
Acyloxy groups can be saponified, for example, with aqueous-alcoholic bases such as aqueousmethanolic potassium carbonate and ether groups can be cleaved by means of aqueousalcoholic mineral acids or organic acids such as oxalic acid or p-toluenesulphonic acid.
The hydrogenation of the ethynyl group according to process embodiment (j) can be carried out in the presence of a noble-metal catalyst such as palladium/calcium carbonate and, conveniently, a deactivator such as pyridine.
The starting materials used in the foregoing process, insofar as they are not known
or insofar as their preparation is not described hereinafter, can be prepared in analogy to known methods or methods described in the
Examples hereinafter.
The D-homosteroids of formula I possess hormonal activity. D-Homosteroids of formula
I in which Rl-aa represents a hydrogen atom
or a lower alkyl group possess, in particular,
androgenic/anabolic activity. D-Homosteroids
of formula I in which RlXat represents an
ethynyl, vinyl or propadienyl group possess,
in particular, gestation-inhibiting and ovula
tion-inhibiting activity.
For example, 17ass - hydroxy - D - homo
androsta - 4,16 - dien - 3 - one shows, on sub
cutaneous administration to juvenile male rats,
an androgenic activity which is comparable with the action of testosterone at one third of
the dosage. The androgenic activity was deter
mined on the basis of the growth of the pros
tate gland and the seminal vesicle. 17afi- Phenylacetoxy- and 1 74/3-phenoxyacetoxy-D- homoadrosta - 4,16 - dien - 3 - one showed
on subcutaneous administration to juvenile
male rats, an extended period of activity com
pared with testosterone enanthate.
The D-homosteroids of formula I can be
used as medicaments; for example in the
form of pharmaceutical preparations which contain them in association with a compatible
pharmaceutical carrier material. This carrier
material can be an organic or inorganic inert
carrier material which is suitable for enteral, percutaneous or parenteral administration such
as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and petroleum jelly. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions).If necessary, the pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatives, stabilisers, wetting agents or emulsifiers, salts for modifying the osmotic pressure or buffers.
They may also contain other therapeutically valuable substances.
The following Examples illustrate the process provided by the present invention; Example 1 relates to an intermediate compound.
Example 1
50.0 g of 3ss - hydroxy - D - homoandrosta5,16 - dien - 17a - one were dissolved in 1000 ml of cyclohexanone and 3000 ml of toluene.
400 ml of solvent were evaporated off from this solution and the solution was cooled to 80"C and treated with 60.0 g of aluminium tert.butylate. Whilst stirring and flushing with argon, the mixture was heated to reflux for 2.5 hours under a water separator. For the working-up, the solution was concentrated in vacuo to about 200 ml, poured on to an icecold mixture of 1500 ml of water and 50 ml of concentrated Taydrochloric acid and extracted with methylene chloride. The organic extract was washed with water, dried over sodium sulphate, evaporated in vacuo and finally dried at 50"C under a high vacuum.
The residue was then recrystallised from acetone/hexane. There were obtained 40.7 g of pure D - homoandrosta - 4,16 - diene3,17a - dione of melting point 1930-1940C; UV: E,,,=21500; lrr]D2j"C=+60" = +60 (c=0.1 in dioxan).
The starting material was prepared as follows:
18.1 g of 3p - acetoxy - D - homoandrost5 - en - 17a - one were dissolved in 800 ml of methanol under argon at 45 C. 23.5 g of copper-II bromide were added to this solution and the mixture was heated under reflux for 18 hours. The mixture was cooled to 35"C and filtered and the residue was then rinsed thoroughly with chloroform. The combined filtrates were poured on to 1.3 litres of water containing 100 g of sodium chloride and 500 g of ice. The mixture was extracted three times with chloroform. The organic phases were washed with sodium chloride solution, dried over magnesium sulphate and evaporated in vacuo.There were obtained 19.8 g of almost pure 17e: - bromo 3p - hydroxy - D - homo- androst - 5 - en - 17a - one, which was used directly in the next step.
35.1 g of calcium carbonate were suspended in 290 g of dimethylacetamide. Whilst flushing with argon, 40 ml of dimethylacetamide were distilled off and then 18.7 g of 17a - bromo - 3j3 - hydroxy - D - homo- androst - 5 - en - 17a - one were added over a period of 20 minutes. The mixture obtained was then boiled under reflux for 30 minutes.
The solution was cooled to 60 C and the precipitate filtered off. The filtrate was poured on to a mixture of 1.25 litres of water, 450 g of ice and 170 g of sodium chloride. The mixture was extracted three times with methylene chloride. The extracts were washed with 1-N hydrochloric acid and water, dried over magnesium sulphate and evaporated in vacuo.
There were obtained 14.7 g of crude product which was dissolved in 170 ml of ethyl acetate and treated with a small amount of active charcoal. After filtering the solution over
Speedex Dicalite, the filtrate was concentrated to 50 ml and left to crystallise. (The words "Speedex" and "Dicalite" are registered
Trade Marks.) There were thus obtained 11.7 g of pure 3/ - hydroxy - D - homoandrosta5,16 - dien - 17a - one of melting point 190 193 C; U.V. #227=13000; [aJD25c=1770 (c=0.1 in dioxan).
Example 2
15.0 g of D - homoandrosta - 4,16 - diene
3,17a - dione were dissolved in 150 ml of methanol and boiled under reflux for 10 minutes with 8.1 ml of pyrrolidine with the exclusion of air. The solution was cooled to - 100C. The enamine which had crystallised
out was filtered off and dried at 20 C under a high vacuum. There were obtained 16.1 g of pure 3 - (1 - pyrrolidinyl) - D - homo
androsta - 3,5,16 - trien - 17a - one of melting point 207 -210 C; W; e2,9=19500; e22T= 13000; [α]D25 C=-295 .
16.1 g of the foregoing enamine were dissolved in 750 ml of absolute tetrahydrofuran
and added dropwise over a period of 15 minutes to a well-stirred solution of 8.0 g of lithium aluminium hydride in 750 ml of
absolute ether at 0 0C. The mixture was then
stirred for a further 1 hour at 0 0C. For the
working-up, the solution was initially
cautiously treated with 300 ml of moist ether.
40 ml of saturated sodium sulphate solution
were then added, the mixture was stirred for a further 10 minutes and the precipitate was filtered off. The filtrate was evaporated in vacuo. There were obtained 15.8 g of sub
stance which was warmed to 50 C with a
mixture of 1000 ml of methanol and 200 ml
of 2-N sodium hydroxide solution for 45
minutes whilst stirring and flushing with argon.
The solution was then poured on to 6 litres of ice-water and 200 ml of acetic acid and extracted three times with methylene chloride.
The organic extract was washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on 650 g of silica gel. Elution with acetone/ hexane (1:1) yielded 13.0 g of pure 17ass- hydroxy - D - homoandrosta - 4,16 - dien - 3one of melting point 183C185 C; UV; #241=16200; [a] D2 C = + 76 Example 3
A solution of 6.3 g of 17ap - hydroxy homoandrosta - 4,16 - dien - 3 - one in 60 ml of pyridine and 60 ml of acetic anhydride was maintained at room temperature overnight.
The solvent was then removed in vacuo and the residue was recrystallised from acetone/ hexane. There were obtained 6.0 g of pure 17ap - acetoxy - D - homoandrosta - 4,16- dien - 3 -one of melting point 1650-1670C; UV: 2w,=17000; [iD2C= +91 (c=0.1 in
dioxan).
The following D - homosteroids were prepared in an analogous manner using the corres
ponding acid anhydride: 17a/ - Propionyloxy - D - homoandrosta4,16 - dien - 3 - one of melting point 139 -
140 C and 17a/ - butyryloxy - D - homoandrosta- 4,16 - dien - 3 - one of melting point 117 -
118 C.
Example 4
2.0 ml of phenylacetyl chloride were added dropwise to a solution of 2.0 g of 17a/- hydroxy - D - homoandrosta - 4,16 - dien - 3one in 20 ml of pyridine over a period of 15 minutes and the mixture was warmed to 60 C for 5 hours. For the working-up, the mixture was poured on to water and extracted with methylene chloride. The organic extract was washed neutral with dilute hydrochloric acid, sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on silica gel.Elution with hexane/acetone (9:1) yielded 1.7 g of pure 17a/ - phenyl
acetoxy - D - homoandrosta - 4,16 - dien - 3one of melting point 1350-1360C (from acetone/hexane); UV: #240=17200; [α]D25 C=108 zc=0.1 in dioxan).
The following D - homosteroids were prepared in an analogous manner using the corresponding chloride: 17a/ - Undecanoyloxy - D - homoandrosta4,16 - dien - 3 - one; amorphous; [α]D25 C= +80 (c=0.1 in dioxan); e- lu=17100, 17ass - heptanoyloxy - D - homoandrosta- 4.16 - dien - 3 - one; oily; [:r]D25 C=+88 (c=0.1 in dioxan) and
17aB - phenoxyacetoxy - D - homoandrosta4,16 - dien - 3 - one of melting point 174 - 176 C.
Example 5
1.0 g of 17a/ - hydroxy - D - homoandrosta4,16 - dien - 3 - one was dissolved in 40 ml of absolute benzene and then 10 ml of benzene were distilled off. A solution of 5 mg of ptoluene - sulphuric acid in 10 ml of benzene and 0.6 ml of dihydropyran was added to the remaining solution and the mixture was held for 30 minutes at room temperature. For the working- up, the solution was washed neutral, in sequence, with sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated in vacuo.The residue was re crvstallised from ether/hexane and gave pure 17ass - (tetrahydropyran - 2 - yloxy) - Dhomo - androsta - 4,16 - dien - 3 - one of melting point 1370-1380C; UV: E24o=16650; [ < r]D25 C=+64 (c=0.1 in dioxan).
Example 6
A solution of 2.0 g of 17ass - hydroxy homoandrosta - 4,16 - dien - 3 - one in 40 ml of cyclopentanone diethyl ketal was warmed to 1200C for 6 hours. The solution was evaporated to drvness in vacuo and the residue was chromatographed on 40 g of aluminium oxide (activity grade II). By elution with benzene there were obtained 1.2 g of pure 17ass- (cyclopent - 1 - enyloxy) - D - homoandrosta4,16 - dien - 3 - one of melting point 135 137 C (from methanol); [a]D25 = + 100 (c=0.1 in dioxan); UV: #240=17200.
Example 7
A solution of 342 mg of 17ass- acetoxy
D - homoandrosta - 4,16 - dien - 3 - one and 328 mg of 2,3 - dichloro - 5,6 - dicyanobenzoquinone (DDQ) in 30 ml of benzene was heated under reflux for 24 hours. The solution was cooled and filtered over a column of 10 g of aluminium oxide (activity grade II). The column was then completely eluted with 200 ml of ethyl acetate. The combined eluates yielded 270 mg of crystalline material which, upon recrystallisation from acetone/hexane, yielded pure 17a/ - acetoxy - D - homoandrosta - 1,4,16 - trien - 3 - one of melting point 222 -224 C; UV: E244=14800; [α]D25 C=+53 .
17aB - Hydroxy - 17aa - methyl - D - homo- androsta - 1,4,16 - trien - 3 - one was prepared in an analogous manner from 17a/- hydroxy - 17a - methyl - D - homoandrosta4,16 - dien - 3 - one. Melting point 148 150 C; W: 245=15500i [St]D = 34 - Example 8
1.95 g of a 50% dispersion of sodium hydride in oil were dissolved in 45 ml of tetrahydrofuran and 10 ml of dimethyl sulphoxide. The solution was stirred at room temperature for 30 minutes and then 1.3 g of 3,3 - ethylenedioxy - 17a/ - hydroxy homoandrosta - 4,16 - diene were added. The mixture was stirred for a further 30 minutes and then 3.9 ml of 1 - iodo - pentane were added.Subsequently, the mixture was stirred at room temperature for 20 hours. For the working-up, the mixture was treated cautiously with water and extracted with methylene chloride. The organic extracts were washed with water, dried over sodium sulphate and evaporated in a vacuum. The residue was dissolved in 65 ml of acetone, treated with 6.5 ml of water and 1.3 g of p - toluenesulphonic acid and stirred at room temperature for 2.5 hours. The mixture was poured on to water, extracted with methylene chloride, dried over sodium sulphate and evaporated. The residue was chromatographed on 110 g of silica gel.
Elution with hexane/acetone (8:1) yielded 0.3 g of pure 17ass - pentyloxy - D - homoandrosta - 4,16 - dien - 3 - one of melting point 580-590C (from methanol/water); [α]D25 C=+112 (c=0.1 in dioxan); e240= 16700.
The starting material was prepared as follows:
3.4 g of 17ap - acetoxy - D - homoandrosta4,16 - dien - 3 - one, 100 ml of ethylene glycol, 100 ml of methylene chloride, 15 ml of triethyl orthoformate and 150 mg of p-toluenesulphonic acid were warmed to 40 C for 75 minutes. Usual working-up yielded 5.2 g of 3,3 - ethylenedioxy - 17a/ - acetoxy homoandrosta - 4,16 - diene which was saponified with 300 ml of 5% methanolic potassium hydroxide in 100 ml of methylene chloride at room temperature to give 3,3 - ethylenedioxy17ass - hydroxy - D - homoandrosta - 4,16diene of melting point 168 173 C.
The following D - homosteroids were pre
pared in a manner analogous to that described in the first paragraph of this Example: 17a/ - n - Decyloxy - D - homoandrosta4,16 - dien - 3 - one; oily; [α]D25 C=+94 (c=0.1 in dioxan); #210=16650, 17ass - benzyloxy - D - homoandrosta- 4,16 - dien - 3 - one of melting point 139 - 1410 C (from acetone/hexane); [α]D25 C= +130 ; eo40=16600, and 17a,ss - cyclohexylmethoxy - D - homoandrosta - 4,16 - dien - 3 - one of melting point 98 -99 C; [α]n25 C=+112 ; = + 112 16700.
Example 9
A solution of 6.0 g of D - homoandrosta4,16 - dien - 3,17a - dione in 100 ml of tetrahydrofuran and 100 ml of ether was added dropwise to a solution of 3.0 g of lithium aluminium hydride in 400 ml of absolute ether while stirring and cooling to 0 C and the mixture was then stirred for a further 1 hour at 0 5 C. For the working-up, the mixture was cautiously treated with 300 ml of moist ether and then with 10 ml of saturated sodium sulphate solution. The mixture was stirred for a further 15 minutes and then the precipitate was filtered off and rinsed thoroughly with methylene chloride. The combined filtrates were evaporated in vacuo.The residue was chromatographed on 330 g of silica gel and yielded 4.1 g of pure 3ss,17alss - dihydroxy
D - homoandrosta - 4,16 - diene of melting point 158 -162 C (from acetone/hexane); [α]D25 C=+23 (c=0.1 in dioxan).
A solution of 3.0 g of 3ss,17a - dihydroxy
D - homoandrosta - 4,16 - diene in 50 ml of pyridine and 50 ml of acetic anhydride was maintained at room temperature for 18 hours.
The solution was then evaporated in vacuo and the residue was recrystallised from methanol. There was obtained pure 3ss,17aj- diacetoxy - D - homoandrosta - 4,16 - diene of melting point 1150-1160C; [lru]D25"C= +12.
Example 10
A solution of 7.0 g of 3,3 - dimethoxy D - homo - Sa - androst - 16 - en - 17a - one in 280 ml of ether was added dropwise to a stirred solution, cooled to 0 C, of 3.5 g of lithium aluminium hydride in 420 ml of ether.
The mixture was stirred for 1 hour at 0- 5 C and then cautiously treated with 250 ml of water-saturated ether. The mixture was stirred for a further 15 minutes at room temperature and the pure precipitate was then filtered off. This precipitate was thoroughly extracted with methylene chloride. The filtrate was evaporated in vacuo. There were obtained 7.0 g of crude product which was dissolved in 140 ml of acetone and treated with a solution of 2.1 g of p-toluenesulphonic acid in 14 ml of water. The solution was maintained at room temperature for 2 hours and then treated with 500 ml of water. The precipitate which separated out was filtered off. For purification, this precipitate was chromatographed on a 50-fold amount of silica gel.Following eluation with methylene chloride/acetone (95 :5) there were obtained 5.0 g of pure 17a/ - hydroxy - Dhomo - 5n - androst - 16 - en - 3 - one of melting point 203 -205 C (from acetone/ hexane); [α]D25 C=+1 (c=0.1 in dioxan).
The starting material was prepared as
follows: 3/ - Acetoxy - D - homoandrost - 5 - en
17a - one was reduced in ethanol using palladium/carbon as the catalyst to give 3ss- acetoxy - D - homo - 5x - androstan - 17aone of melting point 1130-1150C. This was brominated with copper bromide in methanol and converted into 3ss - hydroxy - D - homo - - androst - 16 - en 17a - one of melting point 1770-1790C by treatment with calcium carbonate in dimethylacetamide. Oxidation of the latter compound with Jones' reagent gave D - homo - - androst - 16 - ene - 3,17adione of melting point 2000-2020C (e223= 8700).Reaction of this latter compound with methanol and catalytic amounts of p-toluenesulphonic acid at the reflux temperature finally gave 3,3 - dimethoxy - D - homo - 5 - androst - 16 - en - 17a - one of melting point 125 -127 C (from ether/hexane); [a]D25 C= 330; 822,=8650.
Example 11
A solution of 3.0 g of 3,3 - dimethoxy homo - Sr - androst - 16 - en - 17a - one in 20 ml of tetrahydrofuran and 20 ml of ether was added to 70 ml of a 2-M solution of methyl lithium in ether over a period of 30 minutes while stirring. The solution was stirred overnight at room temperature and then worked-up in the customary manner. There were obtained 3.2 g of crude product which was dissolved in 50 ml of acetone and treated with a solution of 1.0 g of p-toluenesulphonic acid in 5 ml of water. The mixture was maintained at room temperature for 2 hours, treated with water and extracted with methylene chloride.After chromatography on silica gel, the residue gave pure 17aS - hydroxy 17aa - methyl - D homo - Sla - androst - en - 3 - one of molting point 2110-2140C; [a]D25 a=52 (c=0.1 in dioxan).
Example 12
2.0 g of 17a/ - hydroxy - D - homo androst - 16 - en - 3 - one were acetylated at room temperature with 50 ml of pyridine and 50 ml of acetic anhydride. The 17a - acetate obtained by customary working-up was dissolved in 20 ml of dioxan and, after the addition of 3 drops of 40% hydrogen bromide/ glacial acetic acid solution over a period of 30 minutes, treated with a solution of 0.36 ml of bromine and 570 mg of sodium acetate in 37 ml of glacial acetic acid. The mixture was then poured on to ice-water. The crystals which precipitated out were filtered off under suction, washed with water and dried over potassium hydroxide in vacuo. There were obtained 3.1 g of product which was dissolved in 20 ml of dimethylacetamide and added over a period of 20 minutes to a boiling mixture of 5.1 g of calcium carbonate and 45 ml of dimethylacetamide.The mixture was subsequently boiled under reflux for a further 30 minutes, then cooled to 60 C and the calcium salts were filtered off. The filtrate was diluted with water and extracted with methylene chloride. The organic extracts were washed with water, dried over sodium sulphate and evaporated in vacuo. There were obtained 2.2 g of crude product which was chromatographed on a 50-fold amount of silica gel. Elution with methylene chloride yielded 1.2 g of pure 173/ - acetoxy - D - homo - 5a - androsta- 1,16 - dien - 3 - one of melting point 133 - 135 C; [a]D2 = + 55 UV: 229=11100.
Example 13
A solution of 2.5 g of 3p - acetoxy homoandrosta - 5,16 - dien - 17a - one in 15 ml of tetrahydrofuran and 15 ml of ether was added dropwise to 60 ml of a 1 .2-M solution of lithium methyl in ether whilst stirring and flushing with argon over a period of 30 minutes. The mixture was stirred overnight at room temperature, then poured on to icewater and extracted with ether. The ether extracts were washed with water, dried over sodium sulphate and evaporated in vacuo.
After a two-fold recrystallisation from acetone, there was obtained pure 3ss,17ass - dihydroxy17ass - methyl - D - homoandrosta - 5,16diene of melting point 220 -223 C; [α]D25 C=169 'c=0.1 in dioxan).
10 ml of toluene were distilled off from a solution of 1.5 g of 3ss,17ass - dihydroxy - 17amethyl D - homoandrosta - 5,16 - diene in 20 ml of cyclohexanone and 55 ml of toluene.
The mixture was then cooled to 100 C and
1.73 g of aluminium tert.butylate were added.
The mixture was then boiled under reflux for 2 hours under a water separator. Customary working-up (see Example 1 yielded 2.7 g of crude product which was chromatographed on silica gel. There were obtained 1.2 g of pure 17ass - hydroxy - 17arg - methyl - D - homo- androsta - 4,16 - dien - 3 - one of melting point 152 -154 C (from acetone/hexane);
UV: #241=16700; [α]D25 C=+18 (c=0.1 in dioxan).
Example 14
A solution of 2.0 g of 17ass - hydroxy 17 & - methyl - D - homo - androsta - 4,16
dien - 3 - one in 100 ml of absolute tetrahydrofuran and 100 ml of absolute ether was added dropwise to a solution, cooled to 0 C, of 1.0 g of lithium aluminium hydride in 200 ml of ether. After completion of the addition,
the mixture was stirred for a further 1 hour
at 0 C and then worked-up in the customary manner (see Example 2). By recrystallisation
of the crude product from acetone/hexane there was obtained pure 3Q1S, 17ass - dihydroxy 17ae - methyl - D - homoandrosta - 4,16diene of melting point 1370-1410C; [ < r]D25 e=28 (c=0.1 in dioxan).
Example 15
Acetylene was passed into a solution of 2.0 g of potassium in 100 ml of liquid ammonia until the solution became decolorised. A solution of 3.4 g of 3ss - acetoxy - D - homoandrosta - 5,16 - dien - 17a - one in 70 ml of tetrahydrofuran was then added dropwise over a period of 1 hour, a weak stream of acetylene still being passed through the solution. For the working-up, 30 ml of ammonium chloride solution were slowly added dropwise and the ammonia was allowed to evaporate overnight. The mixture was treated with water and extracted with ether/methylene chloride.
The organic extracts were washed with water, dried over sodium sulphate and evaporated in vacuo. The residue was chromatographed on silica gel. Elution with hexane/acetone (5: 1' yielded pure 17a(u - ethynyl - 3P,l7aP - dihydroxy - D - homoandrosta 5,16 - diene of melting point 227 -229 C (from acetone/ isopropyl ether); [α]D25 C=-307 (c=0.1 in dioxan).
1.1 g of 17aa - ethynyl - 3P,17a? - dihydroxy - D - homoandrosta - 5,16 - diene were dissolved in 15 ml of cyclohexanone and 40 ml of toluene. After the distillation ot 8 ml of solvent, 1.27 g of aluminium tert.butylate were added and the mixture was heated at reflux for 2 hours under a water separator.
The mixture was worked-up in the customary manner and gave 1.5 g of crude product which, after chromatography on silica gel, yielded pure 17a2 - ethynyl - 17ap - hydroxy
D - homoandrosta - 4,16 - dien - 3 - one of melting point 2470-2500C; W: S2,,= 16800; [α]D25 C=-138 (c=0.1 in dioxan).
Example 16
649 mg of 17aα - ethynyl - 17aR - hydroxy
D - homoandrosta - 4,16 - dien - 3 - one were dissolved in 40 ml of ethyl acetate and 5 ml of pyridine and, after the addition of 300 mg of palladium/calcium carbonate, the mixture was hydrogenated under normal pressure until 1.1 equivalents of hydrogen had been absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallised from acetone/ hexane. There was thus obtained pure 17a/l- hydroxy - 17a - vinyl - D - homoandrosta4,16 - dien - 3 - one of melting point 120 - 122 C; W: E240=16500; [;a]D2 G=69 (c=0.1 in dioxan).
Example 17
A solution of 16 g of pyridine/sulphur trioxide complex in 64 ml of dimethyl sulphoxide was added dropwise to 8 g of 3# - hydroxy 1 - methyl - 17afi - (tetrahydropyran - 2- yloxy) - D - homo - 51r- androst - 16 - ene in 230 ml of dimethyl sulphoxide and 21.2 ml of triethylamine at 15 C over a period of 45 minutes and the mixture was subsequently stirred for 1 hour at room temperature. The mixture was poured on to ice-water and the precipitate filtered eff, washed and taken up in ether. After drying and evaporation, 7.5 g of ltr - methyl - 17ass - (tetrahydropyranyl - 2- oxy) - D - homo - - androst - 16 - en - 3one were obtained.
The starting material was prepared as follows:
50 g of 17ss - hydroxy - la - methyl androstan - 3 - one were heated at reflux in 1000 ml of absolute benzene, 125 ml of ethyleneglycol and 1.25 g of p - toluenesulphonic acid for 7 hours while stirring under a water separator. The solution was then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated to dryness. 55 g of 3,3 - ethylenedioxy 17ss - hydroxy - lfr - methyl - 5(i' - androstane were obtained.
55 g of 3,3 - ethylenedioxy - 17fi - hydroxy 1α - methyl - 52 - androstane in 550 ml of toluene and 110 ml of cyclohexanone were treated at boiling with a solution of 5.5 g of aluminium isopropylate in 55 ml of toluene and the mixture was heated for 3 hours with slow distillation. The mixture was then treated with ether, washed with ice-cold dilute sulphuric acid and water, evaporated and the residue steam-distilled. After extraction with methylene chloride, the resulting product was recrystallised from diisopropyl ether to give 51 g of 3,3 - ethylenedioxy - la - methyl androstan - 17 - one of melting point 155.5 - 156.6 C.
51 g of 3,3 - ethylenedioxy - la - methyl5a - androstan - 17 - one in 1000 ml of dimethylformamide were treated with 51 g of trimethylsulphonium iodide and 27.2 g of potassium tert.butylate were introduced portionwise over a period of 30 minutes while stirring. After a further 60 minutes, the mixture was stirred into ice-water and the precipitate which had separated out was filtered off, washed thoroughly with water and taken up in methylene chloride. After evaporation, the residue was chromatographed on silica gel.
36.6 g of 3,3 - ethylenedioxy - la - methyl 5a - androstan [17 - 1') - spiro - 3']oxirane were thus obtained. A sample recrystallised from diisopropyl ether melted at 165.5 - 166.5"C.
36.6 g of 3,3 - ethylenedioxy - la - methyl 5a - androstan [17(ss - 1') - spiro - 3']oxirane in 366 ml of dimethylformamide and 145 ml of water were treated with 41.3 g of sodium azide and the mixture was stirred for 3 hours at llO"C. The mixture was then stirred into ice-water and the precipitate which had separated out was filtered off, washed with water and taken up in methylene chloride. After evaporation, 38 g of 3,3 - ethylenedioxy - 17a- azidomethyl - 17,B - hydroxy - Ia - methyl- Sa - androstane were obtained.
38 g of 3,3 - ethylenedioxy - 17α - azidomethyl - 17 - hydroxy - Ia - methyl androstane in 380 ml of methanol and 38 ml of water were treated with 19 g of oxalic acid and the mixture was heated at reflux for 30 minutes. The solution was treated with water and extracted with ether. The ether phase was washed with water, dried and evaporated.
29.5 g of 17α - azidomethyl - 17ss - hydroxy la - methyl - 5'a - androstan - 3 - one were obtained as the residue.
29 g of lithium alanate were suspended in 350 ml of absolute tetrahydrofuran and a solution of 29 g of 17a - azidomethyl - 17,,B- hydroxy - lee - methyl - 5ia - androstan - 3one in 350 ml of absolute tetrahydrofuran was added dropwise while cooling with ice and stirring. The mixture was subsequently stirred for 1 hour at room temperature. The suspension was then cooled again in an ice-bath and cautiously treated, in sequence, with 31.7 ml of water, 31.7 ml of 15% sodium hydroxide solution and 94 ml of water. The precipitate was filtered off, rinsed with ether and exhaustively extracted with ether in a Soxhlet apparatus.The suction - filtered filtrate was then combined with the extraction solution and evaporated to give 27.5 g of 17a - aminomethyl - 317/ - dihydroxy la - methyl- - androstane.
27 g of 17a - aminomethyl - 3t,17i,8 - dihydroxy - la - methyl - Sa - androstane were dissolved in 558 ml of acetic acid and 558 ml of water were treated slowly, while cooling with ice, with 48.5 g of sodium nitrite dissolved in 381 ml of water. The mixture was subsequently stirred for 1 hour at room temperature, diluted with water and the precipitate which had separated out was filtered off. After dissolving the product in methylene chloride, the solution was washed with sodium hydrogen carbonate solution and water, dried and evaporated. The residue was chromatographed on silica gel. 17.5 g of 3# - hydroxy 1, - methyl - D - homo - 5e - androstan- 17a - one were thus obtained.
16 g of 3# - hydroxy - la - methyl homo 5a - androstan - 17a - one were heated at reflux in 320 ml of absolute tetrahydrofuran with 22.5 g of copper-II bromide for 90 minutes while stirring. The copper-I bromide which had separated out was filtered off, the filtrate diluted with ether, washed with ammonium chloride solution and water, dried and evaporated. 19.5 g of 174 - bromo - 3#- hydroxy - 1e - methyl - D - homo - 5,a - androstan - 17a one were obtained.
19.5 g of crude 178- bromo - 30- hydroxy la - methyl - D - homo - 5;x - androstan - 17aone were stirred for 18 hours at 90 C in 195 ml of dimethylformamide with 11.1 g of lithium carbonate and 13 g of lithium bromide.
The mixture was then precipitated in icewater and the precipitate was filtered off, washed with water, taken up in methylene chloride, dried and evaporated. The residue was chromatographed on silica gel and there were obtained 11.5 g of 34 - hydroxy methyl - D - homo - 51a - androst - 16 - enene - 17e - one; UV: e22,=7600.
11 g of 34 - hydroxy - la - methyl - D homo - 51z - androst - 16 - en - 17a - one in 44 ml of pyridine were left to stand for 18 hours at room temperature with 22 ml of acetic anhydride. After precipitation in icewater, the precipitate was filtered off, thoroughly washed out and dried. There were obtained 11.2 g of 35 - acetoxy - la - methyl D - homo - Sa - androst - 16 - en - 17a - one;
UV: e223=7200.
11 g of 35 - acetoxy - la - methyl homo - 5a - androst - 16 - en - 17a - one in 110 ml of absolute tetrahydrofuran were treated with 22 g of lithium tri-tert.butoxyalanate while cooling with ice and the mixture was subsequently stirred for 4 hours while cooling with ice. The solution was diluted with ether, washed with dilute sulphuric acid and water, dried and evaporated. The residue was chromatographed on silica gel and 8.5 g of 3# - acetoxy - 17ass - hydroxy - 1α - methyl
D - homo - 5fF - androst - 16 - ene were obtained.
8.5 g of 3 - acetoxy - 17ass - hydroxy methyl - D - homo - 5α - androst - 16 - ene in 85 ml of absolute tetrahydrofuran were stirred for 1 hour at room temperature with 8.5 ml of 2,3 - dihydro - 4H - pyran and 1 drop of phosphorus oxychloride. The mixture was then diluted with ether, washed with saturated sodium hydrogen carbonate solution and water, dried and evaporated. 9.7 g of 3t- acetoxy - la - methyl - 17afl - (tetrahydropyran - 2 - yloxy) - D - homo - - androst16 - ene were obtained.
9.5 g of 3# - acetoxy - Ia - methyl - 17ass- (tetrahydropyran - 2 - yloxy) - D - homo- 5α - androst - 16 - ene in 95 ml of methanol and 9.5 ml of water were heated at reflux for 1 hour with 4.75 g of potassium carbonate.
The mixture was precipitated in ice-water and the precipitate was filtered off, washed and taken up in methylene chloride. After drying and evaporation, 8.1 g of 35 - hydroxy methyl - 17ass - (tetrahydropyran - 2 - yloxy) D - homo - 5e - androst - 16 - ene were obtained.
Example 18
7 g of la - methyl - 17ass - (tetrahydro- pyran - 2 - yloxy) - D - homo - 5 - androst16 - en - 3 - one in 70 ml of methanol and 7 ml of water were heated at reflux for 30 minutes with 3.5 g of oxalic acid. After precipitation with ice-water, the precipitate was filtered off, washed and taken up in methylene chloride. After drying and evaporation, the residue was chromatographed on silica gel.
Upon recrystallisation from diisopropyl ether, 3.2 g of 17ass - hydroxy - - methyl homo - 5α - androst - 16 - en - 3 - one of melting point 1890-1910C were obtained.
WHAT WE CLAIM IS:
1. D - Homosteroids of the general formula
wherein
The broken lines in the A-ring denote
optional carbon-carbon bonds;
R' represents a hydrogen atom or a methyl
group;
R3 represents an oxo group or, when the
A-ring is unsaturated, an oxo, (a-H, ss-OH) or (H, ss-O-acyl) group;
the 5-hydrogen atom (when present)
has the α-configuration; R' represents a hydrogen atom or a methyl
group; RiTaP represents a hydrogen atom or a
C1-10 alkyl, benzyl, cyclohexylmethyl,
acyl, tetrahydropyranyl or cycloalkenyl
group; and R17a@ represents a hydrogen
atom or a lower alkyl, ethynyl, vinyl or
propadienyl group.
2. D - Homosteroids of formula I given in claim 1, wherein g17ass represents a hydrogen atom or an acyl, tetrahydropyranyl or cycloalkenyl group.
3. D - Homosteroids as set forth in claim 1 or claim 2, wherein R' represents a hydrogen atom, R3 represents an oxo group and the
A-ring contains a double-bond.
4. D - Homosteroids as set forth in claim 1, claim 2 or claim 3, wherein Rl?aa represents a hydrogen atom or a methyl or ethyl group and R17ass represents a hydrogen atom or a lower alkanoyl group.
5. 17ap - Hydroxy D - homoandrosta 4,16-dien- 3-one.
6. 17ap - Acetoxy - D - homoandrosta- 4,16 dien - 3 - one.
7. 17ass - Propionyloxy - D - homoandrosta4,16 - dien- 3 - one.
8. 17afl - Butyryloxy - D - homoandrosta4,16- dien 3 - one.
9. 17ass - Phenylacetoxy - D - homoandrosta -4,16 - dien - 3 - one.
10. 17ass - Undecanoyloxy - D - homoandrosta 4,16 - dien - 3 - one.
11. 17afl - Heptanoyloxy - D - homoandrosta - 4,16 - dien - 3 - one.
12. 17afl - Phenoxyacetoxy - D - homo- androsta 4,16 - dien - 3 - one.
13. 17ass - (Tetrahydropyran - 2 - yloxy) D - homoandrosta - 4,16 - dien - 3 - one.
14. 17ass - (Cyclopent - 1 - enyloxy) homoandrosta - 4,16 - dien - 3 - one.
15. 17afl - Acetoxy - D - homoandrosta1,4,16 - trien - 3 - one.
16. 17ass - Hydroxy - 17aa - methyl homoandrosta - 1,4,16 - trien - 3 - one.
17. 17ap - Benzyloxy - D - homoandrosta4,16-dien-3-one.
18. 17ass - n - Decyloxy - D - homoan drosta-4,16-dien-3 - one.
19. 17ass - Benzyloxy - D - homoandrosta4,16 - dien - 3 - one.
20. 17aP - Cyclohexylmethoxy - D - homoandrosta -4,16 - dien - 3 - one.
21. 3ss,17ass, - Dihydroxy - D - homoandrosta -4,16 - diene.
22. 3ss,17ass - Diacetoxy - D - homoandrosta - 4,16 - diene.
23. 17ass - Hydroxy - D - homo androst - 16 - en - 3 - one.
24. 17ap - Hydroxy - 17azz - methyl homo - 5α - androst - 16 - en - 3 - one.
25. 17ass - Acetoxy - D - homo androsta - 1,16 - dien - 3 - one.
26. 17ass - Hydroxy - 17afg - methyl homoandrosta - 4,16 - dien - 3 - one.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (38)
1. D - Homosteroids of the general formula
wherein
The broken lines in the A-ring denote
optional carbon-carbon bonds;
R' represents a hydrogen atom or a methyl
group;
R3 represents an oxo group or, when the
A-ring is unsaturated, an oxo, (a-H, ss-OH) or (H, ss-O-acyl) group;
the 5-hydrogen atom (when present)
has the α-configuration; R' represents a hydrogen atom or a methyl
group; RiTaP represents a hydrogen atom or a
C1-10 alkyl, benzyl, cyclohexylmethyl,
acyl, tetrahydropyranyl or cycloalkenyl
group; and R17a@ represents a hydrogen
atom or a lower alkyl, ethynyl, vinyl or
propadienyl group.
2. D - Homosteroids of formula I given in claim 1, wherein g17ass represents a hydrogen atom or an acyl, tetrahydropyranyl or cycloalkenyl group.
3. D - Homosteroids as set forth in claim 1 or claim 2, wherein R' represents a hydrogen atom, R3 represents an oxo group and the
A-ring contains a double-bond.
4. D - Homosteroids as set forth in claim 1, claim 2 or claim 3, wherein Rl?aa represents a hydrogen atom or a methyl or ethyl group and R17ass represents a hydrogen atom or a lower alkanoyl group.
5. 17ap - Hydroxy D - homoandrosta 4,16-dien- 3-one.
6. 17ap - Acetoxy - D - homoandrosta- 4,16 dien - 3 - one.
7. 17ass - Propionyloxy - D - homoandrosta4,16 - dien- 3 - one.
8. 17afl - Butyryloxy - D - homoandrosta4,16- dien 3 - one.
9. 17ass - Phenylacetoxy - D - homoandrosta -4,16 - dien - 3 - one.
10. 17ass - Undecanoyloxy - D - homoandrosta 4,16 - dien - 3 - one.
11. 17afl - Heptanoyloxy - D - homoandrosta - 4,16 - dien - 3 - one.
12. 17afl - Phenoxyacetoxy - D - homo- androsta 4,16 - dien - 3 - one.
13. 17ass - (Tetrahydropyran - 2 - yloxy) D - homoandrosta - 4,16 - dien - 3 - one.
14. 17ass - (Cyclopent - 1 - enyloxy) homoandrosta - 4,16 - dien - 3 - one.
15. 17afl - Acetoxy - D - homoandrosta1,4,16 - trien - 3 - one.
16. 17ass - Hydroxy - 17aa - methyl homoandrosta - 1,4,16 - trien - 3 - one.
17. 17ap - Benzyloxy - D - homoandrosta4,16-dien-3-one.
18. 17ass - n - Decyloxy - D - homoan drosta-4,16-dien-3 - one.
19. 17ass - Benzyloxy - D - homoandrosta4,16 - dien - 3 - one.
20. 17aP - Cyclohexylmethoxy - D - homoandrosta -4,16 - dien - 3 - one.
21. 3ss,17ass, - Dihydroxy - D - homoandrosta -4,16 - diene.
22. 3ss,17ass - Diacetoxy - D - homoandrosta - 4,16 - diene.
23. 17ass - Hydroxy - D - homo androst - 16 - en - 3 - one.
24. 17ap - Hydroxy - 17azz - methyl homo - 5α - androst - 16 - en - 3 - one.
25. 17ass - Acetoxy - D - homo androsta - 1,16 - dien - 3 - one.
26. 17ass - Hydroxy - 17afg - methyl homoandrosta - 4,16 - dien - 3 - one.
27. 3ss,17ass - Dihydroxy - 17aα - methyl
D - homoandrosta - 4,16 - diene.
28. 17aα - Ethynyl - 17a;ss - hydroxy homoandrosta - 4,16 - dien - 3 - one.
29. 17ass - Hydroxy - 17aα - vinyl - Dhomoandrosta - 4,16 - dien - 3 - one.
30. 1α - Methyl - 17ass - (tetrahydropyranyl - 2 - oxy) - D - homo - 5e - androst - 16 en -3 - one.
31. 17aB - Hydroxy - 1e - methyl - homo - 5 - androst - 16 - en - 3 - one.
32. A process for the manufacture of the
D - homosteroids of formula I given in claim 1, which process comprises
(a) oxidising the 3-hydroxy or 3-hydroxy Aa grouping in a D-homosteroid of the general formula
wherein R1, R17ass and Rl7 have the significance
given in claim 1 and the broken line
in the 5,6-position denotes an optional
carbon-carbon bond, to the 3-keto or 4-keto-#4 grouping, or
(b) reacting a D-homosteroid of the general formula
wherein Rl, R and the broken lines in the A-ring
have the significance given in claim
1, with an organometallic compound yielding a R" group, a 3-keto group being intermediately protected, or (c) reacting a D-homosteroid of the general formula
wherein Rl, R17ass and R' a have the significance
given in claim 1, with a methyl Grignard compound in the presence of copper-I chloride, or
(d) reacting a D - homosteroid of the general formula
wherein R'7iWi and Rl7ass have the significance given
in claim 1 and the broken line in the
5,6-position denotes an optional carbon
carbon bond, with a methyl Grignard compound in the presence of copper-I chloride and subsequently rearranging a A5 double bond in the reaction product into the 4,5-position by acid treatment, or
(e) acylating the hydroxy group(s) in a
D-homosteroid of formula I in which at least one hydroxy group is present in the 3-position or 17ass position, or
(f) subjecting a D-homosteroid of the general formula
wherein
R3 and the broken lines in the R-ring have
the significance given in claim 1 and
Z represents an oxo or (OR17,0, R'7aa) group to reduction of the 17a-keto group to the hydroxy group (with intermediate protection of a 3-keto group) when Z represents an oxo group or to reduction of the 3-keto group and a 17a-keto group which may be present to the hydroxy group wnen R represents an oxo group and the A-ring is mono-unsaturated, or (g) subjecting a D-homosteroid of formula
I which is saturated or monounsaturated in the
A-ring and in which R3 represents an oxo group to dehydrogenation in the 1,2-position and/or 4,5-position, or
(h) converting the 17ass-hydroxy group in a D homosteroid of formula I in which R17ass represents a hydrogen atom and R1, R, R7, R17ass and the broken lines in the A-ring have the significance given in claim 1 into a cyclo alkenvl, tetrahydropyranyl, C1-C10 alkyl, benzvl or cyclohexylmethyl ether, or
(i) subjecting a D-homosteroid of formula
I in which R17ass represents an acyl, tetra hvdropvranvl or cycloalkenyl group and Rl, R3, R7 R'7aa and the broken lines in the Aring have the significance given in claim 1 to saponification of a 17aS-acyloxy group and a 3-acyloxy group which mav be present or to cleavage of a 17arlDi-tetrahydropyranyl or cycloalkenyl ether, or
(j) hydrogenating the ethynyl group in a
D-homosteroid of the general formula
wherein
R', R3, R7, RI;Jd and the broken lines in the
A-ring have the significance given in
claim 1, to the vinyl group.
33. A process according to claim 32, wherein there is manufactured a D-homosteroid of formula I in which Rl7aa represents a hydrogen atom or an acyl, tetrahydropyranyl or cycloalkenyl group.
34. A process according to claim 32 or claim 33, wherein there is manufactured a homosteroid of formula I in which Rl represents a hydrogen atom, R" represents an oxo group and the A-ring contains a double bond.
35. A process according to claim 32, claim 33 or claim 34, wherein there is manufactured a D-homosteroid of formula I in which Rl7aa represents a hydrogen atom or a methyl or ethyl group and Rl7ass represents a hydrogen atom or a lower alkanoyl group.
36. A process for the manufacture of the
D-homosteroids of formula I given in claim 1, substantially as hereinbefore described with reference to any one of Examples 2 to 18.
37. A D-homosteroid of formula I given in claim 1, when manufactured by the process claimed in any one of claims 32 to 36 inclusive.
38. A pharmaceutical preparation containing a D-homosteroid of formula I given in claim 1 in association with a compatible pharmaceutical carrier material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1456475A CH616436A5 (en) | 1975-11-11 | 1975-11-11 | Process for the preparation of D-homosteroids. |
| CH1160476 | 1976-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1564144A true GB1564144A (en) | 1980-04-02 |
Family
ID=25708627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB46765/76A Expired GB1564144A (en) | 1975-11-11 | 1976-11-10 | D-homosteroids |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5259148A (en) |
| AT (1) | AT354653B (en) |
| AU (1) | AU505624B2 (en) |
| CA (1) | CA1082686A (en) |
| DD (1) | DD128852A5 (en) |
| DE (1) | DE2651364A1 (en) |
| ES (2) | ES461325A1 (en) |
| FR (1) | FR2331329A1 (en) |
| GB (1) | GB1564144A (en) |
| GR (1) | GR70298B (en) |
| IE (1) | IE43985B1 (en) |
| IL (1) | IL50854A (en) |
| LU (1) | LU76161A1 (en) |
| MC (1) | MC1121A1 (en) |
| NL (1) | NL7612538A (en) |
| NZ (1) | NZ182539A (en) |
| PH (1) | PH13603A (en) |
| PL (1) | PL193604A1 (en) |
| PT (1) | PT65821B (en) |
| SU (1) | SU679147A3 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4788218A (en) * | 1984-05-21 | 1988-11-29 | Sri International | 17 a β-hydroxy-7 α-methyl-d-homo-19-norandrost-4,16-diene-3-one and the 17-esters thereof: methods of preparation and uses |
| GB2362648A (en) * | 2000-05-23 | 2001-11-28 | Univerzita Palackeho V Olomouc | Triterpenoid derivatives |
| WO2005021573A1 (en) * | 2003-08-21 | 2005-03-10 | Schering Ag | Δ15-d-homosteroids having an androgenic effect |
-
1976
- 1976-11-05 IL IL50854A patent/IL50854A/en unknown
- 1976-11-05 NZ NZ182539A patent/NZ182539A/en unknown
- 1976-11-06 MC MC761217A patent/MC1121A1/en unknown
- 1976-11-08 IE IE2476/76A patent/IE43985B1/en unknown
- 1976-11-09 PH PH19111A patent/PH13603A/en unknown
- 1976-11-09 AU AU19431/76A patent/AU505624B2/en not_active Expired
- 1976-11-09 JP JP51133847A patent/JPS5259148A/en active Pending
- 1976-11-09 DD DD7600195685A patent/DD128852A5/en unknown
- 1976-11-10 CA CA265,305A patent/CA1082686A/en not_active Expired
- 1976-11-10 LU LU76161A patent/LU76161A1/xx unknown
- 1976-11-10 GR GR52152A patent/GR70298B/el unknown
- 1976-11-10 DE DE19762651364 patent/DE2651364A1/en not_active Withdrawn
- 1976-11-10 PL PL19360476A patent/PL193604A1/en unknown
- 1976-11-10 FR FR7633899A patent/FR2331329A1/en active Granted
- 1976-11-10 PT PT65821A patent/PT65821B/en unknown
- 1976-11-10 SU SU762418751A patent/SU679147A3/en active
- 1976-11-10 AT AT834476A patent/AT354653B/en not_active IP Right Cessation
- 1976-11-10 GB GB46765/76A patent/GB1564144A/en not_active Expired
- 1976-11-11 NL NL7612538A patent/NL7612538A/en not_active Application Discontinuation
-
1977
- 1977-08-03 ES ES461325A patent/ES461325A1/en not_active Expired
- 1977-08-03 ES ES461326A patent/ES461326A1/en not_active Expired
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4788218A (en) * | 1984-05-21 | 1988-11-29 | Sri International | 17 a β-hydroxy-7 α-methyl-d-homo-19-norandrost-4,16-diene-3-one and the 17-esters thereof: methods of preparation and uses |
| GB2362648A (en) * | 2000-05-23 | 2001-11-28 | Univerzita Palackeho V Olomouc | Triterpenoid derivatives |
| WO2005021573A1 (en) * | 2003-08-21 | 2005-03-10 | Schering Ag | Δ15-d-homosteroids having an androgenic effect |
| US7388003B2 (en) | 2003-08-21 | 2008-06-17 | Bayer Schering Pharma Ag | Δ15-D-Homosteroids with androgenic action |
Also Published As
| Publication number | Publication date |
|---|---|
| ES461325A1 (en) | 1978-12-16 |
| NZ182539A (en) | 1979-07-11 |
| FR2331329A1 (en) | 1977-06-10 |
| IE43985B1 (en) | 1981-07-15 |
| JPS5259148A (en) | 1977-05-16 |
| MC1121A1 (en) | 1977-08-12 |
| IL50854A0 (en) | 1977-01-31 |
| LU76161A1 (en) | 1977-12-13 |
| CA1082686A (en) | 1980-07-29 |
| DE2651364A1 (en) | 1977-05-12 |
| SU679147A3 (en) | 1979-08-05 |
| PT65821A (en) | 1976-12-01 |
| ES461326A1 (en) | 1978-12-01 |
| AU505624B2 (en) | 1979-11-29 |
| AU1943176A (en) | 1978-05-18 |
| PT65821B (en) | 1978-10-10 |
| GR70298B (en) | 1982-09-06 |
| PH13603A (en) | 1980-08-05 |
| IL50854A (en) | 1979-12-30 |
| ATA834476A (en) | 1979-06-15 |
| NL7612538A (en) | 1977-05-13 |
| DD128852A5 (en) | 1977-12-14 |
| IE43985L (en) | 1977-05-11 |
| AT354653B (en) | 1979-01-25 |
| PL193604A1 (en) | 1979-03-26 |
| FR2331329B1 (en) | 1981-11-27 |
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| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |