CS276696B6 - Ergoline derivatives, process for their preparation and their use in medicaments - Google Patents
Ergoline derivatives, process for their preparation and their use in medicaments Download PDFInfo
- Publication number
- CS276696B6 CS276696B6 CS905604A CS560490A CS276696B6 CS 276696 B6 CS276696 B6 CS 276696B6 CS 905604 A CS905604 A CS 905604A CS 560490 A CS560490 A CS 560490A CS 276696 B6 CS276696 B6 CS 276696B6
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- ergoline
- didehydro
- compounds
- carbon atoms
- propyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- AWFDCTXCTHGORH-HGHGUNKESA-N 6-[4-[(6ar,9r,10ar)-5-bromo-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carbonyl]piperazin-1-yl]-1-methylpyridin-2-one Chemical class O=C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC(Br)=C(C=34)C2)C1)C)N(CC1)CCN1C1=CC=CC(=O)N1C AWFDCTXCTHGORH-HGHGUNKESA-N 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims description 16
- 239000003814 drug Substances 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims 2
- 208000027219 Deficiency disease Diseases 0.000 claims 1
- 229960003638 dopamine Drugs 0.000 claims 1
- 238000006266 etherification reaction Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- -1 alkyl radical Chemical class 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XJOOMMHNYOJWCZ-UHFFFAOYSA-N Agroclavine Natural products C1=CC(C2C=C(C)CN(C2C2)C)=C3C2=CNC3=C1 XJOOMMHNYOJWCZ-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- DAVNRFCJMIONPO-UHFFFAOYSA-N (7-methyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl)methanol Chemical class C1=CC(C2C=C(CO)CN(C2C2)C)=C3C2=CNC3=C1 DAVNRFCJMIONPO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 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
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- PYPLTTBNKDIDGL-DNVCBOLYSA-N (6ar,10ar)-5-ethenyl-9-methyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C=C(C)CN([C@@H]2C2)CCC)=C3C2=C(C=C)NC3=C1 PYPLTTBNKDIDGL-DNVCBOLYSA-N 0.000 description 2
- AXSDNXVFFJCKJU-UKRRQHHQSA-N (6ar,10ar)-9-(hydroxymethyl)-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-7-carbonitrile Chemical compound C1=CC([C@H]2C=C(CN([C@@H]2C2)C#N)CO)=C3C2=CNC3=C1 AXSDNXVFFJCKJU-UKRRQHHQSA-N 0.000 description 2
- PSAJJNJVRFJVIT-NVXWUHKLSA-N (6ar,10ar)-9-methyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C=C(C)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 PSAJJNJVRFJVIT-NVXWUHKLSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- XGNDUBUGJPTPDF-TZMCWYRMSA-N [(6ar,10ar)-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C1=CC([C@H]2C=C(CN[C@@H]2C2)CO)=C3C2=CNC3=C1 XGNDUBUGJPTPDF-TZMCWYRMSA-N 0.000 description 2
- DRIHQDQTVBPZQT-UKRRQHHQSA-N [(6ar,10ar)-5-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C([C@@H]12)=C(CO)CN[C@@H]1CC1=C(C)NC3=CC=CC2=C31 DRIHQDQTVBPZQT-UKRRQHHQSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- JGHYBJVUQGTEEB-UHFFFAOYSA-M dimethylalumanylium;chloride Chemical compound C[Al](C)Cl JGHYBJVUQGTEEB-UHFFFAOYSA-M 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XGNIKLKOKLJWBW-IUODEOHRSA-N (6aR,10aR)-5-chloro-7-ethyl-9-methyl-6,6a,8,10a-tetrahydro-4H-indolo[4,3-fg]quinoline Chemical compound ClC1=C2C[C@H]3N(CC(=C[C@@H]3C=3C=CC=C(N1)C=32)C)CC XGNIKLKOKLJWBW-IUODEOHRSA-N 0.000 description 1
- MRXMXXZARYQFCQ-UKRRQHHQSA-N (6ar,10ar)-5,9-dimethyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinoline Chemical compound C([C@@H]12)=C(C)CN[C@@H]1CC1=C(C)NC3=CC=CC2=C31 MRXMXXZARYQFCQ-UKRRQHHQSA-N 0.000 description 1
- PWPZCCZQXRPNEL-GDBMZVCRSA-N (6ar,10ar)-5,9-dimethyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-7-carbonitrile Chemical compound C([C@@H]12)=C(C)CN(C#N)[C@@H]1CC1=C(C)NC3=CC=CC2=C31 PWPZCCZQXRPNEL-GDBMZVCRSA-N 0.000 description 1
- SHXOBPWEWXXKRV-CZUORRHYSA-N (6ar,10ar)-5-bromo-9-methyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C=C(C)CN([C@@H]2C2)CCC)=C3C2=C(Br)NC3=C1 SHXOBPWEWXXKRV-CZUORRHYSA-N 0.000 description 1
- CUTKNVLFRQVBNK-IEBWSBKVSA-N (6ar,10ar)-7-(cyclopropylmethyl)-5,9-dimethyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound C([C@@H]1C=2C=CC=C3NC(=C(C[C@H]11)C3=2)C)=C(C)CN1CC1CC1 CUTKNVLFRQVBNK-IEBWSBKVSA-N 0.000 description 1
- HFAGXDZHTLDRSR-SJLPKXTDSA-N (6ar,10ar)-7-(cyclopropylmethyl)-9-methyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline Chemical compound N1([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C=C(C1)C)CC1CC1 HFAGXDZHTLDRSR-SJLPKXTDSA-N 0.000 description 1
- KNXQMYAIQXBYHZ-TZMCWYRMSA-N (6ar,10ar)-9-methyl-4,6,6a,7,8,10a-hexahydroindolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C=C(CN[C@@H]2C2)C)=C3C2=CNC3=C1 KNXQMYAIQXBYHZ-TZMCWYRMSA-N 0.000 description 1
- YKEVBCMCJKBKHC-UKRRQHHQSA-N (6ar,10ar)-9-methyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-7-carbonitrile Chemical compound C1=CC([C@H]2C=C(CN([C@@H]2C2)C#N)C)=C3C2=CNC3=C1 YKEVBCMCJKBKHC-UKRRQHHQSA-N 0.000 description 1
- QROQTSJDRGLJDS-RDTXWAMCSA-N (6ar,10ar)-9-methyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-5-carbaldehyde Chemical compound C1=CC([C@H]2C=C(C)CN([C@@H]2C2)CCC)=C3C2=C(C=O)NC3=C1 QROQTSJDRGLJDS-RDTXWAMCSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GYARKXHCBUXJHT-XMSQKQJNSA-N 4-[[(6ar,10ar)-9-methyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-5-yl]methyl]morpholine Chemical compound C([C@@H]1[C@@H](C=2C=CC=C(C3=2)N2)C=C(C)CN1CCC)C3=C2CN1CCOCC1 GYARKXHCBUXJHT-XMSQKQJNSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000221751 Claviceps purpurea Species 0.000 description 1
- DAVNRFCJMIONPO-UKRRQHHQSA-N Elymoclavine Chemical class C1=CC([C@H]2C=C(CO)CN([C@@H]2C2)C)=C3C2=CNC3=C1 DAVNRFCJMIONPO-UKRRQHHQSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
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- 206010022998 Irritability Diseases 0.000 description 1
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- 238000010478 Prins reaction Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- IKJSSDAYEGAQHT-OXQOHEQNSA-N [(6ar,10ar)-5-(hydroxymethyl)-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methyl acetate Chemical compound C1=CC([C@H]2C=C(COC(C)=O)CN([C@@H]2C2)CCC)=C3C2=C(CO)NC3=C1 IKJSSDAYEGAQHT-OXQOHEQNSA-N 0.000 description 1
- RKLQWNGUUYPJFH-IUODEOHRSA-N [(6ar,10ar)-5-bromo-7-ethyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C1=CC([C@H]2C=C(CO)CN([C@@H]2C2)CC)=C3C2=C(Br)NC3=C1 RKLQWNGUUYPJFH-IUODEOHRSA-N 0.000 description 1
- DPRFVTKWCYFHSK-IUODEOHRSA-N [(6ar,10ar)-5-chloro-7-ethyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C1=CC([C@H]2C=C(CO)CN([C@@H]2C2)CC)=C3C2=C(Cl)NC3=C1 DPRFVTKWCYFHSK-IUODEOHRSA-N 0.000 description 1
- PHAKDFRFOKNZIY-CZUORRHYSA-N [(6ar,10ar)-5-chloro-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C1=CC([C@H]2C=C(CO)CN([C@@H]2C2)CCC)=C3C2=C(Cl)NC3=C1 PHAKDFRFOKNZIY-CZUORRHYSA-N 0.000 description 1
- XNPBCIUTAQHFCF-DYESRHJHSA-N [(6ar,10ar)-5-ethenyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methyl acetate Chemical compound C1=CC([C@H]2C=C(COC(C)=O)CN([C@@H]2C2)CCC)=C3C2=C(C=C)NC3=C1 XNPBCIUTAQHFCF-DYESRHJHSA-N 0.000 description 1
- OHLMQIGSQITELY-OXQOHEQNSA-N [(6ar,10ar)-5-formyl-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methyl acetate Chemical compound C1=CC([C@H]2C=C(COC(C)=O)CN([C@@H]2C2)CCC)=C3C2=C(C=O)NC3=C1 OHLMQIGSQITELY-OXQOHEQNSA-N 0.000 description 1
- HNPIIWVFJKDMHQ-IEBWSBKVSA-N [(6ar,10ar)-7-(cyclopropylmethyl)-5-methyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C([C@@H]1C=2C=CC=C3NC(=C(C[C@H]11)C3=2)C)=C(CO)CN1CC1CC1 HNPIIWVFJKDMHQ-IEBWSBKVSA-N 0.000 description 1
- WWRKFENGMQHUCY-NVXWUHKLSA-N [(6ar,10ar)-7-cyano-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methyl acetate Chemical compound C1=CC([C@H]2C=C(CN([C@@H]2C2)C#N)COC(=O)C)=C3C2=CNC3=C1 WWRKFENGMQHUCY-NVXWUHKLSA-N 0.000 description 1
- ZIXOGYRTGBSSMJ-NVXWUHKLSA-N [(6ar,10ar)-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methanol Chemical compound C1=CC([C@H]2C=C(CO)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 ZIXOGYRTGBSSMJ-NVXWUHKLSA-N 0.000 description 1
- GRJKCWPVESDZMI-IEBWSBKVSA-N [(6ar,10ar)-7-propyl-6,6a,8,10a-tetrahydro-4h-indolo[4,3-fg]quinoline-9-yl]methyl acetate Chemical compound C1=CC([C@H]2C=C(COC(C)=O)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 GRJKCWPVESDZMI-IEBWSBKVSA-N 0.000 description 1
- OGFZEDMIYDGMQJ-UHFFFAOYSA-N [Na].COC(C)=O Chemical compound [Na].COC(C)=O OGFZEDMIYDGMQJ-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004791 alkyl magnesium halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000005520 electrodynamics Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 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
- 230000035929 gnawing Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 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
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001228 spectrum Methods 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
- 239000010959 steel Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension 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
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Vynález se týká nových derivátů agroklavinu a elymoklavinu, jejich výroby a použití v léčivech; jakož i mazisloučenin k jejich výrobě a způsobu výroby mezisloučenin.The invention relates to novel agroclavin and elymoclavin derivatives, their production and their use in pharmaceuticals; as well as the compounds for their production and the method for producing the intermediate compounds.
Agroklavin a elymoklavin jsou vysoce účinné přírodní argotalkaloidy, které se vyskytují na travinách infikovaných Claviceps purpurea. Maji celé spektrum účinků známých u ergotalkaloidů.Agroclavin and elymoclavin are highly potent natural argotalkaloids found on grasses infected with Claviceps purpurea. They have a full spectrum of effects known in ergotalkaloids.
Zavedením uhlovodíků s delším řetězcem do polohy 6 a substituci v poloze 2 se vliv různých receptorů změní a zvýši se metabolické stabilita. Deriváty ergolinu substituované podle vynálezu vykazuji proto ve srovnáni s deriváty agroklavinu a elymoklavinu substituovanými 6-methylem zesílenou dopaminergenni účinnost a větší selektivitu. Současně se zpomaluje metabolický rozklad.The introduction of longer chain hydrocarbons at the 6-position and substitution at the 2-position alters the influence of different receptors and increases metabolic stability. The ergoline derivatives substituted according to the invention therefore show enhanced dopaminergenic activity and greater selectivity compared to the 6-methyl substituted agroclavin and elymoclavine derivatives. At the same time, metabolic decomposition is slowed down.
Vynález se týká sloučenin vzorce I a jejich adičnich soli s kyselinamiThe invention relates to compounds of formula I and their acid addition salts
v& kterémin which
R2 znamená halogen, alkyl s 1 až 4 atomy uhliku, alkanyl se 2 až 4 atomy uhlíku,R 2 is halogen, alkyl having 1 to 4 carbon atoms, alkanyl having 2 to 4 carbon atoms,
RS znamená alkyl se 2 až 6 atomy uhliku, alkenyl se 3 až 6 atomy uhliku nebo cykloalkyl-alkyl se 3 až 5 atomy uhliku v cykloalkylové části a s 1 až 2 atomy uhliku v alkylové části,R s denotes alkyl with 2-6 carbon atoms, alkenyl of 3-6 carbon atoms or cycloalkylalkyl with 3-5 carbon atoms in the cycloalkyl part and 1 to 2 carbon atoms in the alkyl moiety,
X znamená vodík, hydroxyskupinu nebo acyloxyskupinu s 1 až 6 atomy uhliku.X is hydrogen, hydroxy or acyloxy having 1 to 6 carbon atoms.
Fyziologicky snášenlivé adični sole s kyselinami se odvozuji od známých anorganických a organických kyselin, jako například od kyseliny chlorovodíkové, kyseliny sirové, kyseliny bromovodikové, kyseliny citrónové, kyseliny maleinové, kyseliny fumarové, kyseliny vinné a jiných.Physiologically tolerable acid addition salts are derived from known inorganic and organic acids, such as hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, maleic acid, fumaric acid, tartaric acid and others.
Pod alkylem se rozumi alkylový zbytek s přímým nebo rozvětveným řetězcem, jako například methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sek. butyl, terč. butyl, pentyl, hexyl, 2,2-dimethylpropyl, 2-methylbutyl, isopentyl aj.Alkyl is understood to mean a straight or branched chain alkyl radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. butyl, pentyl, hexyl, 2,2-dimethylpropyl, 2-methylbutyl, isopentyl and others.
66
Znači-li R nebo R alkenylový zbytek, pak tento přednostně obsahuje jen jednu dvojnou vazbu, přičemž dvojná vazba v R nemůže sousedit s atomem dusíku. Dako alkenylové zbytky jsou vhodné napřiklad: vinyl, 1-propenyl, 2-propenyl, l-methyl-2-propenyl, 1-butenyl, methallyl.When R or R is an alkenyl radical, it preferably contains only one double bond and the double bond in R cannot be adjacent to the nitrogen atom. Suitable alkenyl radicals are, for example, vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, methallyl.
Znači-li R cykloalkyl-alkylovou skupinu, mini ss například cyklopropylmethyl, cyklopropylethyl nebo cyklobutylmethyl.When R is a cycloalkyl-alkyl group, it is, for example, cyclopropylmethyl, cyclopropylethyl or cyclobutylmethyl.
Acylové skupiny v substituentu X se odvozuji od alifatických karboxylových kyselin jako od kyseliny mravenčí, kyseliny octové, kyseliny propionové, kyseliny máselné, kyseliny kapronové, kyseliny trimsthyloctové, přičemž se přednostně používá kyselina octová. Výhodné prováděcí formy pro R jsou alkyly s alkenyly až se 4 atomy uhliku a cykloalkyl-alkyly až s 5 atomy uhliku.The acyl groups in the substituent X are derived from aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, caproic acid, trimethylhylacetic acid, preferably acetic acid. Preferred embodiments for R are alkyls with alkenyls of up to 4 carbon atoms and cycloalkyl-alkyls of up to 5 carbon atoms.
Sloučeniny vzorce I mohou být jako isomery E nebo Z, v případě, že je přítomné chio rálni centrum ve zbytku R ,' jako diastereomery a jako jejich směsi. Isomery a směsi isomerů jsou ve vynálezu také zahrnuty.The compounds of formula (I) may be as E or Z isomers, if the chiral center in the residue R is present, as diastereomers and as mixtures thereof. Isomers and mixtures of isomers are also included in the invention.
Sloučeniny vzorce I jakož i jejich adični sole s kyselinami jsou na základě své cenCS 276 6 96 B6 trálně dopaminergenni účinnosti použitelné jako léčiva. Protože se vyznačuji zejména dopaminagonistickým účinkem, aniž by nastávaly silné -adrenergní efekty, hodí se sloučeniny podle vynálezu zejména k léčení Parkinsonovy nemoci.The compounds of formula I as well as their acid addition salts are useful as pharmaceuticals because of their cost-effective dopaminergic activity. Since they are particularly characterized by dopaminagonistic activity without producing strong adrenergic effects, the compounds according to the invention are particularly suitable for the treatment of Parkinson's disease.
Dopaminagonistický účinek byl stanoven pomoci metody automatické registrace stereotypů u krys, popsané Horowskim (Arzneim. Forsch. 12, 2281-2286, 1978): hned po intraperitoneálnim podáni zkušební látky, popřípadě vehikula se samci krys druhu Wistar (90 až 120 g) umístí jednotlivě do nádob z akrylátového skla. Elektrodynamickým snímacím systémem umístěným před hlavou zvířete se během 60 minut registruje počet kontaktů s ocelovou nádobkou s centrální kovovou tyčinkou jako následek stereotypních žvýkacich, lízacich a hlodacích pohybů. Střední hodnoty + S.E.M počtu kontaktů během 60 minut pro různé ošetřované skupiny, které mají vždy 12 zvířat, se spočítají a zjisti sa signifikance rozdílů mezi středními hodnotami různých dávek zkušební látky ve srovnáni s kontrolní skupinou ošetřenou vehikulem pomoci jednoduché odchylkové analysy vs spojeni s Ounnettovým testem.The dopaminagonistic effect was determined by the method of automatic stereotyping in rats described by Horowski (Arzneim. Forsch. 12, 2281-2286, 1978): immediately after intraperitoneal administration of the test substance or vehicle, male Wistar rats (90-120 g) were placed individually into acrylic glass containers. The electrodynamic sensing system placed in front of the animal's head registers the number of contacts with the steel container with the central metal rod within 60 minutes as a result of stereotyped chewing, licking and gnawing movements. Mean values + SEM of the number of contacts over 60 minutes for the different treatment groups, each having 12 animals, are counted and the significance of the difference between the mean values of the different doses of the test substance compared to the vehicle treated control group is determined by simple deviation analysis vs. Ounnett test. .
Výsledky jsou uvedené v následující tabulce.The results are shown in the following table.
TabulkaTable
Vyvolání stereotypů u krys během 60 minut po intraperitoneálním ošetření vehikulem popř. různými dávkami ergolinů (x:p<0,01/ xx:p«c0,01, odchylková analysa/Dunnettův test vs.Induction of stereotypes in rats within 60 minutes after intraperitoneal treatment with vehicle or vehicle. different doses of ergolines (x: p < 0.01 / xx: p < 0.01, variance analysis / Dunnett '
kontrola) n: Počet pokusných zvířat pro ošetřovanou skupinucontrol) n: Number of experimental animals per treatment group
Stereotypy (počítáno pro 60 minut) Střední hodnota + S.E.MStereotypes (calculated for 60 minutes) Mean + S.E.M
Dávka zkušební látkyTest substance dose
Oako léčiva se sloučeniny podle vynálezu používají ve formě farmaceutického přípravku, který vedle účinné látky pro enterální nebo parenterálni aplikaci obsahuje vhodné farmaceutické organické nebo anorganické inertní nosné látky, jako například vodu, želatinu, arabskou gumu/ mléčný cukr, škrob, stearát hořečnatý, mastek, rostlinné oleje, polyalkylenglykoly atd. Farmaceutické přípravky mohou být v pevné formě, jako například jako tablety, dražé, čípky, kapsle nebo v kapalné formě, například jako roztoky, suspenze nebo emulse. Mimo to popřípadě obsahuji pomocné látky, jako prostředky konzervační, stabilizační/ smáčeci nebo emulgátory, sole ke změně osmotického tlaku nebo pufry.Oako medicaments are used in the form of a pharmaceutical composition which, in addition to the active ingredient for enteral or parenteral administration, contains suitable pharmaceutical organic or inorganic inert carriers such as water, gelatin, gum arabic / milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, such as as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. In addition, they optionally contain adjuvants such as preservatives, stabilizers / wetters or emulsifiers, salts for varying the osmotic pressure or buffers.
Sloučeniny podle vynálezu se používají v dávce 0,001 až 10 mg aktivní substance ve fyziologicky snášenlivém nosiči. Používání sloučenin podle vynálezu se provádi v dávce 0/00001 až 0,1 mg/kg/den, zejména 0,001 až 0/1 mg/kg/den, analogicky známému prostředku Bromocryptin.The compounds of the invention are used at a dosage of 0.001 to 10 mg of active substance in a physiologically tolerated carrier. The use of the compounds according to the invention is carried out at a dose of 0/00001 to 0.1 mg / kg / day, in particular 0.001 to 0/1 mg / kg / day, analogously to the known composition Bromocryptin.
Výroba sloučenin podle vynálezu vzorce I se může provádět o sobě známými metodami.The preparation of the compounds of the invention of the formula I can be carried out by methods known per se.
Ke sloučeninám vzorce I se například dojde tím,For example, the compounds of formula I are
CS 275 695 85CS 275 695 85
a) že se sloučeniny vzorce IIa) that the compounds of formula II
kde R2 * * * a X máji dřivé uvedený význam, alkyluji nebo alkenyluji na sloučeniny s R s dříve uvedeným významem, nebowherein R 2 * * * and X are as previously defined, alkylate or alkenyl to compounds having R as previously defined, or
b) že se sloučeniny vzorce IIIb) that the compounds of formula III
kde R6 a X mají dříve uvedený význam, halogenuji ná sloučeniny vzorce I s R ve významu halogenu, nebowherein R 6 and X are as previously defined, halogenated compounds of formula I with R in the meaning of halogen, or
c) že se sloučeniny vzorce IVc) the compound of formula IV
c kde R a X máji dřivé uvedený význam, oC) Wittigavou reakci přemění ve sloučeniny s R ve významu alkenylového zbytku se 2 až 4 atomy uhliku nebo /5) převedou v 1-hydroxy-alkylované deriváty s 1 až 4 atomy uhliku v 1-hydroxy-alkylovém zbytku a tyto se pak popřípadě dehydratuji na sloučeniny s R2 ve významu alkenylového zbytku se 2 až 4 atomy uhliku a popřípadě se pak sloučeniny získané podle «) nebo /1), popřípadě po esterifikaci zbytku 2c wherein R and X are as previously defined, oC) convert the Wittig reaction into a compound with R as a C 2 -C 4 alkenyl radical, or (5) convert it into 1-hydroxy-alkylated C 1 -C 4 derivatives of 1- hydroxy alkyl radical and this is then optionally dehydrated to a compound where R 2 in the meaning of alkenyl radical with 2-4 C atoms and optionally then with the compound obtained in ") and / or 1), optionally after esterification residues 2
2-CH20H redukuji na sloučeniny s R ve významu alkylového zbytku s 1 až 4 atomy uhliku a popřípadě se pak acylová skupina v poloze 8 odštěpí, isomery se děli a tvoři ee adiční sole s kyselinami.The 2-CH 2 OH is reduced to compounds having R as C 1 -C 4 alkyl and optionally the acyl group at the 8-position is then cleaved off, the isomers separated to form acid addition salts.
CS 275 696 B6CS 275 696 B6
Substituce v poloze 6 podle způsobu a) ss může napřiklad provádět postupem popsaným A.Černým et al. Coli. Czech. Chem. Comm. 49, 2328 (1984) nebo popsaným v EP 21206 tim, že se 6H-sloučenina vzorce XX nechá reagovat s příslušným R -halogenidem (bromidem, chloridem, jodidem). Účelně se reakce provádi v inertním rozpouštědle jako v dimethylsulfoxidu, dimethylformamidu, acetonitrilu nebo nitromethanu v přítomnosti bázi jako hydroxidů alkalických kovů nebo uhličitanů alkalických kovů.The substitution at position 6 according to method a) ss can, for example, be performed as described by A. Cerny et al. Coli. Czech. Chem. Comm. 49, 2328 (1984) or described in EP 21206 by reacting a 6H-compound of formula XX with an appropriate R-halide (bromide, chloride, iodide). Suitably, the reaction is carried out in an inert solvent such as dimethylsulfoxide, dimethylformamide, acetonitrile or nitromethane in the presence of a base such as alkali metal hydroxides or alkali metal carbonates.
Halogenace sloučenin vzorce XIX podle varianty b) se provádí postupem popsaným v EP-56358 popřípadě EP-141387, přímou halogenaci 2H-sloučeniny vhodným halogenačním prostředkem popř. bromem v přítomnosti bromovodiku.Halogenation of compounds of formula XIX according to variant b) is carried out as described in EP-56358 or EP-141387, direct halogenation of the 2H-compound with a suitable halogenating agent or a halogenating agent. bromine in the presence of hydrogen bromide.
Zavedeni substituentu R může nastat před substitucí nebo po substituci v poloze 6.Introduction of the substituent R may occur before or after substitution at the 6-position.
Přeměna 2-formylovó sloučeniny vzorce XV na sloučeniny vzorce I, kde R znáči alkenylový zbytek,' se provádí podle metody c oc) Wittigovou reakci tim, že se nechá reagovat napřiklad s alkyltrifenylfosfoniumhalodenidem v polárních rozpouštědlech jako cyklických a acyklických etherech, chlorovaných uhlovodicich, dimethylformamidu nebo dimethylsulfoxidu při teplotách -50 °C až +50 °Cj; přičemž k výrobě ylenu se přidávají silné báze jako alkoholáty alkalických l<ovů,J lithiumorganyl aj.The conversion of a 2-formyl compound of formula XV to compounds of formula I wherein R denotes an alkenyl radical is carried out according to method c) by Wittig reaction by reacting, for example, with alkyltriphenylphosphonium halodenide in polar solvents such as cyclic and acyclic ethers, chlorinated hydrocarbons, dimethylformamide or dimethylsulfoxide at temperatures of -50 ° C to +50 ° C ; whereby to produce ylene added a strong base such as alkali l <ov J lithiumorganyl well.
Sloučeniny vzorce X s R ve významu alkenylového zbytku se také mohou vyrábět postupem c$) tim,' že se sloučeniny vzorce IV grignardovánim nebo lithiovou alkylací převedou v 1-hydroxy-alkylované deriváty a potom se dehydratují.’ Grignardováni se může provádět obvyklými Grignardovými reagenciemi jako alkylmagnesium-halogenidy v aprotickém rozpouštědle jako v cyklických a acyklických etherech při hlubokých teplotách (-70 °C až 20 °C). Reakce s alkyllithiem probíhá za analogických podmínek. Následné zavedení dvojné vazby se může provádět obvyklými dehydratačnimi metodami jako například sulfonáty nebo acetáty, jako chloridem kyseliny methansulfonové v polárních rozpouštědlech jako v etherech v přítomnosti báze a popřípadě za zahříváni.Compounds of formula X with R as an alkenyl radical can also be prepared by the process c) by converting compounds of formula IV by grignarding or lithium alkylation to 1-hydroxyalkylated derivatives and then dehydrating. Grignarding can be carried out by conventional Grignard reagents. as alkylmagnesium halides in an aprotic solvent such as cyclic and acyclic ethers at low temperatures (-70 ° C to 20 ° C). The reaction with alkyllithium proceeds under analogous conditions. Subsequent introduction of the double bond may be accomplished by conventional dehydration methods such as sulfonates or acetates such as methanesulfonic acid chloride in polar solvents such as ethers in the presence of a base and optionally with heating.
Obsahuje-li substituent R exocyklickou dvojnou vazbu, tak se tato může redukovat na odpovidajici alkylový derivát. Například se redukce může provádět lithiem nebo sodíkem v kapalném amoniaku v inertním rozpouštědle jako cyklických a acyklických etherech v přítomnosti dárce protonů jako alifatických alkoholů.If the R substituent contains an exocyclic double bond, it may be reduced to the corresponding alkyl derivative. For example, the reduction can be carried out with lithium or sodium in liquid ammonia in an inert solvent such as cyclic and acyclic ethers in the presence of a proton donor such as aliphatic alcohols.
Také 1-hydroxy-alkylované deriváty získané postupem c fi) se mohou obvyklým způsobem redukovat v odpovidajici 2-alkylové deriváty reakcí s NaBH^ v kyselině octové.Also, the 1-hydroxyalkylated derivatives obtained by process c) may be reduced in the usual manner to the corresponding 2-alkyl derivatives by reaction with NaBH4 in acetic acid.
K zavedení skupiny 2-CHg je výhodné, před redukcí zbytku 2-CH20H tento esterlfikovat kyselinami jako kyselinou pivalovou, kyselinou octovou, kyselinou benzoovou a potom redukovat známým způsobem jak js popsán v německé patentové přihlášce P 3923211.5.In order to introduce the 2-CHg group, it is preferable to acidify the ester with acids such as pivalic acid, acetic acid, benzoic acid before reducing the 2-CH 2 OH residue and then reduce it in a known manner as described in German patent application P 3923211.5.
Selektivní odštěpeni acylové skupiny v poloze 8 se provádí známými způsoby esterového štěpeni; jako napřiklad alkoholáty alkalických kovů.Selective cleavage of the acyl group at the 8-position is accomplished by known ester cleavage methods; such as alkali metal alcoholates.
K tvorbě soli se sloučenina vzorca I rozpustí napřiklad v malém množství methanolu nebo methylenchloridu a přidá se koncentrovaný roztok žádané kyseliny.To form a salt, the compound of formula I is dissolved, for example, in a small amount of methanol or methylene chloride, and a concentrated solution of the desired acid is added.
Směsi isomerů se mohou obvyklými metodami, jako napřiklad krystalizaci, chromatografií nsbo tvorbou solí dělit v diastereomery popřípadě E/Z isomery.Mixtures of isomers can be separated into diastereomers or E / Z isomers by conventional methods, such as crystallization, chromatography or salt formation.
Vynález také zahrnuje sloučeniny vzorce IV*; které představují cenné meziprodukty k výrobě farmakologicky účinných sloučenin. Přeměna meziproduktů v účinné látky probíhá podle dřivé popsaných metod k zaváděni žádaných substituentů do polohy 8, 6 nebo 2.The invention also includes compounds of formula IV *; which are valuable intermediates for the production of pharmacologically active compounds. The conversion of intermediates into the active ingredient proceeds according to the methods previously described to introduce the desired substituents at the 8, 6 or 2 position.
Pokud se výroba výchozích sloučenin nepopisuje, jsou tyto známé nsbo vyrobitelné analogicky známým sloučeninám nebo zde popsanými způsoby.If the preparation of the starting compounds is not described, these are known or can be prepared analogously to the known compounds or the methods described herein.
Například výroba 2-formyl-derivátu vzorce IV* podle nároku 6 se může provádět analogicky metodám, které jsou popsané v EP-A-89730164; oxidaci Mannichovy báze nebo 2-hydroxymethylové sloučeniny. Zavedeni 2-hydroxymethylové skupiny se dosáhne například paraformaldehyd/dimethylaluminiumchloridem jak je popsáno v německé patentové přihlášce P 3923211.For example, the preparation of the 2-formyl derivative of the formula IV * according to claim 6 can be carried out analogously to the methods described in EP-A-89730164; oxidation of the Mannich base or the 2-hydroxymethyl compound. The introduction of the 2-hydroxymethyl group is achieved, for example, by paraformaldehyde / dimethylaluminum chloride as described in German patent application P 3923211.
JJ
CS 276 696 B6CS 276 696 B6
Následující příklady mají způsob podle vynálezu vysvětlit.The following examples are intended to explain the process of the invention.
Výchozí sloučeninyStarting compounds
1. ) 8,9-Didehydro-8-methyl-ergolin-S-l<arbonitril g (0,23 mol) agroklavinu sa rozpustí v 1,'4 1 dioxanu p.a. a přidá sa 32,8 g (0,23 mol) uhličitanu draaalného. Ve 300 ml dioxanu sa rozpustí 50 g (O,'47 mol) bromkyanu (jedna láhev, Merck) a najednou sa přidá. Promyje sa 100 ml dioxanu a nechá ae 2 hodiny míchat při teplotě místnosti. Potom se va vakuu oddestiluje (80 °C teplota lázně) největší část rozpouštědla, přičemž se jimač ke zničeni přebytečného bromkyanu plni KOH. Zbytek dioxanu se odstraní na rotační odparce. Zbytek sa extrahuje dichlormethanem a zahusti se. Krystalizaci z methanolu se ziská ve třech frakcích celkem 47,7 g (81 %) čistého produktu. Zbylých 6,0 g matečného louhu se chromatografuje (1 kg silikagelu, diisopropylether/hexan 2:1; 3:1, 6:1 a diisopropylethar). Ziská se dalších 3,6 g (6 %). Výtěžek: 87 % krystaluje,' /oc/D = + 53,5° (c = 1,0 v chloroformu), teplota tání 180 až 190 °C (rozklad).1.) 8,9-Didehydro-8-methyl-ergoline-S-arbonitrile (0.23 mol) agroclavin is dissolved in 1,4 L dioxane AR and 32.8 g (0.23 mol) carbonate is added draaalného. 50 g (0.47 mol) of cyanogen bromide (one bottle, Merck) were dissolved in 300 ml of dioxane and added in one portion. It is washed with 100 ml of dioxane and allowed to stir at room temperature for 2 hours. Then, most of the solvent was distilled off under vacuum (80 ° C bath temperature), while the scavenger was charged with KOH to destroy excess cyanogen bromide. The residual dioxane was removed on a rotary evaporator. The residue was extracted with dichloromethane and concentrated. Crystallization from methanol gave a total of 47.7 g (81%) of pure product in three fractions. The remaining 6.0 g of mother liquor is chromatographed (1 kg of silica gel, diisopropyl ether / hexane 2: 1; 3: 1, 6: 1 and diisopropyl ether). An additional 3.6 g (6%) was obtained. Yield: 87% crystallized, [α] D = + 53.5 ° (c = 1.0 in chloroform), m.p. 180-190 ° C (dec.).
2. ) 8,9-Didehydro-8-hydroxymethyl-6-ergolin-karbonitril2.) 8,9-Didehydro-8-hydroxymethyl-6-ergoline-carbonitrile
Příprava se provádi jako v předchozím příkladu.The preparation is carried out as in the previous example.
Výtěžek: 90 %, /oď/D = + 30° (0,5 % v pyridinu)Yield: 90%, [ .alpha. ] D = + 30 DEG (0.5% in pyridine)
3. ) 8,9-Didehydro-8-methyl-ergolin3.) 8,9-Didehydro-8-methyl-ergoline
K 1,2 1 bezvodého amoniaku (před kondenzaci sušen KOH) se přidá 37,9 g (0,15 mol)To 1.2 L of anhydrous ammonia (KOH dried before condensation) was added 37.9 g (0.15 mol)
8,9-didehydro-8-methyl-ergolin-6-karbonitrilu rozpuštěných v 900 ml tetrahydrofuranu. Nechá se 10 minut míchat aby teplota opět klesla na -78 °C a pak se po malých kouscich přidá celkem 18 g (2,2 mol) draslíku. Potom se roztok zbarvi červeně. Přídavek jednoho ml methanolu vyvolá obvyklé modré zbarvení, které se po 10 minutách přidáním celkem 150 ml methanolu rozruší. Po odpaření amoniaku se rozpouštědlo odstraní ve vakuu a zbytek se důkladně extrahuje dichlormethanem. Extrakt se promyje vodou a nasyceným roztokem NaCl a po sušeni síranem sodným se odpaří. Zbytek krystaluje z methanolu, přičemž se získá 22,’2 g (65 %) čistého produktu ve třech frakcích, Chromatografie matečného louhu dává dalších 3,8 g.8,9-didehydro-8-methyl-ergoline-6-carbonitrile dissolved in 900 ml of tetrahydrofuran. Allow to stir for 10 minutes to bring the temperature back to -78 ° C and then add a total of 18 g (2.2 mol) of potassium in small portions. Then the solution turns red. Addition of one ml of methanol induces the usual blue color, which is disturbed after 10 minutes by adding a total of 150 ml of methanol. After evaporation of the ammonia, the solvent is removed in vacuo and the residue is extracted thoroughly with dichloromethane. The extract was washed with water and saturated NaCl solution and, after drying with sodium sulfate, evaporated. The residue crystallizes from methanol to give 22.22 g (65%) of the pure product in three fractions. Chromatography of the mother liquor gives an additional 3.8 g.
Výtěžek: 76 % krystalizovaného, /eC/D = - 112,8° (c = 1,0 chloroform), teplota táni 125 až 133 °C.Yield: 76% crystallized, [ .alpha. ] D = -1212.8 DEG (c = 1.0 chloroform), m.p. 125 DEG-133 DEG.
4. ) 8,9-Didehydro-8-hydroxYmethyl-ergolin4.) 8,9-Didehydro-8-hydroxylmethyl-ergoline
V asi 2 litrech suchého, kapalného amoniaku se při -78 °C suspenduje 37 g lithiumamidu (1,6 mol) a potom se přidá 54 g 8,9-didehydro-8-hydroxymethyl-6-ergolin-karbonitrilu (0,2 mol) v pevné formě. Po 30 minutách se přidá 7,5 g krájeného lithia, přičemž po 30 minutách vznikne intenzivně modré zbarvení. Po 5 minutách se směs odbarví přidáním chloridu amonného. Přidá se 50 ml vody, amoniak sa odpaří a opatrně sa přidá celkemIn about 2 liters of dry, liquid ammonia, 37 g of lithium amide (1.6 mol) was suspended at -78 ° C, and then 54 g of 8,9-didehydro-8-hydroxymethyl-6-ergoline-carbonitrile (0.2 mol) was added. ) in solid form. After 30 minutes 7.5 g of sliced lithium was added, after 30 minutes a deep blue color developed. After 5 minutes, the mixture was destained by the addition of ammonium chloride. 50 ml of water are added, the ammonia is evaporated and carefully added in total
1,5 1 vody. Směs se michá 30 minut za chlazeni ledem; krystaly se odsají, promyji a suší. Výtěžek: 40,6 g (83 % teorie), /oí/Q = - 99° (0,5 % v pyridinu).1.5 liters of water. The mixture was stirred under ice-cooling for 30 minutes; the crystals are sucked off, washed and dried. Yield: 40.6 g (83% of theory); [.alpha.] D = -99 DEG (0.5% in pyridine).
5. ) 8,9-Didehydro-8-hydroxymethyl-2-methyl-ergolin5.) 8,9-Didehydro-8-hydroxymethyl-2-methyl-ergoline
A) 8-AcetoxYmethYl“8,9-didehydro-2-hydroxYmethyl-6-ergolin-karbonitrilA) 8-Acethoxymethyl-8,9-didehydro-2-hydroxymethyl-6-ergoline carbonitrile
Rozpustí se 44,4 g 8-acetoxymethyl-8,9-didehydro-6-ergolin-karbonitrilu (144 mmol) v 7,5 litrech dichlormethanu, přidá se 65 g paraformaldehydu (2)1 mol) a směs 3e ochladí na -50 °C. K tomu se rychle přikape 800 ml jednomolekulárniho roztoku dimethylaluminiumchloridu v hexanu (800 mmol). Po 10 minutách mícháni se roztok opatrně vlije do 6 litrů vody, směs se míchá 30 minut a potom sa přidá roztok 240 g kyseliny vinné v 1,6 litruDissolve 44.4 g of 8-acetoxymethyl-8,9-didehydro-6-ergoline-carbonitrile (144 mmol) in 7.5 liters of dichloromethane, add 65 g of paraformaldehyde (2) 1 mol) and cool the mixture 3e to -50. Deň: 32 ° C. To this was added dropwise 800 ml of a one-molar solution of dimethylaluminum chloride in hexane (800 mmol). After stirring for 10 minutes, the solution is carefully poured into 6 liters of water, stirred for 30 minutes and then a solution of 240 g of tartaric acid in 1.6 liters is added.
C 276 6 96 B6 vody. Po 30 minutách se zalkalizuje 450 ml koncentrovaného roztoku amoniaku, organická fáze se oddělí, vodná fáze se extrahuje třikrát dichlormethanem, všechny organická fáze se suši síranem sodným a rozpouštědlo ss odpaří. Zbytek se na silikagelu chromatografuje směsi hexan/aceton a nechá se krystalovat ze směsi acstát/diisopropylsthsr.C 276 6 96 B6 water. After 30 minutes, it is basified with 450 ml of concentrated ammonia solution, the organic phase is separated, the aqueous phase is extracted three times with dichloromethane, all the organic phases are dried over sodium sulphate and the solvent is evaporated off. The residue is chromatographed on silica gel with hexane / acetone and crystallized from the acstatate / diisopropylstyrs mixture.
Výtěžek: 17/2 g (35 % teorie), => + 20° (0/5 % v chloroformu).Yield: 17/2 g (35% of theory), => + 20 DEG (0/5% in chloroform).
B) 8-AcetoxYmethyl-8,9-didehydro-2-trimethYlacetoxYmethYl-6-ergolin-karbonitrilB) 8-Acetoxylmethyl-8,9-didehydro-2-trimethylacetoxylmethyl-6-ergoline carbonitrile
10/1 g 8-AcetoxY-8;9-didshydro-2-hYdroxymethyl-6-ergolin-karbonitrilu (3 mmol) se rozpustí ve 150 ml pyridinu a 30 ml chloridu kyseliny pivalové a míchá se 30 minut při teplotě místnosti. Potom se přidá led, michá se opět 30 minut,' zředí se vodou, zalkalizuje amoniakem a extrahuje se dichlormethanem. Organické fáze se suši, odpaří a chromatografuji se dichlormethanem na oxidu hlinitém. Krystalizaci z diisopropyletheru se ziská 8,9 g (70 % teorie), /oó/D a +16° (0,5 % v chloroformu).10/1 g of 8-AcetoxY-8,9-didhydro-2-hydroxymethyl-6-ergolinocarbonitrile (3 mmol) was dissolved in 150 ml of pyridine and 30 ml of pivalic acid chloride and stirred at room temperature for 30 minutes. Ice is then added, stirred again for 30 minutes, diluted with water, basified with ammonia and extracted with dichloromethane. The organic phases are dried, evaporated and chromatographed with dichloromethane on alumina. Crystallization from diisopropyl ether gave 8.9 g (70% of theory), [.alpha.] D and +16 DEG (0.5% in chloroform).
C) 8/9-Oidehydro-8-hydroxymethyl-2-trimethylacetoxYmethyl-6-ergolin-karbonitrilC) 8/9-Oidehydro-8-hydroxymethyl-2-trimethylacetoxylmethyl-6-ergoline carbonitrile
Ve 100 ml methanolu se suspenduje 4,2 g 8-acetoxymethyl-8;9-didehYdro-2-trimethylacstoxymethyl-6-ergolin-karbonitrilu (10 mmol), přidá se 100 mg natriummethylátu a hodinu se michá při teplotě místnosti. Za chlazeni ledem se zředí vodou a sraženina se odsaje.4.2 g of 8-acetoxymethyl-8,9-dihydro-2-trimethylacstoxymethyl-6-ergolinecarbonitrile (10 mmol) was suspended in 100 ml of methanol, 100 mg of sodium methyl acetate was added and stirred at room temperature for 1 hour. Under ice-cooling, it is diluted with water and the precipitate is filtered off with suction.
Výtěžek: 3,65 g (96 % teorie), /«4 /Q = + 31° (0,5 % v chloroformu).Yield: 3.65 g (96%) / "4 / Q = + 31 ° (0.5% in chloroform).
D) 8,9-Didehydro-8-hydroxymethyl-2-methYl-ergolinD) 8,9-Didehydro-8-hydroxymethyl-2-methyl-ergoline
Kondenzuje se 25 ml suchého amoniaku v baňce pod atmosférou argonu, přidá sa 0,7 ml anilinu (7,5 mmol) a 920 mg lithiumamidu (40 mmol) a míchá se 15 minut při -45 °C. Potom se přidá 1,89 g 8,9-didshydro-8-hydroxymethyl-2-trimethylacstoxymethyl-6-ergolin-karbonitrilu (5 mmol) a 30 minut se michá při -45 °C. Potom se ochladl na -70 °C, přidá se 290 mg lithia a michá se dokud nevznikne intensivní modré zbarveni. Po 5 minutách se při dá tolik chloridu amonného/ až zbarveni zmizí/ přikape se trochu vody a amoniak se odpaří. Při dalším zřeňování vodou za ochlazeni ledem vzniká sraženina, která se odsaje a suši.Condense with 25 mL of dry ammonia in a flask under argon, add 0.7 mL of aniline (7.5 mmol) and 920 mg of lithium amide (40 mmol) and stir at -45 ° C for 15 min. Then, 1.89 g of 8,9-didshydro-8-hydroxymethyl-2-trimethylacstoxymethyl-6-ergoline-carbonitrile (5 mmol) was added and stirred at -45 ° C for 30 minutes. It was then cooled to -70 ° C, 290 mg of lithium was added and stirred until an intense blue color was formed. After 5 minutes, so much ammonium chloride is added (until the color disappears) a little water is added dropwise and the ammonia is evaporated. Upon further dilution with water while cooling with ice, a precipitate is formed which is filtered off with suction and dried.
Výtěžek: 782 mg (56 % teorie), /*C/D = - 111° (0/5 % v pyridinu).Yield: 782 mg (56% of theory); [ .alpha .] D = -111 DEG (0/5% in pyridine).
6.) 8;9-Didehydro-2,8-dimethyl-ergolin6.) 8,9-Didehydro-2,8-dimethyl-ergoline
Z 8,9-didehydro-6/8-dimethyl-ergolinu se jak v předchozím příkladu popsáno, Prinsovou reakci (stupeň A) vyrobí 8,9-didehydro-6/8-dimethyl-2-hydroxymethyl-ergolin.From 8,9-didehydro-6/8-dimethyl-ergoline, as described in the previous example, the Prins reaction (step A) was prepared to produce 8,9-didehydro-6/8-dimethyl-2-hydroxymethyl-ergoline.
Výtěžek po krystalizaci z dichlormethanu 67 %/ /oC/Q β - 183° (0,5 % v pyridinu). Acetylací (stupeň B) trimethylacetylchloridem se ziská 8,9-dxdehydro-6/8-dimethyl-2-trimethylacetoxymethyl-ergolin v 80% výtěžku/ /o4/0 => - 147° (0,5 % v chloroformu).Yield after crystallization from 67% dichloromethane / / OC / Q β - 183 ° (0.5% in pyridine). Acetylation (Step B) to provide 8.9 trimethylacetyl-dxdehydro-6/8-dimethyl-2-trimethylacetoxymethyl-ergoline in 80% yield / / O4 / 0 => - 147 ° (0.5% in chloroform).
Z tohoto se redukci lithiem v amoniaku (stupeň D) získá 8/9-didehydro-2,6,8-trimethyl-ergolin v 95% výtěžku, /04·/D » - 179° (0,5 % v chloroformu). Potom se s bromkya-. nem (jak popsáno pod 1) vyrobí 8,9-didehydro-2,8-dimethyl-6-ergolin-karbonitril v 74% výtěžku/ /od/D = + 36° (0,1 % v chloroformu).From this, lithium in ammonia reduction (step D) affords 8? -Didehydro-2,6,8-trimethyl ergoline in 95% yield,? 4? D ? -179 ° (0.5% in chloroform). Then, with cyanogen bromide. nem (as described under 1) produced 8,9-didehydro-2,8-dimethyl-6-ergoline-carbonitrile in 74% yield ([α] D = + 36 ° (0.1% in chloroform).
5,4 g 8/9-Didehydro-2/8-dimethyl-5-ergolin-karbonitrilu (20 mmol) se rozpustí v 1 litru ledové kyseliny octové, přidá se 20 ml vody a 5 g zinkového prachu a 2 hodiny se zahřívá na 110 °C. Po přidáni dalších 3 g zinkového prachu a 10 ml vody reakce je po 90 minutách při 110 °c ukončena. Potom se sraženina odfiltruje, filtrát se hodně zahustí, zalkalizuje roztokem amoniaku a vytřepe se acetátem. Organická fáze se suši síranem sodným a odpaří se/ zbytek krystaluje z acetátu.5.4 g of 8/9-Didehydro-2/8-dimethyl-5-ergoline-carbonitrile (20 mmol) are dissolved in 1 liter of glacial acetic acid, 20 ml of water and 5 g of zinc dust are added and heated for 2 hours. Mp 110 ° C. After the addition of an additional 3 g of zinc dust and 10 ml of water, the reaction is complete after 90 minutes at 110 ° C. The precipitate is then filtered off, the filtrate is much concentrated, basified with ammonia solution and shaken with acetate. The organic phase was dried over sodium sulfate and the residue was crystallized from acetate.
Výtěžek: 2,6 g (53 % teorie)/ ZoC/0 = - 141° (0/5 % v chloroformu).Yield: 2.6 g (53% of theory) [.alpha.] D @ 20 = -141 DEG ( 0 / 5 % in chloroform).
CS 275 6 95 B6CS 275 6 95 B5
7. ) Obecný pracovní předpis k alkylaci v poloze 67.) General working instructions for alkylation in position 6
1,0 mmol ergolinu, 7,0 mmol uhličitanu draselného, 0,5 mmol tetrabutylamoniumhydrosulfátu a 50 ml nitromethanu se dají v uvedeném pořadí dohromady a přidá se 5 mmol alkylačního prostředku (v případě chlormethylcyklopropanu se použije 10 ekvivalentů a navic se přidají 2 ekvivalenty bezvodého lithiumjodidu). Michá se při 20 až 50 °C (mezi 2 a 47 hodinami, DC) a potom se filtruje přes pisek/celit. Zbytek na filtru se důkladně promyje dichlormethanem a rozpouštědlo se ve vakuu odstraní. Zbytek se filtruje přes oxid hlinitý (akt. 3) (acetát) a surový produkt získaný po odtaženi rozpouštědla krystaluje.Ergoline (1.0 mmol), potassium carbonate (7.0 mmol), tetrabutylammonium hydrosulfate (0.5 mmol) and nitromethane (50 mL) were combined and 5 mmol of the alkylating agent were added (10 equivalents for chloromethylcyclopropane plus 2 equivalents anhydrous) lithium iodide). Stir at 20 to 50 ° C (between 2 and 47 hours, DC) and then filter through sand / celite. The filter residue was washed well with dichloromethane and the solvent was removed in vacuo. The residue was filtered through alumina (act. 3) (acetate) and the crude product obtained after removal of the solvent crystallized.
V mnoha případech se potom musi ještě chromatografovát.In many cases, further chromatography is required.
Analogicky se vyrobí;It is prepared analogously;
8.9- Didehydro-8-methyl-6-n-propyl-ergolin8.9-Didehydro-8-methyl-6-n-propyl-ergoline
Výtěžek: 64 % (krystalováno z acetátu), /oC/g - 121,6° (c = 0,5 v chloroformu), teplota táni 127 až 130 °C (z acetátu)Yield: 64% (crystallized from acetate), [α] D / g - 121.6 ° (c = 0.5 in chloroform), melting point 127-130 ° C (from acetate)
6-Allyl-8,9-didehydro-8-methyl-ergolin6-Allyl-8,9-didehydro-8-methyl-ergoline
Výtěžek: 15 % (krystalováno z acetát/hexan), /<?C/D => - 161,5° (c = 0,4 v chloroformu), teplota tání 156 až 158 °C (z acetát/hexan).Yield: 15% (crystallized from acetate / hexane), [α] D => - 161.5 ° (c = 0.4 in chloroform), m.p. 156-158 ° C (from acetate / hexane).
6-Cyklopropylmethyl-8,9-didehydro-8-methyl-ergolin6-Cyclopropylmethyl-8,9-didehydro-8-methyl-ergoline
Výtěžek: 68 % (41 % krystalů z acetát/hexan), /oC/D a - 126,6° (c = 0,5 v chloroformu), teplota tání 192 až 195 °C (z acetát/hexan).Yield: 68% (41% of acetate / hexane crystals), [α] D / D - 126.6 ° (c = 0.5 in chloroform), mp 192-195 ° C (from acetate / hexane).
8.9- Didehydro-6-ethyl-8-methyl-ergolin8.9-Didehydro-6-ethyl-8-methyl-ergoline
Výtěžek: 30 % (25 % krystalů z acetátu), teplota tání 225 až 229 °C, subl. od 180 °C (z acetátu).Yield: 30% (25% acetate crystals), mp 225-229 ° C, subl. from 180 ° C (from acetate).
8. ) 8,9-Dldehyd ro-8~hydroxymethyl-6-n-propyl-ergolin8.) 8,9-Dihydro-8-hydroxymethyl-6-n-propyl-ergoline
Rozpustí se 19 g 8,9-Didehydro-8-hydroxymethyl-ergolinu (80 mmol) v 1,5 litru DMF, přidá se 46 ml diazabicyklondecenu a 73 ml 1-brompropanu (0,8 mol) a michá se 5 hodin při teplotě místnosti a 1 hodinu při 50 °C. Nechá se ochladit, přidá se polonasycený roztok kuchyňské sole a extrahuje sa dichlormethanem. Organické fáze se suší a nakonec po přidáni toluenu se odpaří k suchu. Zbytek se chromatografuje na silikagelu a krystaluje z acetátu.Dissolve 19 g of 8,9-Didehydro-8-hydroxymethyl-ergoline (80 mmol) in 1.5 liters of DMF, add 46 ml of diazabicyclondecene and 73 ml of 1-bromopropane (0.8 mol) and stir at room temperature for 5 hours. room and 1 hour at 50 ° C. Allow to cool, add a half-saturated solution of common salt and extract with dichloromethane. The organic phases are dried and finally evaporated to dryness after addition of toluene. The residue is chromatographed on silica gel and crystallized from acetate.
Výtěžek: 13 g (58 % teorie), /06/Q = - 41° (0,5 % v pyridinu)Yield: 13 g (58% of theory). [.Alpha.] D = -41 DEG (0.5% in pyridine)
Analogickým způsobem se vyrobí:The following are produced in an analogous manner:
6-Ethyl-8,9-didehydro-8-hydroxymethyl-erolin6-Ethyl-8,9-didehydro-8-hydroxymethyl-eroline
Výtěžek 43 %Yield 43%
6-Allyl-8,9-didehydro-8-hydrDXYmethyl-ergolin6-Allyl-8,9-didehydro-8-hydropyloxymethyl-ergoline
Výtěžek 67 %Yield 67%
Příklad 1Example 1
Analogicky pracovnímu předpisu (7) k alkylaci v poloze 6, popsanému u výroby výchozích sloučenin se získají:Analogously to the working procedure (7) for the alkylation at the 6-position described in the preparation of the starting compounds, the following are obtained:
8.9- Didehydro-6-ethyl-2,8-dimethyl-ergolin8.9-Didehydro-6-ethyl-2,8-dimethyl-ergoline
Výtěžek 15 %, /D = - 184° (0,1 % v chloroformu)Yield 15%, [ α ] D = -184 ° (0.1% in chloroform)
8.9- Didehydro-2,8-dimethyl-6-n-propyl-ergolln8.9-Didehydro-2,8-dimethyl-6-n-propyl ergoline
Výtěžek 60 %, /^/q b ~ 152° (0,5 % v chloroformu)Yield 60%, / ^ / q b ~ 152 ° (0.5% in chloroform)
CS 276 696 ΒδCS 276 696
6-Ally1-8,9-didehydro-2,8-dimethyl-ergolin6-Allyl-8,9-didehydro-2,8-dimethyl-ergoline
Výtěžek 18 %, /<x/D = - 192° (0,5 % v chloroformu)Yield 18%, [ .alpha. ] D = -192 DEG (0.5% in chloroform)
6-Cyklopropylmethy1-8,9-didehydro-2,8-dimethyl-ergolin6-Cyclopropylmethyl-8,9-didehydro-2,8-dimethyl-ergoline
Výtěžek 9 %, /oO/D = - 153° (0,!l % v chloroformu)Yield 9% / oO / D = - 153 ° (0,! L%, chloroform)
Přiklad 2Example 2
Analogicky metodě (8) popsané při výrobě výchozich sloučenin se ziskaji:Analogous to the method (8) described in the preparation of the starting compounds, the following are obtained:
8.9- Oidehydro-6-ethyl-8-hYdroxymethyl-2-methYl-ergolin8.9-Oidehydro-6-ethyl-8-hydroxymethyl-2-methyl-ergoline
Výtěžek 29 /<%-/0 3 - 141° (0,'5 % v pyridinu)Yield 29 / <% - / 0 3 - 141 ° (0, of 5% in pyridine)
8.9- Didehydro-8-hydroxyinethyl~2-methyl-6-n-propYl-ergolin8.9-Didehydro-8-hydroxyinethyl-2-methyl-6-n-propyl-ergoline
Výtěžek 13 %; /oC/D = - 78° (0,5 % v pyridinu)Yield 13%; [α] D = -78 ° (0.5% in pyridine)
6-Allyl-8,'9-didehydro-8-hydroxymethyl-2-methyl-ergolin6-Allyl-8,9-didehydro-8-hydroxymethyl-2-methyl-ergoline
Výtěžek 19 %; /oC/D 3 “ 150° (θ*5 % v pyridinu)Yield 19%; / oC / D 3 '150 ° (θ * 5 % in pyridine)
6-Cyklopropylmethyl-8,9-didehydro-8-hydroxymethyl-2-methyl-ergolin6-Cyclopropylmethyl-8,9-didehydro-8-hydroxymethyl-2-methyl-ergoline
Výtěžek 27 %Yield 27%
Přiklad 3Example 3
8-AcetoxYmethYl-8,9-didehYdro-2-methyl-6-n-propYl-ergolin8-Acethoxymethyl-8,9-dihydro-2-methyl-6-n-propyl ergoline
231 ml 8,9 Didehydro-8-hydroxymethyl-2-methyl-6-n-propyl-ergolinu (0,79 mmol) se rozpustí ve 4 ml pyridinu, přidá se 0,8 ml acetanhydridu a míchá se 30 minut při teplotě místnosti. Potom se přidá led, nechá se 1 hodinu stát, zalkalizuje se amoniakem a extrahuje dichlormethanem. Organické fáze se suši síranem sodným a odpaři. Výtěžek po krystalizaci zs směsi diisopropylather/hsxan 160 mg (60 % teorie), /o^/D = - 113° (0,5 % v chlo roformu).231 ml of 8.9 Didehydro-8-hydroxymethyl-2-methyl-6-n-propyl-ergoline (0.79 mmol) are dissolved in 4 ml of pyridine, 0.8 ml of acetic anhydride is added and stirred for 30 minutes at room temperature. . Ice was then added, allowed to stand for 1 hour, basified with ammonia and extracted with dichloromethane. The organic phases are dried over sodium sulphate and evaporated. Yield after crystallization from diisopropyl ether / hexane 160 mg (60% of theory), [ .alpha. ] D = -113 DEG (0.5% in chloroform).
Příklad 4Example 4
2-Chlor-8,9-didehydro-8-hydroxymethyl-6-n-propyl-ergolin2-Chloro-8,9-didehydro-8-hydroxymethyl-6-n-propyl-ergoline
V 900 ml dioxanu se rozpustí 0,97 g 8-acetoxYmethyl-8,9-didehydro-6-n-propyl-ergolinu (3 mmol); přidá se 1 g N-chlorsukcinimidu a michá se 16 hodin při 90 °C. Pak se nechá ochladit, přidá sa nasycený roztok kuchyňské sole a třikrát se vytřepe acetátem. Organické fáze se suši síranem sodným, odpaři se a na oxidu hlinitém se chromatografuje dichloi— methanem a acetátem. Surový produkt se rozpustí ve 20 ml tetrahydrofuranu a 20 ml 1 N lou hu draselného a 4 hodiny sa michá při teplotě místnosti. Zpracuje se jak popsáno shora, zbytek se chromatografuje na silikagelu směsi acetát/methanol a pak krystaluje z dichlormethanu.0.97 g of 8-acetoxylmethyl-8,9-didehydro-6-n-propyl ergoline (3 mmol) is dissolved in 900 ml of dioxane; 1 g of N-chlorosuccinimide is added and stirred for 16 hours at 90 ° C. It is then allowed to cool, saturated sodium chloride solution is added and the mixture is shaken with acetate three times. The organic phases are dried over sodium sulphate, evaporated and chromatographed on alumina with dichloromethane and acetate. The crude product was dissolved in 20 ml of tetrahydrofuran and 20 ml of 1 N potassium hydroxide solution and stirred at room temperature for 4 hours. Working up as described above, the residue is chromatographed on silica gel with an acetate / methanol mixture and then crystallized from dichloromethane.
Výtěžek 53 mg (6 % teorie), /«5/0 = - 126° (0,1 % v pyridinu).Yield: 53 mg (6% of theory); [.alpha.] D = -126 DEG (0.1% in pyridine).
Analogicky sa vyrobí následující sloučeniny:The following compounds are prepared analogously:
2-Chlor-8,9-didehydro-8-methyl-6-n-propyl-argolin2-Chloro-8,9-didehydro-8-methyl-6-n-propyl-argoline
Výtěžek 27 %Yield 27%
2-Chlor-8,9-didehydro-6-ethyl-8-methyl-ergolin2-Chloro-8,9-didehydro-6-ethyl-8-methyl-ergoline
Výtěžek 19 %Yield 19%
2-Chlor-8,9-didehydro-6-ethyl-8-hydroxymethyl-ergolin2-Chloro-8,9-didehydro-6-ethyl-8-hydroxymethyl-ergoline
Výtěžek 29 %Yield 29%
CS 27S 696 B6CS 27S 696 B6
Výchoz! sloučenina 8-acetoxYmethYl-8,9-didehYdro-S-n-propyl-ergolin se zieká analogicky příkladu 3.Out! the compound 8-acetoxylmethyl-8,9-dihydro-S-n-propyl-ergoline is obtained analogously to Example 3.
Výtěžek 52 %, /<jč/D = - 38° (0,5 % v chloroformu)Yield 52%, [.alpha.] D = -38 DEG (0.5% in chloroform)
Přiklad 5Example 5
2-Brom-8,9-didehydro-8-methyl-6-n-propyl-ergolin2-Bromo-8,9-didehydro-8-methyl-6-n-propyl-ergoline
Ve 40 ml dioxanu se rozpustí 533 mg 8,9-didehydro-8-methyl-6-n-propyl-ergolinu (2 mmol) a přidá se 1,092 g pyrrolidon-hydrotribromidu (2,2 mmol) v 6 dávkách, které se přidají v 15 minutových intervalech. K tomu se dá 0,5 ml acetonu, michá se 15 minut a pak se amoniakem zalkalizuje. Směs se zředí vodou a vytřepe dichlormethanem. Organické fáze se suší a odpaří. Zbytek se chromatografuje na silikagelu směsi hexan/aceton a pak krystaluje z acetátu.Dissolve 533 mg of 8,9-didehydro-8-methyl-6-n-propyl-ergoline (2 mmol) in 40 mL of dioxane and add 1.092 g of pyrrolidone hydrotribromide (2.2 mmol) in 6 portions. at 15 minute intervals. To this is added 0.5 ml of acetone, stirred for 15 minutes and then made alkaline with ammonia. The mixture was diluted with water and shaken with dichloromethane. The organic phases are dried and evaporated. The residue is chromatographed on silica gel with hexane / acetone and then crystallized from acetate.
Výtěžek 324 mg (47 % teorie),' /0C/D a - 163° (0,5 % v pyridinu)Yield 324 mg (47%), '/ 0C / D - 163 ° (0.5% in pyridine)
Analogicky se vyrobí:The following are produced analogously:
6-Allyl-2-brom-8,9-didehydro-8-methyl-ergolin6-Allyl-2-bromo-8,9-didehydro-8-methyl-ergoline
Výtěžek 47 %Yield 47%
2-Brom-8,9~didehydro-6-ethyl-8-hydroxYmethYl-ergolin2-Bromo-8,9-didehydro-6-ethyl-8-hydroxymethyl-ergoline
Výtěžek 73 %Yield 73%
2-Bram“8,9-didehydro-8-hydroxYmethyl-6-n-propYl-ergolin2-Potato 8,9-didehydro-8-hydroxymethyl-6-n-propyl-ergoline
Výtěžek 43 %, /o<//D = - 125° (0,5 % v pyridinu)Yield 43%, [α] D = - 125 ° (0.5% in pyridine)
6-Allyl-2-brom-8,9-didehydro-8-hydroxymethyl-ergolin6-Allyl-2-bromo-8,9-didehydro-8-hydroxymethyl-ergoline
Výtěžek 38 %Yield 38%
Přiklad 6Example 6
8,9-Didehydro-8-methyl-6-n-propyl-2-vinyl-ergolin8,9-Didehydro-8-methyl-6-n-propyl-2-vinyl-ergoline
1. 8,9-Didehydro-8-methyl-2-morfolinomethyl-6-n-propyl-ergolin1. 8,9-Didehydro-8-methyl-2-morpholinomethyl-6-n-propyl-ergoline
7,47 g 8,9-Didehydro~8-methyl-6-n-propyl-ergolinu; 24,0 g (0,19 mol) morfolinhydrochloridu; 4;5 g (0;l5 mol) paraformaldehydu a 220 ml suchého dimethylformamidu se dá v uvedeném pořadí dohromady a směs se 30 minut michá na olejové lázni vyhřáté na 100 °C. Ke zpracováni se reakční roztok vylije na led, zalkalizuje se 25% roztokem NHg a extrahuje toluenem, Po sušeni NagSO^ a odtaženi toluenu ve vakuu se získaný surový produkt rozpust! ve na led a zalkalizuje se 25% roztokem NHg. Po extrakci dichlormethanem, sušeni NagSO^ a odtažení rozpouštědla ve vakuu se získá tmavý olej; který se čisti chromatografií.7.47 g of 8,9-Didehydro-8-methyl-6-n-propyl-ergoline; 24.0 g (0.19 mol) of morpholine hydrochloride; 4.5 g (0.15 mol) of paraformaldehyde and 220 ml of dry dimethylformamide are combined in this order, and the mixture is stirred in an oil bath heated to 100 ° C for 30 minutes. For work-up, the reaction solution was poured on ice, basified with 25% NH4 solution and extracted with toluene. in ice and basified with 25% NH 4 solution. Extraction with dichloromethane, drying of Na 2 SO 4 and removal of the solvent in vacuo gave a dark oil; which is purified by chromatography.
Výtěžek: 60 %, /oC/D = - 108,6° (c » 0,5 v chloroformu)Yield: 60%, [α] D = - 108.6 ° (c »0.5 in chloroform)
2. 8,9-Didehydro-2-formyl-8~methyl-6-n-propyl-ergolin2. 8,9-Didehydro-2-formyl-8-methyl-6-n-propyl-ergoline
3,65 g této Mannichovy báze (10 mmol) se rozpustí ve 160 ml tetrahydrofuranu p.a., ochladí se na -40 °C a přidá sa 1,6 až 3,2 ml (11,5 až 23,0 mmol) triethylaminu. Potom se najednou přikape roztok 1,5 ml (12,3 mmol) terč. butylhypochloridu ve 25 ml tetrahydrofuranu. Po 5 minutách se směs kontroluje chromatograficky na tenké vrstvě DC. V případě, že se ještě nechá dokázat edukt, přidá sa ještě hypochlorid. 30 minut po posledním přidáni (DC) se násada vylije na led, alkalizuje se 25% roztokem NHg a extrahuje acetátem. Surový produkt získaný po odtažení rozpouštědla se musi chromatografovat.3.65 g of this Mannich base (10 mmol) are dissolved in 160 ml of tetrahydrofuran p.a., cooled to -40 ° C and 1.6 to 3.2 ml (11.5 to 23.0 mmol) of triethylamine are added. Thereafter, a solution of 1.5 ml (12.3 mmol) of the tert. butyl chloride in 25 ml of tetrahydrofuran. After 5 minutes, the mixture is checked by TLC. If it is still possible to prove the starting material, hypochloride is added. 30 minutes after the last addition (DC), the batch is poured onto ice, basified with 25% NH 4 solution and extracted with acetate. The crude product obtained after removal of the solvent must be chromatographed.
Výtěžek: 38 %, /c^/g = - 223,8° (c β 0,1 v chloroformu)Yield: 38%, [α] 23 D = - 223.8 ° (c β 0.1 in chloroform)
CS 276 696 B6CS 276 696 B6
3. 8,9-DidehYdro-2-(l-hydroxy-ethYl)-8-methyl-6-n-propYl-ergolin3. 8,9-Dimethyl-2- (1-hydroxy-ethyl) -8-methyl-6-n-propyl-ergoline
Ve 150 ml suchého tetrahydrofuranu se rozpustí 1,47 g aldehydu (5,0 mmol) a ochladí se na -65 °C. V 5 až 7 dávkách se přidá 10 až 15 mmol methyllithia (1,6 M roztok v etheru). Po posledním přidáni se nechá roztát a michá se 30 minut při teplotě místnosti. Průběh reakce se sleduje chromatografleky na tenké vrstvě. Ke zpracování ss vylije na lad, zalkalizuje 25% roztokem ΝΗθ a extrahuje se acetátem. Surový produkt získaný po odtažení rozpouštědla se chromatografuje.Dissolve 1.47 g of aldehyde (5.0 mmol) in 150 mL of dry tetrahydrofuran and cool to -65 ° C. Methyl lithium (10-15 mmol, 1.6 M in ether) was added in 5-7 portions. After the last addition, it is thawed and stirred at room temperature for 30 minutes. The progress of the reaction was monitored by thin layer chromatography. For work-up, pour the ice on ice, basify with 25% ΝΗθ solution and extract with acetate. The crude product obtained after stripping off the solvent is chromatographed.
Výtěžek: 63 %.Yield: 63%.
4. 8j9-Didehydro-8-methyl-6-n-propyl-2-vinyl-ergolin4. 8,9-Didehydro-8-methyl-6-n-propyl-2-vinyl-ergoline
300 mg předchozího surového produktu se rozpueti ve 40 ml tetrahydrofuranu p.a. a přidá se 1,4 ml (10 mmol) triethylaminu. Po přidáni 0,8 (10 mmol) chloridu kyseliny methansulfonové se michá ještě 30 minut při teplotě místnosti (DC po 5 minutách). Potom se směs vylije na led, alkalizuje 25% roztokem NH3 a extrahuje se acetátem. Surový produkt získaný po odpařeni rozpouštědla ve vakuu se chromatografuje.300 mg of the previous crude product are dissolved in 40 ml of tetrahydrofuran AR and 1.4 ml (10 mmol) of triethylamine are added. After addition of 0.8 (10 mmol) methanesulfonic acid chloride, it is stirred for 30 minutes at room temperature (DC after 5 minutes). Then the mixture was poured onto ice, basified with 25% NH 3 solution and extracted with acetate. The crude product obtained after evaporation of the solvent in vacuo is chromatographed.
Výtěžek po chromatografii (acetát/dichlormethan 1:1) 41 % (12 % krystaluje z acetát/hexan),' teplota tání 172 až 174,5 °C (rozkl.), /°6/0 = - 201,3° (c = 0,2 v chloroformu).Yield after chromatography (ethyl acetate / dichloromethane 1: 1) 41% (12% crystallized from ethyl acetate / hexane) Melting point 172 DEG-174.5 DEG C. (dec.) / 6 ° / 0 = - 201.3 ° ( c = 0.2 in chloroform).
Přiklad 7Example 7
8.9- Didehydro-8-hYdroxYmethyl-S-n-propyl-2-vinyl~ergolin8.9-Didehydro-8-hydroxymethyl-S-n-propyl-2-vinyl-ergoline
1. 8-Acetoxymethyl-8,9-didehydro-2-hydroxYmethyl-6-n-propYl-ergolin1. 8-Acetoxymethyl-8,9-didehydro-2-hydroxymethyl-6-n-propyl-ergoline
Oak v předcházejícím přikladu popsáno jako stupeň 1,‘ získá se z 5,99 g 8-acetoxymethyl-8,'9-didehydro-6-n-propYl-ergolinu (18,5 mmol) po zpracování a chromatografii 3,86 g 2-hydroxymethyl-slouěeniny (asi 56 % teorie) jako olej.Oak as described in Step 1 above, obtained from 5.99 g of 8-acetoxymethyl-8,9-didehydro-6-n-propyl-ergoline (18.5 mmol) after work-up and chromatography 3.86 g 2 hydroxymethyl compounds (about 56% of theory) as an oil.
2. 8-Acetoxymethyl-8,9-didehydro-2-formyl-6-n-propyl-ergolin2. 8-Acetoxymethyl-8,9-didehydro-2-formyl-6-n-propyl-ergoline
Tento produkt se rozpustí ve 275 ml dichlormethanu, přidá se 12,6 g burele a 5 hodin se michá při teplotě místnosti. Potom se chromatografuje dichlormethanem na oxidu hlinitém a odpaří se.This product was dissolved in 275 ml of dichloromethane, 12.6 g of burel was added and stirred at room temperature for 5 hours. It is then chromatographed on dichloromethane with dichloromethane and evaporated.
Výtěžek: 1,98 g.Yield: 1.98 g.
3. 8-Acetoxymethyl-8,9-didehydro-6-n-propyl-2-vinyl-ergolin3. 8-Acetoxymethyl-8,9-didehydro-6-n-propyl-2-vinyl-ergoline
9,64 g methyl-trifenylfosfoniumbromidu se suspenduje ve 160 ml bezvodého tetrahydrofuranu a za chlazeni ledem se přidá 2,42 g terč. butylátu draselného. Michá se 30 minut za chlazení ledem, teplota se sníží na -50 °C a přikape ss roztok aldehydu v 80 ml tetrahydrofuranu. Během 3 hodin se nechá zahřát na -10 °C; přidá se nasycený roztok kuchyňské sole a vytřepe se acetátem. Produkt se chromatografuje na silikagelu hexan/acetonem.9.64 g of methyl triphenylphosphonium bromide are suspended in 160 ml of anhydrous tetrahydrofuran and 2.42 g of a target are added under ice-cooling. potassium butylate. After stirring for 30 minutes under ice-cooling, the temperature was lowered to -50 ° C and a solution of the aldehyde in 80 ml of tetrahydrofuran was added dropwise. Allow to warm to -10 ° C over 3 hours; add saturated brine and shake with acetate. The product is chromatographed on silica gel with hexane / acetone.
Výtěžek: 1,48 gYield: 1.48 g
4. 8,9-Didahydro-8-hydroxymethyl-6-n-propyl-2-vinYl-ergolin4. 8,9-Didahydro-8-hydroxymethyl-6-n-propyl-2-ynyl-ergoline
Zmýdelnění acetylové skupiny se dosáhne rozpuštěním substance ve 40 ml dichlormethanu a 40 ml methanolu v přítomnosti 80 mg msthylátu sodného za 22 hodin, při teplotě místnosti. Směs se vlije do nasyceného roztoku kuchyňské sole, extrahuje se dichlormethanem, organické fáze se suši síranem sodným a odpaří se. Zbytek se chromatografuje acetátem na oxidu hlinitém.The saponification of the acetyl group is achieved by dissolving the substance in 40 ml of dichloromethane and 40 ml of methanol in the presence of 80 mg of sodium m-methylate in 22 hours at room temperature. The mixture was poured into saturated brine, extracted with dichloromethane, the organic phases were dried over sodium sulfate and evaporated. The residue is chromatographed with acetate on alumina.
Výtěžek: 527 mg, z čehož z acetátu krystaluje 133 mg (celkový výtěžek 2,3 %), /oC/Q = - 141° (0,1 % v pyridinu).Yield: 527 mg, of which 133 mg (2.3% overall yield) crystallized from acetate, [α] D = -141 ° (0.1% in pyridine).
Přiklad 8Example 8
8.9- Didehydro-2-ethyí-8-hydroxYmethyl-6-n-propyl-ergolin8.9-Didehydro-2-ethyl-8-hydroxymethyl-6-n-propyl-ergoline
CS 275 695 BS □ak popsáno při výrobě výchozích sloučenin a 5D (anilin neni nutný) se 370 mg 8,9-didahydro-8-hydroxYmethyl-6-n-propyl-2-vinyl-argollnu (1,2 mmol) redukuje lithiem v amoniaku, zpracuje se, na silikagelu se chromatografuje acetát/methanolem a za směsi dichlormethan/diisopropylether/haxan krystaluje.CS 275 695 BS as described in the preparation of the starting compounds and 5D (aniline not required) with 370 mg of 8,9-didahydro-8-hydroxylmethyl-6-n-propyl-2-vinyl-argoline (1.2 mmol) is reduced with lithium in ammonia, worked up, chromatographed on silica gel with acetate / methanol and crystallized with dichloromethane / diisopropyl ether / haxane.
Výtěžek: 108 mg (29 % teorie), a - 117° (0,1 % v pyridinu)Yield: 108 mg (29% of theory), and - 117 ° (0.1% in pyridine)
Přiklad 9Example 9
8,9-Dxdehydro-2-ethyl-8-methyl-6-n-propyl-ergolin8,9-D-dehydro-2-ethyl-8-methyl-6-n-propyl-ergoline
2)0 mmol didehydro-2-(l-hydroxYmethYl)-8-methyl-6-n-propyl-ergolinu se rozpustí ve 25 ml ledové kyseliny octové a pod argonem se přidá 1,0 g (25,4 mmol) natriumborhydridu (půl tablety). Po ukončení reakce (DC) se vylije na led, za chlazeni alkalizuje 25% roztokem NH3 a extrahuje se dichlormethanem. Po odtažení rozpouštědla ve vakuu se získaný produkt chromatografuje dichlormethanem přes oxid hlinitý.(2) 0 mmol of didehydro-2- (1-hydroxymethyl) -8-methyl-6-n-propyl ergoline is dissolved in 25 ml of glacial acetic acid and 1.0 g (25.4 mmol) of sodium borohydride (25.4 mmol) is added under argon. half a tablet). After completion of the reaction (DC), it was poured onto ice, basified with 25% NH 3 solution under cooling and extracted with dichloromethane. After removal of the solvent in vacuo, the product obtained is chromatographed with dichloromethane over alumina.
Výtěžek: 65 % (52 % krystaly z acetát/diisopropyletheru)) teplota táni 152 až 154 °C, /cC/D s - 149,7° (c = 0,5 % v chloroformu).Yield: 65% (52% acetate / diisopropyl ether crystals) m.p. 152-154 ° C, [α] D -149.7 ° (c = 0.5% in chloroform).
Claims (5)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3938701A DE3938701A1 (en) | 1989-11-20 | 1989-11-20 | NEW AGROCLAVIN AND ELYMOCLAVIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS560490A3 CS560490A3 (en) | 1992-02-19 |
| CS276696B6 true CS276696B6 (en) | 1992-07-15 |
Family
ID=6393974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS905604A CS276696B6 (en) | 1989-11-20 | 1990-11-13 | Ergoline derivatives, process for their preparation and their use in medicaments |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0429153A1 (en) |
| JP (1) | JPH03209378A (en) |
| CA (1) | CA2030340A1 (en) |
| CS (1) | CS276696B6 (en) |
| DE (1) | DE3938701A1 (en) |
| HU (1) | HU208010B (en) |
| IE (1) | IE904174A1 (en) |
| PT (1) | PT95927A (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4382940A (en) * | 1979-12-06 | 1983-05-10 | Farmitalia Carlo Erba S.P.A. | Ercoline derivatives and therapeutic compositions having CNS affecting activity |
| DD237837A1 (en) * | 1983-11-29 | 1986-07-30 | 1086 Berlin,Otto-Nuscke-Str. 2/23,Dd | PROCESS FOR THE PREPARATION OF 2-BROMERGOLINS |
| ATE107647T1 (en) * | 1984-04-09 | 1994-07-15 | Schering Ag | 2-SUBSTITUTED ERGOLINE DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS. |
| DE3708028A1 (en) * | 1987-03-10 | 1988-09-22 | Schering Ag | METHOD FOR PRODUCING 2,3SS-DIHYDROERGOLINES, 2-SUBSTITUTED 2,3SS-DIHYDROERGOLINES AND THEIR USE AS MEDICINAL PRODUCTS |
-
1989
- 1989-11-20 DE DE3938701A patent/DE3938701A1/en not_active Withdrawn
-
1990
- 1990-11-13 CS CS905604A patent/CS276696B6/en unknown
- 1990-11-15 JP JP2307324A patent/JPH03209378A/en active Pending
- 1990-11-19 PT PT95927A patent/PT95927A/en not_active Application Discontinuation
- 1990-11-19 HU HU907198A patent/HU208010B/en not_active IP Right Cessation
- 1990-11-20 EP EP90250287A patent/EP0429153A1/en not_active Withdrawn
- 1990-11-20 CA CA002030340A patent/CA2030340A1/en not_active Abandoned
- 1990-11-20 IE IE417490A patent/IE904174A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3938701A1 (en) | 1991-05-23 |
| CA2030340A1 (en) | 1991-05-21 |
| JPH03209378A (en) | 1991-09-12 |
| HUT56101A (en) | 1991-07-29 |
| HU907198D0 (en) | 1991-05-28 |
| HU208010B (en) | 1993-07-28 |
| PT95927A (en) | 1991-09-13 |
| IE904174A1 (en) | 1991-05-22 |
| CS560490A3 (en) | 1992-02-19 |
| EP0429153A1 (en) | 1991-05-29 |
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