DK161646B - Fremgangsmaade til fremstilling af ergolinderivater og farmaceutisk acceptable salte heraf - Google Patents
Fremgangsmaade til fremstilling af ergolinderivater og farmaceutisk acceptable salte heraf Download PDFInfo
- Publication number
- DK161646B DK161646B DK368382A DK368382A DK161646B DK 161646 B DK161646 B DK 161646B DK 368382 A DK368382 A DK 368382A DK 368382 A DK368382 A DK 368382A DK 161646 B DK161646 B DK 161646B
- Authority
- DK
- Denmark
- Prior art keywords
- acid
- carbon atoms
- acetate
- ergoline
- preparation
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- 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 abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 239000012948 isocyanate Substances 0.000 claims abstract description 7
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000005265 dialkylamine group Chemical group 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000002798 polar solvent Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- -1 alkaline earth metal carbonate Chemical class 0.000 claims description 7
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical class C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 101150009274 nhr-1 gene Proteins 0.000 claims 1
- 150000001412 amines Chemical class 0.000 abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 125000000520 N-substituted aminocarbonyl group Chemical group [*]NC(=O)* 0.000 abstract 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OLDDFPILKFODQU-JGGQBBKZSA-N (6aR,9S,10aR)-7-propyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C(CC)N1C[C@H](C[C@@H]2C=3C=CC=C4NC=C(C[C@@H]12)C=34)C(=O)N OLDDFPILKFODQU-JGGQBBKZSA-N 0.000 description 2
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- GENAHGKEFJLNJB-QMTHXVAHSA-N lysergamide Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(N)=O)=C3C2=CNC3=C1 GENAHGKEFJLNJB-QMTHXVAHSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- YFPQZLKFHUVMEA-IINYFYTJSA-N (6ar,9s)-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-amine Chemical compound C1=CC(C2=C[C@H](N)CN([C@@H]2C2)C)=C3C2=CNC3=C1 YFPQZLKFHUVMEA-IINYFYTJSA-N 0.000 description 1
- MRCIZFUKIDUOPT-BLLLJJGKSA-N (6ar,9s)-7-propyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C2=C[C@@H](CN([C@@H]2C2)CCC)C(N)=O)=C3C2=CNC3=C1 MRCIZFUKIDUOPT-BLLLJJGKSA-N 0.000 description 1
- OEVHDXFBOKGRLN-ZKYQVNSYSA-N (6ar,9s,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC([C@H]2C[C@@H](CN([C@@H]2C2)C)C(N)=O)=C3C2=CNC3=C1 OEVHDXFBOKGRLN-ZKYQVNSYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- FCRJELOYDVBTGW-ILZDJORESA-N 3-[(6ar,9s,10ar)-7-propyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-yl]-1,1-diethylurea Chemical compound C1=CC([C@H]2C[C@@H](CN([C@@H]2C2)CCC)NC(=O)N(CC)CC)=C3C2=CNC3=C1 FCRJELOYDVBTGW-ILZDJORESA-N 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
- WHBMMWSBFZVSSR-UHFFFAOYSA-M 3-hydroxybutyrate Chemical compound CC(O)CC([O-])=O WHBMMWSBFZVSSR-UHFFFAOYSA-M 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- GENAHGKEFJLNJB-UHFFFAOYSA-N 7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C2=CC(CN(C2C2)C)C(N)=O)=C3C2=CNC3=C1 GENAHGKEFJLNJB-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical group OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- ZAGRKAFMISFKIO-UHFFFAOYSA-N Isolysergic acid Natural products C1=CC(C2=CC(CN(C2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
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- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 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 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate 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
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- UGUXTXUAPLJEGU-FMLNKVPISA-N methyl (6aR,10aR)-6a,7,8,9,10,10a-hexahydro-6H-indolo[4,3-fg]quinoline-5a-carboxylate Chemical compound COC(=O)C12C[C@H]3NCCC[C@@H]3C=3C=CC=C(N=C1)C=32 UGUXTXUAPLJEGU-FMLNKVPISA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 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
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
-
- 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
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 161646 B
i
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af ergolinderivater med den almene formel: NHR^
9fS
1 1 2 il N-R , I 10 HN_ hvori C„---C,„ betegner en CC-enkelt-eller dobbeltbinding, y - i u 5 R1 betegner hydrogen eller gruppen C0NR„, hvori R betegner Δ 1 hydrogen, methyl eller ethyl, og grupperingen NR kan være 2 placeret i a- eller β-stilling, og R betegner lavere alkyl med indtil 3 carbonatomer, og syreadditionssalte heraf.
Ergolinerne, der kan fremstilles ved fremgangsmåden ifølge 10 opfindelsen, er enten selv biologisk virksomme forbindelser eller mellemprodukter til fremstilling af sådanne.
Det er kendt, at man ud fra hydraziderne af lysergsyre og isolysergsyre ved hjælp af Curtiusnedbrydning kan fremstille aminer og derivater deraf (urinstoffer, urethaner).
15 Denne fremgangsmåde har imidlertid den ulempe, at det ud fra hydrazidet dannede azid under reaktionsbetingelserne ikke er konfigurationsstabilt, og at den pågældende amin eller det pågældende aminderivat er forurenet med den anden isomer (A. Hoffmann, Helv. 30 44 (1947) og F. Troxler, 20 Helv. 30 163 (1947)).
Det har nu vist sig, at 8a- og 88-aminoergoliner og derivater deraf kan fremstilles på enkel måde og med høj renhed ved fremgangsmåden ifølge opfindelsen, efter der ikke finder nogen isomerisering sted ved C-8-carbonatomet.
25 Fremgangsmåden ifølge opfindelsen er kendetegnet ved, at man behandler carboxylsyreamidet med den tilsvarende C-8 DK 161646 8 2 konfiguration (α eller 3) med bly-IV-acetat i et aprot, polært opløsningsmiddel og omsætter det intermediært dannede isocyanat med vand i nærværelse af en syre, såsom svovlsyre eller perchlorsyre, eller en mono- eller dialkylamin | 5 med indtil 4 carbonatomer og eventuelt derpå omdanner til ?
det tilsvarende salt med en fysiologisk acceptabel syre. I
Bly-IV-acetatet anvendes i et overskud på 1,5 - 4 molækvivalenter, fortrinsvis 1,75 til 2,5 molækvivalenter.
Den påfølgende oparbejdning foregår på sædvanlig måde, 10 såsom ved hjælp af vaskning, filtrering, omkrystallisation, ekstraktion og kromatografi.
Det har vist sig, at tilsætning af et alkali- eller jord-alkalimetalcarbonat, såsom natrium-, kalium- eller cal= ciumcarbonat, er hensigtsmæssig, da dette binder eddike-15 syre, og dannelsen af acylaminer således forhindres ved hjælp af tillejring af eddikesyre fra bly-IV-acetatet til isocyanatet. Det tilsættes i en mængde på 5 - 10 molækvivalenter, regnet i forhold til den benyttede ergolin.
Hvis det ønskede slutprodukt skal opnås i form af et ad-20 ditionssalt, bliver den frie forbindelse opløst i f.eks.
ethanol og omsat med den ønskede syre. Som syrer egner sig alle fysiologisk acceptable syrer. Nævnes skal eksempelvis: Saltsyre, phosphorsyre, svovlsyre, hydrogenbromid-syre, salpetersyrling eller phosphorsyrling, eller organ-25 iske syrer, såsom eksempelvis alifatiske mono- eller di= carboxylsyrer, phenylsubstituerede alkancarboxylsyrer, hy= droxyalkancarboxylsyrer eller alkandicarboxylsyrer, aromatiske syrer eller alifatiske eller aromatiske sulfonsyrer. Fysiologisk acceptable salte af disse syrer er derfor 30 eksempelvis sulfatet, hydrogensulfatet, phosphatet, mono= hydrogenphosphatet, dihydrogenphosphatet, chloridet, bro= midet, acetatet, propionatet, decanoatet, caprylatet, acry= 3
DK 161646 B
latet, formiatet, isobutyratet, capronatet, heptanoatet, propiolatet, malonatet, succinatet, suberatet, sebacatet, hydrogenmaleatet, mandelatet, butyn-l,4-dioatet, hexyn--1,6-dioatet, benzoatet, chlorbenzoatet, methylbenzoatet, 5 hydroxybenzoatet, methoxybenzoatet, phthalatet, terephtha= latet, benzensulfonatet, toluensulfonatet, chlorbenzensul= fonatet, xylensulfonatet, phenylacetatet, phenylpropionat= et, phenylbutyratet, citratet, lactatet, 3-hydroxybutyrat= et, glycollatet, tartratet, methansulfonatet, propansulfo= 10 natet, naphthalen-l-sulfonatet eller naphthalen-2-sulfo- natet.
Forløbet af fremgangsmåden ifølge opfindelsen er overraskende, da det måtte forventes, at bly-IV-acetatet ville indvirke på indoldelen af ergolinmolekylet ved C-3 el-15 ler C-2 eller på det basiske nitrogenatom i 6-stillingen.
Som følge af arbejder vedrørende indoler, såsom eksempelvis af R.J. Sundberg, The Chemistry of Indoles in Organic Chemistry, Vol. 18, Academic Press, N.Y. & London 1970, især side 300, var det at forvente, at indolforbindelser 20 angribes af bly-IV-acetat.
Fremgangsmåden ifølge opfindelsen belyses i de efterfølgende eksempler.
Eksempel 1.
534,6 mg isolysergsyreamid (2 mmol) opløses i 10 ml dime= 25 thylformamid. Efter tilsætning af 0,6 g kaliumcarbonat sætter man portionsvis under køling med isvand 1,8 g bly-IV-acetat (98%-ig, 4 mmol) i løbet af 3 minutter til reaktionsblandingen, omrører i 5 minutter og tildrypper 8 ml frisk destilleret diethylamin, Efter 10 minutter vaskes 30 den med 50 ml methylenchlorid fortyndede reaktionsopløsning 2 gange, hver gang med 10 ml 16% vandig ammoniakopløsning, 4
DK 161646B
og eftervaskes til slut med 500 ml vand. Den over magnesium= sulfat tørrede og inddampede organiske fase filtreres på j 50 g aluminiumoxid (neutralt, aktivitetstrin II) med me= · | thylenchlorid-eddikeester 80:20. Den efter inddampning til- * 5 bageblivende rest, der består af 3-(9,10-didehydro-6-me= thyl-8a-ergolinyl)-1,1-di.eth.ylurinstofopløses i 10 ml ethanol, tilsættes en opløsning af 0,25 g maleinsyre i 5 ml ethanol, inddampes til 2/3 af volumenet og lades krystallisere natten over i køleskab efter podekrystal-10 tilsætning. Man isolerer 0,51 g 3-(9,10-didehydro-6~me= thyl-8a-ergolinyl)-1,1-diethylurinstof-hydrogenmaleat.
[a]^ = +288° (c = 0,5 i methanol) .
— Eksempel 2.
267,3 mg isolysergsyreamid (1 mmol) omsættes med bly-IV-15 acetat som beskrevet i eksempel 1. Reaktionsblandingen indføres forsigtigt i 25 ml IN svovlsyre, der forinden er blevet opvarmet til 85°C, efteromrøres i 5 minutter ved 80°C, tilsættes efter afkøling portionsvis 2 g natrium= hydrogencarbonat og efteromrøres i 15 minutter efter til-20 sætning af 25 ml methylenchlorid. Den samlede reaktionsopløsning filtreres gennem kiselgur, og den vandige fase eks-traheres 2 gange, hver gang med 20 ml methylenchlorid. Ind-dampningsresten af de forenede methylenchloridfaser filtreres gennem kiselgel med methanol-vand 95:5. Man opnår 25 84 mg 9,10-didehydro-6-methyl-ergolin-8a-amin.
[a]^ = +260° (c = 0,5 i pyridin) .
\
Eksempel 3.
Analogt med eksempel 1 omsættes 295 mg 9,10-didehydro-6-n- ... .... propyl-8a-ergolin-carboxylsyreamid med bly-IV-acetat til 5
DK 161646B
dannelse af isocyanatet, der reagerer med diethylamin til dannelse af den tilsvarende urinstofforbindelse. Efter oparbejdning opnår man efter kromatografi på aluminiumoxid med methylenchlorid-eddikeester 120 mg 3-(9,10-didehydro-5 6-n-propyl-8a-ergolinyl)-1,1-diethylurinstof.
Fremstilling af udgangsmaterialet.
Ud fra 3,1 g 9,10-didehydro-6-n-propyl-8|3-ergolin-carboxyl= syremethylester opnår man via henståen i en opløsning af ammoniak i ethylenglycol en blanding af de isomere amider, 10 hvorfra 1,2 g 9,10-didehydro-6-n-propyl-8a-ergolin-car= boxylsyreamid kan fraskilles kromatografisk.
[a]p5 = +297° (c = 0,5 i pyridin).
Eksempel 4.
538 mg 6-methyl-ergolin-8a-carboxylsyreamid (2 mmol) bliver 15 som beskrevet i eksempel 1 omsat med bly-IV-acetat til dannelse af isocyanatet. Dette bliver med diethylamin omdannet til l,l-diethyl-3-(6-methyl-8a-ergolinyl)-urinstofforbindelsen. Udbytte: 290 mg.
[a)^ = +29° (c = 0,5 i chloroform) .
20 Fremstilling af udgangsmaterialet.
I ca. 10 ml vandfri ammoniak opløses 100 mg lithium ved -70°C, og ved denne temperatur tilsættes 1 mmol isolyserg= syreamid og 1,5 mmol anilin i 5 ml tetrahydrofuran i løbet af nogle minutter. Hvis opløsningen affarves, tilsættes 25 yderligere en ringe mængde lithium. Derpå omrøres i 30 minutter ved -70°C, hvorpå ammoniumchlorid tilsættes indtil affarvning, og ammoniakken afdampes. Resten optages i i 6
DK 161646B
mættet natriumhydrogencarbonatopløsning, mættes med kogsalt og udrystes med chloroform eller eddikeester. Den or- ganiske fase tørres med natriumsulfat, inddampes, og resten i . krystalliseres fra ethanol. Der opnås 6-methyl-ergolin- ^ 5 8a-carboxylsyreamid i et udbytte på 90%. ! [a]^5 = +2° (c = o,5 i pyridin).
Eksempel 5.
Analogt med eksempel 1 bliver 6-n-propyl-ergolin-8a-car= boxylsyreamid, der opnås ved reduktion af 9,10-didehydro-10 6-n-propyl-ergolin-8a-carboxylsyreamid med lithium i flydende ammoniak, omsat til dannelse af l,l-diethyl-3-(6-n-pro= pyl-8a-ergolinyl)-urinstof. Efter kromatografi og omsætning med vinsyre opnås forbindelsen som tartratet. Udbytte: 45% af det teoretiske.
15 [a]^5 = +15° (c = 0,5 i pyridin)
Eksempel 6.
Analogt med eksempel 1 bliver 1 mmol lysergsyreamid (267 mg) oxideret med bly-IV-acetat, og det dannede isocyanat omsættes med diethylamin til dannelse af 3-(9,10-didehydro-20 6-methyl-83-ergolinyl)-1,1-diethylurinstof. Udbytte 210 mg.
[a]^ = +110° (c =0,5 i pyridin) .
Eksempel 7.
267 mg lysergsyreamid (1 mmol) bliver som beskrevet i eksempel 2 omsat med bly-IV-acetat og oparbejdet, hvorved 25 man opnår 110 mg 9,10-didehydro-6-methyl-ergolin-8[3-amin.
[a]^5 = +94° (c = 0,5 i pyridin).
Claims (2)
1. Fremgangsmåde til fremstilling af ergoliner med den almene formel: NHR1 { V. 9 , ' I 1 ' 2 N—R , HN_I hvori Cg---C10 betegner en CC-enkelt- eller dobbeltbinding,
5 R1 betegner hydrogen eller gruppen CONR-,, hvori R betegner hydrogen, methyl eller ethyl, og grupperingen NR kan være 2 placeret i a- eller β-stilling, og R betegner lavere al= kyl med indtil 3 carbonatomer, og salte deraf ud fra tilsvarende ergolinylcarboxylsyreamider, kendetegnet 10 ved, at man behandler carboxylsyreamidet med den tilsvarende C-8 konfiguration (a eller β) med bly-IV-acetat i et aprot, polært opløsningsmiddel og omsætter det inter-mediært dannede isocyanat med vand i nærværelse af en syre, såsom svovlsyre eller perchlorsyre, eller en mono- eller 15 dialkylamin med indtil 4 carbonatomer og eventuelt, derpå omdanner til det tilsvarende salt med en fysiologisk acceptabel syre.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at man sætter vandfrit alkali- eller jordalkalimetal-carbonat til reaktionsblandingen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3135305A DE3135305C2 (de) | 1981-09-03 | 1981-09-03 | Verfahren zur Herstellung von 8-Ergolinyl-harnstoffen |
| DE3135305 | 1981-09-03 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK368382A DK368382A (da) | 1983-03-04 |
| DK161646B true DK161646B (da) | 1991-07-29 |
| DK161646C DK161646C (da) | 1992-01-06 |
Family
ID=6141023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK368382A DK161646C (da) | 1981-09-03 | 1982-08-17 | Fremgangsmaade til fremstilling af ergolinderivater og farmaceutisk acceptable salte heraf |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4748248A (da) |
| EP (1) | EP0074921B1 (da) |
| JP (1) | JPS5855483A (da) |
| AT (1) | ATE11289T1 (da) |
| AU (1) | AU555576B2 (da) |
| CA (1) | CA1175813A (da) |
| CS (1) | CS241122B2 (da) |
| DD (1) | DD203544A5 (da) |
| DE (2) | DE3135305C2 (da) |
| DK (1) | DK161646C (da) |
| ES (1) | ES8305361A1 (da) |
| GR (1) | GR76897B (da) |
| HU (1) | HU186969B (da) |
| IE (1) | IE53437B1 (da) |
| IL (1) | IL66679A (da) |
| SU (1) | SU1272988A3 (da) |
| YU (1) | YU199282A (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3151912A1 (de) * | 1981-12-23 | 1983-06-30 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Neue ergolin-aminoderivate, verfahren zu ihrer herstellung und deren verwendung als arzneimittel |
| DE3309493A1 (de) * | 1983-03-14 | 1984-09-20 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue ergolin-derivate, verfahren zu ihrer herstellung sowie verwendung als arzneimittel |
| CH666035A5 (de) * | 1984-12-24 | 1988-06-30 | Sandoz Ag | 8-alpha-acylaminoergolene. |
| DE3915950A1 (de) * | 1989-05-12 | 1990-11-15 | Schering Ag | 8(alpha)-acylamino-ergoline, ihre herstellung und verwendung als arzneimittel |
| US20060171795A1 (en) * | 2005-01-28 | 2006-08-03 | Cromwell Stephen D | Substantial embedment of metallic debris |
| JP2010119349A (ja) * | 2008-11-20 | 2010-06-03 | Shinichi Okamoto | 即席のパンなどの穀物粉加工食品の製造方法 |
| WO2016118539A2 (en) | 2015-01-20 | 2016-07-28 | Xoc Pharmaceuticls, Inc. | Isoergoline compounds and uses thereof |
| EP3253753A4 (en) | 2015-01-20 | 2018-06-27 | Xoc Pharmaceuticals, Inc | Ergoline compounds and uses thereof |
| WO2018223065A1 (en) | 2017-06-01 | 2018-12-06 | Xoc Pharmaceuticals, Inc. | Ergoline derivatives for use in medicine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3063869D1 (en) * | 1979-06-13 | 1983-07-28 | Schering Ag | (ergolin-yl)-n', n'-diethyl urea derivatives, their preparation and pharmaceutical compositions containing them |
-
1981
- 1981-09-03 DE DE3135305A patent/DE3135305C2/de not_active Expired
-
1982
- 1982-08-03 SU SU823470940A patent/SU1272988A3/ru active
- 1982-08-17 DK DK368382A patent/DK161646C/da not_active IP Right Cessation
- 1982-08-23 AT AT82730112T patent/ATE11289T1/de not_active IP Right Cessation
- 1982-08-23 DE DE8282730112T patent/DE3261963D1/de not_active Expired
- 1982-08-23 EP EP82730112A patent/EP0074921B1/en not_active Expired
- 1982-08-30 IL IL66679A patent/IL66679A/xx unknown
- 1982-08-31 DD DD82242909A patent/DD203544A5/de unknown
- 1982-08-31 AU AU87863/82A patent/AU555576B2/en not_active Ceased
- 1982-09-01 GR GR69181A patent/GR76897B/el unknown
- 1982-09-01 ES ES515428A patent/ES8305361A1/es not_active Expired
- 1982-09-02 HU HU822824A patent/HU186969B/hu not_active IP Right Cessation
- 1982-09-02 CA CA000410636A patent/CA1175813A/en not_active Expired
- 1982-09-03 IE IE2156/82A patent/IE53437B1/en not_active IP Right Cessation
- 1982-09-03 YU YU01992/82A patent/YU199282A/xx unknown
- 1982-09-03 CS CS826422A patent/CS241122B2/cs unknown
- 1982-09-03 JP JP57152871A patent/JPS5855483A/ja active Granted
-
1985
- 1985-12-13 US US06/808,804 patent/US4748248A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CS241122B2 (en) | 1986-03-13 |
| AU8786382A (en) | 1983-03-10 |
| CS642282A2 (en) | 1985-07-16 |
| HU186969B (en) | 1985-10-28 |
| IL66679A (en) | 1986-04-29 |
| DE3261963D1 (en) | 1985-02-28 |
| DD203544A5 (de) | 1983-10-26 |
| DK368382A (da) | 1983-03-04 |
| JPS5855483A (ja) | 1983-04-01 |
| YU199282A (en) | 1985-03-20 |
| CA1175813A (en) | 1984-10-09 |
| ATE11289T1 (de) | 1985-02-15 |
| DE3135305C2 (de) | 1983-07-21 |
| EP0074921B1 (en) | 1985-01-16 |
| ES515428A0 (es) | 1983-05-01 |
| GR76897B (da) | 1984-09-04 |
| IL66679A0 (en) | 1982-12-31 |
| DK161646C (da) | 1992-01-06 |
| SU1272988A3 (ru) | 1986-11-23 |
| ES8305361A1 (es) | 1983-05-01 |
| JPH0239511B2 (da) | 1990-09-05 |
| IE53437B1 (en) | 1988-11-09 |
| AU555576B2 (en) | 1986-10-02 |
| DE3135305A1 (de) | 1983-03-10 |
| EP0074921A1 (en) | 1983-03-23 |
| US4748248A (en) | 1988-05-31 |
| IE822156L (en) | 1983-03-03 |
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