NO133670B - - Google Patents
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- Publication number
- NO133670B NO133670B NO430/73A NO43073A NO133670B NO 133670 B NO133670 B NO 133670B NO 430/73 A NO430/73 A NO 430/73A NO 43073 A NO43073 A NO 43073A NO 133670 B NO133670 B NO 133670B
- Authority
- NO
- Norway
- Prior art keywords
- lysergic acid
- ester
- group
- lysergic
- acid
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 46
- -1 phenyl- Chemical group 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 28
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 24
- 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 claims description 17
- 239000002253 acid Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000008511 lysergamides Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 230000009435 amidation Effects 0.000 claims description 4
- 238000007112 amidation reaction Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 239000007858 starting material Substances 0.000 description 19
- 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 17
- 239000000243 solution Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ORBSYPFBZQJNJE-MPKXVKKWSA-N (6ar,9r,10ar)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-carboxylic acid Chemical compound C1=CC([C@H]2C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ORBSYPFBZQJNJE-MPKXVKKWSA-N 0.000 description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001414 amino alcohols Chemical class 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 229940025084 amphetamine Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- ABBZJHFBQXYTLU-UHFFFAOYSA-N but-3-enamide Chemical compound NC(=O)CC=C ABBZJHFBQXYTLU-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- MVCNPXUMKZNDRO-OAHLLOKOSA-N lysergene Chemical compound C1=CC(C2=CC(=C)CN([C@@H]2C2)C)=C3C2=CNC3=C1 MVCNPXUMKZNDRO-OAHLLOKOSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003368 psychostimulant agent Substances 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- FDJLADKRTVQJQP-QMTHXVAHSA-N (2,3,4,5,6-pentachlorophenyl) (6ar,9r)-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxylate Chemical compound O=C([C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)=C1)C)OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl FDJLADKRTVQJQP-QMTHXVAHSA-N 0.000 description 1
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 1
- SCGWHMHVOQPGLS-DFWYDOINSA-N (3s)-3-amino-4-methoxy-4-oxobutanoic acid;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC(O)=O SCGWHMHVOQPGLS-DFWYDOINSA-N 0.000 description 1
- WGZBEDCLEXJQGW-IAQYHMDHSA-N (6ar,9r)-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxylic acid Chemical compound C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CN(C)C3=C1 WGZBEDCLEXJQGW-IAQYHMDHSA-N 0.000 description 1
- FWHSERNVTGTIJE-MLGOLLRUSA-N (6ar,9r)-n,n,7-trimethyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N(C)C)C2)=C3C2=CNC3=C1 FWHSERNVTGTIJE-MLGOLLRUSA-N 0.000 description 1
- ZAGRKAFMISFKIO-IINYFYTJSA-N (6ar,9s)-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxylic acid Chemical compound C1=CC(C2=C[C@@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-IINYFYTJSA-N 0.000 description 1
- HSQFVBWFPBKHEB-UHFFFAOYSA-N 2,3,4-trichlorophenol Chemical compound OC1=CC=C(Cl)C(Cl)=C1Cl HSQFVBWFPBKHEB-UHFFFAOYSA-N 0.000 description 1
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- GENAHGKEFJLNJB-UHFFFAOYSA-N Lysergsaeure-amid Natural products C1=CC(C2=CC(CN(C2C2)C)C(N)=O)=C3C2=CNC3=C1 GENAHGKEFJLNJB-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-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
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003927 aminopyridines Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- AHAQQEGUPULIOZ-WCCKRBBISA-N methyl (2s)-2-aminobutanoate;hydrochloride Chemical compound Cl.CC[C@H](N)C(=O)OC AHAQQEGUPULIOZ-WCCKRBBISA-N 0.000 description 1
- RNHDWLRHUJZABX-IAQYHMDHSA-N methyl (6ar,9r)-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxylate Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)OC)C2)=C3C2=CNC3=C1 RNHDWLRHUJZABX-IAQYHMDHSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005406 washing Methods 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
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- 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
-
- 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
- C07D457/04—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
- C07D457/08—Lysergic acid amides in which the amide nitrogen is a member of a heterocyclic ring
Landscapes
- Health & Medical Sciences (AREA)
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Description
Fremgangsmåte ved fremstilling av lysergamider av generell formel I: Procedure for the preparation of lysergamides of general formula I:
hvor :F"*"y "betegner en -CH=C- eller -CH2~CH-gruppe, where :F"*"y "denotes a -CH=C- or -CH2~CH group,
R^betegner et hydrogenatom eller en methylgruppeog R^ denotes a hydrogen atom or a methyl group and
R2betegner en allylgruppe, en fenyl-, pyridyl-, eller pyrimidylgruppe som eventuelt har én eller flere meth- R2 denotes an allyl group, a phenyl, pyridyl or pyrimidyl group which optionally has one or more met
oxy-, halogen-, trifluormethyl- og/e-ller- nitrosubst-itu-enter, en n-propyl- eller n-butyl-gruppe som eventuelt har- én eller flere cårbomethoxy- og/eller nitroguani-dino-substituenter, eller en glycol-tyrosinol-gruppe. oxy, halogen, trifluoromethyl and/or nitrosubstituents, an n-propyl or n-butyl group which optionally has one or more carbomethoxy and/or nitroguanidino substituents, or a glycol-tyrosinol group.
Med uttrykket "lysergsyre" menes^i denne beskrivelse en fullstendig generell angivelse, og således kan uttrykket angri isolyserg-syre, såvel som D-og Ir antipoder eller de racemiske former av syr-ene. R2-gruppen i forbindelsene av generell former I kan likeledes være avledet fra optisk aktive eller inaktive substituerte aminer. In this description, the term "lysergic acid" means a completely general statement, and thus the term can refer to isolysergic acid, as well as D and Ir antipodes or the racemic forms of the acids. The R 2 group in the compounds of general form I may likewise be derived from optically active or inactive substituted amines.
Det er vel kjent at lysergamider er forbindelser av stor medi-sinsk betydning. Således er f.eks. alle av ergotalkaloidene som foreligger i naturen lysergamider.. De semi synt et i ske fremgangsmåter som utgår fra lysergsyre angår i de fleste tilfeller frems-tilling av lysergamider og lysergalkanolamider, siden disse forbindelser i stor graet-utvider den terapeutiske anvendbarhet av lysrergsyredeFivatene. It is well known that lysergamides are compounds of great medical importance. Thus, e.g. all of the ergot alkaloids that exist in nature are lysergamides. The semi-synthetic methods that start from lysergic acid in most cases concern the production of lysergamides and lysergalkanolamides, since these compounds greatly extend the therapeutic applicability of the lysergic acid derivatives.
Det er utviklet flere fremgangsmåter for semisyntetisk- fremstilling av lysergamider. Den fbrste av de vidt anvendte metoder ble utviklet av A. Stoll og A. Hofman (Helv.Chim. Acta 26, I9U-3). Ifolge denne fremgangsmåte ble. lysergpeptider splittet under dannelse av lyserghydrazid som ble omdannet til lyserg-azid, og denne forbindelse ble anvendt ved acylering av forskjellige aminer. En stor ulempe med denne såkalte azidmetode er imidlertid at den forloper med lavt utbytte, og en betydelig mengde av biprodukter- dannes også. Several methods have been developed for the semi-synthetic production of lysergamides. The first of the widely used methods was developed by A. Stoll and A. Hofman (Helv.Chim. Acta 26, I9U-3). According to this procedure, lyserg peptides cleaved to form lyserg hydrazide which was converted to lyserg azide, and this compound was used in the acylation of various amines. However, a major disadvantage of this so-called azide method is that it proceeds with a low yield, and a significant amount of by-products are also formed.
En annen kjent fremgangsmåte er den såkalte blandede anhydricT-koplingsmetode. Ifolge denne metode dannes, et blandet anhydrid fra lysergsyre- og trifluoreddiksyre (US patentskrift nr. 2.736.728) Another known method is the so-called mixed anhydricT coupling method. According to this method, a mixed anhydride from lysergic and trifluoroacetic acid is formed (US patent no. 2,736,728)
eller fra lysergsyre og svoveltrioxyd (tysk patentskrift nr.1.0^0.560), og det erholdte blandede anhyd-rid anvendes ved acylering av alkanol-aminer. Denne fremgangsmåte tillater imidlertid ikke fremstilling av ens lysergalkanolamider. or from lysergic acid and sulfur trioxide (German Patent No. 1.0^0.560), and the resulting mixed anhydride is used in the acylation of alkanol amines. However, this method does not allow the production of identical lysergalcanolamides.
Ifolge en annen- kjent framgangsmåte utfores acyleringen med lyserghalogenider. Fremstilling av de respektive lyserghalogenider er beskrevet i ungarsk patentskrift nr. 150A25 og 151.8^7. Disse fremgangsmåter er imidlertid ufordelaktige i mange henseende, således kan f.eks. syrekloriddannelsen bare utfores under ekstremt aggressive reaksjonsbetingelser (f.eks. ved bruk av fosfortriklorA3 som løsningsmiddel og fosforoxyklorid og fosforpentaklorid som klor-ineringsmiddel), det erholdte syreklorid inneholder en stor mengde av urenheter (forst av alt lysergsyre, uorganiske fosforforbindelser og lysergklorid klorinert også i 2-stillingen), og endelig er det-ikke utviklet noen fremgangsmåte for rensing av syrekloridet. Videre kan acyleringen ved bruk av lysergklorid bare utfores med et utbytte på maksimalt 70$, og urenhetene av lysergkloridet fremkommer også i lysergamidene fremstilt på denne måte. According to another known procedure, the acylation is carried out with lyser halides. Production of the respective lyser halides is described in Hungarian patent documents No. 150A25 and 151.8^7. However, these methods are disadvantageous in many respects, so e.g. the acid chloride formation is only carried out under extremely aggressive reaction conditions (e.g. using phosphorus trichlorA3 as solvent and phosphorus oxychloride and phosphorus pentachloride as chlorinating agents), the resulting acid chloride contains a large amount of impurities (first of all lysergic acid, inorganic phosphorus compounds and lysergic chloride also chlorinated in 2 position), and finally no method has been developed for purifying the acid chloride. Furthermore, the acylation using lysergic chloride can only be carried out with a maximum yield of 70$, and the impurities of the lysergic chloride also appear in the lysergamides produced in this way.
Østerriksk patentskrift nr. 216.679 beskriver en fremgangsmåte ved fremstilling av monosubstituerte lysergamider, ifolge hvilken lysergsyre og et primært amin kondenseres med hverandre i nærvær av carbodiimider. Ved bruk av denne fremgangsmåte, kan det imidlertid ikke oppnåes betydelige utbytter, siden den optisk aktive lysergsyre praktisk talt fullstendig omdannes til den racemiske form under reaksjonsforlopet. Austrian Patent No. 216,679 describes a process for the preparation of monosubstituted lysergamides, according to which lysergic acid and a primary amine are condensed with each other in the presence of carbodiimides. Using this method, however, significant yields cannot be obtained, since the optically active lysergic acid is practically completely converted to the racemic form during the course of the reaction.
Av ytterligere kjente fremgangsmåter ved fremstillingen av lysergalkanolamider skal nevnes den direkte kondensasjon av lysergsyre med aminoalkoholer (Collection 3ij 3^15, 1966), og amidering av lysergsyremethylester (Collection 22, 101^, 1957). Disse fremgangsmåter krever imidlertid meget hoye temperaturer (190 til 200°C) og Of further known methods for the production of lysergic acid canolamides, mention should be made of the direct condensation of lysergic acid with amino alcohols (Collection 3ij 3^15, 1966), and amidation of lysergic acid methyl ester (Collection 22, 101^, 1957). However, these methods require very high temperatures (190 to 200°C) and
lange reaksjonstider (8 til 10 timer), og de forloper med meget lave utbytter. long reaction times (8 to 10 hours), and they proceed with very low yields.
Ved foreliggende oppfinnelse tilveiebringes det en ny fremgangsmåte ved fremstilling av lysergamider, fri for de ulemper som de hit-til kjente metoder er beheftet med, og hvor det fremstilles et meget rent produkt med et godt utbytte ved en lett gjennomfbrbar reaksjon uten dannelse av biprodukter. The present invention provides a new method for the production of lysergamides, free from the disadvantages with which the hitherto known methods have been affected, and where a very pure product is produced with a good yield by an easily carried out reaction without the formation of by-products.
■ Fremgangsmåten ifolge oppfinnelsen er basert på den oppdagelse at lysergamider dannes i fullstendig ren tilstand når aktive lysergsyreestere omsettes med forbindelser inneholdende en primær eller sekundær aminogruppe., Hverken isomerisering eller racematdannelse foregår under reaksjonsforlopet, og syntesen forloper med praktisk talt kvantitativt utbytte. Denne fremgangsmåte kan anvendes uten unntak ved fremstillingen av et hvilket som helst syreamid av lyserg- ■ The method according to the invention is based on the discovery that lysergamides are formed in a completely pure state when active lysergic acid esters are reacted with compounds containing a primary or secondary amino group. Neither isomerization nor racemate formation takes place during the course of the reaction, and the synthesis proceeds with a practically quantitative yield. This method can be used without exception in the preparation of any acid amide of lyserg-
syre, N-alkyl-iysergsyrer, 9,10-dihydro-lysergsy.re og N-alkyl-9,10-dihydro-lysergsyrer. acid, N-alkyl-lysergic acids, 9,10-dihydro-lysergic acids and N-alkyl-9,10-dihydro-lysergic acids.
Foreliggende oppfinnelse angår altså en ny fremgangsmåte ved fremstilling av lysergsyreamider av generell formel I, og deres syreaddisjonssalter, hvilken fremgangsmåte erkarakterisert vedat en aktiv lysergsyreester av gererell formel II: The present invention therefore relates to a new process for the production of lysergic acid amides of general formula I, and their acid addition salts, which process is characterized by an active lysergic acid ester of general formula II:
hvor x~^"y og R-, har de tidligere angitte betydninger^ Z betegner where x~^"y and R-, have the previously indicated meanings^ Z denotes
halogenatomer og/eller nitrogrupper, og n er en faktor fra 1 - 55amideres med en forbindelse inneholdende en primær eller sekundær aminogruppe, og om onskes, at den erholdte forbindelse av generell formel I omdannes til et syreaddisjonssalt ved omsetning med en farmasøytisk akseptabel syre. halogen atoms and/or nitro groups, and n is a factor from 1 - 55 is amidated with a compound containing a primary or secondary amino group, and if desired, the resulting compound of general formula I is converted into an acid addition salt by reaction with a pharmaceutically acceptable acid.
En gruppe av de nye forbindelser utviser spesifikk antisero-"tonisk aktivitet. Ifolge utforte forsok på isolerte organer under in vitro betingelser inhiberte disse forbindelser den glattmuskel-kontraksjonsaktivitet som var fremkalt av serotonin, mens de under in vivo betingelser virket som antagonister i lave doser til de inflammasjons-induserende og sirkulasjons-influerende virkninger av serotonin. En annen gruppe av de nye forbindelser utviste en betydelig depressiv aktivitet på det sentrale nervesystem, således under-trykker de den spontane motilitet hos testdyr og virker som antagon-ist til den stimuelerende aktivitet fremkalt av psykostimulerende farmasoytika, f.eks. amfetamin. En ytterligere gruppe av forbindelsene med antidepressiv aktivitet utviste aktiviteter tilsvarende de tricycliske antidepressiva. Ved "forsok utfort på rotter og mus virket de som antagonister til de neuroleptiske aktiviteter fremkalt av reserpin og potensiverte den psykostimulerende aktivitet til amfetamin. Disse forbindelser er imidlertid forskjellige fra de tricycliske antidepressiva på det vis at de ikke oker vasopressorakti-viteten av noradrenalin. A group of the new compounds exhibits specific antiserotonic activity. According to experiments carried out on isolated organs under in vitro conditions, these compounds inhibited the smooth muscle contraction activity induced by serotonin, while under in vivo conditions they acted as antagonists at low doses to the inflammation-inducing and circulation-influencing effects of serotonin. Another group of the new compounds exhibited a significant depressant activity on the central nervous system, thus suppressing the spontaneous motility of test animals and acting as an antagonist to the stimulating activity evoked of psychostimulant pharmaceuticals, e.g. amphetamine. A further group of compounds with antidepressant activity exhibited activities similar to the tricyclic antidepressants. In "experiments carried out on rats and mice, they acted as antagonists to the neuroleptic activities elicited by reserpine and potentiated the psychostimulant activity of amphetamine . However, these compounds differ from the tricyclic antidepressants in that they do not increase the vasopressor activity of norepinephrine.
Forbindelsene av generell formel II, som anvendes som utgangs-materialer ved fremgangsmåten ifolge oppfinnelsen, kan fremstilles ved at lysergsyrer av generell formel III: hvor R-, og har de tidligere angitte betydninger, omsettes med fenoler av generell formel IV: The compounds of general formula II, which are used as starting materials in the process according to the invention, can be prepared by reacting lysergic acids of general formula III: where R-, and have the previously indicated meanings, with phenols of general formula IV:
hvor Z og n har de tidligere angitte betydninger, i nærvær av de-hydratiseringsmidler. where Z and n have the previously stated meanings, in the presence of dehydrating agents.
Blant de aktive lysergsyreestere kan fortrinnsvis pentaklor-fenolater anvendes. Reaksjonen utfores fortrinnsvis i nærvær av et inert løsningsmiddel, slik som tetrahydrofuran, acetonitril, methylen-klorid eller dimethylformamid. De aktive lysergsyreestere kan anvendes i isolert form, men reaksjonen kan også utfores ved bruk av den reaksjonsblanding hvor disse aktive estere er dannet. Among the active lysergic acid esters, pentachlorophenolates can preferably be used. The reaction is preferably carried out in the presence of an inert solvent, such as tetrahydrofuran, acetonitrile, methylene chloride or dimethylformamide. The active lysergic acid esters can be used in isolated form, but the reaction can also be carried out using the reaction mixture in which these active esters are formed.
Som aminoreagenser kan en hvilken som helst substituert amin-forbindelse anvendes slik som mono- eller fle-rverdige aminoalkoholer, mono- eller disubstituerte- alkylaminer, aminosyrer, di- eller tri-peptider, monosubstituerte piperaziner, arylaminer, f.eks. anilin og anilinderivater, aminopyridiner etc_ As amino reagents, any substituted amine compound can be used such as mono- or polyhydric amino alcohols, mono- or di-substituted alkyl amines, amino acids, di- or tri-peptides, mono-substituted piperazines, aryl amines, e.g. aniline and aniline derivatives, aminopyridines etc_
Oppfinnelsen åpenbarer flere fordeler,, blant hvilke folgende spesielt skal nevnes: a) den nye fremgangsmåte kan utfores uten unntak ved fremstilling av et hvilket som helst substituert lysergamid,. The invention reveals several advantages, among which the following should be particularly mentioned: a) the new method can be carried out without exception in the preparation of any substituted lysergamide.
b) reaksjonen kan utfores i en enkel prosess, b) the reaction can be carried out in a simple process,
c) ingen biprodukter dannes under reaksjonsforlopet, c) no by-products are formed during the course of the reaction,
d) reaksjonen forloper med hoyt utbytte, d) the reaction proceeds with a high yield,
e) forbindelsene er av hoy renhetsgrad og utviser verdifulle e) the compounds are of high purity and exhibit valuable properties
farmakologiske egenskaper. pharmacological properties.
Oppfinnelsen skal ytterligere illustreres ved de etterfølgende eksempler. The invention shall be further illustrated by the following examples.
Eksempel 1 Example 1
Fremstilling av l- methyl- 9. 10- dihydro- d- lysergsyre- C^- methoxy)- anilid Preparation of l- methyl- 9. 10- dihydro- d- lysergic acid- C^- methoxy)- anilide
5,53 g l-methyl-9,10-dihydro-d-lysergsyre-pentaklorfenolester ble lost i 100 ml torr kloroform under omrbring, deretter ble lbsningen avkjblt med isvann og 1,35 g p-methoxy-anilin lost i 10 ml kloroform ble dråpevis tilsatt. Lbsningen ble omrbrt ved romtemperatur i en time, deretter ble den ekstrahert - med 6x25 ml 1%- ig vandig vinsyrelbsning. De vandige ekstrakter ble kombinert, og blandingens pH ble justert til 8 ved tilsats av noen milliliter 10$-ig vandig aiiimoniumhydroxydlbsning. Den vandige lbsning ble rystet med 5x50 ml kloroform. Kloroformlbsningen ble kombinert, tbrket over natrium-sulfat, filtrert og fordampet i vakuum. Residuet ble lost i 10 ml 5.53 g of l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was dissolved in 100 ml of dry chloroform with stirring, then the solution was quenched with ice water and 1.35 g of p-methoxy-aniline was dissolved in 10 ml of chloroform was added dropwise. The solution was stirred at room temperature for one hour, then it was extracted - with 6x25 ml of 1% aqueous tartaric acid solution. The aqueous extracts were combined, and the pH of the mixture was adjusted to 8 by the addition of a few milliliters of 10 µg aqueous ammonium hydroxide solution. The aqueous solution was shaken with 5x50 ml of chloroform. The chloroform solution was combined, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was dissolved in 10 ml
benzen og benzenlosningen ble helt over i 300 ml torr petroleumether. Det utskilte bunnfall ble filtrert fra, og vasket med en liten mengde petroleumether og tbrket i vakuum. Produktet ble underkastet kromatografi på en aluminiumoxydkolonne, ved bruk av en 8:2 blanding av kloroform og benzen som elueringsmiddel. På denne måte ble det erholdt 3,56 g (91$) l-methyl-9,10-dihydro-d-lysergsyre-(^-methoxy)-anilid med smeltepunkt I59°C. benzene and the benzene solution was poured into 300 ml of dry petroleum ether. The separated precipitate was filtered off, washed with a small amount of petroleum ether and dried in vacuo. The product was subjected to chromatography on an aluminum oxide column, using an 8:2 mixture of chloroform and benzene as eluent. In this way, 3.56 g (91$) of 1-methyl-9,10-dihydro-d-lysergic acid-(^-methoxy)-anilide with a melting point of 159°C were obtained.
Utgangsmaterialet, l-methyl-9,10-dihydro-d-lysergsyre-pentaklorfenolester ble fremstilt som folger: l,1+3 g l-methyl-9,10-dihydro-d-lysergsyre fritt for vann ble suspendert i en blandinga av 60 ml absolutt tetrahydrofuran og 60 ml absolutt diklormethan, hvoretter 1,35 g pentaklorfenol ble tilsatt. Den erholdte losning ble avkjblt under omrbring til en temperatur mellom 0° og 5°C, og i små porsjoner ble 1,25 g dicyclohexylcarbo-diimid tilsatt i lopet av 2 timer. Losningen ble gradvis oppvarmet til 20° og omrbrt i flere timer. Dicyclohexylurea utskilt i krys-tallinsk form ble filtrert og vasket med 10 ml tetrahydrofuran. Filtratet og vaskevæsken ble forent og fordampet til tbrrhet under redusert trykk. Det torre residuum ble opplost varmt i 5 ml benzen og- den erholdte losning ble helt over under omrbring i 50 ml petroleumether. Den erholdte suspensjon ble behandlet med is i lbpet av 2h timer, hvoretter produktet ble filtrert, vasket med 20 ml kald petroleumether og tbrket under vakuum. The starting material, l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared as follows: 1.1+3 g of l-methyl-9,10-dihydro-d-lysergic acid free of water was suspended in a mixture of 60 ml of absolute tetrahydrofuran and 60 ml of absolute dichloromethane, after which 1.35 g of pentachlorophenol was added. The resulting solution was cooled with stirring to a temperature between 0° and 5°C, and 1.25 g of dicyclohexylcarbodiimide was added in small portions over the course of 2 hours. The solution was gradually heated to 20° and stirred for several hours. Dicyclohexylurea separated in crystalline form was filtered and washed with 10 ml of tetrahydrofuran. The filtrate and washings were combined and evaporated to dryness under reduced pressure. The dry residue was dissolved hot in 5 ml of benzene and the solution obtained was poured under stirring into 50 ml of petroleum ether. The resulting suspension was treated with ice for 2 hours, after which the product was filtered, washed with 20 ml of cold petroleum ether and dried under vacuum.
Utbytte: 2,0 g (75$), (a>p° = -20° (c- = 0,5 ethanol). Yield: 2.0 g ($75), (a>p° = -20° (c- = 0.5 ethanol).
Eksempel 2 Example 2
Fremstilling av d- lysergsyre-(^- methoxy)- anilid Preparation of d-lysergic acid-(^-methoxy)-anilide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1, fra 5,37 g d-lysergsyrepentaklorfenolester og 1,5 g p-methoxy-anilin. Produktet ble erholdt med et utbytte på 8*f$ (3,1^ g) og smeltet ved 127°C. This compound was prepared as described in Example 1, from 5.37 g of d-lysergic acid pentachlorophenol ester and 1.5 g of p-methoxyaniline. The product was obtained in a yield of 8% (3.1 g) and melted at 127°C.
Utgangsforbindelsen, d-lysergsyrepentaklorfenolester ble fremstilt fra d-lysergsyre og pentaklorfenol på tilsvarende måte som beskrevet i Eksempel 1. The starting compound, d-lysergic acid pentachlorophenol ester was prepared from d-lysergic acid and pentachlorophenol in a similar manner as described in Example 1.
Utbytte: 62$(a)^° = +31° (c = 0,5 ethanol). Yield: 62$(a)^° = +31° (c = 0.5 ethanol).
Eksempel 3 Example 3
Fremstilling av 9. 10- dihydro- d- lysergsyre-( 1+- methoxy)- anllid Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 fra 5,39 g 9,10-dihydro-d-lysergsyrepentaklorfenolester og 1,5 g p-methoxy-anilin. 3,1 g (82,5$) av tittelforbindelsen ble erholdt, sm.p. l6k°C. Preparation of 9. 10-dihydro-d-lysergic acid-(1+-methoxy)-anllide This compound was prepared as described in Example 1 from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.5 g of p- methoxyaniline. 3.1 g (82.5$) of the title compound was obtained, m.p. 16k°C.
Utgangsforbindelsen 9,10-dihydro-d-lysergsyrepentaklorfenolester ble fremstilt fra 9,10-dihydro-d-lysergsyre og pentaklorfenol på tilsvarende måte som beskrevet i Eksempel 1. The starting compound 9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared from 9,10-dihydro-d-lysergic acid and pentachlorophenol in a similar way as described in Example 1.
Utbytte: 69,5$, (a)^° = +3° (c = 0,5 ethanol). Yield: 69.5$, (a)^° = +3° (c = 0.5 ethanol).
Eksempel h Example h
Fremstilling av d- lysergsyre- 6-( If- klor- 5- nitropyi imidin)- amid Preparation of d-lysergic acid-6-(If-chloro-5-nitropyimidine)-amide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 This compound was prepared as described in Example 1
fra 5,37 g d-lysergsyrepentaklorfenolester og 2,0 g ^-klor-5-nitro-6-amir.o-pyrimidin. 3,2 g (7*+$) av tittelf orbindelsen ble erholdt, sm.p. 2<>>+0°C. from 5.37 g of d-lysergic acid pentachlorophenol ester and 2.0 g of ^-chloro-5-nitro-6-amir.o-pyrimidine. 3.2 g (7*+$) of the title compound were obtained, m.p. 2<>>+0°C.
Utgangsforbindelsen, d-lysergsyrepentaklorfenolester ble fremstilt som beskrevet i Eksempel 2. The starting compound, d-lysergic acid pentachlorophenol ester was prepared as described in Example 2.
Eksempel 5 Example 5
Fremstilling av 9«10- dihydro- d- lysergsyre- 2-( 5- brom- pyridin)- amid Preparation of 9,10-dihydro-d-lysergic acid-2-(5-bromo-pyridine)-amide
Forbindelsen ble fremstilt som beskrevet i Eksempel 1 fra The compound was prepared as described in Example 1 from
^,70 g 9,10-dihydro-d-lysergsyre-(2,lf, 5-triklorfenol)-ester og 2,0 g 2-amino-5-brompyridin. Det ble erholdt 3,5 g (80$) av tittelforbindelsen med sm.p. 132°C. ^.70 g of 9,10-dihydro-d-lysergic acid-(2,1f,5-trichlorophenol)-ester and 2.0 g of 2-amino-5-bromopyridine. 3.5 g (80$) of the title compound was obtained, m.p. 132°C.
Utgangsmaterialene 9,10-dihydro-d-lysergsyre-(2,^1-, 5-triklor-fenol)-ester, ble fremstilt fra 9,10-dihydro-d-lysergsyre og triklor-fenol på tilsvarende måte som beskrevet i Eksempel 1. The starting materials 9,10-dihydro-d-lysergic acid-(2,^1-,5-trichlorophenol)-ester were prepared from 9,10-dihydro-d-lysergic acid and trichlorophenol in a similar manner as described in Example 1.
Eksempel 6 Example 6
Fremstilling av l- methyl- 9. 10- dihydro- d- lysergylglycyl- tyrosinol Preparation of l- methyl- 9. 10- dihydro- d- lysergylglycyl- tyrosinol
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 This compound was prepared as described in Example 1
fra 5,53 g l-methyl-9,10-d-lysergsyrepentaklorfenolester og 2,8 g glycyl-tyrosinol. Det ble erholdt ^,5 g (89$) av tittelforbindelsen med sm.p. 152°C. from 5.53 g of l-methyl-9,10-d-lysergic acid pentachlorophenol ester and 2.8 g of glycyl-tyrosinol. There was obtained ^.5 g (89$) of the title compound, m.p. 152°C.
Utgangsmaterialet, l-methyl-9,10-d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 1. The starting material, 1-methyl-9,10-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 1.
Eksempel 7 Example 7
Fremstilling av 9. lO- dihydro- d- lysergsyre- f3- trifluormethyl)- anilid Preparation of 9. lO- dihydro- d- lysergic acid- (3- trifluoromethyl)- anilide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 fra 5?39g 9,10-dihydro-d-lysergsyrepentaklorfenolester og 2,0 g 3-trifluormethyl-anilin. 3,1 g (72$) av tittelforbindelsen ble erholdt. This compound was prepared as described in Example 1 from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 2.0 g of 3-trifluoromethyl-aniline. 3.1 g (72$) of the title compound was obtained.
Sm.p. 130°C.- Sm.p. 130°C.-
Utgangsmaterialet 9,10-dihydro-d-lysergsyrepentaklorfenolester ble fremstilt som beskrevet i Eksempel 3»The starting material 9,10-dihydro-d-lysergic acid pentachlorophenol ester was prepared as described in Example 3"
Eksempel 8 Example 8
Fremstilling av l-methyl-9,10-dihydro-d-lysergsyre-(3-trifluormethyl)- anilid Preparation of l-methyl-9,10-dihydro-d-lysergic acid-(3-trifluoromethyl)-anilide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 This compound was prepared as described in Example 1
fra ^,.05 g l-methyl-9,10-dihydro-d-lysergsyre-(^-nitro-f enol-ester og 2,0 g 3-trifluormethylanilin. 2,9 g (68$) av tittelforbindelsen ble erholdt. Sm.p. 2l+2°C. from ^.05 g of 1-methyl-9,10-dihydro-d-lysergic acid-(^-nitro-phenol ester and 2.0 g of 3-trifluoromethylaniline. 2.9 g (68$) of the title compound was obtained Melting point 2l+2°C.
Utgangsmaterialet, l-methyl-9,10-dihydro-d-lysergsyre-(lf-nitro-fenol)-ester ble fremstilt fra l-methyl-9,10-dihydro-d-lysergsyre og ^--nitrofenol som beskrevet i Eksempel 1, med det unntak at amideringen ble utfort i losningen av aktiv ester erholdt etter frafiltrering av dicyclohexylurea. The starting material, l-methyl-9,10-dihydro-d-lysergic acid (l-nitrophenol) ester was prepared from l-methyl-9,10-dihydro-d-lysergic acid and ^-nitrophenol as described in Example 1, with the exception that the amidation was carried out in the solution of active ester obtained after filtering off dicyclohexylurea.
Eksempel 9 Example 9
Fremstilling av d- lysergsyre- allylamidmaleat Preparation of d-lysergic acid allyl amide maleate
Den fri base ble fremstilt som beskrevet i Eksempel 1 fra The free base was prepared as described in Example 1 from
5,37 g d-lysergsyrepentaklorfenolester og 1,0 g 1-allylamin. Den erholdte fri base etter kromatografi ble lost i 20 ml varm ethanol, og 1,2 g maleinsyre lost i 5 ml ethanol ble tilsatt til losningen. Det utskilte krystallinske salt ble filtrert fra,' vasket med en liter, mengde ka]d ethanol og tbrket. Det ble erholdt 3,6 g (8^-$) av tittelforbindelsen, med sm.p. 179°C. 5.37 g of d-lysergic acid pentachlorophenol ester and 1.0 g of 1-allylamine. The free base obtained after chromatography was dissolved in 20 ml of hot ethanol, and 1.2 g of maleic acid dissolved in 5 ml of ethanol was added to the solution. The separated crystalline salt was filtered off, washed with one liter of ethanol and used. 3.6 g (8^-$) of the title compound were obtained, m.p. 179°C.
Utgangsmaterialet, d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 2. The starting material, d-lysergic acid pentachlorophenol ester, was prepared as described in Example 2.
Eksempel 10 Example 10
Fremstilling av 1- me thyl- 9 ., 10- dihydro- d- lysergsyre- allylamid Preparation of 1-methyl-9,10-dihydro-d-lysergic acid allylamide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 fra 5,53 g l-methyl-9,10-dihydro-d-lysergsyrepentaklorfenolester og 1,0 g 1-allylamin. 3,1 g (96$) av tittelforbindelsen ble erholdt. Sm.p. 189°C. This compound was prepared as described in Example 1 from 5.53 g of 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.0 g of 1-allylamine. 3.1 g ($96) of the title compound was obtained. Sm.p. 189°C.
Utgangsmaterialet, l-methyl-9,10-dihydro-d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 1. The starting material, 1-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 1.
Eksempel 11 Example 11
Fremstilling av d- lysergsyre- 2-( l- hydroxy- butan)- amid- maleat Preparation of d-lysergic acid-2-(1-hydroxy-butane)-amide maleate
Denne forbindelse ble fremstilt som beskrevet i Eksempel 9 This compound was prepared as described in Example 9
fra 5,37 g d-lysergsyrepentaklorfenolester og 1,1 g (+)-1-hydroxy-.2-amino-butan. 3,85 g (8^,5$) av tittelforbindelsen ble erholdt. Sm.p. 200°C; (a)^° +^7,0° (c = 1,0 i vann). from 5.37 g d-lysergic acid pentachlorophenol ester and 1.1 g (+)-1-hydroxy-.2-amino-butane. 3.85 g (8^.5$) of the title compound was obtained. Sm.p. 200°C; (a)^° +^7.0° (c = 1.0 in water).
Utgangsforbindelsen d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 2. The starting compound d-lysergic acid pentachlorophenol ester was prepared as described in Example 2.
Eksempel 12 Example 12
Fremstilling av l- methyl- d- lysergsyre- 2-( l- hydroxybutan)- amidmaleat Preparation of l-methyl-d-lysergic acid-2-(l-hydroxybutane)-amide maleate
Denne forbindelse ble fremstilt som beskrevet i Eksempel 9 This compound was prepared as described in Example 9
fra 5,51 g 1-methyl-d-lysergsyrepentaklorfenolester og 1,1 g (+)-l-hydroxy-2-aminobutan. ^jl2 g (85$) av tittelforbindelsen ble erholdt, sm.p. 183°C, (cOp = +^2,0° (c = 0, k i vann). from 5.51 g of 1-methyl-d-lysergic acid pentachlorophenol ester and 1.1 g of (+)-1-hydroxy-2-aminobutane. ^jl2 g (85$) of the title compound was obtained, m.p. 183°C, (cOp = +^2.0° (c = 0, k in water).
Utgangsforbindelsen, 1-methyl-d-lysergsyrepentaklorfenolester ble fremstilt fra 1-methyl-d-lysergsyre og pentaklorfenol på tilsvarende måte som beskrevet i Eksempel 1. The starting compound, 1-methyl-d-lysergic acid pentachlorophenol ester was prepared from 1-methyl-d-lysergic acid and pentachlorophenol in a similar way as described in Example 1.
Utbytte: 68$, (a)^° = + lk° (c = 0,5, ethanol). Yield: 68$, (a)^° = + lk° (c = 0.5, ethanol).
Eksempel 13 Example 13
■Fremstilling av 9,10-dihydro-d-lysergsyre-(If-p-hydroxypropyl)-piperazidmaleat ■Preparation of 9,10-dihydro-d-lysergic acid-(If-p-hydroxypropyl)-piperazide maleate
Denne forbindelse ble fremstilt som beskrevet i Eksempel 9 This compound was prepared as described in Example 9
fra 5,39 g 9,10-dihydro-d-lysergsyrepentaklorfenolester og 1,75 g p-hydroxy-propyl-piperazin. Det ble erholdt U-,9 g (93$) av tittelforbindelsen. Sm.p. 207°C; ( a)^ ° = - k9° (c = 0,5 i 50$ vandig ethanol). from 5.39 g of 9,10-dihydro-d-lysergic acid pentachlorophenol ester and 1.75 g of p-hydroxy-propyl-piperazine. U-.9 g ($93) of the title compound was obtained. Sm.p. 207°C; ( a)^ ° = - k9° (c = 0.5 in 50$ aqueous ethanol).
Utgangsforbindelsen, 9,10-dihydro-d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 3-The starting compound, 9,10-dihydro-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 3-
Eksempel lh Example lh
Fremstilling av l-methyl-9,10-dihydro-d-lysergyl-uj-nitro-L-arglninmethylester Preparation of l-methyl-9,10-dihydro-d-lysergyl-uj-nitro-L-arglnine methyl ester
5,53 g l-methyl-9,10-dihydro-d-lysergsyrepentaklorfenolester ble lost i en blanding av 50 ml kloroform Og 50 ml tetrahydrofuran under omroring, og 3?5-g L-u)-nitro-L-argininmethylester-hydroklorid lost i en blanding av 20 ml- kloroform og 8 ml triethylamin ble tilsatt til den avkjolte losning". Reaks jons bl an ding en ble omrort ved romtemperatur i 2 timer, deretter ble den ekstrahert med 5 x 30 ml l$-ig vandig vinsyre. Deretter gikk man frem som beskrevet i Eksempel 1. h, 2 g (86,5$) av tittelforbindelsen ble erholdt. Sm.p. 5.53 g of l-methyl-9,10-dihydro-d-lysergic acid pentachlorophenol ester was dissolved in a mixture of 50 ml of chloroform and 50 ml of tetrahydrofuran with stirring, and 3?5 g of L-u)-nitro-L-arginine methyl ester hydrochloride was dissolved in a mixture of 20 ml chloroform and 8 ml triethylamine was added to the cooled solution". The reaction mixture was stirred at room temperature for 2 hours, then it was extracted with 5 x 30 ml 1% aqueous tartaric acid. The procedure then proceeded as described in Example 1. h, 2 g (86.5$) of the title compound was obtained.
220°C. 220°C.
Utgangsf orbindelsen l-methyl-9 ,10-dihydro-d-r.lysergsyrepentaklorfenolester ble fremstilt som beskrevet i Eksempel 1. The starting compound 1-methyl-9,10-dihydro-d-r.lysergic acid pentachlorophenol ester was prepared as described in Example 1.
Eksempel 15 Example 15
Fremstilling av d- lysergsyredimethylamid Preparation of d-lysergic acid dimethylamide
Denne forbindelse ble fremstilt som beskrevet i Eksempel 1 fra 2,7 g d-lysergsyrepentaklorfenolester og 0,5 g dlmethylamin.- 1,3 g This compound was prepared as described in Example 1 from 2.7 g d-lysergic acid pentachlorophenol ester and 0.5 g dlmethylamine.- 1.3 g
■ (88$) av tittelforbindelsen ble erholdt, (a>^0 =-+30° fi-pyridin). ■ (88$) of the title compound was obtained, (a>^0 =-+30° fi-pyridine).
Utgangsforbindelsen, d-lysergsyrepentaklorfenolester, ble fremstilt som beskrevet i Eksempel 2. The starting compound, d-lysergic acid pentachlorophenol ester, was prepared as described in Example 2.
Eksempel 16 Example 16
Fremstilling av d- lysergyl- L-( + ) - cc- aminosmorsyre- methylestermaleat Preparation of d-lysergyl-L-( + )-cc- aminosuccinic acid methyl ester maleate
1,7 g L-(+)-2-amino-smorsyremethylesterhydroklorid (sm.p. 9<*>+-96°C; (a)p° = +21° (c =-5, i- 20$ saltsyre) ble suspendert i 150 ml kloroform,- og suspensjonen ble avkjolt til 10°C. h ml triethylamin ble dråpevis tilsatt til den omrorte susp"ensjon, deretter ble 5,37 g d-lysergsyrepentaklorfenylester drysset til den erholdte suspensjon, og blandingen ble omrort i 30 minutter. Reaksjonsblandingen ble for-tynnet med 30u ml kloroform og ekstrahert med 2 x 50 ml 1%- ig vandig vinsyre. pH til de kombinerte vandige ekstrakter .ble justert til 7 til 7,5 ved bruk av 10$ vandig ammoniumhydroxyd, og denne vandige 1.7 g of L-(+)-2-amino-butyric acid methyl ester hydrochloride (m.p. 9<*>+-96°C; (a)p° = +21° (c =-5, i- 20$ hydrochloric acid ) was suspended in 150 ml of chloroform, and the suspension was cooled to 10°C. 1 ml of triethylamine was added dropwise to the stirred suspension, then 5.37 g of d-lysergic acid pentachlorophenyl ester was sprinkled into the obtained suspension, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with 30 µl chloroform and extracted with 2 x 50 ml 1% aqueous tartaric acid. The pH of the combined aqueous extracts was adjusted to 7 to 7.5 using 10 µl aqueous ammonium hydroxide, and this watery one
losning ble ekstrahert med h x 50 ml kloroform. De organiske faser ble kombinert, tbrket over vannfritt magnesiumsulfat,. filtrert og fordampet til torrhet i vakuum. Residuet ble lost i 30 ml varm ethanol og 1,6 g maleinsyre lost i 6 ml ethanol ble tilsatt til denne los- solution was extracted with h x 50 ml chloroform. The organic phases were combined, dried over anhydrous magnesium sulfate. filtered and evaporated to dryness in vacuo. The residue was dissolved in 30 ml of hot ethanol and 1.6 g of maleic acid dissolved in 6 ml of ethanol was added to this solution.
ning. Den erholdte suspensjon ble kjolt i is i flere timer, hvoretter bunnfallet ble filtrert fra, vasket med 10 ml ethanol og torket i vakuum. Det ble erholdt 3,17 g (86$) av tittelforbindelsen. Sm.p. 200°C (spaltning), ( oc)^ ° = +35° (c = 1, i 50$ vandig ethanol). nothing. The obtained suspension was cooled in ice for several hours, after which the precipitate was filtered off, washed with 10 ml of ethanol and dried in vacuum. 3.17 g (86$) of the title compound was obtained. Sm.p. 200°C (decomposition), (oc)^ ° = +35° (c = 1, in 50$ aqueous ethanol).
Utgangsforbindelsen, d-lysergsyrepentaklorfenolester,. ble fremstilt som beskrevet i Eksempel 2. The starting compound, d-lysergic acid pentachlorophenol ester,. was prepared as described in Example 2.
Eksempel 17 Example 17
Fremstilling av l-methyl-d-lysergyl-L-(+)-a-aminosmorsyre-methylestermaleat Preparation of l-methyl-d-lysergyl-L-(+)-α-aminosuccinic acid methyl ester maleate
Denne forbindelse ble fremstilt som beskrevet i Eksempel 16, fra 5,55 g 1-methyl-d-lysergsyrepentaklorfenolester og 1,7 g L-(+)-2-aminosmorsyre-methylesterhydroklorid. Det ble erholdt This compound was prepared as described in Example 16, from 5.55 g of 1-methyl-d-lysergic acid pentachlorophenol ester and 1.7 g of L-(+)-2-aminosuccinic acid methyl ester hydrochloride. It was obtained
3,21 g (8^f$) av tittelforbindelsen. Sm.p. 178°C (spaltning); 3.21 g (8^f$) of the title compound. Sm.p. 178°C (decomposition);
(oc)p° = +17,3° (c = 1, i 50$ vandig ethanol). (oc)p° = +17.3° (c = 1, in 50$ aqueous ethanol).
Utgangsforbindelsen, 1-methyl-d-lysergsyrepentaklorf enolester, ble fremstilt som beskrevet i Eksempel 12. The starting compound, 1-methyl-d-lysergic acid pentachlorophenol ester, was prepared as described in Example 12.
Eksempel 18 Example 18
Fremstilling av d- lysergyl- l- alaninmethylester Preparation of d-lysergyl-l-alanine methyl ester
Denne forbindelse ble.fremstilt som beskrevet i Eksempel 1 This compound was prepared as described in Example 1
fra h, 82 g d-lysergsyre-2,1+, 5-triklorfenylester og 1,6 g 1-alanin-methylesterhydroklorid. Det ble erholdt 3,1 g(88$) av tittelforbindelsen. (a) D = -6^-° (c = 1 i kloroform), from h, 82 g of d-lysergic acid-2,1+, 5-trichlorophenyl ester and 1.6 g of 1-alanine methyl ester hydrochloride. 3.1 g ($88) of the title compound was obtained. (a) D = -6^-° (c = 1 in chloroform),
Utgangsmaterialet, d-lysergsyre-2, k,5-trlklorfenylester, ble fremstilt fra d-lysergsyre og 2,*+, 5-triklorf enol som beskrevet i Eksempel 1 med det unntak at amideringen ble utfort i losniagen The starting material, d-lysergic acid-2,k,5-trichlorophenyl ester, was prepared from d-lysergic acid and 2,*+,5-trichlorophenol as described in Example 1 with the exception that the amidation was carried out in solvent
av den aktive ester erholdt efter _frafiltrering av dicyclohexylurea. of the active ester obtained after filtration of dicyclohexylurea.
Claims (3)
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HUGO001186 HU164051B (en) | 1972-02-04 | 1972-02-04 | |
HUGO001187 HU163546B (en) | 1972-02-04 | 1972-02-04 |
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AU (1) | AU475943B2 (en) |
BE (1) | BE794888A (en) |
BG (1) | BG22832A3 (en) |
CA (1) | CA994342A (en) |
CH (1) | CH589079A5 (en) |
CS (1) | CS191212B2 (en) |
DD (1) | DD104299A5 (en) |
DE (1) | DE2305514A1 (en) |
DK (1) | DK141531B (en) |
EG (1) | EG10823A (en) |
FI (1) | FI54118C (en) |
FR (1) | FR2190440B1 (en) |
GB (1) | GB1401155A (en) |
IL (1) | IL41409A (en) |
NL (1) | NL178256C (en) |
NO (1) | NO133670C (en) |
SE (1) | SE421424B (en) |
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HU172649B (en) * | 1975-04-24 | 1978-11-28 | Gyogyszerkutato Intezet | Process for producing new, biologically active lysergamides |
DE2802023A1 (en) * | 1977-01-28 | 1978-08-03 | Sandoz Ag | NEW ERGOT DERIVATIVES, THEIR PRODUCTION AND USE |
JPH0438472U (en) * | 1990-07-31 | 1992-03-31 | ||
IT1260156B (en) * | 1992-08-03 | 1996-03-28 | Fidia Spa | NEURAMINIC ACID DERIVATIVES |
MX2013015373A (en) * | 2011-06-23 | 2014-02-11 | Map Pharmaceuticals Inc | Novel fluoroergoline analogs. |
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AT291446B (en) * | 1968-11-22 | 1971-07-12 | Richter Gedeon Vegyeszet | Process for the preparation of new apovincaminic amides |
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1973
- 1973-01-29 IL IL41409A patent/IL41409A/en unknown
- 1973-01-31 SE SE7301353A patent/SE421424B/en unknown
- 1973-01-31 NL NLAANVRAGE7301369,A patent/NL178256C/en not_active IP Right Cessation
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- 1973-02-01 EG EG41/73A patent/EG10823A/en active
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- 1973-02-02 FR FR7303737A patent/FR2190440B1/fr not_active Expired
- 1973-02-02 YU YU0266/73A patent/YU36730B/en unknown
- 1973-02-02 SU SU1880877A patent/SU468419A3/en active
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- 1973-02-02 CH CH152173A patent/CH589079A5/xx not_active IP Right Cessation
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JPS4886900A (en) | 1973-11-15 |
BE794888A (en) | 1973-05-29 |
NL178256C (en) | 1986-02-17 |
CS191212B2 (en) | 1979-06-29 |
FR2190440A1 (en) | 1974-02-01 |
JPS5221516B2 (en) | 1977-06-10 |
AU475943B2 (en) | 1976-09-09 |
YU26673A (en) | 1982-02-25 |
DD104299A5 (en) | 1974-03-05 |
NO133670C (en) | 1976-06-09 |
GB1401155A (en) | 1975-07-16 |
SU468419A3 (en) | 1975-04-25 |
EG10823A (en) | 1976-07-31 |
FI54118C (en) | 1978-10-10 |
FI54118B (en) | 1978-06-30 |
FR2190440B1 (en) | 1976-09-03 |
NL178256B (en) | 1985-09-16 |
NL7301369A (en) | 1973-08-07 |
CA994342A (en) | 1976-08-03 |
IL41409A (en) | 1977-04-29 |
DE2305514A1 (en) | 1973-08-16 |
AU5163373A (en) | 1974-08-01 |
IL41409A0 (en) | 1973-03-30 |
YU36730B (en) | 1984-08-31 |
DK141531B (en) | 1980-04-14 |
SE421424B (en) | 1981-12-21 |
BG22832A3 (en) | 1977-04-20 |
CH589079A5 (en) | 1977-06-30 |
DK141531C (en) | 1980-10-06 |
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