NO751210L - - Google Patents
Info
- Publication number
- NO751210L NO751210L NO751210*[A NO751210A NO751210L NO 751210 L NO751210 L NO 751210L NO 751210 A NO751210 A NO 751210A NO 751210 L NO751210 L NO 751210L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- methyl
- lower alkyl
- optionally
- acid addition
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- -1 phenoxy, hydroxy Chemical group 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 3
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 102000003946 Prolactin Human genes 0.000 description 13
- 108010057464 Prolactin Proteins 0.000 description 13
- 229940097325 prolactin Drugs 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- WZWHHCYTJDBJPY-TZMCWYRMSA-N (6ar,10ar)-7-methyl-4,6,6a,8,10,10a-hexahydroindolo[4,3-fg]quinoline-9-one Chemical compound C1=CC([C@H]2CC(=O)CN([C@@H]2C2)C)=C3C2=CNC3=C1 WZWHHCYTJDBJPY-TZMCWYRMSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 230000028327 secretion Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- YTFYAKJCTLIUKC-GERZZCHPSA-N (6ar,10ar)-7-methyl-n-pyridin-3-yl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline-9-amine Chemical compound CN([C@H]1[C@@H](C=2C=CC=C3NC=C(C=23)C1)C1)CC1NC1=CC=CN=C1 YTFYAKJCTLIUKC-GERZZCHPSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- 230000006651 lactation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- VGOXYEVIOFBLQY-ZFJSRUIDSA-N (6aR,9R,10aR)-7-methyl-N-(6-phenoxypyridin-3-yl)-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinolin-9-amine Chemical compound CN1C[C@@H](C[C@@H]2C=3C=CC=C4NC=C(C[C@@H]12)C=34)NC=1C=CC(=NC=1)OC1=CC=CC=C1 VGOXYEVIOFBLQY-ZFJSRUIDSA-N 0.000 description 1
- LAASAAVOUUBUBD-SZVBFZGTSA-N (6aR,9R,10aR)-N-(6-methoxypyridin-3-yl)-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinolin-9-amine Chemical compound CN1C[C@@H](C[C@@H]2C=3C=CC=C4NC=C(C[C@@H]12)C=34)NC=1C=CC(=NC=1)OC LAASAAVOUUBUBD-SZVBFZGTSA-N 0.000 description 1
- HAFWELDDNUXLCK-ODZAUARKSA-N (z)-but-2-enedioic acid;hydrate Chemical compound O.OC(=O)\C=C/C(O)=O HAFWELDDNUXLCK-ODZAUARKSA-N 0.000 description 1
- VLXSIHLNPYRFFN-UHFFFAOYSA-N 1,4-dioxane;methanol Chemical compound OC.C1COCCO1 VLXSIHLNPYRFFN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HRLHJWKMOMDDND-UHFFFAOYSA-N 6-[(2-methylpropan-2-yl)oxy]pyridin-3-amine Chemical compound CC(C)(C)OC1=CC=C(N)C=N1 HRLHJWKMOMDDND-UHFFFAOYSA-N 0.000 description 1
- DAFKCYYRSZSMAJ-UHFFFAOYSA-N 6-butoxypyridin-3-amine Chemical compound CCCCOC1=CC=C(N)C=N1 DAFKCYYRSZSMAJ-UHFFFAOYSA-N 0.000 description 1
- UXIPFCIFZLFXNC-UHFFFAOYSA-N 6-ethoxypyridin-3-amine Chemical compound CCOC1=CC=C(N)C=N1 UXIPFCIFZLFXNC-UHFFFAOYSA-N 0.000 description 1
- UUVDJIWRSIJEBS-UHFFFAOYSA-N 6-methoxypyridin-3-amine Chemical compound COC1=CC=C(N)C=N1 UUVDJIWRSIJEBS-UHFFFAOYSA-N 0.000 description 1
- DETKIRMPBJPJRQ-UHFFFAOYSA-N 6-phenoxypyridin-3-amine Chemical compound N1=CC(N)=CC=C1OC1=CC=CC=C1 DETKIRMPBJPJRQ-UHFFFAOYSA-N 0.000 description 1
- ZHOGVKFSKSGQRC-UHFFFAOYSA-N 6-propan-2-yloxypyridin-3-amine Chemical compound CC(C)OC1=CC=C(N)C=N1 ZHOGVKFSKSGQRC-UHFFFAOYSA-N 0.000 description 1
- ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- VFZRZRDOXPRTSC-UHFFFAOYSA-N DMBA Natural products COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 1
- 206010017600 Galactorrhoea Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000010626 work up procedure 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
- C07D457/10—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
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye heterocykliske forbindelser med formel I The present invention relates to a method for the production of new heterocyclic compounds of formula I
hvori R står for en 3-pyridinrest, som eventuelt er enkelt eller flersubstituert med lavere alkyl, lavere alkoksy, lavere alkyltio, fenoksy, halogen, hydroksy eller in which R stands for a 3-pyridine residue, which is optionally single or polysubstituted by lower alkyl, lower alkoxy, lower alkylthio, phenoxy, halogen, hydroxy or
gruppen, hvori R.^og Rj the group, in which R.^and Rj
hver betyr hydrogen eller lavere alkyl, og deres syreaddisjonssalter med syrer. each means hydrogen or lower alkyl, and their acid addition salts with acids.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at forbindelsen med formel II reduseres i nærvær av et amin med formel The peculiarity of the method according to the invention is that the compound of formula II is reduced in the presence of an amine of formula
hvori R har den ovennevnte betydning. wherein R has the above meaning.
Det erholdes derved forbindelser med formel I i form av isomer-blandinger, som eventuelt oppdeles på i og for seg kjent måte i en forbindelse med formel I a Compounds of formula I are thereby obtained in the form of isomer mixtures, which are optionally divided in a manner known per se into a compound of formula I a
henholdsvis I b respectively I b
hvori R har den ovennevnte betydning, og de erholdte forbindelser overfores eventuelt i sine fysiologisk tålbare salter med syrer. in which R has the above-mentioned meaning, and the compounds obtained are optionally transferred in their physiologically tolerable salts with acids.
De som substituenter i pyridinringen anforte alkyl-, alkoksy- og alkyltiogrupper inneholder, såvel som de ved R^og R£ symboliserte alkylgrupper foretrukket 1 til 4 karbonatomer. The alkyl, alkoxy and alkylthio groups mentioned as substituents in the pyridine ring contain, as well as the alkyl groups symbolized by R^ and R^, preferably 1 to 4 carbon atoms.
For reduksjonen i henhold til oppfinnelsen har den katalytiske hydrogenering i nærvær av en edel metallkatalysator, foretrukket ;palladiummetall, som eventuelt anvendes på bærere som f.eks. aktivt kull, vist seg egnet. Man arbeider foretrukket i et egnet organisk losningsmiddel, f.eks. lavere alifatiske alkoholer eller karboksylsyrer, ved normalrbetingelser. Forbindelsene med formel I kan også erholdes ved reduksjon av den ved omsetningen av forbindelsen med formel II med et amin med formel III i nærvær av et kondensasjonsmiddel dannede schiffske base, som ikke behover å isoleres. Som reduksjonsmiddel er f.eks. egnet hydrider, som natriumborhydrid eller natriumcyanoborhydrid, ved temperaturer på omtrent 0°C. For the reduction according to the invention, the catalytic hydrogenation in the presence of a noble metal catalyst, preferably palladium metal, which is optionally used on carriers such as e.g. activated charcoal, proven suitable. One preferably works in a suitable organic solvent, e.g. lower aliphatic alcohols or carboxylic acids, under normal conditions. The compounds of formula I can also be obtained by reduction of the Schiff base formed by the reaction of the compound of formula II with an amine of formula III in the presence of a condensing agent, which does not need to be isolated. As a reducing agent, e.g. suitable hydrides, such as sodium borohydride or sodium cyanoborohydride, at temperatures of about 0°C.
Oppdelingen av den erholdte isomerblanding kan skje ved i og for seg kjente metoder, f.eks. ved kromatografering med en egnet 'losningsmiddelblanding som klorerte hydrokarboner/la vere alifatiske alkoholer med vekslende sammensetning, idet forbindelsene med formel I a og I b erholdes i ren form. The separation of the isomer mixture obtained can be done by methods known per se, e.g. by chromatography with a suitable solvent mixture such as chlorinated hydrocarbons/lower aliphatic alcohols of varying composition, the compounds of formula I a and I b being obtained in pure form.
Fremgangsmåten i henhold til oppfinnelsen kan foretrukket gjennomfores på folgende måte: En blanding av forbindelsen med formel II med en forbindelse med formel III, lost i en lavere alkohol, foretrukket metanol, eller en lavere learboksylsyre, foretrukket eddiksyre, hydrogeneres i nærvær av palladium på aktivt kull ved normal-betingelser. Den resulterendeEeaksjonsblanding videre-forarbeides for rensing på i og for seg kjent måte og produktet oppdeles ved kromatografering på kiselgel med metylenklorid/vekslende tilsetninger av metanol i isomerene. Det som utgangsforbindelse anvendte 6-metyl-8-okso-ergolin (formel II) kan f.eks. fremstilles ved at et reaksjonsdyktig, funksjonelt^ derivat av 6-metyl- 8 ' 9-ergolen-8-karboksylsyre med formel IV ved hjelp av et alkaliazid i et inert, tort losningsmiddel overfores i syreazidet med formel V The method according to the invention can preferably be carried out as follows: A mixture of the compound of formula II with a compound of formula III, dissolved in a lower alcohol, preferably methanol, or a lower carboxylic acid, preferably acetic acid, is hydrogenated in the presence of palladium on active coal under normal conditions. The resulting reaction mixture is further processed for purification in a manner known per se and the product is separated by chromatography on silica gel with methylene chloride/alternating additions of methanol in the isomers. The 6-methyl-8-oxo-ergoline (formula II) used as starting compound can e.g. is prepared by transferring a reactive, functional derivative of 6-methyl-8'-9-ergolene-8-carboxylic acid of formula IV with the aid of an alkali azide in an inert, dry solvent to the acid azide of formula V
som deretter oppvarmes under innvirkning av syre. which is then heated under the influence of acid.
reaksjonsdyktig funksjonelt derivat 6-metyl—Z^P' ^-ergolen-8-karboksylsyre kan f.eks. anvendes addisjonsproduktet med et kompleks, dannet av et N-di(lavere)alkylsubstituert syreamid av en alifatisk monokarboksylsyre med 1-3 karbonatomer, foretrukket dimetylforamid, og et halogeneringsmiddel som oxalylklorid, forsgen eller tionylklorid. reactive functional derivative 6-methyl-Z^P' ^-ergolene-8-carboxylic acid can e.g. the addition product is used with a complex, formed from an N-di(lower)alkyl-substituted acid amide of an aliphatic monocarboxylic acid with 1-3 carbon atoms, preferably dimethylformamide, and a halogenating agent such as oxalyl chloride, forsgene or thionyl chloride.
Likeledes kan syreklorid-hydrokloridet, addisjonsproduktet med karbodiimid eller blandede anhydridér av syren med formel IV med svovelsyre eller trifluoreddiksyre anvendes, som kan fremstilles på kjent måte. Likewise, the acid chloride hydrochloride, the addition product with carbodiimide or mixed anhydrides of the acid of formula IV with sulfuric acid or trifluoroacetic acid can be used, which can be prepared in a known manner.
Den ved omsetningen av det reaksjonsdyktige derivat av syrenThe by the turnover of the reactive derivative of the acid
med formel IV med alkaliazid ved temperaturer på -20 til +20°C erholdte 6-metyl- -ergolen-8-karboksylsyreazid overfores ved oppvarming f.eks. med saltsyre til avsluttet nitrogenutvikiing og opparbeidelse av reaksjonsblandingen på i og for seglgent måte i det onskede 6-metyl-8-okso~erg~6lin =meå formel III i optisk aktiv form. with formula IV with alkali azide at temperatures of -20 to +20°C, the 6-methyl--ergolene-8-carboxylic acid azide obtained is transferred by heating, e.g. with hydrochloric acid until nitrogen evolution is complete and work-up of the reaction mixture in an i and too sealed manner into the desired 6-methyl-8-oxo~erg~6lin =meå formula III in optically active form.
De ved fremgangsmåten i henhold til oppfinnelsen fremstilte forbindelser med formel I såvel som i form av 8a- (formel I a) og 8(3-isomeren (formel I b) er ved romtemperatur krystallinske substanser som med organiske eller uorganiske syrer danner bestandige ved romtemperatur krystalliserte salter. The compounds of formula I produced by the method according to the invention as well as in the form of the 8a- (formula I a) and the 8(3-isomer (formula I b) are at room temperature crystalline substances which with organic or inorganic acids form stable at room temperature crystallized salts.
Forbindelsene med formel I og deres fysiologisk tålbare salter med syrer viser ved den farmakologiske provning verdifulle egenskaper og kan derfor finne anvendelse som legemiddel. The compounds of formula I and their physiologically tolerable salts with acids show valuable properties in the pharmacological test and can therefore find use as pharmaceuticals.
Således fremviser forbindelsene en ZNS-aktivitet påvist ved antagonisering av den ved tetrabenazin utloste katalepsi i rotter i doser på omtrent 5-50 mg/kg og utlosning av dreieforhold ved rotter, hvis nigrostriatale baner var odelagt ved injeksjon av 6-OHDA, i doser på 0,5-5 mg/kg s.c. Thus, the compounds exhibit ZNS activity as demonstrated by antagonizing tetrabenazine-induced catalepsy in rats at doses of approximately 5-50 mg/kg and eliciting turns in rats, whose nigrostriatal pathways were disrupted by injection of 6-OHDA, at doses of 0.5-5 mg/kg s.c.
Videre viser spesielt forbindelsene med formel I a, som f.eks. 6-metyl-8S-(3-pyridylamino)-ergolin en utpreget prolactin- sekresjonshemming. De er på grunn av deres innvirkning på prolaétinsekresjonen indikert ved bestemte prolactinavhengige funksjonsforstyrrelser for å tlbakefore den aktuelle funksjons-tilstand til utgangsituasjonen. Furthermore, especially the compounds of formula I a, which e.g. 6-methyl-8S-(3-pyridylamino)-ergoline a marked prolactin secretion inhibitor. Due to their effect on prolactin secretion, they are indicated for certain prolactin-dependent functional disorders in order to restore the functional state in question to the initial situation.
Således er de aktive forbindelser f.eks. egnet for profylaxe og terapi av fysiologisk lactasjon og galactorroe, av mamma-carcinomer. Videre kan de finne anvendelse ved nefropatier og kroniske nyrebe^gennelser: for regulering av vann- og elektrolyttstoffskiftet, ved odemer, for behandling av essensielle og renale hypertoniformer såvel ved akutte tilstander som for migreneangrep og ved premenstruelt syndrom. Thus, the active compounds are e.g. suitable for prophylaxis and therapy of physiological lactation and galactorrhoea, of mammary carcinomas. Furthermore, they can be used in nephropathies and chronic kidney disorders: for regulation of water and electrolyte metabolism, in oedemas, for the treatment of essential and renal hypertonia both in acute conditions and for migraine attacks and in premenstrual syndrome.
De egenskaper, som de ovennevnte anvendelsesmuligheter er basert på, lar seg bekrefte ved dyreforsok ved hjelp av - alt etter indikasjonen av forskjellige - kjente testmetoder og ved klinisk provning. The properties, on which the above-mentioned application possibilities are based, can be confirmed by animal testing using - depending on the indication of different - known test methods and by clinical testing.
Prolactin-sekresjonshemmingen kunne gjores tydelig i rotter.The prolactin secretion inhibition could be made clear in rats.
Ved lacterende rotter, som for en tid var adskilt fra deres barn, kommer det ved fornyet kontakt-tagning til en massiv prolactin-utskilling, som f.eks. kan oppfattes som deplesjon av det hypofysere prolactin-innhold. Dette fenomenet (beskrevet av Grosvenor og Mena i J. Endocr. 5_2, 11 /T972J7 gir en reproduserbar forsoksanordning, for å bestemme prolactinsekresjonshemmingen farmakologisk. Det viste seg at 5 mg/kg s.c. av en forbindelse med formel I a ikke bare i sterk grad hemmer den ved sensorisk stimulering utloste prolactin-frigivelse, men samtidig forer til en lett stigning av prolactininnholdet, hvorved det gjores tydelig at forbindelsen formår å hemme den fysiologisk/..."" ) stimulerte prolactinsekresjon. In the case of lactating rats, which were separated from their children for a time, upon renewed contact there is a massive prolactin secretion, which e.g. can be perceived as depletion of the pituitary prolactin content. This phenomenon (described by Grosvenor and Mena in J. Endocr. 5_2, 11 /T972J7) provides a reproducible experimental device to determine the inhibition of prolactin secretion pharmacologically. It was found that 5 mg/kg s.c. of a compound of formula I a not only strongly inhibits the prolactin release triggered by sensory stimulation, but at the same time leads to a slight rise in the prolactin content, making it clear that the compound manages to inhibit the physiologically/..."" ) stimulated prolactin secretion.
Også i hannrotter kunne det konstateres en virkning på prolactin-speilet. Forbindelsene med formel I a hemmer den toniske prolactinsekresjon med ED5Q-verdier mellom 0,005 og 1,0 mg/kg s.c. An effect on the prolactin level could also be observed in male rats. The compounds of formula Ia inhibit tonic prolactin secretion with ED5Q values between 0.005 and 1.0 mg/kg s.c.
(ved prolactin-bestemmelser av rottesera ved hjelp av radio-immuno-assay) (in prolactin determinations of rat sera by radio-immunoassay)
Likeledes kunne det i rotter vises en lactasjonshemmende virkning med en ED^Q på ca. 6,5 mg/kg s.c. Hemming av DMBA-induserte mammatumorer kunne likeledes påvises i rotter. Med doser på 5 Likewise, a lactation-inhibiting effect could be shown in rats with an ED^Q of approx. 6.5 mg/kg s.c. Inhibition of DMBA-induced mammary tumors could also be demonstrated in rats. With doses of 5
og 15 mg/kg kroppsvekt av forsoksdyret daglig tilfort kunne det konstateres en tydelig hemming av tumorene såvel med hensyn til antall som storrelse. and 15 mg/kg body weight of the experimental animal added daily, a clear inhibition of the tumors could be observed both with regard to number and size.
Den daglig tilforte dose av aktiv substans avhenger selvfolgelig av tilforselsmåten og den tilstand som skal behandles. Vanlig oppnås tilfredsstillende resultater i et doseområde fra omtrent 0,1 til 15 mg pr. kg kroppsvekt av forsoksdyret, om nodvendig tilfort i 2-3 porsjoner. For storre pattedyr utgjor den daglige dose omtrent 0,5 til 50 mg aktiv substans. The daily administered dose of active substance naturally depends on the method of administration and the condition to be treated. Satisfactory results are usually obtained in a dose range from about 0.1 to 15 mg per kg body weight of the experimental animal, if necessary supplemented in 2-3 portions. For larger mammals, the daily dose amounts to approximately 0.5 to 50 mg of active substance.
De nye forbindelser med formel I henhv. deres fysiologisk tålbare syreaddisjonssalter kan anvendes som legemiddel alene eller i tilsvarende preparatformer for oral, énteral eller parenteral tilforsel. For fremstilling av egnede preparatformer forarbeides forbindelsene med uorganiske eller organiske, farmasoytisk indifferente hjelpestoffer som faste eller flytende bærersubstanser eller fotynningsmidler. The new compounds of formula I respectively their physiologically tolerable acid addition salts can be used as medicine alone or in corresponding preparation forms for oral, enteral or parenteral administration. For the production of suitable preparation forms, the compounds are processed with inorganic or organic, pharmaceutically indifferent excipients such as solid or liquid carrier substances or foot thinners.
De etterfolgende eksempler skal illustrere oppfinnelsen nærmere. Alle temperaturangivelser er i °C. The following examples will illustrate the invention in more detail. All temperature indications are in °C.
Eksempel 1: 6- metyl- 8-( 3- pvridyl) amino- erqolih Example 1: 6-methyl-8-(3-pyridyl)amino-erqolih
24,0 g 6-^metyl-8-okso-ergolin, 34,0 g 3-aminopyridin og 4,0 g kaliumkarbonat oppvarmes under nitrogen i en sulfideringskolbe ved 150°C og etterlates i 6 timer ved denne temperatur. 24.0 g of 6-^methyl-8-oxo-ergoline, 34.0 g of 3-aminopyridine and 4.0 g of potassium carbonate are heated under nitrogen in a sulphiding flask at 150°C and left for 6 hours at this temperature.
Etter denne reaksjonstid opploses den i form av et sort slam erholdte schiffske base i 400 ml metanol-dioksan (1:1), avkjoles til 0°C og reduseres ved porsjonsvis tilsetning av 18,9 g natriumborhydrid under omroring ved 0°C i lopet av 1 time. Reaksjonsblandingen inndampes til torrhet på rotasjonsfordamper, opptas After this reaction time, the Schiff base obtained in the form of a black sludge is dissolved in 400 ml of methanol-dioxane (1:1), cooled to 0°C and reduced by portionwise addition of 18.9 g of sodium borohydride while stirring at 0°C in the batch of 1 hour. The reaction mixture is evaporated to dryness on a rotary evaporator, collected
i 2,5 1 metylenklorid og vaskes 6 ganger med 1 1 vann. Vann- in 2.5 1 methylene chloride and washed 6 times with 1 1 water. Water-
fasene utrystes i rekkefolge ytterligere med 1 1 metylenklorid.the phases are further shaken in order with 1 1 methylene chloride.
De forenede organiske faser torres over natriumsulfat, behandles med 3 g aktiv kull, filtreres gjennom talkum og inndampes. Den i form av et brunt skum erholdte rest loses for rensing i 500 ml etanol og felles som tartrat ved tilsetning av en løsning av 22,5 g L(+)-vinsyre ill etanol. Tartratet frafiltreres, vaskes med The combined organic phases are dried over sodium sulphate, treated with 3 g of activated carbon, filtered through talc and evaporated. The residue obtained in the form of a brown foam is dissolved for purification in 500 ml of ethanol and collected as tartrate by adding a solution of 22.5 g of L(+)-tartaric acid in ethanol. The tartrate is filtered off, washed with
200 ml eter og torres. Det erholdte salt loses varmt i 1,5 1200 ml of ether and dried. The obtained salt is dissolved hot in 1.5 1
vann, denne losning innstilles^med. 2 N" Jrariumhy^r6"skyd_"til_ pH og ekstraheres 3 ganger med hver gang 2 1 metylenklorid. Metylen-kloridfasene torres over natriumsulfat,. filtreres gjennom talkum og inndampes. Den således erholdte rå base kromatograferes på water, this solution is set^with. 2 N" Jrarium hy^r6"shoot_"to_ pH and extract 3 times with each time 2 1 of methylene chloride. The methylene chloride phases are dried over sodium sulfate, filtered through talc and evaporated. The crude base thus obtained is chromatographed on
800 g kiselgel (merk 0,05-0,2 mm) ved hjelp av metylenklorid-metanol (98:2). Det oppnås en ren base i form av et skum. Basen loses i 20 ml metanol og tilsettes 3 ml destillert vann, hvorved 6-metyl-8-(3-pyridyl)amino-ergolin utkrystalliseres, smp. 128-131°C;, 800 g silica gel (note 0.05-0.2 mm) using methylene chloride-methanol (98:2). A clean base in the form of a foam is obtained. The base is dissolved in 20 ml of methanol and 3 ml of distilled water is added, whereby 6-methyl-8-(3-pyridyl)amino-ergoline crystallizes out, m.p. 128-131°C;,
/<a>7o° = 70,1° (c = 0,998, pyridin)/<a>7o° = 70.1° (c = 0.998, pyridine)
/ ffl^ 0 =100,4° (c = 0,954, kloroform) / ffl^ 0 =100.4° (c = 0.954, chloroform)
Bis-^ S- metyl- 8- ( 3- pyridyl ) amino- erqolin-- 7tritatratBis-^S- methyl- 8-( 3- pyridyl ) amino- erqoline-- 7tritatrate
Til 14,5 g 6-metyl-8-(3-pyridyl)amino-ergolin, opplost i 300 ml etanol, tilsettes en varm losning av 10,2 g li( + )-vinsyre i 300 ml etanol. Tritartratet utfelles med en gang. Blandingen holdes i 1 time ved 0°C og filtreres. Krystallene vaskes med 30 ml etanol og torres deretter i hoyvakuum ved 80°C. På denne måte erholdes bis-/I-metyl-8-(3-pyridyl)amino-ergolin-7tritartrat med smp. To 14.5 g of 6-methyl-8-(3-pyridyl)amino-ergoline, dissolved in 300 ml of ethanol, a hot solution of 10.2 g of l( + )-tartaric acid in 300 ml of ethanol is added. The tritartrate precipitates immediately. The mixture is kept for 1 hour at 0°C and filtered. The crystals are washed with 30 ml of ethanol and then dried in high vacuum at 80°C. In this way bis-[1-methyl-8-(3-pyridyl)amino-ergoline-7-tritartrate is obtained with m.p.
på 151-153°C. /a7^° = n.57,9° (c = 0,342, etanol) at 151-153°C. /a7^° = n.57.9° (c = 0.342, ethanol)
Eksempel 2: 6- metvl- 8-( 3- pyridvlamino)- erqolinExample 2: 6-methyl-8-(3-pyridylamino)-ergoline
17,8 g 6-metyl-8-okso-ergolin-hydrogennaleinat og 23,5 g 3-amino-pyridirn i 500 ml metanol hydrogeneres under tilsetning av 12 g 10% palladium på aktivt kull under noramlbetingelser. Etter avsluttet hydrogenopptagning (ca. 120 timer) frafiltreres katalysatoren, filtratet inndampes i vakuum ved en vannbad-temperatur på 60°C og den tilbakeblivende rest kromatograferes for rensing og adskillelse på den 30-dobbelte mengde kiselgel med metylenklorid under tilsetning av stigende mengder av metanol. 17.8 g of 6-methyl-8-oxo-ergoline hydrogen naleinate and 23.5 g of 3-amino-pyridine in 500 ml of methanol are hydrogenated with the addition of 12 g of 10% palladium on activated carbon under normal conditions. After completion of hydrogen uptake (approx. 120 hours), the catalyst is filtered off, the filtrate is evaporated in vacuum at a water bath temperature of 60°C and the remaining residue is chromatographed for purification and separation on the 30-fold amount of silica gel with methylene chloride while adding increasing amounts of methanol .
Den kromatografiske oppdeling i isomerene gjennomfores på folgende måte: Ved eluering med metylenklorid under anvendelse av 2 henhv. 3% metanol erholdes isomeren I a The chromatographic division into the isomers is carried out in the following way: By elution with methylene chloride using 2 or 3% methanol, the isomer I a is obtained
Éz m?^yiz 8§zi^zPZ riÉy-'-52}i222z e£22ii n 'Éz m?^yiz 8§zi^zPZ riÉy-'-52}i222z e£22ii n '
Smp. 160-161°C (fra aceton); Temp. 160-161°C (from acetone);
/«7d° = +70 + 3°C (c = 0,58; pyridin) henhv. = +41 + 2°G/«7d° = +70 + 3°C (c = 0.58; pyridine) resp. = +41 + 2°G
(c = 0,56; metanol). (c = 0.56; methanol).
Dihydrokloridet krystalliseres fra isopropanol/eter med smp. fra 2 2 0°C (spalting/vakuum); The dihydrochloride is crystallized from isopropanol/ether with m.p. from 2 2 0°C (fission/vacuum);
/«7d° = -38°C(c = 0,48, 50% etanol)./«7d° = -38°C (c = 0.48, 50% ethanol).
Ved videre eluering med metylenklorid under tilsetning av 3 tilBy further elution with methylene chloride while adding 3 to
5% metanol erholdes etter blandingérl den rene isomer^I b Éz5}®iZiz8?z ^zPyEiÉZlami2°2zS£S2ii^i. 5% methanol is obtained after mixing the pure isomer.
Smp. 230-232°C (fra aceton); Temp. 230-232°C (from acetone);
/a7p° = -82 + 3°C (c = 0,52; pyridin) henhv.=-40+ 2°C/a7p° = -82 + 3°C (c = 0.52; pyridine) resp.=-40+ 2°C
(c = 0,52; metanol). (c = 0.52; methanol).
Eksempel 3: 6- metyl- 8-( 2- metoksv- 5- pyridylamino)- erqolinExample 3: 6-methyl-8-(2-methoxys-5-pyridylamino)-erqoline
Til 35 g 10% palladium på aktivt kull og 18,6 g 2-metoksy-5-aminopyridin i 400 rrcb iseddik tildryppes under samtidig hydrogenering under noramlbetingelser langsomt en losning av 35,6 g 6-metyl-8-okso-ergolin i.1,4 1 iseddik. Varighet av tilsetningen ca. 7 timer. Etter avsluttet hydrogenopptagning frafiltreres katalysatoren, filtratet inndampes i vakuum og den tilbakeblivende rest opptaes"/.! metylenklorid (+15% isopropanol) og vaskes med isavkjolt ammoniakk og vann. Den etter torring av de forenede organiske faser og inndamping tilbakeblivende rest kromatograferes for rensing og adskillelse av isomerene på den 80-dobbelte mercjdekisel-gel med metylenklorid under tilsetning av stigende mengder av metanol. To 35 g of 10% palladium on activated carbon and 18.6 g of 2-methoxy-5-aminopyridine in 400 rrcb of glacial acetic acid, a solution of 35.6 g of 6-methyl-8-oxo-ergoline is slowly added dropwise during simultaneous hydrogenation under normal conditions. 1.4 1 glacial acetic acid. Duration of the addition approx. 7 hours. After completion of hydrogen absorption, the catalyst is filtered off, the filtrate is evaporated in vacuo and the remaining residue is taken up in methylene chloride (+15% isopropanol) and washed with ice-cooled ammonia and water. The residue remaining after drying the combined organic phases and evaporation is chromatographed for purification and separation of the isomers on the 80x silica gel with methylene chloride while adding increasing amounts of methanol.
Ved eluering med metylenklorid under tilsetning av 2% metanol erholdes isomeren Ia By elution with methylene chloride with the addition of 2% methanol, the isomer Ia is obtained
6-mety^-8S-_(2-metoksy-5-pyridyl amino)-ergolin6-methyl-8S-_(2-methoxy-5-pyridyl amino)-ergoline
Dihydroklorid: smp. fra 225°C sp.alting (fra metanol-aceton) Dihydrochloride: m.p. from 225°C sp.althing (from methanol-acetone)
/«7q° -78 + 3°C (c = 0,5 i etanol-vann 1:1) /«7q° -78 + 3°C (c = 0.5 in ethanol-water 1:1)
Ved videre eluering med metylenklorid under tilsetning av 4% metanol erholdes isomeren I b By further elution with methylene chloride while adding 4% methanol, the isomer I b is obtained
6-metyl-8R-(2-metoksy-5-pyridylamino)-ergolin6-methyl-8R-(2-methoxy-5-pyridylamino)-ergoline
Smp. fra 265°C spalting (fra metanol-aceton)Temp. from 265°C cleavage (from methanol-acetone)
/«7o° = -78 +3°C (c = 0,5 i pyridin)/«7o° = -78 +3°C (c = 0.5 in pyridine)
Dihydrokloridet: smp. fra 220°C spalting (fra isopropanol)The dihydrochloride: m.p. from 220°C decomposition (from isopropanol)
ry s\ , ry s\ ,
/a7D = -38 + 3 C (c = 0,5 i etanol-vann 1:1) /a7D = -38 + 3 C (c = 0.5 in ethanol-water 1:1)
Eksempel 4: 6- metyl- 8- ( 2- etoksy- 5- pyridylamino)- ero;olin Example 4: 6-methyl-8-(2-ethoxy-5-pyridylamino)-ero;olin
Analogt med eksempel 3 erholdes fra 2~etoksy-5-amino-pyridin og 6-metyl-8-okso-ergolin i nærvær av palladium de folgende forbindelser (isomerene I a og Ib): Analogous to example 3, the following compounds (isomers I a and Ib) are obtained from 2-ethoxy-5-amino-pyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Smp. 148 - ■ 150°C (fra aceton-eter)Temp. 148 - ■ 150°C (from acetone-ether)
/«7^° = +68 + 3°C (c = 055 i pyridin) /«7^° = +68 + 3°C (c = 055 in pyridine)
6-metyl-8R-(2-etosky-5-pyridylamino)-ergolin6-methyl-8R-(2-etosky-5-pyridylamino)-ergoline
Smp. fra 270°G spalting (fra metanol-eter)Temp. from 270°G cleavage (from methanol-ether)
/«7q<0>-79 + 3°C (c = 0,5 i pyridin)/«7q<0>-79 + 3°C (c = 0.5 in pyridine)
Eksempel 5: 6- metyl- 8-( 2- isopropoksy- 5- pyridylamino)- erqolin Example 5: 6-methyl-8-(2-isopropoxy-5-pyridylamino)-erqoline
Analogt med eksempel 3 erholdes fra 2-isopropoksy-5-aminopyridin og 6-metyl-8-okso-ergolin i nærvær av palladium de folgende forbindelser (isomerer I a og I b): Analogously to example 3, the following compounds are obtained from 2-isopropoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium (isomers I a and I b):
^I™2!!:Z:L~§§lA2-is^propok^^I™2!!:Z:L~§§lA2-is^propok^
Smp. 104 - 105°C (fra aceton^-eter)Temp. 104 - 105°C (from acetone^-ether)
/<a>7Q°<=>+65 + 3°C (c = 0,5 i pyridin) /<a>7Q°<=>+65 + 3°C (c = 0.5 in pyridine)
6-metyl-8R-^2-isoprop^ksy-5-pyr6-methyl-8R-2-isopropoxy-5-pyr
Smp. 243 - 244°C (fra aceton-eter)Temp. 243 - 244°C (from acetone-ether)
/a7^°/a7^°
Eksempel 6: 6- metvl- 8- ( 2- n- butoksy- 5- pyridylamino)- erqolin Example 6: 6-methyl-8-(2-n-butoxy-5-pyridylamino)-erqoline
Analogt med. eksempel: 3 erholdes fra 2-n-butoksy-5-amino-pyridin og 6-metyl-8-okso-ergolin i nærvær av palladium de folgende forbindelser (isomerer I a og I b): Analogous to. example: 3 is obtained from 2-n-butoxy-5-amino-pyridine and 6-methyl-8-oxo-ergoline in the presence of palladium the following compounds (isomers I a and I b):
6-metyl-8S-^2-n-butoksy-5-pyr6-methyl-8S-^2-n-butoxy-5-pyr
Smp. 81. - 82°C (fira eter-petroleter)Temp. 81. - 82°C (four ether-petroleum ether)
/a7^° = +67 + 3°C (c = 0,5 i pyridin)/a7^° = +67 + 3°C (c = 0.5 in pyridine)
Dihydrobromid: Smip. fra 2 0<5>°^ spaltingDihydrobromide: Smip. from 2 0<5>°^ cleavage
/«7^° = -37 + 3°C (c = 0,5 i etanol-vann 1:1) /«7^° = -37 + 3°C (c = 0.5 in ethanol-water 1:1)
6-metyl-8R-(2-n-butoksy-5-^yridyla^6-methyl-8R-(2-n-butoxy-5-[yridyl]).
Smp. 185 - 187°C (fra metanol-eter)Temp. 185 - 187°C (from methanol-ether)
/ a7p° = -67 3°C (c = 0,5 i pyridin)/ a7p° = -67 3°C (c = 0.5 in pyridine)
Dihydrobromid: Smp. fra 225°C spalting (fra metanol-eter)Dihydrobromide: mp. from 225°C decomposition (from methanol-ether)
/a7^° = -35 + 3°C ( c = 0,5 i etanol-vann 1:1) /a7^° = -35 + 3°C ( c = 0.5 in ethanol-water 1:1)
Eksempel 7; 6-metyl-8-( 2- tert.- butoksv- 5- pyridvlamino)- erqolin Example 7; 6-methyl-8-(2-tert.-butox-5-pyridylamino)-erqoline
Analogt med eksempel 3 erholdes fra 2-tert.-butoksy-5-aminopyridin og 6-metyl-8-okso-ergolin i nærvær av palladium de folgende forbindelser (isomerer I a og I b): Él^tZilÉ^liH-te<rt>^-<b>^toks^^Analogous to example 3, the following compounds (isomers I a and I b) are obtained from 2-tert.-butoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium: Él^tZilÉ^liH-te< rt>^-<b>^toks^^
Hydrogenmaleinat.hydrat: Smp. 112-114°C (fra aceton-eter)Hydrogen maleate hydrate: mp. 112-114°C (from acetone-ether)
/a7p° -35 + 3°C (c 0,5 i etanol-vann 1:1) /a7p° -35 + 3°C (c 0.5 in ethanol-water 1:1)
6-metyl-8R-(2-tert.-butoksy-5-pyridylamino)-ergolin6-methyl-8R-(2-tert-butoxy-5-pyridylamino)-ergoline
Smp. 244 - 246°C (fra metanol-eter)Temp. 244 - 246°C (from methanol-ether)
/a7^° = -78 + 3°C (c = 0,5 i pyridin)/a7^° = -78 + 3°C (c = 0.5 in pyridine)
Eksempel 8: 6-, metyl- 8- ( 2- f enoksy- 5- pyridylamino)- era;olin Example 8: 6-, methyl-8-(2-phenoxy-5-pyridylamino)-era;olin
Analogt med eksempel 3 erholdes fra 2-fenoksy-5-amino-pyridin og 6-metyl-8-okso-ergolin i nærvær av palladium de folgende forbindelser (isomerer I a og I b): Analogous to example 3, the following compounds are obtained from 2-phenoxy-5-amino-pyridine and 6-methyl-8-oxo-ergoline in the presence of palladium (isomers I a and I b):
6-metyl-8S-(2-fenoksy-5-pyridylamino)-ergolin6-methyl-8S-(2-phenoxy-5-pyridylamino)-ergoline
Smp. 186 - 188°C (fra aceton-etylacetat)Temp. 186 - 188°C (from acetone-ethyl acetate)
/«7q° = +64 + 3°C (c = 0,5 i pyridin) /«7q° = +64 + 3°C (c = 0.5 in pyridine)
6-metyl-8R-(2-fenoksy-5-pyridylamino)-ergolin6-methyl-8R-(2-phenoxy-5-pyridylamino)-ergoline
Smp. 240 - 241°C (fra metanol-aceton)Temp. 240 - 241°C (from methanol-acetone)
/a7^° = -70 + 3°C (c = 0,5 i pyridin)/a7^° = -70 + 3°C (c = 0.5 in pyridine)
Analogt med eksemplene 2 til 8 kan ved anvendelse av de tilsvarende aminer også de folgende forbindelser, hvor likeledes isomer-adskillelse kan gjennomfores, fremstilles: Analogous to examples 2 to 8, by using the corresponding amines, the following compounds can also be prepared, where isomer separation can also be carried out:
Eksempel 14: 6- metyl- 8-( 2 - tiometyl- 5- pyridylamino)- erqolin Example 14: 6-methyl-8-(2-thiomethyl-5-pyridylamino)-erqoline
Analogt med eksempel 1 erholdes fra 2-tiometyl-5-aminopyridinAnalogous to example 1 is obtained from 2-thiomethyl-5-aminopyridine
og 6-metyl-8-okso-ergolin i nærvær av natriumborhydrid den folgende forbindelse: § I™® t I §§I i i I !:i2!I}? and 6-methyl-8-oxo-ergoline in the presence of sodium borohydride the following compound: § I™® t I §§I i i I !:i2!I}?
Tartrat.hemihydrat: Smp. spalting fra 218°C (fra metanol-aceten) Tartrate hemihydrate: mp. cleavage from 218°C (from methanol-acetene)
/a7p° = +70 + 5°G (c = 0,1 i pyridin)/a7p° = +70 + 5°G (c = 0.1 in pyridine)
Det som utgangsmaterial anvendte 6-metyl-8-okso-ergolin kan fremstilles på folgende måte: The 6-methyl-8-oxo-ergoline used as starting material can be produced in the following way:
a) A8 ' g-ergolen-8-karboksylsyreazid-hydroklorida) A8 'g-ergolene-8-carboxylic acid azide hydrochloride
I en sulfideringskolbe innfores under nitrogen 23 ml abs. Into a sulphiding flask, introduce under nitrogen 23 ml of abs.
dimetylformamid i 100 ml abs. kloroform og avkjoles til -20°C. Under omroring lar man en losning av 10,4 ml oxalylklorid i 50 ml abs. kloroform tilflyte i lopet av 15 - 20 minutter og det omrores videre ennå i omtrent 20 minutter. dimethylformamide in 100 ml abs. chloroform and cooled to -20°C. While stirring, a solution of 10.4 ml of oxalyl chloride in 50 ml of abs. chloroform flow over the course of 15 - 20 minutes and stirring continues for approximately 20 minutes.
- _, i . c _ u_ A8 ' g-ergolen-8-karboksylsyre tilsettes under nitrogen 77 ml abs. dimetylformamid og avkjoles til -30°C. Deretter tilsettes under nitrogenstrom den ovenfor beskrevne fremstilte losning. Derved stiger temperaturen noe og den forst gråbrune farge slår om til fiolett. Den således erholdte reaksjonsblanding tilsettes under nitrogen- - _, i . c _ u_ A8 ' g-ergolene-8-carboxylic acid is added under nitrogen 77 ml abs. dimethylformamide and cooled to -30°C. Then, under a stream of nitrogen, the prepared solution described above is added. Thereby, the temperature rises somewhat and the initially grey-brown color changes to violet. The reaction mixture thus obtained is added under nitrogen
strom en suspensjon av 14,3 g pulverisert natriumazid i 300 ml abs. kloroform ved -20°C under kraftig omroring og etterspyles med litt abs. kloroform. Det omrores ennå i 1 time uten kjolebad, hvorved temperaturen stiger til ca. +15°C og reaksjonsblandingen erholder en gronnsort farge. Deretter sentrifugeres i en sentri-fuge ved 3000 omdreininger/minutt i 20 minutter. Den gronnsorte losning avdekanteres, den tilbakeblivende rest opptas på nytt i 300 ml kloroform og filtreres på et glass-sinterfilter ( Gf 3). Filterresten oppslemmes 3 ganger med hver gang 200 ml isblandet vann, avsuges i det enkelte tilfelle på nytt og vaskes til sist med 300 ml dietyleter. 6-metyl- -ergolen-8-karboksylsyreazid-hydroklorid blir tilbake som et morkegront produkt og videre-forarbeides utorret i det neste trinn. strom a suspension of 14.3 g of powdered sodium azide in 300 ml of abs. chloroform at -20°C with vigorous stirring and rinsed with a little abs. chloroform. It is still stirred for 1 hour without a coat bath, whereby the temperature rises to approx. +15°C and the reaction mixture acquires a greenish-black colour. It is then centrifuged in a centrifuge at 3000 revolutions/minute for 20 minutes. The green-black solution is decanted, the remaining residue is taken up again in 300 ml of chloroform and filtered on a glass sintered filter (Gf 3). The filter residue is slurried 3 times with 200 ml of ice-mixed water each time, suctioned off again in each case and finally washed with 300 ml of diethyl ether. 6-Methyl-ergolene-8-carboxylic acid azide hydrochloride remains as a green product and is further processed undried in the next step.
6-metyl-8-okso-ergolin6-methyl-8-oxo-ergoline
A8 ' g<->ergolen-8-karboksylsyreazid-hydroklorid fra trinn a) overhelles med 1000 ml kokende 0,2 N saltsyre, hvorved det med en gang begynner en intens nitrogen-utvikling. Det oppvarmes videre i forhåndsoppvarmet oljebad ved 150 - 160°C til nitrogenutvikiingen er avsluttet og den sortbrune suspensjon er blitt klar. Deretter avkjoles ti lf.rom temperatur, overhelles med :}2000 ml dietyleter og innstilles alkalisk under omroring med ca. 150 ml 1 N natriumhydrogenkarbonat (pH 8). A8 ' g<->ergolene-8-carboxylic acid azide hydrochloride from step a) is poured over with 1000 ml of boiling 0.2 N hydrochloric acid, whereby intense nitrogen evolution immediately begins. It is further heated in a preheated oil bath at 150 - 160°C until the evolution of nitrogen has ended and the black-brown suspension has become clear. It is then cooled to room temperature, poured over with :}2000 ml of diethyl ether and made alkaline while stirring with approx. 150 ml of 1 N sodium bicarbonate (pH 8).
Etter adskillelse av sij:iktene etterekstraheres den vandige fase ennå 3 ganger med hver gang 500 ml dietyleter og eterfasene vaskes 2 ganger med hver gang 200 ml vann. Eterekstraktene torres over natriumsulfat, tilsettes 2 g aktivt kull, omrores i 3 minutter og filtreres klart gjennom et "Hyflo"-sjikt. After separation of the layers, the aqueous phase is further extracted 3 times with 500 ml of diethyl ether each time and the ether phases are washed 2 times with 200 ml of water each time. The ether extracts are dried over sodium sulphate, 2 g of activated carbon are added, stirred for 3 minutes and filtered clearly through a "Hyflo" layer.
Filtratet inndampes i vakuum til ca. 50 ml, hvorved 6-metyl-8-okso-ergolin utkrystalliseres som en gul til lysebrun forbindelse, The filtrate is evaporated in vacuum to approx. 50 ml, whereby 6-methyl-8-oxo-ergoline crystallizes out as a yellow to light brown compound,
smp. 206°C (spalting) henhv. i hoyvakuum 228°C (spalting); m.p. 206°C (decomposition) resp. in high vacuum 228°C (decomposition);
/«72<0>_78oc (c = 0 5^ pvridin)> /«72<0>_78oc (c = 0 5^ pvridin)>
Claims (3)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH523274 | 1974-04-16 | ||
CH189375 | 1975-02-14 | ||
CH189475 | 1975-02-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO751210L true NO751210L (en) | 1975-10-17 |
Family
ID=27173325
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO751210*[A NO751210L (en) | 1974-04-16 | 1975-10-08 |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS50137998A (en) |
AU (1) | AU8011475A (en) |
DD (1) | DD121638A5 (en) |
DE (1) | DE2515100A1 (en) |
DK (1) | DK147775A (en) |
ES (1) | ES436569A1 (en) |
FI (1) | FI751031A (en) |
FR (1) | FR2267781A1 (en) |
IL (1) | IL47085A0 (en) |
NL (1) | NL7504330A (en) |
NO (1) | NO751210L (en) |
SE (1) | SE7504036L (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1573621A (en) * | 1976-01-02 | 1980-08-28 | Sandoz Ltd | Acylated 6-methyl-8a-amino-ergoline i compounds |
JPS5448880A (en) * | 1977-09-02 | 1979-04-17 | Tetra Pak Int | Method of designing packaging laminate and packaging laminate |
DE3227122A1 (en) * | 1982-07-20 | 1984-01-26 | Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim | STABLE SOLUTIONS OF MOTHER CORNAL CALOIDS |
-
1975
- 1975-04-07 FI FI751031A patent/FI751031A/fi not_active Application Discontinuation
- 1975-04-07 DE DE19752515100 patent/DE2515100A1/en active Pending
- 1975-04-07 DK DK147775A patent/DK147775A/da not_active IP Right Cessation
- 1975-04-08 SE SE7504036A patent/SE7504036L/en unknown
- 1975-04-11 NL NL7504330A patent/NL7504330A/en unknown
- 1975-04-14 AU AU80114/75A patent/AU8011475A/en not_active Expired
- 1975-04-14 IL IL47085A patent/IL47085A0/en unknown
- 1975-04-14 ES ES436569A patent/ES436569A1/en not_active Expired
- 1975-04-15 JP JP50044910A patent/JPS50137998A/ja active Pending
- 1975-04-15 DD DD185464A patent/DD121638A5/xx unknown
- 1975-04-16 FR FR7511771A patent/FR2267781A1/en active Granted
- 1975-10-08 NO NO751210*[A patent/NO751210L/no unknown
Also Published As
Publication number | Publication date |
---|---|
FI751031A (en) | 1975-10-17 |
FR2267781A1 (en) | 1975-11-14 |
SE7504036L (en) | 1975-10-17 |
IL47085A0 (en) | 1975-08-31 |
DK147775A (en) | 1975-10-17 |
DD121638A5 (en) | 1976-08-12 |
NL7504330A (en) | 1975-10-20 |
ES436569A1 (en) | 1977-04-01 |
AU8011475A (en) | 1976-10-21 |
FR2267781B1 (en) | 1978-08-04 |
JPS50137998A (en) | 1975-11-01 |
DE2515100A1 (en) | 1975-11-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI310378B (en) | Pyrazine-2-carboxamide derivatives as mglur5 antagonists | |
US6159962A (en) | 3-substituted 3,4-dihydro-thieno[2,3-D]pyrimidine derivatives and production and use of the same | |
NO811040L (en) | DIAMINOPYRIDINES AND PROCEDURES FOR THEIR PREPARATION | |
NO159724B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE IMIDAZO (1,2-A) PYRAZINES. | |
IE55156B1 (en) | Pharmacologically active pyrazolo(4,3-c)pyridines | |
US6222034B1 (en) | 3-substituted pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine derivatives, their preparation and their use | |
AU2006212192B2 (en) | Non steroidal glucocorticoid receptor modulators | |
NO751210L (en) | ||
US6355647B1 (en) | 3-substituted 3,4,5,7-tetrahedropyrrolo[3′,4′:4,5]thieno-[2,3-d]pyrimidine derivatives, their preparation and use | |
NZ581186A (en) | Triazolo [1, 5-a] quinolines as adenosine a3 receptor ligands | |
AU700730B2 (en) | Imidazopyridine-azolidinones | |
US4004011A (en) | 3-Pyridylamine substituted ergolines | |
CN111393318A (en) | Synthesis of novel sildenafil acid amide derivative and application of novel sildenafil acid amide derivative in antitumor drugs | |
NO312463B1 (en) | Pyrimide [4,5-b] indoles and compounds | |
CN111247143B (en) | Pyridoquinazoline derivatives useful as inhibitors of protein kinases | |
US6159981A (en) | 3-substituted pyrido [3',4':4,5] Thieno [2,3-d] pyrimidine derivatives, and production and use of the same | |
NO811065L (en) | PROCEDURE FOR THE PREPARATION OF CERTAIN PYRIMIDON DERIVATIVES | |
AU640831B2 (en) | Process for preparing benzo(c)phenanthridinium derivatives, and novel compounds prepared by said process | |
US6815449B2 (en) | LK6-A derivatives | |
CA3089666A1 (en) | Ghrelin o-acyltransferase inhibitors | |
CA1136632A (en) | 2-amino-3(4 or 5)-pyridinyl)-phenols, preparation and cardiotonic use | |
SU1189349A3 (en) | Method of producing 6-substituted hexahydroindazolisoquinolines | |
CN113493447B (en) | GLP-1 receptor agonists | |
DK164867B (en) | PYRIMIDOOE4,5-GAAQUINOLINE DERIVATIVES OR SALTS THEREOF AND PHARMACEUTICAL FORMS CONTAINING THESE | |
NO153851B (en) | PREPARATION OF THERAPEUTIC ACTIVE 2,6-BIS- (AMINOACYLAMINO) -BENZO- (1,2-D: 5,4-D`) -BISTIAZOLES. |