NO163736B - Analogifremgangsmaate for fremstilling av terapeutisk aktive fenoxy-substituerte beta-carbolin-derivater. - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive fenoxy-substituerte beta-carbolin-derivater. Download PDFInfo
- Publication number
- NO163736B NO163736B NO864517A NO864517A NO163736B NO 163736 B NO163736 B NO 163736B NO 864517 A NO864517 A NO 864517A NO 864517 A NO864517 A NO 864517A NO 163736 B NO163736 B NO 163736B
- Authority
- NO
- Norway
- Prior art keywords
- carboline
- methoxymethyl
- carboxylic acid
- melting point
- denotes
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 title abstract 2
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical group O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 title 1
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 claims abstract description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 32
- -1 nitroamino Chemical group 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 145
- 230000008018 melting Effects 0.000 description 145
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 229960002200 flunitrazepam Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000004300 GABA-A Receptors Human genes 0.000 description 3
- 108090000839 GABA-A Receptors Proteins 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- JCDJTNBLRQYGTO-UHFFFAOYSA-N ethyl 4-(methoxymethyl)-5-phenoxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=CC=C1 JCDJTNBLRQYGTO-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- NKXJUXVTVJZRME-UHFFFAOYSA-N propan-2-yl 4-(methoxymethyl)-5-phenoxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 NKXJUXVTVJZRME-UHFFFAOYSA-N 0.000 description 3
- 210000004129 prosencephalon Anatomy 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 2
- FBAOVPVVMDOHPK-UHFFFAOYSA-N 2-(1h-imidazol-2-ylsulfinyl)-1h-imidazole Chemical compound N=1C=CNC=1S(=O)C1=NC=CN1 FBAOVPVVMDOHPK-UHFFFAOYSA-N 0.000 description 2
- HYGJKOYHOWEYAR-UHFFFAOYSA-N 4-(methoxymethyl)-5-phenoxy-9h-pyrido[3,4-b]indole-3-carbonitrile Chemical compound C=12C=3C(COC)=C(C#N)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 HYGJKOYHOWEYAR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- SLYDYLLJUXFULK-UHFFFAOYSA-N Gedocarnil Chemical compound C=12C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=CC=1OC1=CC=C(Cl)C=C1 SLYDYLLJUXFULK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- FBMZLRWNPUSEEZ-UHFFFAOYSA-N N'-hydroxy-4-(methoxymethyl)-5-phenoxy-9H-pyrido[3,4-b]indole-3-carboximidamide Chemical compound C=12C=3C(COC)=C(C(N)=NO)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 FBMZLRWNPUSEEZ-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101150052863 THY1 gene Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
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- 229910052786 argon Inorganic materials 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- 235000019438 castor oil Nutrition 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical compound [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- SVQZRISZGDYYOG-UHFFFAOYSA-N ethyl 4-(methoxymethyl)-5-(4-nitrophenoxy)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=C([N+]([O-])=O)C=C1 SVQZRISZGDYYOG-UHFFFAOYSA-N 0.000 description 2
- TWYLSBATIICROG-UHFFFAOYSA-N ethyl 5-(4-aminophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C=12C3=C(COC)C(C(=O)OCC)=NC=C3NC2=CC=CC=1OC1=CC=C(N)C=C1 TWYLSBATIICROG-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- TVZISJTYELEYPI-UHFFFAOYSA-N hypodiphosphoric acid Chemical compound OP(O)(=O)P(O)(O)=O TVZISJTYELEYPI-UHFFFAOYSA-N 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- RLZPCFQNZGINRP-UHFFFAOYSA-N n'-hydroxypropanimidamide Chemical compound CCC(N)=NO RLZPCFQNZGINRP-UHFFFAOYSA-N 0.000 description 2
- WUHLVXDDBHWHLQ-UHFFFAOYSA-N pentazole Chemical compound N=1N=NNN=1 WUHLVXDDBHWHLQ-UHFFFAOYSA-N 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- PNANPFPQMWFWEU-UHFFFAOYSA-N propan-2-yl 6-(3-chloro-4-nitrophenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=C2C=3C(COC)=C(C(=O)OC(C)C)N=CC=3NC2=CC=C1OC1=CC=C([N+]([O-])=O)C(Cl)=C1 PNANPFPQMWFWEU-UHFFFAOYSA-N 0.000 description 2
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
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- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
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- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 description 1
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 1
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
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- PFKRVEBWKLVZHU-UHFFFAOYSA-N 3-ethyl-5-(4-methyl-5-phenoxy-9h-pyrido[3,4-b]indol-3-yl)-1,2,4-oxadiazole Chemical compound CCC1=NOC(C=2C(=C3C4=C(OC=5C=CC=CC=5)C=CC=C4NC3=CN=2)C)=N1 PFKRVEBWKLVZHU-UHFFFAOYSA-N 0.000 description 1
- WVIRSFKIXRPXHT-UHFFFAOYSA-N 3-ethyl-5-(4-methyl-6-phenoxy-9h-pyrido[3,4-b]indol-3-yl)-1,2,4-oxadiazole Chemical compound CCC1=NOC(C=2C(=C3C4=CC(OC=5C=CC=CC=5)=CC=C4NC3=CN=2)C)=N1 WVIRSFKIXRPXHT-UHFFFAOYSA-N 0.000 description 1
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- QNWNOCXLABPNIV-UHFFFAOYSA-N ethyl 5-(4-ethoxycarbonylphenoxy)-4-(methoxymethyl)-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=CC(C(=O)OCC)=CC=C1OC1=CC=CC2=C1C1=C(COC)C(C(=O)OCC)=NC=C1N2 QNWNOCXLABPNIV-UHFFFAOYSA-N 0.000 description 1
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- IPPKNZFBRGGEHP-UHFFFAOYSA-N ethyl 5-phenoxy-9h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=NC(C(=O)OCC)=CC(C=23)=C1NC3=CC=CC=2OC1=CC=CC=C1 IPPKNZFBRGGEHP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
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Description
Foreliggende oppfinnelse angår fremstilling av nye fenoxysubstituerte 8-carbolinderivater.
I EP-A-130140, som inneholder 6-(4-methoxy-fenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, og i EP-A-54507 som inneholder 5-fenoxy-4-methyl-0-carbolin-3-carboxylsyreethylester, er det beskrevet forbindelser som utviser virkning på sentralnervesystemet som er kjent for (3-carboliner.
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive fenoxysubstituerte 3-carbolinderivater av generell formel I
hvori
X er en oxadiazolylrest av formel
hvori
R <2>betegner H, C,-C.-alkyl eller cyclopropyl, eller X er 3 3 en COOR -gruppe, hvori R betegner lavere alkyl, eller X er CONHC,_,-alkyl, og
4
R betegner hydrogen, C-^-C^-alkyl eller C-^-C^-alkoxy-C^-C^-alkyl, og
R1 betegner hydrogen, halogen, C^-C^-alkyl, C^-C4~alkoxy, C,-C.-alkanoyl, trifluormethyl, nitrilo, nitroamino, 6 6 C,-C.-alkoxycarbonyl, piperidinazo, SO-R , hvori R 7 8 7 R betegner C^-C^-alkyl, S02NR R , hvorved R og R betegner C^-C^-alkyl eller kan sammen med nitrogenatomet danne en morfolinring og n er 1 eller 2, hvorved
X ikke er COOEt når grupperingen
er 5-fenoxy og R'* er methyl, eller 6-(4-methoxyf enoxy) og R^ betegner methoxymethyl.
De nye forbindelser utviser på overraskende måte i sammenlikning med de tidligere kjente p-carboliner overlegne psykotrope egenskaper i farmakologiske tester, slik det fremgår fra tabellen for enkelte av de nye forbindelser.
De nye forbindelser utviser i særdeleshet anxiolytisk og antikonvulsiv virksomhet. For undersøkelse av den anti-konvulsive virkning ble opphevelsen av kramper fremkalt med pentylentetrazol (pentazol) undersøkt. Pentazol ble i en mengde på 150 mg/kg som saltsyreløsning (pH 2-3) administrert subkutant 15-30 min. etter intraperitoneal admini-strering av testforbindelsen. Denne mengde fremkalte kloniske og toniske kramper som på ubehandlede dyr fører til døden. Antall mus som utviser krampe, og antallet derav som 30 min. etter pentazoladministreringen var døde, ble regi-strert (PTS krampeantagonisme).
ED5Q-verdiene angitt i tabellen, ble bestemt etter metoden ifølge Litchfield og Wilcoxon [J. Pharmacol. exp. Ther., 9j5 (1949) 99-103] som den mengde av den antagonistisk virkende substans som beskyttet 50 % av dyrene mot krampe og død.
Det er kjent at bestemte steder i sentralnervesystemet hos virveldyr utviser en høy spesifikk affinitet for binding av 1,4- og 1,5-benzodiazepiner [Squires, r.f. og Braestrup, C, Nature (London) 266 (1977), 734]. Disse steder betegnes som benzodiazepinreseptorer.
De farmakologiske egenskaper av de nye forbindelser ble bestemt ved undersøkelse av fortrengningsevnen av radioaktivt merket flunitrazepam fra benzodiazepinreseptorer.
Fortrengningsaktiviteten av de nye forbindelser angis som IC5Q- og E<D>5Q-verdier. I<C>5ø-verdien angir den konsen-trasjon som bevirker en 50 % fortrengning av den spesifikke binding av H-^-f lunitrazepam (1,0 nM, 0°C) i prøver med et totalt volum på 0,55 ml av en suspensjon av hjernemembran, eksempelvis fra rotter.
Fortrengningstesten ble utført som følger:
0,5 ml av en suspensjon av ubehandlet rotteforhjerne i 25 mM KH2P04, pH = 7,1 (5-10 mg vevprøve) ble inkubert i 40-60 min. ved 0°C sammen med -^H-diazepam (spesifikk aktivitet 14,4 Ci/mmol, 1,9 nM) eller <3>H-flunitrazepam (spesifikk aktivitet 87 Ci/mmol, 1,0 nM). Etter inkubering ble suspen-sjonen filtrert gjennom en glassfritte, residuet ble vasket to ganger med kald bufferløsning, og radioaktiviteten ble målt i en scintillasjonsteller.
Forsøket ble deretter gjentatt, imidlertid slik at det før tilsetning av det radioaktivt merkede benzodiazepin ble tilsatt en mengde eller en overskytende mengde av den forbindelse hvis fortrengningsaktivitet skulle bestemmes. På grunnlag av de erholdte verdier kan deretter IC5g-verdien beregnes.
ED5Q-verdien angir den dose av en forsøkssubstans som bevirker en reduksjon av den spesifikke binding av flunitrazepam til benzodiazepinreseptoren i en levende hjerne til 50 % av kontrollverdien.
In vivo-testen ble utført som følger:
Grupper av mus ble normalt intraperitonealt injisert forsøkssubstansen med forskjellige doser. Etter 15 min. ble musene intravenøst administrert -%-flunitrazepam. Etter ytterligere 20 min. ble musene avlivet, forhjernen ble fjer-net, og radioaktiviteten av forhjernen ble målt ved hjelp av scintillasjonstelling. ED5ø-verdien ble bestemt fra dose/ virkningskurvene.
De nye forbindelser av generell formel I utviser verdifulle farmakologiske egenskaper. I særdeleshet virker de på sentralnervesystemet og er dermed egnet som psyko-farmaka innen humanmedisinen, hvorved de særlig kan anvendes for behandling av angst ledsaget av depresjoner, epilepsi, søvnforstyrrelser, spastisiteter og muskelrelaksasjoner under anestesi. Også amnestiske hhv. hukommelsesfremmende egenskaper finnes hos de nye forbindelser.
De nye forbindelser kan således anvendes til formulering av farmasøytiske preparater, f.eks. for oral eller parenteral anvendelse på mennesker etter i og for seg kjente metoder innen den galeniske farmasi.
Som hjelpestoffer for formulering av farmasøytiske preparater er slike fysiologisk akseptable, organiske og uorganiske bærersubstanser for enteral og parenteral anvendelse egnet som er inerte overfor de nye forbindelser.
Som bærersubstanser kan eksempelvis nevnes vann, salt-løsninger, alkoholer, polyethylenglykoler, polyhydroxyethoxylert rizinusolje, gelatin, laktose, amylose, magnesium-stearat, talkum, kieselsyre, fettsyremono- og diglycerider, pentaerythritolfettsyreestere, hydroxymethylcellulose og polyvinylpyrrolidon.
De farmasøytiske preparater kan steriliseres og/eller tilsettes hjelpestoffer slik som smøremidler, konserverings-midler, stabilisatorer, fuktemidler, emulgatorer, buffere og fargestoffer.
For parenteral anvendelse er i særdeleshet injeksjons-løsninger eller suspensjoner, i særdeleshet vandige løs-ninger av den aktive forbindelse i polyhydroxyethoxylert rizinusolje, egnet. For oral anvendelse er i særdeleshet tabletter, drasjéer eller kapsler med talkum og/eller en hydrocarbonbærer eller bindemiddel egnet, slik som f.eks. laktose, mais- eller potetstivelse. Anvendelsen kan også skje i flytende form, slik som f.eks. saft som eventuelt tilsettes et søtningsmiddel.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at
a) en forbindelse av generell formel II
hvori R<1> og R<4> har de ovenfor angitte betydninger, omsettes med en forbindelse av formel
hvori R<2> har den ovenfor angitte betydning, til en forbindelse av generell formel I, hvori X betegner resten hvori R<2> har den ovenfor angitte betydning, b) en forbindelse av generell formel III hvori R-'- og R<4> har de ovenfor angitte betydninger, omsettes med et carboxylsyreanhydrid (R<2>CO)20, hvori R<2> har de ovenfor angitte betydninger, til en forbindelse av generell formel I, hvori X betegner resten rivori R<2> har den ovenfor angitte betydning, c) en forbindelse av generell formel IV
hvori R<3> og R<4> har de ovenfor angitte betydninger, omsettes med en forbindelse av formel
hvori Hal betegner halogen, og R<1> har den ovenfor angitte betydning, og R<1>' betegner en elektrontrekkende substituent, hvorpå eventuelt
a) en nitrogruppe reduseres til en aminogruppe, og om ønsket at den således erholdte aminogruppe desamineres eller utbyttes mot halogen eller azid, eller
(3) såfremt R<1> er halogen, katalytisk dehalogeneres, eller
y) at en estergruppe omestres eller forsåpes, og eventuelt at den således erholdte carboxylsyre amideres.
For innføring av 1,2-oxadiazol-5-yl-resten kondenseres p-carbolincarboxylsyren av generell formel II med et amid-oxim av formel i et inert løsningsmiddel som koker over 100°C og er inert overfor reaktantene ved reaksjonsblandingens tilbakeløpstem-peratur. Egnede løsningsmidler for kondensasjonsreaksjonen er eksempelvis toluen og dimethylformamid. Hensiktsmessig aktiveres den fri p-carbolin-3-carboxylsyre før kondensasjonsreaksjonen på egnet måte. Herved kan den fri syre f.eks. overføres i det blandete anhydrid, i den aktiverte ester eller i klorid.
En aktivering til imidazolid med imidazol/thionyl-klorid eller også carbonyldiimidazol i et aprotisk løsnings-middel slik som dioxan, tetrahydrofuran, dimethylformamid eller N-methylpyrrolidon ved temperaturer mellom 0 og 50°C, fortrinnsvis romtemperatur, har også vist seg fordelaktig.
For innføring av 1,2,4-oxadiazol-3-yl-resten omsettes eksempelvis 3-carboxylsyrenitrilet med hydroxylamin til forbindelsen av generell formel III. Det således erholdte |3-carbolin-3-carboxamidoxim tilsettes ved romtemperatur syre-anhydridet (R<2>CO)20, og blandingen oppvarmes deretter til koketemperatur. Reaksjonen er fullført etter ca. 7 timer, og reaksjonsblandingen opparbeides etter vanlige metoder.
Innføring av fenoxyresten skjer fortrinnsvis ved omsetning av forbindelsen av generell formel IV med et fluor-benzenderivat, som hensiktsmessig bærer en ytterligere elektrontrekkende substituent.
Som elektrontrekkende substituenter R<1>' kan eksempelvis menes følgende for R^ angitte rester: ni tro, lavere alkoxycarbonyl, lavere alkylsulfonyl, trifluormethyl, cyano osv. Omsetningen med det substituerte halogenbenzenderivat utføres i basisk miljø i dipolare aprotiske løsningsmidler ved temperaturer opptil løsningsmidlets kokepunkt.
Som løsningsmiddel er eksempelvis dimethylformamid, dimethylsulfoxyd, dimethylacetamid, n-methylpyrrolidinon, hexamethylfosforsyretriamid egnet.
Som baser kommer alkaliforbindelser slik som f.eks. natrium- eller kaliumhydroxyd, natrium- eller kaliumcarbont i betraktning, eventuelt også i nærvær av faseoverførings-katalysatorer slik som f.eks. kroneethere slik som 18-krone-6, dicyclohexyl-18-krone-6, dibenzo-18-krone-6 eller Ali-quat$ 336.
Hensiktsmessig arbeides det under inert gassatmosfære, eksempelvis under nitrogen eller argon.
Reduksjonen av nitrogruppen til aminogruppen skjer eksempelvis katalytisk i polare løsningsmidler ved romtemperatur .
Som katalysator anvendes fortrinnsvis palladium på en bærer slik som carbon, eller platina i finfordelt form, og ved forbindelser med halogen anvendes det som katalysator fortrinnsvis Raney-nikkel.
Alle inerte løsningsmidler er egnet for reduksjonen, slik som f.eks. alkoholer eller ethere slik som methanol, ethanol, diethylether, tetrahydrofuran eller blandinger derav.
Hydrogeneringen kan utføres under normalt trykk eller H2-trykk.
Desamineringen skjer eksempelvis etter den litteratur-kjente Sandmeyer-metoden. Herved kokes reduktivt den med et nitritt intermediært dannede diazoniumforbindelse, i nærvær av kopper-I-oxyd og hypofosforsyre, ved forhøyet temperatur.
Innføringen av halogenene klor, brom eller jod over aminogruppen kan eksempelvis også skje ifølge Sandmeyer, idet det med nitritter, intermediært dannede diazoniumsalter omsettes med Cu(I)klorid eller Cu(I)bromid i nærvær av de tilsvarende syrer, dvs. saltsyre eller hydrobromsyre, eller med kaliumjodid.
Innføringen av fluor skjer eksempelvis ved Balz Schniemann-reaksjonen av diazoniumtetrafluorboratet.
Innføringen av azidogruppen skjer over Sandmeyer-reaksjonen av diazoniumsaltet med eksempelvis alkaliazid.
Den katalytiske dehalogenering utføres eksempelvis med palladium på carbon (10 %) under tilsetning av organiske baser slik som f.eks. triethylamin i alkoholer.
For å unngå omestringer, anvendes hensiktsmessig alko-holen av esterkomponenten som løsningsmiddel.
ønskes en omestring, kan det eksempelvis omsettes med den tilsvarende alkohol eller alkalialkoholat, eventuelt kan titantetra-isopropylat i vannfri alkohol tilsettes som katalysator. Vanligvis utføres omestringen ved temperaturer på 60-120°C og er fullført etter 2-6 timer.
Innføringen av den tert.-butylestergruppe skjer eksempelvis ved omsetning av carboxylsyren med tert.-butoxy-bis-dimethylaminomethan. Generelt utføres reaksjonen under inert gassatmosfære, slik som argon eller nitrogen, og under utelukkelse av fuktighet, ved forhøyet temperatur.
Forsåpningen av estergruppen kan skje surt eller alkalisk, fortrinnsvis alkalisk, idet esteren oppvarmes med fortynnet vandig alkalilut, slik som kalium- eller natri-umhydroxyd, i et protisk løsningsmiddel slik som f.eks. methanol, ethanol eller ethylenglykol til temperaturer opptil reaksjonsblandingens tilbakeløpstemperatur.
Carboxylsyreamider erholdes eksempelvis ved omsetning med aminer fra de tilsvarende imidazolider, som intermediært fremstilles fra carboxylsyren og carbonyl- eller thionyldiimidazol. Reaksjonen utføres ved romtemperatur i dipolare aprotiske løsningsmidler slik som f.eks. dimethylformamid, dimethylacetamid o.1.
Fremstilling av utgangsforbindelsene er kjente eller kan.skje etter kjente metoder, eksempelvis som beskrevet i EP-Å-130140. Således kan esteren fremstilles over aktivering av den tilsvarende syre og etterfølgende omsetning med den ønskede alkohol.
De etterfølgende eksempler illustrerer oppfinnelsen.
Eksempel 1
5-( 4- klorfenoxy)- 3-( 3- ethyl- l, 2, 4- oxadiazol- 5- yl)- 4- methoxymethyl- 3- carbolin
5,74 g 5-(4-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyre ble oppløst i 150 ml absolutt dimethylformamid, ble tilsatt 2,91 g carbonyldiimidazol og ble omrørt i 3 timer ved romtemperatur. Til denne løsning ble tilsatt 3,96 g propionamidoxim, reaksjonsblandingen ble omrørt i 8 timer, hvorpå ytterligere 1 g propionamidoxim ble tilsatt, og blandingen ble omrørt i 8 timer. Etter inndampning ved oljepumpevakuum ble residuet tatt opp i toluen og kokt under tilbakeløpskjøling i 8 timer. Etter inndampning ble produk-
tet kromatografert to ganger over kieselgel, først med methylenklorid/ethanol = 10:1 og deretter med hexan:aceton = 1:1 som elueringsmiddel. Etter omkrystallisering fra eddikester/hexan og tørking over fosforpentoxyd ved 80°C i vakuum ble det erholdt 2,2 g 5-(4-klorfenoxy)-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4-methoxymethyl-pJ-carbolin med smeltepunkt 170°C.
På analog måte ble fremstilt: 5-fenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 245-248°C,
5- (4-nitrofenoxy)-3-(3-ethyl-l, 2,4-oxadiazol-5-yl) -B-carbolin, smeltepunkt 290°C,
5- (4-klorfenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 193-194°C,
6- (4-acetylfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-&-carbolin, smeltepunkt 213-216°C,
5-(4-nitrofenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 287°C,
5-(4-nitrofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 125-180°C,
5- fenoxy-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 168-171°C,
6- fenoxy-3-(3-eth<y>l-l,2,4-oxadiazol-5-<y>l)-B-carbolin, smeltepunkt 205-208°C,
6-fenoxy-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 247-250°C,
6-(4-nitrofenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 288-294°C,
6-(4-aminofenoxy)-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 207-210°C,
6-(4-klorfenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 245-250°C,
6-(4-nitrofenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 250-258°C,
6-(4-aminofenoxy)-4-methyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 245-255°C,
6-(4-klorfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 178-192°C,
6-(4-klorfenoxy)-4-methoxymethy1-3-(3-cyclopropy1-1,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 192-193°C,
6-(4-bromfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt > 280°C,
6-fenoxy-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 164°C, 6 - ( 4 -ni trof enoxy) - 4 -me thoxyme thy 1 - 3 - ( 3 -e thy 1 -1,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 223-225°C,
6-(4-nitrofenoxy)-4-methoxymethyl-3-(3-cyclopropy1-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 226°C,
6-(2-nitrofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 206-211°C,
6-(2-nitrofenoxy)-4-methoxymethyl-3-(3-cyclopropy1-1,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 154-155°C,
6-(4-aminofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 249-255°C,
6-(2-methyl-4-nitrofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 208-209°C,
6-(4-morfolinosulfamoylfenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 113°C,
6-(4-morfolinosulfamoylfenoxy)-4-methoxymethyl-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 139-140°C,
6-(4-diethylsulfamoylfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 184-189°C,
6-(4-methylsulf onylfenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 150°C,
6-(4-ethoxycarbonylfenoxy)-4-methoxymethyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 185-191°C,
6-(2-klorfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 158-161°C,
6-(4-cyanofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 224-225°C,
6-(2-klor-4-nitrofenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-p-carbolin, smeltepunkt 200-213°C,
6-(2-klor-4-aminofenoxy)-4-methoxymethyl-3-(3-ethyl-
1,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 235-247°C,
6-(2,4-diklorfenoxy)-4-methoxymethy1-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 160-174°C,
6-(4-fluorfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 240-242°C,
5-(3-klorfenoxy)-4-methoxymethyl-3-(3-ethyl-l,2,4-oxadiazol-5-yl)-B-carbolin, smeltepunkt 170-172°C.
Eksempel 2
4- methoxymethyl- 5- fenoxy- 3-( 3-( 5- ethyl- l, 2, 4- oxadiazol)- yl-B- carbolin
0,7 mmol 4-methoxymethyl-5-fenoxy-B-carbolin-3-carboxamidoxim og 1 ml propionsyreanhydrid ble omrørt i 2 timer ved 20°C og deretter i 5 timer ved 120°C. Etter inndampning ble 10 ml tetrahydrofuran tilsatt, reaksjonsblandingen fikk stå over natten og ble deretter konsentrert i vakuum, hvorpå reaksjonsproduktet ble ekstrahert med 30 ml methylenklorid som oljeaktig substans, 71%, smeltepunkt 185-187°c.
Utgangsmaterialet ble fremstilt som følger:
a) 5- fenoxy- 4- methoxymethyl- 3- carbolin- 3- carboxamid
Til en løsning av 30 mmol thionyldiimidazol i 150 ml
tetrahydrofuran ble tilsatt 2,7 g 5-fenoxy-4-methoxymethyl-p-carbolin-3-carboxylsyre. Reaksjonsblandingen ble omrørt i 5 timer og ble filtrert. Filtratet ble tilsatt 12 ml 25 % NH3 i vann, ble omrørt over natten og inndampet til 50 ml i vakuum. Etter tilsetning av 100 ml vann ble 2 g av det ønskede produkt erholdt som gule krystaller.
b) 5- fenoxy- 3- cyano- 4- methoxyme thyl- B- carbolin
Til en omrørt løsning av 1,8 g (15 mmol) trifenylfos-fin i 50 ml methylenklorid ble ved 0°C dråpevis tilsatt 1,1 g Br2 i 10 ml methylenklorid. Deretter ble 2 g 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxamid og 1,9 ml triethylamin tilsatt. Reaksjonsblandingen ble omrørt i en time ved 0°C og ble deretter kraftig omrørt med 25 ml methylenklorid og 25 ml vann i 5 min. Etter fjerning av den vandige fase ble 0,8 g av det ønskede produkt erholdt ved inndampning av den organiske fase.
c) 4- methoxymethyl- 5- fenoxy- B- carbolin- 3- carboxamidoxim
En blanding av 329 mg (0,001 mol) 3-cyano-4-methoxymethyl-5-fenoxy-B-carbolin, 100 mg hydroxylamin-hydroklorid, 20 ml ethanol (99 %) og 0,52 ml av en 20 %-ig vandig kalium-carbonatløsning ble kokt i 22 timer under tilbakeløpskjøl-ing. Reaksjonsblandingen ble filtrert, og filtratet ble inndampet. Residuet ble tilsatt 10 ml vann, det krystal-linske faste materiale ble filtrert fra og vasket med vann.
Eksempel 3
5-( 4- nitrofenoxy)- 4- methoxymethyl- B- carbolin- 3- carboxylsyreethylester 6 g 5-hydroxy-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester ble under nitrogen og i 200 ml dimethylformamid tilsatt 5,5 g vannfri kaliumcarbonat og ble omrørt i en time ved romtemperatur.
Etter tilsetning av 2,8 g 4-fluornitrobenzen ble reaksjonsblandingen oppvarmet til 100°C badtemperatur i 2 timer. Etter ytterligere tilsetning av 1,4 g 4-fluornitrobenzen ble reaksjonsblandingen oppvarmet til 100°C i ytterligere 45 min. Etter avkjøling ble reaksjonsblandingen helt over i is og filtrert. Filterkaken ble kromatografert over kieselgel med aceton:hexan = 1:1 som drivmiddel. Det ble erholdt 5,7 g (70 % av teoretisk) av 5-(4-nitrofenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyre-ethylester med smeltepunkt 231-232°C.
På analog måte ble fremstilt: 5- (2-nitrofenoxy)-4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 241-242°C,
6- 3-(4-cyanofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 226-227°C,
6-(2-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 147-150°C,
6-(2-formylfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreisopropylester, smeltepunkt 188-192°C,
6-(2-cyanofenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 170°C,
6-(2-cyano-3-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 117-125°C,
6-(2-acetylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 112-117°C,
6-(2-cyano-4-fluorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 228-230°C,
6-(2-acetylfenoxy)-4-methoxymethyl-8-carbolin-3-carboxylsyreisopropylester, smeltepunkt 233°C,
5-(4-nitrofenoxy)-4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 225°C,
5-(4-nitrofenoxy)-4-ethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 217-218°C,
5-(4-nitrofenoxy)-B-carbolin-3-carboxylsyre-ethyl-ester, smeltepunkt > 242°C,
5-(4-nitro-3-methylfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 212-213°C,
5-(4-nitro-2-methylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 190-192°C,
5- (4-ethoxycarbonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 157°C,
6- (4-nitrofenoxy)-B-carbolin-3-carboxylsyreethylester, smeltepunkt > 250°C,
6-( 4-n"itrof enoxy) -4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 288-292°C,
6-(4-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 231-232°C,
6-(2-cyano-3-klorfenoxy)-4-methyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 230-232°C,
6-(2-cyano-6-fluorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 175°C,
6-(2-cyano-3-fluorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 208°C,
6-(2-isopropoxycarbonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 145°C,
6-(2-t-butoxycarbonylfenoxy)-4-methoxymethy1-8-carbolin-3-carboxylsyreisopropylester, smeltepunkt 136°C,
6-(4-nitro-3-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 105-115°C,
6-(2-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 153-155°C,
6-(4-nitro-3-methoxyfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 192-203°C,
6-(4-nitro-2-methylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 184-185°C,
6-(4-nitro-2-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 195°C,
6-(4-nitro-3-methyl-fenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 183-184°C,
6-(2-nitro-4-trifluormethylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 90°C,
6-(4-ethoxycarbonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 181°C,
6-(4-trifluormethylfenoxy)-4-methoxymethyl-3-carbolin-3-carboxylsyreethylester, smeltepunkt 226-227°C,
6-(4-methylsulfonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 204-205°C,
5-(4-formylfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 190-192°C,
5-(2-nitro-4-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 160-162°C,
5- (2-nitro-5-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 155-170°C,
6- (2-nitrofenoxy)-4-ethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 182-183°C,
6-(4-morfolinosulfamoylfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 100°C (spaltning),
6-(4-diethylsulfamoylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 179°C,
6-(2-ethylsulfonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 196-198°C.
Eksempel 4
5-( 4- aminofenoxy)- 4- methoxymethyl- p- carbolin- 3- carboxylsyre-ethy lester 15 g 5-(4-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester ble i 450 ml methanol:tetrahydrofuran =1:1 hydrogenert med 7,5 g palladium på carbon (10 %) ved romtemperatur og ved hydrogennormaltrykk. Etter filtrering og inndampning ble produktet omkrystallisert fra ethanol, og det ble erholdt 10,8 g (77 % av teoretisk) av 5-(4-amino-fenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester med smeltepunkt 222-224°C.
På analog måte ble fremstilt: 5-(4-aminofenoxy)-4-methyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 170-172°C,
5- (4-aminofenoxy)-4-ethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 235°C,
6- (4-aminofenoxy)-4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 144-148°c,
6-(4-aminofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 204-234°C,
5-(4-aminofenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt > 250°C.
På hovedsakelig samme måte, men under anvendelse av Raney-nikkel som katalysator og tetrahydrofuran som løs-ningsmiddel, ble følgende forbindelser fremstilt: 5-(4-amino-3-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 202-204°C,
5- (4-amino-2-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 204°C,
6- (4-amino-2-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 95-106°C.
Eksempel 5
5- fenoxy- 4- methoxymethyl- B- carbolin- 3- carboxylsyreethylester
978 mg 5-(4-aminofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester ble suspendert i 2 ml vann og 10 ml 50 % tetrafluorborsyre. Etter avkjøling til 0°C ble reaksjonsblandingen dråpevis tilsatt en løsning av 224 mg natriumnitritt i 2 ml vann og ble omrørt i en halv time ved 0°C. Ved samme temperatur ble deretter 4 ml av en 60 %-ig hypofosforsyreløsning og 150 ml kopper(I)oxyd tilsatt, blandingen ble fortynnet med 10 ml vann og deretter oppvarmet en halv time på dampbadet. Etter innstilling av pH-verdien til 8 med soda og tilsetning av ammoniakk ble reaksjonsblandingen ekstrahert med eddikester. Eddikesterfasen ble inndampet, og residuet ble kromatografert over kieselgel med acetonthexan = 1:1 som elueringsmiddel. Det ble erholdt 540 mg (57 % av teoretisk) av 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester med smeltepunkt 174-176°C.
På analog måte ble fremstilt: 5-fenoxy-B-carbolin-3-carboxylsyreethylester, smeltepunkt 246°C,
5-(3-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 194-197°C,
5- (2-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 175-177°C,
6- fenoxy-B-carbolin-3-carboxylsyreethylester, smeltepunkt 241-242°C,
6-fenoxy-4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 173-175°C,
6-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 172-174°C,
6-(3-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 164°C,
6-(3-methylfenoxy)-4-methoxymethyl-B-carbolin-3-car-boxylsyreisopropylester, smeltepunkt 170-174°C,
6-(3,5-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-car-
boxylsyreisopropylester, smeltepunkt 210°C,
6-(2-methylfenoxy)-4-methoxymethyl-3-carbolin-3-car-boxylsyreisopropylester, smeltepunkt 165-170°C,
5- (2,5-diklorfenoxy-4-methoxymethyl-3-carbolin-3-carboxylsyreethylester, smeltepunkt 194-196°C,
6- (4-methoxyfenoxy)-4-methoxymethyl-0-carbolin-3-car-boxylsyreisopropylester, smeltepunkt 161-162°c,
6-(3-methoxyfenoxy)-4-methoxymethyl-B-carbolin-3-car-boxylsyreisopropylester, smeltepunkt 250°c,
6-(4-methylfenoxy)-4-methoxymethyl-p-carbolin-3-car-boxylsyreisopropylester, smeltepunkt 228-230°c.
Eksempel 6
5-( 4- klorfenoxy)- 4- methoxymethyl- 3- carbolin- 3- carboxylsyreethylester
195 mg 5-(4-aminofenoxy)-4-methoxymethyl-3-carbolin-3-carboxylsyreethylester ble suspendert i en blanding av 2 ml vann og 2 ml konsentrert saltsyre og ble etter avkjøling til 0°C dråpevis tilsatt en løsning av 35 mg natriumnitritt i 0,5 ml vann. Etter endt tilsetning ble blandingen omrørt ved 0°C i 45 min., hvorved en lysegul løsning ble dannet. Til løsningen ble ved 0°C dråpevis tilsatt en løsning fremstilt ved tilsetning av 69 mg natriumsulfitt i 0,5 ml vann til 250 mg kopper(II)sulfat, 5H20 og 87 mg koksalt i 1 ml vann, separering av bunnfallet og oppløsning i 0,5 ml konsentrert saltsyre. Etter endt tilsetning fant det sted en gul utfelling, og blandingen ble deretter oppvarmet på dampbad inntil gassutviklingen var avsluttet. Reaksjonsblandingen ble deretter fortynnet med vann, gjort alkalisk med ammoniakkløsning og ekstrahert med eddikester. Etter inndampning av den organiske fase ble residuet kromatp-grafert over kieselgel med methylenklorid :ethanol .= 1.0:1 som elueringsmiddel. Det ble erholdt 130 mg (55 % av teoretisk) 5-(4-klorfenoxy)-4-methoxymethyl-3-carbolin-3-carboxylsyreethylester med smeltepunkt 207°C.
På analog måte ble fremstilt: 5-(4-klorfenoxy)-4-methyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 234°C,
5- (2,4-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 156-158°C,
6- (4-klorfenoxy)-4-methyl-B_carbolin-3-carboxylsyreethylester, smeltepunkt 176-188°C,
6-(4-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 178°C,
6-(2,4-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 230-239°C,
5- (4-jodfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 200°C,
6- (2-bromfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 152-160°C,
6-(4-fluor-2-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 134-144°C,
6-(2,3-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 100-101°C,
6-(4-piperidinoazofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 168-174°C,
6-(4-bromfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester, smeltepunkt 169-175°C,
6-(4-azidofenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreethylester, smeltepunkt 169-175°C.
Eksempel 7
5- fenoxy- 4- methoxymethyl- B- carbolin- 3- carboxylsyreisopropyl-ester
540 mg 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyreethylester ble i 30 ml isopropanol kokt under tilbake-løpskjøling med 0,2 ml titan(IV)isopropylat i 2 timer. Etter inndampning ble 0,5 n saltsyre tilsatt, og reaksjonsblandingen ble ekstrahert med eddikester. Eddikesterfasen ble tørket, filtrert og inndampet og triturert med diiso-propylether. Det ble erholdt 450 mg (82 % av teoretisk) 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropyl-ester med smeltepunkt 207-209°C.
På analog måte ble fremstilt: 5-fenoxy-4-methyl-B-carbolin-3-carboxylsyreisopropyl-ester, smeltepunkt 226-228°C, 5-(4-klorfenoxy)-4-methyl-B-carbolin-3-carboxylsyre-isopropylester, smeltepunkt 266-268°C, 5-(4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 216-218°C, 5-(4-nitrofenoxy)-4-methyl-B-carbolin-3-carboxylsyre-isopropylester, smeltepunkt 262°C, 5- (4-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester , smeltepunkt 207-209°C, 6- fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyreiso-propylester, smeltepunkt 181°C, 6-(4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 178-181°C, 6-(4-cyanofenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 226-227°C, 6-(2-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 103-109°C, 6-(4-isopropoxycarbonylfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 167°C, 6-(3-klor-4-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 105-115°C, 6-(2,4-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 75-78°C, 6-(4-fluorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 104-116°C, 5- (3-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyreisopropylester, smeltepunkt 187-189°C, 6- (3,4-diklorfenoxy)-4-methoxymethyi-B-carbolin-3-carboxylsyreisopropylester, smeltepunkt 66-68°C. Eksempel 8 5- fenoxy- 4- methoxymethyl- B- carbolin- 3- carboxylsyreisopropyl-ester 2 g 5-(4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-car-boxylsyreisopropylester ble i 40 ml isopropanol hydrogenert med 200 mg palladium på carbon (10 %) og 0,9 ml triethylamin ved romtemperatur og under normalt hydrogentrykk. Etter avfiltrering av katalysator, inndampning av filtratet og oppslutning av residuet med diisopropyletner ble det erholdt 1,4 g 5-fenoxy-4-methoxymethyl-p-carbolin-3-carboxylsyreiso-propylester med smeltepunkt 201-203°C.
Eksempel 9
5- fenoxy- 4- methoxymethyl- 3- carbolin- 3- carboxylsyre- t- butyl-ester
300 mg 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyre ble oppvarmet til 120°C i 3 timer med 2 ml aminalester, hvorved en løsning ble dannet. Etter fortynning med vann ble løsningen ekstrahert med eddikester. Den organiske fase ble tørket, filtrert, ihndampet og kromatografert over kieselgel med aceton:hexan = 1:1 som elueringsmiddel. Det ble erholdt 130 mg 5-fenoxy-4-methoxymethyl-S-carbolin-3-carboxylsyre-t-butylester med et spaltningspunkt på 150°C.
På analog måte ble fremstilt: 5- (4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 209-210°C,
6- (3-klorfenoxy)-4-methoxymethyl-Ø-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 159-160°C,
6-(2-cyanofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 144°C,
6-(2-cyano-3-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 100°C,
6-(2,3-diklorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 203-204°C,
6-(4-fluorfenoxy)-4-methoxymethyl-8-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 189-191°C,
5- (4-nitrofenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 221-222°C,
6- (4-klorfenoxy)-4-methyl-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 175-182°C,
6-fenoxy-4-methoxymethy1-B-carbolin-3-carboxylsyre-t-butylester, smeltepunkt 176-183°C.
Eksempel 10
5-( 4- klorfenoxy)- 4- methoxyinethyl- B- carbolin- 3- carboxylsyre-isopropylamid
382 mg 5-(4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carboxylsyre ble i 10 ml dimethylformamid tilsatt 380 mg carbonyldiimidazol. Etter 2 timers omrøring ved romtemperatur ble 1 ml isopropylamin tilsatt, og blandingen ble omrørt over natten. Etter tilsetning av vann ble reaksjonsblandingen ekstrahert med eddikester. Eddikesterfasen ble tørket, filtrert og inndampet. Residuet ble kromatografert over kieselgel med methylenklorid:aceton = 1:1 som elueringsmiddel. Det ble erholdt 90 mg 5-(4-klorfenoxy)-4-methoxymethyl-p-carbolin-3-carboxylsyreisopropylamid med smeltepunkt 255°C.
På analog måte ble fremstilt: 5-fenoxy-4-methoxymethyl-B-carbolin-3-carboxylsyre-methylamid, smeltepunkt 235°C,
5-(4-klorfenoxy)-4-methoxymethyl-B-carbolin-3-carbox-ylsyremethylamid, smeltepunkt 236°C.
Carboxylsyrene anvendt som utgangsforbindelser, ble fremstilt ved alkalisk forsåpning av esteren med vandig NaOH i ethanol.
Claims (3)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive fenoxysubstituerte 8-carbolinderivater av generell
formel I
hvori
X er en oxadiazolylrest av formel
hvori
R 2 betegner H, C,-C4-alkyl eller cyclopropyl, eller X er en COOR 3 -gruppe, hvori R 3 betegner lavere alkyl, eller 4X er CONHC, -.-alkyl, og
R betegner hydrogen, C^-C^-alkyl eller C^-C^-alkoxy-C^-C^-alkyl, og
R^" betegner hydrogen, halogen, C-^-C^-alkyl, C^-C^-alkoxy, C,-C•-alkanoyl, trifluormethyl, nitrilo, nitroamino, C,-C.-alkoxycarbonyl, piperidinazo, SO?R 6 , hvori R<6 >7 8 7 8 betegner C-^- C^-alkyl, S02NR R , hvorved R og R betegner C^-C^-alkyl eller kan sammen med nitrogenatomet danne en morfolinring og n er 1 eller 2, hvorved X ikke er COOEt når grupperingen
er 5-fenoxy og R<4> er methyl, eller 6-(4-methoxyfenoxy)
og R<4> betegner methoxymethyl,
karakterisert ved at a) en forbindelse av generell formel II
n
hvori R<1> og R<4> har de ovenfor angitte betydninger, omsettes med en forbindelse av formel
hvori R<2> har den ovenfor angitte betydning, til en forbindelse av generell formel I, hvori X betegner resten
hvori R<2> har den ovenfor angitte betydning, b) en forbindelse av generell formel III
hvori R-<1-> og R<4> har de ovenfor angitte betydninger, omsettes med et carboxylsyreanhydrid (R<2>CO)20, hvori R<2> har de ovenfor angitte betydninger, til en forbindelse av generell formel I, hvori X betegner resten
hvori R<2> har den ovenfor angitte betydning, c) en forbindelse av generell formel IV
hvori R.3 og R<4> har de ovenfor angitte betydninger, omsettes med en forbindelse av formel
hvori Hal betegner halogen, og R<1> har den ovenfor angitte betydning, og R-<*->' betegner en elektrontrekkende substituent, hvorpå eventuelt a) en nitrogruppe reduseres til en aminogruppe, og om ønsket at den således erholdte aminogruppe desamineres eller utbyttes mot halogen eller azid, eller 3) såfremt R<1> er halogen, katalytisk dehalogeneres, eller y) at en estergruppe omestres eller forsåpes, og eventuelt at den således erholdte carboxylsyre amideres.
2. Fremgangsmåte ifølge krav 1 for fremstilling av: 5-fenoxy-4-methoxymethyl-3-(3-ethyl-l,2-4-oxadiazol-5-yl)-8-carbolin,karakterisert ved at tilsvarende utgangs-materialer anvendes.
3. Fremgangsmåte ifølge krav 1 for fremstilling av 6-(2-cyano-fenoxy)-4-methoxymethy1-0-carbolin-3-carboxylsyre-isopropylester,
karakterisert ved at tilsvarende utgangs-materialer anvendes.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853540654 DE3540654A1 (de) | 1985-11-13 | 1985-11-13 | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO864517D0 NO864517D0 (no) | 1986-11-12 |
| NO864517L NO864517L (no) | 1987-05-14 |
| NO163736B true NO163736B (no) | 1990-04-02 |
| NO163736C NO163736C (no) | 1990-07-11 |
Family
ID=6286132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO864517A NO163736C (no) | 1985-11-13 | 1986-11-12 | Analogifremgangsmaate for fremstilling av terapeutisk aktive fenoxy-substituerte beta-carbolin-derivater. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4945090A (no) |
| EP (1) | EP0234173B1 (no) |
| JP (1) | JPH0699431B2 (no) |
| AT (1) | ATE90678T1 (no) |
| AU (1) | AU602497B2 (no) |
| CA (1) | CA1269377A (no) |
| DD (1) | DD254201A5 (no) |
| DE (2) | DE3540654A1 (no) |
| DK (1) | DK169702B1 (no) |
| ES (1) | ES2058064T3 (no) |
| FI (1) | FI84067C (no) |
| HU (1) | HU198046B (no) |
| IE (1) | IE61661B1 (no) |
| IL (1) | IL80618A (no) |
| NO (1) | NO163736C (no) |
| NZ (1) | NZ218244A (no) |
| PT (1) | PT83726B (no) |
| ZA (1) | ZA868631B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3540653A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Neue 3-oxadiazol- und 3-carbonsaeure-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3540654A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3608089A1 (de) * | 1986-03-08 | 1987-09-10 | Schering Ag | Heteroaryl-oxy-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3730667A1 (de) * | 1987-09-09 | 1989-03-23 | Schering Ag | Neue ss-carboline |
| DE3729370C2 (de) * | 1987-08-31 | 1995-04-20 | Schering Ag | Verfahren zur Herstellung von 4-Alkoxyalkyl-beta-carbolinen |
| DE4029389A1 (de) * | 1990-09-13 | 1992-03-26 | Schering Ag | Verfahren zur herstellung von (beta)-carbolin-derivaten |
| DE4109342A1 (de) * | 1991-03-19 | 1992-09-24 | Schering Ag | Selektive phenylierung von 5-hydroxy-ss-carbolinderivaten |
| US5350750A (en) * | 1991-04-27 | 1994-09-27 | Schering Aktiengesellschaft | β-carboline-3-hydroxyalkylcarboxylic acid ester derivatives, process for their production and their use in pharmaceutical agents |
| DE4120109A1 (de) * | 1991-06-15 | 1992-12-17 | Schering Ag | 3-aryl- oder 3-hetaryl-(beta)-carboline, deren herstellung und verwendung in arzneimitteln |
| US5543519A (en) * | 1991-06-15 | 1996-08-06 | Schering Aktiengesellschaft | 3-aryl or 3-hetaryl-β-carbolines, their production and use in pharmaceutical agents |
| RS53941B1 (en) * | 2009-01-12 | 2015-08-31 | Pfizer Limited | SULFONAMID DERIVATIVES |
| US9145407B2 (en) | 2010-07-09 | 2015-09-29 | Pfizer Limited | Sulfonamide compounds |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57123180A (en) * | 1980-12-17 | 1982-07-31 | Schering Ag | 3-substituted beta-carboline, manufacture and psychotropic drug containing same |
| DE3322895A1 (de) * | 1983-06-23 | 1985-01-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Neue ss-carboline, verfahren zur ihrer herstellung und ihre verwendung als arzneimittel (s) |
| DE3504045A1 (de) * | 1985-02-04 | 1986-08-07 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von ss-carbolinen durch dehydrierung |
| DE3540654A1 (de) * | 1985-11-13 | 1987-05-14 | Schering Ag | Phenoxy-substituierte ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
-
1985
- 1985-11-13 DE DE19853540654 patent/DE3540654A1/de not_active Withdrawn
-
1986
- 1986-11-11 EP EP86730188A patent/EP0234173B1/de not_active Expired - Lifetime
- 1986-11-11 NZ NZ218244A patent/NZ218244A/xx unknown
- 1986-11-11 DE DE8686730188T patent/DE3688594D1/de not_active Expired - Lifetime
- 1986-11-11 ES ES86730188T patent/ES2058064T3/es not_active Expired - Lifetime
- 1986-11-11 AT AT86730188T patent/ATE90678T1/de active
- 1986-11-12 NO NO864517A patent/NO163736C/no unknown
- 1986-11-12 CA CA000522771A patent/CA1269377A/en not_active Expired - Lifetime
- 1986-11-12 PT PT83726A patent/PT83726B/pt not_active IP Right Cessation
- 1986-11-12 DD DD86296211A patent/DD254201A5/de not_active IP Right Cessation
- 1986-11-12 HU HU864678A patent/HU198046B/hu not_active IP Right Cessation
- 1986-11-12 IL IL80618A patent/IL80618A/xx not_active IP Right Cessation
- 1986-11-13 FI FI864619A patent/FI84067C/fi not_active IP Right Cessation
- 1986-11-13 DK DK543886A patent/DK169702B1/da not_active IP Right Cessation
- 1986-11-13 US US06/929,861 patent/US4945090A/en not_active Expired - Fee Related
- 1986-11-13 IE IE299686A patent/IE61661B1/en not_active IP Right Cessation
- 1986-11-13 JP JP61268799A patent/JPH0699431B2/ja not_active Expired - Lifetime
- 1986-11-13 ZA ZA868631A patent/ZA868631B/xx unknown
- 1986-11-13 AU AU65170/86A patent/AU602497B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU602497B2 (en) | 1990-10-18 |
| NZ218244A (en) | 1990-05-28 |
| ATE90678T1 (de) | 1993-07-15 |
| DE3540654A1 (de) | 1987-05-14 |
| PT83726A (en) | 1986-12-01 |
| DE3688594D1 (de) | 1993-07-22 |
| DK543886D0 (da) | 1986-11-13 |
| FI864619A0 (fi) | 1986-11-13 |
| EP0234173A2 (de) | 1987-09-02 |
| DK169702B1 (da) | 1995-01-16 |
| NO864517L (no) | 1987-05-14 |
| IL80618A0 (en) | 1987-02-27 |
| ES2058064T3 (es) | 1994-11-01 |
| HU198046B (en) | 1989-07-28 |
| EP0234173A3 (en) | 1988-07-06 |
| IE862996L (en) | 1987-05-13 |
| PT83726B (pt) | 1989-05-12 |
| NO163736C (no) | 1990-07-11 |
| EP0234173B1 (de) | 1993-06-16 |
| US4945090A (en) | 1990-07-31 |
| JPS62167780A (ja) | 1987-07-24 |
| HUT43067A (en) | 1987-09-28 |
| JPH0699431B2 (ja) | 1994-12-07 |
| AU6517086A (en) | 1987-05-21 |
| CA1269377A (en) | 1990-05-22 |
| FI864619A (fi) | 1987-05-14 |
| IL80618A (en) | 1990-09-17 |
| FI84067B (fi) | 1991-06-28 |
| IE61661B1 (en) | 1994-11-16 |
| NO864517D0 (no) | 1986-11-12 |
| DK543886A (da) | 1987-05-14 |
| FI84067C (fi) | 1991-10-10 |
| ZA868631B (en) | 1987-06-24 |
| DD254201A5 (de) | 1988-02-17 |
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