DK164554B - 3-vinyl- og 3-ethynyl-beta-carbolinderivater og fremgangsmaade til fremstilling heraf - Google Patents
3-vinyl- og 3-ethynyl-beta-carbolinderivater og fremgangsmaade til fremstilling heraf Download PDFInfo
- Publication number
- DK164554B DK164554B DK471586A DK471586A DK164554B DK 164554 B DK164554 B DK 164554B DK 471586 A DK471586 A DK 471586A DK 471586 A DK471586 A DK 471586A DK 164554 B DK164554 B DK 164554B
- Authority
- DK
- Denmark
- Prior art keywords
- methoxymethyl
- carboline
- ethynyl
- benzyloxy
- tosyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 6
- 229920002554 vinyl polymer Polymers 0.000 title description 5
- KWSSIHKQVCBVJN-UHFFFAOYSA-N 3-ethynyl-9h-pyrido[3,4-b]indole Chemical class N1C2=CC=CC=C2C2=C1C=NC(C#C)=C2 KWSSIHKQVCBVJN-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Chemical group 0.000 claims abstract description 9
- 150000002367 halogens Chemical group 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- -1 4-chlorophenoxy Chemical group 0.000 claims description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 150000004820 halides Chemical class 0.000 claims description 3
- QKRCVOCTVKDFFB-UHFFFAOYSA-N 3-(2-bromoethynyl)-4-(methoxymethyl)-5-phenylmethoxy-9h-pyrido[3,4-b]indole Chemical group C=12C=3C(COC)=C(C#CBr)N=CC=3NC2=CC=CC=1OCC1=CC=CC=C1 QKRCVOCTVKDFFB-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RDMFHRSPDKWERA-UHFFFAOYSA-N 5H-Pyrido[4,3-b]indole Chemical compound C1=NC=C2C3=CC=CC=C3NC2=C1 RDMFHRSPDKWERA-UHFFFAOYSA-N 0.000 claims 1
- OLRJXMHANKMLTD-UHFFFAOYSA-N silyl Chemical compound [SiH3] OLRJXMHANKMLTD-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 6
- 125000005842 heteroatom Chemical group 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 8
- 150000002430 hydrocarbons Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 102000004300 GABA-A Receptors Human genes 0.000 description 7
- 108090000839 GABA-A Receptors Proteins 0.000 description 7
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-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
- 238000006073 displacement reaction Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 150000002168 ethanoic acid esters Chemical class 0.000 description 4
- 229960002200 flunitrazepam Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000012433 hydrogen halide Substances 0.000 description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CUWHUKYQMCYWKV-UHFFFAOYSA-N 3-ethenyl-4-(methoxymethyl)-9-(4-methylphenyl)sulfonyl-5-phenylmethoxypyrido[3,4-b]indole Chemical compound C=12C=3C(COC)=C(C=C)N=CC=3N(S(=O)(=O)C=3C=CC(C)=CC=3)C2=CC=CC=1OCC1=CC=CC=C1 CUWHUKYQMCYWKV-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- BPMFPOGUJAAYHL-UHFFFAOYSA-N 9H-Pyrido[2,3-b]indole Chemical class C1=CC=C2C3=CC=CC=C3NC2=N1 BPMFPOGUJAAYHL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 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
- 238000010666 hydroalumination reaction Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 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
- 239000012528 membrane Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000002798 polar solvent 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
- 210000004129 prosencephalon Anatomy 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-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
- GPWNWKWQOLEVEQ-UHFFFAOYSA-N 2,4-diaminopyrimidine-5-carbaldehyde Chemical compound NC1=NC=C(C=O)C(N)=N1 GPWNWKWQOLEVEQ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- BRZWQHJWSMPNCE-UHFFFAOYSA-N 3-(2-bromoethynyl)-4-(methoxymethyl)-5-phenoxy-9h-pyrido[3,4-b]indole Chemical group C=12C=3C(COC)=C(C#CBr)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 BRZWQHJWSMPNCE-UHFFFAOYSA-N 0.000 description 1
- UPMQOIVVLNFXSC-UHFFFAOYSA-N 3-(2-bromoethynyl)-4-methyl-5-phenylmethoxy-9h-pyrido[3,4-b]indole Chemical group C=12C=3C(C)=C(C#CBr)N=CC=3NC2=CC=CC=1OCC1=CC=CC=C1 UPMQOIVVLNFXSC-UHFFFAOYSA-N 0.000 description 1
- UJAMXTSOBADGFZ-UHFFFAOYSA-N 3-ethenyl-4-(methoxymethyl)-5-phenylmethoxy-9h-pyrido[3,4-b]indole Chemical compound C=12C=3C(COC)=C(C=C)N=CC=3NC2=CC=CC=1OCC1=CC=CC=C1 UJAMXTSOBADGFZ-UHFFFAOYSA-N 0.000 description 1
- OHQCNKYLTYEUTD-UHFFFAOYSA-N 3-ethynyl-4-(methoxymethyl)-6-phenoxy-9h-pyrido[3,4-b]indole Chemical compound C1=C2C=3C(COC)=C(C#C)N=CC=3NC2=CC=C1OC1=CC=CC=C1 OHQCNKYLTYEUTD-UHFFFAOYSA-N 0.000 description 1
- GTUQGWDCRMVRGL-UHFFFAOYSA-N 3-ethynyl-4-methyl-5-phenoxy-9h-pyrido[3,4-b]indole Chemical compound C=12C=3C(C)=C(C#C)N=CC=3NC2=CC=CC=1OC1=CC=CC=C1 GTUQGWDCRMVRGL-UHFFFAOYSA-N 0.000 description 1
- QLPNRLIFNWIVIL-UHFFFAOYSA-N 3-ethynyl-4-methyl-5-propan-2-yloxy-9h-pyrido[3,4-b]indole Chemical compound N1C2=CN=C(C#C)C(C)=C2C2=C1C=CC=C2OC(C)C QLPNRLIFNWIVIL-UHFFFAOYSA-N 0.000 description 1
- VZYLHTOXQSELTA-UHFFFAOYSA-N 3-ethynyl-4-methyl-6-phenoxy-9H-pyrido[3,4-b]indole Chemical compound O(C1=CC=CC=C1)C=1C=C2C=3C(=C(N=CC=3NC2=CC=1)C#C)C VZYLHTOXQSELTA-UHFFFAOYSA-N 0.000 description 1
- FISKZPNYUOGGSV-UHFFFAOYSA-N 3-ethynyl-6-phenoxy-9H-pyrido[3,4-b]indole Chemical compound C1=NC(C#C)=CC(C2=C3)=C1NC2=CC=C3OC1=CC=CC=C1 FISKZPNYUOGGSV-UHFFFAOYSA-N 0.000 description 1
- DRXXJEMLDGVHCV-UHFFFAOYSA-N 4-ethyl-3-ethynyl-6,7-dimethoxy-9H-pyrido[3,4-b]indole Chemical compound N1C2=CC(OC)=C(OC)C=C2C2=C1C=NC(C#C)=C2CC DRXXJEMLDGVHCV-UHFFFAOYSA-N 0.000 description 1
- RKRBOERMEZUFNN-UHFFFAOYSA-N 4-methyl-9-(4-methylphenyl)sulfonyl-5-(morpholin-4-ylmethyl)pyrido[3,4-b]indole-3-carbaldehyde Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CN=C(C=O)C(C)=C2C2=C(CN3CCOCC3)C=CC=C21 RKRBOERMEZUFNN-UHFFFAOYSA-N 0.000 description 1
- NFRILWAMHVTDTL-UHFFFAOYSA-N 5-(1-ethoxyethyl)-3-ethynyl-4-methyl-9h-pyrido[3,4-b]indole Chemical compound N1C2=CN=C(C#C)C(C)=C2C2=C1C=CC=C2C(C)OCC NFRILWAMHVTDTL-UHFFFAOYSA-N 0.000 description 1
- HMUKBNPLBHBBLT-UHFFFAOYSA-N 5-(methoxymethyl)-4-methyl-9-(4-methylphenyl)sulfonylpyrido[3,4-b]indole-3-carbaldehyde Chemical compound C12=CN=C(C=O)C(C)=C2C=2C(COC)=CC=CC=2N1S(=O)(=O)C1=CC=C(C)C=C1 HMUKBNPLBHBBLT-UHFFFAOYSA-N 0.000 description 1
- REDMIKFVMOUZJD-UHFFFAOYSA-N 5-ethyl-4-methyl-9-(4-methylphenyl)sulfonylpyrido[3,4-b]indole-3-carbaldehyde Chemical compound C12=CN=C(C=O)C(C)=C2C=2C(CC)=CC=CC=2N1S(=O)(=O)C1=CC=C(C)C=C1 REDMIKFVMOUZJD-UHFFFAOYSA-N 0.000 description 1
- KOFCYRDJPBRBLY-UHFFFAOYSA-N 6-(4-chlorophenoxy)-3-ethynyl-4-methyl-9h-pyrido[3,4-b]indole Chemical compound C1=C2C=3C(C)=C(C#C)N=CC=3NC2=CC=C1OC1=CC=C(Cl)C=C1 KOFCYRDJPBRBLY-UHFFFAOYSA-N 0.000 description 1
- SQHUDWRUXNAWEX-UHFFFAOYSA-N 9-(4-methylphenyl)sulfonyl-5-phenylmethoxypyrido[3,4-b]indole-3-carbaldehyde Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CN=C(C=O)C=C2C2=C(OCC=3C=CC=CC=3)C=CC=C21 SQHUDWRUXNAWEX-UHFFFAOYSA-N 0.000 description 1
- PSZNNPYQYFYWDP-UHFFFAOYSA-N 9-(4-methylphenyl)sulfonyl-6-phenoxypyrido[3,4-b]indole-3-carbaldehyde Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=CN=C(C=O)C=C2C2=CC(OC=3C=CC=CC=3)=CC=C21 PSZNNPYQYFYWDP-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- LQWJSHQGLDKCHY-UHFFFAOYSA-N C(C)(C)O[AlH]OC(C)C.[Ca] Chemical compound C(C)(C)O[AlH]OC(C)C.[Ca] LQWJSHQGLDKCHY-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002539 anti-aggressive effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- HJUGFYREWKUQJT-UHFFFAOYSA-N carbon tetrabromide Natural products BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- YSSSPARMOAYJTE-UHFFFAOYSA-N dibenzo-18-crown-6 Chemical compound O1CCOCCOC2=CC=CC=C2OCCOCCOC2=CC=CC=C21 YSSSPARMOAYJTE-UHFFFAOYSA-N 0.000 description 1
- BBGKDYHZQOSNMU-UHFFFAOYSA-N dicyclohexano-18-crown-6 Chemical compound O1CCOCCOC2CCCCC2OCCOCCOC2CCCCC21 BBGKDYHZQOSNMU-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- OPIOGSLCBYLTGS-UHFFFAOYSA-N ethyl 3-(9h-pyrido[3,4-b]indol-3-yl)prop-2-enoate Chemical compound N1C2=CC=CC=C2C2=C1C=NC(C=CC(=O)OCC)=C2 OPIOGSLCBYLTGS-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- WUHLVXDDBHWHLQ-UHFFFAOYSA-N pentazole Chemical compound N=1N=NNN=1 WUHLVXDDBHWHLQ-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HJUGFYREWKUQJT-OUBTZVSYSA-N tetrabromomethane Chemical compound Br[13C](Br)(Br)Br HJUGFYREWKUQJT-OUBTZVSYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1
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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Transformer Cooling (AREA)
- Fats And Perfumes (AREA)
- Lubricants (AREA)
Description
i
DK 164554 B
Opfindelsen angår hidtil ukendte 3-vinyl- og 3-ethyny 1 -/3-car-bolinderivater samt en fremgangsmåde til fremstilling heraf.
Fra DK patentansøgning nr. 5541/81 kendes /S-carbol i nderivater 5 med virkning på centralnervesystemet, som er egnede til brug i psykofarmaceuti ske præparater. De farmakologiske egenskaber hos disse /5-carbol inderivater er undersøgt ved bestemmelse af deres evne til at fortrænge radioaktivt mærket f1 un itrazepam fra benzodiazepinreceptorer, ved undersøgelse af deres antiag-10 gresive effekt på mus og deres evne til at modvirke pentazol-inducerede kramper.
Forbindelserne ifølge opfindelsen besidder værdifulde farmakologiske egenskaber. De påvirker især centralnervesystemet og 15 egner sig dermed som psykofarmaka. Forbindelserne ifølge opfindelsen har en klar overlegen affinitet til benzodiazepinreceptorer i forhold til de kendte forbindelse fra DK-patentan-søgning nr. 5541/81.
20 Forbindelserne ifølge opfindelsen er ejendommelige ved den almene formel I: R3
Ir2 RA--Q O ' (I)- I ^
H
30 hvori r2 betegner -CH=CR4 eller -CsCR4 med R4 i betydningen hydrogen 2 eller halogen, R3 betegner Cj_4 alkyl eller 0^.4 alkoxyalkyl, og 35 2
DK 164554 B
Ra er til stede en eller flere gange og betegner OR7, hvor R7 betegner alkyl, eventuelt med halogen sub stitueret phenyl eller phenyl-Ci_2-alkyl.
5
De hidtil ukendte 3-vinyl- eller 3-ethynyl-β-carboli nderivater med den almene formel I kan være substitueret i A-ringen i stillingen 5 - 8 én eller flere gange, hvor substitutionen i 5-, 6- eller 7-stillingen foretrækkes.
10
Ved lavere alkyl skal forstås såvel ligekædede som forgrenede rester med 1-6 carbonatomer. Der kan f.eks. nævnes de foretrukne Ci_4alkylrester, såsom methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl og tert.-butyl.
15
Som halogen foretrækkes brom og chlor.
Arylresten R7 kan være substitueret én eller flere gange med halogen, som f.eks. fluor, chlor, brom eller jod, med Ci-gal-20 kyl- eller med Ci_2alkoxygrupper.
Aralkyl resten R7 har fortrinsvis 1-2 carbonatomer i alkyl-resten. Der kan f.eks. nævnes benzyl- og phenethylresterne 1-phenethyl og 2-phenethyl.
25
Det er kendt, at bestemte steder i det centrale nervesystem hos hvirveldyr udviser en høj specifik affinitet for bindingen af 1,4- og 1,5-benzodiazepiner (R. F. Squires og C. Braestrup, Nature (London) 266 (1977) 734). Bindingsstederne benævnes 30 benzodiazepinreceptorer.
Det har vist sig, at de substituerede β-carboliner ifølge opfindelsen, selv om de adskiller sig meget fra benzodiazepi-nerne i deres kemiske struktur, overraskende udviser en stærk 35 affinitet og specificitet for bindingen til benzodiazepinre- ceptorerne, idet de fortrænger radioaktivt mærket flunitraze-pam fra disse benzodiazepinreceptorer. Forbindelserne ifølge 3
DK 164554 B
opfindelsen egner sig især som anxiolytikum og antiepilepti-kum.
Fortrængningsaktiviteten af forbindelserne ifølge opfindelsen 5 ' angives som IC50“ eller EDsg-værdi. ICso-værdien angiver den koncentration, som bevirker en 50% fortrængning af den specifikke binding af 3H-flunitrazepam (1,0 nM, 0°C) i prøver med et samlet volumen på 0,55 ml af en suspension af hjernemembraner, f.eks. fra rotter.
10
Fortrængningsaktiviteten bestemmes i in vi tro-forsøget som følger: 0,5 ml af en suspension af ubehandlet rotte-forhjerne i 25 mM KH2PO4, pH-værdi 7,1 (5-10 mg væv/prøve) inkuberes i 40 - 60 minutter ved 0eC sammen med 3H-diazepam (specifik ak-15 tivitet 14,4 Ci/mmol, 1,9 nM) eller 3H-flunitrazepam (specifik aktivitet 87 Ci/mmol, 1,0 nM). Efter inkubation filtreres suspensionen gennem en glasfritte, remanensen vaskes 2 gange med kold pufferopløsning, og radioaktiviteten måles på scintilla-tionstæller.
20
Forsøget gentages derefter, dog således, at der før tilsætningen af den radioaktivt mærkede benzodiazepin tilsættes en bestemt mængde eller en overskydende mængde af den forbindelse, hvis fortrængningsaktivitet skal bestemmes. På grundlag af 25 de opnåede værdier beregnes ICsø-værdien.
Fortrængningsaktiviteten hos forbindelserne ifølge opfindelsen blev bestemt som angivet ovenfor, og til sammenligning hermed for en β-carbolin-3-acrylsyreethylester, der er kendt fra DK 30 patentansøgning nr. 5541/81 (svarende til EP-A-54 507). Resultaterne fremgår af tabellen.
35 4
DK 164554 B
TABEL
Fortrængningsaktivitet in vitro 5 R3 ra_I_ j I (I)
10 H
R2 R3 RA IC50-værdi _(nq/ml) -CsCH CH2OCH3 5-benzyloxy 0,75 15 -CsC-Br CH2OCH3 5-phenoxy 1,3 -CsCH CH2OCH3 5-phenoxy 0,39 -CsCH CH20CH3 5-(4-C1-phenoxy) 1,2 -C=CH CH3 5-isopropoxy 3,7 -CsCH CH2OCH3 6-benzyloxy 0,72 20 -CH=CH2_CH2OCH3 _5-benzyloxy_13_ EP-A-54507 (DK 5541/81) -CH=CH-C02C2H5 H_H_58_
Det fremgår klart af tabellen, at forbindelserne ifølge opfin-25 delsen har en klart overlegen affinitet til benzodiazepinre ceptorer i forhold til den fra DK patentansøgning nr. 5541/81 kendte /3-carbolin-3-acrylsyreethylester.
ED5o~værdien angiver den dosis af et forsøgsstof, som bevirker 30 en reduktion af den specifikke binding af f1unitrazepam til benzodiazepinreceptoren i en levende hjerne til 50% af kontrolværdien .
In-vivoforsøget udføres som følger:
Forsøgsstoffet injiceres i forskellige doser og normalt subkutant i grupper af mus. Efter 15 minutters forløb indgives mus- 35 5
DK 164554 B
ene intravenøst 3H-flunitrazepam. Efter yderligere 20 minut-ters forløb aflives musene, deres forhjerne fjernes og den til hjernemembranen specifikt bundne radioaktivitet måles ved scintillationstælling. EDsg-værdien bestemmes ved hjælp af 5 dosis/virkningskurven.
Forbindelserne ifølge opfindelsen viser sig på grund af deres biologiske virkning egnet som psykofarmaka til humanmedicinen.
De kan herved anvendes formuleret til psykofarmaceutiske præ- 10 parater, f.eks. til oral og parenteral anvendelse.
Som formuleringshjælpestoffer egner sig fysiologisk forligelige organiske og uorganiske bærestoffer, som er inerte over for forbindelserne ifølge opfindelsen.
15
Som bærestoffer kan f.eks. nævnes vand, saltopløsninger, alkoholer, polyethylenglycoler, polyhydroxyethoxyleret ricinusolie, gelatine, lactose, amylose, magnesiumstearat, talkum, . kiselsyre, fedtsyremono- og -diglycerider, pentaerythritol-20 fedtsyreestere, hydroxymethylcellulose og polyvinylpyrrolidon.
De farmaceutiske præparater kan steriliseres og/eller tilsættes hjælpestoffer, såsom smøremidler, konserveringsstoffer, stabilisatorer, befugtningsmidler, emulgatorer, puffermidler 25 og farvestoffer.
Til den parenterale anvendelse egner sig især injektionsopløsninger eller suspensioner, især vandige opløsninger af de aktive forbindelser i polyhydroxyethoxyleret ricinusolie.
30
Til den orale anvendelse egner sig især tabletter, drageer eller kapsler med talkum og/eller en hydrocarbonbærer eller et hydrocarbonbindemiddel, som f.eks. lactose eller majs- eller kartoffelstivelse. Anvendelsen kan også foregå i flydende 35 form, f.eks. som saft, der eventuelt tilsættes et sødestof.
Forbindelserne ifølge opfindelsen indføres i en dosisenhed på 0,05 til 100 mg aktivt stof i en fysiologisk forligelig bærer.
6
DK 164554 B
Forbindelserne ifølge opfindelsen anvendes i en dosis fra .0,1 til 300 mg/dag, fortrinsvis 1-30 mg/dag.
Fremstillingen af forbindelserne ifølge opfindelsen med den 5 almene formel I foregår efter i og for sig kendte metoder.
Opfindelsen angår også en fremgangsmåde til fremstilling af forbindelserne med den almene formel I, hvilken fremgangsmåde er ejendommelig ved, at man omsætter en forbindelse med den 10 almene formel II
R3
CHO
; 20 hvori R3 og RA har den ovenfor angivne betydning, og
Ri betegner en beskyttelsesgruppe valgt blandt en alkyl-, acyl-, aralkyl-, arylsulfonyl- eller silylrest, med et Wit-25 tigreagens valgt blandt tri phenylphosphin/tetrahalogenmethan eller alkyltriphenylphosphoniumhalogenid i et inert opløsningsmiddel ved en temperatur fra -50°C til reaktionsblandingens kogetemperatur til en forbindelse med den almene formel la 30 R3 4
I /R
rA Θ O J (la) , R1 hvori R3, Ra og Ra har den ovenfor angivne betydning, og 7
DK 164554 B
Ri betegner en beskyttelsesgruppe som ovenfor defineret, og derefter fraspalter beskyttelsesgruppen og om ønsket, såfremt R* betegner halogen, omsætter med baser og afha 1 ogenerer 5 de således opnåede 3-ha 1 ogenethy ny 1-Ø-car bo li nderivater og om ønsket hydrerer.
Før gennemførelsen af Wittig-reaktionen er det fordelagtigt at udbytte i molekylet tilstedeværende protondonorer efter sæd-10 vanlige fremgangsmåder med beskyttelsesgrupper. Som beskyttelsesgrupper egner sig alle sædvanligvis anvendte beskyttelsesgrupper, som f.eks. en alkyl-, alkanoyl-, aralkyl-, arylsulfo-nyl- eller silylrest, hvor arylsulfonyl- eller trialkylsilyl-resten, især tosylresten eller tert.-butyl-dimethylsilylre-15 sten, foretrækkes.
Til indførsel af vinylgruppen i 3-stillingen anvendes de sædvanlige Wittig-reagenser, som f.eks. triphenylphosphin/tetra-halogenmethan eller alkyltriphenylphosphoniumhalogenider, hvor 20 halogen fortrinsvis omfatter chlor eller brom.
Såfremt der skal fremstilles forbindelser med den almene formel la med R* i betydningen halogen, så omsættes aldehydet med den almene formel II med triphenylphosphin og tetrahalogenme-25 than.
Reaktionen gennemføres i inerte polære opløsningsmidler ved temperaturer fra -50°C til reaktionsblandingens kogepunkt, fortrinsvis ved temperaturer fra -20°C til +50eC. Som egnede 30 opløsningsmidler kan f.eks. nævnes: chlorerede hydrocarboner, såsom dichlormethan, dichlorethan, ethere, såsom diethylether, tetrahydrofuran, dioxan, dimethylformamid og dimethylsulfoxid.
Reaktionstiden andrager 15 - 20 timer og kan ved arbejde under 35 ultralyd og ved tilsætning af zink accelereres betydeligt til ca. 6-8 timer.
DK 164554B
8 Såfremt der skal fremstilles forbindelser med den almene formel la med R4 i betydningen hydrogen, så omsættes aldehydet med den almene formel II med methyl-triphenylphosphoniumhalo-genider, fortrinsvis bromiderne eller chloriderne, i nærvær-5 else af baser.
Til opnåelse af ylenen kan anvendes alle stærke, fortrinsvis alkali-organiske baser, som f.eks. alkalialkoholater, såsom kalium-tert.-butylat, 1ithium-organyler, såsom tert.-butyl- 10 lithium eller lithiumdiisopropylamid, natriumamid eller i givet tilfælde natriumhydrid/dimethylsulfoxid, men også kalium-carbonat eller natriumhydroxid.
De ovenfor nævnte inerte polære opløsningsmidler og også i 15 særlige tilfælde hydrocarboner, f.eks. hexan eller pentan, kan anvendes som opløsningsmiddel.
Omsætningen foregår ved temperaturer fra -50°C til reaktions-blandingens kogepunkt og er sædvanligvis afsluttet efter 1-4 20 timers forløb.
Der arbejdes hensigtsmæssigt under en atmosfære af inert gas, f.eks. under nitrogen eller argon.
25 Wittig-reaktionen kan gennemføres i homogen eller heterogen fase. Ved en tofasereaktion er det også hensigtsmæssigt at tilsætte en faseoverførselskatalysator, f.eks. en kroneether, såsom 18-krone-6, dicyklohexyl-18-krone-6, dibenzo-18-krone-6 eller "Aliquat 336".
30 Såfremt beskyttelsesgruppen R* er til stede, kan den fraspaltes efter sædvanlige metoder, f.eks. ved behandling med baser, såsom natrium- eller kaliumalkoholat eller syrer, såsom fortyndet uorganisk syre eller trif1uoreddikesyre i inerte opløs-35 ningsmidler, såsom alkoholer, hydrocarboner og andre, ved stuetemperatur.
9
DK 164554 B
Fra den geminale dihalogenforbindelse med den almene formel la kan der ved omsætning med baser ved forhøjet temperatur (fortrinsvis 20°C til 100°C) fraspaltes hydrogenhalogenid. Reaktionen er sædvanligvis afsluttet efter 2-6 timers forløb.
5
Til hydrogenha 1 ogen idfraspaltningen kan anvendes uorganiske eller organiske baser, som f.eks. kaliumhydroxid, natriumhydroxid (i fast form), alkalialkoholater, såsom natrium- eller kaliumethylat, -methylat eller -tert.-butylat, alkylerede 10 aminer, såsom HUnig-basen, cykliske aminer, såsom 1,5-diazabi-cyklo-(5.4.0)-undec-5-en, l,4-diazabicyklo(2.2.2)-octan og andre .
Hydrogenhalogenidfraspaltningen kan gennemføres i alle inerte 15 aprotiske og protiske opløsningsmidler. Der kan f.eks. nævnes ethere, såsom diethylethere og tetrahydrofuran, hydrocarboner, såsom hexan og pentan og alkoholer, såsom methanol og ethanol.
Såfremt der i 9-sti11 ingen findes en beskyttelsesgruppe, så 20 fraspaltes denne under reaktionsbetingelserne.
Også tofasereaktioner med anvendelse af en faseoverførselskatalysator som beskrevet ovenfor er mulig.
25 3-halogenethynyl-ø-carbolinderivaterne med den almene formel I
omdannes ved omsætning med 1 ithium-organylforbindelser og efterfølgende spaltning med vand til 3-ethynyl-/5-carbol inderi-vaterne.
30 Alle kendte 1 ithium-organylforbindelser kan anvendes til om sætningen, hvor lithiumphenyl- og 1 i thiuma1 kyl forbi ndel ser, som f.eks. tert.-butyl!i thium, foretrækkes.
Halogen-1i thium-udbytningen foretages ved lave temperaturer 35 (fortrinsvis 0°C til -90°C) og er afsluttet efter en % til 2 timers forløb. Derpå efterrøres i 1 - 2 timer ved stuetemperatur .
10
DK 164554 B
Der arbejdes hensigtsmæssigt under en atmosfære af inert gas, f.eks. under nitrogen eller argon.
Til afhalogeneringen egner sig aprotiske opløsningsmidler, så-5 som ether eller hydrocarbon, f.eks. tetrahydrofuran, dioxan, diethylether, toluen, hexan og andre.
3-ethyny l-/3-carbol inderivaterne kan hydreres delvis til 3-vi-nyIderivaterne efter kendte fremgangsmåder, f.eks. i nærvær-10 else af Lindlar-katalysatorer eller ved hydroalumi nering og efterfølgende protolytisk spaltning.
Hydreringen i nærværelse af Lindlar-katalysatorer foretages, eventuelt under tilsætning af en katalysatorgift, som -f.eks.
15 quinolin eller pyridin, ved stuetemperatur i et inert opløsningsmiddel, som f.eks. hydrocarboner eller alkoholer og andre.
Hydroalumineringen kan gennemføres med aluminiumorganiske for-20 bindeiser, som f.eks. diisobutylaluminiumhydrid ved temperaturer fra -80°C til stuetemperatur og efterfølgende opvarmning op til 80eC. Der arbejdes hensigtsmæssigt under en atmosfære af beskyttelsesgas i inerte opløsningsmidler, som f.eks. eth-ere eller hydrocarboner. Fraspaltningen foretages med syrer, 25 fortrinsvis uorganiske syrer, som f.eks. saltsyre, ved stuetemperatur. Udgangsforbindelserne er kendte eller kan fremstilles efter kendte fremgangsmåder.
Fremstilling af udgangsmaterialet 5-benzyloxy-4-methoxymethy1-30 9-tosyl-/3-carbol in-3-carbaldehyd.
3,9 g 5-benzyloxy-4-methoxymethyl-|3-carbol in-3-carboxy 1 syre-ethylester opløses i 70 ml dichlormethan med 1,84 ml tri-ethylamin og 0,54 g dimethylaminopyridin. Opløsningen afkøles 35 til 0°C og tilsættes derefter portionsvis 2,54 g tosylchlorid. Efter 2 timers omrøring ved stuetemperatur og henstand natten over udrystes tre gange med natriumhydrogencarbonatopløsning, 11
DK 164554 B
og den organiske fase inddampes og omkrystalliseres fra eddikesyreester. Der opnås 4 g 5-benzy1oxy-4-methoxymethy1-9-to-syl-/3-carbol in-3-carboxylsyreethylester med smeltepunkt 149-150°C. Disse 4 g opløses i 40 ml tetrahydrofuran under argon 5 og tilsættes ved stuetemperatur 17 ml af en 1,7 molær opløsning af calciumdiisopropoxyaluminiumhydrid i tetrahydrofuran ("Capal"). Efter 1 times opvarmning til tilbagesvaling tilsættes endnu engang 17 ml "Capal", og der opvarmes i 2 timer til tilbagesvaling. Efter afkøling tilsættes 2N natronlud, og 10 der udrystes med eddikesyreester. Den organiske fase inddampes, og der opnås 3,1 g 5-benzyloxy-4-methoxymethyl-9-tosyl-3-hydroxymethyl-Ø-carbol in, der suspenderes i 57 ml toluen og tilsættes 1 ml azodicarboxylsyreester. Efter 12 timers opvarmning under tilbagesvaling inddampes, og ved kromatografi 15 over kiselgel med cyklohexan :eddikesyreester = 1:1 som elue-ringsmiddel opnås 1,8 g 5~benzyloxy-4-methoxymethyl-9-tosyl-/3-carbolin-3-carbaldehyd med smeltepunkt 125 - 127°C.
På samme måde fremstilles: 20 5-isopropoxy-4-methyl - 9-tosyl -/3-carbol i n-3-carbaldehyd, smp. 172 - 175eC, 5-phenoxy-4-methoxymethy1-9-tosyl-ø-carboli n-3-carbaldehyd, 25 smp. 150 - 153, 5- benzyloxy-9-tosyl-Ø-carbolin-3-carbaldehyd, smp. 185 -187eC, 30 6-benzyloxy-4-methoxymethy 1 -9-tosy1 -/S-carbo 1 in-3-carbaldehyd, smp. 188 - 190eC, 6- phenoxy-4-methoxymethyl-9-tosyl^-carbolin-3-carbaldehyd, 35 6-isopropoxy-4-methoxymethyl-9-tosyl-/S-carbol in-3-carbaldehyd, 6-phenoxy-4-methy1-9-tosy1-Ø-carbol i n-3-car bal dehyd, 12
DK 164554 B
6-(4-chlorphenoxy)-4-methoxymethy1-9-tosyl-β-carbolin-3-carb-aldehyd, smp. 215 - 217°C, 6-phenoxy-9-tosyl-β-carboli n-3-carbaldehyd, 5 6,7-dimethoxy-9-tosyl-4-ethyl-β-carboli n-3-carbaldehyd, 5-(1-ethoxyethyl)-4-methyl-9-tosy1-β-carboli n-3-carbaldehyd, 10 5-(methoxymethyl)-4-methyl-9-tosyl-β-carbolin-3-carbaldehyd, 5-(morpholinomethyl)-4-methyl-9-tosyl-β-carbolin-3-carbaldehyd, 15 6-piperidino-4-methyl-9-tosyl^-carbolin-3-carbaldehyd og 5-ethyl-4-methyl-9-tosyl-β-carbolin-3-carbaldehyd.
De følgende eksempler skal belyse fremgangsmåden ifølge 20 opfindelsen.
5(—4—f1 uorbenzyloxy)-4-methoxymethyl-9-tosyl-β-carbolin-3-carbaldehyd, smp. 170 - 172°C, 25 5(-4-chlorphenoxy)-4-methoxymethyl-9-tosyl-β-carbolin-3-carfa- aldehyd .
Eksempel 1.
30 5-benzyloxy-3-(1,1-dibromvi ny1)-4-methoxymethyl-9-tosyl-β- carbolin.
2,5 g 5-benzyloxy-4-methoxymethyl-9-tosyl^-carbolin-3-carbox-aldehyd og 2,6 g triphenylphosphin opløses i 27 ml dichlorme-35 than og afkøles til +5°C. Til denne opløsning dryppes under omrøring 1,82 g tetrabrommethan, opløst i 7 ml dichlormethan, således at reaktionstemperaturen ikke overskrider +5°C. Efter 13
DK 164554 B
endt tilsætning omrøres reaktionsblandingen i 16 timer ved stuetemperatur, opløsningsmidlet afdampes, og remanensen kro-matograferes over kiselgel med dichlormethan/ethanol = 1000 + 25 som elueringsmiddel. Der opnås 2 g 5-benzyloxy-3-(l,l-di-5 bromvinyl)-4-methoxymethyl-9-tosy1-β-carbol in med smp. 149 - 152°C.
Eksempel 2.
10 Analogt med eksempel 1 fremstilledes: 5-isopropoxy-3-(l , l-dibromvinyi)-4-Bethoxymethyl-9-tosyl-/J-carboli n, i 15 5-phenoxy-3-(l,l-dibromvinvi \ . ^ , ^ Λ . a y 1 )-4-methoxymethyl-9-tosyl-0-car- bolin, smp. 179 - 183°C, 5-(4-chlorphenoxy)-3-(1,l-diu ,, . , _ , Λ K y ait>romvmyl)-4-methoxymethyl-9-to sy l-/S-carbol in, smp. 165 - l67°c 20 5-benzyloxy-3-(l,l-dibromvinw,. . , Λ . K.
,nyi)-4-methyl-9-tosyl-β-carbolin, 5-isopropoxy-3-(l,l-dibromvir.. ·. % , ^ a 1 nyl)-4-methyl-9-tosyl-/5-carbolin, smp. 168 - 171°C, 25 5-phenoxy-3-(1,1-dibromvinvi \ , „ . ..
* y 1 )-4-methyl-9-tosyl-j5-carbol in, 5- benzyloxy-3-(l,l-dibromvirvw1, _ , . Λ lnyl)-9-tosy1-β-carbolin, smp. 160 - 162°C, 30 6- benzyloxy-3-(l,l-dibromvih.,·.. _ _ _ . . . ,e nyi)-4-methoxymethyl-9-tosy1-β-carbol in, 6-phenoxy-3-(l,1-dibromvinvi \ 4 ^___, .
J y1)-4-methoxymethyl-9-tosyl-A-car- 6-i sopropoxy-3-(1, l-dibromvsr.. ·. v . . .
r K 3 V1|nyl )-4-methoxymethyl-9-tosyl-6- carbolin, 35 bolin, 14
DK 164554 B
6-phenoxy-3-(1,1-dibromvinyl)-4-methy1-9-tosyl-β-carbol in, 6-(4-ch 1 orphenoxy)-3-(1,1-dibromvinyl)-4-methy 1 -9-tosy 1 -β-car-bolin, 5 5- (4-fluorbenzyloxy)-3-(1,1-di bromvi nyl)-4-methoxymethyl-9-tosyl-Ø-carbolin, smp. 144 - 145°C, 6- phenoxy-3-(l,1-dibromvinyl)-9-tosyl-β-carboli n, 10 6,7-dimethoxy-3-(1,1-di bromvi nyl)-4-ethyl-9-tosy1-β-carbolin, 5-(1-ethoxyethy 1)-4-methy 1-3-(1,1-dibromvi nyl)-9-tosyl-β-car-boli n, 15 5-methoxymethyl-4-methy 1-3-(1,1-di bromvi nyl)-9-tosyl-β-carbo-1 i n, 5- morpholinomethyl-4-methy1-3-(1,1-dibromviny1)-9-tosyl-β-car- 20 bolin, 6- piperi dino-4-methyl-3-(1,1-dibromvinyl)-9-tosy1-β-carbolin og 25 5-ethyl-4-methy1-3-(1,1-dibromvinyl)-9-tosy1-β-carbolin.
Eksempel 3.
l-brom-2-(5-benzyloxy-4-methoxymethyl-β-carbolin-3-yl)-acety- 30 len.
En opløsning af 0,141 g natrium i 12 ml methanol dryppes under omrøring til en opløsning af 2 g 5-benzyloxy-3-(1,1-dibromvi-nyl)-4-methoxymethyl-9-tosyl-β-carbolin i 25 ml methanol. Re-35 aktionen omrøres ved stuetemperatur i 3 timer og inddampes derefter til tørhed. Remanensen kromatograferes over kiselgel med dichlormethan/ethano1 = 10/1 som elueringsmiddel. Der op- 16
DK 164554 B
nås 0,7 g l-brom-2-(5-benzyloxy-4-methoxymethyl-0-carbolin-3-yl)-acetylen med smeltepunkt 160°C (dekomponering).
Eksempel 4.
5
Analogt med eksempel 3 fremstilledes: 1-brom-2-(5-isoproxy-4-methoxymethy1-/S-carbolin-3-y1)-acetylen, 10 l-brom-2-(5-phenoxy-4-methoxymethyl-β-carboli n-3-yl)-acetylen, smp. 210 - 212eC (dekomponering), l-brom-2-[5-(4-chlorphenoxy)-4-methoxymethyl-0-carbolin-3-yl]-acetylen, smp. 207 - 209eC (dekomponering), 15 l-brom-2 -(5-benzyloxy-4-methyl-Ø-carbol in-3-yl)-acetylen, l-brom-2 - (5-isopropoxy-4-methyl -/S-carbol in-3-yl)-acetylen, smp. 170eC (dekomponering), 20 l-brom-2-[5-(4-f1uorbenzy1oxy)-4-methoxymethyl-/S-carbolin-3-yl)]-acetylen, smp. 151 - 153°C (dekomponering).
Eksempel 5.
25 5-benzyloxy-3-ethynyl-4-methoxymethy 1-/5-carbol in.
En opløsning af 0,164 g l-brom-2-(5-benzyloxy-4-methoxymethyl-/3-carbol i n-3-y 1)-acety 1 en i 5 ml absolut tetrahydrof uran af-30 køles under ^-atmosfære til -78eC og tilsættes 0,46 ml af en 1,4 molær opløsning af tert.-butyl 1 i thium i pentan. Efter 1 times omrøring ved -78°C opvarmes reaktionsblandingen til stuetemperatur og omrøres i yderligere 1,5 time. Derefter tilsættes forsigtigt vand og ekstraheres med dichlormethan. De orga-35 niske faser forenes og tørres, og opløsningsmidlet afdampes. Remanensen kromatograferes over kiselgel med acetone/hexan = 1 + 1 som elueringsmiddel. Der opnås 0,056 g 5-benzy1oxy-3-ethy-nyl-4-methoxymethyl-/S-carbolin med smeltepunkt 207 - 209eC.
DK 164554 B
16
Eksempel 6.
Analogt med eksempel 5 fremstilledes: 5 5-i sopropoxy-3-ethyny1-4-methoxymethy1-β-carbolin,
5-phenoxy-3-ethynyl-4-methoxymethyl-|3-carbol in, smp. 115°C
(dekomponering), 10 5-(4-chlorphenoxy)-3-ethynyl-4-methoxymethyl-0-carbolin, smp.
260 - 263°C (dekomponering), 5-benzy 1 oxy-3-ethyny 1 -4-methyl -/5-carbol i n, 15 5-isopropoxy-3-ethynyl-4-methyl-£-carbolin, smp. 205 - 207°C, 5-phenoxy-3-ethynyl-4-methyl-β-carbolin, 5- benzyloxy-3-ethynyl-/3-carbol in, smp. 206 - 210°C, 20 6- benzyloxy-3-ethynyl-4-methoxymethy 1 -β-carbol in, smp. 205 _-209°C, 6-phenoxy-3-ethynyl-4-methoxymethyl-β-carbol i n, 25 6-i sopropoxy-3-ethyny1-4-methoxymethy1-β-carbol i n , 6-phenoxy-3-ethynyl-4-methyl-β-carbolin, 3 0 6-(4-chlorphenoxy)-3-ethyny1-4-methyl-β-carboli n, 6-phenoxy-3-ethyny1-β-carboli n, 6,7-di methoxy-3-ethyny1-4-ethyl-β-carboli n, 5-(1-ethoxyethyl)-4-methyl-3-ethyny!-β-carboli n, 35 17
DK 164554 B
5-methoxymethy1-4-methyl-3-ethynyl-/S-carbol in, 5-»orpholi nornethyl-4-methyl-3-ethynyl-β-carbol i n, 5 6-piperidino-4-methyl-3-ethynyl-/3-carbol in, 5-ethyl-4-methyl-3-ethynyl-/J-carbol in og 5-(4-fluorbenzyloxy) - 3-ethyny1-4-methoxymethyl-/3-carbol in, 10 smp. 181 - 184eC (dekomponering).
Eksempel 7.
5-benzyloxy-4-methoxymethy1-9-tosy1-3-vinyl -Ø-carbol in.
15 1,0 g methyltriphenylphosphoniumbromid + natriumamid (tilstand - ylid) omrøres i 8 ml absolut tetrahydrofuran ved stuetemperatur under argon i 15 minutter. Dertil sættes 500 mg 5-benzyl-oxy-4-methoxymethyl-9-tosyl-0-carbolin-3-carbaldehyd, og reak-20 tionsblandingen opvarmes i 4 timer til tilbagesvaling. Efter afdampningen af opløsningsmidlet kromatograferes remanensen o ver kiselgel med cyklohexan/eddikesyreester = 8 + 2 som elue-ringsmiddel. Der opnås 0,153 mg 5-benzy1oxy-4-methoxymethyl-9-tosyl-3-vinyl-Ø-carbolin med smeltepunkt 141 - 143eC.
25
Eksempel 8.
5-benzyloxy-4-methoxymethyl-3-vinyl-/S-carbol in.
30 En opløsning af 0,23 g natrium i 10 ml methanol dryppes under omrøring til en suspension af 0,5 g 5-benzyloxy-4-methoxyme-thy 1-9-tosy 1-3-vi ny 1-j3-carbol i n i 20 ml methanol. Efter 72 timers omrøring ved stuetemperatur inddampes til tørhed, og remanensen kromatograferes over kiselgel med dichlormethan/etha-35 nol = 10/1 som elueringsmiddel. Der opnås 0,135 g 5-benzyloxy- 4-methoxymethyl-3-vinyl-/s-carbolin med smeltepunkt 183 185°C.
Claims (2)
1 CHO foj (II>’
2. N /\/ R1 hvori r3 og R^ har den ovenfor angivne betydning, og 30 R1 betegner en beskyttelsesgruppe valgt blandt en alkyl-, acyl-, aralkyl-, ary1su1fony1 - eller silylrest, med et Wit-tigreagens valgt blandt triphenylphosphin/tetrahalogenmethan eller alkyltriphenylphosphoniumhalogenid i et inert opløs-35 ningsmiddel ved en temperatur fra -50°C til reaktionsblandingens kogetemperatur til en forbindelse med den almene formel la DK 164554 B f I CH=C 5 ^(I-, . R1 hvori R3, R4 og R4 har den ovenfor angivne betydning, og 10 R* betegner en beskyttelsesgruppe som ovenfor defineret, og derefter fraspalter beskyttelsesgruppen og om ønsket, såfremt R4 betegner halogen, omsætter med baser og afhalogenerer IS de således opnåede 3-halogenethynyl-/S-carbol inderivater og om ønsket hydrerer. 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853535927 DE3535927A1 (de) | 1985-10-04 | 1985-10-04 | 3-vinyl- und 3-ethinyl-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3535927 | 1985-10-04 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK471586D0 DK471586D0 (da) | 1986-10-02 |
| DK471586A DK471586A (da) | 1987-04-05 |
| DK164554B true DK164554B (da) | 1992-07-13 |
| DK164554C DK164554C (da) | 1992-11-30 |
Family
ID=6283082
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK471586A DK164554C (da) | 1985-10-04 | 1986-10-02 | 3-vinyl- og 3-ethynyl-beta-carbolinderivater og fremgangsmaade til fremstilling heraf |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4719210A (da) |
| EP (1) | EP0218541B1 (da) |
| JP (1) | JPH0772187B2 (da) |
| AT (1) | ATE58535T1 (da) |
| AU (1) | AU597001B2 (da) |
| CA (1) | CA1266049A (da) |
| DE (2) | DE3535927A1 (da) |
| DK (1) | DK164554C (da) |
| ES (1) | ES2039361T3 (da) |
| FI (1) | FI84066C (da) |
| GR (1) | GR3001356T3 (da) |
| HU (1) | HU194881B (da) |
| IE (1) | IE58897B1 (da) |
| IL (1) | IL80216A0 (da) |
| NO (1) | NO165072C (da) |
| ZA (1) | ZA867617B (da) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3608089A1 (de) * | 1986-03-08 | 1987-09-10 | Schering Ag | Heteroaryl-oxy-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| AU619203B2 (en) * | 1987-08-28 | 1992-01-23 | Schering Aktiengesellschaft | Isoxazole-beta-carboline derivatives |
| US5585490A (en) * | 1991-10-08 | 1996-12-17 | Neurogen Corporation | Certain cycloalkyl and azacycloalkyl pyrrolopyrimidines; a new class of GABA brain receptor ligands |
| AU4117493A (en) * | 1992-04-08 | 1994-11-21 | Neurogen Corporation | Certain aryl fused pyrrolopyrimidines; a new class of gaba brain receptor ligands |
| US5367077A (en) * | 1992-04-08 | 1994-11-22 | Neurogen Corporation | Certain cycloalkyl and azacycloalkyl pyrrolopyridines; a new class of gaba rain receptor ligands |
| US5286860A (en) * | 1992-11-12 | 1994-02-15 | Neurogen Corporation | Certain aryl substituted pyrrolopyrazines; a new class of GABA brain receptor ligands |
| DE4308788A1 (de) * | 1993-03-18 | 1994-09-22 | Bayer Ag | Hetero-tricyclisch-substituierte Phenyl-cyclohexan-carbonsäurederivate |
| US5750702A (en) * | 1993-10-27 | 1998-05-12 | Neurogen Corporation | Certain pyrrolo pyridine-3-carboxamides; a new class of GABA brain receptor ligands |
| US5484944A (en) * | 1993-10-27 | 1996-01-16 | Neurogen Corporation | Certain fused pyrrolecarboxanilides and their use as GABA brain receptor ligands |
| DE19502753A1 (de) * | 1995-01-23 | 1996-07-25 | Schering Ag | Neue 9H-Pyrido[3,4-b]indol-Derivate |
| US6211365B1 (en) | 1996-01-19 | 2001-04-03 | Neurogen Corporation | Fused pyrrolecarboxamides; a new class of GABA brain receptor ligands |
| US5804686A (en) * | 1996-01-19 | 1998-09-08 | Neurogen Corporation | fused pyrrolecarboxamides; a new class of GABA brain receptor ligands |
| WO1997034870A1 (en) | 1996-03-22 | 1997-09-25 | Neurogen Corporation | Certain fused pyrrolecarboxamides as gaba brain receptor ligands |
| US5723462A (en) * | 1996-04-26 | 1998-03-03 | Neurogen Corporation | Certain fused pyrrolecarboxamides a new class of GABA brain receptor ligands |
| OA12015A (en) | 1999-08-31 | 2006-04-19 | Neurogen Corp | Fused pyrrolecarboxamides: gaba brain receptor ligands. |
| US20050014939A1 (en) * | 1999-08-31 | 2005-01-20 | Neurogen Corporation | Fused pyrrolecarboxamides: GABA brain receptor ligands |
| GB2452199A (en) | 2006-06-09 | 2009-02-25 | Igt Reno Nev | Progressive award selection in a wager game |
Family Cites Families (6)
| 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 |
| DE3240511A1 (de) * | 1982-10-29 | 1984-05-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Verfahren zur herstellung von ss-carbolinderivaten |
| DE3240513A1 (de) * | 1982-10-29 | 1984-05-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Indolderivate, verfahren zu ihrer herstellung und deren verwendung zur weiterverarbeitung |
| DE3240514A1 (de) * | 1982-10-29 | 1984-05-03 | Schering AG, 1000 Berlin und 4709 Bergkamen | Ss-carboline, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
| DK149270C (da) * | 1983-05-27 | 1986-08-25 | Schering Ag | Analogifremgangsmaade til fremstilling af beta-carbolin-3-carboxylsyrederivater |
| DE3335323A1 (de) * | 1983-09-27 | 1985-04-04 | Schering AG, 1000 Berlin und 4709 Bergkamen | Substituierte ss-carboline, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
-
1985
- 1985-10-04 DE DE19853535927 patent/DE3535927A1/de not_active Withdrawn
-
1986
- 1986-10-02 DK DK471586A patent/DK164554C/da not_active IP Right Cessation
- 1986-10-02 IL IL80216A patent/IL80216A0/xx not_active IP Right Cessation
- 1986-10-03 NO NO863961A patent/NO165072C/no unknown
- 1986-10-03 DE DE8686730155T patent/DE3675733D1/de not_active Expired - Lifetime
- 1986-10-03 FI FI864017A patent/FI84066C/fi not_active IP Right Cessation
- 1986-10-03 ES ES198686730155T patent/ES2039361T3/es not_active Expired - Lifetime
- 1986-10-03 AT AT86730155T patent/ATE58535T1/de not_active IP Right Cessation
- 1986-10-03 EP EP86730155A patent/EP0218541B1/de not_active Expired - Lifetime
- 1986-10-03 HU HU864183A patent/HU194881B/hu not_active IP Right Cessation
- 1986-10-03 JP JP61234691A patent/JPH0772187B2/ja not_active Expired - Lifetime
- 1986-10-06 ZA ZA867617A patent/ZA867617B/xx unknown
- 1986-10-06 US US06/915,360 patent/US4719210A/en not_active Expired - Fee Related
- 1986-10-06 CA CA000519907A patent/CA1266049A/en not_active Expired - Lifetime
- 1986-10-06 IE IE263086A patent/IE58897B1/en not_active IP Right Cessation
- 1986-10-07 AU AU63663/86A patent/AU597001B2/en not_active Ceased
-
1991
- 1991-01-22 GR GR90401072T patent/GR3001356T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE58897B1 (en) | 1993-12-01 |
| DK471586A (da) | 1987-04-05 |
| FI84066B (fi) | 1991-06-28 |
| FI864017A7 (fi) | 1987-04-05 |
| ES2039361T3 (es) | 1993-10-01 |
| IL80216A0 (en) | 1987-01-30 |
| DE3535927A1 (de) | 1987-04-09 |
| EP0218541A3 (en) | 1988-05-25 |
| AU597001B2 (en) | 1990-05-24 |
| GR3001356T3 (en) | 1992-09-11 |
| ATE58535T1 (de) | 1990-12-15 |
| FI864017A0 (fi) | 1986-10-03 |
| NO165072C (no) | 1990-12-19 |
| ZA867617B (en) | 1987-05-27 |
| NO863961D0 (no) | 1986-10-03 |
| JPH0772187B2 (ja) | 1995-08-02 |
| EP0218541A2 (de) | 1987-04-15 |
| US4719210A (en) | 1988-01-12 |
| DE3675733D1 (de) | 1991-01-03 |
| NO165072B (no) | 1990-09-10 |
| JPS62174076A (ja) | 1987-07-30 |
| FI84066C (fi) | 1991-10-10 |
| CA1266049A (en) | 1990-02-20 |
| IE862630L (en) | 1987-04-04 |
| DK471586D0 (da) | 1986-10-02 |
| HU194881B (en) | 1988-03-28 |
| EP0218541B1 (de) | 1990-11-22 |
| HUT42092A (en) | 1987-06-29 |
| DK164554C (da) | 1992-11-30 |
| AU6366386A (en) | 1987-04-09 |
| NO863961L (no) | 1987-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK164554B (da) | 3-vinyl- og 3-ethynyl-beta-carbolinderivater og fremgangsmaade til fremstilling heraf | |
| US6667313B1 (en) | 8-substituted-6-triflouromethyl-9-pyrido [3,2-G] quinoline compounds as androgen receptor modulators | |
| CN102066384B (zh) | 作为α-7烟碱乙酰胆碱受体配体的奎宁环化合物 | |
| Anzini et al. | Novel, potent, and selective 5-HT3 receptor antagonists based on the arylpiperazine skeleton: synthesis, structure, biological activity, and comparative molecular field analysis studies | |
| KR100295128B1 (ko) | 인돌로일구아니딘유도체 | |
| EP3917911A1 (en) | 15-pgdh inhibitors | |
| CN102112476A (zh) | 糖皮质激素模拟物、其制备方法、药物组合物及其用途 | |
| HU205928B (en) | Process for producing 2-substituted ergoline derivatives and pharmaceutical compositions containing them | |
| HUT59403A (en) | Process for producing new beta-carboline derivatives and pharmaceutical compositions comprising same | |
| DK169270B1 (da) | 3-oxadiazol- og 3-carbonsyre-beta-carbolinderivater og fremgangsmåde til deres fremstilling | |
| US5506234A (en) | β-carboline derivatives for use as pharmaceutical agents | |
| RU2034843C1 (ru) | Производные r(-)-3-хинуклидинола в виде смеси их диастереомеров или индивидуальных диастериомеров или их солей | |
| AU2006298164A1 (en) | Novel fused pyrrole derivative | |
| EP2150543A2 (en) | Heterocyclic compounds with affinity to muscarinic receptors | |
| HU182035B (en) | Process for producing vincadifformine and derivatives | |
| CA1283411C (en) | 9-(substituted thio)-4h-pyrido[1,2-a]-pyrimidin-4-one derivatives | |
| KR20070107108A (ko) | 화학적 화합물 | |
| US8735388B2 (en) | Heterocyclic compounds with affinity to muscarinic receptors | |
| Meketa | Part one. Total syntheses of ageladine A; Part two. Studies directed towards a total synthesis of actinophyllic acid | |
| Aldabbagh | Radical cyclisations onto imidazoles | |
| HK1147480A (en) | Heterocyclic compounds with affinity to muscarinic receptors | |
| HK1118540A (en) | Novel fused pyrrole derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |