HRP20000847A2 - 4,5,6 i 7 - INDOLE AND INDOLINE DERIVATIVES, THEIR PREPARATION AND USE - Google Patents
4,5,6 i 7 - INDOLE AND INDOLINE DERIVATIVES, THEIR PREPARATION AND USE Download PDFInfo
- Publication number
- HRP20000847A2 HRP20000847A2 HR20000847A HRP20000847A HRP20000847A2 HR P20000847 A2 HRP20000847 A2 HR P20000847A2 HR 20000847 A HR20000847 A HR 20000847A HR P20000847 A HRP20000847 A HR P20000847A HR P20000847 A2 HRP20000847 A2 HR P20000847A2
- Authority
- HR
- Croatia
- Prior art keywords
- indol
- piperazine
- ethyl
- chloro
- benzofuranyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 10
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title description 4
- 150000002476 indolines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 90
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 34
- -1 C1-6-alk(en/yn)yl Chemical group 0.000 claims description 31
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 229940076279 serotonin Drugs 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 230000009103 reabsorption Effects 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 230000005764 inhibitory process Effects 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 claims description 12
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 102000034527 Retinoid X Receptors Human genes 0.000 claims description 6
- 108010038912 Retinoid X Receptors Proteins 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 102000003702 retinoic acid receptors Human genes 0.000 claims description 6
- 108090000064 retinoic acid receptors Proteins 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 5
- IEAPSZTWAQJSLE-UHFFFAOYSA-N 4-chloro-3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=2C(Cl)=CC=CC=2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 IEAPSZTWAQJSLE-UHFFFAOYSA-N 0.000 claims description 5
- INSUHQMOGXBBBP-UHFFFAOYSA-N 7-bromo-3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C=1NC=2C(Br)=CC=CC=2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 INSUHQMOGXBBBP-UHFFFAOYSA-N 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 208000019022 Mood disease Diseases 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 230000008485 antagonism Effects 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 208000019906 panic disease Diseases 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- KZBQKNHKHLMMIM-UHFFFAOYSA-N 1-benzyl-4-[4-[2-(1h-indol-3-yl)ethyl]piperazin-1-yl]indole Chemical compound C=1NC2=CC=CC=C2C=1CCN(CC1)CCN1C(C=1C=C2)=CC=CC=1N2CC1=CC=CC=C1 KZBQKNHKHLMMIM-UHFFFAOYSA-N 0.000 claims description 3
- YYTPZWYTPKXSFX-UHFFFAOYSA-N 1-benzyl-4-[4-[2-(5-fluoro-1h-indol-3-yl)ethyl]piperazin-1-yl]indole Chemical compound C12=CC(F)=CC=C2NC=C1CCN(CC1)CCN1C(C=1C=C2)=CC=CC=1N2CC1=CC=CC=C1 YYTPZWYTPKXSFX-UHFFFAOYSA-N 0.000 claims description 3
- YQPDLHQWAGGSDB-UHFFFAOYSA-N 1-benzyl-4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]indole Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C(C=1C=C2)=CC=CC=1N2CC1=CC=CC=C1 YQPDLHQWAGGSDB-UHFFFAOYSA-N 0.000 claims description 3
- GRUDTMHMQAGHLH-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C=1NC2=CC=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 GRUDTMHMQAGHLH-UHFFFAOYSA-N 0.000 claims description 3
- HHCBWJJRMRBBCB-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-1h-indole-7-carbonitrile Chemical compound C=1NC=2C(C#N)=CC=CC=2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 HHCBWJJRMRBBCB-UHFFFAOYSA-N 0.000 claims description 3
- MMOGIDGHFQGENT-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-2h-indazole Chemical compound N=1NC2=CC=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 MMOGIDGHFQGENT-UHFFFAOYSA-N 0.000 claims description 3
- PJHWEBQBXPDXRE-UHFFFAOYSA-N 3-[3-[4-(1h-indol-4-yl)piperazin-1-yl]propyl]-1h-indole Chemical compound C1=CC=C2C(CCCN3CCN(CC3)C=3C=4C=CNC=4C=CC=3)=CNC2=C1 PJHWEBQBXPDXRE-UHFFFAOYSA-N 0.000 claims description 3
- DOUDAIRYOIPBNR-UHFFFAOYSA-N 4-[4-(1-benzofuran-3-ylmethyl)piperazin-1-yl]-1h-indole Chemical compound C1=CC=C2C(CN3CCN(CC3)C=3C=4C=CNC=4C=CC=3)=COC2=C1 DOUDAIRYOIPBNR-UHFFFAOYSA-N 0.000 claims description 3
- DVNUHRSTSJFZBG-UHFFFAOYSA-N 4-[4-[2-(1h-indol-3-yl)ethyl]piperazin-1-yl]-1-prop-2-ynylindole Chemical compound C1=CC=C2C(CCN3CCN(CC3)C3=C4C=CN(C4=CC=C3)CC#C)=CNC2=C1 DVNUHRSTSJFZBG-UHFFFAOYSA-N 0.000 claims description 3
- DOHAKZXOJZQTFL-UHFFFAOYSA-N 4-[4-[2-(1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(CCN3CCN(CC3)C=3C=CC=C4NC=C(C=34)C#N)=CNC2=C1 DOHAKZXOJZQTFL-UHFFFAOYSA-N 0.000 claims description 3
- WKGSILDXQBJVCC-UHFFFAOYSA-N 4-[4-[2-(5-bromo-1h-indol-3-yl)ethyl]piperazin-1-yl]-1-prop-2-ynylindole Chemical compound C12=CC(Br)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2CC#C WKGSILDXQBJVCC-UHFFFAOYSA-N 0.000 claims description 3
- AGVJFECVGZMPST-UHFFFAOYSA-N 4-[4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C12=CC(Cl)=CC=C2OC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 AGVJFECVGZMPST-UHFFFAOYSA-N 0.000 claims description 3
- UQQVWSLOBRRCHZ-UHFFFAOYSA-N 4-[4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C12=CC(F)=CC=C2OC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 UQQVWSLOBRRCHZ-UHFFFAOYSA-N 0.000 claims description 3
- HTXUCZURQGCALZ-UHFFFAOYSA-N 4-[4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole-3-carbonitrile Chemical compound C12=CC(F)=CC=C2OC=C1CCN(CC1)CCN1C1=CC=CC2=C1C(C#N)=CN2 HTXUCZURQGCALZ-UHFFFAOYSA-N 0.000 claims description 3
- VBRDWACMHZFSLL-UHFFFAOYSA-N 4-[4-[2-(5-fluoro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1-prop-2-ynylindole Chemical compound C12=CC(F)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2CC#C VBRDWACMHZFSLL-UHFFFAOYSA-N 0.000 claims description 3
- JKHASOQAHXASCK-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1-prop-2-ynylindole Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2CC#C JKHASOQAHXASCK-UHFFFAOYSA-N 0.000 claims description 3
- CWCXSYDWHLRBLZ-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-3-carbonitrile Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C(C#N)=CN2 CWCXSYDWHLRBLZ-UHFFFAOYSA-N 0.000 claims description 3
- OOPAXCAOYWFOLB-UHFFFAOYSA-N 4-[4-[2-(6-methyl-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C=1OC2=CC(C)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 OOPAXCAOYWFOLB-UHFFFAOYSA-N 0.000 claims description 3
- BOXSMMZSRLUSCW-UHFFFAOYSA-N 4-[4-[2-(7-chloro-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C=1OC=2C(Cl)=CC=CC=2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 BOXSMMZSRLUSCW-UHFFFAOYSA-N 0.000 claims description 3
- SONZEIXSBAWMLA-UHFFFAOYSA-N 5-chloro-3-[2-[4-(1h-indol-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=C2NC=CC2=CC(N2CCN(CC2)CCC2=CNC3=CC=C(C=C32)Cl)=C1 SONZEIXSBAWMLA-UHFFFAOYSA-N 0.000 claims description 3
- CCKRDWKRSKNOEN-UHFFFAOYSA-N 6-chloro-3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 CCKRDWKRSKNOEN-UHFFFAOYSA-N 0.000 claims description 3
- GXWQDXLPDRHDCY-UHFFFAOYSA-N 6-chloro-3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-2h-indazole Chemical compound N=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 GXWQDXLPDRHDCY-UHFFFAOYSA-N 0.000 claims description 3
- HLNWTLBQXXXWBY-UHFFFAOYSA-N 6-fluoro-3-[3-[4-(1h-indol-4-yl)piperazin-1-yl]propyl]-1,2-benzoxazole Chemical compound N=1OC2=CC(F)=CC=C2C=1CCCN(CC1)CCN1C1=CC=CC2=C1C=CN2 HLNWTLBQXXXWBY-UHFFFAOYSA-N 0.000 claims description 3
- DWMYBRIWIIKWBJ-UHFFFAOYSA-N [4-[4-[2-(5-bromo-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indol-6-yl]methanol Chemical compound C1=C(Br)C=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)CO)=CNC2=C1 DWMYBRIWIIKWBJ-UHFFFAOYSA-N 0.000 claims description 3
- VOJRANLPQBBQCI-UHFFFAOYSA-N [4-[4-[2-(5-fluoro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indol-6-yl]methanol Chemical compound C1=C(F)C=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)CO)=CNC2=C1 VOJRANLPQBBQCI-UHFFFAOYSA-N 0.000 claims description 3
- FVHATTZHFQNZJP-UHFFFAOYSA-N [4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indol-6-yl]methanol Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)CO)=CNC2=C1 FVHATTZHFQNZJP-UHFFFAOYSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- VPWYYLAXAUQFGH-UHFFFAOYSA-N methyl 4-[4-[2-(1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-6-carboxylate Chemical compound C1=CC=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)C(=O)OC)=CNC2=C1 VPWYYLAXAUQFGH-UHFFFAOYSA-N 0.000 claims description 3
- SYJFLCMSBJPPSG-UHFFFAOYSA-N methyl 4-[4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole-6-carboxylate Chemical compound C1=C(F)C=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)C(=O)OC)=COC2=C1 SYJFLCMSBJPPSG-UHFFFAOYSA-N 0.000 claims description 3
- OHLZRWXXNBGJLI-UHFFFAOYSA-N methyl 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-6-carboxylate Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)C(=O)OC)=CNC2=C1 OHLZRWXXNBGJLI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000003441 thioacyl group Chemical group 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- LMWGAMWDWHNJDN-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-5-methyl-1h-indole Chemical compound C12=CC(C)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 LMWGAMWDWHNJDN-UHFFFAOYSA-N 0.000 claims description 2
- KIOPWNRRUQEUTR-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-6-(trifluoromethyl)-1h-indole Chemical compound C=1NC2=CC(C(F)(F)F)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 KIOPWNRRUQEUTR-UHFFFAOYSA-N 0.000 claims description 2
- GRCKVWBWSWHGMB-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperazin-1-yl]ethyl]-6-methyl-1h-indole Chemical compound C=1NC2=CC(C)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 GRCKVWBWSWHGMB-UHFFFAOYSA-N 0.000 claims description 2
- PKBYZVAIOXKLQM-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperidin-1-yl]ethyl]-1h-indole Chemical compound C=1NC2=CC=CC=C2C=1CCN(CC1)CCC1C1=CC=CC2=C1C=CN2 PKBYZVAIOXKLQM-UHFFFAOYSA-N 0.000 claims description 2
- LMBHNEPPNWMRPK-UHFFFAOYSA-N 3-[2-[4-(1h-indol-4-yl)piperidin-1-yl]ethyl]-5-methyl-1h-indole Chemical compound C12=CC(C)=CC=C2NC=C1CCN(CC1)CCC1C1=CC=CC2=C1C=CN2 LMBHNEPPNWMRPK-UHFFFAOYSA-N 0.000 claims description 2
- AYNLVGHMSHMAHD-UHFFFAOYSA-N 4-[1-[3-(4-methyl-1-benzofuran-3-yl)propyl]piperidin-4-yl]-1h-indole Chemical compound C1=2C(C)=CC=CC=2OC=C1CCCN(CC1)CCC1C1=CC=CC2=C1C=CN2 AYNLVGHMSHMAHD-UHFFFAOYSA-N 0.000 claims description 2
- CDPQAABIPTUSQM-UHFFFAOYSA-N 4-[1-[3-(5-fluoro-1-benzofuran-3-yl)propyl]-3,6-dihydro-2h-pyridin-4-yl]-1h-indole Chemical compound C12=CC(F)=CC=C2OC=C1CCCN(CC=1)CCC=1C1=CC=CC2=C1C=CN2 CDPQAABIPTUSQM-UHFFFAOYSA-N 0.000 claims description 2
- HDXTWLXCOPFXCP-UHFFFAOYSA-N 4-[4-[2-(1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C=1OC2=CC=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 HDXTWLXCOPFXCP-UHFFFAOYSA-N 0.000 claims description 2
- WHVKIZNJOFOVQB-UHFFFAOYSA-N 4-[4-[2-(4,5,6,7-tetrafluoro-2-methyl-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound CC=1OC2=C(F)C(F)=C(F)C(F)=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 WHVKIZNJOFOVQB-UHFFFAOYSA-N 0.000 claims description 2
- OLAWEGKMWAGCSU-UHFFFAOYSA-N 4-[4-[2-(4-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-3-carbonitrile Chemical compound C1=2C(Cl)=CC=CC=2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1C(C#N)=CN2 OLAWEGKMWAGCSU-UHFFFAOYSA-N 0.000 claims description 2
- KOXLCYACERNFQT-UHFFFAOYSA-N 4-[4-[2-(4-methyl-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C1=2C(C)=CC=CC=2OC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 KOXLCYACERNFQT-UHFFFAOYSA-N 0.000 claims description 2
- ZSLMASYEALIUIK-UHFFFAOYSA-N 4-[4-[2-(5-bromo-1-benzofuran-3-yl)ethyl]piperazin-1-yl]-1h-indole Chemical compound C12=CC(Br)=CC=C2OC=C1CCN(CC1)CCN1C1=CC=CC2=C1C=CN2 ZSLMASYEALIUIK-UHFFFAOYSA-N 0.000 claims description 2
- DXCVKKBJZUQIBV-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-2-carbonitrile Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=CC2=C1C=C(C#N)N2 DXCVKKBJZUQIBV-UHFFFAOYSA-N 0.000 claims description 2
- SEAQDHYGZRVZFZ-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-6-carbonitrile Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC(C#N)=CC2=C1C=CN2 SEAQDHYGZRVZFZ-UHFFFAOYSA-N 0.000 claims description 2
- RVLIODWZMRKBCS-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-1h-indole-7-carbonitrile Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCN1C1=CC=C(C#N)C2=C1C=CN2 RVLIODWZMRKBCS-UHFFFAOYSA-N 0.000 claims description 2
- YTMJLTSIXRWRDH-UHFFFAOYSA-N 4-[4-[2-(6-chloro-1h-indol-3-yl)ethyl]piperazin-1-yl]-6-fluoro-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C=3C=C(C=C4NC=CC4=3)F)=CNC2=C1 YTMJLTSIXRWRDH-UHFFFAOYSA-N 0.000 claims description 2
- LXRCFKCRPSWFSI-UHFFFAOYSA-N 4-[4-[3-(4-chloro-1-benzofuran-3-yl)propyl]piperazin-1-yl]-1h-indole Chemical compound C1=2C(Cl)=CC=CC=2OC=C1CCCN(CC1)CCN1C1=CC=CC2=C1C=CN2 LXRCFKCRPSWFSI-UHFFFAOYSA-N 0.000 claims description 2
- LOZKUNKUFQIECJ-UHFFFAOYSA-N 4-[4-[3-(4-methyl-1-benzofuran-3-yl)propyl]piperazin-1-yl]-1h-indole Chemical compound C1=2C(C)=CC=CC=2OC=C1CCCN(CC1)CCN1C1=CC=CC2=C1C=CN2 LOZKUNKUFQIECJ-UHFFFAOYSA-N 0.000 claims description 2
- NDMUORRVNRLHAH-UHFFFAOYSA-N 4-chloro-3-[2-[4-(1h-indol-4-yl)piperidin-1-yl]ethyl]-1h-indole Chemical compound C1=2C(Cl)=CC=CC=2NC=C1CCN(CC1)CCC1C1=CC=CC2=C1C=CN2 NDMUORRVNRLHAH-UHFFFAOYSA-N 0.000 claims description 2
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- 238000001727 in vivo Methods 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical class C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WZHJKEUHNJHDLS-QTGUNEKASA-N metergoline Chemical compound C([C@H]1CN([C@H]2[C@@H](C=3C=CC=C4N(C)C=C(C=34)C2)C1)C)NC(=O)OCC1=CC=CC=C1 WZHJKEUHNJHDLS-QTGUNEKASA-N 0.000 description 1
- 229960004650 metergoline Drugs 0.000 description 1
- WLXQZCQWRQKPTC-UHFFFAOYSA-N methyl 2-(5-fluoro-1-benzofuran-3-yl)acetate Chemical compound C1=C(F)C=C2C(CC(=O)OC)=COC2=C1 WLXQZCQWRQKPTC-UHFFFAOYSA-N 0.000 description 1
- LXPJDFYUYVHZGX-UHFFFAOYSA-N methyl 4-[4-[2-(5-fluoro-1h-indol-3-yl)-2-oxoacetyl]piperazin-1-yl]-1h-indole-6-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)C(=O)N3CCN(CC3)C=3C=C(C=C4NC=CC4=3)C(=O)OC)=CNC2=C1 LXPJDFYUYVHZGX-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 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
- 230000010807 negative regulation of binding Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 239000003723 serotonin 1A agonist Substances 0.000 description 1
- 229940126570 serotonin reuptake inhibitor Drugs 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- OEAMZRWFIQSVJQ-UHFFFAOYSA-N tert-butyl 4-(1h-indol-4-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1C=CN2 OEAMZRWFIQSVJQ-UHFFFAOYSA-N 0.000 description 1
- YDUXKTCAHJCIGB-UHFFFAOYSA-N tert-butyl 4-(3-cyano-1h-indol-4-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1C(C#N)=CN2 YDUXKTCAHJCIGB-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Description
Ovaj izum odnosi se na novi 4, 5, 6 i 7-indol i derivate indolina koji su jaki inhbitori reapsorpcije serotonina, farmaceutskih smjesa koje sadrže ove spojeve, a primjena kojih je liječenje poremećaja ili bolesti koje uzrokuju inhibiciju reabsorpcije serotonina. Spojevi prema ovom izumu također imaju antagonističko djelovanje kod 5-HT1A receptora, pa se smatraju posebno korisnima u liječenju depresije.
Pozadina izuma
Selektivni inhibitori reapsorpcije serotonina ili 5-HT (SSRI-i) kao što su fluoksetin, paroksetin, sertralin, fluvoksamin i citalopram predstavljaju veliki korak naprijed u liječenju depresije, jer su im u usporedbi s prvom generacijom antidepresiva (triciklički i neselektivni MAO inhibitori) broj i žestina popratnih pojava manji. Popratne pojave povezane s prvom generacijom antidepresiva takve su da zbog njih neki bolesnici odustaju od liječenja.
SSRI-i i svi drugi trenutno raspoloživi antidepresivi imaju ozbiljan nedostatak u tome da je za postizanje terapeutskog učinka potrebno nekoliko tjedana. Zakašnjeli početak djelovanja ozbiljan je problem, posebno kod liječenja bolesnika s teškom depresijom i suicidalnim namjerama. Osim toga, na jednog od tri bolesnika SSRI-i nemaju učinka.
Elektrofiziološki pokusi na štakorima pokazali su da akutna primjena SSRI-ja smanjuje uključivanje jezgre N. Raphe u mozgu glodavca, dok trajno liječenje pomoću SSRI-ja dovodi do normalizacije uključivanja djelovanja 5-HT neurona (Arborelius, L. i sur.,Naunyn-Schmiedeberg’s Arch. Pharmacol. 1995, 352, 157; Gartside, S.E. i sur., Br. J. Pharmacol. 1995, 115, 1064; Chaput, Y. i sur., Naunyn-Schmiedeberg’s Arch. Pharmacol. 1986, 33, 342).
Osim toga, pokazalo se da je oporavak uključivanja 5-HT neurona povezan s desenzibilizacijom somatodendritičkih 5-HT1A autoreceptora ( Le Poul, E. i sur., Naunyn-Schmiedeberg’s Arch. Pharmacol. 1995, 352, 141; Invernizzi, R. i sur., Eur. J. Pharmacol. 1994, 260, 243).
Tako je iznijeto mišljenje da bi istovremena primjena SSRI-ja i nekog čimbenika koji uzrokuje brzu desenzibilizaciju ili inhibiciju povratnog mehanizma na koji djeluje 5-HT1A receptor dovela do brzog početka antidepresivnog djelovanja (Artigas, F. i sur., Trends Neurosci. 1996, 19, 378; De Vry, J. i sur., Drug News Perspec. 1996, 9, 270).
Djelovanje kombinirane primjene spoja koji inhibira reabsorpciju serotonina i antagonista 5-HT1A receptora ocijenjeno je u nekoliko studija (Innis, R.B. i sur., Eur. J. Pharmacol. 1987, 143, str. 195-204 i Gartside, S.E., Br. J. Pharmacol. 1995, 115, str. 1064-1070; Blier, P. i sur., Trends Pharmacol. Sci. 1994, 15, 220). U ovim je studijama otkriveno da antagonisti 5-HT1A receptora inhibiraju smanjenje uključivanja koje uzrokuje akutna primjena inhibitora reabsorpcije serotonina.
Nadalje, liječenje kombinacijom pindolola (poznati 5-HT1A receptor i antagonist β-adrenoreceptora) i SSRI-ma ocijenjeno je u kliničkim pokusima. U roku od jednog tjedna prikazano je značajno poboljšanje raspoloženja bolesnika. Osim toga, pokazalo se da kombinirana primjena pindolola i nekog SSRI-ja dobro djeluje na bolesnike koji nisu reagirali na liječenje s trenutno raspoloživim antidepresivima (Artigas, F. i sur., Arch. Gen. Psychiatry, 1994, 51, str. 248-251 i Blier, P. i sur., J. Clin. Psychopharmacol. 1995, 15, str. 217-222).
Prijavljeno je nekoliko patenata koji se tiču primjene kombinacije 5-HT1A antagonista i inhibitora reabsorpcije serotonina u liječenju depresije (vid EP-A2-687 472 i EP-A2-714 663).
DE patentna prijava broj 4414113 obznanjuje izvjesne 4-(indol-3-yl)-1-(indol-3-yl-alkilene)-piperidine koji imaju opću formulu
[image]
u kojoj je n 2-6 a ostali supstituenti su definirani kao u prijavi. Za navedene spojeve se tvrdi da imaju serotonin antagonističko i agonističko djelovanje te utječu na DOPA-akumulaciju u striatumu i 5-HTP akumulaciju u N. Raphe. Nisu podneseni nikakvi biološki podaci.
Objavljeni WO patent br. 94/21626 obznanjuje komponente s općom formulom
[image]
u kojoj je R2 heteroaril a ostali supstituenti su prema definiciji u prijavi. Tu se posebno spominje spoj u kojem R2 predstavlja 5-indolil koji je po strukturi vrlo brlizak spojevima ovog izuma. Nisu podneseni nikakvi podaci. Samo je rečeno da spojevi u testu za izbacivanje 3H spiperona iz podtipova D4 receptora ljudskog dopamina u klonskim staničnim nizovima daju K1 vrijednosti manje od 1,5 μM. Objavljeni WO patenti br. 94/21627 i br. 94/21630 odnose se na slične spojeve koji pokazuju sklonost za D4 receptore.
Objavljeni WO patent br. 95/33721 odnosi se na 1-(indanemetil, dihidrobenzo-furanilmetil, dihidrobenzotiofenilmetil) piperidin, tetrahidro-piridin ili derivate piperazina koji imaju opću formulu
[image]
u kojoj jedan X i Y predstavljaju CH2 a drugi se odabire iz skupine koja se sastoji od CH2, O ili S, Ar je aril ili heteroaril, tj. 1-, 2- ili 3-indolil a ostali supstituenti su prema definiciji u prijavi. Ovi su spojevi u interakciji s centralnim 5-HT receptorima, posebno s 5-HT1A i 5-HT2A receptorima. Neki od spojeva navodno utječu na inhibiciju 5-HT apsorpcije.
Predmet izuma
Predmet ovog izuma je da pribavi spojeve s jakim djelovanjem inhibicije reapsorpcije serotonina kao i antagonističkih svojstava kod 5-HT1A receptora. Takvi spojevi mogu biti korisni kao brzi početak djelovanja lijekova za liječenje afektivnih poremećaja, kao što je depresija.
Daljnji predmet ovog izuma je pribavljanje farmaceutske smjese koja bi se sastojala od ovih spojeva kao aktivnih sastojaka.
Sažetak izuma
Izum, dakle, između ostalog, podrazumijeva slijedeći sam ili u kombinaciji:
A supstituirani 4-, 5-, 6- ili 7-indol ili derivat indolina s formulom (I)
[image]
u kojoj W predstavlja N, C, CH ili COH a iscrtkane linije prikazuju opcionalne veze i
u kojoj A predstavlja skupinu s formulom
[image]
u kojoj X predstavlja CR1A, CHR1A, N, NR1B, O ili S, gdje je R1A prema definiciji za R3 do R9 u nastavku, te gdje je R1B prema definiciji za R10 u nastavku;
Y je CR2A, CHR2A, N, NR2B, O ili S, gdje je R2A prema definiciji za R3 do R9 u nastavku i gdje je R2B prema definiciji za R10 u nastavku, a
iscrtkane linije predstavljaju opcionalne veze;
pod uvjetom da X i Y nisu niti O niti S;
A je skupina koja ima formulu
[image]
gdje X predstavlja CR1A, CHR1A, N, NR1B, O ili S, gdje je R1A prema definiciji za R3 do R9 u nastavku, te gdje je R1B prema definiciji za R10 u nastavku;
U je C, CH ili N, a
iscrtkane linije predstavljaju opcionalne veze;
A je skupina koja ima formulu
[image]
gdje U predstavlja C, CH ili N;
Y je CR2A, CHR2A, N, NR2B, O ili S, gdje je R2A prema definiciji za R3 do R9 u nastavku te gdje je R2B prema definiciji za R10 u nastavku;
a iscrtkane linije predstavljaju opcionalne veze;
n je 0, 1, 2, 3, 4 ili 5, a m je 0, 1, 2, 3, 4 ili 5:
Z je CH2, O, S, CO, SO ili SO2, pod uvjetom da ako je n 0 onda je Z CH2;
R3 – R9 i R11 do R12 neovisno su odabrani između hidrogena, halogena, cijano, nitro, C1-6-alk(en/in)ila, C1-6 aloksi, C1-6-alkitio, hidroksi, hidroksi-C1-6-alkila, C1-6-alkoksikarbonila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, C1-6-alkilkarbonila, fenilkarbonila, halogena, supstistuiranog fenilkarbonila, trifluorometila, trifluorometilsulfoniloksila, C1-6 alkilsulfonila, arila i heteroarila i/ili dvije susjedne skupine uzete iz R3 – R9 mogu zajedno tvoriti metilendioksidnu skupinu,
i/ili dvije susjedne skupine R7 – R9 mogu zajedno formirati ciklopentilni ili cikloheksilni prsten koji može biti supstituiran jednom ili više metilnih skupina,
i/ili jedan od R3-R9 može alternativno biti skupina –NR13R14 u kojoj je R13 prema definiciji za R10 u nastavku a R14 je vodik, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6 alk(en/in)il, heteroaril, aril-C1-6-alkil ili heteroaril-C1-6-alkil;
R10 je
• vodik, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, aril, heteroaril, aril-C1-6-alkil, heteroaril-C1-6-alkil, acil, tioacil, C1-6-alkilsulfonil, trifluorometilsulfonil, arilsulfonil ili heteroarilsulfonil;
• R15VCO – gdje V predstavlja O ili S a R15 je C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8cikloalk(en)il-C1-6-alk(en/in/il), aril ili heteroaril; ili
• skupina R16R17NCO- ili R16R17NCS- gdje su R16 i R17 neovisno odabrani između vodika, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, heteroarila ili arila ili R16i R17 zajedno s N-atomom s kojim su povezani, čini skupinu pirolidinila, piperidinila, morfolinila ili perhidroazepina;
ili njihova kiselinska sol.
U posebnoj izvedbi, spojevi prema ovom izumu su spojevi u kojima je A skupina formula (IIA) koja uključuje takve spojeve u kojima je A skupina koja ima u nastavku prikazane formule:
[image]
gdje su R3 do R6 i iscrtkane linije prema prethodnoj definiciji.
U posebnoj izvedbi A je skupina koja ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema prethodnoj definiciji.
U drugoj posebnoj izvedbi ovaj se izum odnosi na spojeve koji imaju formulu
[image]
gdje su R7 do R12, W, A, Z, n, m i iscrtkane linije prema prethodnoj definiciji.
U posebnoj izvedbi Z je CH2, a n + m je 0, 1, 2, 3, 4, 5 ili 6.
U drugoj izvedbi ovaj se izum odnosi na spojeve koji imaju gornju formulu II, a A je skupina koja ima gornju formulu IIA.
U drugoj posebnoj izvedbi ovaj izum odnosi se na spojeve koji imaju gornju formulu II, a A je skupina koja ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema prethodnoj definiciji.
U daljnjoj posebnoj izvedbi ovaj izum odnosi se na spojeve koji imaju gornju formulu II, a A je skupina koja ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema prethodnoj definiciji.
U posebnoj izvedbi spojevi prema ovom izumu su spojevi u kojima je R3-R9 i R11-R12 vodik, halogen, cijan, dušik, C1-6-alkil, C1-6-alkoksi hidroksi, hidroksi-C1-6-alkil, C1-6-alkoksikarbonil i trifluorometil; a R10 je vodik.
U drugoj posebnoj izvedbi ovog izuma W je N.
Primjeri spojeva prema ovom izumu su
1-(2-(3-benzofuranil)etil)-4-(11H-indol-4-yl)piperazin,
1-(3-benzofuranilmetil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(4-(5-fluoro-3-benzofuranil)-1-butil)-4-(1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(3-(1H-indol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(4-(1H-indol-3-yl)-1-butil)-4-(1H-indol-4-yl)piperazin,
1-(3-(5-fluoro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(2-metil-4,5,6,7-tetrafluoro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(3-indazolil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-3-indazolil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(7-cijano-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin,
1-(2-(7-bromo-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(1-alil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin,
1-(1-alil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)etil)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)etil)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)etil)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin,
1-(2-(5-kloro-1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin,
1-(3-(6-fluoro-1,2-benzioksazol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-3-benzofuranil)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(5-fluoro-3-benzofuranilmetil)-4-(1H-indol-4-yl)piperazin,
1-(3-cijano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin,
1-(3-cijano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranil)etil)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,
1-(2-(3-benzofuranil)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(5-metil-3-benzofuranil)etil)piperazin,
1-(1H-indol-4-yl)-4-(2-(4-metil-3-benzofuranil)etil)piperazin,
1-(3-(5-fluoro-3-benzofuranil)-1propil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin,
1-(2-(5-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(6-metil-3-benzofuranil)etil)piperazin,
1-(2-(7-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol.3.yl)-4-(1H-indol-4-yl)piperidin,
1-(2-(5-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(7-bromo-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-trifluorometil-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(5-metil-1H-indol-3-yl)etil)piperazin,
1-(1H-indol-4-yl)-4-(2-(6-metil-1H-indol-3-yl)etil)piperazin,
1-(1H-indol-4-yl)-4-(1-(7-metil-1H-indol-3-yl)etil)piperazin,
1-(2-(4,5-dikloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-bromo-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperidin,
4-(1H-indol-4-yl)-1-(2-(5-metil-1H-indol-3-yl)etil)piperidin,
4-(1H-indol-4-yl)-1-(2-(1H-indol-3-yl)etil)piperidin,
1-(1H-indol-4-yl)-4-(3-(4-metil-3-benzofuranil)-1-propil)piperazin,
4-(1H-indol-4-yl)-1-(3-(4-metil-3-benzofuranil)-1-propil)piperidin,
1-(3-(4-kloro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-kloro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-fluoro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(7-kloro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(7-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(2-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indolin-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-6-yl)piperazin i
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-7-yl)piperazin
ili neka njihova kiselinska sol.
Ovaj se izum također odnosi na farmaceutsku smjesu koja se sastoji od bilo kojeg spoja ovog izuma ili njegove farmaceutski prihvatljive kiselinske soli te od najmanje jednog farmaceutski prihvatljivog nositelja ili razrjeđivača.
U drugom vidu ovaj se izum odnosi na primjenu spoja ovog izuma ili njegove farmaceutski prihvatljive kiselinske soli u svrhu pripreme lijeka za liječenje poremećaja ili bolesti zbog kojih dolazi do inhibicije reapsorpcije serotonina i antagonizma 5-HT1A receptora.
U svojoj konačnoj namjeni, ovaj se izum odnosi na način liječenja poremećaja ili bolesti živog životinjskog tijela, uključujući čovjeka, zbog kojih dolazi do inhibicije reapsorpcije serotonina i antagonizma 5-HT1A receptora, koje liječenje obuhvaća primjenu na takvo živo životinjsko tijelo, uključujući čovjeka, terapeutski djelotvorne količine sastojka kako je naprijed opisan ili njegove farmaceutski prihvatljive kiselinske soli.
Bolesti ili poremećaji zbog kojih dolazi do inhibicije reapsorpcije serotonina i antagonističkog djelovanja 5-HT1A receptora obuhvaćaju afektivne poremećaje, kao što su depresija, psihoza, poremećaji vezani na tjeskobu uključujući opću tjeskobu i paniku te opsesivno-kompulzivni poremećaj.
Zahvaljujući svom kombiniranom djelovanju na antagonizam 5-HT1A receptora i na inhibiciju reapsorpcije serotonina, spojevi ovog izuma posebno su korisni zbog brzog početka djelovanja lijekova za liječenje depresije. Ti spojevi mogu također biti korisni u liječenju depresije kod bolesnika koji ne reagiraju na liječenje trenutno raspoloživim antidepresivima.
U skupinama formule (IIA), (IIB) i (IIC) postojanje i položaj dvostrukih veza u prstenu koji sadrži X, U i Y ovise o značenju koje imaju X, U i Y.
Tako, što se tiče skupine formule (IIA), stručnjaku je potpuno jasno da kad iscrtkana linija koja počinje od X predstavlja vezu, onda je X N ili CR1A, a kad iscrtkana linija nije veza, X je CHR1A, NR1B, O ili S; a kad iscrtkana linija koja počinje od Y predstavlja vezu, onda je Y N ili CR1B te kad iscrtkana linija nije veza Y je CHR2A, NR2B, O ili S.
Nadalje, što se tiče skupine formule (IIB), stručnjaku je potpuno jasno da kad iscrtkana linija koja počinje od X predstavlja vezu onda je X N ili CR1A, a kad iscrtkana linija nije veza X je CHR 1A, NR1B, O ili S; kad iscrtkana linija koja počinje od U predstavlja vezu unda je U C, a kad iscrtkana linija nije veza U je CH ili N.
I konačno, što se tiče skupine formule (IIC), stručnjaku je potpuno jasno da kad iscrtkana linija koja počinje od U predstavlja vezu, onda je U C, a kad iscrtkana linija nije veza U je CH ili N; kad iscrtkana linija koja počinje od Y predstavlja vezu onda je Y N ili CR2A, a kad iscrtkana linija nije veza Y je CHR2A, NR2B, O ili S.
Isto se odnosi na W, koje je N, CH ili COH kad iscrtkana linija koja počinje od W ne predstavlja vezu, a C kad je predstavlja.
Izraz C1-6-alk(en/in)il znači skupinu C1-6-alkila, C2-6-alkenila ili C2-6-alkinila. Izraz C3-8-cikloalk(en)il znači skupinu C3-8-cikloalkila ili cikloalkenila.
Izraz C1-6-alkil odnosi se na razgranatu ili nerazgranatu alkilnu skupinu koja ima od jednog do uključivo šest atoma ugljika, uključujući ali ne ograničujući se na metil, etil, 1-propil, 2-propil, 1-butil, 2-butil, 2-metil-2-propil i 2-metil-1-propil.
Slično time, C2-6 alkenil odnosno C2-6 alkinil predstavljaju takve skupinu koje imaju od dva do šest atoma ugljika, uključujući jednu dvostruku odnosno jednu trostruku vezu, uključujući ali ne ograničujući se na etenil, propenil, butenil, etinil, propini i butinil.
Izrazi C1-6 alkoksil, C1-6 alkitio, C1-6 alkilsulfonil, C1-6 alkilamino, C1-6 alkilkarbonil, hidroksil-C1-6-aklil itd. označavaju takve skupine u kojima je C1-6 alkil prema prethodnoj definiciji.
Izraz C3-8 cikloalkil označava monociklični ili biciklični karbociklus koji ima tri do osam atoma ugljika, uključujući ali ne ograničujući se na ciklopropil, ciklopentil, cikloheksil itd.
Izraz C3-8 cikloalkenil označava monociklični ili bicikličnii karbociklus koji ima tri do osam atoma ugljika i uključuje jednu dvostruku vezu.
U izrazu C3-8-cikloalk(en)il-C1-6-alk(en/in)il, C3-8-cikloalk(en)il i C1-6-alk(en/in)il su prema prethodnoj definiciji.
Izraz aril odnosi se na karbocikličnu aromatsku grupu, kao što je fenil, naptil, a posebno fenil. Prema primjeni u ovom izumu aril može biti jednom ili više puta zamijenjen halogenom, dušikom, cijanom, trifluorometilom, C1-6-alkilom, hidroksilom i C1-6-alkoksilom.
Izraz heteroaril odnosi se na mono- ili bicikličnu heterocikličnu skupinu kao što je indolil, tienil, pirimidil, oksazolil, izoksazolil, tiazolil, izotiazolil, imidazolil, benzofuranil, benzotienil, piridil i furanil, posebno pirimidil, indolil i tienil.
Prema primjeni u ovom izumu heteroaril može biti jednom ili više puta zamijenjen halogenom, dušikom, cijanom, trifluorometilom, C1-6-alkilom, hidroksilom i C1-6-alkoksilom.
U aril-C1-6-alkilu i heteroaril-C1-6-alkilu, heteroaril i C1-6-alkil su prema prethodnoj definiciji.
Halogen znači, fluor, klor, brom ili jod.
Prema primjeni u ovom izumu izraz acil odnosi se na formil, C1-6-alk(en/in)ilkarbonil, arilkarbonil, aril-C1-6-alk(en/in)ilkarbonil, C3-8-cikloalk(en)ilkarbonil ili C3-8-cikloalk(enil-C1-6alk(en/in)il-karbonil skupinu, a izraz tioacil je kao odgovarajuća acil skupina u kojoj je karbonil skupina zamijenjena tiokarbonil skupinom.
Kiselinskim solima prema ovom izumu daje se prednost kod farmaceutski prihvatljivih soli spojeva ovog izuma stvorenih pomoću netoksičnih kiselina. Primjeri takvih organskih soli su one iz malenske, fumarne, benzojeve, askorbinske, jantarne, oksalne, bi-metilensalicilne, metansulfonske, etandisulfonske, octene, propionske, vinske, salicilne, limunske, glukonske, mliječne, jabučne, bademove, cinamične, citrakonske, asparaginske, stearinske, palmitinske, itakonske, glikolne, p-aminobenzojeve, glutaminske, benzensulfonske i teofilin octene kiseline, kao i iz 8-haloteofilina, na primjer iz 8-bromteofilina. Primjeri takvih anorganskih soli su one iz solne, hidrobromne, sumporne, sulfaminske, fosforne i dušične kiseline.
Nadalje, spojevi prema ovom izumu mogu biti u otopljenom ili neotopljenom obliku s farmaceutski prihvatljivim otapalima kao što su voda, etanol i slično. Općenito, za svrhe ovog izuma otopljeni oblici smatraju se jednakima neotopljenim oblicima.
Neki od spojeva prema ovom izumu sadrže kiralne centre i takvi spojevi postoje u obliku izomera (tj. enantiomera). Ovaj izum uključuje sve takve izomere i sve bilo kakve njihove mješavine uključujući racemičke mješavine.
Racemički oblici mogu se otopiti u optičke antipode pomoću poznatih metoda, na primjer, separacijom njihovih diastereomeričnih soli pomoću optički aktivne kiseline i oslobađanjem optički aktivnog amino spojeva tretiranjem pomoću baze. Druga metoda otapanja racemata u optičke antipode temelji se na kromatografiji optički aktivne matrice. Racemini spojevi prema ovom izumu mogu se također otopiti u njihove optičke antipode, to jest, frakcionalnom kristalizacijom d- ili 1- soli (tartarne, bademove ili kamforosulfonske kiseline), na primjer. Spojevi prema ovom izumu mogu se također otopiti stvaranjem dijastereomeričkih derivata.
Mogu se koristiti još i dodatne metode otapanja optičkih izomera, koje su stručnjacima poznate. Među takve metode spadaju i one o kojima rasoravljaju J- Jacques, A. Collet i S. Wilen u “Enantiomers, Racemates, and Resolution”, John Wiley and Sons, New York (1981).
Optički aktivni spojevi mogu se također pripremiti od optički aktivnih početnih materijala.
Konačno, formula (I) uključuje svaki tautomerički oblik spojeva prema ovom izumu.
Spojevi prema ovom izumu mogu se pripremiti jednom od slijedećih metoda, kao što su:
a) redukcija karbonil skupine spoja formule (III)
[image]
gdje su R3-R12, W I iscrtkane linije prema prethodnom opisu;
b) alkilacija amina formule (IV)
[image]
gdje su R7-R12, W i iscrtkane linije prema prethodnom opisu s reagensom formule (V)
G-(CH2)n-Z-(CH2)m-A (V)
gdje su A, Z, n i m prema prethodnom opisu aG je odgovarajući ostatak kao što je halogen, mesilat ili tosilat;
c) reduktivna alkilacija amina formule
[image]
gdje su R7-R12, W i iscrtkane linije prema prethodnoj definiciji s reagensom formule (VI)
E-(CH2)n-Z-(CH2)m-A (VI)
gdje su A, Z, n i m prema prethodnoj definiciji a E je ili aldehid ili karboksilnakiselinska grupa;
d) redukcija dvostruke veze indolskog prstena koji je vezan na polovicu cikličkog amina formule (I) kako bi se dobili odgovarajući derivati 2,3-dihidroindola;
e) redukcija dvostruke veze tetrahidropirina formule (VII)
[image]
gdje su R7-R12, A, Z, n, m i iscrtkane linije prema ranijoj definiciji, kako bi se dobili odgovarajući derivati piperidina;
f) redukcija amidne grupe spoja formule (VIII)
[image]
gdje su R7-R12, a, W, Z, n, m i iscrtkane linije prema prethodnoj definiciji;
g) reduktivno otklanjanje jednog ili više halogenih supstituenata R3-R9 i R11-R12 u spoju formule (I) u kojoj je jedan ili više ovih supstituenata odabrano između klora, broma ili joda;
h) dialkilacija amina formule (IX)
[image]
gdje su R7-R12 i iscrtkane linije prema prethodnoj definiciji s reagensom formule (X)
[image]
gdje su A, Z, n i m prema prethodnoj definiciji a G je odgovarajući ostatak kao što je halogen, mesilat ili tosilat;
i) dialkilacija amina formule (XI)
H2N-(CH2)-Z-(CH2)m-A (IX)
gdje su A, Z, n i m prema prethodnoj definiciji s reagensom formule (XII)
[image]
gdje su R7-R12, W i iscrtkane linije prema prethodnoj definiciji a G je odgovarajući ostatak kao što je halogen, mesilat ili tosilat;
j) alkilacija, arilacija ili acilacija jednog ili oba indolova atoma dušika iz spoja formule (I) u kojoj je R10 vodik , a/ili H i/ili Y je NH; ili
k) redukcija spoja formule (I) u kojoj je R7, R8 ili R9 alkoksikarbonilna grupa kako bi se dobila hidroksimetilna frupa;
zbog čega su spojevi formule (I) izolirani kao slobodna baza ili u obliku njezine kiselinske soli.
Redukciju prema metodi a) najbolje je provoditi u intertnom organskom otapalu poput dietil etera ili tetrahidrofurana uz prisutnost litij aluminij hidrida na temperaturi refluksa. Početni spojevi formule (III) općenito se pripremaju pomoću kondenzacije 3-klorooksalil-indola (pripremljenih prema opisu kod Houben-Weyl, Methoden der Organischen Chemie, Vol E6B2, str. 1058) a aminima formule (IV) uz prisutnost baze poput trietilamina ili kalijevog karbonata.
Alkilacija prema metodi b) odgovarajuće se priprema u intertnom organskom otapalu poput prikladno kipućeg alkohola ili ketona, najbolje uz prisutnost organske ili inorganske baze (kalijev karbonat ili trietilamin) na temperaturi refluksa.
Derivati indolpiperazina formule (IV) odgovarajuće se pripremaju iz odgovarajućeg arilamina prema metodi loju su opisali Martin i sur., J. Med. Chem. 32 (1989) 1052, ili prema metodi koju su opisali Kruse i sur., Rec. Trav. Chim. Pays-Bas 107 (1988) 303. Početni arilamini su ili komercijalno na raspolaganju ili su dobro opisani u literaturi.
Derivati indol tetrahidropirina formule (IV) poznati su iz literature (vidi, napr., francuski Patent 2458549). Odgovarajuće, 1-zaštićeni 4,5,6 ili 7-bromindol tretira se litijem s BuLi nakon čega se dodaje 1-zaštićen 4-piperidon i daljnja dehidracija kako je prikazano u primjeru u nastavku. Početni bromindoli su ili komercijalno na raspolaganju ili su dobro opisani u literaturi. Reagensi formule (V) su ili komerfijalno na raspolaganju ili se mogu pripremiti prema metodama iz literature, tj. iz odgovarajućeg derivata karboksilne kiseline redukcijom na odgovarajuće derivate hidroksila i naknadnim pretvaranjem hidroksi grupe u grupu G uobičajenim metodama.
Reduktivna alkilacija prema metodi c) obavlja se prema standardnim metodama iz literature. Ta se reakcija može obaviti u dvije faze, tj. povezivanjem derivata formule (IV) i reagensa formule (VI) standardnim metodama preko klorida karboksilne kiseline ili primjenom veznih reagensa kao što su napr. dicikloheksil karbodiimid nakon čega slijedi redukcija dobivenim amidom s litij aluminij hidridom ili alanom. Ova se reakcija također može izvesti pomoću standardne procedure u jednoj reakcionoj posudi. Karboksilne kiseline ili aldehidi formule (VI) su ili komercijalno na raspolaganju ili opisani u literaturi.
Redukcija dvostruke veze indola prema metodi d) prikladno se obavlja tretiranjem diboranom ili prereagensom diborana poput kompleksa trimetilamina ili dimetilsulfida u inertnom otapalu kao što je napr. tetrahidrofuran ili dioksan od 0oC do temperature refluksa za kojom slijedi kiselinom katalizirana hidroliza intermedierom derivata borana. Redukcija se alternativno može izvesti tretiranjem natrijevim cijanoborhidridom u trifluorooctenoj kiselini.
Redukcija dvostrukih veza prema metodi e) naprikladnije se obavlja hidrogenacijom u alkoholu uz prisutnost plemenitog metala kao katalizatora, kao što su napr. platina ili paladij.
Redukcija amidnih grupa prema metodi f) najprikladnije se obavlja pomoću litij aluminij hidrida ili alana u inertnom organskom otapalu kao što je napr. tetrahidrofuran ili dietileter od 0oC do temperature refluksa.
Uklanjanje halogenih supstituenata prema metodi g) prikladno se obavlja pomoću katalitičke hidrogenacije u alkoholu uz prisutnost paladija kao katalizatora ili tretiranjem s amonijevim formatom u alkoholu na povišenoj temperaturi uz prisutnost paladija kao katalizatora.
Dialkilacija amina prema metodama h) i i) najprikladnije se provodi na povišenim temperaturama u inertnom otapalu kao što su napr. klorobenzen, toluen, N.metilpirolidinon, dimetilformamid ili acetonitril. Reakcija se može obaviti uz prisutnost baze poput kalijevog karbonata ili trietilamina. Početni materijal za procese h) i i) je komercijalno na raspolaganju ili se može pripremiti prema uobičajenim metodama.
N-alkilacija ili N-acilacija indola obavljaju se u intertnom otapalu kao što je na pr. alkohol ili keton, na povišenim temperaturama i uz prisutnost baze, tj. kalijevog karbonata ili trietilamina. Alternativno, može se upotrebiti međufazni reagens. Odgovarajuća N-arilacija najbolje se može provesti pod Ullmannovim uvjetima opisanima u literaturi.
Redukcija alkoksikarbonilskih grupa prema metodi k) najprikladnije se obavlja pomoću litij aluminij hidrida ili alana u inertnom organskom otapalu kao što je na pr. tetrahidrofuran.
Slijedeći primjeri još će bolje ilustrirati ovaj izum. Međutim, ne treba ih smatrati graničavajućima.
Primjeri
Tališta su određivana na aparatu Büchi B-540 i neispravljena su. Maseni spektri dobiveni su na sustavu Quatro MS-MS proizvođača VG Biotech, Fisons Instruments ili na Sciex API 150EX Perkin Elmera. Sprektri su dobiveni na dva kompleta operativnih uvjeta uz primjenu elektrosprej ionizacije: jedan komplet za dobivanje podataka o molekularnoj težini (MH+, 20 eV), a drugi komplet za uvođenje obrazaca fragmentacije (70-100 eV). Podloga je substrahirana. Relativni intenziteti iona dobiveni su iz obrasca fragmentacije. Kad intenzitet molekularnog iona nije prikazan (MH+), taj ion je bio prisutan samo u prvom kompletu operativnih uvjeta. 1H NMR spektri registrirani su na 250 MHz na Bruker AC 250 ili na 500 MHz na Bruker DRX 500. Kao otapala su upotrebljena deuterizirani kloroform (99,8% D) ili dimetilsulfoksid (99,9% D). TMS je upotrebljen kao interni referentni standard. Kemijski pomaci su izraženi kao vrijednosti u ppm . Slijedeće kratice predstavljaju množinu NMR signala: s=singlet, d=dublet, t=triplet, q=kvartet, qv=kvintet, h=heptet, dd=dvostruki dublet, dt=dvostruki triplet, dq=dvostruki kvartet, tt=trostruki triplet, m=multiplet, b=široki. NMR signali koji odgovaraju kiselinskim protonima u izvjesnoj su mjeri izostavljeni. Sadržaj vode u kristalinskim spojevima određen je titriranjem po Karl Fischeru. Dobivena je točna analiza elemenata za sve ciljane spojeve. Postupci standardne dorade odnose na ekstrakciju pomoću indiciranog organskog otapala iz propisane vodene otopine, sušenje kombiniranih oganskih ekstrakta (nehidrirani MgSO4 ili NaSO4), filtriranje i uparavanje otapala in vacuo. Za kromatografiju u koloni korišten je silika gel tipa Keselgel 60, 40-60 mesh ASTM.
Priprema intermediera
A. Priprema 1-(1H-indol-yl)piperazina:
1-(1-H-indol-4-yl)piperazin
Dinitrotoluen (25 g) je otopljen u DMSO (60 mL). Dodan je triton-B (40% u metanolu, 6,4 mL), a rezultat je bila tamnoljubičasta otopina. Mješavina je zagrijana na 30ºC i polako joj je dodavana otopina paraformaldehida (4,5 g) u DMSO (40 mL). Nakon dodavanja mješavina je 1,5 sat grijana na 65ºC. Standardna dorada etil acetatom dala je 2-(2,6-dinitrofenil)etanol (29 g) u obliku tamnocrvenog ulja. To ulje (27 g) otopljeno je u etanolu (250 mL) i dodano je 5% paladija na ugljenu (3 g). Mješavina je tijekom 16 sati u Parrovom aparatu tretirana plinovitim vodikom pod tlakom od 3 atmosfere. Filtriranje i uklanjanje otapala in vacuo dali su 2-(2,6-diaminofenil)etanol (19,4 g) u obliku smeđeg ulja koje se nakon stajanja kristaliziralo. Dio ovog proizvoda (15,8 g) otopljen je u toluenu (250 mL) i dodan je tris(trifenilfosfin)rutenij(II)klorid (2,9 g). Mješavina je tijekom 8 sati refluksirana pomoću vodenog separatora, a zatim je uslijedilo otklanjanja otapala in vacuo.
Preostala mješavina reakcije pročišćena je flash kromatografijom (eluent: heptan/etil acetat 3:1) što je dalo 4-amino-1H-indol kao kristalizirana krutina (7,6 g). Ta krutina otopljena je u klorobenzenu (150 mL) i dodan je bis(2-kloroetil)amin hidroklorid (9 g), nakon čega je uslijedio 90-satni refluks. Filtriranjem je dobiven kristalni proizvod (9,2 g) koji je tijekom 15 minuta zagrijavan u mješavini koncentrirane vodene otopine amonijaka (50 mL) i etil acetata (200 mL). Separacijom organske faze, sušenjem i uparavanjem dobiven je spoj iz naslova u obliku kristalnog materijala (5,6 g).
Na analogan način pripremljeni su i sljedeći piperazini:
1-(6-metoksikarbonil-1H-indol-4-yl)piperazin
1-(6-t-butil-5-metoksi-1H-indol-4-yl)piperazin
1-(6-t-butil-7-metoksi-1H-indol-4-yl)piperazin
1-(6,7-dihidro-6,6,8,8-tetrametilciklopent(g)-1H-indol-4-yl)piperazin
1-(1H-indol-5-yl)piperazin
Ovaj piperazin pripremljen je tretiranjem 5-aminoindola s bis(2-kloretil)aminom prema postupku analognom prethodno opisanom postupku za pripremu 1-(1H-indol-4-yl)piperazina.
1-(3-cijano-1H-indol-4-yl)piperazin
Mješavina 1-(1H-indol-4-yl)piperazin hidroklorida (1g) i kalijevog karbonata (2,9 g) u tetrahidrofuranu (25 mL) i vodi (25 mL) miješana je tijekom 15 minuta, a zatim joj je dodana otopina di-t-butil dikarbonata (2,3 g) u 1:1 mješavini tetrahidrofurana i vode (20 mL). Ta je mješavina 16 sati miješana na 50ºC. Standardna dorada etil acetatom dala je 1-t-butoksikarbonil-4-(1H-indol-4-yl)piperazin u obliku teškog ulja (1,1 g).
Ulje je otopljeno u acetonitrilu (50 mL) a zatim je kap po kap dodavan klorosulfonil izocijanat (1 mL) na -20ºC. Mješavina je preko 20 minuta, za vrijeme kap-po-kap dodavanja dimetilformamida (5 mL), držana na niskoj temperaturi. Konačno je mješavina 30 min miješana na 0ºC. Dodana je vodena otopina natrijevog karbonata (30 mL) i mješavina je miješana 30 min.
Organska faza je separirana, osušena i koncentrirana. Dobiveno ulje pročišćemo je pomoću kromatografije u koloni (eluent: etil acetat/heptan/metanol 16:3:1), a rezultat je bio 1-t-butoksikabonil-4-(3-cijano-1H-indol-4-yl)piperazin u obliku žutog ulja (0,5 g).
Ulje je otopljeno u metanolu (2 mL) i dodan je eteral hidrogenklorid (20mL). Miješanjem tijekom 2 sata I filtracijom dobiven je spoj iz naslova u obliku kristalnog materijala (0,34 g).
1-(1-alil-1H-indol-4-yl)piperazin
Otopina 1-butoksikarbonil-4-(1H-indol-4-yl)piperazina (pripremljena prema gornjem opisu) u tetrahidrofuranu (50mL) dodana je kap po kap suspenziji natrijevog hidrida (0,7 g 60% suspenzije mineralnog ulja) u tetrahidrufuranu (150 mL) na sobnoj temperaturi. Nakon miješanja tijekom daljnjih 30 min kap po kap je dodana otopina alil bromida (3,5 mL) u tetrahidrofuranu (50 mL). Nakon 48-satnog miješanja mješavina je ulivena u ledenu vodu nakon čega je uslijedila standardna obrada etil acetatom i dobivanjem ulja koje je pročišćeno flash kromatografijom (eluent: heptan/etil acetat 85:15) i dalo 1-t-butoksikarbonil-4-(1-alil-1H-indol-4-yl)piperazin u obliku ulja (3,2 g). To je ulje otopljeno u metanolu (15 mL) i dodana je zasićena otopina HCl u dietil eteru (100 mL). Nakon 16 sati miješanja na sobnoj temperaturi, filtriranjem i sušenjem in vacuo dobiveni su bezbojni kristali koji su se sastojali od hidroklorida spoja iz naslova (2,5 g).
Na analogan način pripremljeni su sljedeći piperazini:
1-(1-benzil-1H-indol-4-yl)piperazin
1-(1-propargil-1H-indol-4-yl)piperazin
B. priprema 4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirina
Otopina 4-brom-1H-indol (36 g) u dimetilformamidu (80 mL) tretirana je suspenzijom NaH (60% u mineralnom ulju, 6.9 g) u dimetilformamidu (200 mL) na 20ºC. Nakon 30 min miješanja mješavina je ohlađena na -10ºC i u malim porcijama tretirana t-butildimetilsilil kloridom (38 g) i opet 1 sat miješana na sobnoj temperaturi. Standardnom doradom etil acetatom dobiveno je ulje koje je pročišćeno pomoću flash kromatografije, što je dalo 4-brom-1-(t-butildimetilsilil)-1H-indol (38 g) u obliku kristalnog materijala.
Proizvod je otopljen u suhom tetrahidrofuranu (500 mL), ohlađen na -78ºC i kap po kap tretiran s 1.6 M BuLi u heksanu (154 mL). Nakon 30 minuta miješanja na -78ºC, kap po kap je dodana otopina 1-karbetoksi-4-piperidona (18,2 mL) u tetrahidrofuranu (299 mL), nakon čega je uslijedilo miješanje tijekom 16 sati uz polagano povišenje temperature do sobne temperature. Standardnom doradom dietil eterom dobiveno je ulje koje je pročišćeno pomoću flash kromatografije (eluent: heptan/etil acetat/trietilamin 6:3:1), što je dalo 1-(t-butildimetilsilil)-4-(1-karbetoksi-4-hidroksi-4-piperidinil)-1H-indol kao kristalni spoj (20,5 g).
Tretiranje ovog proizvoda trifluorooctenom kiselinom (15 mL) u metilen kloridu (250 mL) na 0ºC tijekom 20-30 min (za reakcijom slijedi kromatografija tankog sloja na silika gelu, eluent etil acetat/heptan/trietilamin 10:9:1). Dodavanje 2M natrijevog hidroksida, separacija organske faze, sušenej i uklanjanje otapala in vacuo rezultiralo je uljem koje je pročišćeno flash kromatografijom (eluent isti kao gore za TLC) i dalo 1-karbetoksi-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin (9,1 g) u obliku kristalnog materijala.
Tretiranje kalijevim hidroksidom (5g) u etanolu (150 mL) s malom količinom vode (2 mL) na refluksu tijekom 3 dana dalo je nakon standardne dorade spoj iz naslova u obliku žutog ulja (4,5 g).
C. Priprema 5-fluorobenzofuran-3-octene kiseline
Otopina 5-fluorobenzofuran-3-karboksilne kiseline (56 g) i zasićene eteralne otopine hidroklornog plina (300 mL) u metanolu (600 mL) miješano je 16 sati na sobnoj temperaturi. Dodan je daljnji eteralni HCl (300 mL) i miješanje je nastavljeno još 24 sata. Koncentracija in vacuo dala je tamni kristalni materijal, metil 5-fluorobenzofuran-3-karboksilat (58 g).
Nakon suspenzije litij aluminij hidrida (15 g) u tetrahidrofuranu (400 mL) u dušičnoj atmosferi uslijedilo je kap-po-kap dodavanje otopine metil 5-fluorobenzofuran-3-karboksilata (58 g) u tetrahidrofuran (300 mL). Tijekom dodavanja temperatura je povisivana do 55ºC. Nakon dvosatnog miješanja reakcija je sukcesivno ohlađena vodom (30 mL), 15% vodenom otopinom natrijevog hidroksida (15 mL) i vodom (75 mL). Dodano je još tetrahidrofurana (500 mL) i mješavina je miješana 1 sat. Mješavina je filtrirana, a talog ekstrahiran s mješavinom metilen klorida (1 L) i etanola (0,5 L). Kombinirane organske faze koncentrirane su in vacuo dajući ulje koje je podvrgnuto silica gel flash kromatografiji (eluent: metilen klorid/25% vodena otopina NH3 99:1). Dobiveno žuto ulje, 5-fluorobenzofuran-3-ilmetanol (14,4 g), stajanjem se kristaliziralo.
Otopina 5-fluorobenzofuran-3-ilmetanol (14 g) u metilen kloridu (250 mL) sukcesivno je tretirana s 5 kapi dimetilformamida i tionil klorida (28 mL). Nakon 16-satnog miješanja na sobnoj temperaturi reakcija je koncentrirana in vacuo dajući 3-klorometil-5-fluorobenzofuran u obliku ulja (19,4 g).
Suspenzija natrijevodg cijanida (10 g) u dimetilsulfoksidu (150 mL) zagrijana je na 80ºC nakon čega je uslijedilo brzo dodavanje otopine 3-klorometil-5-fluorobenzofurana (10 g) u dimetilsulfoksidu (50 mL). Mješavina je 1⁄2 sata održavana na 80ºC a zatim nalivena na led. Standardnom doradom dietil eterom dobiven je tamni kristalni materijal, 5-fluorobenzofuran-3-ilacetonitril (8,8 g).
Otopina 5-fluorobenzofuran-3-ilacetonitrila (8,8 g) u metanolu (350 mL) tretirana je zasićenom eteralnom otopinom hidroklornog plina (350 mL) i na sobnoj temperaturi miješana 16 sati. Mješavina je koncentrirana in vacuo, a standardna dorada dietil eter/vodom dala je metil-5-fluorobenzofuran-3-ilacetat (9,4 g) u obliku ulja.
Dobiveni metilni ester otopljen je u metanolu (200 mL) i dodana je 6 M vodena otopina natrijevog hidroksida (400 mL) nakon čega je uslijedilo 16-satno miješanje na sobnoj temperaturi. Organsko otapalo je uklonjeno in vacuo, a zatim je uslijedilo zakiseljavanje pomoću 6 M hidroklorne kiseline. Standardnom doradom etil acetatom dobivena je 5-fluorobenzofuran-3-ilacetilna kiselina (9,2 g) u obliku kristalnog materijala.
Na analogan način pripremljene su sljedeće benzofuran-3-octene kiseline:
2-metil-4,5,6,7-tetrafluorobenzofuran-3-octena kiselina
benzofuran-3-octena kiselina
6-metilbenzofuran-3-octena kiselina
5-metilbenzofuran-3-octena kiselina
4-metilbenzofuran-3-octena kiselina
7-klorobenzofuran-3-octena kiselina
5-klorobenzofuran-3-octena kiselina
5-fluorobenzofuran-3-propionska kiselina i –butanoična kiselina pripremljene su procedurama produženja lanca analogno gore opisanoj proceduri.
6-klorindazol-3-octena kiselina pripremljena je prema J. Med. Chem. 35 (1992) 2155.
3-(6-fluorobenz[1,2]izoksazol-3-yl)propionska kiselina pripremljena je prema Drug Design Discov. 8 (1992) 225.
Priprema spojeva ovog izuma
Primjer 1
1a. 1-(2-(3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin, oksalat
Mješavina 2-(3-benzofuranil)octene kiseline (0,95 g), 1-(1H-indol-4-yl)piperazina (1,3 g) i N,N-dicikloheksilkarbodiimida (1,3 g) u mješavini suhog tetrahidrofurana (50 mL) i suhog dimetilfromamida (10 mL) miješana je 16 sati na sobnoj temperaturi. Filtriranjem i uklanjanjem otapala in vacuo dobilo se uljem koje je pročišćeno flash kromatografijom (eluent: etil acetat/heptan/trietilamin 10:9:1) i dalo 1-(3-benzofuranil)metilkarbonil-4-(1H-indol-4-yl) piperazin (0,5 g) u obliku ulja. Ulje je otopljeno u tetrahidrofuranu (20 mL) i tretirano suspenzijom litij aluminij hidrida (0,26 g) u tetrahidrofuranu (20 mL) na sobnoj temperaturi u dušičnoj atmosferi iza koje je uslijedio 4-satni refluks. Mješavina reakcije ohlađena je na 0ºC i sukcesivno tretirana vodom (1 mL), 15% vodenom otopinom natrijevog hidroksida (0,5 mL) i vodom (2,5 mL). Nakon 30 min miješanja mješavina je filtrirana i koncentrirana. Preostalo ulje otopljeno je u acetonu, a nakon toga je uslijedilo dodavanje oksalne kiseline i filtriranje, što je dalo spoj iz naslova u obliku kristalnog materijala (0,4 g). Talište 130-32ºC. 1H NMR (DMSO-d6):3.05-3.15 (m, 2H); 3.15-3.30 (m, 6H); 3.35 (s, 4H); 6.45 (s, 1H); 6.55 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.20-7.40 (m, 3H); 7.60 (d, 1H); 7.75 (d, 1H); 7.90 (s, 1H), 11.10 (s, 1H). MS m/z (%): 346 (MH+, 3%), 214 (31%), 199 (19%, 171 (14%).
Analogno su pripremljeni sljedeći spojevi:
1b, 1-(3-benzofuranilmetil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 226-28ºC. 1H NMR (DMSO-d6):3.10-3.20 (m, 4H); 3.20-3.40 (m, 4H); 4.25 (s, 2H); 6.40 (t, 1H); 6.45 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.25 (dt, 1H); 7.30-7.45 (m, 2H); 7.65 (dd, 1H); 7.95 (dd, 1H); 8.15 (s, 1H); 11.10 (s, 1H).
MS m/z (%): 332 (MH+, 10%), 158 (10%, 131 (100%).
1c, 1-(2-(5-fluoro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 196-97ºC, 1H NMR (DMSO-d6): 3.05 (t, 2H); 3.20-3.45 (m, 10H); 6.44 (s 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.20 (dt, 1H); 7.30 (t, 1H); 7.55-7.65 (m, 2H); 8.00 (s, 1H); 11.12 (s, 1H). MS m/z (%): 364 (MH+, 7%), 214 (42%), 199 (20%), 171 (14%).
1d, 1-(4-(5-fluoro-3-benzofuranil)-1-butil)-4-(1H-indol-4-yl)piperazin,
dihidroklorid.
Talište 241-44ºC, 1H NMR (DMSO-d6): 1.65-1.95 (m, 4H); 2.70 (t, 2H); 3.15-3.40 (m, 6H); 3.60 (d, 2H); 3.70 (d, 2H); 6.50 (s, 1H); 6.55 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.15 (dt, 1H); 7.30 (t, 1H); 7.45-7.60 (m, 2H); 7.90 (s, 1H); 10.95 (b, 1H); 11.20 (s, 1H). MS m/z (%): 392 (MH?, 90%), 234 (19%), 199 (23%), 163 (49%), 131 (11%).
1e, 1-(2-(1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, hemioksalat.
Talište 167-69ºC, 1H NMR (DMSO-d6): 3.05 (s, 4H); 3.15 (s, 4H); 3.30 (s, 4H); 6.40 (s, 1H); 6.50 (d, 1H); 6.90-7.15 (m, 4H); 7.25 (dd, 2H); 7.35 (d, 1H); 7.60 (d, 1H); 10.90 (s, 1H); 11.10 (s, 1H). MS m/z (%): 345 (MH+, 5%), 199 (13%), 144 (54%), 107 (9%).
1f, 1-(3-(1H-indol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 198-204ºC. 1H NMR (DMSO-d6): 2.05 (qv, 2H); 2.75 (t, 2H); 3.15 (t, 2H); 3.35 (s, 8H); 6.45 (s, 1H); 6.50 (d, 1H); 7.00 (t, 2H); 7.10 (t, 2H); 7.20 (d, 1H); 7.25 (t, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.85 (b, 1H); 11.15 (b, 1H).
1g, 1-(4-(1H-indol-3-yl)-1-butil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 189-93ºC. 1H NMR (DMSO-d6): 1.60 (m, 4H); 2.75 (t, 2H); 3.05 (t, 2H); 3.15-3.50 (m, 8H); 6.45 (s, 1H); 6.50 (s, 1H); 6.90-7.20 (m, 5H); 7.30 (s, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 8.20 (b, 2H); 10.90 (s, 1H); 11.20 (s, 1H).
1h, 1-(3-(5-fluoro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)piperazin, dihidroklorid.
Talište 230-34ºC. 1H NMR (DMSO-d6): 2.20 (qv, 2H); 2.75 (t, 2H); 3.20-3.30 (m, 2H); 3.30-3.45 (m, 4H); 3.55-3.80 (m, 4H); 6.55 (s, 1H); 6.65 (d, 1H); 7.00 (tm 1H); 7.10-7.20 (m, 2H); 7.30 (t, 1H); 7.50-7.65 (m, 2H); 7.95 (s, 1H); 11.25 (s, 1H); 11.40 (b, 1H). MS m/z (%): 378 (MH+, 70%), 220 (26%), 199 (25%), 177 (18%), 159 (100%).
1i, 1-(2-(2-metil-4,5,6,7-tetrafluoro-3-benzofuranetil)-4-(1H-indol-4-yl)
piperazin, dihidroklorid.
Talište 181-87ºC. 1H NMR (DMSO-d6): 2.50 (s, 3H); 3.15-3.50 (m, 8H); 3.65-3.85 (m, 4H); 6.50 (s, 1H); 6.60 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H); 7.35 (d, 1H); 11.20 (s, 1H); 11.75 (b, 1H). MS m/z (%): 414 (MH+ - F, 13%), 396 (11%), 214 (72%), 199 (23%), 195 (34%), 159 (26%).
1j, 1-(2-(3-indazolil)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 149-51ºC. 1H NMR (DMSO-d6): 3.05-3.15 (m, 4H); 3.15-3.20 (m, 2H); 3.20-3.35 (m, 6H); 6.40 (s, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.05 (d, 1H); 7.10 (t, 1H); 7.25 (s, 1H); 7.35 (t, 1H); 7.50 (d, 1H); 7.80 (d, 1H); 11.10 (s, 1H). MS m/z (%): 346 (MH+, 40%); 199 (80%); 144 (199%).
1k, 1-(2-(6-kloro-3-indazolil)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 255-58ºC. 1H NMR (DMSO-d6): 3.10-3.15 (m, 4H); 3.15-3.20 (m, 2H); 3.20-3.30 (m, 6H; 6.40 (s, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.25 (s, 1H); 7.55 (s, 1H); 7.85 (d, 1H). MS m/z (%): 380 (MH+, 100%), 214 (30%), 139 (50%).
1l, 1-(2-(7-cijano-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 241-43ºC. 1H NMR (DMSO-d6): 3.15 (t, 2H); 3.30 (t, 2H); 3.30-3.50 (m, 8H); 6.45 (s, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.20 (t, 1H); 73.70 (s, 1H); 7.50 (s, 1H); 7.60 (d, 1H); 8.00 (d, 1H); 11.15 (s, 1H); 11.90 (s, 1H). MS m/z (%): 370 (MH+, 100%), 214 (28%), 156 (42%).
Primjer 1
2a, 1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Otopina 6-kloro-1H-indola (15 g) u dietil eteru (300 mL) ohlađena je na 0ºC i tretirana otopinom oksalil klorida (9,4 mL) u dietil eteru (30 mL). Mješavina je 16 sati miješana na sobnoj temperaturi. Filtriranjem je dobiven 2-(6-kloro-1H-indol-3-yl)-2-oksoacetil klorid u obliku kristalnog materijala (15,5 g).
Dio ovog proizvoda (2,5 g) otopljen je u suhom tetrahidrofuranu (25 mL) i kap po kap dodan otopini 1-(1H-indol-4-yl)piperazina (1,4 g) i trietilamina (15 mL) u tetrahidrofuranu (100 mL). Nakon 16-satnog miješanja mješavina reakcije koncentrirana je in vacuo. Preostalo ulje pročišćeno je flash kromatografijom (eluent: etil acetat/metanol/trietilamin 85:10:5) i dobiven je 1-(2-(6-kloro-1H-indol-3-yl)-1,2-dioksoetil)-4-(1H-indol-4-yl)piperazin (1,6 g) u obliku kristalnog materijala. Suspenzija ovog proizvoda napravljena je u tetrahidrofuranu (25 mL) i kap po kap dodana suspenziji litij aluminij hidrida (1,5 g) u tetrahidrofuranu (50 mL). Ova je mješavina refluksirana tijekom 4 sata i ohlađena na 0ºC, nakon čega joj je dodano vode (3 mL), 15% vodene otopine natrijevog hidroksida (1,5 mL) i vode (7,5 mL). Filtriranjem i standardnom doradom dobiveno je žuto ulje koje je pretvoreno u sol oksalata iz naslova (1,5 g) iz otopine acetona dodavanjem oksalne kiseline. Talište 229-31ºC. 1H NMR (DMSO-d6): 3.10 (t, 2H); 3.25-3.55 (m, 10H); 6.45 (s, 1H); 6.50 (d, 1H); 6.90-7-10 (3,3H); 7.25-7.35 (m, 2H); 7.45 )s, 1H); 7.65 (d, 1H); 11.12 (s, 2H). MS m/z (%): 379 (MH+, 18%), 214 (16%), 199 (17%), 178 (16%), 143 (13%).
Analogno su pripremljeni sljedeći spojevi:
2b, 1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 245-47ºC. 1H NMR (DMSO-d6): 3.30-3.50 (m, 12H); 6.45 (s, 1H); 6.50 (d, 1H); 6.95-7.10 (m, 4H); 7.30 (s, 1H); 7.35-7.40(m, 2H); 11.15 (s, 1H); 11.40 (s, 1H). MS m/z (%): 379 (MH+, 28%), 178 (41%), 143 (100%).
2c, 1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, fumarat.
Talište 212-15ºC. 1H NMR (DMSO-d6): 2.75-3.10 (m, 8H); 3.10-3.35 (m, 4H); 6.40 (s, 1H); 6.50 (d, 1H); 6.60 (s, 2H), 6.85-7.10 (m, 3H); 7.20-7.40 (m, 4H); 10.95 (s, 1H); 11.05 (s, 1H). MS m/z (%): 363 (MH+, 18%), 214 (100%), 202 (34%), 199 (19%), 171 (12%), 162 (87%).
2g, 1-(2-(6-kloro-1H-indol-3-yl)etil-4-(1H-indol-4-yl)-1,2,3,6-
tetrahidropiridin, 1.5 fumarat.
Talište 225-26ºC. 1H NMR (DMSO-d6): 2.60-2.70 (m, 2H); 2.85-3.10 (m, 6H); 3.40-3.50 (m, 2H); 6.10 (s, 1H); 6.60 (s, 3H); 6.90-7.10 (m, 3H); 7.20-7.40 (m, 3H); 7.40 (d, 1H); 7.60 (d, 1H); 11.05 (s, 1H); 11.15 (s, 1H). MS m/z (%): 376 (MH+, 12%), 179 (80%), 143 (100%).
2h, 1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin, trifumarat.
Talište 204-6ºC. 1H NMR (DMSO-d6): 2.70-2.85 (m, 2H); 3.00-3.20 (m, 4H); 3.25 (t, 2H); 3.70-3.80 (m, 2H); 6.05-6.15 (m, 1H); 6.60 (s, 6H); 6.85-7.00 (m, 2H); 7.10 (t, 1H); 7.30-7.45 (m, 6H); 11.00 (s, 1H); 11.20 (s, 1H). MS m/z (%): 360 (MH+), 162 (100%).
2i, 1-(2-(7-bromo-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin, hemioksalat.
Talište 149-51ºC. 1H NMR (DMSO-d6): 2.95-3.20 (m, 8H); 3.20-3.40 (m, 4H); 6.40 (s, 1H); 6.50 (d, 1H); 7.00 (dt, 2H); 7.10 (d, 1H); 7.25 (t, 1H); 7.30-7.40 (m, 2H); 7.60 (d, 1H); 11.05 (s, 1H); 11.10 (s, 1H). MS m/z (%): 423 (MH+, 9%), 222 (20%), 214 (29%), 143 (100%).
2j, 1-(1-alil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin, fumarat.
Talište 230-32ºC. 1H NMR (DMSO-d6): 2.70-3.00 (m, 8H); 3.10-3.30 (m, 4H); 4.75 (d, 2H); 5.00 (d, 1H); 5.15 (d, 1H); 5.85-6.05 (m, 1H); 6.40 (d, 1H); 6.55 (dd, 1H); 6.60 (s, 2H); 6.95-7.10 (m, 3H); 7.20-7.30 (m, 2H); 7.40 (d, 1H); 7.55 (d, 1H). MS m/z (%): 419 (MH+, 13%), 254 (21%), 143 (100%).
2k, 1-(1-alil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)etil)piperazin, 1.25 fumarat
Talište 210-12ºC. 1H NMR (DMSO-d6): 2.75-3.00 (m, 8H); 3.10-3.30 (m, 4H); 4.80 (d, 2H); 5.00 (d, 1H); 5.15 (d, 1H); 7.00-7.10 (m, 1H); 7.20-7.40 (m, 4H); 10.95 (s, 1H). MS m/z (%): 403 (MH+, 25%), 239 (30%), 162 (100%).
2l, 1-(1-benzil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin, hemifumarat.
Talište 237-39ºC. 1H NMR (DMSO-d6): 2.65-2.85 (m, 6H); 2.90 (t, 2H); 3.10-3.25 (m, 4H); 5.40 (s, 2H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.95-7.10 (m, 3H); 7.15 (d, 1H); 7.20-7.35 (m, 5H); 7.35-7.45 (m, 2H); 7.60 (d, 1H), 11.00 (s, 1H). MS m/z (%): 469 (MH+, 20%), 304 (32%), 289 (22%), 143 (100%).
2m, 1-(1-benzil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)etil)piperazin, fumarat.
Talište 178-80ºC. 1H NMR (DMSO-d6): 2.70-3.00 (m, 8H); 3.10-3.30 (m, 4H); 5.40 (s, 2H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 2H); 6.90 (dt, 1H); 7.00 (d, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.20-7.40 (m, 5H); 7.45 (d, 1H); 10.95 (s, 1H). MS m/z (%): 453 (MH+, 28%), 304 (39%), 162 (100%).
2n, 1-(1-benzil-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)etil)piperazin, fumarat.
Talište 230-32ºC. 1H NMR (DMSO-d6): 2.75-3.05 (m, 8H); 3.10-3.35 (m, 4H); 5.45 (s, 2H); 6.45 (d, 1H); 6.60 (s, 2H); 7.00 (t, 1H); 7.10 (d, 1H); 7.10-7.20 (m, 2H); 7.20-7.40 (m, 5H); 7.40 (d, 1H); 7.80 (s, 1H); 11.05 (s, 1H). MS m/z (%): 513 (MH+, 14%) 304 (30%), 142 (100%).
2o, 1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin.
Talište 197-99ºC. 1H NMR (DMSO-d6): 2.70-2.95 (m, 6H); 3.00 (t, 2H); 3.20-3.40 (m, 5H); 4.85 (d, 2H); 6.50 (d, 1H); 6.65 (d, 1H); 7.00-7.30 (m, 5H); 7.35 (s, 1H); 7.55 (d, 1H); 8.00 (s, 1H). MS m/z (%): 417 (MH+, 15%), 252 (24%), 237 (17%), 143 (100%).
2p, 1-(2-(1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin, hemifumarat.
Talište 193-95ºC. 1H NMR (DMSO-d6): 2.60-2.85 (m, 6H); 2.90 (t, 2H); 3.10-3.25 (m, 4H); 3.35 (t, 1H); 5.00 (d, 2H); 6.45 (d, 1H); 6.55 (d, 1H); 6.60 (s, 1H); 6.90-7.25 (m, 5H); 7.25-7.40 (m, 2H); 7.55 (d, 1H), 10.75 (s, 1H). MS m/z (%): 383 (MH+, 44%), 252 (55%), 143 (100%).
2q, 1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin
Talište 153-55ºC. 1H NMR (DMSO-d6): 2.70-2.90 (m, 6H); 2.90-3.10 (m, 3H); 3.25-3.45 (m, 4H); 4.85 (d, 2H); 6.55 (d, 1H); 6.65 (d, 1H); 6.95 (dt, 1H); 7.00-7.35 (m, 6H); 8.00 (s, 1H). MS m/z (%): 401 (MH+, 48%), 237 (27%), 162 (81%), 115 (100%).
2r, 1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin.
Talište 154-56ºC. 1H NMR (DMSO-d6): 2.70-2.90 (m, 6H); 2.90-3.00 (m, 3H); 3.25-3.40 (m, 4H); 4.85 (d, 2H); 6.55 (d, 1H); 6.65 (d, 1H); 7.00-7.10 (m, 2H); 7.10-7.35 (m, 4H); 7.75 (s, 1H); 8.05 (s, 1H). MS m/z (%): 461 (MH+, 5%), 252 (16%), 237 (12%), 143 (100%).
2s, 1-(1-benzil-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin, hemifumarat.
Talište 188-90ºC. 1H NMR (DMSO-d6): 2.65-2.85 (m, 6H); 2.95 (t, 2H); 3.10-3.30 (m, 4H); 5.45 (s, 2H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.90-7.10 (m, 4H); 7.10-7.35 (m, 7H); 7.40 (d, 1H);7.55 (d, 1H); 10.80 (s, 1H. MS m/z (%): 435 (MH+, 22%), 304 (52%), 143 (100%).
2t, 1-(2-(5-bromo.1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin, fumarat.
Talište 231-33ºC. 1H NMR (DMSO-d6): 2.80 (t, 2H); 2.80-2.90 (m, 4H); 2.95 (t, 2H); 3.10-3.20 (m, 4H); 6.30 (s, 1H); 6.60 (s, 2H); 6.85 (dd, 1H); 7.05 (s, 1H); 7.20 (dd, 1H); 7.25 (t, 1H); 7.25-7.30 (m, 2H); 7.35 (d, 1H); 7.75 (s, 1H); 10.80 (s, 1H); 11.05 (s, 1H). MS m/z (%): 425 (MH+, 11%), 223 (14%), 143 (100%).
2u, 1-(2-(5-kloro-1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin, hemifurmarat.
Talište 232-34ºC. 1H NMR (DMSO-d6): 2.70 (t, 2H); 2.70-2.80 (m, 4H); 2.90 (t, 2H); 3.05-3.15 (m, 4H); 6.30 (s, 1H); 6.60 (s, 1H); 6.85 (dd, 1H); 7.00 (s, 1H); 7.05 (d, 1H); 7.25 (t, 1H); 7.25-7.30 (m, 2H); 7.35 (d, 1H); 7.60 (s, 1H); 10.80 (s, 1H): 11.00 (s, 1h). MS m/z (%): 379 (MH+, 18%), 143 (100%).
Primjer 3
3a, 1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin
Otopina 1-(2-(5-fluoro-1H-indol-3-yl)-1,2-dioksoetil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazina (1,8 g, pripremljenog od 2-(5-fluoro-1H-indol-3-yl)-2-oksoacetil klorida i 1-(6-metoksikarbonil-1H-indol-4-yl)piperazina prema proceduri opisanoj u Primjeru 2) u tetrahidrofuranu (50 mL) dodana je kap po kap suspenziji litij aluminij hidrida (1,7 g) u tetrahidrofuranu (125 mL) na sobnoj temperaturi, a zatim je uslijedio refluks od 4 sata. Mješavina reakcije ohlađena je na 5ºC nakon čega joj je sukcesivno dodana voda (3,4 mL), 15% vodena otopina natrijevog hidroksida (1,7 mL) i voda (8,5 mL). Filtriranje i otklanjanje otapala in vacuo dalo je ulje koje je pročišćeno pomoću flash kromatografije (eluent: etil acetat/metanol/trietilamin 85:10:5) i dobiven je proizvod iz naslova (0,9 g), koji je kristaliziran iz diizopropilnog etera. Talište 198-200ºC. 1H NMR (DMSO-d6): 2.60-2.80 (m, 6H); 2.85 (t, 2H); 3.15 (s, 4H); 4.45-4.55 (m, 2H); 4.90-5.00 (m, 1H); 6.30 (s, 1H); 6.40 (s, 1H); 6.90 (dd, 1H); 7.00 (s, 1H); 7.20 (s, 1H); 7.25-7.35 (m, 3H); 10.85 (s, 1H); 10.95 (s, 1H).
Analogno su pripremljeni sljedeći spojevi:
3b, 1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin.
Talište 194-96ºC. 1H NMR (DMSO-d6): 2.60-2.80 (m, 6H); 2.90 (t, 2H); 3.1-3.20 (m, 4H); 4.50 (fd, 2H); 4.95 (t, 1H); 6.35 (s, 1H); 6.45 (s, 1H); 6.95-7.05 (m, 1H); 7.20 (t, 1H); 7.25 (d, 1H); 7.55 (d, 1H); 10, 95 (s, 2H).
3c, 1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin.
Talište 163-65ºC. 1H NMR (DMSO-d6): 2.65 (t, 2H); 2.70 (s, 4H); 2.90 (t, 2H); 3.15 (s, 4H); 4.50 (d, 2H); 4.95 (t, 1H); 6.35 (s, 1H); 6.45 (s, 1H); 7.00 (s, 1H); 7.10-7.20 (m, 2H); 7.25 (s, 1H); 7.30 (d, 1H); 7.70 (s, 1H); 10.90 (s, 1H); 11.00 (s, 1H).
Primjer 4
4a, 1-(3-(6-fluoro-1,2-benzisoksazol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin, fumarat.
Otopina 3-(3-bromo-1-propil)-6-fluoro-1,2-benzisoksazola (1,1 g), 1-(1H-indol-4-yl)piperazina (1,0 g), kalijevog karbonata (1,9 g) i kalijevog jodida (50 mg) u 4-metil-2-pentanonu (100 mL) refluksirana je 16 sati. Filtriranje i uklanjanje otapala in vacuo dali su ulje koje je pročišćeno flash kromatografijom (eluent: heptan/etil acetat/trietilamin 75:20:5), što je rezultiralo uljem (1,0 g) koje je iz acetona dodavanjem fumarne kiseline kristalizirano u fumarat iz naslova. Talište 187-89ºC. 1H NMR (DMSO-d6): 2.00 (qv, 2H); 2.55 (t, 2H); 2.60-2.80 (m, 4H); 3.05 (t, 2H); 3.05-3.20 (m, 4H); 6.40 (s, 1H); 6.45 (d, 1H); 6.60 (s, 2H); 6.90-7.05 (m, 2H); 7.20-7.35 (m, 2H); 7.70 (dd, 1H); 8.00 (dd, 1H); 11.00 (s, 1H). MS m/z (%): 379 (MH+, 10%), 178 (100%), 159 (24%).
Analogno su pripremljeni sljedeći spojevi:
4f, 1-(2-(1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin, oksalat.
Talište 213-16ºC. 1H NMR (DMSO-d6): 3.10 (t, 2H); 3.20-3.60 (m, 10H); 3.80 (s, 3H); 6.55 (s, 1H); 6.90-7.10 (m, 3H); 7.25 (s, 1H); 7.35 (d, 1H); 7.50 (s, H); 7.60 (d, 1H); 7.75 (s, 1H); 10.90 (s, 1H); 11.55 (s, 1H).
4g, 1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin, oksalat.
Talište 228-30ºC. 1H NMR (DMSO-d6): 3.10 (t, 2H); 3.3= (t, 2H); 3.45 (s, 8H); 3.85 (s, 3H); 6.55 (s, 1H); 7.05 (dd, 1H); 7.10 (s, 1H); 7.33 (s, 1H); 7.45 (s, 1H); 7.55 (t, 1H); 7.65 (d, 1H); 7.85 (s, 1H); 11.15 (s, 1H); 11.65 (s, 1H).
4h, 1-(2-(5-fluoro-3-benzofuranil)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin, oksalat.
Talište 227-28ºC. 1H NMR (DMSO-d6): 3.05 (t, 2H); 3.25 (t, 2H); 3.25-3-35 (m, 4H); 3.35-3.45 (m, 4H); 3.85 (s, 3H); 6.55 (s, 1H); 7.10 (s, 1H); 7.15 (t, 1H); 7.55 (t, 1H); 7.55-7.65 (m, 2H); 7.80 (s, 1H); 8.00 (s, 1H); 11.55 (s, 1H).
4l, 1-(5-fluoro-3-benzofuranilmetil)-4-(1H-indol-4-yl)piperazin, dihidroklorid.
Talište 238-40ºC. 1H NMR (DMSO-d6: 3.20-3.50 (m, 4H); 3.60 (d, 2H); 3.75 (d, 2H); 4.60 (s, 2H); 6.50 (s, 1H); 6.55 (d, 1H); 7.00 (t, 1H); 7.15 (d, 1H); 7.25 (dt, 1H); 7.25-7.30 (m, 1H); 7.70 (dd, 1H); 8.00 (dd, 1H); 8.40 (s, 1H); 11.22 (s, 1H); 11.65 (b, 1H). MS m/z (%): 350 (MH+, 7%), 201 (34%), 159 (100%), 149 (20%).
4m, 1-(3-cijano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin, fumarat.
Talište > 250ºC. 1H NMR (DMSO-d6): 2.70-3.00 (m, 8H); 3.10 (s, 4H); 6.60 (s, 1H); 6.75 (dd, 1H); 6.95-7.10 (m, 2H); 7.15-7.20 (m, 3H); 7.35 (d, 1H); 8.20 (s, 1H); 10.80 (s, 1H); 12.20 (s, 1H). MS m/z (%): 370 (MH+, 9%), 239 (100%), 227 (25%), 224 (27%), 144 (65%).
4n, 1-(3-cijano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranil)etil)piperazin, hemifumarat.
Talište 235-37ºC. 1H NMR (DMSO-d6): 2.60-2.95 (m, 8H); 3.10 (s, 4H); 6.60 (s, 2H); 6.75 (d, 1H); 7.05-7.25 (m, 3H); 7.45-7.60 (m, 2H); 7.95 (s, 1H); 8.20 (s, 1H); 12.15 (s, 1H). MS m/z (%): 389 (100%), 224 (38%), 208 (14%), 163 (15%).
4o, 1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(3-cijano-1H-indol4yl)piperazin, hemifumarat.
Talište 234-36ºC. 1H NMR (DMSO-d6): 2.70 (t, 2H); 2.80 (b, 4H); 2.90 (t, 2H); 3.10 (b, 4H); 6.60 (d, 2H); 6.75 (d, 1H); 7.00 (d, 1H); 7.15-7.20 (m, 2H); 7.25 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 8.20 (s, 1H); 10.90 (s, 1H); 12.10 (s, 1H). MS m/z (%): 404 (MH+, 8%), 239 (100%), 227 (18%), 224 (39%), 178 (25%).
4p, 1-(2-(3-benzofuranil)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,seskvioksalat.
Talište 221-23ºC. 1H NMR (DMSO-d6): 3.10 (t, 2H); 3.20-3.45 (m, 10H); 6.80 (d, 1H); 7.15-7.40 (m, 4H; 7.60 (dd, 1H); 7.75 (dd, 1H); 7.90 (s, 1H); 8.25 (d, 1H); 12.30 (s, 1H). MS m/z (%): 371 (MH+, 20%), 239 (63%), 145 (100%).
4q, 1-(1H-indol-4-yl)-4-(2-(5-metil-3-benzofuranil)etil)piperazin, hidroklorid.
Talište 258-60ºC. 1H NMR (DMSO-d6): 2.40 (s, 3H); 3.15-3.55 (m, 8H); 3.65-3.80 (m, 4H); 6.50 (d,1H); 6.60 (d, 1H); 7.00 (t, 1H); 7.15 (d, 1H); 7.20 (d, 1H); 7.30 (t, 1H); 7.45 (d, 1H); 7.60 (s, 1H); 7.90 (s, 1H); 11.20 (s, 1H). MS m/z (%): 360 (MH+, 10%), 214 (97%), 143 (100%).
4r, 1-(1H-indol-4-yl)-4-(2-(4-metil-3-benzofuranil)etil)piperazid, oksalat.
Talište 204-6ºC. 1H NMR (DMSO-d6): 2.05 (s, 3H); 3.30-3.50 (m, 12H); 6.45 (d, 1H); 6.50 (d, 1H); 6.95-7.05 (m, 2H); 7.10 (d, 1H); 7.20 (t, 1H); 7.30 (t, 1H); 7.40 (d, 1H); 7.85 (s, 1H); 11.10 (s, 1H). MS m/z (%): 360 (MH+, 23%), 214 (81%), 199 (199%), 143 (53%).
4s, 1-(3-(5-fluoro-3-benzofuranil)-1-propil)-4-(iH-indol-4-yl)-1,2,3,6-tetrahidropiridin, fumarat.
Talište 183-85ºC. 1H NMR (DMSO-d6): 1.70-2.00 (m, 2H); 2.40-2.90 (m, 8H); 3.20-3.35 (m, 2H); 6.00-6.10 (m, 1H); 6.55 (s, 1H); 6.60 (s, 2H); 6.90 (d, 1H); 7.05 (t, 1H); 7.15 (dt, 1H); 7.25-7.40 (m, 2H); 7.50 (dd, 1H); 7.55 (dd, 1H); 7.90 (s, 1H); 11.10 (s, 1H), MS m/z (%): 375 (MH+, 90%), 206 (100%), 149 (90%).
4t, 1-(2-(5-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin, oksalat.
Talište 200-2ºC. 1H NMR (DMSO-d6): 3.10 (t,2H); 3.30-3.50 (m, 10H); 6.45 (d, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.10 (d,1H); 7.30 (t, 1H); 7.40 (dd, 1H); 7.65 (d, 1H); 7.90 (s, 1H); 8.00 (s,1H); 11.10 (s, 1H). MS m/z (%): 380 (MH+, 50%), 214 (100%), 143 (80%).
4u, 1-(1H-indol-4-yl)-4-(2-(6-metil-3benzofuranil)etil)piperazin, oksalat.
Talište 190-92ºC. 1H NMR (DMSO-d6): 2.10 (s, 3H); 3.10 (t, 2H); 3.25-3.50 (m, 10H); 6.45(d, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.10 (t, 2H); 7.30 (t, 1H); 7.40 (s, 1H); 7.65 (d, 1H); 7.80 (s, 1H); 11.15 (s, 1H). MS m/z (%): 360 (MH+, 14%), 214 (44%), 143 (199%).
4v, 1-(2-(7-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin, hemioksalat.
Talište 216-18ºC. 1H NMR (DMSO-d6): 2.85-3.15 (m, 8H); 3.15-3.40 (m, 4H); 6.40 (d, 1H); 6.50 (d, 1H); 7.00 (t, 1H); 7.05 (d, 1H); 7.25 (t, 1H); 7.30 (d, 1H); 7.45 (d, 1H); 7.75 (d, 1H); 8.00 (s, 1H); 11.05 (s, 1H). MS m/z (%): 380 (MH+, 13%), 199 (30%), 143 (100%).
4x, 1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(cijano-1H-indol-4yl)piperazin,
hemifumarat.
Talište > 250ºC.1H NMR (DMSO-d6): 2.65-3.00 (m, 6H); 3.00-3.30 (m, 6H); 6.60 (s, 1H); 6.75 (dd, 1H); 6.90-7.10 (m, 2H); 7.10-7.25 (m, 2H); 7.25-7.40 (m, 2H); 8.20 (d, 1H); 11.20 (s, 1H); 12.10 (s, 1H). MS m/z (%): 404 (MH+, 14%), 224 (15%), 184 (18%), 143 (100%).
Primjer 5
5a, 1-(2-(6-kloro-1H-indol-3-yl)-4-(1H-indol-4-yl)piperidin.
Otopina spoja 2g (o,5 g) otopljena je u ledenoj ostenoj kiselini. Dodana je platina kao katalizator (10% na ugljenu, 10 mg) i mješavina je tijekom 16 sati hidrogenizirana u Parrovom aparatu pod tlakom od 3 atmosfere plinovitog vodika. Filtriranjem i uklanjanjem otapala dobiven je spoj iz naslova kao kristalni materijal (0,4 g). Talište 205-6ºC. 1H NMR (DMSO-d6): 1.75-1.90 (m, 4H); 2.10-2.20 (m, 2H); 2.60-2.70 (m, 2H); 2.85-2.95 (m, 3H); 3.15 (d, 2H); 6.50 (s, 1H); 6.80-6.90 (m, 2H); 6.95-7.10 (m, 2H); 7.20 (s, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.55 (d, 1H); 10.90 (s, 1H); 11.00 (s, 1H). MS m/z (%): 378 (MH+, 18%), 178 (100%), 143 (47%).
Farmakološko ispitivanje
Afinitet spojeva ovog izuma prema 5-HT1A receptorima određen ja mjerenjem inhibicije vezanja radioaktivnog liganda na 5-HT1A receptore, kako je opisano u sljedećem testu:
Inhibicija vezanja 3H-5-CT na ljudske 5-HT1A receptore
Ovom je metodom inhibicija pomoću lijekova vezanja 5-HT1A agonista 3H-5-karboksamido triptamina (3H-5-CT) na klonirane 5-ht1A receptore stabilno izražena u transficiranim HeLa stanicama (HA7) (Fargin, A. i sur., J. Biol. Chem., 1989, 264, 14848) određena in vitro. Pokus je obavljen kao modifikacija metode koju opisuje Harrington, M.A. i sur, J. Pharmacol. Exp. Ther., 1994, 263, 1098. Ljudski 5-HT1A receptori (40 μg staničnog homogenata) inkubirani su 15 min na 37ºC u 50 mM Tris bufera na pH 7.7 u prisutnosti 3H-5-CT. Nespecifično vezanje određeno je dodavanjem 10 μM metergolina. Reakcija je dovršena brzim filtriranjem kroz Unifilter GF/B filtere na Tomtec Cell Havesteru. Filteri su brojeni na Packard Top Counteru. Dobivene rezultate prikazuje tabela 1:
[image]
Tabela 1 – referentni spojevi
Spojevi ovog izuma također su ispitani s obzirom na njihov učinak na reapsorpciju serotonina pomoću sljedećeg testa:
Inhibicija apsorpscije 3H-5-HT u moždanim sinaptosomama štakora
Pomoću ove metode određuje se in vitro sposobnost lijekova da inhibiraju nakupljanje 3H-5-HT u sinaptosomama čitavog mozga štakora. Pokus je obavljen prema opisu Hytel, J., Psychopharmacology 1978, 60, 13.
[image] Tabela 1 – referentni spojevi, nt = nije testirano
Antagonističko djelovanje 5-HT1A nekih spojeva prema ovom izumu ocijenjeno je in vitro na kloniranim 5-HT1A receptorima stabilno izraženima u tranficiranim HeLa stanicama (HA7). U tom je testu antagonističko djelovanje ocijenjeno mjerenjem sposobnosti spojeva da se suprotstave pomoću 5-HT induciranoj inhibicji akumulaciji cAMP induciranoj forskolinom. Pokus je obavljen kao modifikacija metode koju su opisali Pauwels, P.J. i sur., Biochem. Pharmacol. 1993, 45, 375.
Neki od spojeva prema ovom izumu također su ispitani na njihovo in vivo djelovanje na 5-HT1A receptorima u pokusu opisanom od Sánchez, C. i sur., Eur. J. Pharmacol., 1996, 315, str. 245. U ovom testu određuju se antagonistička djelovanja ispitanih spojeva mjerenjem sposobnosti ispitanih spojeva da inhibiraju pomoću 5-MeO-DMT induciran 5-HT sindrom.
Spojevi prema ovom izumu imaju vrijedno djelovanje kao inhibitori reapsorpcije serotonina i imaju antagonističko djelovanje na 5-HT1A receptorima. Spojevi ovog izuma zato se smatraju korisnima u liječenju bolesti i poremećaja zbog kojih dolazi do inhibicije reapsorpcije serotonina i antagonističkog djelovanja na 5-HT1A receptorima. Bolesti kod kojih dolazi do inhibicije reapsorpcije serotonina dobro su poznate u struci i uključuju afektivne poremećaje kao što su depresija, psihoza, tjeskoba uključivo poremećaj opće tjeskobe i panike, opsesivni kompulzivni poremećaj itd.
Kao što je naprijed objašnjeno, predviđeno je da će antagonističko djelovanje na 5-HT1A receptorima spojeva ovog izuma spriječiti mehanizam negativnog povratnog efekta induciranog inhibicijom reapsorpcije serotonina. Tako se očekuje da će antagonističko djelovanje na 5-HT1A receptorima poboljšati djelovanje spojeva prema ovom izumu nainhibiciju reapsorpcije serotonina.
Spojevi prema ovdje iznesenim zahtjevima zato se smatraju posebno korisnima kao brzi pokretači djelovanja lijekova za liječenje depresije. Ovi spojevi mogu također biti korisni kod liječenja depresija koje ne reagiraju na trenutno raspoložive SSRI.
Farmaceeutska formulacija
Farmaceutske formulacije ovog izuma mogu se pripremiti prema metodama uobičajenima u struci. Na primjer: tablete se mogu pripremiti miješanjem aktivnog sastojka s uobičajenim pomagalima i/ili razrjeđivačima i nakon toga komprimiranjem mješavine u konvencionalnim strojevima za tabletiranje. Primjeri pomagala ili razrjeđivača su: žitarični škrob, krumpirov škrob, talk, magnezijev stearat, želatina, laktoza, smole i slično. Mogu se upotrebljavati bilo koja druga pomagala i razrjeđivači upotrebljeni u svrhu bojenja, aromatiziranja, prezervacije itd., pod uvjetom da su kompatibilni s aktivnim sastojcima.
Otopine za ubrizgavanje mogu se pripremiti otapanjem aktivnih sastojaka i eventualnih aditiva u dijelu otapala za ubrizgavanje, najbolje sterilnoj vodi, podešavanjem otopine na željeni volumen, sterilizacijom otopine i punjenjem u odgovarajuće ampule ili bočice. Mogu se dodati svi aditivi u konvencionalnoj uporabi, kao što su tonizirajući agensi, prezervati, antioksidanti itd.
Farmaceutske smjese prema ovom izumu ili one koje se proizvode u skladu s ovim izumom mogu se primjenjivati na bilo koji odgovarajući način, na primjer oralno u obliku tableta, kapsula, praška, sirupa itd. ili parenteralno u obliku otopina za ubrizgavanje. Za pripremu tih smjesa mogu se koristiti u struci dobro poznate metode, kao i bilo koji farmaceutski prihvatljiv nositelj, razrjeđivač, ekscipijent ili drugi normalno upotrebljavan aditiv u struci.
Prikladno, spojevi prema ovom izumu primjenjuju se u obliku jedinične dosaže koja sadrži navedene spojeve u količini od 0.01 do 100 mg. Ukupna dnevna doza obično se kreće između 0.05 – 500 mg, a najbolje oko 0.1 do 50 mg aktivnog spoja prema ovom izumu.
Claims (18)
1. Supstituirani 4-,5-,6- ili 7-indol ili derivat indolina naznačen time da ima formulu
[image]
gdje W predstavlja N, C, CH ili COH a iscrtkane linije prikazuju opcionalne veze i
gdje A grupa ima formulu
[image]
gdje X predstavlja CR1A, CHR1A, N, NR1B, O ili S, gdje je R1A prema definiciji za R3 do R9 u nastavku, a gdje je R1B prema definiciji za R10 u nastavku;
Y je CR2A, CHR2A, N, NR2B, O ili S, gdje je R2A prema definiciji za R3 do R9 u nastavku a gdje je R2B prema definiciji za R10 u nastavku, a
iscrtkane linije označavaju opcionalne veze;
pod uvjetom da X i Y nisu ni O ni S;
A je grupa koja ima formulu
[image]
gdje X predstavlja CR1A, CHR1A, N, NR1B, O ili S, gdje je R1A prema definiciji za R3 do R9 u nastavku, a gdje je R1B prema definiciji za R10 u nastavku;
U je C, CH ili N, a
iscrtkane linije predstavljaju opcionalne veze; ili
je A grupa koja ima formulu
[image]
gdje U predstavlja C, CH ili N;
Y je CR2A, CHR2A, N, NR2B, O ili S, gdje je R2A prema definiciji za R3 do R9 u nastavku a gdje je R2B prema definiciji za R10 u nastavku, a
iscrtkane linije označavaju opcionalne veze;
n je O, 1, 2, 3, 4, ili 5, a m je 0, 1, 2, 3, 4 ili 5.
Z je CH2, =, S, CO, SO ili SO2 pod uvjetom da ako je n O onda je Z CH2;
R3 – R9 i R11 do R12neovisno su odabrani između vodika, halogena, cijana, nitro, C1-6-alk(en/in)ila, C1-6-alkoksi, C1-6-alkitio, hidroksi, hidroksi-C1-6-alkila, C1-6-alkoksikarbonila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, C1-6-alkilkarbonila, fenokarbonila, halogenom zamijenjenog fenokarbonila, trifuorometila, trifluorometilsulfoniloksila, C1-6-alkilsulfonila, arila i heteroarila i/ili dvije susjedne grupe uzete iz R3 – R9 mogu zajedno tvoriti metilendioksi grupu,
a/ili dvije susjedne grupe R7 – R9 mogu zajedno biti grupa –NR13R14 gdje je R13 prema definiciji za R10 u nastavku a R14 je vodik, C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6 alke(en/in)il, aril, heteroaril, aril-C1-6 alkil ili heteroaril-C1-6-alkil;
R10 je
- vodik, C1-6-alk(en/in)il, C3-8cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, aril, heteroaril, aril-C1-6-alkil, acil, tioacil, C1-6-alkilsulfonil, trifluorometilsulfonil, arilsulfonil ili heteroarilsulfonil;
- R15VCO – gdje je V O ili S a R15 je C1-6-alk(en/in)il, C3-8-cikloalk(en)il, C3-8-cikloalk(en)il-C1-6-alk(en/in)il, aril ili heteroaril; ili
- grupa R16R17NCO- ili R16R17NCS- gdje su R16 i R17 neovisno odabrani između vodika, C1-6-alk(en/in)ila, C3-8-cikloalk(en)ila, C3-8-cikloalk(en)il-C1-6-alk(en/in)ila, heteroarila ili arila ili gdje R16 i R17 zajedno s N-atomom s kojim su povezani tvore pirolinidilsku, piperinidilsku, morfolinilsku ili perhidroazepinsku grupu
ili njihovu kiselinsku sol.
2. Spoj prema zahtjevu 1 naznačen time da grupa A u njemu ima formulu
[image]
gdje su X, Y, iscrtkane linije i R3 – R6 prema definiciji u zahtjevu 1.
3. Spoj prema zahtjevu 2 naznačen time da u njemu grupa A ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema definiciji u zahtjevu 2.
4. Spoj prema zahtjevu 3 naznačen time da u njemu grupa A ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema deriniciji u zahtjevu 3.
5. Spoj prema zahtjevu 1 naznačen time da ima formulu
[image]
gdje su R7 do R12, W, A, Z, n, m i iscrtkane linije prema definiciji u zahtjevu 1.
6. Spoj prema zahtjevima 1 do 5 naznačen time da u njemu Z znači CH2, a n + m je 0, 1, 2, 3, 4, 5, ili 6.
7. Spoj prema zahtjevu 1 – 6 naznačen time da u njemu W znači N.
8. Spoj prema zahtjevu 1 naznačen time da ima formulu
[image]
gdje su R7 do R12, W, Z, n, m i iscrtkane linije prema definiciji u zahtjevu 1, a A je grupa koja ima formulu
[image]
u kojoj su H, Y, iscrtkane linije i R3 – R6 prema definiciji u zahtjevu 1.
9. Spoj prema zahtjevu 8 naznačen time da u njemu grupa A ima formulu
[image]
gdje su R3 do R6 i iscrtkabe linije prema definiciji u zahtjevu 8.
10. Spoj prema zahtjevu 9 naznačen time da u njemu grupa A ima formulu
[image]
gdje su R3 do R6 i iscrtkane linije prema definiciji u zahtjevu 9.
11. Spoj prema zahtjevima 1 – 10 naznačen time da u njemu Z znači CH2, a n+m je 0, 1, 2, 3, 4, 5 ili 6, a R3 – R9 i R11 – R12 je vodik, halogen, cijano, nitro, C1-6-alkil, C1-6-alkoksi hidroksil, hidroksi-C1-6-alkil, C1-6-alkoksikarbonil i trifluorometil; a R10 je vodik.
12. Spoj prema zahtjevima 8 –11 naznačen time da u njemu W znači N.
13. Spoj prema zahtjevu 1 naznačen time da je
1-(2-(3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(3-benzofuranilmetil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-3-benzofuranil)etil)-4-(1H-indol-4yl)piperazin,
1-(4-(5-fluoro-3-benzofuranuil)-1-butil)-4-(1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(3-(1H-indol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(4-(1H-indol-3-yl)-1-butil)-4-(1H-indol-4-yl)piperazin
1-(3-(5-fluoro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(2-metil-4,5,6,7-tetrafluoro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(3-indazolil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-3-indazolil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(7-cijano-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piprazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropirin,
1-(2-(7-bromo-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(1-alil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin,
1-(1-alil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(6-kloro-1H-indol-3-yl)etil)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)etil)piperazin,
1-)1-benzil-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)etil)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(1-propargil-1H-indol-4-yl)piperazin,
1-(1-benzil-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin,
1-(2-(5-kloro-1H-indol-3-yl)etil)-4-(1H-indol-5-yl)piperazin,
1-(2-(5-fluoro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4yl)piperazin,
1-(2-(5-bromo-1H-indol-3-yl)etil)-4-(6-hidroksimetil-1H-indol-4-yl)piperazin,
1-(3-(6-fluoro-1,2-benzisoksazol-3-yl)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(2-(5-fluoro-3-benzofuranil)etil)-4-(6-metoksikarbonil-1H-indol-4-yl)piperazin,
1-(5-fluoro-3-benzoburanilmetil)-4-(1H-indol-4-yl)piperazin,
1-(3-cijano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)etil)piperazin,
1-(3-cijano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranil)etil)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,
1-(2-(3-benzofuranil)etil)-4-(cijano-1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(-metil-3-benzofuranil)etil)piperazin,
1-(1H-indol-4-yl)-4-(2-(4-metil-3-benzofuranil)etil)piperazin,
1-(3-(5-fluoro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)-1,2,3,6-tetrahidropiridin,
1-(2-(5-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(6-metil-3-benzofuranil)etil)piperazin,
1-(2-(7-kloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(3-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)-4-(1H-indol-4-yl)piperidin,
1-(2-(5-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(7-bromo-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-trifluorometil-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperazin,
1-(1H-indol-4-yl)-4-(2-(5-metil-1H-indol-3-yl)etil)piperazin,
1-(1H-indol-4-yl)-4-(2-(6-metil-1H-indol-3-yl)etil)piperazin,
1-(1H-indol-4-yl)-4-(7-metil-1H-indol-3-yl)etil)piperazin,
1-(2-(4,5-dokloro-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(5-bromo-3-benzofuranil)etil)-4-(1H-indol-4-yl)piperazin,
1-(2-(4-kloro-1H-indol-3-yl)etil)-4-(1H-indol-4-yl)piperidin,
4-(1H-.indol-4-yl)-1-(2-(5-metil-1H-indol-3yl)etil)piperidin,
4-(1H-indol-4-yl)-1-(2-(1H-indol-3-yl)etil)piperidin,
1-(1H-indol-4-yl)-4-(3-(4-metil-3-benzofuranil)-1-propil)piperazin,
4-(1H-indol-4-yl)-1-(3-(4-metil-3-benzofuranil)-1-propil)piperidin,
1-(3-(4-kloro-3-benzofuranil)-1-propil)-4-(1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-kloro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-fluoro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(6-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(7-kloro-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(7-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3yl)etil)-4-(2-cijano-1H-indol-4-yl)piperazin,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indolin-4-yl)piperazi,
1-(2-(6-kloro-1H-indol-3-yl)etil)-4-(1H-indol-6-yl)piperazin i
1-(2-(6-kloro-1H-indol-3yl)etil)-4-(1H-indol-7yl)piperazin ili
njihova farmaceutski prihvatljiva kiselinska sol.
14. Farmaceutska smjesa naznačena time da sadrži spoj prema zahtjevima 1 do 13 ili njihovu farmaceutski prihvatljivu kiselinsku sol te bar jedan farmaceutski prihvatljiv nositelj ili razrjeđivač.
15. Upotreba spoja prema zahtjevima 1 do 13 ili njihove farmaceutski prihvatljive kiselinske soli naznačena time da služi za pripremu lijeka za liječenje poremećaja ili bolesti koje uzrokuju inhibiciju reapsorpcije serotonina i antagonizam 5-HT1A receptora.
16. Upotreba spoja prema zahtjevima 1 do 13 ili njihove farmaceutski prihvatljive kiselinske soli naznačena time da služi za pripremu lijeka za liječenje afektivnih poremećaja kao što su depresija, psihoze, poremećaji u vidu tjeskobe uključujući opću tjeskobu i paniku te opsesivni kompulzivni poremećaj.
17. Metoda liječenja naznačena time da se odnosi na poremećaj ili bolest živog životinjskog tijela, uključujući čovjeka, zbog čega dolazi do inhibicije reapsorpcije serotonina i antagonizma 5-HT1A receptora uključujući primjenu na takvo živo životinjsko tijelo, ukljućujući čovjeka, terapeutski djelotvorne količine spoja prema zahtjevima 1 do 13 ili njihgove farmaceurtski prihvatljive kiselinske soli.
18. Metoda liječenja naznačena time da se odnosi na afektivni poremećaj, uključujući depresiju, psihoze, poremećaj u vidu tjeskobe uključujući opću tjeskobu I paniku te opsesivni kompulzivni poremećaj kod živog životinjskog tijela, uključujući čovjeka, koja se sastoji od primjene terapeutski djelotvorne količine spoja prema zahtjevima 1 do 13 ili njihove farmaceutski prihvatljive kiselinske soli.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DK82098 | 1998-06-19 | ||
US9282398P | 1998-07-14 | 1998-07-14 | |
PCT/DK1999/000326 WO1999067237A1 (en) | 1998-06-19 | 1999-06-14 | 4,5,6 and 7-indole and indoline derivatives, their preparation and use |
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HRP20000847A2 true HRP20000847A2 (en) | 2001-12-31 |
Family
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HR20000847A HRP20000847A2 (en) | 1998-06-19 | 2000-12-11 | 4,5,6 i 7 - INDOLE AND INDOLINE DERIVATIVES, THEIR PREPARATION AND USE |
Country Status (10)
Country | Link |
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EP (1) | EP1089997A1 (hr) |
JP (1) | JP2003521443A (hr) |
AU (1) | AU765317C (hr) |
BG (1) | BG105136A (hr) |
CA (1) | CA2335711A1 (hr) |
HR (1) | HRP20000847A2 (hr) |
HU (1) | HUP0101475A3 (hr) |
NO (1) | NO20006460L (hr) |
NZ (1) | NZ508506A (hr) |
WO (1) | WO1999067237A1 (hr) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
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ZA9711376B (en) * | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
GB9912417D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
GB9912413D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
DE60021194T2 (de) * | 1999-08-23 | 2005-12-22 | Solvay Pharmaceuticals B.V. | Phenylpiperazin-derivate als inhibitoren der serotonin-wiederaufnahme |
AR032712A1 (es) | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Un mesilato de derivados de fenilpiperazina y composiciones farmaceuticas que lo contienen |
AR032711A1 (es) * | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Derivados de fenilpiperazina, un metodo para la preparacion de los mismos y una composicion farmaceutica que los contiene |
AU2003233231B2 (en) * | 2002-05-13 | 2009-02-26 | F. Hoffmann-La Roche Ag | Benzoxazine derivatives as 5-HT6 modulators and uses thereof |
TW200409777A (en) * | 2002-08-12 | 2004-06-16 | Janssen Pharmaceutica Nv | C-substituted tricyclic isoxazoline derivatives and their use as anti-depressants |
EP1554286B1 (en) | 2002-08-15 | 2010-01-27 | Janssen Pharmaceutica N.V. | Fused heterocyclic isoxazoline derivatives and their use as anti-depressants |
WO2004020437A1 (en) * | 2002-08-29 | 2004-03-11 | H. Lundbeck A/S | S-(+)-3-{1-[2-(2,3-dihydro-1h-indol-3-yl)ethyl]-3,6-dihydro-2h-pyridin-4-yl}-6-chloro-1h-indole and acid addition salts thereof |
GB0227240D0 (en) * | 2002-11-21 | 2002-12-31 | Glaxo Group Ltd | Compounds |
US7235569B2 (en) | 2003-05-02 | 2007-06-26 | Wyeth | Piperidinyl indole and tetrohydropyridinyl indole derivatives and method of their use |
US7276603B2 (en) | 2003-05-02 | 2007-10-02 | Wyeth | Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use |
AU2005313390A1 (en) * | 2004-12-08 | 2006-06-15 | Solvay Pharmaceuticals B.V. | Aryloxyethylamine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition |
US7807671B2 (en) * | 2006-04-25 | 2010-10-05 | Bristol-Myers Squibb Company | Diketo-piperazine and piperidine derivatives as antiviral agents |
MX2009004898A (es) | 2006-11-09 | 2009-05-19 | Hoffmann La Roche | Derivados de indol y de benzofurano-2-carboxamida. |
KR20100134664A (ko) * | 2008-03-14 | 2010-12-23 | 메르크 파텐트 게엠베하 | 중추신경계 장애들의 치료를 위한 아자인돌 화합물들 |
CN103420989B (zh) * | 2012-05-15 | 2016-03-23 | 华中科技大学 | 苯并二噁烷类衍生物及其应用 |
EP3027607B1 (en) | 2013-07-29 | 2020-08-26 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use thereof |
CN105732591B (zh) * | 2014-12-31 | 2019-10-25 | 广东东阳光药业有限公司 | 取代的哌嗪化合物及其使用方法和用途 |
CN106795160B (zh) * | 2015-07-23 | 2019-04-19 | 广东东阳光药业有限公司 | 取代的吲哚化合物及其使用方法和用途 |
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GB9305641D0 (en) * | 1993-03-18 | 1993-05-05 | Merck Sharp & Dohme | Therapeutic agents |
DE4414113A1 (de) * | 1994-04-22 | 1995-10-26 | Merck Patent Gmbh | 3-Indolylpiperidine |
ZA9711376B (en) * | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
-
1999
- 1999-06-14 EP EP99926281A patent/EP1089997A1/en not_active Withdrawn
- 1999-06-14 JP JP2000555890A patent/JP2003521443A/ja not_active Withdrawn
- 1999-06-14 CA CA002335711A patent/CA2335711A1/en not_active Abandoned
- 1999-06-14 WO PCT/DK1999/000326 patent/WO1999067237A1/en not_active Application Discontinuation
- 1999-06-14 AU AU43592/99A patent/AU765317C/en not_active Ceased
- 1999-06-14 HU HU0101475A patent/HUP0101475A3/hu unknown
- 1999-06-14 NZ NZ508506A patent/NZ508506A/en unknown
-
2000
- 2000-12-11 HR HR20000847A patent/HRP20000847A2/hr not_active Application Discontinuation
- 2000-12-18 NO NO20006460A patent/NO20006460L/no not_active Application Discontinuation
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2001
- 2001-01-10 BG BG105136A patent/BG105136A/xx unknown
Also Published As
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CA2335711A1 (en) | 1999-12-29 |
AU765317C (en) | 2004-05-20 |
WO1999067237A1 (en) | 1999-12-29 |
NO20006460D0 (no) | 2000-12-18 |
HUP0101475A3 (en) | 2003-01-28 |
EP1089997A1 (en) | 2001-04-11 |
NZ508506A (en) | 2004-01-30 |
NO20006460L (no) | 2001-02-19 |
JP2003521443A (ja) | 2003-07-15 |
HUP0101475A2 (hu) | 2001-10-28 |
AU4359299A (en) | 2000-01-10 |
BG105136A (en) | 2001-09-28 |
AU765317B2 (en) | 2003-09-18 |
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