NO318610B1 - Indole and 2,3-dihydroindole derivatives, their preparation and use - Google Patents
Indole and 2,3-dihydroindole derivatives, their preparation and use Download PDFInfo
- Publication number
- NO318610B1 NO318610B1 NO20000372A NO20000372A NO318610B1 NO 318610 B1 NO318610 B1 NO 318610B1 NO 20000372 A NO20000372 A NO 20000372A NO 20000372 A NO20000372 A NO 20000372A NO 318610 B1 NO318610 B1 NO 318610B1
- Authority
- NO
- Norway
- Prior art keywords
- ethyl
- indole
- piperazin
- chloro
- benzodioxan
- Prior art date
Links
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims description 15
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims description 7
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical class C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
- 239000002253 acid Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- -1 Hydroxy, Formyl Chemical group 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 208000027534 Emotional disease Diseases 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- ZCSOSOJRZLWBHX-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC(Cl)=CC=C21 ZCSOSOJRZLWBHX-UHFFFAOYSA-N 0.000 claims description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
- 208000028017 Psychotic disease Diseases 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 208000019906 panic disease Diseases 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- ZEOHNZGZRBLBEE-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-6-chloro-1h-indole Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC=1)CCC=1C1=CC=CC2=C1OC=C2 ZEOHNZGZRBLBEE-UHFFFAOYSA-N 0.000 claims description 3
- MGSXTFHOBYGPSP-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1h-indole Chemical compound C=1NC2=CC(Cl)=CC=C2C=1CCN(CC1)CCC1C1=CC=CC2=C1OC=C2 MGSXTFHOBYGPSP-UHFFFAOYSA-N 0.000 claims description 3
- NCVSGEWRPWTQLP-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1h-indole Chemical compound C1NC2=CC=CC=C2C1CCN1CCN(C=2C=3OCCOC=3C=CC=2)CC1 NCVSGEWRPWTQLP-UHFFFAOYSA-N 0.000 claims description 3
- LDEJBPOKDDCNEC-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(OC)C=C21 LDEJBPOKDDCNEC-UHFFFAOYSA-N 0.000 claims description 3
- OKHHVISOMOASKT-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-5-methyl-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(C)C=C21 OKHHVISOMOASKT-UHFFFAOYSA-N 0.000 claims description 3
- QEWACROIUAUOPN-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-6-methyl-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC(C)=CC=C21 QEWACROIUAUOPN-UHFFFAOYSA-N 0.000 claims description 3
- XCAHSIJMFBBUAR-UHFFFAOYSA-N 3-[2-[4-(5-chloro-2,2-dimethyl-3h-1-benzofuran-7-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=CC=C2C(CCN3CCN(CC3)C=3C=C(Cl)C=C4CC(OC4=3)(C)C)=CNC2=C1 XCAHSIJMFBBUAR-UHFFFAOYSA-N 0.000 claims description 3
- CLTMVMRLBJKYCU-UHFFFAOYSA-N 5-bromo-3-[2-[4-(2h-thiochromen-8-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(Br)C=C21 CLTMVMRLBJKYCU-UHFFFAOYSA-N 0.000 claims description 3
- XLLFQXQVQYEAOE-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2h-thiochromen-8-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(Cl)C=C21 XLLFQXQVQYEAOE-UHFFFAOYSA-N 0.000 claims description 3
- DQEYMROKSMKXAE-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2h-thiochromen-8-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C1=CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC(Cl)=CC=C21 DQEYMROKSMKXAE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- KRJUFHLSRSVBPO-UHFFFAOYSA-N 1-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-5-fluoroindole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCN1C2=CC=C(F)C=C2C=C1 KRJUFHLSRSVBPO-UHFFFAOYSA-N 0.000 claims description 2
- QCGARPXKMBPGDL-UHFFFAOYSA-N 1-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCN1C2=CC=CC=C2C=C1 QCGARPXKMBPGDL-UHFFFAOYSA-N 0.000 claims description 2
- RNOOBPKDDXVVSN-UHFFFAOYSA-N 1-[2-[4-(2,3-dihydro-1-benzofuran-7-yl)piperazin-1-yl]ethyl]indole Chemical compound C1=CC2=CC=CC=C2N1CCN(CC1)CCN1C1=CC=CC2=C1OCC2 RNOOBPKDDXVVSN-UHFFFAOYSA-N 0.000 claims description 2
- VGXHXBSJXFFUKH-UHFFFAOYSA-N 1-benzyl-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-2,3-dihydroindole Chemical compound C1CN(C=2C=3OCCOC=3C=CC=2)CCN1CCC(C1=CC=CC=C11)CN1CC1=CC=CC=C1 VGXHXBSJXFFUKH-UHFFFAOYSA-N 0.000 claims description 2
- GKEJVFGHHNKBBH-UHFFFAOYSA-N 1-butyl-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]indole Chemical compound C12=CC=CC=C2N(CCCC)C=C1CCN1CCN(C=2C=3OCCOC=3C=CC=2)CC1 GKEJVFGHHNKBBH-UHFFFAOYSA-N 0.000 claims description 2
- VQJMKSUQNUFCCR-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-5-bromo-1h-indole Chemical compound C12=CC(Br)=CC=C2NC=C1CCN(CC=1)CCC=1C1=CC=CC2=C1OC=C2 VQJMKSUQNUFCCR-UHFFFAOYSA-N 0.000 claims description 2
- KNGNXSZCIGMUOJ-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1h-indole Chemical compound C12=CC(Br)=CC=C2NC=C1CCN(CC1)CCC1C1=CC=CC2=C1OC=C2 KNGNXSZCIGMUOJ-UHFFFAOYSA-N 0.000 claims description 2
- LBTDKQMYLVNDQY-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound C12=CC(F)=CC=C2NC=C1CCN(CC1)CCC1C1=CC=CC2=C1OC=C2 LBTDKQMYLVNDQY-UHFFFAOYSA-N 0.000 claims description 2
- UOHZIYMGNUPKGZ-UHFFFAOYSA-N 3-[2-[4-(1-benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1h-indole Chemical compound C12=CC(Cl)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1SC=C2 UOHZIYMGNUPKGZ-UHFFFAOYSA-N 0.000 claims description 2
- IAPCMQKVBJVLBV-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound O1CCOC2=C1C=CC=C2C(CC1)=CCN1CCC1=CNC2=CC=C(F)C=C21 IAPCMQKVBJVLBV-UHFFFAOYSA-N 0.000 claims description 2
- BZCFIGHALGNGLH-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1-prop-2-ynylindole Chemical compound C12=CC=CC=C2N(CC#C)C=C1CCN1CCN(C=2C=3OCCOC=3C=CC=2)CC1 BZCFIGHALGNGLH-UHFFFAOYSA-N 0.000 claims description 2
- VGUZWIMELPTSEJ-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(F)C=C21 VGUZWIMELPTSEJ-UHFFFAOYSA-N 0.000 claims description 2
- MKWRPOSGVSFULF-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound O1CCOC2=C1C=CC=C2C(CC1)CCN1CCC1=CNC2=CC=C(F)C=C21 MKWRPOSGVSFULF-UHFFFAOYSA-N 0.000 claims description 2
- GQFCOTAIGJVEEU-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1,4-benzodithiin-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound S1CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(F)C=C21 GQFCOTAIGJVEEU-UHFFFAOYSA-N 0.000 claims description 2
- KZSQTLWIXMAILY-UHFFFAOYSA-N 3-[2-[4-(2,3-dihydro-1-benzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound C12=CC(F)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1OCC2 KZSQTLWIXMAILY-UHFFFAOYSA-N 0.000 claims description 2
- IZLKJFICLUKLTQ-UHFFFAOYSA-N 4-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=C1C(Cl)=CC=C2 IZLKJFICLUKLTQ-UHFFFAOYSA-N 0.000 claims description 2
- PUCINGHJBLPJNE-UHFFFAOYSA-N 5-bromo-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(Br)C=C21 PUCINGHJBLPJNE-UHFFFAOYSA-N 0.000 claims description 2
- IELZPKPPDYDXQJ-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2C(CC1)=CCN1CCC1=CNC2=CC=C(Cl)C=C21 IELZPKPPDYDXQJ-UHFFFAOYSA-N 0.000 claims description 2
- SILHGCIEDCKVDB-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(Cl)C=C21 SILHGCIEDCKVDB-UHFFFAOYSA-N 0.000 claims description 2
- WBWRALWPFSWLSM-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1h-indole Chemical compound O1CCOC2=C1C=CC=C2N(CC1)CCN1CCC1CNC2=CC=C(Cl)C=C21 WBWRALWPFSWLSM-UHFFFAOYSA-N 0.000 claims description 2
- BMYUAJXMNWXTCJ-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2,3-dihydro-1-benzofuran-7-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound C12=CC(Cl)=CC=C2NC=C1CCN(CC1)CCN1C1=CC=CC2=C1OCC2 BMYUAJXMNWXTCJ-UHFFFAOYSA-N 0.000 claims description 2
- NBBNKVQKQQNAHF-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,2,5-trimethyl-3h-1-benzofuran-7-yl)piperidin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCC(CC3)C=3C=4OC(C)(C)CC=4C=C(C=3)C)=CNC2=C1 NBBNKVQKQQNAHF-UHFFFAOYSA-N 0.000 claims description 2
- LXFGWNGEPQNAST-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,2-dimethyl-3h-1-benzofuran-7-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CC=C(CC3)C=3C=CC=C4CC(OC4=3)(C)C)=CNC2=C1 LXFGWNGEPQNAST-UHFFFAOYSA-N 0.000 claims description 2
- MRCCJKYODWCEKI-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,2-dimethyl-3h-1-benzofuran-7-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C=3C=CC=C4CC(OC4=3)(C)C)=CNC2=C1 MRCCJKYODWCEKI-UHFFFAOYSA-N 0.000 claims description 2
- OROIMMGSEUXWCR-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperidin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC=C2C(CC1)CCN1CCC1=CNC2=CC(Cl)=CC=C21 OROIMMGSEUXWCR-UHFFFAOYSA-N 0.000 claims description 2
- GRBDZBGYRLKOKG-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodithiin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound S1CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC(Cl)=CC=C21 GRBDZBGYRLKOKG-UHFFFAOYSA-N 0.000 claims description 2
- AMXOSLZVTWTRKN-UHFFFAOYSA-N 6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2h-1-benzofuran-7-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C3=CC(Cl)=CC4=C3OCC4(C)C)=CNC2=C1 AMXOSLZVTWTRKN-UHFFFAOYSA-N 0.000 claims description 2
- HWVSTOSGKRUMLP-UHFFFAOYSA-N 6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydrochromen-8-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCN(CC3)C=3C=C(Cl)C=C4CCC(OC4=3)(C)C)=CNC2=C1 HWVSTOSGKRUMLP-UHFFFAOYSA-N 0.000 claims description 2
- JAQSSFCSXWMBLE-UHFFFAOYSA-N 6-chloro-3-[2-[4-(6-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound O1CCOC2=C1C=CC(Cl)=C2N(CC1)CCN1CCC1=CNC2=CC(Cl)=CC=C21 JAQSSFCSXWMBLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- BMNZIQXVNSZAAM-UHFFFAOYSA-N 3-[2-[4-(1-benzofuran-7-yl)-3,6-dihydro-2h-pyridin-1-yl]ethyl]-5-fluoro-1h-indole Chemical compound C12=CC(F)=CC=C2NC=C1CCN(CC=1)CCC=1C1=CC=CC2=C1OC=C2 BMNZIQXVNSZAAM-UHFFFAOYSA-N 0.000 claims 1
- AJYCLPLVVGLPDE-UHFFFAOYSA-N 5-chloro-3-[2-[4-(2,3-dihydro-1,4-benzodithiin-5-yl)piperazin-1-yl]ethyl]-1h-indole Chemical compound S1CCSC2=C1C=CC=C2N(CC1)CCN1CCC1=CNC2=CC=C(Cl)C=C21 AJYCLPLVVGLPDE-UHFFFAOYSA-N 0.000 claims 1
- NXQRMQIYCWFDGP-UHFFFAOYSA-N 5-fluoro-2,3-dihydro-1h-indole Chemical compound FC1=CC=C2NCCC2=C1 NXQRMQIYCWFDGP-UHFFFAOYSA-N 0.000 claims 1
- GYEPJTOCGOLUMW-UHFFFAOYSA-N 6-chloro-3-[2-[4-(2,2-dimethyl-3h-1-benzofuran-7-yl)piperidin-1-yl]ethyl]-1h-indole Chemical compound ClC1=CC=C2C(CCN3CCC(CC3)C=3C=CC=C4CC(OC4=3)(C)C)=CNC2=C1 GYEPJTOCGOLUMW-UHFFFAOYSA-N 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 47
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- 239000000243 solution Substances 0.000 description 16
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- Indole Compounds (AREA)
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Description
Foreliggende oppfinnelse vedrører nye indol- og 2,3-di-hydroindolderivater, hvilke er potente serotoninreopptaksinhibitorer, farmasøytiske sammensetninger inneholdende disse forbindelser og anvendelsen av forbindelsene for fremstilling av et medikament for behandling av forstyrrelser eller sykdommer mottakelige for inhiberingen av sero-toninopptak. Forbindelsene av oppfinnelsen besitter også antagonistaktivitet på 5-HTiR-reseptorer og er ansett for å være spesielt nyttige ved behandlingen av depresjon. The present invention relates to new indole and 2,3-dihydroindole derivatives, which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and the use of the compounds for the production of a drug for the treatment of disorders or diseases susceptible to the inhibition of serotonin uptake. The compounds of the invention also possess antagonist activity at 5-HTiR receptors and are considered to be particularly useful in the treatment of depression.
Bakgrunn Background
Selektive serotonin(eller 5-HT)reopptaksinhibitorer (SSRI-er), slik som fluoksetin, paroksetin, sertralin, fluvoksa-min og citalopram, representerer et viktig skritt fremover i behandlingen av depresjon fordi de har færre og mindre alvorlige bieffekter sammenlignet med første generasjon antidepressiva (trisykliske og ikke-selektive MAO-inhibi-torer). Bieffektene forbundet med første generasjonen antidepressiva er av en slik art at de forårsaker at noen pasienter fjernes fra behandling. Selective serotonin (or 5-HT) reuptake inhibitors (SSRIs), such as fluoxetine, paroxetine, sertraline, fluvoxamine and citalopram, represent an important step forward in the treatment of depression because they have fewer and less severe side effects compared to the first generation antidepressants (tricyclic and non-selective MAO inhibitors). The side effects associated with the first generation of antidepressants are of such a nature that they cause some patients to be withdrawn from treatment.
SSRI-er og alle andre antidepressiva som for tiden er tilgjengelige, lider under en alvorlig ulempe ved at flere ukers behandling er nødvendig for å frembringe den terapeu-tiske effekt. Den sene virkningsinntreden er et betydelig problem, spesielt ved behandlingen av pasienter med alvorlig depresjon og selvmordspotensial. Videre responderer ikke én av tre pasienter på SSRI-er. SSRIs and all other antidepressants currently available suffer from a serious disadvantage in that several weeks of treatment are necessary to produce the therapeutic effect. The late onset of action is a significant problem, especially in the treatment of patients with severe depression and suicidal potential. Furthermore, one in three patients does not respond to SSRIs.
Elektrofysiologiske eksperimenter i rotter har vist at akutt administrasjon av SSRI-er reduserer avgivelsen av 5-HT-neuroner fra dorsal raphe nucleus i gnagerhjernen, mens derimot vedvarende behandling med SSRI-er fører til normalisering av avgivelsesaktiviteten av 5-HT-neuronene (Arborelius, L. et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 1995, 352, 157; Gartside, S.E. et al., Br. J. Pharmacol., 1995, 115, 1064; Chaput, Y. et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 1986, 33, 342). Electrophysiological experiments in rats have shown that acute administration of SSRIs reduces the release of 5-HT neurons from the dorsal raphe nucleus in the rodent brain, while, on the other hand, persistent treatment with SSRIs leads to normalization of the release activity of the 5-HT neurons (Arborelius, L. et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 1995, 352, 157; Gartside, S. E. et al., Br. J. Pharmacol., 1995, 115, 1064; Chaput, Y. et al., Naunyn- Schmiedeberg's Arch. Pharmacol., 1986, 33, 342).
Videre er det blitt vist at gjenopprettelsen av avgivelsesaktiviteten av 5-HT-neuroner er knyttet til desensibiliser-ing av somatodendrittiske 5-HTiA-autoreseptorer (Le Poul, Furthermore, it has been shown that the restoration of the release activity of 5-HT neurons is linked to the desensitization of somatodendritic 5-HTiA autoreceptors (Le Poul,
E. et al., Naunyn-Schmiedeberg<1>s Arch. Pharmacol., 1995, 352, 141; Invernizzi, R. et al., Eur. J. Pharmacol., 1994, 260, 243) . E. et al., Naunyn-Schmiedeberg<1>'s Arch. Pharmacol., 1995, 352, 141; Invernizzi, R. et al., Eur. J. Pharmacol., 1994, 260, 243).
Det er således blitt foreslått at samtidig administrasjon av SSRI-er og et middel som forårsaker hurtig desensibili-sering eller inhibering av den 5-HTiA-reseptormedierte feedbackmekanisme vil føre til hurtig inntreden av antidepressiv effekt (Artigas, F. et al., Trends Neurosci., 1996, 19, 378; De Vry, J. et al., Drug News Perspec, 1996, 9, 270) . It has thus been proposed that simultaneous administration of SSRIs and an agent that causes rapid desensitization or inhibition of the 5-HTiA receptor-mediated feedback mechanism will lead to rapid onset of antidepressant effect (Artigas, F. et al., Trends Neurosci ., 1996, 19, 378; De Vry, J. et al., Drug News Perspec, 1996, 9, 270).
Effekten av kombinert administrasjon av en forbindelse som inhiberer serotoninreopptak og en 5-HTiA-reseptorantagonist, er blitt evaluert i flere studier (Innis, R.B. et al., Eur. J. Pharmacol., 1987, 143, s. 195-204, og Gartside, S.E., Br. J. Pharmacol., 1995, 115, s. 1064-1070, Blier, P. et al., Trends Pharmacol. Sei., 1994, 15, 220). I disse studiene ble det funnet at 5-HTiA-reseptorantagonis-ter inhiberer senkningen av avgivelse forårsaket ved akutt administrasjon av serotoninreopptaksinhibitorer. The effect of combined administration of a compound that inhibits serotonin reuptake and a 5-HTiA receptor antagonist has been evaluated in several studies (Innis, R.B. et al., Eur. J. Pharmacol., 1987, 143, pp. 195-204, and Gartside, S.E., Br. J. Pharmacol., 1995, 115, pp. 1064-1070, Blier, P. et al., Trends Pharmacol. Sci., 1994, 15, 220). In these studies, 5-HTiA receptor antagonists were found to inhibit the lowering of release caused by acute administration of serotonin reuptake inhibitors.
Videre har behandling med en kombinasjon av pindolol (en velkjent 5-HTiA-reseptor og p-adrenerg reseptorantagonist) og SSRI-er blitt evaluert i kliniske forsøk. En bemerkel-sesverdig forbedring av pasientenes humør ble rapportert innen 1 uke. I tillegg ble kombinert administrasjon av pindolol og en SSRI vist å ha en god effekt på pasienter som var ikke-responsive ved behandling med nåværende tilgjengelige antidepressiva (Artigas, F. et al., Arch. Gen. Psychiatry, 1994, 51, s. 248-251, og Blier, P. et al., J. Clin. Psychopharmacol., 1995, 15, s. 217-222). Furthermore, treatment with a combination of pindolol (a well-known 5-HTiA receptor and β-adrenergic receptor antagonist) and SSRIs has been evaluated in clinical trials. A remarkable improvement in the patients' mood was reported within 1 week. In addition, combined administration of pindolol and an SSRI was shown to have a good effect on patients who were unresponsive to treatment with currently available antidepressants (Artigas, F. et al., Arch. Gen. Psychiatry, 1994, 51, p. 248-251, and Blier, P. et al., J. Clin. Psychopharmacol., 1995, 15, pp. 217-222).
Flere patentsøknader er blitt inngitt, hvilke dekker anvendelsen av en kombinasjon av en 5-HTjA-antagonist og en serotoninreopptaksinhibitor for behandlingen av depresjon (se EP-A2-687 472 og EP-A2-714 663). Several patent applications have been filed covering the use of a combination of a 5-HT 1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687472 and EP-A2-714663).
I EP-A1-529 462 vises visse 1,4-benzodioksanderivater som har den generelle formel EP-A1-529 462 discloses certain 1,4-benzodioxane derivatives having the general formula
hvor B er en valgfritt substituert indol-3-yl-gruppe, og Q er CnH2n hvor n er 1, 2, 3, 4, 5 eller 6. Disse forbindelsene sies å ha serotoninagonist- og serotoninantagonistak-tivitet, samt serotoningjenopptaksinhiberende aktivitet og å være nyttige som anxiolytika, antidepressiva, antipsyko-tika, antihypertensiva og cerebrobeskyttende midler. I US-patent nr. 5 200 948, Perregaard et al., viser beslek-tede indoler, indazoler, 2-indoloner og 2,3-dihydroderi-vater derav som har formel hvor X er -CH-, -CH2-, -NH- eller -CO-; og Ar er where B is an optionally substituted indol-3-yl group, and Q is CnH2n where n is 1, 2, 3, 4, 5 or 6. These compounds are said to have serotonin agonist and serotonin antagonist activity, as well as serotonin reuptake inhibitory activity and to be useful as anxiolytics, antidepressants, antipsychotics, antihypertensives and cerebroprotective agents. In US patent no. 5,200,948, Perregaard et al., shows related indoles, indazoles, 2-indolones and 2,3-dihydroderivatives thereof having the formula where X is -CH-, -CH2-, - NH- or -CO-; and Ar is
hvor Y er 0 eller S# Z er 0, S eller -CH2-, og n er 1, 2, eller 3. where Y is 0 or S# Z is 0, S or -CH2-, and n is 1, 2, or 3.
Disse forbindelsene er verdifulle 5-HTiA-reseptorligander. These compounds are valuable 5-HTiA receptor ligands.
Oppfinnelsens mål The object of the invention
Den foreliggende oppfinnelses mål er å frembringe forbindelser med potent serotoninreopptaksinhiberende aktivitet samt antagonistiske egenskaper på 5-HTiA-reseptorer. Slike forbindelser kan være nyttige som medikamenter med hurtig virkningsinntreden for behandlingen av emosjonelle forstyrrelser, slik som depresjon. The aim of the present invention is to produce compounds with potent serotonin reuptake inhibitory activity as well as antagonistic properties on 5-HTiA receptors. Such compounds may be useful as fast-acting drugs for the treatment of emotional disorders, such as depression.
Et ytterligere mål for den foreliggende oppfinnelse er å frembringe en farmasøytisk sammensetning omfattende forbindelsene over som aktive ingredienser. A further aim of the present invention is to produce a pharmaceutical composition comprising the compounds above as active ingredients.
Oppsummering av oppfinnelsen Summary of the invention
Oppfinnelsen omfatter, inter alia, det følgende alene eller i kombinasjon: The invention includes, inter alia, the following alone or in combination:
Et indol- eller 2,3-dihydroindolderivat som har formel An indole or 2,3-dihydroindole derivative having the formula
eller et syreaddisjonssalt derav, hvor: or an acid addition salt thereof, where:
X er -0-, -S- eller -CR<4>R<5->; og X is -0-, -S- or -CR<4>R<5->; and
Y er -CR<6>R<7->, -CR<6>R<7->CR<8>R<9-> eller -CR<6>=CR<7->; eller Y is -CR<6>R<7->, -CR<6>R<7->CR<8>R<9-> or -CR<6>=CR<7->; or
X og Y danner sammen en gruppe -CR<4>=CR<5-> eller -CR^CR5-CR<6>R<7->; X and Y together form a group -CR<4>=CR<5-> or -CR^CR5-CR<6>R<7->;
Z er -0- eller -S-; Z is -0- or -S-;
Her N, C eller CH; Here N, C or CH;
A er en gruppe valgt fra en gruppe med formlene (II), (III) og (IV) A is a group selected from a group of formulas (II), (III) and (IV)
hvor den stiplede binding betyr en valgfri binding; where the dotted bond means an optional bond;
R<1>, R<2>, R<3>, R<12>, R<13>, R<14>, R<15>, R<16> og R1<7> er hver uavhengig valgt fra hydrogen, halogen, trifluormetyl, Ci-4-alkyl, C2-4-alkenyl, Ca-4-alkynyl, C3_7-sykloalkyl, Ci-4-alkoksy, hydrok-sy, formyl, -CO-Ci-4-alkyl, amino, Ci-4-alkylamino, di-Ci-4-alkylamino, -CO-Ci-4-alkylamino, Ci-4-alkoksykarbonylamino, aminokarbonylamino, Ci-4-alkylaminokarbonylamino, di-Ci-4-al-kylaminokarbonylamino, nitro og cyano; R<1>, R<2>, R<3>, R<12>, R<13>, R<14>, R<15>, R<16> and R1<7> are each independently selected from hydrogen , halogen, trifluoromethyl, C1-4-alkyl, C2-4-alkenyl, C1-4-alkynyl, C3-7-cycloalkyl, C1-4-alkoxy, hydroxy, formyl, -CO-C1-4-alkyl, amino, Ci-4-alkylamino, di-Ci-4-alkylamino, -CO-Ci-4-alkylamino, Ci-4-alkoxycarbonylamino, aminocarbonylamino, Ci-4-alkylaminocarbonylamino, di-Ci-4-alkylaminocarbonylamino, nitro and cyano ;
R<4>, R<5>, R<6>, R<7>, R<8> og R<9> er hver uavhengig valgt fra hydrogen og Ci-4-alkyl; og R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are each independently selected from hydrogen and C 1-4 alkyl; and
R<11> velges fra hydrogen, Ci_4-alkyl, C2-4-alkenyl, C2-4-alky-nyl, C3_7-sykloalkyl, fenyl, naftyl, fenyl-Ci-4-alkyl, naftyl-Ci-4-alkyl, -CO-Ci-4-alkyl og formyl. R<11> is selected from hydrogen, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, C3-7-cycloalkyl, phenyl, naphthyl, phenyl-C1-4-alkyl, naphthyl-C1-4-alkyl, -CO-Ci-4-alkyl and formyl.
I én utførelse av oppfinnelsen er Z -0-, og de andre substituentene er som definert over. In one embodiment of the invention, Z is -0-, and the other substituents are as defined above.
I en annen utførelse av oppfinnelsen er Z -S-, og de andre substituentene er som definert over. In another embodiment of the invention, Z is -S-, and the other substituents are as defined above.
I en tredje utførelse av oppfinnelsen er A en gruppe med formel (II), og de andre substituentene er som definert over. In a third embodiment of the invention, A is a group of formula (II), and the other substituents are as defined above.
I en fjerde utførelse av oppfinnelsen er A en gruppe med formel (III), og de andre substituentene er som definert over. In a fourth embodiment of the invention, A is a group of formula (III), and the other substituents are as defined above.
I en femte utførelse av oppfinnelsen er A en gruppe med formel (IV), og de andre substituentene er som definert over. In a fifth embodiment of the invention, A is a group of formula (IV), and the other substituents are as defined above.
I en spesiell utførelse av oppfinnelsen er således A en gruppe med formel (II), og Z er -0-; A er en gruppe med formel (III), og Z er -0-; A er en gruppe med formel (IV), og Z er -0-; A er en gruppe med formel (II), og Z er -S-; A er en gruppe med formel (III), og Z er -S-; eller A er en gruppe med formel (IV), og Z er -S-. In a particular embodiment of the invention, A is thus a group of formula (II), and Z is -0-; A is a group of formula (III), and Z is -O-; A is a group of formula (IV), and Z is -O-; A is a group of formula (II), and Z is -S-; A is a group of formula (III), and Z is -S-; or A is a group of formula (IV), and Z is -S-.
I en ytterligere utførelse av oppfinnelsen er R<4>, R<5>, R6, R<7>, R<8> og R9 valgt fra hydrogen eller metyl. In a further embodiment of the invention, R<4>, R<5>, R6, R<7>, R<8> and R9 are selected from hydrogen or methyl.
Eksempler på forbindelser i henhold til oppfinnelsen er: 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, Examples of compounds according to the invention are: 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-brom-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,
3-(2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2-metyl-lH-indol 3-(2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indole
6-klor-3-[2-[4-(2,2,5-trimetyl-2,3-dihydrobenzofuran-7-yl)-piperidin-l-yl]etyl]-lH-indol, 6-chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)-piperidin-1-yl]ethyl]-1H-indole,
3-[2-[4-{1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-4-klor-lH-indol, 3-[2-[4-{1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole,
6-klor-3-[2-[4-(2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)- 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-
piperidin-l-yl]etyl]-lH-indol, piperidin-1-yl]ethyl]-1H-indole,
6-klor-3-[2-[4-(2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-l-pyridyl]etyl]-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indol, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indole , 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-metoksy-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-metyl-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-metyl-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(5-klor-2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)piperazin-l-yl] etyl]-lH-indol, 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
6-klor-3-[2-[4-(5-klor-3,3-dimetyl-2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-lH-indol, 6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
6-klor-3-[2-[4-(6-klor-2,2-dimetyl-3,4-dihydro-2H-l-benzo-pyran-8-yl)piperazin-l-yl]etyl]-lH-indol, 6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzo-pyran-8-yl)piperazin-1-yl]ethyl]- 1H-indole,
6-klor-3-[2-[4-(2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)piperazin-l-yl] etyl]-lH-indol, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-4-metyl-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-methyl-1H-indole,
3-[2-[4-(7-klor-l,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(7-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
2- [2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 2-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3- [2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-2,3-dihydroindol 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-2,3-dihydroindole
6-klor-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]-etyl]-lH-indol, 6-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]-ethyl]-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)-1,2,3,6-tetrahydro-l-pyri-dyl] etyl]-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydro-1-pyridyl] ethyl]-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperidin-l-yl]etyl]-6-klor- 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-
lH-indol, 1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(benzofuran-7-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(benzofuran-7-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(1,3-benzodioksan-4-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(1,3-benzodioxan-4-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
6-klor-3-[2-[4-(6-klor-l,4-benzodioksan-5-yl)piperazin-l-yl] etyl] -lH-indol, 6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole,
5- klor-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]-etyl]-lH-indol, 5-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]-ethyl]-1H-indole,
3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(benzotiofen-7-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, 3-[2-[4-(benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, 3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl]-5-brom-lH-indol, 3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole,
3-{2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl}-6-klor-lH-indol, 3-{2-[4-(benzothiopyran-8-yl)piperazin-1-yl]ethyl}-6-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]etyl]-5-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperidin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperidin-l-yl]etyl]-5-klor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-(1,4-benzodioksan-5-yl)piperidin-l-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,
6- klor-3- [2- [4- (.2, 3-dihydrobenzofuran-7-yl) -1,2, 3, 6-tetra-hydropyridin-l-yl]etyl]-1-indol, 6-chloro-3-[2-[4-(.2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetra-hydropyridin-1-yl]ethyl]-1-indole,
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-l-yl]-etyl]-6-klor-lH-indol, 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl]-6-chloro-1H-indole,
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-l-yl]-etyl]-5-brom-lH-indol, 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl]-5-bromo-1H-indole,
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-l-yl]- 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]-
etyl]-5-fluor-lH-indol, ethyl]-5-fluoro-1H-indole,
3-[2-[4-(benzofuran-7-yl)piperidin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole,
3- [2- [4- (benzofuran-7-yl)piperidin-l-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(benzofuran-7-yl)piperidin-l-yl]etyl]-5-brom-lH-indol, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole,
l-acetyl-3-[2-[4-{1,4-benzodioksan-4-yl)piperazin-l-yl]-etyl]-2,3-dihydro-lH-indol, 1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indol, 1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1H-indol, 1-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2,3-di-hydro-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2,3-di-hydro-5-fluor-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-klor-2, 3-dihydro-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1-butyl-lH-indol, l-allyl-3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]-etyl]-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1-propargyl-lH-indol, 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2,3-di-hydro-l-methyl-lH-indol, 3-[2-[4-{1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1-benzyl-2,3-dihydro-lH-indol, l-allyl-3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]-etyl]- 2,3-dihydro-lH-indol, l-acetyl-3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]-etyl]-lH-indol, 1-acetyl-3-[2-[4-{1,4-benzodioxan-4-yl)piperazin-1-yl]-ethyl]-2,3-dihydro-1H-indole, 1-[2-[4 -(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin- 1-yl]ethyl]-6-chloro-1H-indole, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole, 1-[ 2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin- 1-yl]ethyl]-2,3-dihydro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3 -dihydro-5-fluoro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2, 3-dihydro -1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-butyl-1H-indole, 1-allyl-3-[2- [4-(1,4-benzodioxan-5-yl)piperazin-1-yl]-ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1 -yl]ethyl]-1-propargyl-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro- 1-methyl-1H-indole, 3-[2-[4-{1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-benzyl-2,3-dihydro-1H-indole, 1-allyl-3-[2-[4-(1,4-benzo dioxan-5-yl)piperazin-1-yl]-ethyl]- 2,3-dihydro-1H-indole, l-acetyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazine -1-yl]-ethyl]-1H-indole,
3-[2-[4-(benzo-1,4-ditian-5-yl)piperazin-l-yl]etyl]-5-klor- 3-[2-[4-(benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-chloro-
lH-indol, 1H-indole,
3-[2-[4-{benzo-1,4-ditian-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, 3-[2-[4-{benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole,
3-[2-[4-{benzo-1,4-ditian-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-{benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
3-[2-[4-(benzo-l-thia-4-oksan-5-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, 3-[2-[4-(benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole,
3-[2-[4-{benzo-l-thia-4-oksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, og 3-[2-[4-{benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, and
3-[2-[4-{benzo-l-thia-4-oksan-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indol, 3-[2-[4-{benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,
eller et syreaddisjonssalt derav. or an acid addition salt thereof.
Oppfinnelsen vedrører også en farmasøytisk sammensetning omfattende en forbindelse med formel (I) eller et farmasøy-tisk akseptabelt salt derav, og minst én farmasøytisk ak-septabel bærer eller et fortynningsmiddel. The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or a diluent.
En forbindelse med formel (I) eller et farmasøytisk akseptabelt syreaddisjonssalt derav kan anvendes i behandlingen av en forstyrrelse eller sykdom mottakelig for inhiberingen av serotoninreopptak og antagonisme av 5-HTiA-reseptorer. A compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof can be used in the treatment of a disorder or disease susceptible to the inhibition of serotonin reuptake and antagonism of 5-HTiA receptors.
Spesielt vedrører oppfinnelsen anvendelsen av en forbindelse i henhold til oppfinnelsen eller et farmasøytisk akseptabelt syreaddisjonssalt derav, for fremstillingen av et medikament for behandlingen av emosjonelle forstyrrelser, slik som depresjon, psykose, angstforstyrrelser, inklusive generell angstforstyrrelse, panikkforstyrrelse eller obsessiv-kompulsiv forstyrrelse. In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a drug for the treatment of emotional disorders, such as depression, psychosis, anxiety disorders, including general anxiety disorder, panic disorder or obsessive-compulsive disorder.
Forbindelsene av oppfinnelsen kan anvendes i en fremgangsmåte ved behandlingen av en forstyrrelse eller sykdom i en levende animalsk kropp, inklusive et menneske, som er mottakelig for inhiberingen av serotonin- reopptak og antagonisme av 5-HTiA-reseptorer, omfattende å administrere til en slik levende animalsk kropp, inklusive et menneske, en terapeutisk effektiv mengde av en forbindelse med formel (I) eller et farmasøytisk akseptabelt syreaddisjonssalt derav. The compounds of the invention can be used in a method for the treatment of a disorder or disease in a living animal body, including a human, which is susceptible to the inhibition of serotonin reuptake and antagonism of 5-HTiA receptors, comprising administering to such living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
Spesielt kan forbindelsen benyttes i en fremgangsmåte ved behandling av emosjonelle forstyrrelser, slik som depresjon, psykoser, angstforstyrrelser, inklusive generell angstforstyrrelse, panikkforstyrrelse eller obsessiv-kompulsiv forstyrrelse, omfattende å administrere en terapeutisk effektiv mengde av en forbindelse med formel (I) eller et farmasøytisk akseptabelt syreaddisjonssalt derav til en levende animalsk kropp, inklusive et menneske, som trenger dette. In particular, the compound can be used in a method for the treatment of emotional disorders, such as depression, psychosis, anxiety disorders, including general anxiety disorder, panic disorder or obsessive-compulsive disorder, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical acceptable acid addition salt thereof to a living animal body, including a human, in need thereof.
På grunn av deres kombinerte antagonisme av 5-HTiA-reseptorer og serotoninreopptaksinhiberende effekt er forbindelsene av oppfinnelsen ansett å være spesielt nyttige som medikamenter med hurtig virkningsinntreden ved behandlingen av depresjon. Forbindelsene kan også være nyttige ved behandlingen av depresjon hos pasienter som er resistente mot behandling med nåværende tilgjengelig antidepressiva. Because of their combined antagonism of 5-HTiA receptors and serotonin reuptake inhibitory effect, the compounds of the invention are considered to be particularly useful as fast-acting drugs in the treatment of depression. The compounds may also be useful in the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
Forbindelsene krevd her, er ansett spesielt nyttige ved behandlingen av depresjon som krever hurtig inntreden av antidepressiv effekt, eller en depresjon som er resistent mot andre antidepressiva. The compounds claimed herein are considered particularly useful in the treatment of depression which requires rapid onset of antidepressant effect, or a depression which is resistant to other antidepressants.
Halogen betyr fluor, klor, brom eller jod. Halogen means fluorine, chlorine, bromine or iodine.
Ci_4-alkyl betyr en rett eller forgrenet kjede av 1-4 karbonatomer, inklusive f.eks. metyl, etyl, propyl, isopro-pyl og butyl. Ci_4-alkyl means a straight or branched chain of 1-4 carbon atoms, including e.g. methyl, ethyl, propyl, isopropyl and butyl.
C2-4~alkenyl betyr en kjede av fra 2 til 4 karbonatomer inneholdende en dobbeltbinding, inklusive f.eks. etenyl, 1-,2-propenyl, 2-,3-propenyl etc. C2-4~alkenyl means a chain of from 2 to 4 carbon atoms containing a double bond, including e.g. ethenyl, 1-,2-propenyl, 2-,3-propenyl etc.
C2-4-alkynyl betyr en kjede av fra 2 til 4 karbonatomer inneholdende en trippelbinding, inklusive f.eks. etynyl, 1-,2-propynyl, 2-,3-propynyl etc. C2-4-alkynyl means a chain of from 2 to 4 carbon atoms containing a triple bond, including e.g. ethynyl, 1-,2-propynyl, 2-,3-propynyl etc.
C3-7-sykloalkyl betyr syklisk alkyl med fra 3 til 7 karbonatomer, inklusive syklopropyl, syklobutyl etc. C3-7-cycloalkyl means cyclic alkyl with from 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl etc.
Ci-4-alkoksy er -0-Ci_4-alkyl, hvor Ci-4-alkyl er som definert over. C1-4-Alkoxy is -O-C1-4-alkyl, where C1-4-alkyl is as defined above.
Ci-4-alkylamino betyr -NH-Ci-4-alkyl, og di-C^-alkylamino betyr -N- (Cx_4-alkyl) 2, hvor Ci_4-alkyl er som definert over. C1-4-alkylamino means -NH-C1-4-alkyl, and di-C1-4-alkylamino means -N-(C1-4-alkyl) 2 , where C1-4-alkyl is as defined above.
Acylamino betyr -NH-acyl, hvor acyl er som definert over. Acylamino means -NH-acyl, where acyl is as defined above.
Ci-4-alkoksykarbonylamino betyr Ci-4-alkyl-O-CO-NH-, hvor Ci-4-alkyl er som definert over. C1-4-Alkoxycarbonylamino means C1-4-alkyl-O-CO-NH-, where C1-4-alkyl is as defined above.
Ci_4-alkylaminokarbonylamino betyr Ci-4-alkyl-NH-CO-NH-, hvor Ci-4-alkyl er som definert over. C1-4-alkylaminocarbonylamino means C1-4-alkyl-NH-CO-NH-, where C1-4-alkyl is as defined above.
Di-Ci-4-alkylaminokarbonylamino betyr (Ci-4-alkyl) 2-NH-CO--NH-, hvor Ci_4-alkyl er som definert over. Di-Ci-4-alkylaminocarbonylamino means (Ci-4-alkyl) 2-NH-CO--NH-, where Ci-4-alkyl is as defined above.
Aryl-Ci_4-alkyl betyr aryl-Ci-4-alkyl, hvor aryl og Ci-4-alkyl er som definert over. Aryl-Ci-4-alkyl means aryl-Ci-4-alkyl, where aryl and Ci-4-alkyl are as defined above.
Eksempler på organiske syreaddisjonssalter i henhold til oppfinnelsen er de med malein-, fumar-, benzo-, askorbin-, rav-, oksal-, bis-metylensalisyl-, metansulfon-, etandisul-fon-, eddik-, propion-, vin-, salisyl-, sitron-, glukon-, melke-, eple-, mandel-, kanel-, citrakon-, asparagin-, stearin-, palmitin-, itakon-, glykol-, p-aminobenzo-, glu-tamin-, benzensulfon- og teofyllineddiksyrer, samt 8-halo-teofyllinene, f.eks. 8-bromteofyllin. Eksempler på uorga-niske syreaddisjonssalter i henhold til oppfinnelsen er de med salt-, hydrobrom-, svovel-, sulfam-, fosfor- og salpe-tersyrer. Syreaddisjonssaltene av oppfinnelsen er fortrinnsvis farmasøytisk akseptable salter dannet med ikke-toksiske syrer. Examples of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, amber, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, vinic , salicylic, lemon, glucone, milk, apple, almond, cinnamon, citracone, asparagine, stearin, palmitin, itacone, glycol, p-aminobenzo, glutamine, benzenesulphonic and theophylline acetic acids, as well as the 8-halo-theophyllines, e.g. 8-bromotheophylline. Examples of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Videre kan forbindelsene av oppfinnelsen eksistere i usolvatiserte samt i solvatiserte former med farmasøytisk akseptable løsemidler, slik som vann, etanol og lignende. Generelt er solvatformene betraktet ekvivalente med de usolvatiserte former for oppfinnelsens formål. Furthermore, the compounds of the invention can exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents, such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.
Forbindelsene av oppfinnelsen kan fremstilles ved én av de følgende fremgangsmåter, omfattende: a) å redusere karbonylgruppene til en forbindelse med formel The compounds of the invention can be prepared by one of the following methods, comprising: a) reducing the carbonyl groups to a compound of formula
hvor R1-!*3, R12, R14-R<17>, X, Y, W og den stiplede linje er som definert over; where R1-!*3, R12, R14-R<17>, X, Y, W and the dotted line are as defined above;
b) å alkylere et amin med formel b) to alkylate an amine of formula
hvor R<1->R<3>, X, Y, Z, W og den stiplede linje er som definert over, med et reagens med formel G-CH2-A, hvor A er som definert over, og G er et egnet utgående gruppe, slik som halogen, mesylat, eller tosylat; c) å reduktivt alkylere et amin med formel where R<1->R<3>, X, Y, Z, W and the dotted line are as defined above, with a reagent of formula G-CH2-A, where A is as defined above, and G is a suitable leaving group, such as halogen, mesylate, or tosylate; c) reductively alkylating an amine of formula
hvor Rx<->R<3>, X, Y, Z, W og den stiplede linje er som definert over, med et reagens med formel B-CH2-A, hvor A er som definert over, og B er enten et aldehyd eller en karboks-ylsyregruppe; where Rx<->R<3>, X, Y, Z, W and the dotted line are as defined above, with a reagent of formula B-CH2-A, where A is as defined above, and B is either an aldehyde or a carboxylic acid group;
d) å redusere dobbeltbindingen i indoler med formel d) to reduce the double bond in indoles of formula
hvor R<1->R<3>, X, Y, Z, W og den stiplede linje er som definert over og A' er en gruppe med formel (II), (III) eller (IV) som over, hvor den stiplede linje representerer en binding, for å oppnå de tilsvarende 2,3-dihydroindolderi-vater; e) å redusere dobbeltbindingen i tetrahydropyridinene med formel hvor R<1->!*<3>, A, X, Y og Z er som tidligere definert, for å oppnå de tilsvarende piperidinderivater; f) å behandle en forbindelse med generell formel (I) hvor Y er -CR<6>=CR<7->, eller hvor X og Y sammen danner en gruppe -CR<4>=CR<5-> eller -CR<4>=CR<5->CR<6>R<7>, med et reduksjonsmiddel for å redusere dobbeltbindingen, for derved å oppnå et tilsvarende redusert ringsystem; g) reduktiv fjerning av én eller flere av substituentene R<1->R<3> eller R12-R<17> i en forbindelse med generell formel (I), where R<1->R<3>, X, Y, Z, W and the dotted line are as defined above and A' is a group of formula (II), (III) or (IV) as above, where the dashed line represents a bond, to obtain the corresponding 2,3-dihydroindole derivatives; e) to reduce the double bond in the tetrahydropyridines of formula where R<1->!*<3>, A, X, Y and Z are as previously defined, to obtain the corresponding piperidine derivatives; f) treating a compound of general formula (I) where Y is -CR<6>=CR<7->, or where X and Y together form a group -CR<4>=CR<5-> or -CR <4>=CR<5->CR<6>R<7>, with a reducing agent to reduce the double bond, thereby obtaining a correspondingly reduced ring system; g) reductive removal of one or more of the substituents R<1->R<3> or R12-R<17> in a compound of general formula (I),
hvor én eller flere av disse substituenter er valgt fra klor, brom eller jod; wherein one or more of these substituents is selected from chlorine, bromine or iodine;
h) å dialkylere et amin med formel h) to dialkylate an amine of formula
hvor R^R3, X, Y og Z er som definert over, med et reagens where R^R3, X, Y and Z are as defined above, with a reagent
med formel with formula
hvor A er som definert over, og G er en egnet utgående gruppe, slik som halogen, mesylat eller tosylat; where A is as defined above, and G is a suitable leaving group, such as halogen, mesylate or tosylate;
i) å dialkylere et amin med formel i) to dialkylate an amine of formula
hvor A er som definert over, med et reagens med formel hvor R<1->!*<3>, X, Y, Z og W er definert over, og G er en egnet utgående gruppe, slik som halogen, mesylat eller tosylat; eller j) å alkylere eller acylere indolnitrogenatomet til forbindelser med formel where A is as defined above, with a reagent of formula where R<1->!*<3>, X, Y, Z and W are defined above, and G is a suitable leaving group, such as halogen, mesylate or tosylate ; or j) to alkylate or acylate the indole nitrogen atom to compounds of formula
hvor Rx<->R<3>, X, Y, Z, W og den stiplede linje er som definert over, og A" er en gruppe valgt fra en gruppe med formel (III) eller (IV) som over, hvor R<11> er hydrogen, med et alkylerings- eller acyleringsreagens med formel Rll-G, hvor G er en egnet utgående gruppe, slik som halogen, mesylat eller tosylat, og R<11> er som definert over, men ikke er hydrogen; where Rx<->R<3>, X, Y, Z, W and the dashed line are as defined above, and A" is a group selected from a group of formula (III) or (IV) as above, wherein R <11> is hydrogen, with an alkylating or acylating reagent of formula R11-G, where G is a suitable leaving group, such as halogen, mesylate or tosylate, and R<11> is as defined above, but is not hydrogen;
hvorved forbindelsene med formel (I) isoleres som den frie base eller i form av et syreaddisjonssalt derav. whereby the compounds of formula (I) are isolated as the free base or in the form of an acid addition salt thereof.
Reduksjonen i henhold til fremgangsmåte a) utføres fortrinnsvis i et inert, organisk løsemiddel, slik som dietyleter eller tetrahydrofuran, i nærvær av litiumaluminiumhydrid ved reflukstemperatur. Startforbindelsene med formel (V) fremstilles generelt fra reagenser med formel (VI), 1,3-usubstituerte indoler og oksalylklorid, som beskrevet i eksemplene som følger. The reduction according to method a) is preferably carried out in an inert, organic solvent, such as diethyl ether or tetrahydrofuran, in the presence of lithium aluminum hydride at reflux temperature. The starting compounds of formula (V) are generally prepared from reagents of formula (VI), 1,3-unsubstituted indoles and oxalyl chloride, as described in the examples that follow.
Alkyleringen i henhold til fremgangsmåte b) utføres hensiktsmessig i et inert, organisk løsemiddel, slik som en passe kokende alkohol eller et keton, fortrinnsvis i nærvær av en base (kaliumkarbonat eller trietylamin) ved reflukstemperatur . The alkylation according to method b) is suitably carried out in an inert, organic solvent, such as a suitably boiling alcohol or a ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature.
Arylpiperazinderivater med formel (VI) fremstilles hensiktsmessig fra det tilsvarende arylamin i henhold til fremgangsmåten beskrevet av Martin et al., J. Med. Chem., 1989, 32, 1052, eller fremgangsmåten beskrevet av Kruse et al., Ree. Trav. Chim. Pays-Bas, 1988, 107, 303. Startarylaminene er enten kommersielt tilgjengelige eller de er godt beskrevet i litteraturen. Arylpiperazine derivatives of formula (VI) are conveniently prepared from the corresponding arylamine according to the method described by Martin et al., J. Med. Chem., 1989, 32, 1052, or the method described by Kruse et al., Ree. Trot. Chim. Pays-Bas, 1988, 107, 303. The starting arylamines are either commercially available or they are well described in the literature.
Aryltetrahydropyridinderivater med formel (VI) er kjent fra litteraturen, jf. US-Patent nr. 2 891 066; McElvain et al., J. Amer. Chem. Soc, 1959, 72, 3134. Hensiktsmessig litieres det tilsvarende arylbromid med BuLi, etterfulgt av tilsetning av l-benzyl-4-piperidon. Etterfølgende behandling med syre gir N-benzylaryltetrahydropyridinet. Benzylgruppen kan fjernes ved katalytisk hydrogenering eller ved behandling med f.eks. etylklorformiat for å gi det tilsvarende etylkarbamat, etterfulgt av sur eller basisk hydrolyse. Startarylbromidene er enten kommersielt tilgjengelige eller de er godt beskrevet i litteraturen. Aryltetrahydropyridine derivatives of formula (VI) are known from the literature, cf. US Patent No. 2,891,066; McElvain et al., J. Amer. Chem. Soc, 1959, 72, 3134. Conveniently, the corresponding aryl bromide is lithiated with BuLi, followed by addition of 1-benzyl-4-piperidone. Subsequent treatment with acid gives the N-benzylaryltetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to give the corresponding ethyl carbamate, followed by acid or basic hydrolysis. The starting aryl bromides are either commercially available or they are well described in the literature.
Reagenser med formel G-CHZCH2-A er enten kommersielt tilgjengelige eller kan fremstilles ved litteraturfremgangs-måter, f.eks. fra det tilsvarende eddiksyrederivat ved reduksjon til 2-hydroksyetylderivatet og konversjon av hyd-roksygruppen til gruppen G ved konvensjonelle fremgangsmåter . Reagents of formula G-CHZCH2-A are either commercially available or can be prepared by literature procedures, e.g. from the corresponding acetic acid derivative by reduction to the 2-hydroxyethyl derivative and conversion of the hydroxy group to the group G by conventional methods.
Den reduktive alkylering i henhold til fremgangsmåte c) ut-føres ved standard litteraturmetoder. Reaksjonen kan ut-føres i to trinn, det vil si kobling av (VI) og reagenset med formel B-CH2-A ved standardmetoder via karboksylsyre-kloridet, eller ved anvendelse av koblingsreagenser, slik som f.eks. disykloheksylkarbodiimid, etterfulgt av reduksjon av det resulterende amid med litiumaluminiumhydrid. Reaksjonen kan også utføres ved en standard "one-pot"-pro-sedyre. Karboksylsyrer eller aldehyder med formel B-CH2-A er enten kommersielt tilgjengelige eller beskrevet i litteraturen . The reductive alkylation according to method c) is carried out by standard literature methods. The reaction can be carried out in two steps, i.e. coupling of (VI) and the reagent of formula B-CH2-A by standard methods via the carboxylic acid chloride, or by using coupling reagents, such as e.g. dicyclohexylcarbodiimide, followed by reduction of the resulting amide with lithium aluminum hydride. The reaction can also be carried out by a standard "one-pot" procedure. Carboxylic acids or aldehydes with the formula B-CH2-A are either commercially available or described in the literature.
Reduksjon av indoldobbeltbindingen i henhold til fremgangsmåte d) utføres hensiktsmessig ved behandling med diboran eller en diboranforløper, slik som trimetylamin, eller dimetylsulfidkomplekset, i et inert løsemiddel, slik som f.eks. tetrahydrofuran eller dioksan, fra 0 °C til reflukstemperatur, etterfulgt av sur katalytisk hydrolyse av intermediatboranderivatet. Reduksjonen kan alternativt ut-føres ved behandling med natriumcyanborhydrid i trifluoreddiksyre. Reduction of the indole double bond according to method d) is conveniently carried out by treatment with diborane or a diborane precursor, such as trimethylamine, or the dimethyl sulphide complex, in an inert solvent, such as e.g. tetrahydrofuran or dioxane, from 0 °C to reflux temperature, followed by acid catalytic hydrolysis of the intermediate borane derivative. The reduction can alternatively be carried out by treatment with sodium cyanoborohydride in trifluoroacetic acid.
Reduksjon av dobbeltbindingene i henhold til fremgangsmåtene e) og f) utføres mest hensiktsmessig ved hydrogenering i en alkohol i nærvær av en edelmetallkatalysator, slik som f.eks. platina eller palladium. Reduction of the double bonds according to methods e) and f) is most conveniently carried out by hydrogenation in an alcohol in the presence of a noble metal catalyst, such as e.g. platinum or palladium.
Fjerning av halogensubstituenter i henhold til fremgangsmåte g) utføres hensiktsmessig ved katalytisk hydrogenering i en alkohol i nærvær av en palladiumkatalysator, eller ved behandling med ammoniumformiat i en alkohol ved hevede temperaturer i nærvær av en palladiumkatalysator. Removal of halogen substituents according to method g) is suitably carried out by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst, or by treatment with ammonium formate in an alcohol at elevated temperatures in the presence of a palladium catalyst.
Dialkylering av aminer i henhold til fremgangsmåtene h) og i) utføres mest hensiktsmessig ved hevede temperaturer i et inert løsemiddel, slik som f.eks- klorbenzen, toluen, N-me-tylpyrrolidon, dimetylformamid eller acetonitril. Reaksjonen kan utføres i nærvær av en base, slik som f.eks. kaliumkarbonat eller trietylamin. Startmaterialene for pro-sessene h) og i) er kommersielt tilgjengelige, eller kan fremstilles fra kommersielt tilgjengelige materialer ved å anvende konvensjonelle fremgangsmåter. Dialkylation of amines according to methods h) and i) is most conveniently carried out at elevated temperatures in an inert solvent, such as e.g. chlorobenzene, toluene, N-methylpyrrolidone, dimethylformamide or acetonitrile. The reaction can be carried out in the presence of a base, such as e.g. potassium carbonate or triethylamine. The starting materials for the processes h) and i) are commercially available, or can be produced from commercially available materials by using conventional methods.
N-alkyleringen i henhold til fremgangsmåte j) utføres i et inert løsemiddel, slik som f.eks. en alkohol eller et keton, ved hevede temperaturer i nærvær av base, f.eks. kaliumkarbonat eller trietylamin, ved reflukstemperatur. Alternativt kan et faseoverføringsreagens anvendes. The N-alkylation according to method j) is carried out in an inert solvent, such as e.g. an alcohol or a ketone, at elevated temperatures in the presence of a base, e.g. potassium carbonate or triethylamine, at reflux temperature. Alternatively, a phase transfer reagent can be used.
De følgende eksempler vil illustrere oppfinnelsen ytterligere . The following examples will further illustrate the invention.
Eksempler Examples
Halogen-, metyl- eller metoksysubstituerte indoler anvendt som beskrevet i eksempel 1, er kommersielt tilgjengelige. Halogen-, methyl- or methoxy-substituted indoles used as described in Example 1 are commercially available.
Substituerte 2-(1-indolyl)eddiksyrer anvendt som beskrevet i eksempel 3, fremstilles fra den tilsvarende substituerte indol og etylbromacetat ved konvensjonelle fremgangsmåter. Substituted 2-(1-indolyl)acetic acids used as described in example 3 are prepared from the correspondingly substituted indole and ethyl bromoacetate by conventional methods.
Substituerte 3-(2-brometyl)indoler anvendt som beskrevet i eksempel 2, fremstilles fra den tilsvarende 2-(1-indolyl)-eddiksyreester ved reduksjon til alkoholen med litiumaluminiumhydrid og etterfølgende behandling med tetrabromme-tan/trifenylfosfin i henhold til standard litteraturmetoder. Substituted 3-(2-bromomethyl)indoles used as described in example 2 are prepared from the corresponding 2-(1-indolyl)-acetic acid ester by reduction to the alcohol with lithium aluminum hydride and subsequent treatment with tetrabromoethane/triphenylphosphine according to standard literature methods.
Arylpiperaziner anvendt som beskrevet i eksempler 1, 2 og 3, fremstilles fra det tilsvarende arylamin i henhold til fremgangsmåten beskrevet av Martin et al., J. Med. Chem., 32 (1989), 1052, eller fremgangsmåten beskrevet av Kruse et al., Ree. Trav. Chim. Pays-Bas, 107 (1988), 303. Arylpiperazines used as described in Examples 1, 2 and 3 are prepared from the corresponding arylamine according to the method described by Martin et al., J. Med. Chem., 32 (1989), 1052, or the method described by Kruse et al., Ree. Trot. Chim. Pays-Bas, 107 (1988), 303.
Startarylaminene er enten kommersielt tilgjengelige eller er beskrevet i litteraturen som følger: Syntesen av 5-amino-l,4-benzodioksan er beskrevet av Dauksas et al., Zh. Org. Khim., 3 (1967), 1121. De tilsvarende klorerte derivater lages på en tilsvarende måte. Syntesen av 7-amino-2,3-dihydrobenzofuran er beskrevet i US patentsøknad nr. 4302592. The starting arylamines are either commercially available or are described in the literature as follows: The synthesis of 5-amino-1,4-benzodioxane is described by Dauksas et al., Zh. Org. Khim., 3 (1967), 1121. The corresponding chlorinated derivatives are prepared in a similar manner. The synthesis of 7-amino-2,3-dihydrobenzofuran is described in US patent application no. 4302592.
Syntesen av 7-aminobenzofuran er beskrevet av Van Wijngaarden et al., J. Med. Chem., 31 (1988), 1934. The synthesis of 7-aminobenzofuran is described by Van Wijngaarden et al., J. Med. Chem., 31 (1988), 1934.
Syntesen av 7-aminobenzo[b]tiofen er beskrevet av Boswell et al-, J. Heterocycl. Chem., 5 (1968) 69. The synthesis of 7-aminobenzo[b]thiophene is described by Boswell et al., J. Heterocycl. Chem., 5 (1968) 69.
7- amino-2,3-dimetylbenzofuran og de tilsvarende 5-klor- og 5-metylderivater fremstilles i henhold til tysk tilgjengelig DE 3526510. 7-amino-2,3-dimethylbenzofuran and the corresponding 5-chloro and 5-methyl derivatives are prepared according to German available DE 3526510.
4-aminobenzotiopyran ble fremstilt i henhold til europeisk patentsøknad EP 79683. 4-aminobenzothiopyran was prepared according to European patent application EP 79683.
8- amino-6-klor-2,2-dimetylbenzopyran ble fremstilt ved kon-vensjonell nitrering av 6-klor-2,2-dimetylbenzopyran (fremstilt i henhold til Bolzoni et al., Angew. Chem., 90 8-amino-6-chloro-2,2-dimethylbenzopyran was prepared by conventional nitration of 6-chloro-2,2-dimethylbenzopyran (prepared according to Bolzoni et al., Angew. Chem., 90
(1978), 727-) med etterfølgende reduksjon av det oppnådde 8-nitroderivat. På en tilsvarende måte ble 7-amino-5-klor-3,3-dimetylbenzofuran oppnådd fra 5-klor-3,3-dimetylbenzo-furan (fremstilt i henhold til europeisk patentsøknad EP 7719800206). De tilsvarende deklorderivater ble oppnådd ved behandling med hydrogengass i nærvær av en edelmetallkatalysator i henhold til standardprosedyrer. (1978), 727-) with subsequent reduction of the obtained 8-nitro derivative. In a similar way, 7-amino-5-chloro-3,3-dimethylbenzofuran was obtained from 5-chloro-3,3-dimethylbenzofuran (prepared according to European patent application EP 7719800206). The corresponding dechloro derivatives were obtained by treatment with hydrogen gas in the presence of a noble metal catalyst according to standard procedures.
Aryltetrahydropyridinderivater er kjent fra litteraturen (jf. US-patent nr. 2 891 066, eller McElvain et al., J. Amer. Chem. Soc, 12 (1959), 3134). Mest hensiktsmessig litieres det tilsvarende arylbromid med BuLi, etterfulgt av tilsetning av l-benzyl-4-piperidon. Etterfølgende behandling med mineralsyre eller trifluoreddiksyre gir N-benzylaryltetrahydropyridinet. Benzylgruppen kan fjernes ved katalytisk hydrogenering eller ved behandling med f.eks. etylklorformiat til det tilsvarende etylkarbamat, etterfulgt av sur eller basisk hydrolyse. De tilsvarende piperidinderivater kan oppnås ved reduktiv fjerning av dobbeltbindingen i tetrahydropyridinringen. Alle disse prosedyrer er velkjente for fagmannen. Startarylbromidene er godt beskrevet i litteraturen. På denne måten ble 4-(1,4-benzodioksan-5-yl)-1,2,3,6-tetrahydropyridin, 4-(2,3-dihydro-2,2-dimetylbenzofuran-7-yl)-1,2,3,6-tetrahydropyridin, 4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin, 4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin og de tilsvarende piperidiner oppnådd. Aryltetrahydropyridine derivatives are known from the literature (cf. US Patent No. 2,891,066, or McElvain et al., J. Amer. Chem. Soc, 12 (1959), 3134). Most expediently, the corresponding aryl bromide is lithiated with BuLi, followed by the addition of 1-benzyl-4-piperidone. Subsequent treatment with mineral acid or trifluoroacetic acid gives the N-benzylaryltetrahydropyridine. The benzyl group can be removed by catalytic hydrogenation or by treatment with e.g. ethyl chloroformate to the corresponding ethyl carbamate, followed by acid or basic hydrolysis. The corresponding piperidine derivatives can be obtained by reductive removal of the double bond in the tetrahydropyridine ring. All of these procedures are well known to those skilled in the art. The starting aryl bromides are well described in the literature. In this way, 4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridine, 4-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1, 2,3,6-tetrahydropyridine, 4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridine, 4-(benzofuran-7-yl)-1,2,3,6- tetrahydropyridine and the corresponding piperidines obtained.
Smeltepunkter ble bestemt på et Biichi SMP-20-apparat og er ukorrigerte. Massespektre ble tatt opp på et Quattro MS-MS-system fra VG Biotech, Fisons Instruments. MS-MS-systemet var tilknyttet et HP 1050-modular-HPLC-system. Et volum på 20-50 (al av prøven (10 ug/ml) løst i en blanding av 1 % ed-diksyre i acetonitril/vann 1:1 ble introdusert via auto-prøvetakeren i en strøm på 30 (xl/minutt inn i elektrospray-kilden. Spektrene ble oppnådd ved to standardsett med operasjonsbetingelser. Ett sett for å oppnå molekylvektin-formasjon (MH+) (21 eV) og det andre settet for å indusere fragmenteringsmønstre (70 eV). Bakgrunnen ble trukket fra. De relative intensiteter av ionene oppnås fra fragmen-teringsmønstre. Når ingen intensitet var indikert for mole-kylionet (MH+), var dette ionet til stede bare under det første settet med operasjonsbetingelser. lH-NMR-spektre ble tatt opp av alle nye forbindelser ved 250 MHz på en Bruker AC 250 eller ved 500 MHz på en Bruker DRX 500. Deuterert kloroform (99,8 % D) eller dimetylsulfoksid (99,9 % D) ble anvendt som løsemidler. TMS ble anvendt som intern referan-sestandard. Kjemiske skift uttrykkes som ppm-verdier. De følgende forkortelser anvendes for multiplisitet av NMR-signaler: s = singlett, d = dublett, t = triplett, q = kvartett, qui = kvintett, h = heptett, dd = dobbeldublett, dt = dobbeltriplett, dq = dobbelkvartett, tt = triplett av tripletter, m = multiplett. NMR-signaler som tilsvarer sure protoner, er generelt utelatt. Vanninnholdet i krystallinske forbindelser ble bestemt ved Karl Fischer-titrering. Standard opparbeidingsprosedyrer refererer til ekstraksjon med det indikerte organiske løsemiddel fra riktige vandige løsninger, tørking av kombinerte organiske ekstrakter (vannfritt MgS04 eller NaS04), filtrering og inndamping av løsemidlet i vakuum. For kolonnekromatografi ble silikagel av typen Kieselgel 60, 230-400 mesh ASTM anvendt. Melting points were determined on a Biichi SMP-20 apparatus and are uncorrected. Mass spectra were recorded on a Quattro MS-MS system from VG Biotech, Fisons Instruments. The MS-MS system was coupled to an HP 1050 modular HPLC system. A volume of 20-50 µl of the sample (10 µg/ml) dissolved in a mixture of 1% acetic acid in acetonitrile/water 1:1 was introduced via the auto-sampler at a flow of 30 µl/minute into the electrospray source. The spectra were obtained at two standard sets of operating conditions. One set to obtain molecular weight formation (MH+) (21 eV) and the other set to induce fragmentation patterns (70 eV). The background was subtracted. The relative intensities of ions are obtained from fragmentation patterns. When no intensity was indicated for the molecular ion (MH+), this ion was present only under the first set of operating conditions. 1H-NMR spectra were recorded of all new compounds at 250 MHz on a Bruker AC 250 or at 500 MHz on a Bruker DRX 500. Deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) were used as solvents. TMS was used as the internal reference standard. Chemical shifts are expressed as ppm -values The following abbreviations are used for multiplicity of NMR signals ler: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet. NMR signals corresponding to acidic protons are generally omitted. The water content of crystalline compounds was determined by Karl Fischer titration. Standard work-up procedures refer to extraction with the indicated organic solvent from appropriate aqueous solutions, drying of combined organic extracts (anhydrous MgSO 4 or NaSO 4 ), filtration and evaporation of the solvent in vacuo. For column chromatography, silica gel of the type Kieselgel 60, 230-400 mesh ASTM was used.
Eksempel 1 Example 1
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 5- klor-lH- indoloksalat 3-[ 2-[ 4-( 1, 4- benzodioxan- 5- yl) piperazin- 1- yl] ethyl]- 5- chloro- 1H- indoloxalate
En løsning av 5-klorindol (5,0 g) i dietyleter (130 ml) ble avkjølt til 0 °C under en nitrogenatmosfære, etterfulgt av dråpevis tilsetning av en løsning med oksalylklorid (4,6 g) i dietyleter (20 ml). Etter omrøring i 16 timer ble det krystallinske produkt, 2-(5-klor-lH-indol-3-yl)-2-oksoace-tylklorid samlet ved filtrering (7,2 g). A solution of 5-chloroindole (5.0 g) in diethyl ether (130 mL) was cooled to 0 °C under a nitrogen atmosphere, followed by dropwise addition of a solution of oxalyl chloride (4.6 g) in diethyl ether (20 mL). After stirring for 16 hours, the crystalline product, 2-(5-chloro-1H-indol-3-yl)-2-oxoacetyl chloride, was collected by filtration (7.2 g).
En løsning av dette produktet (2,0 g) i tørt tetrahydrofuran (25 ml) ble tilsatt dråpevis til en blanding av 1-(1,4-benzodioksan-5-yl)piperazin (1,2 g) og trietylamin (7,5 ml) i tetrahydrofuran (75 ml) ved romtemperatur. Blandingen ble omrørt i 16 timer, etterfulgt av filtrering og fjerning av løsemidlet i vakuum for å gi ubehandlet 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]-1,2-dioksoetyl]-5-klor-lH-indol som et fast stoff. Dette produktet ble løst i tetrahydrofuran {25 ml) og tilsatt dråpevis til en suspensjon av litiumaluminiumhydrid (2,1 g) i tetrahydrofuran ved romtemperatur under en nitrogenatmosfære. Etter refluks i 3,5 timer ble reaksjonen stoppet med vandig natriumhydroksid, etterfulgt av standardopparbeiding med etylacetat. Den resulterende olje ble renset ved flashkromatografi (eluent: heptan/etanol/etylacetat/trietylamin 15:2:2:1). Oksalat-saltet ble erholdt fra en acetonløsning ved tilsetning av oksalsyre og omkrystallisering fra metanol/tetrahydrofuran (1:5), som ga 0,8 g av la, smp. 224-28 °C. A solution of this product (2.0 g) in dry tetrahydrofuran (25 mL) was added dropwise to a mixture of 1-(1,4-benzodioxan-5-yl)piperazine (1.2 g) and triethylamine (7, 5 mL) in tetrahydrofuran (75 mL) at room temperature. The mixture was stirred for 16 h, followed by filtration and removal of the solvent in vacuo to give crude 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]-1,2- dioxoethyl]-5-chloro-1H-indole as a solid. This product was dissolved in tetrahydrofuran (25 mL) and added dropwise to a suspension of lithium aluminum hydride (2.1 g) in tetrahydrofuran at room temperature under a nitrogen atmosphere. After refluxing for 3.5 hours, the reaction was quenched with aqueous sodium hydroxide, followed by standard work-up with ethyl acetate. The resulting oil was purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine 15:2:2:1). The oxalate salt was obtained from an acetone solution by addition of oxalic acid and recrystallization from methanol/tetrahydrofuran (1:5), which gave 0.8 g of 1a, m.p. 224-28 °C.
<1>H-NMR (DMSO-d6): 3,05 (t, 2 H); 3,10-3,50 (m, 10 H); 4,15-4,30 (m, 4 H); 6,50 (d, 1 H); 6,55 (d, 1 H); 6,75 (t, 1 H); 7,10 (d, 1 H); 7,30 (s, 1 H); 7,40 (d, 1 H); 7,65 (s, 1 H); 11,15 (s, 1 H). <1>H-NMR (DMSO-d 6 ): 3.05 (t, 2 H); 3.10-3.50 (m, 10 H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.10 (d, 1H); 7.30 (s, 1H); 7.40 (d, 1H); 7.65 (s, 1H); 11.15 (p, 1 H).
MS m/z (%): 398 (MH+, 9 %), 233 (100 %), 221 (29 %) , 218 (19 %), 178 (59 %). MS m/z (%): 398 (MH+, 9%), 233 (100%), 221 (29%), 218 (19%), 178 (59%).
De følgende forbindelser ble fremstilt analogt: 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-brom-lH-indoloksalat, lb, smp. 236-40 40 °C. <1>H-NMR (DMSO-d6) : 3,10 (t, 2 H) ; 3,15-3,45 (m, 10 H) ; 4,15-4,30 (m, 4 H); 6,50 (d, 1 H) ; 6,60 (d, 1 H) ; 6,75 (t, 1 H) ; 7,20 (d, 1 H); 7,30 (s, 1 H); 7,35 (d, 1 H); 7,80 (s, 1 H); 11,20 (s, 1 H). MS m/z (%): 444 (MH+, 5 %), 442 {5 %), 233 (80 %), 224 (21 %), 222 (22 %), 221 (25 %), 218 (23 %), 190 (19 %), 70 (100 %). 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2-metyl-lH-indoloksalat, lc, smp. 205-8 °C. <1>H-NMR (DMSO-ds) : 2,35 (s, 3 H.) ; 2,95-3,15 (m, 4 H) ; 3,15-3,45 (m, 8 H); 4,15-4,30 (m, 4 H); 6,50 (d, 1 H); 6,60 (d, 1 H); 6,75 (t, 1 H), 6,95 (t, 1 H); 7,00 (t, 1 H); 7,25 (d, 1 H); 7,50 (d, 1 H); 10,85 (s, 1 H) . MS m/z (%): 378 (MH+, 5 %), 233 (9 %), 221 (7 %) , 218 (5 %), 158 (100 %). 6-klor-3-[2-[4-(2,2,5-trimetyl-2,3-dihydrobenzofuran-7-yl)-piperidin-l-yl]etyl]-lH-indol fumarat, ld, smp. 232-37 °C. Hi-NMR (DMSO-de) : 1,40 (s, 6 H) ; 1, 65-1,85 (m, 4 H) ; 2,20 (s, 3 H); 2,30 (t, 2 H); 2,60 (t, 2 H); 2,70-2,85 (m, 3 H); 2,90 (s, 3 H); 3,10-3,30 (m, 2 H); 6,60 (s, 2 H); 6,70 (s, 1 H); 6,80 (s, 1 H); 7,00 (d, 1 H); 7,20 (s, 1 H); 7,35 (s, 1 H); 7,55 (d, 1 H) ; 10,95 (s, 1 H) . The following compounds were prepared analogously: 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indoloxalate, 1b, m.p. 236-40 40 °C. <1>H-NMR (DMSO-d6) : 3.10 (t, 2H); 3.15-3.45 (m, 10 H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 7.35 (d, 1H); 7.80 (s, 1H); 11.20 (p, 1H). MS m/z (%): 444 (MH+, 5%), 442 {5%), 233 (80%), 224 (21%), 222 (22%), 221 (25%), 218 (23% ), 190 (19%), 70 (100%). 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indoloxalate, 1c, m.p. 205-8°C. <1>H-NMR (DMSO-ds): 2.35 (s, 3 H.); 2.95-3.15 (m, 4H); 3.15-3.45 (m, 8H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H), 6.95 (t, 1H); 7.00 (h, 1 H); 7.25 (d, 1H); 7.50 (d, 1H); 10.85 (s, 1H) . MS m/z (%): 378 (MH+, 5%), 233 (9%), 221 (7%), 218 (5%), 158 (100%). 6-chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)-piperidin-1-yl]ethyl]-1H-indole fumarate, ld, m.p. 232-37 °C. Hi-NMR (DMSO-de): 1.40 (s, 6 H); 1.65-1.85 (m, 4H); 2.20 (s, 3H); 2.30 (t, 2H); 2.60 (t, 2H); 2.70-2.85 (m, 3H); 2.90 (s, 3H); 3.10-3.30 (m, 2H); 6.60 (s, 2H); 6.70 (s, 1H); 6.80 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (pp, 1H) .
MS m/z (%): 423 (MH+, 11 %), 258 (100 %), 178 (14 %), 70 (41 %) . MS m/z (%): 423 (MH+, 11%), 258 (100%), 178 (14%), 70 (41%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-4-klor-lH-indoloksalat, le, smp. 210-18 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indoloxalate, le, m.p. 210-18 °C.
^-NMR (DMSO-de): 3,10-3,50 (m, 12 H) ; 4,10-4,30 (m, 4 H) ; 6,50 (d, 1 H); 6,60 (d, 1 H); 6,75 (t, 1 H); 7,00 (d, 1 H); 7,05 (t, 1 H); 7,30-7,40 (m, 2 H); 11,40 (s, 1 H). 3-NMR (DMSO-de): 3.10-3.50 (m, 12 H); 4.10-4.30 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.00 (d, 1H); 7.05 (t, 1H); 7.30-7.40 (m, 2H); 11.40 (p, 1 H).
MS m/z {%): 398 (MH+, 10 %), 233 (100 %), 221 (47 %), 218 (18 %) , 180 (25 %) , 178 (84 %) . MS m/z {%): 398 (MH+, 10%), 233 (100%), 221 (47%), 218 (18%), 180 (25%), 178 (84%).
6-klor-3-[2-[4-(2,2,-dimetyl-2,3-dihydrobenzofuran-7-yl)-piperidin-l-yl]etyl]-lH-indoloksalat, lf, smp. 190-93 °C. <X>H-NMR (DMSO-de): 1,40 (s, 6 H) ; 1,75-, 1,95 (m, 4 H) , 2,50-2,70 (m, 2 H); 2,70-2,80 (m, 1 H); 2,85-3,05 (m, 6 H); 3,25-3,40 (m, 2 H); 6,75 (t, 1 H); 6,95 (d, 1 H); 6,95-7,10 (m, 2 H); 7,25 (s, 1 H); 7,40 (s, 1 H); 7,55 (d, 1 H); 11,00 (s, 1 H). 6-chloro-3-[2-[4-(2,2,-dimethyl-2,3-dihydrobenzofuran-7-yl)-piperidin-1-yl]ethyl]-1H-indoloxalate, mp, m.p. 190-93 °C. <X>H-NMR (DMSO-de): 1.40 (s, 6 H); 1.75-, 1.95 (m, 4H), 2.50-2.70 (m, 2H); 2.70-2.80 (m, 1H); 2.85-3.05 (m, 6H); 3.25-3.40 (m, 2H); 6.75 (t, 1H); 6.95 (d, 1H); 6.95-7.10 (m, 2H); 7.25 (s, 1H); 7.40 (s, 1H); 7.55 (d, 1H); 11.00 (p, 1 H).
MS m/z (%): 409 (M H+, 6 %), 244 (100 %), 232 (9 %), 178 (16 %). MS m/z (%): 409 (M H+, 6%), 244 (100%), 232 (9%), 178 (16%).
6-klor-3-[2-[4-(2,2-dimetyl-2,3-dihydrohydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-l-pyridyl]etyl]-lH-indoloksalat, lg, smp. 200-4 °C. 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrohydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl]-1H-indoloxalate , lg, m.p. 200-4 °C.
<1>H-NMR (DMSO-de): 1,40 (s, 6 H) ; 2, 70-2, 80 (m, 2 H) ; 3,00 (s, 2 H); 3,15 (t, 2 H); 3,30 (t, 2 H); 3,35-3,50 (m, 2 H); 3,85-4,00 (m, 2 H); 6,35 (s, 1 H); 6,85 (t, 1 H); 7,00 (d, 1 H); 7,05-7,15 (m, 2 H); 7,30 (s, 1 H); 7,40 (s, 1 H); <1>H-NMR (DMSO-de): 1.40 (s, 6 H); 2.70-2.80 (m, 2H); 3.00 (p, 2H); 3.15 (t, 2H); 3.30 (t, 2H); 3.35-3.50 (m, 2H); 3.85-4.00 (m, 2H); 6.35 (s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.05-7.15 (m, 2H); 7.30 (s, 1H); 7.40 (s, 1H);
7,60 (d, 1 H) ; 11,15 (s, 1 H) . 7.60 (d, 1H); 11.15 (p, 1H) .
MS m/z (%): 407 (MH+, 2 %), 207 (8 %), 180 (33 %), 178 MS m/z (%): 407 (MH+, 2%), 207 (8%), 180 (33%), 178
(100 %). (100%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indoloksalat, lh, smp. 224-26 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoloxalate, 1h, m.p. 224-26 °C.
<1>H-NMR (DMS0-d6): 3,10 (t, 2 H) ; 3,10-3,50 (m, 10 H) ; 4,15-4,35 (m, 4 H); 6,50 (d, 1 H) ; 6,60 (d, 1 H) ; 6,75 (t, 1 H) ; 6,95 (t, 1 H); 7,30 (s, 1 H); 7,30-7,50 (m, 2 H); 11,10 (s, 1 H). <1>H-NMR (DMS0-d6): 3.10 (t, 2H); 3.10-3.50 (m, 10 H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 6.95 (t, 1H); 7.30 (s, 1H); 7.30-7.50 (m, 2H); 11.10 (p, 1H).
MS m/z (%): 382 (MH+, 9 %), 233 (78 %), 221 (30 %), 218 MS m/z (%): 382 (MH+, 9%), 233 (78%), 221 (30%), 218
(22 %), 190 (20 %), 162 (97 %), 70 (100 %). (22%), 190 (20%), 162 (97%), 70 (100%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-me-toksy-lH-indolhemioksalat, li, smp. 189-96 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1H-indole hemioxalate, 1i, m.p. 189-96 °C.
<1>H-NMR (DMSO-de): 3,00 (t, 2 H) ; 3,05-3,30 (m, 10 H) ; 3,80 (s, 3 H); 4,15-4,35 (m, 4 H) ; 6,50 (d, 1 H) ; 6,55 (d, 1 H) ; 6,70-6,80 (m, 2 H); 7,10 (s, 1 H); 7,15 (s, 1 H); 7,25 (d, 1 H); 10,70 (s, 1 H). <1>H-NMR (DMSO-de): 3.00 (t, 2 H); 3.05-3.30 (m, 10 H); 3.80 (s, 3H); 4.15-4.35 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.70-6.80 (m, 2H); 7.10 (s, 1H); 7.15 (s, 1H); 7.25 (d, 1H); 10.70 (p, 1H).
MS m/z (%): 394 (MH+, 7 %), 233 (79 %), 218 (21 %), 190 (21 %) , 174 (61 %), 70 (100 %). MS m/z (%): 394 (MH+, 7%), 233 (79%), 218 (21%), 190 (21%), 174 (61%), 70 (100%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-metyl-lH-indolhemifumarat, lj, smp. 147-54 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indole hemifumarate, m.p. 147-54 °C.
<1>H-NMR (DMSO-de): 2,40 (s, 3 H) ; 2,60-2,80 (m, 6 H) ; 2,85 (t, 2 H); 2,95-3,15 (m, 4 H); 4,15-4,30 (m, 4 H); 6,45 (d, 1 H); 6,50 (d, 1 H); 6,60 (s, 1 H); 6,70 (t, 1 H); 6,90 (d, <1>H-NMR (DMSO-de): 2.40 (s, 3 H); 2.60-2.80 (m, 6H); 2.85 (t, 2H); 2.95-3.15 (m, 4H); 4.15-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 6.90 (d,
1 H); 7,10 (s, 1 H); 7,20 (d, 1 H); 7,30 (s, 1 H); 10,65 (s, 1 H) . 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-metyl-lH-indolhemifumarat, lk, smp. 204-7 °C. <1>H-NMR (DMSO-de): 2,35 (s, 3 H) ; 2,60-2,80 (m, 6 H) ; 2,90 (t, 2 H); 2,95-3,15 (rn, 4 H); 4,10-4,30 (m, 4 H); 6,45 (d, 1 H); 6,50 (d, 1 H) ; 6,60 (s, 1 H) ; 6,70 (t, 1 H) ; 6,80 (d, 1 H); 7,05 (s, 1 H); 7,10 (s, 1 H) ; 7,40 (d, 1 H) ; 10,60 (s, 1 H). 6-klor-3-[2-[4-(7-klor-l,4-benzodioksan-5-yl)piperazin-l-yl] etyl] -lH-indoloksalat, 11, smp. 237-38 °C. <1>H-NMR (DMSO-de): 3,00-3,15 (m, 2 H) ; 3,15-3,40 (m, 10 H) ; 4,20 (s, 4 H); 6,50 (d, 1 H); 6,65 (d, 1 H); 7,00 (dd, 1 H); 7,25 (d, 1 H); 7,40 (d, 1 H); 7,60 (d, 1 H); 10,95 (s, 1 H) . 1H); 7.10 (s, 1H); 7.20 (d, 1H); 7.30 (s, 1H); 10.65 (s, 1H) . 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indole hemifumarate, lk, m.p. 204-7 °C. <1>H-NMR (DMSO-de): 2.35 (s, 3 H); 2.60-2.80 (m, 6H); 2.90 (t, 2H); 2.95-3.15 (rn, 4H); 4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1 H); 6.70 (t, 1 H); 6.80 (d, 1H); 7.05 (s, 1H); 7.10 (p, 1 H); 7.40 (d, 1H); 10.60 (p, 1H). 6-chloro-3-[2-[4-(7-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl] ethyl] -1H-indoloxalate, 11, m.p. 237-38 °C. <1>H-NMR (DMSO-de): 3.00-3.15 (m, 2H); 3.15-3.40 (m, 10 H); 4.20 (s, 4H); 6.50 (d, 1H); 6.65 (d, 1H); 7.00 (dd, 1 H); 7.25 (d, 1H); 7.40 (d, 1H); 7.60 (d, 1H); 10.95 (pp, 1H) .
MS m/z (%): 432 (MH+, 3 %), 267 (42 %), 252 (12 %), 224 MS m/z (%): 432 (MH+, 3%), 267 (42%), 252 (12%), 224
(10 %), 178 (27 %), 70 (100 %). (10%), 178 (27%), 70 (100%).
6-klor-3-[2-[4-(6-klor-l,4-benzodioksan-5-yl)piperazin-l-yl] etyl] -lH-indoloksalat, lm, smp. 216-17 °C. 6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl] ethyl] -1H-indoloxalate, lm, m.p. 216-17 °C.
<1>H-NMR (DMSO-de): 2,60 (t, ?H) ; 2,85 (t, 2 H) ; 3,10 (b, <1>H-NMR (DMSO-de): 2.60 (t, ?H); 2.85 (t, 2H); 3.10 (b,
4 H); 3,30 (s, 4 H); 4,15-4,30 (m, 4 H); 6,15 (d, 1 H); 6,35 (d, 1 H); 7,00 (dd, 1 H); 7,20 (d, 1 H); 7,35 (d, 1 H); 7,55 (d, 1 H); 10,95 (s, 1 H). 4H); 3.30 (s, 4H); 4.15-4.30 (m, 4H); 6.15 (d, 1H); 6.35 (d, 1H); 7.00 (dd, 1 H); 7.20 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.95 (pp, 1 H).
MS m/z {%): 432 (MH+, 2 %), 267 (47 %), 252 (16 %), 224 (16 %) , 178 (30 %), 70 (100 %). MS m/z {%): 432 (MH+, 2%), 267 (47%), 252 (16%), 224 (16%), 178 (30%), 70 (100%).
5- klor-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl] etyl] -lH-indoloksalat, ln, smp. 134-38 °C. 5-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indoloxalate, ln, m.p. 134-38 °C.
<1>H-NMR (DMSO-de): 2, 65-2,80 (m, 6 H) ; 2,90 (t, 2 H) ; 3,00-3,25 (m, 6 H); 4,50 (t, 2 H); 6,60 (s, 1 H); 6,65 (d, 1 H); 6,75 (t, 1 H); 6,85 (d, 1 H); 7,05 (d, 1 H); 7,25 (s, 1 H); 7,35 (d, 1 H); 7,60 (s, 1 H); 11,05 (s, 1 H). <1>H-NMR (DMSO-de): 2.65-2.80 (m, 6 H); 2.90 (t, 2H); 3.00-3.25 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.05 (d, 1H); 7.25 (s, 1H); 7.35 (d, 1H); 7.60 (s, 1H); 11.05 (p, 1 H).
MS m/z (%): 382 (MH+), 217 (39 %), 205 (17 %), 178 (38 %), 143 (11 %), 70 (100 %). MS m/z (%): 382 (MH+), 217 (39%), 205 (17%), 178 (38%), 143 (11%), 70 (100%).
6- klor-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]-etyl]-lH-indoloksalat, lo, smp. 205-7 °C. 6-Chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]-ethyl]-1H-indoloxalate, lo, m.p. 205-7°C.
<1>H-NMR (DMSO-de): 2, 60-2,75 (m, 6 H) ; 2,90 (t, 2 H) ; 3,00-3,20 (m, 6 H); 4,50 (t, 2 H); 6,60 (s, 1 H); 6,65 (d, 1 H); 6,75 (t, 1 H); 6,80 (d, 1 H); 6,95 (d, 1 H); 7,20 (s, 1 H); 7,35 (s, 1 H); 7,55 (d, 1 H); 10,95 (s, 1 H). <1>H-NMR (DMSO-de): 2.60-2.75 (m, 6 H); 2.90 (t, 2H); 3.00-3.20 (m, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.80 (d, 1H); 6.95 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (pp, 1H).
MS m/z (%): 382 (MH+), 217 (33 %), 202 (18 %), 70 (100 %). MS m/z (%): 382 (MH+), 217 (33%), 202 (18%), 70 (100%).
3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-5-fluor-lH-indoloksalat, lp, smp. 145-49 °C. 3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoloxalate, mp, m.p. 145-49 °C.
<1>H-NMR (DMSO-de): 2,65-2,85 (m, 6 H) ; 2,90 (t, 2 H) ; 3,00- <1>H-NMR (DMSO-de): 2.65-2.85 (m, 6 H); 2.90 (t, 2H); 3.00-
3,20 (rn, 6 H); 4,50 (t, 2 H); 6,60 (s, 1 H); 6,65 <d, 1 H); 6.75 (t, 1 H); 6,85 (d, 1 H) ; 6,90 (t, 1 H) ; 7,25 (s, 1 H) ; 7,25-7,35 (m, 2 H); 10,95 {s, 1 H). 3.20 (rn, 6H); 4.50 (t, 2H); 6.60 (s, 1H); 6.65 <d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 6.90 (t, 1 H); 7.25 (s, 1 H); 7.25-7.35 (m, 2H); 10.95 {p, 1H).
MS m/z (%): 366 (MH+, 4 %), 217 (31 %), 205 (18 %), 174 MS m/z (%): 366 (MH+, 4%), 217 (31%), 205 (18%), 174
(16 %), 162 (81 %) 70 (100 %). (16%), 162 (81%) 70 (100%).
3-[2-[4-(benzotiofen-7-yl)piperazin-l-yl]etyl]-5-klor-lH-indoloksalat, lq, smp. 175,2-176,6 °C. 3-[2-[4-(benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indoloxalate, 1q, m.p. 175.2-176.6 °C.
<1>H-NMR (DMSO-d6): 3,10 (m, 2 H) , 3,26 (m, 2 H) , 3,38-3,36 (m, 6 H), 7,05 (d, 1 H), 7,09 (d, 1 H), 7,33 (s, 1 H), 7, 40-7,37 (m, 3 H) , 7,47 (d, 1 H) , 7,62 (d, 1 H) , 7,69 (s, 1 H), 7,76 (d, 1 H). <1>H-NMR (DMSO-d6): 3.10 (m, 2H) , 3.26 (m, 2H) , 3.38-3.36 (m, 6H), 7.05 ( d, 1H), 7.09 (d, 1H), 7.33 (s, 1H), 7.40-7.37 (m, 3H), 7.47 (d, 1H), 7.62 (d, 1H), 7.69 (s, 1H), 7.76 (d, 1H).
MS m/z 398,1 (MH+, 1,1 % (37C1) ) , 396,1 (MH+, 2,8 % (35C1) ) , 230,9 (1005), 177,8 (58 %), 69,8 (50,8 %). MS m/z 398.1 (MH+, 1.1% (37C1) ), 396.1 (MH+, 2.8% (35C1) ), 230.9 (1005), 177.8 (58%), 69 .8 (50.8%).
3-[2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl]-5-klor-lH-indol, lr, smp. 152-153 °C. 3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 1r, m.p. 152-153 °C.
<1>H-NMR (CDC13): 2,08 (rn, 2 H) , 2,75 (m, 6 H) , 2,83 (rn, <1>H-NMR (CDCl 3 ): 2.08 (rn, 2 H), 2.75 (m, 6 H), 2.83 (rn,
2 H), 2,98 (rn, 4 H) , 3,05 (m, 2 H) , 6,80 (d, 1 H) , 6,99-6,94 (m, 2 H), 7,08 (s, 1 H), 7,14 (d, 2 H), 7,26 (d, 1 H), 7,59 (s, 1 H), 8,00 (s, 1 H). 2H), 2.98 (rn, 4H) , 3.05 (m, 2H) , 6.80 (d, 1H) , 6.99-6.94 (m, 2H), 7, 08 (s, 1 H), 7.14 (d, 2 H), 7.26 (d, 1 H), 7.59 (s, 1 H), 8.00 (s, 1 H).
MS m/z 412,3 (MH+, 100 % (35C1) ) , 414,5 (MH+, 63,% (37C1) ) , 247, 1 (23, 7 %) . MS m/z 412.3 (MH + , 100% (35Cl) ), 414.5 (MH + , 63.% (37Cl) ), 247.1 (23.7%).
3-[2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl]-5-brom-lH-indol, ls, smp. 166-167 °C. 3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole, ls, m.p. 166-167 °C.
<X>H-NMR (CDCI3) : 2,04 (m, 2 H), 2,75 (m, 6 H), 2,82 (m, <X>H-NMR (CDCl 3 ) : 2.04 (m, 2 H), 2.75 (m, 6 H), 2.82 (m,
2 H), 2,98 (m, 4 H), 3,05 (m, 4 H), 6,81 (d, 1 H), 6,98-6,93 (m, 2 H), 7,05 (s, 1 H) , 7,21 (d, 1 H) , 7,26 (d, 1 H) , 7.76 (s, 1 H), 8,02 (s, 1 H). 2 H), 2.98 (m, 4 H), 3.05 (m, 4 H), 6.81 (d, 1 H), 6.98-6.93 (m, 2 H), 7, 05 (s, 1H), 7.21 (d, 1H), 7.26 (d, 1H), 7.76 (s, 1H), 8.02 (s, 1H).
MS m/z 458,4 (MH+, 21,7 % (81Br) ) , 456,3 (MH+, 23,9 % MS m/z 458.4 (MH+, 21.7% (81Br) ), 456.3 (MH+, 23.9%
(<79>Br)), 232, 0 (58,7 %) , 143, 1 (100 %) . (<79>Br)), 232.0 (58.7%) , 143.1 (100%) .
3-[2-[4-(benzotiopyran-8-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, lt, smp. 178-179 °C. 3-[2-[4-(Benzothiopyran-8-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, lt, m.p. 178-179 °C.
<1>H-NMR (CDCI3) : 2,07 (m, 2 H) , 2,75 (m, 6 H) , 2,83 (m, <1>H-NMR (CDCl 3 ) : 2.07 (m, 2 H), 2.75 (m, 6 H), 2.83 (m,
2 H), 2,98 (m, 4 H), 3,04 (m, 4 H), 6,80 (d, 1 H), 6,98-6,92 (m, 2 H), 7,04 (s, 1 H), 7,08 (d, 1 H), 7,33 (s, 1 H), 7,52 (d, 1 H), 7,95 (s, 1 H) . 2 H), 2.98 (m, 4 H), 3.04 (m, 4 H), 6.80 (d, 1 H), 6.98-6.92 (m, 2 H), 7, 04 (s, 1 H), 7.08 (d, 1 H), 7.33 (s, 1 H), 7.52 (d, 1 H), 7.95 (s, 1 H) .
MS m/z 412,3 (MH+, 31,8% (35C1) ) , 247, 3 ( 81, 8 %), 232,0 (63,9 %), 178,1 (63,6 %), 143,1 (100 %). MS m/z 412.3 (MH + , 31.8% (35C1) ), 247.3 ( 81.8 %), 232.0 (63.9 %), 178.1 (63.6 %), 143 .1 (100%).
3-[2-[4-(benzofuran-7-yl)piperazin-l-yl]etyl]-6-klor-lH-indol, lu, smp. 202-4 °C. 3-[2-[4-(benzofuran-7-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, lu, m.p. 202-4 °C.
<1>H-NMR {DMSO-d6) : 2, 65-2, 85 (m, 6 H) ; 2,90 (t, 2 H) ; 3,20-3,40 (m, 4 H); 6,60 (s, 1 H) ; 6,80 (d, 1 H) ; 6,90 (d, 1 H) ; 7,00 (d, 1 H); 7,05-7,30 (m, 3 H); 7,40 (d, 1 H); 7,55 (d, 1 H); 7,95 (d, 1 H); 11,00 (s, 1 H). <1>H-NMR (DMSO-d 6 ): 2.65-2.85 (m, 6 H); 2.90 (t, 2H); 3.20-3.40 (m, 4H); 6.60 (s, 1 H); 6.80 (d, 1H); 6.90 (d, 1H); 7.00 (d, 1H); 7.05-7.30 (m, 3H); 7.40 (d, 1H); 7.55 (d, 1H); 7.95 (d, 1H); 11.00 (p, 1 H).
MS m/z (%): 380 (MH+, 4 %), 215 (100 %), 200 (12 %), 178 (36 %), 172 (20 %). MS m/z (%): 380 (MH+, 4%), 215 (100%), 200 (12%), 178 (36%), 172 (20%).
3-[2-[4-(1,4-benzodioksan-5-yl)-1,2,3,6-tetrahydropyridin-l-yl] etyl] -6-klor-lH-indoloksalat, lv, smp. 240-47 °C. <X>H-NMR (DMSO-de): 2,70 (s, 2 H) ; 3,10 (t, 2 H) ; 3,20-3,70 (m, 4 H); 3,80 (s, 2 H); 4,25 (s, 4 H); 5,85 (s, 1 H); 6,75 (t, 1 H); 6,80 (d, 2 H); 7,05 (d, 1 H); 7,30 (s, 1 H); 7,40 (s, 1 H); 7,60 (d, 1 H); 11,10 (s, 1 H). 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl] ethyl] -6-chloro-1H-indoloxalate, lv, m.p. 240-47 °C. <X>H-NMR (DMSO-de): 2.70 (s, 2 H); 3.10 (t, 2H); 3.20-3.70 (m, 4H); 3.80 (s, 2H); 4.25 (s, 4H); 5.85 (s, 1H); 6.75 (t, 1H); 6.80 (d, 2H); 7.05 (d, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (p, 1H).
MS m/z (%): 395 (MH+, 1 %), 178 (100 %). MS m/z (%): 395 (MH+, 1%), 178 (100%).
6-klor-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetra-hydropyridin-l-yl] etyl] -lH-indoloksalat, lx, smp. 211-14 °C. 6-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetra-hydropyridin-1-yl] ethyl] -1H-indoloxalate, 1x, m.p. . 211-14 °C.
<1>H-NMR (DMSO-de): 2,75 (s, 2 H) ; 3,05-3,15 (m, 2 H) ; 3,20 (t, 2 H), 3,25-3,50 (m, 4 H); 3,85 (s, 2 H); 4,55 (t, 2 H); 6,30 (s, 1 H); 6,85 (t, 1 H); 7,00 (d, 1 H); 7,10 (d, 1 H); 7,15 (d, 1 H); 7,30 (s, 1 H); 7,40 (s, 1 H); 7,60 (d, 1 H); 11,10 (s, 1 H) . <1>H-NMR (DMSO-de): 2.75 (s, 2 H); 3.05-3.15 (m, 2H); 3.20 (t, 2H), 3.25-3.50 (m, 4H); 3.85 (s, 2H); 4.55 (t, 2H); 6.30 (s, 1H); 6.85 (t, 1H); 7.00 (d, 1H); 7.10 (d, 1H); 7.15 (d, 1H); 7.30 (s, 1H); 7.40 (s, 1H); 7.60 (d, 1H); 11.10 (p, 1H) .
MS m/z (%): 379 (MH+, 3 %), 178 (100 %) . MS m/z (%): 379 (MH + , 3%), 178 (100%).
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-l-yl]-etyl]-6-klor-lH-indolhemifumarat, ly, smp. 214-20 °C. 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl]-6-chloro-1H-indole hemifumarate, ly, m.p. 214-20 °C.
<*>H-NMR (DMSO-de): 2,65 (s, 2 H) ; 2,75-2,85 (m, 4 H) ; 2,90-3,00 (m, 2 H); 3,10-3,50 (m, 3 H) ; 6,55 (s, 2 H) ; 6,90-7,00 (m, 2 H); 7,15-7,30 (m, 3 H); 7,35 (s, 1 H); 7,50-7,60 (rn, 2 H); 8,00 (s, 1 H); 10,90 (s, 1 H). <*>H-NMR (DMSO-de): 2.65 (s, 2 H); 2.75-2.85 (m, 4H); 2.90-3.00 (m, 2H); 3.10-3.50 (m, 3H); 6.55 (s, 2 H); 6.90-7.00 (m, 2H); 7.15-7.30 (m, 3H); 7.35 (s, 1H); 7.50-7.60 (rn, 2H); 8.00 (p, 1H); 10.90 (p, 1 H).
MS m/z (%): 377 (MH+, 25 %), 178 (73 %), 143 (22 %). MS m/z (%): 377 (MH+, 25%), 178 (73%), 143 (22%).
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-l-yl]-etyl]-5-brom-lH-indoloksalat, lz, smp. 185-94 °C. 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl]-5-bromo-1H-indoloxalate, 1z, m.p. 185-94 °C.
<1>H-NMR (DMSO-de): 2,90 (s, 2 H) ; 3,10-3,20 (m, 2 H) ; 3,25-3,55 (m, 4 H); 3,95 (s, 2 H) ; 6,60 (s, 1 H) ; 7,00 (s, 1 H) ; 7,20 (d, 1 H); 7,20-7,45 (m, 4 H); 7,60 (d, 1 H); 7,80 (s, 1 H); 8,05 (s, 1 H); 11,20 (s, 1 H). <1>H-NMR (DMSO-de): 2.90 (s, 2 H); 3.10-3.20 (m, 2H); 3.25-3.55 (m, 4H); 3.95 (s, 2 H); 6.60 (s, 1 H); 7.00 (p, 1H) ; 7.20 (d, 1H); 7.20-7.45 (m, 4H); 7.60 (d, 1H); 7.80 (s, 1H); 8.05 (s, 1H); 11.20 (p, 1 H).
MS m/z (%) : 423 (MH+ (eiBr) , 22 %), 421 (MH+ (79Br) , 20 %), 224 (70 %), 222 (72 %), 143 (33 %). MS m/z (%) : 423 (MH+ (eiBr) , 22%), 421 (MH+ (79Br) , 20%), 224 (70%), 222 (72%), 143 (33%).
3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropytidin-l-yl]-etyl]-5-fluor-lH-indolhemioksalat, laa, smp. 176-79 °C. <X>H-NMR (DMSO-de): 2,75 (s, 2 H) ; 2,90-3,25 (m, 6 H) ; 3,65 (s, 2 H) ; 6,60 (s, 1 H) ; 6,85-6,95 (m, 1 H) ; 7,00 (s, 1 H) ; 7,20-7,40 (m, 5 H); 7,60 (d, 1 H); 8,00 (s, 1 H); 11,00 (s, 1 H) . 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropytidin-1-yl]-ethyl]-5-fluoro-1H-indole hemioxalate, laa, m.p. 176-79 °C. <X>H-NMR (DMSO-de): 2.75 (s, 2 H); 2.90-3.25 (m, 6H); 3.65 (s, 2H); 6.60 (s, 1 H); 6.85-6.95 (m, 1H); 7.00 (p, 1H) ; 7.20-7.40 (m, 5H); 7.60 (d, 1H); 8.00 (p, 1H); 11.00 (p, 1 H) .
MS m/z (%): 361 (MH+, 12 %), 162 (100 %), 115 (13 %) . MS m/z (%): 361 (MH+, 12%), 162 (100%), 115 (13%).
3-[2-[4-(benzofuran-7-yl)piperidin-l-yl]etyl]-6-klor-lH-indolhemifumarat, Ibb, smp. 245-50 °C. 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole hemifumarate, Ibb, m.p. 245-50 °C.
Hl-NMR (DMSO-de): 1,85-2, 00 (m, 4 H) ; 2,75 (t, 2 H) ; 2,90 (t, 2 H); 3,05 (tt, 1 H); 3,25 (d, 2 H); 6,55 (s, 2 H); 6,95 (s, 1 H); 7,00 (d, 1 H); 7,15-7,25 (m, 3 H); 7,40 (s, 1 H); 7,50 (d, 1 H); 7,55 (d, 1 H); 8,00 (s, 1 H); 10,95 (s, 1 H) . H1-NMR (DMSO-de): 1.85-2.00 (m, 4H); 2.75 (t, 2H); 2.90 (t, 2H); 3.05 (tt, 1H); 3.25 (d, 2H); 6.55 (s, 2H); 6.95 (s, 1H); 7.00 (d, 1H); 7.15-7.25 (m, 3H); 7.40 (s, 1H); 7.50 (d, 1H); 7.55 (d, 1H); 8.00 (p, 1H); 10.95 (pp, 1H) .
MS m/z {%): 379 (MH+, 5 %), 214 (10 %), 178 (20 %), 143 (100 %) . MS m/z {%): 379 (MH + , 5%), 214 (10%), 178 (20%), 143 (100%).
3-[2-[4-(benzofuran-7-yl)piperidin-l-yl]etyl]-5-fluor-lH-indoloksalat, lcc, smp. 191-94 °C. 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indoloxalate, m.p. 191-94 °C.
<X>H-NMR (DMSO-de): 2,05-2,25 (m, 4 H) ; 3,05-3,20 (m, 4 H) ; 3,20-4,40 (m, 3 H); 3,60-3,70 (m, 2 H); 6,90-7,00 (m, 2 H); 7,15-7,25 (m, 2 H); 7,35-7,45 (m, 3 H); 7,55 (d, 1 H); 8,00 (s, 1 H); 11,05 (s, 1 H). <X>H-NMR (DMSO-de): 2.05-2.25 (m, 4H); 3.05-3.20 (m, 4H); 3.20-4.40 (m, 3H); 3.60-3.70 (m, 2H); 6.90-7.00 (m, 2H); 7.15-7.25 (m, 2H); 7.35-7.45 (m, 3H); 7.55 (d, 1H); 8.00 (p, 1H); 11.05 (p, 1 H).
MS m/z (%): 363 (MH+, 5 %), 214 (9 %), 161 (10 %), 143 MS m/z (%): 363 (MH+, 5%), 214 (9%), 161 (10%), 143
(24 %) . (24%) .
3-[2-[4-(benzofuran-7-yl)piperidin-l-yl]etyl]-5-brom-lH-indoloksalat, Idd, smp. 153-57 °C. 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indoloxalate, Idd, m.p. 153-57 °C.
<1>H-NMR (DMSO-de): 2,05-2,20 (m, 4 H); 3,05-3,20 (m, 4 H); 3,20-3,40 (m, 3 H); 3,70 (d, 2 H); 6,95 (s, 1 H); 7,15-7,25 (m, 3 H); 7,30-7,40 (m, 2 H); 7,55 (d, 1 H); 7,80 (s, 1H); 8,00 (s, 1 H); 11,20 (s, 1 H). <1>H-NMR (DMSO-de): 2.05-2.20 (m, 4 H); 3.05-3.20 (m, 4H); 3.20-3.40 (m, 3H); 3.70 (d, 2H); 6.95 (s, 1H); 7.15-7.25 (m, 3H); 7.30-7.40 (m, 2H); 7.55 (d, 1H); 7.80 (s, 1H); 8.00 (p, 1H); 11.20 (p, 1 H).
MS m/z (%): 423 (MH+, 36 %), 224 (27 %), 202 (45 %), 143 (27 %), 117 (18 %). MS m/z (%): 423 (MH+, 36%), 224 (27%), 202 (45%), 143 (27%), 117 (18%).
Eksempel 2 Example 2
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 1H-indolhemifumarat, 2a 3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl] ethyl]- 1H-indole hemifumarate, 2a
En blanding av 3-(2-brometyl)-lH-indol (1,5 g), l-(l,4-benzodioksan-5-yl)piperazin (1,2 g), kaliumkarbonat (1,9 g) og kaliumjodid (0,1 g) i metylisobutylketon (100 ml) ble refluksert i 16 timer. Standard opparbeiding med etylacetat ga en olje som ble renset ved flashkromatografi (eluent: heptan/etanol/etylacetat/trietylamin 15:2:2:1). Fumarat-saltet ble erholdt fra en etanolløsning ved tilsetning av fumarsyre. Omkrystallisering fra etanol ga hemifumaratet 2a (0,9 g), smp. 204-7 °C. A mixture of 3-(2-bromomethyl)-1H-indole (1.5 g), 1-(1,4-benzodioxan-5-yl)piperazine (1.2 g), potassium carbonate (1.9 g) and potassium iodide (0.1 g) in methyl isobutyl ketone (100 mL) was refluxed for 16 h. Standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane/ethanol/ethyl acetate/triethylamine 15:2:2:1). The fumarate salt was obtained from an ethanol solution by the addition of fumaric acid. Recrystallization from ethanol gave the hemifumarate 2a (0.9 g), m.p. 204-7 °C.
<X>H-NMR (DMSO-de): 2, 60-2,80 (m, 6 H) ; 2,90 (t, 2 H) ; 2,95-3,10 (m, 4 H); 4,15-4,30 (m, 4 H) ; 6,50 (d, 1 H) ; 6,55 (d, 1 H); 6,60 (s, 1 H) ; 6,75 (t, 1 H) ; 7,00 (t, 1 H) ; 7,10 (t, <X>H-NMR (DMSO-de): 2.60-2.80 (m, 6 H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 4.15-4.30 (m, 4H); 6.50 (d, 1H); 6.55 (d, 1H); 6.60 (s, 1 H); 6.75 (t, 1H); 7.00 (h, 1 H) ; 7.10 (h,
1 H); 7,20 (s, 1 H); 7,35 (d, 1 H); 7,55 (d, 1 H); 10,75 (s, 1 H) . MS m/z (%): 364 (MH+, 5 %), 233 (57 %), 218 (21 %), 190 (19 %) , 144 (54 %) , 70 (100 %) . l-acetyl-3-[2-[4-{1,4-benzodioksan-4-yl)piperazin-l-yl]-etyl]-2,3-dihydro-lH-indol, 2b, smp. 119-20 °C. 1H); 7.20 (s, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.75 (s, 1H) . MS m/z (%): 364 (MH+, 5%), 233 (57%), 218 (21%), 190 (19%), 144 (54%), 70 (100%). 1-acetyl-3-[2-[4-{1,4-benzodioxan-4-yl)piperazin-1-yl]-ethyl]-2,3-dihydro-1H-indole, 2b, m.p. 119-20 °C.
<1>H-NMR (DMSO-d6): 1,90 (d, 1 H) ; 2,20 (s, 4 H) ; 2,95-3,30 (m, 11 H); 3,40-3,50 (m, 1 H); 3,75-3,85 (rn, 1 H); 4,20-4,30 (m, 4 H); 6,45 (dd, 1 H); 6,55 (dd, 1 H); 6,75 (t, 1 H); 7,00 (t, 1 H) ; 7,20 (t, 1 H) ; 7,30 (d, 1 H) ; 8,05 (d, 1 <1>H-NMR (DMSO-d 6 ): 1.90 (d, 1 H); 2.20 (s, 4H); 2.95-3.30 (m, 11 H); 3.40-3.50 (m, 1H); 3.75-3.85 (rn, 1H); 4.20-4.30 (m, 4H); 6.45 (dd, 1H); 6.55 (dd, 1H); 6.75 (t, 1H); 7.00 (h, 1 H) ; 7.20 (t, 1 H); 7.30 (d, 1H); 8.05 (d, 1
H) . H).
MS m/z (%): 408 (MH+, 54 %), 233 (17 %), 178 (100 %), 119 (20 %) . MS m/z (%): 408 (MH+, 54%), 233 (17%), 178 (100%), 119 (20%).
Eksempel 3 Example 3
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 6- klor-lH- indolhemifumarat, 3a 3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl] ethyl]- 6- chloro- 1H- indole hemifumarate, 3a
En blanding av 2-(6-klor-lH-indol-3-yl)eddiksyre (2,0 g), 1-(1,4-benzodioksan-5-yl)piperazin (3,6 g), N,N-disykloheksylkarbodiimid (2,4 g) og 4-dimetylaminopyridin (0,2 g) i tørt tetrahydrofuran (100 ml) ble omrørt i 16 timer ved romtemperatur under en nitrogenatmosfære. Filtrering og standard opparbeiding med metylenklorid ga en olje som ble renset ved flashkromatografi (eluent: etylacetat/heptan/ metanol 16:3:1, som ga 3-[2-[4-(1,4-benzodioksan-5-yl)-piperazin-l-yl]-2-oksoetyl]-6-klor-lH-indol som en olje. A mixture of 2-(6-chloro-1H-indol-3-yl)acetic acid (2.0 g), 1-(1,4-benzodioxan-5-yl)piperazine (3.6 g), N,N -dicyclohexylcarbodiimide (2.4 g) and 4-dimethylaminopyridine (0.2 g) in dry tetrahydrofuran (100 ml) were stirred for 16 hours at room temperature under a nitrogen atmosphere. Filtration and standard work-up with methylene chloride gave an oil which was purified by flash chromatography (eluent: ethyl acetate/heptane/methanol 16:3:1, which gave 3-[2-[4-(1,4-benzodioxan-5-yl)- piperazin-1-yl]-2-oxoethyl]-6-chloro-1H-indole as an oil.
Oljen ble løst i tetrahydrofuran (25 ml) og tilsatt dråpevis til en suspensjon av litiumaluminiumhydrid (0,9 g) i tørt tetrahydrofuran (50 ml) ved romtemperatur, etterfulgt av refluks i 3 timer. Stopping med 2 M vandig natriumhydroksid og standard opparbeiding ga den frie basen av 3a som en olje (1,9 g). Hemifumaratsaltet, 3a (1,0 g), ble erholdt fra en etanolløsning ved tilsetning av fumarsyre, smp. 215-16 °C. The oil was dissolved in tetrahydrofuran (25 mL) and added dropwise to a suspension of lithium aluminum hydride (0.9 g) in dry tetrahydrofuran (50 mL) at room temperature, followed by reflux for 3 hours. Quenching with 2 M aqueous sodium hydroxide and standard workup gave the free base of 3a as an oil (1.9 g). The hemifumarate salt, 3a (1.0 g), was obtained from an ethanol solution by addition of fumaric acid, m.p. 215-16 °C.
<1>H-NMR (DMSO-de): 2, 60-2, 85 (m, 6 H) ; 2,85-2,95 (m, 2 H) ; 2,95-3,10 (m, 4 H) ; 4,10-4,30 (m, 4 H) ; 6,45 (d, 1 H) ; 6,50 (d, 1 H); 6,60 (s, 1 H); 6,70 (t, 1 H); 7,0 (dd, 1 H); 7,25 (d, 1 H); 7,40 (d, 1 H); 7,55 (d, 1 1H); 10,95 (s, 1 H). MS m/z {%): 398 (MH+, 10 %), 234 (13 %), 233 (100 %), 178 (12 %) . <1>H-NMR (DMSO-de): 2.60-2.85 (m, 6 H); 2.85-2.95 (m, 2H); 2.95-3.10 (m, 4H); 4.10-4.30 (m, 4H); 6.45 (d, 1H); 6.50 (d, 1H); 6.60 (s, 1H); 6.70 (t, 1H); 7.0 (dd, 1 H); 7.25 (d, 1H); 7.40 (d, 1H); 7.55 (d, 1 1H); 10.95 (pp, 1 H). MS m/z {%): 398 (MH + , 10%), 234 (13%), 233 (100%), 178 (12%).
De følgende forbindelser ble fremstilt analogt: 3-[2-[4-(5-klor-2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)-piperazin-l-yl]etyl]-lH-indolhemifumarat, 3b, smp. 210-12 °C. <1>H-NMR (DMSO-de): 1,40 (s, 6 H) ; 2,55-2,75 (m, 6 H) ; 2,80-3,00 (m, 4 H); 3,05-3,20 (m, 4 H); 6,60 (s, 1 H); 6,65 (d, 1 H); 6,80 (d, 1 H); 6,95 (t, 1 H); 7,05 (t, 1 H); 7,15 (d, 1 H); 7,35 (d, 1 H); 7,55 (d, 1 H); 10,70 (s, 1 H). The following compounds were prepared analogously: 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-piperazin-1-yl]ethyl]-1H-indole hemifumarate, 3b, m.p. 210-12 °C. <1>H-NMR (DMSO-de): 1.40 (s, 6 H); 2.55-2.75 (m, 6H); 2.80-3.00 (m, 4H); 3.05-3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.80 (d, 1H); 6.95 (t, 1H); 7.05 (t, 1H); 7.15 (d, 1H); 7.35 (d, 1H); 7.55 (d, 1H); 10.70 (p, 1H).
MS m/z {%): 410 (MH+, 18 %), 281 (32 %), 279 (100 %), 144 (39 %). MS m/z {%): 410 (MH+, 18%), 281 (32%), 279 (100%), 144 (39%).
6-klor-3-[2-[4-(5-klor-3,3-dlmetyl-2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-lH-indolhemifumarat, 3c, smp. 130-32 °C. 6-chloro-3-[2-[4-(5-chloro-3,3-dlmethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole hemifumarate, 3c, m.p. 130-32 °C.
<X>H-NMR (DMSO-d6): 1,25 (s, 6 H) ; 2,55-2,70 (m, 6 H) ; 2,85 (t, 2 H); 3,00-3,20 (m, 4 H); 4,25 (s, 2 H); 6,60 (s, 1 H); 6,65 (s, 1 H); 6,85 (s, 1 H); 7,00 (d, 1 H); 7,20 (s, 1 H); 7,35 (s, 1 H); 7,55 (d, 1 H); 10,90 (s, 1 H). <X>H-NMR (DMSO-d 6 ): 1.25 (s, 6 H); 2.55-2.70 (m, 6H); 2.85 (t, 2H); 3.00-3.20 (m, 4H); 4.25 (s, 2H); 6.60 (s, 1H); 6.65 (s, 1H); 6.85 (s, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.90 (p, 1 H).
MS m/z {%): 446 (8 %), 444 (MH+, 11 %) , 281 (34 %), 280 MS m/z {%): 446 (8%), 444 (MH+, 11%), 281 (34%), 280
(16 %), 279 (100 %), 178 (15 %). (16%), 279 (100%), 178 (15%).
6-klor-3-[2-[4-(6-klor-2,2-dimetyl-3,4-dihydro-2H-l-benzo-pyran-8-yl)piperazin-l-yl]etyl]-lH-indolfumarat, 3d, smp. 224-25 °C. 6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzo-pyran-8-yl)piperazin-1-yl]ethyl]- 1H-indole fumarate, 3d, m.p. 224-25 °C.
<1>H-NMR (DMSO-de): 1,30 (s, 6 H) ; 1,70 (t, 2 H) ; 2,60-2,75 (m, 8 H) ; 2,90 (t, 2 H) ; 2,95-3,10 (m, 4 H) ; 6,60 (s, 1 H) ; 6,65 (d, 1 H); 6,70 (d, 1 H); 7,00 (d, 1 H); 7,20 (s, 1 H); 7,35 (s, 1 H); 7,55 (d, 1 H); 10,95 (s, 1 H). <1>H-NMR (DMSO-de): 1.30 (s, 6 H); 1.70 (t, 2H); 2.60-2.75 (m, 8H); 2.90 (t, 2H); 2.95-3.10 (m, 4H); 6.60 (s, 1 H); 6.65 (d, 1H); 6.70 (d, 1H); 7.00 (d, 1H); 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1H); 10.95 (pp, 1 H).
MS m/z (%) 458 (MH+, 11 %), 295 (32 %), 293 (100 %), 259 (11 %), 178 (14 %) . MS m/z (%) 458 (MH+, 11%), 295 (32%), 293 (100%), 259 (11%), 178 (14%).
6-klor-3-[2-[4-(2,2-dimetyl-2,3-dihydrobenzofuran-7-yl)-piperazin-l-yl] etyl]-lH-indol fumarat, 3e, smp. 165-67 °C. ""■H-NMR (DMSO-de): 1,40 (s, 6 H) ; 2,65-2,80 (m, 6 H) ; 2,90 (t, 2 H); 2,95 (s, 2 H); 3,00-3,20 (m, 4 H); 6,60 (s, 1 H); 6,65 (d, 1 H); 6,70 (t, 1 H) ; 6,75 (d, 1 H) ; 7,00 (d, 1 H) ; 7,20 (s, 1 H); 7,35 (s, 1 H); 7,55 (d, 1 H). 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-piperazin-1-yl] ethyl]-1H-indole fumarate, 3e, m.p. 165-67 °C. ""■H-NMR (DMSO-de): 1.40 (s, 6 H); 2.65-2.80 (m, 6H); 2.90 (t, 2H); 2.95 (s, 2H); 3.00-3.20 (m, 4H); 6.60 (s, 1H); 6.65 (d, 1H); 6.70 (t, 1 H); 6.75 (d, 1H); 7.00 (d, 1H) ; 7.20 (s, 1H); 7.35 (s, 1H); 7.55 (d, 1 H).
MS m/z (%): 410 (MH+, 6 %), 245 (67 %), 209 (39 %) , 178 MS m/z (%): 410 (MH+, 6%), 245 (67%), 209 (39%), 178
(8 %) , 127 (51 %) , 45 (100 %) . (8%) , 127 (51%) , 45 (100%) .
1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-lH-indoloksalat, 3f, smp. 234-35 °C. 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indoloxalate, 3f, m.p. 234-35 °C.
<X>H-NMR (DMSO-de): 2,85 (s, 4 H) ; 2,95-3,15 (m, 6 H); 4,15-4,30 (m, 4 H); 4,40 (t, 2 H); 6,45-6,55 (m, 3 H); 6,70 (t, 1 H); 7,05 (d, 1 H); 7,45 (d, 1 H); 7,55 (d, 1 H); 7,70 (s, <X>H-NMR (DMSO-de): 2.85 (s, 4 H); 2.95-3.15 (m, 6H); 4.15-4.30 (m, 4H); 4.40 (t, 2H); 6.45-6.55 (m, 3H); 6.70 (t, 1H); 7.05 (d, 1H); 7.45 (d, 1H); 7.55 (d, 1H); 7.70 (s,
1 H) . 1H).
MS m/z (%): 398 (MH+, 45 %) , 218 (100 %), 178 (50 %). MS m/z (%): 398 (MH+, 45%), 218 (100%), 178 (50%).
1-[2-[4-(1,4-Benzodioksan-5-yl)piperazin-l-yl]etyl]-5-klor-lH-indoloksalat, 3g, smp. 234-35 °C. 1-[2-[4-(1,4-Benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indoloxalate, 3g, m.p. 234-35 °C.
<1>H-NMR (DMSO-de): 2,85 (s, 4 H) ; 2,95-3,15 (m, 6 H) ; 4,15-4,30 (m, 4 H); 4,45 (t, 2 H); 6,40-6,50 (m, 2 H); 6,55 (d, 1 H); 6,70 (t, 1 H); 7,15 (d, 1 H) ; 7,50 (s, 1 H) ; 7,55-7, 65 (m, 2 H) . <1>H-NMR (DMSO-de): 2.85 (s, 4 H); 2.95-3.15 (m, 6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.70 (t, 1H); 7.15 (d, 1H); 7.50 (p, 1 H) ; 7.55-7.65 (m, 2 H).
MS m/z (%): 398 (MH+; 44 %), 218 (100 %) , 178 (62 %). MS m/z (%): 398 (MH+; 44%), 218 (100%), 178 (62%).
1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-fluor-lH-indoloksalat, 3h, smp. 230-31 °C. 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indoloxalate, 3h, m.p. 230-31 °C.
<1>H-NMR (DMSO-dg) : 2,90 (s, 4 H) ; 2, 95-3,20 (rn, 6 H) ; 4,15-4,30 (m, 4 H); 4,45 (t, 2 H); 6,40-6,50 (m, 2 H); 6,55 (d, 1 H); 6,75 (t, 1 H); 7,00 (t, 2 H); 7,30 (d, 1 H); 7,50 (s, 1 H); 7,50-7,55 (m, 1 H). <1>H-NMR (DMSO- dg ) : 2.90 (s, 4 H); 2.95-3.20 (rn, 6H); 4.15-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.75 (t, 1H); 7.00 (h, 2H); 7.30 (d, 1H); 7.50 (s, 1H); 7.50-7.55 (m, 1 H).
MS m/z (%): 382 (M H+, ?), 218 (63 %) , 162 (100 %) . MS m/z (%): 382 (M H + , ?), 218 (63 %), 162 (100 %).
1-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1H-indoloksalat, 3i, smp. 225-29 °C. 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indoloxalate, 3i, m.p. 225-29 °C.
<1>H-NMR (DMS0-d6): 2,95 (s, 4 H) ; 3,05-3,20 (m, 6 H) ; 4,10-4,30 (m, 4 H); 4,45 (t, 2 H); 6,40-6,50 (m, 2 H); 6,55 (d, 1 H); 6,75 (t, 1 H); 7,05 (t, 1 H); 7,40 (s, 1 H); 7,55 (t, <1>H-NMR (DMS0-d6): 2.95 (s, 4H); 3.05-3.20 (m, 6H); 4.10-4.30 (m, 4H); 4.45 (t, 2H); 6.40-6.50 (m, 2H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.40 (s, 1H); 7.55 (h,
2 H) . 2H).
MS m/z {%): 364 (MH+, 100 %), 218 (85 %), 146 (80 %). MS m/z {%): 364 (MH+, 100%), 218 (85%), 146 (80%).
1-(2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-l-yl]etyl]-lH-indoloksalat, 3j, smp. 223-26 °C. 1-(2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indoloxalate, 3j, mp 223-26 °C.
<X>H-NMR (DMSO-d6): 2,85 (s, 4 H); 3,00 (t, 2 H); 3,05-3,20 (m, 6 H); 4,40 (t, 2 H); 4,50 (t, 2 H); 6,45 (d, 1 H); 6,65 (d, 1 H); 6,75 (t, 1 H); 6,85 (d, 1 H); 7,00 (t, 1 H); 7,15 (t, 1 H); 7,40 (d, 1 H); 7,55 (dd, 2 H). <X>H-NMR (DMSO-d 6 ): 2.85 (s, 4 H); 3.00 (h, 2H); 3.05-3.20 (m, 6H); 4.40 (t, 2H); 4.50 (t, 2H); 6.45 (d, 1H); 6.65 (d, 1H); 6.75 (t, 1H); 6.85 (d, 1H); 7.00 (h, 1 H); 7.15 (t, 1H); 7.40 (d, 1H); 7.55 (dd, 2 H).
MS m/z (%): 348 (MH+, 38 %), 231 (50 %), 201 (100 %) , 174 (25 %), 162 (41 %), 146 (98 %). MS m/z (%): 348 (MH+, 38%), 231 (50%), 201 (100%), 174 (25%), 162 (41%), 146 (98%).
Eksempel 4 Example 4
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 2, 3- di-hydro- lH- indolseskvioksalat, 4a 3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl] ethyl]- 2, 3- dihydro- 1H- indole squioxalate, 4a
En løsning av 2a (16 g) i trifluoreddiksyre (200 ml) ble behandlet i porsjoner med natriumborhydrid (2 x 2,9 g, A solution of 2a (16 g) in trifluoroacetic acid (200 mL) was treated in portions with sodium borohydride (2 x 2.9 g,
1,5 times intervall) ved romtemperatur, etterfulgt av om-røring i 2,5 timer ved romtemperatur. Reaksjonsblandingen ble helt på is og gjort alkalisk med vandig natriumhydroksid, etterfulgt av standard opparbeiding. Den resulterende olje ble renset ved flashkromatografi (eluent: heptan/etylacetat/etanol/trietylamin 15:2:2:1), som ga tittelbasen som en gul olje (13,8 g). Titteloksalatet ble erholdt fra den frie basen (1,4 g) som krystallinsk materiale fra etanol ved tilsetning av oksalsyre (0,9 g), smp. 145-50 °C. 1.5 hour interval) at room temperature, followed by stirring for 2.5 hours at room temperature. The reaction mixture was poured onto ice and made alkaline with aqueous sodium hydroxide, followed by standard work-up. The resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 15:2:2:1), which gave the title base as a yellow oil (13.8 g). The title oxalate was obtained from the free base (1.4 g) as crystalline material from ethanol by addition of oxalic acid (0.9 g), m.p. 145-50 °C.
<1>H-NMR (DMSO-de): 1,75-1, 85 (m, 1 H); 2,05-2,15 (m, 1 H) ; 2, 95-3,30 (m, 12 H) ; 3,60 (t, 1 H) ; 4,20 (d, 4 H) ; 6,50 (d, 2 H); 6,60 (d, 2 H) ; 6,75 (t, 1 H) ; 6,95 (t, 1 H) ; 7,10 (d, <1>H-NMR (DMSO-de): 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.95-3.30 (m, 12 H); 3.60 (t, 1 H); 4.20 (d, 4H); 6.50 (d, 2H); 6.60 (d, 2H); 6.75 (t, 1H); 6.95 (t, 1 H); 7.10 (d,
1 H) . 1H).
MS m/z (%): 366 (MH+, 10 %), 221 (10 %), 178 (14 %), 150 (20 %), 118 (100 %). MS m/z (%): 366 (MH+, 10%), 221 (10%), 178 (14%), 150 (20%), 118 (100%).
De følgende forbindelser ble fremstilt analogt: 3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-2,3-di-hydro-5-fluor-lH-indolhemioksalat, 4b, smp. 201-5 °C. <X>H-NMR (DMSO-d6) : 1, 60-1,80 (m, 1 H) ; 1,95-2,10 (rn, 1 H) ; 2,60-3,30 (m, 12 H); 3,35 (t, 1 H); 4,20 (d, 4 H); 6,35-6,55 (rn, 3 H) ; 6,15-6,25 (m, 2 H) ; 6,90 (d, 1 H) . The following compounds were prepared analogously: 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-5-fluoro-1H-indole hemioxalate , 4b, m.p. 201-5 °C. <X>H-NMR (DMSO-d 6 ): 1.60-1.80 (m, 1 H); 1.95-2.10 (rn, 1H); 2.60-3.30 (m, 12 H); 3.35 (t, 1H); 4.20 (d, 4H); 6.35-6.55 (rn, 3H); 6.15-6.25 (m, 2H); 6.90 (d, 1 H).
MS m/z (%): 384 (MH+, 32 %), 178 (28 %), 150 (12 %), 136 (100 %). MS m/z (%): 384 (MH+, 32%), 178 (28%), 150 (12%), 136 (100%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-5-klor-2,3-dihydro-lH-indoloksalat, 4c, smp. 153-57 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2,3-dihydro-1H-indoloxalate, 4c, m.p. 153-57 °C.
<X>H-NMR (DMSO-de): 1,70-1,85 (m, 1 H) ; 2,05-2,20 (rn, 1 H) ; 2,85-3,05 (m, 2 H); 3,05-3,35 (m, 10 H); 3,60 (t, 2 H); 4,15-4,30 (m, 4 H); 6,45-6,60 (m, 3 H); 6,75 (t, 1 H); 6,95 <X>H-NMR (DMSO-de): 1.70-1.85 (m, 1H); 2.05-2.20 (rn, 1H); 2.85-3.05 (m, 2H); 3.05-3.35 (m, 10 H); 3.60 (t, 2H); 4.15-4.30 (m, 4H); 6.45-6.60 (m, 3H); 6.75 (t, 1H); 6.95
{dd, 1 H); 7,10 (d, 1 H). {dd, 1H); 7.10 (d, 1H).
MS m/z (%): 400 (MH+, 39 %), 178 (39 %), 152 (100 %). MS m/z (%): 400 (MH+, 39%), 178 (39%), 152 (100%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-6-klor-2,3-dihydro-lH-indoloksalat, 4d, smp. 185-88 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-2,3-dihydro-1H-indoloxalate, 4d, m.p. 185-88 °C.
Hi-NMR (DMSO-de): 1,75-1, 85 (m, 1 H) ; 2,00-2,10 (rn, 1 H) ; 2,90-3,30 (m, 12 H); 3,60 (t, 1 H); 4,15-4,30 (m, 4 H); 6,45 (s, 1 H); 6,50 (d, 1 H); 6,55 (t, 2 H); 6,75 (t, 1 H); 7,05 (d, 1 H). H1 NMR (DMSO-de): 1.75-1.85 (m, 1H); 2.00-2.10 (rn, 1H); 2.90-3.30 (m, 12 H); 3.60 (t, 1H); 4.15-4.30 (m, 4H); 6.45 (s, 1H); 6.50 (d, 1H); 6.55 (t, 2H); 6.75 (t, 1H); 7.05 (d, 1 H).
MS m/z (%): 400 (MH+, 14 %), 221 (52 %), 180 (22 %), 152 (100 %). MS m/z (%): 400 (MH+, 14%), 221 (52%), 180 (22%), 152 (100%).
Eksempel 5 Example 5
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 1-butyl- lH- indoloksalat, 5a 3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl] ethyl]- 1-butyl- 1H- indoloxalate, 5a
En løsning av 2a (1,0 g) i tørt i tørt tetrahydrofuran A solution of 2a (1.0 g) in dry tetrahydrofuran
(50 ml) ble tilsatt dråpevis til en suspensjon av natriumhydrid (60 % i mineralolje, 0,14 g) i tetrahydrofuran (25 ml) ved romtemperatur. Etter omrøring i 30 minutter ble en løsning av 1-brombutan (0,85 g) i tørt tetrahydrofuran (100 ml) tilsatt dråpevis. Omrøring i 1 time etterfulgt av standard opparbeiding med etylacetat ga en olje som ble renset ved flashkromatografi (eluent: heptan/etylacetat/trietylamin 15:3:2). Den resulterende olje ble konvertert til titteloksalatsaltet (0,7 g) fra aceton ved tilsetning av oksalsyre, smp. 168-74 °C. (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.14 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 minutes, a solution of 1-bromobutane (0.85 g) in dry tetrahydrofuran (100 ml) was added dropwise. Stirring for 1 hour followed by standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2). The resulting oil was converted to the title oxalate salt (0.7 g) from acetone by addition of oxalic acid, m.p. 168-74 °C.
<*>H-NMR (DMSO-de): 0,90 (t, 3 H) ; 1,25 (qv, 2 H) ; 1,70 (qv, <*>H-NMR (DMSO-de): 0.90 (t, 3 H); 1.25 (qv, 2H); 1.70 (qv,
2 H); 3,05 (t, 2 H); 3,15-3,40 (m, 8 H); 4,10 (t, 2 H); 4,15-4,30 (m, 4 H) ; 6,55 (d, 1 H) ; 6,60 (d, 1 H) ; 6,75 (t, 1 H); 7,05 (t, 1 H); 7,15 (t, 1 H); 7,25 (s, 1 H); 7,45 (d, 1 H); 7,60 (d, 1 H). 2H); 3.05 (t, 2H); 3.15-3.40 (m, 8H); 4.10 (t, 2H); 4.15-4.30 (m, 4H); 6.55 (d, 1H); 6.60 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.45 (d, 1H); 7.60 (d, 1 H).
MS m/z (%): 420 (MH+, 33 %) , 233 (39 %), 200 (100 %), 158 (36 %) . MS m/z (%): 420 (MH+, 33%), 233 (39%), 200 (100%), 158 (36%).
De følgende forbindelser ble fremstilt analogt: The following compounds were prepared analogously:
l-allyl-3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl-lH-indoloksalat, 5b, smp. 187-90 °C. <X>H-NMR (DMSO-d6) : 3,05 (t, 2 H) ; 3,10-3,40 (m, 10 H) ; 4,20 {d, 4 H); 4,75 {d, 2 H); 5,05 (d, 1 H); 5,15 (d, 1 H) ; 5,90-6,05 (m, 1 H) ; 6,50 (d, 1 H) ; 6,55 (d, 1 H) ; 6,75 (t, 1 H); 7,05 (t, 1 H); 7,15 (t, 1 H); 7,25 (s, 1 H); 7,40 (d, 1 H) ; 7,60 (d, 1 H) . 1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl-1H-indoloxalate, 5b, m.p. 187-90 °C. <X>H-NMR (DMSO-d6) : 3.05 (t, 2H); 3.10-3.40 (m, 10 H); 4.20 {d, 4H); 4.75 (d, 2H); 5.05 (d, 1H); 5.15 (d, 1H); 5.90-6.05 (m, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.15 (t, 1H); 7.25 (s, 1H); 7.40 (d, 1H); 7.60 (d, 1 H).
MS m/z (%): 404 (MH+, 38 %), 233 (38 %), 184 (43 %), 120 (29 %) . MS m/z (%): 404 (MH+, 38%), 233 (38%), 184 (43%), 120 (29%).
3-[2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1-pro-pargyl-lH-indoloksalat, 5c, smp. 168-72 °C. 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-pro-pargyl-1H-indoloxalate, 5c, m.p. 168-72 °C.
<X>H-NMR (DMSO-de): 3, 00-3,30 (m, 12 H) ; 3,40 (t, 1 H) ; 4,25 (d, 4 H); 5,05 (d, 2 H); 6,50 (d, 2 H); 6,55 (d, 1 H); 7,10 (t, 1 H); 7,20 (t, 1 H); 7,30 (s, 1 H); 7,50 (d, 1 H); 7,65 (d, 1 H) . <X>H-NMR (DMSO-de): 3.00-3.30 (m, 12 H); 3.40 (t, 1 H); 4.25 (d, 4H); 5.05 (d, 2H); 6.50 (d, 2H); 6.55 (d, 1H); 7.10 (t, 1 H); 7.20 (t, 1 H); 7.30 (s, 1H); 7.50 (d, 1H); 7.65 (d, 1H).
MS m/z (%): 402 (MH+, 52 %), 233 (50 %), 182 (57 %), 167 (100 %). MS m/z (%): 402 (MH+, 52%), 233 (50%), 182 (57%), 167 (100%).
Eksempel 6 Example 6
3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl] etyl]- 2, 3- di-hydro- 1- metyl- lH- indoloksalat, 6a 3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl] ethyl]- 2, 3- dihydro- 1- methyl- 1H- indoloxalate, 6a
En løsning av 4a (1,5 g) i tørt tetrahydrofuran (50 ml) ble tilsatt dråpevis til en suspensjon av natriumhydrid (60 % i mineralolje, 0,21 g) i tetrahydrofuran (25 ml) ved romtemperatur. Etter omrøring i 30 minutter ble en løsning av jodmetan (0,75 g) i tørt tetrahydrofuran (25 ml) tilsatt dråpevis. Omrøring i 1 time etterfulgt av standard opparbeiding med etylacetat ga en olje som ble renset ved flashkromatografi (eluent: heptan/etylacetat/trietylamin 15:3:2. Den resulterende olje ble konvertert til titteloksalatsaltet (0,3 g) fra aceton ved tilsetning av oksalsyre, smp. 155-65 °C. A solution of 4a (1.5 g) in dry tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.21 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 minutes, a solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 ml) was added dropwise. Stirring for 1 hour followed by standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2. The resulting oil was converted to the title oxalate salt (0.3 g) from acetone by addition of oxalic acid, mp 155-65 °C.
<1>H-NMR (DMSO-de): 1,75-1,85 (m, 1 H) ; 2,05-2,15 (m, 1 H) ; 2,70 (s, 3 H); 2,90-3,25 (rn, 12 H); 3,40 (t, 1 H); 4,15-4,30 (m, 4 H) ; 6, 45-6,55 (m, 3 H) ; 6,65 (t, 1 H) ; 6,75 (t, 1 H); 7,05 (t, 1 H); 7,10 (d, 1 H). <1>H-NMR (DMSO-de): 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.70 (s, 3H); 2.90-3.25 (rn, 12 H); 3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, 3H); 6.65 (t, 1 H); 6.75 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H).
MS m/z (%) : 380 (MH+, 4 %) , 178 (4 %), 132 (53 %) . MS m/z (%): 380 (MH+, 4%), 178 (4%), 132 (53%).
De følgende forbindelser ble fremstilt analogt: 3-[2-[4-{1,4-benzodioksan-5-yl)piperazin-l-yl]etyl]-1-benzyl-2,3-dihydro-lH-indoloksalat, 6b, smp. 158-65 °C. ^-NMR (DMSO-de): 1, 75-1, 85 (rn, 1 H) ; 2,10-2,20 (m, 1 H) ; 2,90-3,30 (m, 12 H); 3,45 (t, 1 H); 4,15-4,25 (m, 5 H); 4,35 (d, 1 H) ; 6,50 (d, 1 H) ; 6,55 (d, 1 H) ; 6, 65-6,70 (rn, 2 H); 6,75 (t, 1 H); 7,00 (t, 1 H); 7,10 (d, 1 H); 7,30 (t, 1 H); 7,35 (s, 4 H). MS m/z (%): 456 (MH+, 19 %), 236 (25 %), 178 (100 %), 130 (11 %)• l-allyl-3-[ 2-[4-(1,4-benzodioksan-5-yl)piperazin-l-yl]-etyl]-2,3-dihydro-lH-indoloksalat, 6c, smp. 133-36 °C. <X>H-NMR (DMSO-de): 1,75-1,85 (m, 1 H); 2,10-2,20 (m, 1 H) ; 2,95-3,35 (m, 12 H) ; 3,50 (t, 1 H) ; 3,65 (dd, 1 H) ; 3,75 (dd, 1 H); 4,25 (d, 1 H); 5, 15 (d, 1 H); 5,30 (d, 1 H); 5,85-5,95 (m, 1 H); 6,50 (d, 1 H); 6,55 (d, 2 H); 6,65 (t, 1 H); 6,75 (t, 1 H); 7,00 (t, 1 H); 7,10 (d, 1 H). The following compounds were prepared analogously: 3-[2-[4-{1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-benzyl-2,3-dihydro-1H-indoloxalate, 6b , m.p. 158-65 °C. 3-NMR (DMSO-de): 1.75-1.85 (rn, 1H); 2.10-2.20 (m, 1H); 2.90-3.30 (m, 12 H); 3.45 (t, 1H); 4.15-4.25 (m, 5H); 4.35 (d, 1H); 6.50 (d, 1H); 6.55 (d, 1H); 6.65-6.70 (rn, 2H); 6.75 (t, 1H); 7.00 (h, 1 H); 7.10 (d, 1H); 7.30 (h, 1 H); 7.35 (p, 4 H). MS m/z (%): 456 (MH+, 19%), 236 (25%), 178 (100%), 130 (11%)• l-allyl-3-[ 2-[4-(1,4 -benzodioxan-5-yl)piperazin-1-yl]-ethyl]-2,3-dihydro-1H-indoloxalate, 6c, m.p. 133-36 °C. <X>H-NMR (DMSO-de): 1.75-1.85 (m, 1 H); 2.10-2.20 (m, 1H); 2.95-3.35 (m, 12 H); 3.50 (t, 1 H); 3.65 (dd, 1 H); 3.75 (dd, 1H); 4.25 (d, 1H); 5, 15 (d, 1H); 5.30 (d, 1H); 5.85-5.95 (m, 1H); 6.50 (d, 1H); 6.55 (d, 2H); 6.65 (t, 1H); 6.75 (t, 1H); 7.00 (h, 1 H); 7.10 (d, 1H).
MS m/z (%): 406 (MH+, 15 %), 178 (178 %), 158 (24 %), 130 (31 %), 117 (20 %) . MS m/z (%): 406 (MH+, 15%), 178 (178%), 158 (24%), 130 (31%), 117 (20%).
Eksempel 7 Example 7
l- acetyl- 3-[ 2-[ 4-( 1, 4- benzodioksan- 5- yl) piperazin- l- yl]-etyl]- lH- indoloksalat, 7a 1- Acetyl-3-[ 2-[ 4-( 1, 4- benzodioxan-5- yl) piperazin- 1- yl]-ethyl]- 1H- indoloxalate, 7a
En blanding av 2a (2,0 g), tetrabutylammoniumhydrogensulfat (0,2 g), natriumhydroksid (1,0 g) og metylenklorid (40 ml) ble omrørt i 10 minutter, etterfulgt av dråpevis tilsetning av en løsning med acetylklorid (0,97 g) i metylenklorid ved romtemperatur. Etter omrøring i 1 time ble vann tilsatt, etterfulgt av standard opparbeiding. Den resulterende olje ble renset ved flashkromatografi (eluent: heptan/etylacetat/etanol/trietylamin 17:1:1), som ga en gul olje som ble konvertert til titteloksalatsaltet (0,75 g) fra aceton ved tilsetning av oksalsyre, smp. 199-202 °C. A mixture of 2a (2.0 g), tetrabutylammonium hydrogen sulfate (0.2 g), sodium hydroxide (1.0 g), and methylene chloride (40 mL) was stirred for 10 min, followed by the dropwise addition of a solution of acetyl chloride (0. 97 g) in methylene chloride at room temperature. After stirring for 1 hour, water was added, followed by standard work-up. The resulting oil was purified by flash chromatography (eluent: heptane/ethyl acetate/ethanol/triethylamine 17:1:1), which gave a yellow oil which was converted to the title oxalate salt (0.75 g) from acetone by addition of oxalic acid, m.p. 199-202 °C.
<1>H-NMR (DMSO-de): 2,65 <s, 3 H) ; 3,05 (t, 2 H) ; 3,15 (s, <1>H-NMR (DMSO-de): 2.65 <s, 3H); 3.05 (t, 2H); 3.15 (s,
10 H); 4,20 (d, 2 H); 4,25 (d, 2 H); 6,50 (d, 1 H); 6,55 (d, 1 H); 6,75 (t, 1 H); 7,30-7,40 (m, 2 H); 7,70 (d, 1 H); 7,80 (s, 1 H); 8,35 (d, 1 H). 10H); 4.20 (d, 2H); 4.25 (d, 2H); 6.50 (d, 1H); 6.55 (d, 1H); 6.75 (t, 1H); 7.30-7.40 (m, 2H); 7.70 (d, 1H); 7.80 (s, 1H); 8.35 (d, 1 H).
MS m/z (%): 406 (MH+, 28 %), 233 (44 %), 218 (39 %), 144 (100 %). MS m/z (%): 406 (MH+, 28%), 233 (44%), 218 (39%), 144 (100%).
Farmakologisk testing Pharmacological testing
Affiniteten til forbindelsene av oppfinnelsen for 5-HTiA-reseptorer ble bestemt ved å måle bindingsinhiberingen til en radioaktiv ligand på 5-HTiA-reseptorer, som beskrevet i den følgende test: Inhibering av 3H- 5- CT- binding til humane 5- HTiA- reseptorer Ved denne fremgangsmåten bestemmes inhiberingen med lege-midler på bindingen av 5-HTiA-agonisten, <3>H-5-karboksamido-tryptamin (<3>H-5-CT), til klonede humane 5-HTiA-reseptorer stabilt uttrykt i transfekterte HeLa-celler (HA7) (Fargin, A. et al., J. Biol, Chem., 1989, 264, 14848) in vitro. Testen ble utført som en modifikasjon av fremgangsmåten beskrevet av Harrington, M.A. et al., J. Pharmacol. Exp. Ther., 1994, 268, 1098. Humane 5-HTiA-reseptorer (40 ug cellehomogenat) ble inkubert i 15 minutter ved 37 °C i 50 mM Tris-buffer ved pH 7,7 i nærvær av <3>H-5-CT. Ikke-spesi-fikk binding ble bestemt ved å inkludere 10 uM metergolin. Reaksjonen ble terminert ved hurtig filtrering gjennom Unifilter GF/B-filtre på en Tomtec cellehøster. Filtre ble tellet i en Packard-toppteller. De oppnådde resultater er presentert i tabell 1: The affinity of the compounds of the invention for 5-HTiA receptors was determined by measuring the binding inhibition of a radioactive ligand on 5-HTiA receptors, as described in the following test: Inhibition of 3H- 5- CT binding to human 5-HTiA- receptors This method determines the inhibition by drugs of the binding of the 5-HTiA agonist, <3>H-5-carboxamido-tryptamine (<3>H-5-CT), to cloned human 5-HTiA receptors stably expressed in transfected HeLa cells (HA7) (Fargin, A. et al., J. Biol, Chem., 1989, 264, 14848) in vitro. The test was performed as a modification of the method described by Harrington, M.A. et al., J. Pharmacol. Exp. Ther., 1994, 268, 1098. Human 5-HTiA receptors (40 µg cell homogenate) were incubated for 15 min at 37°C in 50 mM Tris buffer at pH 7.7 in the presence of <3>H- 5-CT. Non-specific binding was determined by including 10 µM metergoline. The reaction was terminated by rapid filtration through Unifilter GF/B filters on a Tomtec cell harvester. Filters were counted in a Packard top counter. The results obtained are presented in table 1:
Forbindelsene av oppfinnelsen er også blitt testet for sine effekter på reopptak av serotonin i den følgende test: Inhibering av 3H- 5- HT- reopptak i rottehjernesynaptosomer Ved å anvende denne fremgangsmåten, bestemmes legemidlenes evne til å inhibere akkumuleringen av <3>H-5-HT i hele rottehjernesynaptosomer in vitro. Testen ble utført som beskrevet Hyttel, J., Psychopharmacology, 1978, 60, 13. De oppnådde resultater er presentert i tabell 2: The compounds of the invention have also been tested for their effects on reuptake of serotonin in the following test: Inhibition of 3H-5-HT reuptake in rat brain synaptosomes By using this method, the ability of the drugs to inhibit the accumulation of <3>H-5 is determined -HT in whole rat brain synaptosomes in vitro. The test was performed as described Hyttel, J., Psychopharmacology, 1978, 60, 13. The results obtained are presented in table 2:
Den 5-HTiA-antagonistiske aktivitet til noen av forbindelsene av oppfinnelsen er blitt estimert in vitro og klonede 5-HTiA-reseptorer stabilt uttrykt i transfekterte HeLa-celler (HA7). I denne testen estimeres 5-HTiA-antagonistisk aktivitet ved å måle forbindelsenes evne til å antagonisere den 5-HT-induserte inhibering av forskolinindusert cAMP-akkumulering. Testen ble utført som en modifikasjon av fremgangsmåten beskrevet av Pauwels, P.J. et al., Biochem. Pharmacol., 1993, 45, 375. De oppnådde resultater er presentert i tabell 3: The 5-HTiA antagonistic activity of some of the compounds of the invention has been estimated in vitro and cloned 5-HTiA receptors stably expressed in transfected HeLa cells (HA7). In this test, 5-HTiA antagonistic activity is estimated by measuring the ability of the compounds to antagonize the 5-HT-induced inhibition of forskolin-induced cAMP accumulation. The test was performed as a modification of the method described by Pauwels, P.J. et al., Biochem. Pharmacol., 1993, 45, 375. The results obtained are presented in table 3:
Noen av forbindelsene av oppfinnelsen er også blitt testet for sin in vivo-effekt på 5-HTiA-reseptorer i testen beskrevet av Sånchez, C. et al., Eur. J. Pharmacol., 1996, 315, s. 245. I denne testen bestemmes antagonistiske effekter av testforbindelser ved å måle testforbindelsenes evne til å inhibere 5-MeO-DMT-indusert 5-HT-syndrom. Some of the compounds of the invention have also been tested for their in vivo effect on 5-HTiA receptors in the test described by Sånchez, C. et al., Eur. J. Pharmacol., 1996, 315, p. 245. In this test, antagonistic effects of test compounds are determined by measuring the ability of the test compounds to inhibit 5-MeO-DMT-induced 5-HT syndrome.
Forbindelsene av den foreliggende oppfinnelse besitter ver-difull aktivitet som serotoninreopptaksinhibitorer og har antagonistisk effekt på 5-HTiA-reseptorer. Forbindelsene av oppfinnelsen er derfor ansett som nyttige ved behandlingen av sykdommer og forstyrrelser mottakelige for inhiberingen av serotoninreopptak og antagonistisk aktivitet på 5-HTiA-reseptorer. Sykdommer som er mottakelige for inhiberingen av antagonistisk effekt på 5-HTiA-reseptorer, er vel kjent i faget og inkluderer emosjonelle forstyrrelser, slik som depresjon, psykose, angstforstyrrelser, inklusive generell angstforstyrrelse, panikkforstyrrelse, obsessiv-kompulsiv forstyrrelse etc. The compounds of the present invention possess valuable activity as serotonin reuptake inhibitors and have antagonistic effect on 5-HTiA receptors. The compounds of the invention are therefore considered useful in the treatment of diseases and disorders susceptible to the inhibition of serotonin reuptake and antagonistic activity on 5-HTiA receptors. Diseases susceptible to the inhibition of the antagonistic effect on 5-HTiA receptors are well known in the art and include emotional disorders, such as depression, psychosis, anxiety disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, etc.
Som forklart over, vil antagonistaktiviteten på 5-HTiA-reseptorer av forbindelsene av oppfinnelsen motvirke den negative feedbackmekanisme indusert ved inhiberingen av serotoninreopptak, og er derved forventet å forbedre effekten av den serotoninreopptaksinhiberende aktivitet av forbindelsene av oppfinnelsen. As explained above, the antagonist activity on 5-HTiA receptors of the compounds of the invention will counteract the negative feedback mechanism induced by the inhibition of serotonin reuptake, and is thereby expected to improve the effect of the serotonin reuptake inhibitory activity of the compounds of the invention.
Forbindelsene som krevd her, er derfor ansett å være spesielt nyttige som medikamenter med hurtig virkningsinntreden ved behandlingen av depresjon. Forbindelsene kan også være nyttige ved behandlingen av depresjoner, hvilke er ikke-mottakelige for nåværende tilgjengelige SSRI-er. The compounds claimed herein are therefore considered to be particularly useful as fast-acting drugs in the treatment of depression. The compounds may also be useful in the treatment of depression, which is unresponsive to currently available SSRIs.
Farmasøytisk formulering Pharmaceutical formulation
De farmasøytiske formuleringer av oppfinnelsen kan fremstilles ved konvensjonelle fremgangsmåter i faget. For eksempel kan tabletter fremstilles ved å blande den aktive ingrediens med ordinære hjelpestoffer og/eller fortynningsmidler, og deretter sammenpresse blandingen i en konvensjo-nell tabletteringsmaskin. Eksempler på hjelpestoffer eller fortynningsmidler omfatter: maisstivelse, potetstivelse, talkum, magnesiumstearat, gelatin, laktose, gummier og lignende. Hvilke som helst andre hjelpestoffer eller additiver som vanligvis anvendes for slike formål, slik som farge-stoffer, smaksstoffer, konserveringsmidler etc, kan anvendes, forutsatt at de er kompatible med de aktive ingredienser. The pharmaceutical formulations of the invention can be prepared by conventional methods in the art. For example, tablets can be prepared by mixing the active ingredient with ordinary excipients and/or diluents, and then compressing the mixture in a conventional tableting machine. Examples of excipients or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other auxiliaries or additives which are usually used for such purposes, such as colourants, flavourings, preservatives etc, can be used, provided they are compatible with the active ingredients.
Løsninger for injeksjon kan fremstilles ved å løse den aktive ingrediens og mulige tilsetningsstoffer i en del av løsemidlet for injeksjon, fortrinnsvis sterilt vann, og justere løsningen til ønsket volum, sterilisering av løs-ningen og fylling på egnede ampuller eller flasker. Alle egnede tilsetningsstoffer som konvensjonelt anvendes i faget, kan tilsettes, slik som tonisitetsmidler, konserveringsmidler, antioksidanter etc. Solutions for injection can be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, and adjusting the solution to the desired volume, sterilizing the solution and filling suitable ampoules or bottles. All suitable additives that are conventionally used in the field can be added, such as tonic agents, preservatives, antioxidants etc.
De farmasøytiske sammensetninger av denne oppfinnelsen, eller de som fremstilles i overensstemmelse med denne oppfinnelsen, kan administreres via en hvilken som helst egnet rute, f.eks. oralt i form av tabletter, kapsler, pulvere, siruper etc; eller parenteralt i form av løsninger for injeksjon. For å fremstille slike sammensetninger kan fremgangsmåter som er vel kjent i faget anvendes, og alle farmasøytisk akseptable bærere, fortynningsmidler, eksi-pienser eller andre tilsetningsstoffer som normalt anvendes i faget, kan anvendes. The pharmaceutical compositions of this invention, or those prepared in accordance with this invention, may be administered by any suitable route, e.g. orally in the form of tablets, capsules, powders, syrups etc; or parenterally in the form of solutions for injection. To prepare such compositions, methods that are well known in the art can be used, and all pharmaceutically acceptable carriers, diluents, excipients or other additives that are normally used in the art can be used.
Hensiktsmessig administreres forbindelsene av oppfinnelsen i enhetsdoseringsform inneholdende forbindelsene i en mengde på ca. 0,01-1000 mg. Den totale daglige dose er vanligvis i området fra ca. 0,05-500 mg, og mest foretrukket ca. 0,1-50 mg av den aktive forbindelse av oppfinnelsen. Appropriately, the compounds of the invention are administered in unit dosage form containing the compounds in an amount of approx. 0.01-1000 mg. The total daily dose is usually in the range from approx. 0.05-500 mg, and most preferably approx. 0.1-50 mg of the active compound of the invention.
Claims (16)
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PCT/DK1998/000336 WO1999005140A1 (en) | 1997-07-25 | 1998-07-20 | Indole and 2,3-dihydroindole derivatives, their preparation and use |
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HK (3) | HK1030220A1 (en) |
IL (1) | IL133990A (en) |
IS (1) | IS2024B (en) |
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PL (1) | PL190924B1 (en) |
SK (1) | SK284866B6 (en) |
TR (1) | TR200000231T2 (en) |
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PL338194A1 (en) | 2000-10-09 |
CN1265107A (en) | 2000-08-30 |
SK952000A3 (en) | 2001-03-12 |
CN1127501C (en) | 2003-11-12 |
IL133990A (en) | 2003-09-17 |
NO20000372L (en) | 2000-03-21 |
SK284866B6 (en) | 2006-01-05 |
HK1066807A1 (en) | 2005-04-01 |
BR9810790A (en) | 2000-07-25 |
IS5334A (en) | 2000-01-11 |
CN1293075C (en) | 2007-01-03 |
NO20000372D0 (en) | 2000-01-25 |
EA001890B1 (en) | 2001-10-22 |
IS2024B (en) | 2005-08-15 |
HK1066806A1 (en) | 2005-04-01 |
UA59408C2 (en) | 2003-09-15 |
TR200000231T2 (en) | 2000-07-21 |
IL133990A0 (en) | 2001-04-30 |
HK1030220A1 (en) | 2001-04-27 |
CN1515568A (en) | 2004-07-28 |
AR013206A1 (en) | 2000-12-13 |
CN1515569A (en) | 2004-07-28 |
EA200000162A1 (en) | 2000-10-30 |
PL190924B1 (en) | 2006-02-28 |
ZA986237B (en) | 1999-03-31 |
CN1286833C (en) | 2006-11-29 |
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