NO325259B1 - Substituerte N1-(benzensulfonyl) indoler, slike forbindelser for bruk i terapi, anvendelse av slike forbindelser samt farmasoytiske preparat inneholdende nevnte forbindelser. - Google Patents
Substituerte N1-(benzensulfonyl) indoler, slike forbindelser for bruk i terapi, anvendelse av slike forbindelser samt farmasoytiske preparat inneholdende nevnte forbindelser. Download PDFInfo
- Publication number
- NO325259B1 NO325259B1 NO20031589A NO20031589A NO325259B1 NO 325259 B1 NO325259 B1 NO 325259B1 NO 20031589 A NO20031589 A NO 20031589A NO 20031589 A NO20031589 A NO 20031589A NO 325259 B1 NO325259 B1 NO 325259B1
- Authority
- NO
- Norway
- Prior art keywords
- indole
- piperazinyl
- hydrochloride
- phenyl
- sulfonyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 149
- 238000002560 therapeutic procedure Methods 0.000 title claims 2
- VDWLCYCWLIKWBV-UHFFFAOYSA-N 1-(benzenesulfonyl)indole Chemical class C1=CC2=CC=CC=C2N1S(=O)(=O)C1=CC=CC=C1 VDWLCYCWLIKWBV-UHFFFAOYSA-N 0.000 title description 2
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 68
- -1 (2) naphthyl Chemical group 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 125000004193 piperazinyl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 108091005435 5-HT6 receptors Proteins 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- YBZUJCJMFCFJSZ-UHFFFAOYSA-N 4-piperazin-1-yl-1-pyridin-3-ylsulfonylindole;hydrochloride Chemical compound Cl.C1=CC2=C(N3CCNCC3)C=CC=C2N1S(=O)(=O)C1=CC=CN=C1 YBZUJCJMFCFJSZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000032544 Cicatrix Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 231100000241 scar Toxicity 0.000 claims description 4
- 230000037387 scars Effects 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 3
- SPADOBCFWOJMAX-UHFFFAOYSA-N 1-(2,4-difluorophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.FC1=CC(F)=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 SPADOBCFWOJMAX-UHFFFAOYSA-N 0.000 claims description 3
- ZSONFEJSWICLKA-UHFFFAOYSA-N 1-(2,4-difluorophenyl)sulfonyl-5-(4-methylpiperazin-1-yl)indole Chemical compound C1CN(C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C(=CC(F)=CC=3)F)C2=C1 ZSONFEJSWICLKA-UHFFFAOYSA-N 0.000 claims description 3
- QHKPPLCPYZAQOQ-UHFFFAOYSA-N 1-(2,5-dimethoxyphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.COC1=CC=C(OC)C(S(=O)(=O)N2C3=CC=CC(=C3C=C2)N2CCNCC2)=C1 QHKPPLCPYZAQOQ-UHFFFAOYSA-N 0.000 claims description 3
- LSMUXFVVSTXKNU-UHFFFAOYSA-N 1-(2-methylsulfonylphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 LSMUXFVVSTXKNU-UHFFFAOYSA-N 0.000 claims description 3
- QCEWVKZGAFFFOJ-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)sulfonyl-5-(4-methylpiperazin-1-yl)indole Chemical compound C1=C(OC)C(OC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(C)CC3)C=C2C=C1 QCEWVKZGAFFFOJ-UHFFFAOYSA-N 0.000 claims description 3
- LTCQHJOUSNIUCG-UHFFFAOYSA-N 1-(3-chloro-2-methylphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.CC1=C(Cl)C=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 LTCQHJOUSNIUCG-UHFFFAOYSA-N 0.000 claims description 3
- HHVBKKJQFBDESI-UHFFFAOYSA-N 1-(3-fluorophenyl)sulfonyl-5-(4-propylpiperazin-1-yl)indole Chemical compound C1CN(CCC)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=C(F)C=CC=3)C2=C1 HHVBKKJQFBDESI-UHFFFAOYSA-N 0.000 claims description 3
- UMRXUXYDSUQMEF-UHFFFAOYSA-N 1-(3-fluorophenyl)sulfonyl-5-piperazin-1-ylindole Chemical compound FC1=CC=CC(S(=O)(=O)N2C3=CC=C(C=C3C=C2)N2CCNCC2)=C1 UMRXUXYDSUQMEF-UHFFFAOYSA-N 0.000 claims description 3
- IQJMVQFWIHYBRM-UHFFFAOYSA-N 1-(4-butoxyphenyl)sulfonyl-5-piperazin-1-ylindole Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCNCC3)C=C2C=C1 IQJMVQFWIHYBRM-UHFFFAOYSA-N 0.000 claims description 3
- JCNAHIMZWCCNPC-UHFFFAOYSA-N 1-(4-fluorophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 JCNAHIMZWCCNPC-UHFFFAOYSA-N 0.000 claims description 3
- KAWOWBDBJOLFIT-UHFFFAOYSA-N 1-(4-methoxyphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 KAWOWBDBJOLFIT-UHFFFAOYSA-N 0.000 claims description 3
- IEFWXRZKTNRMCM-UHFFFAOYSA-N 1-(4-methoxyphenyl)sulfonyl-5-piperazin-1-ylindole Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCNCC3)C=C2C=C1 IEFWXRZKTNRMCM-UHFFFAOYSA-N 0.000 claims description 3
- QKDXOMCVUMIMBW-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonyl-5-(4-methylpiperazin-1-yl)indole Chemical compound C1CN(C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=CC(C)=CC=3)C2=C1 QKDXOMCVUMIMBW-UHFFFAOYSA-N 0.000 claims description 3
- ROXBNUKZHDDLIW-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonyl-5-(4-propan-2-ylpiperazin-1-yl)indole Chemical compound C1CN(C(C)C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=CC(C)=CC=3)C2=C1 ROXBNUKZHDDLIW-UHFFFAOYSA-N 0.000 claims description 3
- DXCQEVKPNDTXBF-UHFFFAOYSA-N 1-(4-phenylphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC2=C(N3CCNCC3)C=CC=C2N1S(=O)(=O)C(C=C1)=CC=C1C1=CC=CC=C1 DXCQEVKPNDTXBF-UHFFFAOYSA-N 0.000 claims description 3
- GCRXSPZZMIZVFT-UHFFFAOYSA-N 1-(4-phenylphenyl)sulfonyl-5-piperazin-1-ylindole Chemical compound C1=CC2=CC(N3CCNCC3)=CC=C2N1S(=O)(=O)C(C=C1)=CC=C1C1=CC=CC=C1 GCRXSPZZMIZVFT-UHFFFAOYSA-N 0.000 claims description 3
- DUFPVOODAWSKMS-UHFFFAOYSA-N 1-(5-chloro-1,3-dimethylpyrazol-4-yl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.CC1=NN(C)C(Cl)=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 DUFPVOODAWSKMS-UHFFFAOYSA-N 0.000 claims description 3
- XLTWZKMMVHMFFC-UHFFFAOYSA-N 1-(benzenesulfonyl)-2-iodo-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.IC1=CC2=C(N3CCNCC3)C=CC=C2N1S(=O)(=O)C1=CC=CC=C1 XLTWZKMMVHMFFC-UHFFFAOYSA-N 0.000 claims description 3
- QKMRXAFTDMWFRK-UHFFFAOYSA-N 1-(benzenesulfonyl)-4-(1,4-diazepan-1-yl)indole;hydrochloride Chemical compound Cl.C1=CC2=C(N3CCNCCC3)C=CC=C2N1S(=O)(=O)C1=CC=CC=C1 QKMRXAFTDMWFRK-UHFFFAOYSA-N 0.000 claims description 3
- KMTAAPCWBXHPGM-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-(4-methylpiperazin-1-yl)indole Chemical compound C1CN(C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=CC=CC=3)C2=C1 KMTAAPCWBXHPGM-UHFFFAOYSA-N 0.000 claims description 3
- UVAQRCSVMXEMFG-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-(4-propan-2-ylpiperazin-1-yl)indole Chemical compound C1CN(C(C)C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=CC=CC=3)C2=C1 UVAQRCSVMXEMFG-UHFFFAOYSA-N 0.000 claims description 3
- WHUZUSSVPDNFIQ-UHFFFAOYSA-N 1-(benzenesulfonyl)-5-piperazin-1-ylindole Chemical compound C1=CC2=CC(N3CCNCC3)=CC=C2N1S(=O)(=O)C1=CC=CC=C1 WHUZUSSVPDNFIQ-UHFFFAOYSA-N 0.000 claims description 3
- QDXBREOSPADMAU-UHFFFAOYSA-N 1-naphthalen-2-ylsulfonyl-5-piperazin-1-ylindole Chemical compound C=1C=C2C=CC=CC2=CC=1S(=O)(=O)N(C1=CC=2)C=CC1=CC=2N1CCNCC1 QDXBREOSPADMAU-UHFFFAOYSA-N 0.000 claims description 3
- KADIKJPQQGYEID-UHFFFAOYSA-N 2,2,2-trifluoro-1-[7-(4-piperazin-1-ylindol-1-yl)sulfonyl-3,4-dihydro-1h-isoquinolin-2-yl]ethanone;hydrochloride Chemical compound Cl.C1=C2CN(C(=O)C(F)(F)F)CCC2=CC=C1S(=O)(=O)N(C1=CC=C2)C=CC1=C2N1CCNCC1 KADIKJPQQGYEID-UHFFFAOYSA-N 0.000 claims description 3
- WBBGHIZRJLPRQU-UHFFFAOYSA-N 2-chloro-5-[4-(4-piperazin-1-ylindol-1-yl)sulfonylphenoxy]benzonitrile;hydrochloride Chemical compound Cl.C1=C(C#N)C(Cl)=CC=C1OC1=CC=C(S(=O)(=O)N2C3=CC=CC(=C3C=C2)N2CCNCC2)C=C1 WBBGHIZRJLPRQU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- YKDDAPCECVIJHB-UHFFFAOYSA-N 3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1-(4-fluorophenyl)sulfonylindole Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1C2=CC=CC=C2C(C=2C3CCN(CC3)C=2)=C1 YKDDAPCECVIJHB-UHFFFAOYSA-N 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- PZEBFZNJAUOZMN-UHFFFAOYSA-N 4-piperazin-1-yl-1-(2,4,6-trimethylphenyl)sulfonylindole;hydrochloride Chemical compound Cl.CC1=CC(C)=CC(C)=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 PZEBFZNJAUOZMN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- XSGMFWNSTRUFKG-UHFFFAOYSA-N 5-(4-benzylpiperazin-1-yl)-1-(4-butoxyphenyl)sulfonylindole Chemical compound C1=CC(OCCCC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(CC=4C=CC=CC=4)CC3)C=C2C=C1 XSGMFWNSTRUFKG-UHFFFAOYSA-N 0.000 claims description 3
- VFZVWMPPFXEMTK-UHFFFAOYSA-N 5-(4-benzylpiperazin-1-yl)-1-(4-methoxyphenyl)sulfonylindole Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(CC=4C=CC=CC=4)CC3)C=C2C=C1 VFZVWMPPFXEMTK-UHFFFAOYSA-N 0.000 claims description 3
- UEPJQQKYGBLQKD-UHFFFAOYSA-N 5-(4-benzylpiperazin-1-yl)-1-(4-phenylphenyl)sulfonylindole Chemical compound C1=CC2=CC(N3CCN(CC=4C=CC=CC=4)CC3)=CC=C2N1S(=O)(=O)C(C=C1)=CC=C1C1=CC=CC=C1 UEPJQQKYGBLQKD-UHFFFAOYSA-N 0.000 claims description 3
- CCFWLABVWVAMTD-UHFFFAOYSA-N 5-(4-benzylpiperazin-1-yl)-1-(4-propylphenyl)sulfonylindole Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(CC=4C=CC=CC=4)CC3)C=C2C=C1 CCFWLABVWVAMTD-UHFFFAOYSA-N 0.000 claims description 3
- OOPIJMKPRBRNLQ-UHFFFAOYSA-N 5-(4-benzylpiperazin-1-yl)-1-naphthalen-2-ylsulfonylindole Chemical compound C=1C=C2C=CC=CC2=CC=1S(=O)(=O)N(C1=CC=2)C=CC1=CC=2N(CC1)CCN1CC1=CC=CC=C1 OOPIJMKPRBRNLQ-UHFFFAOYSA-N 0.000 claims description 3
- IYSCJFMSPDDFSO-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)-1-(4-phenylphenyl)sulfonylindole Chemical compound C1CN(C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=CC(=CC=3)C=3C=CC=CC=3)C2=C1 IYSCJFMSPDDFSO-UHFFFAOYSA-N 0.000 claims description 3
- XNOZLDCDNLLWFB-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)-1-(4-propylphenyl)sulfonylindole Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(C)CC3)C=C2C=C1 XNOZLDCDNLLWFB-UHFFFAOYSA-N 0.000 claims description 3
- XFBYJIXGENCVTR-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)-1-naphthalen-1-ylsulfonylindole Chemical compound C1CN(C)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C4=CC=CC=C4C=CC=3)C2=C1 XFBYJIXGENCVTR-UHFFFAOYSA-N 0.000 claims description 3
- WUHULEWMNHLWBC-UHFFFAOYSA-N 5-piperazin-1-yl-1-(4-propylphenyl)sulfonylindole Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCNCC3)C=C2C=C1 WUHULEWMNHLWBC-UHFFFAOYSA-N 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- RJTZUHVCZIGJMB-UHFFFAOYSA-N hydron;1h-indole;chloride Chemical compound Cl.C1=CC=C2NC=CC2=C1 RJTZUHVCZIGJMB-UHFFFAOYSA-N 0.000 claims description 3
- TWHUSDMTTVWFJU-UHFFFAOYSA-N 1-(1,1-diphenylethylsulfonyl)-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(S(=O)(=O)N1C2=CC=CC(=C2C=C1)N1CCNCC1)(C)C1=CC=CC=C1 TWHUSDMTTVWFJU-UHFFFAOYSA-N 0.000 claims description 2
- MRYARIHHYCDWLM-UHFFFAOYSA-N 1-(2,5-dichlorophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.ClC1=CC=C(Cl)C(S(=O)(=O)N2C3=CC=CC(=C3C=C2)N2CCNCC2)=C1 MRYARIHHYCDWLM-UHFFFAOYSA-N 0.000 claims description 2
- BYPYNAHQJPBQCK-UHFFFAOYSA-N 1-(2-methylphenyl)sulfonyl-4-(3-methylpiperazin-1-yl)indole;hydrochloride Chemical compound Cl.C1CNC(C)CN1C1=CC=CC2=C1C=CN2S(=O)(=O)C1=CC=CC=C1C BYPYNAHQJPBQCK-UHFFFAOYSA-N 0.000 claims description 2
- ZHWDJPYNVCXHIP-UHFFFAOYSA-N 1-(2-methylphenyl)sulfonyl-4-(4-methylpiperazin-1-yl)indole;hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=CC=CC2=C1C=CN2S(=O)(=O)C1=CC=CC=C1C ZHWDJPYNVCXHIP-UHFFFAOYSA-N 0.000 claims description 2
- SDWIGEYRDWKNSE-UHFFFAOYSA-N 1-(2-methylphenyl)sulfonyl-4-(4-propan-2-ylpiperazin-1-yl)indole;hydrochloride Chemical compound Cl.C1CN(C(C)C)CCN1C1=CC=CC2=C1C=CN2S(=O)(=O)C1=CC=CC=C1C SDWIGEYRDWKNSE-UHFFFAOYSA-N 0.000 claims description 2
- JKYYIRRRAICXNY-UHFFFAOYSA-N 1-(2-methylphenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.CC1=CC=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 JKYYIRRRAICXNY-UHFFFAOYSA-N 0.000 claims description 2
- DCHGOAKSFRTTDD-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)sulfonyl-5-(4-propylpiperazin-1-yl)indole Chemical compound C1CN(CCC)CCN1C1=CC=C(N(C=C2)S(=O)(=O)C=3C=C(OC)C(OC)=CC=3)C2=C1 DCHGOAKSFRTTDD-UHFFFAOYSA-N 0.000 claims description 2
- VXUNVRFNBGBLCC-UHFFFAOYSA-N 1-(4-bromophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC(Br)=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 VXUNVRFNBGBLCC-UHFFFAOYSA-N 0.000 claims description 2
- LNBIHDBWJUYVPO-UHFFFAOYSA-N 1-(4-chlorophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 LNBIHDBWJUYVPO-UHFFFAOYSA-N 0.000 claims description 2
- GBRVKJGONYSHJT-UHFFFAOYSA-N 1-(4-methoxyphenyl)sulfonyl-5-(4-methylpiperazin-1-yl)indole Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1C2=CC=C(N3CCN(C)CC3)C=C2C=C1 GBRVKJGONYSHJT-UHFFFAOYSA-N 0.000 claims description 2
- NTLFABYQKAIIFR-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonyl-4-(4-methylpiperazin-1-yl)indole;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCN1C1=CC=CC2=C1C=CN2S(=O)(=O)C1=CC=C(C)C=C1 NTLFABYQKAIIFR-UHFFFAOYSA-N 0.000 claims description 2
- LLCWZXWYBZEIAD-UHFFFAOYSA-N 1-(4-nitrophenyl)sulfonyl-4-piperazin-1-ylindole;hydrochloride Chemical compound Cl.C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)N1C2=CC=CC(N3CCNCC3)=C2C=C1 LLCWZXWYBZEIAD-UHFFFAOYSA-N 0.000 claims description 2
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- 239000007892 solid unit dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JIDRDOSAKUEXPQ-UHFFFAOYSA-N tert-butyl 4-(1h-indol-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC2=CC=CC=C2N1 JIDRDOSAKUEXPQ-UHFFFAOYSA-N 0.000 description 1
- PDPSXASABIORPX-UHFFFAOYSA-N tert-butyl-(4-chloroindol-1-yl)-dimethylsilane Chemical compound C1=CC=C2N([Si](C)(C)C(C)(C)C)C=CC2=C1Cl PDPSXASABIORPX-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Description
Den foreliggende oppfinnelsen vedrører nye substituerte Nl-(benzensulfonyl) indolforbindelser, slike forbindelser for medisinsk bruk, farmasøytiske sammensetninger som omfatter forbindelsene og anvendelse av forbindelsene ved framstilling av et medikament for behandling av fedme og CNS-forstyrrelser.
Fedme er en tilstand som karakteriseres ved en økning av kroppsfettinnhold som resulterer i overskuddskroppsvekt utover aksepterte nonner. Fedme er den viktigste emæringsforstyrrelsen i den vestlige verden og representerer et stort helseproblem i alle industrialiserte land. Denne forstyrrelsen fører til økt dødelighet på grunn av økte forekomster av sykdommer slik som kardiovaskulær sykdom, fordøyelighetssykdom, åndedrettssykdom, kreft og NIDDM (type II diabetes). Leting etter forbindelser som reduserer kroppsvekt har pågått i mange tiår. En forskningslinje har vært aktivering av serotonergiske systemer, enten ved direkte aktivering av serotoninreseptorundertyper eller ved å hemme serotoningjenopptak. Den eksakte reseptorundertypeprofilen som kreves er imidlertid ikke kjent.
Serotonin (5-hydroksytryptamin eller 5-HT), en nøkkeltransmitter av det perifere og sentrale nervesystemet, modulerer et bredt omfang av fysiologiske og patologiske funksjoner, inkludert angst, søvnregulering, aggresjon, matinntak og depresjon. Flere serotoninreseptorundertyper er identifisert og klonet. En av disse, 5-HT6-reseptoren, ble klonet av flere grupper i 1993 (M Ruat, E Traiffort, J-M Arrang, J Tardivel-Lacombe, J Diaz, R Leurs, J-C Shwartz, Biochem. Biophys. Res. Commun. 1993,193 (1) 268-276: M Sebben, H Ansanay, J Bockaert, A Dumuis, NeuroReport 5, 2553-2557 (1994)). Denne reseptoren koples positivt til adenylylcyklase og viser affinitet for antipsykotiske midler slik som klozapin. Nylig ble effekten av 5-HT6-atagonist og 5-HT6-antisense oligonukleotider for å redusere matinntak hos rotter rapportert (JC Bentley, CA Mardsen, AJ Sleight og KC Fone, Effect of 5-HT6 antagonist Ro 04-6790 on food consumption in rats trained to a fixed feeding regime. Br J Pharmacol. 1999 Suppl. 126, P66; JC Bentley, AJ Sleight, CA Mardsen, KCF Fone, 5-HT6 antisense oligonucleotide ICV affects rat performance in the water maze and feeding. J Psychopharmacol Suppl A64,1997, 255).
Forbindelser med økt affinitet og selektivitet for 5-FnVreseptoren er blitt identifisert f.eks. i WO 00/34242 og av N. Isaac, A. Slassi, T. Xin, N. MacLean, J. Wilson, K. McCallum, H. Wang og L. Demchyshyn: 6-Bicyclopiperazinyl-l-arylsulfonylindoles and 6-Bicyclopiperidinyl-l-arylsulfonylindoles derivatives as novel, potent and selective 5-HT6 receptor antagonists; Bioorganic & Medicinal Chemistry Letters 2000,10, 1719-1721.
Ifølge den foreliggende oppfinnelsen er det funnet at forbindelsene med formel (I) viser affinitet for 5-HT6-reseptoren som antagonister ved et lav-nanomolarområde. 5-HT6-antagonistforbindelsene ifølge den foreliggende oppfinnelsen er nyttige ved behandling eller profylakse av fedme og ved behandling eller profylakse av hukommelses- og CNS-forstyrrelser (schizofreni, Parkinson's sykdom og depresjon), Attention Deficit Hyperactive Disorders (ADHD), legemiddelmisbruk/narkotikamisbruk.
Ifølge den foreliggende oppfinnelsen tilveiebringes en forbindelse med den generelle formel (I):
der
Ar er
(1) fenyl,
(2) naftyl,
(3) tienyl, pyrazolyl, pyridyl, tetrahydrokinolyl, tetrahydroisokinolyl, benzotienyl, imidazolyl, benzoxadiazolyl, eller
(4) -R<9->fenyl:
der hver av fenyl, naftyl og heterocyklisk ring uavhengig av hverandre eventuelt er substituert med halogen, C« alkyl, CF3, Ci-6 alkoksy, OCF3, COCF3, CN, N02 fenyloksy, fenyl, Ci.6 alkylsulfonyl, -Ci.6 alkyl-NH-CO-fenyl; og R<9> er Ci-6 alkyl eller C2-6 alkenyl, der hver av disse eventuelt er substituert med fenyl;
R<2> er H, fenyl, I eller Cu alkyl;
R<3> er H eller 3-(l-azabicyklo[2.2.2]okt-2-en)yl;
R<4> er en heterocyklisk ring valgt fra gruppen bestående av:
hvori R<6> ef H, Ci.6 alkyl eller benzyl; og
R<5> er Heller
forutsatt at R<4> er H når R<5> er R<6->piperazinyl;
eller et farmasøytisk akseptabelt salt, hydrat eller stereoisomer derav.
Betegnelsen "Ci-6 alkyl" angir en rettkjedet eller forgrenet alkylgruppe med fra 1 til 6 karbonatomer. Eksempler på nevnte lavere alkyl inkluderer metyl, etyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl og rettkjedet eller forgrenet pentyl og heksyl.
Betegnelsen "Ci-6 alkoksy" angir en rettkjedet eller forgrenet alkoksygruppe med fra 1 til 6 karbonatomer. Eksempler på nevnte lavere alkoksy inkluderer metoksy, etoksy, n-propoksy, iso-propoksy, n-butoksy, iso-butoksy, sec-butoksy, t-butoksy og rettkjedet og forgrenet pentoksy og heksoksy.
Betegnelsen "halogen" skal bety fluor, klor, brom eller jod.
Betegnelsen "heterocyklisk ring" inkluderer umettede, såvel som mettede eller delvis mettede heterocykliske ringer.
Foretrukne forbindelser ifølge oppfinnelsen er forbindelser med den generelle formel (I) der:
Ar er
(1) fenyl,
(2) 1-naftyl eller 2-naftyl,
(3) tienyl, pyrazolyl, pyridyl, tetrahydrokinolyl, tetrahydroisokinolyl, benzotienyl, imidazolyl, benzoxadiazolyl, eller (4) -R<9->fenyl;
der hver av fenyl, naftyl, og heterocyklisk ring uavhengig av hverandre eventuelt er substituert med F, Cl, Br, Ci-6 alkyl, CF3, Ci-6 alkoksy, OCF3, fenyl eller C2-6 alkenyl; og R<9> er Ci-2 alkyl;
R<2> er H, fenyl, I eller Ci.6 alkyl;
R<4> er valgt fra gruppen bestående av:
R<5> er valgt fra H eller R<6->piperazinyl.
Andre foretrukne forbindelser ifølge oppfinnelsen inkluderer de der:
(a) Ar er fenyl, eventuelt substituert med F, Cl, Br, metyl, CF3, CM alkoksy,OCF3, CN,
NO2, fenyloksy eller fenyl.
(b) Ar er 1-naftyl eller 2-naftyl, der hver av disse eventuelt kan være substituert med F,
Cl, Br, metyl, CF3, Cm alkoksy, OCF3, CN, N02, fenyloksy, metylsulfonyl eller fenyl. (c) Ar er en heterocyklisk gruppe valgt fra gruppen bestående av pyridyl, tienyl, imidazolyl, pyrazolyl, benzotienyl og benzoksadiazolyl, der hver av disse eventuelt kan være substituert med halogen, Ci-6 alkyl, CF3, Q-6 alkoksyl, OCF3, CN, NO2, fenyloksy, fenyl, Ci-6 alkylsulfonyl, C2-6 alkenyl. (d) Ar er en heterocyklisk ring valgt fra gruppen bestående av pyridyl, tienyl,
imidazolyl, pyrazolyl, benzotienyl og benzoksadiazolyl, der hver av disse eventuelt kan være substituert med halogen eller Ci-6 alkyl.
(e) Ar er 2-pyridyl, 3-pyridyl eller 4-pyridyl.
(f) Ar er -R<9->fenyl, der R<9> er C].3 alkyl eller C2-3 alkenyl, der hver av disse eventuelt
kan være substituert med fenyl og der fenyl eventuelt er substituert med fenyl. Ytterligere foretrukne forbindelser ifølge oppfinnelsen er forbindelser med den generelle formel (I) der R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci-3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
De følgende forbindelsene er særlig foretrukne utførelsesformer av oppfinnelsen: 1 -fenylsulfonyl-4-piperazinylindol hydroklorid, 1 -[(2,5-dimetoksyfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -(mesitylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -(1 -naftylsulfonyl)-4-) 1 -piperazinyl)-1 H-indol hydroklorid, N,N-dimetyl-5 {[4-(l -piperazinyl)-1 H-indol-1 -yljsulfonyl} -1 - naftalenaminhydroklorid 1 [(4-propoksyfenyl)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1- [(2,5-diklor-3-tienyl)sulfonyl]-4-(l-piperazinyl-lH-indol hydroklorid, 1 - [(4-metoksyfenyl)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 [(2,4-difluorfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -([ 1,1' -bifenyl] -4-ylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -[(3,4-dimetoksyfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 5 -metyl-2-metoksy- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenyleter hydroklorid, 1 -[(2,5-diklorfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -[(5 -klor-1,3 -dimetyl-1 H-pyrazol-4-yl)sulfonyl] -4-(l -piperazinyl)-1 H-indol hydroklorid, 1 - [(3 -klor-2-metylfenyl)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid,
2- klor-5 -(4- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenoksy)benzonitril hydroklorid,
4-brom-2- {[4-(l -piperazinyl)-1 H-indol-1 -yl]sulfonyl} fenylmetyleter hydroklorid,
4-( 1 -piperazinyl)-1 -(3 -pyridylsulfonyl)-1 H-indol hydroklorid,
7- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} -2-(trifluoracetyl)-1,2,3,4-tetrahydroisokinolin hydroklorid,
metyl 2- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenylsulfon hydroklorid, 1 -[(4-fluorfenyl)sulfonyl]-4-(l -piperazinyl)- lH-indol hydroklorid, 1 -[(5-klor-3-metyl- l-benzotien-2-yl)sulfonyl]-4-(l -piperazinyl)- lH-indol hydroklorid,
4-(4-metyl-1 -piperazinyl)-1 -(4-metylbenzensulfonyl)-1 H-indol hydroklorid hydroklorid,
4-piperazino-N-(4-trifluormetyl)fenylsulfonyl)indol hydroklorid,
4-(3-metylpiperazin)-(N-(4-trifluormetyl)fenylsulfonyl)indol
dihydroklorid,
4-(4-metyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-etyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol
hydroklorid,
4-( 1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid, 4-(5 -aza-indolizidinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-metyl-1 -homopiperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(3 -metyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid, 4-(cw-3,5-dimetyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-isopropyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-((l S,4S)-2-metyl-2,5-diazabicyklo[2.2.1 ]heptyl)-l -(2-metylbenzensulfonyl)- lH-indol hydroklorid,
4-(4-metyl-1 -homopiperazinyl)-1 -(benzensulfonyl)-1 H-indol
hydroklorid,
4-( cis 3,5-dimetyl-1 -piperazinyl)-1 -(benzensulfonyl)-1 H-indol hydroklorid,
4-(4-etyl-1 -piperazinyl)-1 -(benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-nitro-benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-brom-benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-klor-benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-\-{ E 2-fenyl-etensulfonyl)-lH-indol hydroklorid,
4-piperazinyl-1 -(3 -trifluormetyl-benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-cyanobenzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-klor-7-klor-2,1,3-benzoksadiazolsulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(3-cyanobenzensulfonyl)-l H-indol hydroklorid,
4-piperazinyl-1 -(4-fenoksybenzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-klorfenylmetansulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-metylfenylmetansulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(1,1 -difenyletansulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(4-trifluormetoksybenzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-l-(5-[(benzoylamino)metyl]tiofen-2-sulfonyl)-lH-indol hydroklorid, l-[(N-metyl-lH-imidazolyl-4-yl)sulfonyl]4-(l-piperazinyl)-lH-indol hydroklorid,
N-benzensulfonyl5 -(4-metylpiperazin-1 -yl)-indol,
N-(4-metylbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol,
N-benzensulfonyl-5 -(4-isopropylpiperazin-1 -yl)-indol,
N-(4-metylbenzensulfonyl)-5-(4-isopropylpiperazin-1 -yl)-indol,
N-(3,4-dimetoksybenzensulfonyl)-5-(4-propylpiperazin-l-yl)-indol, hydroklorid,
N-(3 -fluorbenzensulfonyl)-5 -(4-propylpiperazin-1 -yl)-indol, hydroklorid,
N-(4-propylbenzensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-( 1 -naftalensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-(bifenyl-4-sulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid,
N-(4-metoksybenzensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-(3,4-dimetoksybenzensulfonyl)-5 -(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-(2,4-difluorbenzensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid, N-(4-metoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(2,4-difluorbenzensulfonyl)-5-84-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(4-butoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(3,4-dimetoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(bifenyl-4-sulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(naftalen-2-sulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(4-propylbenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(3 -fluorbenzensulfonyl)-5 -(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(4-metoksybenzensulfonyl)-5-(piperazin-l -yl)-indol, hydroklorid,
N-(2,4-difluorbenzensulfonyl)-5-piperazin-l -yl)-indol, hydroklorid,
N-(4-butoksybenzensulfonyl)-5-(piperazin-1 -yl)-indol, hydroklorid,
N-(3,4-dimetoksybenzensulfonyl)-5-piperazin-l-yl)-indol, dihydroklorid,
N-(bifenyl-4-sulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid,
N-(naftalen-2-sulfonyl)-5 -(piperazin-1 -yl)-indol, dihydroklorid,
N-(4-propylbenzensulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid,
N-(3-fluorbenzensulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid,
N-benzensulfonyl-5-(piperazin-l -yl)-indol, dihydroklorid,
3- (l-azabicyklo[2.2.2]okt-2-en-3-yl)-l-[(4-fluorfenyl)sulfonyl]-lH-indol,
2-j od-1 -(fenylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
2-fenyl-1 -(fenylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
4- piperazinyl-2-metyl-l-benzosulfonylindol trifluoracetat, eller
1 -fenylsulfonyl-4-(homopiperazinyl)-indol hydroklorid.
Visse forbidnelser med formel (I) kan foreligge som stereoisomere former inkludert diastereomere og enantiomere og oppfinnelsen omfatter hver av disse stereoisomere formene og blandinger derav inkludert racemater. De forskjellige stereoisomere formene kan separeres fra hverandre ved konvensjonelle metoder. Enhver angitt isomer kan oppnås ved stereospesifikk eller asymmetrisk syntese. Oppfinnelsen omfatter også alle tautomere former og blandinger derav.
Forbindelsene med formel (I) kan danne syreaddisjonssalter med syrer slik som konvensjonelle farmasøytisk akseptable syrer, for eksempel maleinsyre, saltsyre, hydrobromsyre, fosforsyre, eddiksyre, fumarsyre, salicylsyre, sitronsyre, melkesyre, mandelsyre, vinsyre og metansulfonsyre.
Forbindelsene med formel (I) kan også danne solvater slik som hydrater og oppfinnelsen omfatter også disse formene. Når det her refereres til, skal det forstås at betegnelsen "forbindelse med formel (I)" også inkluderer disse formene.
Forbindelsene ifølge formel (I) kan administreres konvensjonelt i en farmasøytisk sammensetning som inneholder forbindelsen i forening med farmakologiske og farmasøytisk akseptable bærere. Slike farmasøytiske sammensetninger kan fremstilles ved metoder og inneholde bærere eller eksipienter som er velkjente innenfor fagområdet. Et generelt anerkjent kompendium med slike metoder og ingredienser er Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15. utgave, 1975). Forbindelsene og sammensetningene kan administreres oralt, parenteralt (for eksempel ved intravenøs, intraperitonal eller intramuskulær injeksjon), transdermalt eller rektalt.
For oral terapeutisk administrering kan den aktive forbindelsen forenes med en eller flere eksipienter og benyttes på formen av tabletter, bukkale tabletter, trokéer, kapsler, eliksirer, suspensjoner, siruper, oblater og lignende. Slike sammensetninger og preparater bør inneholde minst 0.1% av aktiv forbindelse. Prosenten av sammensetningene og preparatene kan naturligvis variere og kan konvensjonelt være mellom omtrent 2 til omtrent 60 vekt% av en gitt enhetsdoseirngsform. Mengden av aktiv forbindelse i slike terapeutisk anvendbare sammensetninger er slik at et effektivt doseringsnivå vil oppnås.
Tablettene, trokéene, pillene, kapslene og lignende kan også inneholde følgende: bindmidler slik som gummitragant, akasie, maisstivelse eller gelatin; eksipienter slik som dikalsiumfosfat; et desintegreringsmiddel slik som maisstivelse, potetstivelse, alginsyre og lignende; et smøremiddel slik som magnesiumstearat; et søtningsmiddel slik som sukrose, fruktose, laktose eller aspartan eller et smaksstoff slik som peppermynte, vintergrønnolje, eller kirsebærsmak kan tilsettes. Når enhetsdoserings-formen er en kapsel, kan den inneholde en flytende bærer slik som en vegetabilsk olje eller en polyetylenglykol i tillegg til materialer av den ovennevnte typen. Forskjellige andre materialer kan være tilstede som belegg eller på annen måte å modifisere den fysiske formen av den faste enhetsdoseirngsformen. For eksempel kan tabletter, piller eller kapsler belegges med gelatin, voks, skjellakk eller sukker og lignende. En sirup eller eliksir kan inneholde den aktive forbindelsen, sukrose eller fruktose som et søtningsmiddel, metyl og polyparabener som konserveringsmidler, et fargestoff og smaksstoff slik som kirsebær eller appelsinaroma. Naturligvis bør ethvert materiale som benyttes ved fremstilling av en hvilken som helst enhetsdoseringsform være farmasøytisk akseptabel og i det alt vesentlige ikke-toksisk i mengdene som benyttes. I tillegg kan den aktive forbindelsen innarbeides i vedvarende frigivelsespreparater og innretninger.
Forbindelsene eller sammensetningene kan også administreres intravenøst, eller intraperitonalt ved infusjon eller injeksjon. Løsninger av den aktive forbindelsen eller dets salter kan fremstilles i vann, eventuelt blandet med et ikke-toksisk overflateaktivt stoff. Dispersjoner kan også fremstilles i glyserol, flytende polyetylenglykoler, triacetin, og blandinger derav og i oljer.
Anvendelige doseringer av forbindelsene med formel I kan bestemmes ved å sammenligne deres in vifro-aktivitet og in vivo-aktivitet ved dyremodeller. Metoder for ekstrapolering av effektive doseringer hos mus og andre dyr, til mennesker er kjent innenfor fagområdet; se for eksempel U.S. patent nr. 4,938,949.
Forbindelsen kan administreres på enhetsdoseringsform; for eksempel som inneholder omtrent 0.05 mg til omtrent 500 mg, konvensjonelt omtrent 0.1 mg til omtrent 250 mg, mest konvensjonelt omtrent 1 mg til omtrent 150 mg av aktiv ingrediens pr enhetsdoseringsform. Den ønskede dosen kan være tilstede i en enkelt dose eller som oppdelte doser som administreres ved passende intervaller.
Sammensetningene kan administreres oralt, sublingualt, transdermalt eller parenteralt ved doseringsnivåer på omtrent 0.01 til omtrent 150 mg/kg, foretrukket omtrent 0.1 til omtrent 50 mg/kg, og mer foretrukket omtrent 0.1 til omtrent 30 mg/kg av pattedyrets kroppsvekt.
TABELL 1
Forbindelser fremstilt ifølge syntetisk skjema 1 eller 2.
Alle forbindelser i tabell I er hydrokloirdsalter.
Generelle synteseskjemaer
Skjema 1: (i) NaH, THF, TBDMSC1 eller TIPSC1 i CH2C12; (ii) X = Br: t-Bu3P, Pd(OAc)2, Diamin valgt fra NaOt-Bu, xylen; (ii) BU4NF IM, THF eller NaF, Etylacetat;
(iv) Ar-S02Cl, Py eller NaOH eller NaH CH2C12; (v) HC1 i eter.
Skjema 2: (i) (CF3S02)20, Et3NCH2Cl2; (ii) Ar-S02Cl, Py eller NaOH eller NaH CH2C12; (iii) X = Br: t-Bu3P, Pd(OAc)2, Diamin valgt fra, Na-Ot-Bu, xylen; (iv) Hel i titer
■ De angitt strukturene ble bekreftet ved standard spektroskopiske metoder og elementanalyse og/eller høyoppløsnings-MS.
NMR-spekter ble oppnådd ved bruk av en Bruker 500 M Hz eller JEOL 270 M Hz spektrometre ved 25°C, og de kjemiske skiftverdiene er rapportert som parts pr million (8). MS-spekteret ble oppnådd på en 2690 separasjonsmodul (Waters) med en plattform LCZ (mikromasse). Flashkromatografi ble utført på silikagel 60 (Merck) eller LiChroprep RP-18 (Merck). HPLC-analyse ble utført på en HP Series 1100, med GROM-SIL 100 ODS-0 AB-kolonne, 4.6x50 mm. HPLC-rensingene ble utført på preparativt HPLC/massesystem ved å benytte YMC Combi prep ODSAQ-kolonne, 56x20 mm, Gilson pumper, Dynamax UV-l-detektor og Finnigan massedetektor. De benytte eluentene var H2O og CH3CN, begge med 0.1% TF A. Renheten av forbindelsene ble bestemt ved HPLC. Elementanalyse ble utført ved strukturkjemiavdelingen, Biovitrum AB, Stockholm. Smeltepunkter ble tatt med et Biichi eller Gallenkamp smeltepunktapparat når de er oppgitt og er ukorrigerte.
Generelle Syntesemetoder
Metode 1: Buchwald-kopling mellom aryltriflater eller arylhalider og aminer
Til en løsning av aryltriflat (1 ekv.) i xylen tilsettes, under N2 spyling, Pd(OAc)2 (0.6 ekv.), (i?)-2,2'-bis(difenylfosfino)-l,l'-binaftyl (BINAP) (0.1 ekv.) og Cs2C03 (3 ekv.), etterfulgt av amin (2 ekv.). Blandinger varmes til 100°C-120°C under røring (TLC-registrering). Rensing ved flashkromatografi [Si02, CHCI3 til MeOH:CHCL3:aq NH3 (10:90:0.,4%)] ga sluttforbindelsene. Sluttforbindelsene omdannes til deres hydrokloridsalter ved å oppløse de frie basene i metanol og dietyleter (1:9) etterfulgt av tilsetning av HC1 i dietyleter.
Metode 2: Buchwald-kopling mellom arylhalider og aminer
Til en blanding av 4-bromindoler (1 ekv.), f-B^P (9.05 kvi.) eller 2-(dicykloheksylfosfino)bifenyl (0.05 ekv.), og Pd (Oac)2 (0.02 ekv.) i xylen tilsettes aminer (2.8 ekv.) og NaOt-Bu (2.8 ekv.). Reaksjonen varmes opp ved 120°C i 4 timer, filtreres gjennom celitt og løsningsmiddelet fjernes. Råblandingene renses ved kolonnekromatografi (SiCh, CH2Cl2/heptan 1:4) for å gi sluttforbindelser. Sluttforbindelsene omdannes til deres hydrokloridsalter ifølge samme prosedyre som beskrevet i metode 1.
Metode 3: Sulfonylering i nærvær av NaOH
Arylsulfonylklorider (0.75 mmol) tilsettes en kald (0°C) løsning av indolderivater (0.5 mmol), knust NaOH (3 mmol) og tetrabutylammoniumhydrogensulfat (0.05 mmol) i
CH2CI2 (3 ml). Blandingene ristes i 30 minutter ved 0°C og 30 minutter ved romtempreatur. Hver blanding blir deretter filtrert gjennom et sjikt av hydromatriks (Varian; 3 cm) og silikagel (0.5 cm). Systemet vaskes med CH2CI2 (2x3 ml) og løsningsmiddelet fordampes under vakuum. De oppnådde restene (sluttprodukter som fri base) oppløses i CH2CI2 (3 ml) og HC1 i eter tilsettes (2 ml) og ristes i 2 timer ved romtemperatur. De oppnådde utfellingene samles opp ved filtrering til å gi sluttforbindelsene som hydrokloirdsalter. Renheten av forbindelsene analyseres ved LC og renses til slutt ved LC/MS om nødvendig.
Metode 4: Sulfonylering i nærvær av NaH
Sulfonylklorider (1.5 ekv.) tilsettes til indolderivater (1 ekv.) og NaH 60% dispersjon i olje (2 ekv.) i CH2Cl2-holdig DNF (1%). Etter 1 time ved romtemperatur avkjøles reaksjonen med vann, filtreres og løsningsmiddelet fjernes. Rensing ved kolonnekromatografi (Si02, CH2Cl2:MeOH 9:1:0.4% NH3) ga sluttforbindelsene. Sluttforbindelsene overføres til deres hydrokloirdsalter ved prosedyren som er beskrevet i metode 1.
Metode 5: Sulfonylering av natriumsalt av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A)
NaH (163 mg, 6.5 mmol) tilsettes til en løsning av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (1.50 g, 6.50 mmol) i THF (45 ml). Reaksjonen røres ved romtemperatur i 0.5 t. Suspensjonen fortynnes til 60 ml med THF og fordeles i 30 reaksjonsglass (beholdsningsløsning A). Diverse sulfonylklorider (0.25 mmol) i THF (2 ml) tilsettes til beholdningsløsningen A (2 ml). Reaksjonene ristes i 3 t etterfulgt av tilsetning av MeOH (100 |oL). Polysyren-trisamin (PS-trisamin) tilsettes i blandingene og reaksjonene røres ved romtemperatur over natten. Blandingene filtreres gjennom en kort silikakolonne og de flyktige forbindelsene fjernes. Råproduktene oppløses i MeOH (2 ml) etterfulgt av tilsetning av HCl/eter 2 M (4 ml). Etter 0.5 t ble prøven sentrifugert og supernatanten ble dekantert etter 0.5 timer. Det gjenværende faste stoffet ble vasket med (eter) og tørket under vakuum til å gi hydrokloirdsaltene.
EKSEMPEL 1 (Mellomprodukt)
4-Brom-l-(tri-isopropylsilyl)-lH-indoI (Skjema 1)
NaH 60% dispersjonen i olje (0.94 g, 23.4 mmol) ble tilsatt til en løsning av 4-bromindol (3.07 g, 15.6 mmol) og triisopropylsilylklorid (3,62 g, 18.8 mmol) i CH2C12 (50 ml) og DMF (2 ml). Reaksjonen ble rørt ved romtempratur i 1 time og avkjølt med vann. Det uløselige materialet ble filtrert fra og løsningsmiddelet ble fjernet. Rensing med kolonnekromatografi (Si02, CH2Cl2/heptan 1:4) ga 3.44 g (63%) av tittelforbindelsen: <!>H NMR (CDC13) 8 7.42-6.63 (m, 5H), 1.66 (sept, 7 = 8 Hz, 3H), 1.10 (d, J= 8 Hz, 18H; MS (ESI) 354.4 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 2 (Mellomprodukt)
N-tert-Butyl-trimetylsilyl-4-klorindol (Skjema 1)
4-Klorindol (131.1 g, 0.871 mol) ble oppløst i tørr THF (0.5 L). Løsningen ble avkjølt til 0°C (isbad, røring). t-BuOK (97.6 g, 0.871 mol) ble tilsatt i en porsjon og røringen ble fortsatt i ytterligere 5 minutter. Tert-butyldimetylklorsilan (131.3 g, 0.871 mol) ble tilsatt porsjonsvis i løpet av 10 minutter med en god røring. Reaksjonen er eksoterm. Etter 30 minutter ble reaksjonen avkjølt med vann (20 ml) og pH ble justert til 8-9 og ekstrahert med etylacetat (3 x 50 ml). De organiske fasene ble tørket (MgSCu), filtrert og de flyktige stoffene ble eliminert ved vakuum. Resten ble finfordelt og krystallisert fra heptan til å gi 181 g (78%) av tittelforbindelsen. <*>H NMR (CDC13) 8 7.45 (dd, J= 7.9 Hz, J= 0.8 Hz, 1H), 7.25 (d, J= 3.0 Hz, 1H), 7.18-7.07 (m, 2H), 6.77 (d, 1H), 0.96 (s, 9H), 0.62 (s, 6H); <13>C NMR (CDC13) 141.8; 131.7; 130.3; 125.9; 122.0; 119.7; 112.5; 103.5; 26.3; 19.5; -3.9; MS (ESI) 266.1 (M+H).
EKSEMPEL 3 (Mellomprodukt)
4-(4-Metyl-l-Piperazinyl)-l-(triisopropylsilyl)-lH-indoI (Skjema 1)
Forbindelsen ble fremstilt ifølge metode 2 fra 4-brom-l-(triisopropylsilyl)indol (0.090 g, 0.255 mmol), r-Bu3P (3.6 mg, 0.014 mmol) og Pd (Oac)2 (1 mg,0.0036 mmol) i xylen (3 ml) og 4-metyl-l-piperazin (0.135 g, 0.73 mmol) og NaOf-Bu (69 mg, 0.72 mmol). Råmaterialet ble renset ved kolonnekromatografi (Si02, CH2Cl2/heptan 1:4) til å gi 90 mg (84%) rent materiale: <!>H NMR (CDC13) 8 7.19-6.56 (m, 5H), 3.31-3.25 (m, 4H), 2.71-2.63 (m, 4H), 2.36 (s, 3H), 1.76 (sept, J= 8 Hz, 3H), 1.11 (d, J= 8 Hz, 18H); MS (ESI) 372.5 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 4 (Mellomprodukt)
N-tert-ButyldimetylsilyI-2-(4-Boc-piperazinyI)-indol (Skjema 1)
Forbindelsen ble fremstilt ifølge metode 2 fra N-tert-butyldimetylsilyl-4-klorindol (100 g, 376 mmol, 1 ekv.), tert-butyl 1-piperazinkarboksylat (84 g, 451mmol), Palladium(U) acetat (1.26 g, 5.62 mmol, 2%), 2-(dicykloheksylfosfmo)-bifenyl (3.95 g, 11.28 mmol %), tert-BuONa (50 g, 520 mmol, 1.4 ekv.) i toluen. Løsningen ble avkjølt i romtemperatur og KH2PO4 (150 ml, 13% vandig løsning) ble tilsatt og pH ble justert (pH = 8-9) etterfulgt av ekstraksjon med toluen (2 x 100 ml), tørket (MgSQ*) og fordampet. Resten ble krystallisert fra heptan til å gi 124.4 g (79.6%). 'H NMR (CDC13) 8 7-10 (d, J= 8.4 Hz, 1H), 7.13 (d, J= 3.2 Hz, 1H), 7.06 (t, 1H), 6-60-6.57 (m, 2H), 3.65 (t, 4H), 3.16 (t, 4H), 1.48 (s, 9H), 0.91 (s, 9H), 0.58 (s, 6H); <13>C NMR (CDCI3) 8 155.0; 145.5; 142.2; 129.9; 124.9; 122.0; 109.3; 107.2; 102.9; 79.8; 77.3; 51.5; 28.5; 26.4; 19.5; -3.8; MS (ESI 416.4 (M+H).
EKSEMPEL 5 (Mellomprodukt)
4-(4-Boc-piperazinyl)-indoI (Skjema 1)
En blanding av N-tert-butyldimetylsilyl-4-(4-tert-butyloksykarbonat-piperazinyl)-indol (4) (116.9 g, 281 mmol), NaF (30 g, 714 mmol), AcOEt (440 g), vann (200 ml) og BU4NSO4 (2 g, 6 mmol) ble varmet under kraftig røring ved 50-60°C under N2 i 21. Den organiske fasen ble separert og vannfasen ble ekstrahert en gang til med AcOEt (100 ml). De organiske fasene ble tørket (MgS04), fordampet og co-fordampet med etanol. Resten ble krystallisert fra eter.heksan (1:3) til å gi 81.0 g (95.6%) av tittelforbindelsen.
'H NMR (CDCI3) 8 8.59 (bs, 1H); 7.12-7.02 (m, 3H), 6.58 (d, J= 6.9 Hz, 1H), 7.53 (t, 1H), 3.69 (t, 4H), 3.19 (t, 4H), 1.53 (s, 9H); <13>C NMR (CDC13) 8 155.1; 145.5; 137.1; 123.3; 122.6; 121.4; 106.9; 106.5; 100.8; 80.0; 77.4; 51.4; 28.6; MS (ESI 302.2 (M+H).
EKSEMPEL 6 (Mellomprodukt)
4-(4-Metyl-l-piperazinyl)-lH-indol (Skjema 1)
En blanding av 4-(l-metyl-l-piperazinyl)-l-(triisopropylsilyl)-lH-indol (110 mg, 0.296 mmol) og BU4NF IN i THF (1 ml) ble rørt ved romtemperatur i 11. En blanding av CH2Cl2/heptan 1:1 (10 ml) ble tilsatt etterfulgt av filtrering gjennom silika. Produktet ble renset ved kolonnekromatografi (Si02, CH2Cl2:MeOH 9:1 0.4% NH3) til å gi 60 mg (94%) av tittelproduktet: !H NMR (CD3OD) 8 7.11-6.41 (m, 5H), 3.30-3.23 (m, 4H), 2.7-2.66 (m, 4H), 2.37 (s, 3H); MS (ESI) 216.4 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 7
1 -Fenylsulfonyl-4-piperazinylindol dihydroklorid
Tittelforbindelsen ble fremstilt fra 4-boc-piperazinyl-indol og fenylsulfonylklorid ifølge metode 3: lK NMR (DMSO-d6) 8 9.64 (brs, 2H), 7.98-7.94 (m, 4H), 7.80-7.77 (m, 1H), 7.70-7.65 (m, 1H), 7.63-7.55 (m, 3H), 7.27-7.22 (m, 1H), 6.95 (d, J= 3.76 Hz, 1H), 6.81-6.77 (m, 1H), 3.31.-320 (n, 4H); <13>C NMR (DMSO-de) 5 144.79,137.02,135.22, 134.62,129.82,126.65,125.54,123.49,111.15,107.87,107.76,47.81,42.86. Anal.
(C18H19N3Q2S 2HC1 0.5 H20) C, H, N.
EKSEMPEL 8
1 - [(2,5-Dimetoksyfenyl)sulfonyl] -4-(l -piperazinyl)-l H-indol hydroklorid
(Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2,5-dimetoksyfenyl)sulfonylklorid ifølge metode 3: 'H NMR (500 M Hz, DMSO-d6) 8 8.95 (br, 1H), 7.71 (d, J= 5 Hz, 1H), 7.52 (d, J= 5 Hz, 1H), 7.38 (d, J= 8 Hz, 1H), 7.27 (d, <y>=8Hz, lH),7.14(t,J=8 Hz, 1H), 7.13 ( d, J= 8 Hz, 1H), 6.86 (d, J= 5 Hz, 1H), 6.77 (d, J= 8 Hz, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 3.40-3.20 (m, 8H); MS (ESI+) for m/ z 402 M+H)<+>.
EKSEMPEL 9
l-(Mesitylsulfonyl)-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og mesitylsulfonylklorid ifølge metode 3: <!>H NMR (270 M Hz, DMSO-d6) 8 9.10 (br, 1H), 7.71 (d, J= 5 Hz, 1H), 7.40-7.20 (m, 3H), 7.00-6.80 (m, 2H), 6.51 (d, J= 8 Hz, 1H), 3.30-3.20 (m, 8H, 2.41 (s, 6H), 2.27 (s, 3H); MS (ESI+) for m/ z 384 (M+H)<+>.
EKSEMPEL 10
l-(l-Naftylsulfonyl)-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og naftylsulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.03 (br, 1H), 8.63 (d, J= 8 Hz, 1H), 8.43 (d, J= 8 Hz, 1H), 8.34 (d, J= 8 Hz, 1H), 8.15-8.05 (m, 2H), 7.80-7.65 (m, 3H), 7.41 (d, J= 8 Hz, 1H), 7.18 (t, J= 8 Hz, 1H), 6.93 (d, J= 5 Hz, 1H, 3.30-3.20 (m, 8H); MS (ESI+) for m/ z 392 (M+H)<+>.
EKSEMPEL 11
N,N-Dimetyl-5-{[4-(l-piperazinyl)-lH-indol-l-yI]sulfonyl}-l-naftalenamin hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 5-N,N-dimetyl-naftalenamin-l-sulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.25 (br, 1H), 8.63 (d, J = 8 Hz, 1H), 8.41 (d, J = 8 Hz, 1H), 8.29 (d, J= 8 Hz, 1H), 8.12 (m, 2H), 7.80-7.65 (m, 3H), 7.41 (d, J= 8 Hz, 1H), 7.18 (t, J= 8 Hz, 1H), 6.93 (d, J= 5 Hz, 1H), 6.74 (d, J= 8 Hz, 1H), 3.30-3.20 (m, 8H), 2.82 (m, 6H); NS (ESI+) for m/ z 435
(M+H)<+.>
EKSEMPEL 12 l-[(4-Propoksyfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 4-propoksyfenylsulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.03 (br. 1H), 7.89 (d, J= 8 Hz, 2H), 7.78 (d, J= 5 Hz, 1H), 7.61 (d, J= 8 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.07 (d, J= 8 Hz, 2H), 6.93 (d, J= 5 Hz, 1H), 6.67 (d, J= 8 Hz, 1H), 4.01 (t, J= 7 Hz, 2H), 3.28 (m, 8H), 1.66 (m, 2H), 1.38 (m, 2H), 0.88 (t, J= 7 Hz, 2H), MS (ESI+) for m/ z 414 (M+H)<+>.
EKSEMPEL 13
l-[(2,5-Diklor-3-tienyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2,5-diklor-3-tienylsulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.24 (br 1H), 7.78 (d, J= 5 Hz, 1H), 7.72 (s, 1H), 7.57 (d, J= 8 Hz, 1H), 7.29 (t, J= 8 Hz, 1H), 7.01 (d, J= 5 Hz, 1H), 6.86 (d, J= 8 Hz, 1H), 3.31 (m, 8H). MS (ESI+) for m/ z 416 (M+H)<+.>
EKSEMPEL 14
l-[(4-Metoksyfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 4-metoksyfenylsulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.07 (br 1H), 7.90 (d, J= 8 Hz, 2H), 7.78 (d, J= 5 Hz, 1H), 7.61 (d, J= 8 Hz, 1H), 7.25 (t, J= 8 Hz, 1H), 7.09 (d, J= 8 Hz, 2H), 6.92 (d, J= 5 Hz, 1H), 6.68 (d, J= 8 Hz, 1H), 3.79 (s, 3H), 3.24 (n, 8H); MS (ESI+) for m/ z 371 (M+H)<+>.
EKSEMPEL 15
l-[(2,4-Difluorfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2,4-di-fluorfenylsulfonylklorid ifølge metode 3: 'H NMR (270 M Hz, DMSO-d6) 8 9.41 (br, 1H), 8.25 (m, 1H), 7.75 (m, 1H), 7.58 (m, 1H), 7.47-7.33 (m, 2H), 7.23 (t, J = 8 Hz, 1H), 6.99 (d, /= 5 Hz, 1H), 6.70 (d, J= 8 Hz, 1H), 3.25 (m, 8H). MS (ESI+) for m/ z 378 (M+H)<+>.
EKSEMPEL 16
l-([l,l'-Bifenyl]-4-yl-sulfonyl)-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og l,l'-bifenyl-4-ylsulfonylklorid ifølge metode 3: <]>H NMR (270 M Hz, DMSO-d6) 8 9.26 (br, 1H), 8.04 (m, 2H), 7.88 (m, 3H), 7.67 (m, 3H), 7.46 (m, 3H), 7.27 (t, J= 8 HZ, 1H), 6.96 (d, J = 5 Hz, 1H), 6.80 (d, J= 8 Hz, 1H), 3.25 (m, 8H); MS (ESI+) for m/ z 418 (M+H)<+>.
EKSEMPEL 17
1 -[(3,4-Dimetoksyfenyl)sulfonyl]-4-(l-piperazinyl)-1 H-indol hydroklorid (Skjerna 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 3,4-dimetoksyfenylsulfonylklorid ifølge metode 3: <*>H NMR (270 M Hz, DMSO-d6) 8 9.00 (br, 1H), 7.82 (d, J5 Hz, 1H), 7.66 (d, J= 8 Hz, 1H), 7.57 (m, 1H), 7.40 (d, J = 3 Hz, 1H), 7.24 (t, J = 8 Hz,lH), 7.10 (d, J= 8 Hz, 1H), 6.90 (d, J= 5 Hz, 1H), 6.78 (d, J= 8 Hz, 1H), 3.78 (s, 6H), 3.24 (m, 8H); MS (ESI+) for m/ z 402 (M+H)<+>.
EKSEMPEL 18
5-Metyl-2-metoksyl-{[4-(l-piperazinyl)-lH-indol-l-yI]sulfonyl}fenyleter hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 5-metyl-2-metoksyfenylsulfonylklorid ifølge metode 3: 'H NMR (270 M Hz, DMSO-d6) 8 9.45 (br, 1H), 7.92 (d, J= 8 HZ, 1H), 7.70 (d, J= 5 Hz, 1H), 7.30 (d, J= 8 Hz, 1H), 7.13 (t, J = 8 Hz, 1H), 7.01-6.92 (m, 2H), 6.83 (d, J = 5 Hz, 1H), 6.73 (d, J= 8 Hz, 1H), 3.70 (s, 3H), 3.26 (m, 8H, 3.32 (s, 3H); MS (ESI+) for m/ z 386 (M+H)<+>.
EKSEMPEL 19
l-[(2,5-Diklorfenyl)sulfonyl]-4-(l-piperazinyI)-lH-indol hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2,5-diklorfenylsulfonylklorid ifølge metode 3: <]>H NMR (270 M Hz, DMSO-d6) 8 9.09 (br, 1H), 8.25 (d, J= 3 Hz, 1H), 7.91-7.81 (m, 2H), 7.72 (d, J= 8 Hz, 1H), 7.36 (d, J= 8 Hz, 1H), 7.23 (t, J= 8 Hz, 1H), 6.98 (d, J= 3 Hz, 1H), 6.82 (d, J= ( Hz, 1H), 3.26 (m, 8H).
EKSEMPEL 20
1- [(5-Klor-l,3-dimetyl-lH-pyrazol-4-yl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 5-klor-l,3-dimetyl-lH-pyrazol-4-yl-sulfonylklorid ifølge metode 3: 'H NMR (270 M Hz, DMSO-d6) 8 9.17 (br, 1H), 7.78 (d, J= 3 Hz, 1H), 7.49 (d, J = 8 Hz, 1H), 7.28 (t, J= 8 Hz, 1H), 6.93 (d, J = 3 Hz, 1H), 6.87 (d, J= 8 Hz, 1H), 3.72 (s, 3H), 3.28 (m, 8H), 2.34 (s, 3H); MS (ESI+) form/z 394 (M+H)<+>.
EKSEMPEL 21
1 -[(3-Klor-2-metylfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjerna 1)
Forbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 3-klor-2-metoksyfenylsulfonylklorid ifølge metode 3: 'H NMR (270 MHz, DMSO-d6) 8 9.21 (br, 1H), 7.89 (d, J= 3 Hz, 1H), 7.82 (t, J= 8 Hz, 1H), 7.51 (t, J= 8 Hz, 1H), 7.19 (d, J = 8 Hz, 1H), 7.10 (t, J= 8 Hz, 1H), 7.01 (d, J= 3 Hz, 1H), 6.81 (d, J= 8 Hz, 1H), 3.29 (m, 8H), 2.54 (s, 3H); MS (ESI+) for m/ z 390 (M+H)<+>.
EKSEMPEL 22
2- Klor-5-(4-{[4-(l-piperazinyl)-lH-indol-l-yl]sulfonyl}fenoksy)benzonitril hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstil fra 4-(4-boc-piperazinyl)-indol og 2-klor-5-[(4-(piperazinyl)-lH-indol-l-yl]-sulfonylklorid ifølge metode 3: <]>H NMR (270 M Hz, DMSO-d6) 8 9.20 (br, 1H), 8.06 (d, J= 8 Hz, 2H), 7.81 (d, J= 3 Hz, 1H), 7.75-7.55 (m, 3H), 7.30-7.15 (m, 4H), 6.97 (d, J= 3 Hz, 1H), 6.82 (d, J8 Hz, 1H), 3.27 (m, 8H); MS (ESI+) for m/ z 493 (M)<+>, 495.
EKSEMPEL 23
4-Brom-2-{[4-(l-piperazinyl)-lH-indoI-l-yl]sulfonyl}fenylmetyleter hydroklorid
(Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 4-brom-2-fenylmetyletersulfonylklorid ifølge metode 3: <*>H NMR (270 MHz, DMSO-d6) 5 9.40 (br, 1H), 8.12 (d, J= 3 Hz, 1H), 7.88 (d, J= 8 Hz, 1H), 7.72 (d, J= 5 Hz, 1H), 7.37 (d, J = 8 Hz, 1H), 7.25-7.10 (m, 2H), 6.89 (d, J= 3 Hz, 1H), 6.78 (d, J = (Hz, 1H), 3.71 (s, 3H), 3.29 (m, 8H); MS (ESI+) for m/ z 450 (M)<+>, 452.
EKSEMPEL 24
4-(l-Piperazinyl)-l-(3-pyridinylsulfonyl)-lH-indol hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra metode 3: <*>H NMR (270 MHz, DMSO-d6) 5 9.37 (br, 1H), 9.19 (d, J= 3 Hz, 1H), 8.86 (d, J= 5 Hz, 1H), 8.39 (d, J= 8 Hz, 1H), 7.85 (d, J = 3 Hz, 1H), 7.70-7.60 (m, 2H), 7.27 (t, J= 8 Hz, 1H), 7.00 (d, J= 3 Hz, 1H), 6.82 (d, J=
8 Hz, 1H), 3.24 (m, 8H); MS (ESI+) for m/ z 343 (M+H)<+>.
EKSEMPEL 25
7-{[4-(l-Piperazinyl)-lH-indol-l-yl]sulfonyl}-2-(trifluoracetyl)-l,2,3,4-tetrahydroisokinolin hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2-(trifluoracetyl)-1,2,3,4-tetrahydroisokinolinsulfonylklorid ifølge metode 3: <*>H NMR (270 MHz, DMSO-de). Eksperimentet ble gjort ved 100°C 5 9.25 (br, 1H), 7.94 (br, 1H), 7.75 (d, J = 8 Hz, 1H), 7.71 (d, J = 3 Hz, 1H), 7.63 (d, 7= 8 Hz, 1H), 7.41 (d, J= 8 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 6.90 (d, J= 3 Hz, 1H), 6.81 (d, J= 8 Hz, 1H), 4.80 (s, 2H), 3.79 8m, 2H), 3.35-3.25 (m, 8H), 2.97 (m, 2H); MS (ESI+) for m/ z 493 (m+H)<+>.
EKSEMPEL 26
Metyl 2-{[4-(l-piperazinyl)-lH-indol-l-yI]sulfonyl}fenylsulfon hydroklorid
(Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2-metylsulfonyl-fenylsulfonylklorid ifølge metode 3: 'H NMR (270 MHz, DMSO-d6) 5 9.22 (br, 1H), 8.29 (d, J= 8 Hz, 1H), 7.99 (t, J = 8 Hz, 1H), 7.90-7.80 (m, 2H), 7.43 (d, J= 8 Hz, 1H), 7.30-7.15 (m, 2H), 7.04 (d, J= 3 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 3.56 (s, 3H), 3.29 (m, 8H): MS (ESI+) for m/ z 410 (M+H)<+>.
EKSEMPEL 27
l-[(4-fluorfenyl)suIfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og 2-metylsulfonyl-fenylsulfonylklorid ifølge metode 4 for å gi hydrokloridet (utbytte 70%), HPLC renhet
>95%; <!>H NMR (DMSO-d6) 8 3.26 (bs, 8H), 6.80 (bs, 1H), 6.95 (bs, 1H), 7.26 (bs,lH), 7.61 (app t, 2H), 7.80 (bs 1H), 8.06 (bs, 1H), 9.30 (bs, 1H); <1>3C NMR DMSO-d6) 8 165.20,144.94, 135.14, 133.31,130.60 (2C), 125.62 (2C), 123.50, 117.25,117.06, 111.15,107.92,107.71,47.82 (2C), 42.98 (2C); MS (posES-FIA) m/ z 360 (M+H).
EKSEMPEL 28
l-[(5-klor-3-metyl-l-benzotien-2-yl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-boc-piperazinyl)-indol og l-[(5-klor-3-metyl-l-benzotien-2-yl)sulfonylklorid ifølge metode 4 til å gi hydrokloridsaltet (utbytte 45%), HPLC renhet >95%; <J>H NMR (DMSO-d6) 8 2.65 (s, 3H), 3.26 (bs, 8H), 6.82 (app d, 1H), 7.00 (appd. 1H), 7.28 (app t, 1H), 7.60 (app dd, 2H), 7.87 (app d, 1H), 8.08-8.12 (m, 2H); <13>C NMR (DMSO-d6) 8 145.05,139.82,139.35,137.46,135.14,133.31, 130.96,128.70 (2C), 125.62, (124.89,124.12,123.52, 111.41,107.91,107.71,47.87 (2C), 43.03 (2C), 12.27; MS (posES-FIA) m/ z 446 (M+H).
EKSEMPEL 29
4-(4-Metyl-l-piperazinyl)-l-(4-metylenzensulfonyl)-lH-indol hydroklorid
(Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-(4-metyl-l-piperazinyl)-1 H-indol og p-metylbenzensulfonylklorid ifølge metode 4 (45%): <!>H NMR (CD3OD) 8 7.81-6.77 (m, 9H), 3.62-3.02 (m, 8H), 2.98 (s, 3H), 2.34 (s, 3H): MS (SEI) 370 (M+H)<+>; Renhet (HPLC) >95%
EKSEMPEL 30 (Mellomprodukt)
Syntese av 4-(trifluormetylsulfonyloksy)indol (Skjema 2)
Et3N (1.6 ml, 11.3 mmol) ble tilsatt til en løsning av 4-hydroksylindol (1.0 g, 7.5 mmol) i CH2CI2 (20 ml). Reaksjonen ble avkjølt (isbad) etterfulgt av forsiktig tilsetning av en løsning av N-fenyl-bis(trifluormetansulfonamid) (2.6 g, 7.5 mmol) i CH2CI2. Reaksjonen ble vasket med vandig K2CO3 etter 10 minutter, tørket (K2CO3) og filtrert. De flyktige stoffene ble eliminert med vakuum til å gi 2.9 g av et lysebrun olje som ble renset ved flashkromatografi (Si02, CHC13). Dette ga 2.47 g (62%) av tittelproduktet som en lys oransje olje. Renhet ifølge GC-analyse var 92%. 'H NMR (MeOH-d3): 8 7.45 (d, 1H), 7.35 (d, 1H), 7.15 (t, 1H), 7.00 (d, 1H), 6.50 (d, 1H).
EKSEMPEL 31 (Mellomprodukt)
Syntese av 4-(trifluormetylsulfonyloksy) (N-(4-trifluormetyl)fenylsulfonyl)indol
(Skjema 2)
En løsning av 4-(trifluormetylsulfonyloksy)indol (2.28 g, 8.6 mmol) i CH2CI2 ble tilsatt dråpevis iløpet av 10 minutter til en blanding av NaH (619 mg, 25.8 mmol forvasket med heptan) CH2C12 (20 ml) og DMF (0.5 ml) under N2. En løsning av 4-(trifluormetyl)-benzensulfonylklorid (2.31 g, 9.5 mmol) i CH2CI2 (1 ml) ble deretter tilsatt langsom ved 0°C. Blandingen ble hensatt ved romtemperatur under røring i 11. Reaksjonen ble deretter forsiktig avkjølt med vann, den organiske fasen ble isolert, tørket, filtrert gjennom silika og konsentrert til å gi 3.3 g råprodukt som en rød olje. Produktet ble renset ved flashkromatografi (Si02), heptan til heptan(EtOAc 10:1 til å gi 2.43 g (59%) av tittelproduktet som en fargeløs olje. HPLC-analyse 100%. MS m/z = 496 (M + Na<+>). lU NMR (MeOH-d3): 8 8.20 (d, 2H), 8.1 (d, 1H), 7.85 (m, 3H), 7.45 (t, 1H), 7.30 (d, 1H), 6.85 (d, 1H).
EKSEMPEL 32
4-Piperazino-N-(4-trifluormetyl)fenylsulfonyl)indol hydroklorid (Skjema 2) Tittelforbindelsen ble fremstilt fra 4-(trifluormetylsulfonyloksy) (N-(4-trifluormetyl)-fenylsulfonyl)indol (200 mg, 0.42 mmol) og piperazin (72 mg, 0.84 mmol) ifølge metode 1. Rensing med flashkromatografi (Si02, CHC13 til MeOH:CHCl310:90: 0.4% aq NH3) ga 10 mg av en gul olje. Denne ble oppløst i etanol og HCl/eter ble tilsatt og ble rørt i noen få timer. Det faste stoffet ble filtrert til å gi 10 mg av sluttproduktet som et beige fast stoff som ble videre renset ved preparat HPLC til å gi sluttproduktet etter dannelse av HCl-saltet (38 mg, 51%) som et off-white fast stoff. HPLC 97%. MS (posEI) m/z = 410 (M+H). <*>H NMR (CD3OD) 8 8.12 (d, 2H, J = 8.3 Hz),7.94 (d, 2H, J
= 8.3 Hz), 7.76-7.68 (m, 2H), 7.33-7.27 (m, 1H), 6.88-6.85 (m, 2H), 3.44-3.30 (m, 8H, delvis skjult).
EKSEMPEL 33
4-(3-Metylpiperazin)-(N-(4-trifluormetyl)fenylsuIfonyI)indol dihydroklorid
(Skjema 2)
Tittelforbindelsen ble fremstilt fra 4-(trifluormetylsulfonyloksy)(N-(4-trifluormetyl)-fenylsulfonyl)indol og røc-2-metylpiperazin ifølge metode 1. Filtrering gjennom silika ved å benytte CHC13 til MeOH:CHCL3 10:90: 0.4% aq NH3 som eluent ga 48 mg av sluttprodukt som et beige fast stoff. Smp. 145° (dekomponerte); <*>H NMR (MeOH-d3): 8 8.10 (d, 2H), 7.85 (d, 2H), 7.75 (d, 1H), 7.65 (d, 1H), 7.30 (t, 1H), 6.85 (m, 2H), 3.50 (m, 5H), 3.00 (t, 1H), 2.85 (t, 1H), 1.35 (d, 3H); HPLC 94%; MS (pos EI) m/z = 424 (M+H). Anal.(C2oH2oF3N302S.2HCl) C,H,N,S. N beregnet 8.47, funnet 9.32.
EKSEMPEL 34 (Mellomprodukt)
4-Brom-l-(benzensulfonyl)-lH-indol (Skjema 2)
4-Brom-2-(benzensulfonyl)-l H-indol ble fremstilt fra 4-bromindol og fenylsulfonylklorid ifølge metode 4 til å gi 3.1 g (91%) av et lyst purpurfarget fast stoff: 'H NMR (CDC13) 8 7.94 (d, J = 8 Hz, 1H), 7.89-7.84 (m, 2H), 7.62 (d, 4 Hz, 1H), 7.57-7.51 (m, 1H), 7.46-7.37 (m, 3H), 7.19-7.13 (m, 1H), 6.72 (dd, J = 1,4 Hz, 1H); MS (ESI) 419.9 + 421.9 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 35 (Mellomprodukt)
4-Brom-l-(2-metyl-benzensulfonyl)-lH-indoI (Skjema 2)
Forbindelsen ble fremstilt fra 4-bromindol (1.02 g, 5.25 mmol) og o-metylbenzensulfonylklorid (a 9:1 blanding av ortho og para metylisomerer) (1.29 g, 6.78 mmol( ifølge metode 4. Rensing ved kolonnekromatografi (Si02, CH2Cl2:heptan) ga 1.6 g (87%) av tittelforbindelsen som inneholder ca 10% av p-metylisomer) som en lys purpurfarget viskøs olje: 'H NMR (CD3OD) 8 7.94-6.68 (m, 9H), 2.52 (s, 3H); MS (ESI) 352.3 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 36
4-(4-Metyl-l-piperazinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 2)
Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-lH-indol (0.135 mg, 0.385 mmol) og 4-metyl-l-piperazin (0.143 mg, 0.77 mmol) ifølge metode 2. Produktet ble renset ved flashkolonnekromatografi (Si02, CH2Cl2:MeOH 9:1:0.4% NH3) og omdannet til dets HCl-salt til å gi 15 mg (10%): "H NMR (CD3OD) 8 7.97-6.79 (m, 9H), 3.72-3.07 (m, 8H), 3.01 (s, 3H), 2.48 (s, 3H); MS(ESI) 370.0 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 37
4-(4-Etyl-l-piperazinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1) Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-l H-indol og 4-etyl-l-piperazin ifølge metode 1. Produktet ble isolert ved kolonnekromatografi (Si02, CH2Cl2:MeOH/heptan:0.4% NH3) og omdannet til et hydrokloridsalt ved tilsetning av HCl/eter til å gi 85 mg (40%) av et hvitt fast stoff: <!>H NMR (CD3OD) 8 7.94-6.61 (m, 9H), 3.41-3.26 (m, 8H), 3.10-3.07 (m, 2H), 2.47 (s, 3H), 1.42 (t, J= 7 Hz, 3H); MS (ESI) 384.0 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 38
4-(l-Piperazinyl-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-l H-indol og piperazin ifølge metode 1 til å gi 25 mg (12%) av et hvitt fast stoff: <*>H NMR (CD3OD) 8 7.91-6.79 (m, 9H), 3.49-3.30 (m, 8H), 2.48 (s, 3H); MS (ESI 356.1 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 39
4-(5-Aza-indolizidinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-lH-indol og 5-aza-indolizidinyl ifølge metode 1 til å gi 30 mg (13%) av et hvitt fast stoff 'H NMR på fri base (CD3OD) 8 7.85-766 (m, 9H), 3.63-3.47 (m, 1H), 3.16-2.93 8m, 3H), 2.67-2.45 (m, 5H), 2.51 (s, 3H), 2.33-2.19 (m, 2H), 1.92-1.74 (m, 4H), 1.52-1.44 (m, 1H); MS (ESI) 396.0 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 40
4-(4-Metyl-l-homopiperazinyl)-l-(2-metylbenzensulfonyl)-lH-indoI (Skjema 1)
Forbindelsene ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-l H-indol og 4-metyl-l-homopiperazin ifølge metode 1 til å gi 20 mg (13%) av et hvitt fast stoff: <!>H NMR (CD3OD) 5 7.91-6.73 (m, 9H), 3.74-3.45 (m, 8H), 3.00 (s, 3H), 2.47 (s, 3H), 2.34-2.26 (m, 2H); MS (ESI) 384.0 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 41
4-(3-Metyl-l-piperazinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1) Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-lH-indol og 3-metylpiperazin ifølge metode 1 til å gi 110 mg (30%) av et hvitt fast stoff: <*>H NMR (CD3OD) 5 7.92-6.82 (m, 9H), 3.64-3.39 (m, 5H), 3.12-3.03 (m, 1H), 2.92-2.83 (m, 1H), 2.47 (s, 3H), 1.40 (d, J= 7 Hz, 3H); MS (ESI) 370.0 (M+H)<+>; Renhet (HPLC) 94%.
EKSEMPEL 42
4-(c/s-3,5-dimetyl-l-piperazinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1) Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-lH-indol og cis- 3, 5-dimetyl-l-piperazin ifølge metode 1 til å gi 10 mg (4) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.90-6.82 (m, 9H), 3.69-3.58 (m, 4H), 2.83-2.74 (m, 2H), 2.45 (s, 3H), 1.41 (d, J= 7 Hz, 6H); MS (ESI) 492.1 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 43
4-(4-IsopropyI-l-piperazinyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1) Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-l H-indol og 4-isopropyl-l-piperazin ifølge metode 1 til å gi 75 mg (56%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.92-6.81 (m, 9H), 3.75-3.56 (m, 5H), 3.48-3.40 (m, 2H), 3.19-3.09 (m, 2H), 2.47 (s, 3H), 1.44 (d, J = 7 Hz, 6H); MS (ESI) 398.1 (M+H)<+>; Renhet (HPLC)
>95%.
EKSEMPEL 44
4-((lS,4S)-2-Metyl-2,5-diazabicyklo[2.2.1]heptyl)-l-(2-metylbenzensulfonyl)-lH-indol (Skjema 1)
Forbindelsen ble fremstilt fra 4-brom-l-(2-metyl-benzensulfonyl)-l H-indol og (IS.4S)-2-metyl-2,5-diazabicyklo[2.2.1]heptan ifølge metode 1 til å gi 25 mg (19%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.91-6.44 (m, 9H), 4.67-4.63 (m, 1H), 4.35-4.33 (m, 1H), 4.09-4.07 (m, 1H), 3.99-3.95 (m, 1H), 3.72-3.70 (m, 1H), 3.21-3.17 (m, 1H), 2.95 (s, 3H), 2.33-2.31 (m, 2H); MS (ESI) 382.1 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 45
4-(4-Mety 1-1 -homopiperazinyl)-l -(benzensulfony 1)-1 H-indol (Skj ema 1)' Forbindelsen ble fremstilt fra 4-brom-l-(benzensulfonyl)-lH-indol og 4-metyl-l-homopiperazin ifølge metode 1 til å gi 4 mg (2%) av et hvitt fast stoff: <*>H NMR for fri base (CDC13) 8 7.86-711 (m, 8H), 6.71 (d, J= 4 Hz, 1H), 6.54 (d, J= 8 Hz, 1H), 3.60-3.57 (m, 2H), 3.52-3.48 (m, 2H), 2.81-2.78 (m, 2H) 2.68-2.64 (m, 2H), 2.39 (s, 3H), 2.04-2.00 (m, 2H); MS (ESI) 370.1 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 46
4-(c/s 3,5-Dimetyl-l-piperazinyl)-l-(benzensulfonyl)-lH-indol (Skjema 1) Tittelforbindelsen ble fremstilt fra 4-brom-l-(benzensulfonyl)-1 H-indol og cis 3,5-dimetyl-l-piperazin ifølge metode 1 til å gi 138 mg (52%) av et hvitt fast stoff: <*>H NMR (CD3OD) 8 7.93-6.82 (n, 10H), 3.64-3.59 (m, 4H), 2.77-2.68 (m, 2H),.1.36 (d, J= 6 Hz, 6H); MS (ESI) 370.0 (M+H)<+>; Renhet (HPLC) >95%.
EKSEMPEL 47
4-(4-Etyl-l-piperazinyl)-l-(benzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt fra 4-brom-l-(benzensulfonyl)-1 H-indol og 4-etylpiperazin ifølge metode 1 til å gi 129 mg (48%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.94-6.81 (m, 10H), 3.69-3.62 (m, 4H), 2.34-3.26 (delvis skjult) (m, 4H), 3.14-3.04 (m, 2H), 1.40 (t, J= 7 Hz, 3H); MS (ESI) 370.1 (M+H)<+>; Renhet (HPLC)
>95%.
EKSEMPEL 48
4-Piperazinyl-l-(4-nitro-benzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-nitrobenzensulfonylklorid og natriumsaltet av 4-(4-?-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 60.3 mg (86%) som HCl-salt: 'H NMR (CD3OD) 8 8.34 (d, 2H; J= 9.0 Hz), 8.18 (d, 2H, J= 9.0 Hz), 7.76-7.69 (m, 2H), 7.33-7.27 (m, 1H), 6.90-6.85 (m, 2H), 3.44-3.30 (m, 8H, delvis skjult); MS (ESI) 386.9 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 49
4-Piperazinyl-l-(4-brom-benzensulfonyl)-lH-indoI (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-brombenzensulfonylklorid og natriumsaltet av 4-(4-f-butyloksykarbonyl)-piperazinylindol (beholdningsløsning A) til å gi 40.3 mg (53%) som HCl-salt: 'H NMR (CD3OD) 6 7.81-7-61 (m, 6H), 7.30-7.24 (m, 1H), 6.86-6.83 (m, 2H), 3.44-3.30 (m, 8H); MS (ESI) 419.9,421.9 (M+H)<+>; Renhet (HPLC) 98%.
EKSEMPEL 50
4-Piperazinyl-l-(4-klor-benzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-klor-benzensulfonylklorid og natriumsaltet av 4-(4-r-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 42 mg (61%) som HCl-salt: 'H NMR (CD3OD) 5 7.88 (d, 2H), J= 8.7 Hz), 7.72-7.63 (m, 2H), 7.50 (d, 2H), J= 8.7 Hz), 7.30-7.24 (m, 1H), 6.86-6.84 (m, 2H), 3.44-3.31 (m, 8H); ME (ESI) 375.9, 3.77.9 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 51
4-Piperazinyl-l-(E 2-fenyl-etensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra \-{ E 2-fenyl-etensulfonylklorid og natriumsaltet av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 8 mg (11%) som HCl-salt: 'H NMR (CD3OD) 8 7.78 (d, 1H, J= 15.5 Hz9 7.68-7.25 (M, 9H), 7.16 (D, 1H,; = 15.4), 6.88-6.84 (m, 2H) 3.46-3.34 (m, 8H); MS (ESI) 368.0 (M+H)<+>; Renhet (HPLC) 97%.
EKSEMPEL 52
4-Piperazinyl-l-(3-trifluormetyl-benzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 3-trifluormetyl-benzensulfonylklorid og natriumsaltet av 4-(4-/-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 42 mg (61%) av et hvitt fast stoff: <*>H NMR (CD3OD) 8 8.21-8.16 (m, 2H), 7.96-7.93 (m, 1H), 7.34-7.27 (m, 1H), 6.89-6.85 (m, 2H), 3.44-3.32 (m, 8H); MS (ESI) 410.0 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 53
4-Piperazinyl-l-(4-cyanobenzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-cyanobenzensulfonylklorid og natriumsaltet av 4-(4-^-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 28 mg (42%) av et hvitt fast stoff: MS (ESI) 367.0 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 54
4-Piperazinyl-l-(4-klor-7-klor-2,l,3-benzoksadiazolsulfonyl)-lH-indol (Skjema 1) Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-klor-7-klorsulfonyl-2,l,3-benzoksadiazolsulfonylklorid og natriumsaltet av 4-(4-r-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 12 mg (16% av et hvitt fast stoff: <*>H NMR (CD3OD) 6 8.42 (d, 2H, J= 7-1 Hz), 7.84-7.63 (m, 3H), 7.27-7.21 (m, 1H), 6.85-6.81 (m, 2H), 3.43-3.27 (m, 8H, delvis skjult); MS (ESI 418.0 (M+H)<+>; Renhet (HPLC) 91.
EKSEMPEL 55
4-Piperazinyl-l-(3-cyanobenzensulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-triflurometyl-benzensulfonylklorid og natriumsaltet av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 68 mg (50%) av et hvitt fast stof. MS (ESI) 367.1 (M+H)<+>; Renhet (HPLC) 93%.
EKSEMPEL 56
4-Piperazinyl-l-(4-fenoksybenzensuIfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-fenoksybenzensulfonylklorid og natriumsaltet av 4-(4-?-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 68 mg (87%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.82-7.59 (m, 4H), 7.76-7.34 (m, 4H), 6.88-6.78 (m, 6H), 3.45-3.30 (m, 8H); MS (ESI) 434.1 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 57
4-Piperazinyl-l-(4-klorfenylmetansuIfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-klorfenylmetansulfonylklorid og natriumsaltet av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 3 mg (4%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 7.44 (d, 1H, J= 8.2 Hz), 7.24-7.18 (m, 4H), 6.87-6.84 (m, 3H), 6.69-6.67 (m, 1H), 4.72 (s, 2H 3.43-3.31 (m, 8H, delvis skjult); MS (ESI) 390.0, 392.1 (M+H)<+>; Renhet (HPLC) 91%.
EKSEMPEL 58
4-Piperazinyl-l-(4-metylfenylmetansulfonyl)-lH-indol (Skjema 1) Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-metylfenylmetansulfonylklorid og natriumsaltet av 4-(4-/-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 9 mg (13%) av et hvitt fast stoff: <*>H NMR (CD3OD) 5 7.46 (d, 1H, J= 8.4 Hz),
7.24-7.18 (m, 1H), 7.0t (d, 1H, J= 4.0 Hz), 6.95-6.85 (m, 3H), 6.76-6.64 (m, 3H), 4.65 (s, 2H), 3.47-3.35 (m, 8H), 2.24 (s, 3H); MS (ESI) 370.1 (M+H)<+>; Renhet (HPLC) 95%.
EKSEMPEL 59
4-Piperazinyl-l-(l,l-difenyletansulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 1,1-difenyletansulfonylklorid og natriumsaltet av 4-(4-/-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 57 mg (71%) av et hvitt fast stoff: <*>H NMR (CD3OD) 5 7.59 (d, 1H, J= 8-.4 Hz), 7.31-7.25 (m, 1H), 7.12-7.05 (n, 10H), 6.86-6.83 (m, 1H), 6.50-6.48 (m, 1H), 6.42 (t, 1H, J= 6.6 Hz), 4.28 (d, 2H), J= 6.6 Hz), 3.47-3.32 (m, 8H); MS (ESI) 446.1 (M+H)<+>; Renhet (HPLC) 92%.
EKSEMPEL 60
4-Piperazinyl-l-(4-trifluormetoksybenzensulfonyl)-lH-indol (Skjema 1) Tittelforbindelsen ble fremstilt ifølge metode 5 fra 4-trifluormetoksybenzensulfonyl-klorid og natriumsaltet av 4-(4-?-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 46 mg (60%) av et hvitt fast stoff: 'H NMR (CD3OD) 8 8.07-8.04 (m, 2H), 7.75-7.72 (m, 1H), 7.67-7.68 (m, 1H), 7.43-7.40 (m, 2H), 7.32-7.20 (m, 1H), 6.87-6.85 (m, 2H), 3.44-3.31 (m, 8H, delvis skjult); MS (ESI) 426.1 (M+H)<+>; Renhet (HPLC) 93%.
EKSEMPEL 61
4-Piperazinyl-l-(5-[(benzoylamino)metyl]tiofen-2-sulfonyl)-lH-indol (Skjema 1)
Tittelforbindelsen ble fremstilt ifølge metode 5 fra 5-[(benzoylamino)metyl]tiofen-2-sulfonylklorid og natriumsaltet av 4-(4-f-butyloksykarbonyl)-piperazinyl-indol (beholdningsløsning A) til å gi 5 mg (6%) av et hvitt fast stoff: lB. NMR (CD3OD) 8 7.79-7.42 (m, 8H), 7.30-7.24 (m, 1H), 7.00-6.98 (m, 1H), 6.85-6.81 (m, 2H), 3.39-3.28 (m, 8H, delvis skjult); MS (ESI) 481.1 (M+H)<+>; Renhet (HPLC) 91%.
EKSEMPEL 62 l-[(N-metyl-lH-imidazol-4-yl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid Tittelforbindelsen ble fra 4-(4-boc-piperazinyl)-indol og 1 -metyl- lH-imidazol-4-yl)sulfonylklorid ifølge metode 3: Utbytte: 74%. <*>H NMR 270 MHz, DMSO-d6) 8 9.23 (br, 1H), 8.25 (s, 1H), 7.75 (s, 1H), 7.61 (d, J = 3 Hz, 1H), 7.53 (d, J= 8 Hz, 1H), 7.22 (t, J= 8Hz, 1H), 6.86 (d, J= 3 Hz, 1H), 6.79 (d, J= 7 Hz, 1H), 3.65 (s, 3H), 3.27 (m, 8H); MS (ESI+) for m/ z 346 (M+H)<+>.
Skjema 3 (i) (iPr)3Si, NaH, dimetylformamid/diklormetan; R<5> (når den er forskjellig fra H) (tBu)3P,Pd(OAc)2, NaOtBu; (iii) BU4NF i THF, acetonitril; (iv) R<1> (ArS02- som angitt i. tabell II), NaOH, diklormetan.
J / TABELL H.
Forbindelser fremstilt ifølge synteseskjema 3.
EKSEMPEL 63 (Mellomprodukt)
5-Brom-l-triisopropylsilyl-indol
5-Bromindol (3.92 g; 20 mmol) ble oppløst i DCM (100 ml) og DMF (1 ml). NaH (0.88 g, 22 mmmol; 60% i olje) ble tilsatt til den avkjølte løsningen. Etter røring i 15 minutter ble triisopropylsilylklorid (3.86 g, 20 mmol) tilsatt dråpevis til reaksjonsblandingen. Etter 3 t ble vann (1 ml) tilsatt etterfulgt av MgS04. Blandingen ble filtrert og konsentrert og resten ble kjørt gjennom en silikakolonne med heksan som eluent. Produktet ble oppnådd som en blek gul olje (5.96 g, 17 mmol; utbytte 85%). <]>H NMR (CDC13) 8 1.13 (18H, d, J= 8), 1.67 (3H, m), 6.55 (1H, d, J= 3), 7.21 (1H, dd, 7= 9,2), 7.24 (1H, d, J= 3), 7.36 (1H, d, 7= 9) og 7.74 (1H, d, J = 2).
EKSEMPEL 64 (Mellomprodukt)
5-(4-Metylpiperazin-l-yl)-indol
5-Brom-l-triisopropylsilyl-indol (5.8 g, 16.4 mmol), N-metylpiperazin (1.8 g, 18 mmol), NaOt-Bu (2.2 g, 23 mmol), Pd(OAc)2 (37 mg, 0.16 mmol), P*-Bu3 (66 mg, 0.33 mmol) og xylen (30 ml) ble blandet og varmet til 130°C under røring i 5 t. Råmaterialet ble kromatografert på en silikakolonne ved å benytte DCM/MeOH 95/5 som eluent.
Konsentrering av hovedfraksjonene ga 5.6 g av en olje som ble oppløst i MeCN (10 ml), 20 ml av en 1 M løsning av tetrabutylammoniumfluorid i THF ble tilsatt og blandingen ble hensatt over natten. Reaksjonsblandingen ble satt på en silikakolonne og eluert med DCM/MeOH 95/5 til å gi produktet som en olje (2 g, 9.3 mmol; utbytte 57%) <*>H NMR (CDCI3) 8 2.37 (3H, s), 2.64 (4H, t, J= 5), 3.19 (4H, t, J= 5), 6.44-6.48 (1H, m), 6.95-7.00 (1H, m), 7.16 (1H, d, J= 3), 7.18 (1H, d, J= 2), 7.29 (1H, d, J= 9) og 8.12 (1H, bs).
Mellomprodukt 65-67 ble fremstilt ved å benytte den samme metoden som for mellomprodukt 64.
EKSEMPEL 65 (Mellomprodukt)
5-(4-Isopropylpiperazin-l-yl)-indol
(0.64 g, 1.9 mmol; utbytte 63%), 'H NMR (CDC13) 5 1.12 (6H, d, J= 7), 2.70-2.78 (5H, m), 3.15-3.22 (4H, m), 6.45-6.49 (1H, m), 6.97-7.01 (1H, dm), 7.14-7.19 (2H, m), 7.30 (1H, d,y=9) og 8.05 (1H, bs).
EKSEMPEL 66 (Mellomprodukt)
5-(4-Benzylpiperazin-l-yl)-indol
(3.6 g, 12.4 mmol; utbytte 55%), <]>H NMR (CDC13) 8 2.67 (4H, t, J= 5), 3.18 (4H, t, J= 5), 3.60 (1H, s), 6.44-6.47 (1H, m), 6.97 (2H, dd, J= 9,3), 7.13-7.17 (2H, m), 7.25-7.39 (5H, m) og 8.01 (1H, bs).
EKSEMPEL 67 (Mellomprodukt)
5-(4-Propylpiperazin-l-yl)-indol
(0.54 g, 2.2 mmol; utbytte 24%, <!>H NMR (CDC13) 8 0.94 (3H, t, J= 7), 1.53-1.62 (2H, m), 2.37-2.43 (2H, m), 2.65-2.73 (4H, m), 3.17-3.22 (4H, m), 6.45-6.48 (1H, m), 6.96-7.00 (1H, dm), 7.14-7.19 (2H, m), 7.30 (1H, d, J= 9) og 8.13 (1H, bs).
EKSEMPEL 68
N-Benzensulfonyl-5-(4-metylpiperazin-l-yl)-indol
5-(4-Metylpiperazin-l-yl)-indol (215 mg, 1 mmol), benzensulfonylklorid (265 mg, 1.5 mmol) og Aliquot 336 (10 mg) ble oppløst i DCM (10 ml). Vandig NaOH (20%, 2 ml) ble tilsatt og blandingen ble rørt kraftig i 61. Det organiske laget ble separert, tørket og konsentrert til å gi råmaterialet som en olje som ble renset på en silikakolonne ved å benytte DCM ogMeOH som eluent. De rene fraksjonene ble konsentrert til å gi en olje (260 mg, 0.66 mmol) 'H NMR (CDC13) 8 2.35 (3H, s), 2.59 (4H, t, J= 5), 3.18 (4H, t, J = 5), 6.57 (1H, d, J= 4), 6.98-7.03 (2H, m), 7.38-7.54 (4H, m), 7.82-7.90 (3H, m); MS (posES-FIA) 355.1345 M+; Renhet (HPLC kromsil C18) >98%.
Eksemplene 69-87 ble fremstilt ved å benytt den samme metoden som i eksempel 1. Eksemplene 72-87 er rapportert som hydrokloridsalter.
EKSEMPEL 69
N-(4-Metylbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol
(0.24 g, utbytte 59%) "H NMR (CDC13) 8 2.33 (3H), s), 2.37 (3H, s), 2.61 (4H, 5 J = 5), 3.18 (4H, t, J = 5), 6.55 (1H, d, J = 3), 6.99-7.30 (2H, m), 7.19 (2H, d, 7.47 (1H, d, j = 4), 7.72 (2H, d. J = 9) og 7.86 (1H, d, J = 9; MS (posES-FIA) 369.1502 M+; Renhet (HPLC kromsil Cl 8) >98%.
EKSEMPEL 70
N-BenzensuIfonyl-5-(4-isopropylpiperazin-l-yl)-indol
0.24 g, utbytte 57%), 'H NMR (CDC13) 8 1.12 (6H, d, J = 7), 2.68-2.77 (5H, m), 3.15-3.25 (4H, m), 6.57 (1H, d, J = 5), 6.98-7.04 (2H, m), 7.39-7.44 (2H, m), 7.46-7.54 (1H, m) og 7.81-7.89 (3H, m); MS (posES-FIA) 383.1655 M*; Renhet (HPLC kromsil C18)
>98%.
EKSEMPEL 71
N-(4-Metylbenzensulfonyl)5-(4-isopropylpiperazin-l-yl)-indol
(0.29 g, utbytte 67%), <*>H NMR (CDC13) 8 1.11 (6H, d, J = 6), 2.33 (3H, s), 2.67-2.78 (5H, m), 3.15-3.25 (4H, m), 6.54 (1H, d, J = 4), 6.97-7.03 (2H, m), 7.19 (2H, d, J = 8), 7.46 (1H, d, J = 4), 7.67-7.81 (3H, m) og 7.86 (1H, d, J = 9); MS (posES-FIA) 397.1823 M<+>; Renhet (HPLC kromsil Cl8) >90%.
EKSEMPEL 72
N-3,4-DimetoksybenzensuIfonyl)-5-(4-propylpiperazin-l-yl)-indol, hydroklorid 0.27 g, utbytte 67%), 'H NMR (CDC13) 8 1.10 (3H, t, J = 7), 1.93-2.03 (2H, m), 3.10-3.20 (2H, m), 3.63-3.70 (4H, m), 3.88 (3H, s), 3.90 (3H, s), 4.30-4.42 (2H, m), 4.82-4.94 (2H, m), 6.76 (1H, d, J = 4), 6.87-6.94 (2H, m), 7.53-7.60 (2H, m), 7.72-7.76 (1H, m), 7.83-7.88 (1H, m), 8.08-8.12 (1H, m), 8.16-8.20 (1H, m) og 13.45 (1H, bs); MS (posES-FIA) 443.1871 M<+>; Renhet (HPLC kromsil C18) >75%.
EKSEMPEL 73
N-(3-Fluorbenzensulfonyl)-5-(4-propylpiperazin-l-yl)-indol, hydroklorid
(0.16 g, utbytte 67%), 'H NMR (MeOH d6) 8 1.02 (3H, t, J = 7,1.72-1.84 (2H, m), 3.02-3.18 (4H, m), 3.19-3.26 (2H, m), 3.60-3.68 (2H, m), 3.71-3.80 (2H, m), 6-67 (1H, d, J = 4), 7.08-7.13 (1H, m), 7.15-7.18 (1H, m), 7.30-7.37 (1H, m), 7.46-7.54 (1H, m), 7.58-7.64 (2H, m), 7.66-7-72 (1H, m) og 7.86-7.91 (lh, m); MS (posES-FIA) 401.1585 M<+>; Renhet (HPLC kromsil Cl8) >90%.
EKSEMPEL 74
N-(4-Propylbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid
(0.15 g, utbytte 38%) 'H NMR (CDC13) 8 0.90 (3H, t, J = 7), 1.56-1.66 (2H, m), 2.60 (2H, t. J = 8, 2.98 (3H, s), 3.56-3.68 (4H, m), 4.27-4.40 (2H, m), 4.64-4.74 (2H, m), 6.74 (1H, d, J = 3), 7.25-7.29 (2H, m), 7.71-7.81 (4H, m), 8.06-8.13 (2H, m) og 13.89 (1H, bs); MS (posES-FIA) 397.1813 M<+>; Renhet (HPLC kromsil C18) >93%.
EKSEMPEL 75
N-(l-Naftalensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid
(0.18 g, utbytte 45%) 'H NMR (CDC13) 8 2.97 (3H, s), 3.59 (4H, t, J = 15), 4.35-4.46 (2H, m), 4.68-4.78 (2H, m), 6.75 (1H, d, J = 3), 7.50-7.76 (4H, m), 7.88-7.98 (3H, m), 8.11-8.15 (2H, m), 8.34-8.38 (1H, m), 8.62 (1H, d, J = 9) og 13.94 (1H, bs); MS (posES-FIA) 405.1503 M<+>; Renhet (HPLC kromsil Cl8) >90%.
EKSEMPEL 76
N-(Bifenyl-4-sulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid
(0.13 g, utbytte 30%) 'H NMR (MeOH-d6) 8 2.93 (3H, s), 3.05-3.15 (2H, m), 3.20-3.30 (2H, m), 3.50-3.60 (2H, m), 3.70-3.80 (2H, m), 6.66 (1H, d, J = 5), 7.11 (1H, dd, J = 9,3), 7.16 (1H, d, J = 3), 7.32-7.43 (3H, m), 7.51-7.56 (2H, m), 7.61 (1H, d, J = 4), 7.66-7.70 (2H, m) og 7.88-7.94 (3H, m); MS (posES-FIA) 431.1662 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 77
N-4-Metoksybenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid
(0.17 g, utbytte 44%) <!>H NMR (CDC13) 8 2.98 (3H, s), 3.55-3.68 (4H, m), 3.82 (3H, s9, 4.30-4.45 (2H, m), 4.66-4.76 (2H, m), 6.72 (1H, d, J = 4), 6.93 (2H, d, J = 9), 7.71 (1H, d, J = 4), 7.74-7.79 (1H, m), 7.83 (2H, d, J = 9), 8.10 (2H, d, J = 9) og 13.97 (1H, bs); MS (posES-FIA) 385.1456 M*; Renhet (HPLC kromsil C18) >95%.
EKSEMPEL 78
N-(3,4-Dimetoksybenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid (0.13 g, utbytte 28%) 'H NMR (CDC13) 8 2.98 (3H), s), 3.55-3.70 (4H, m), 3.88 (3H, s), 3.89 (3H, s), 4.32-4.45 (2H, m), 4.66-4.78 (2h, m), 6.75 (1H, d, J = 4), 6.85-6.93 (2H, m), 7.53-7.58 (1H, m), 7.73 (1H, d, J = 4), 7.77-7.82 (1H, m), 8.08-8.14 (2H, m) og 13.97 (1H, bs); MS (posES-FIA) 415.1561 M<+>; Renhet (HPLC kromsil C18) >80%.
EKSEMPEL 79
N-(2,4-Difluorbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid
(0.23 g, utbytte 53%) JH NMR (CDCI3) 8 2.99 (3H, s), 3.55-3.68 (4H, m), 4.35-4.45 (2H, m), 4.71-7.82 (2H, m), 6.77 (1H, d, J = 4), 6.84-6.93 (2H, m), 7.04^7.12 (1H, m), 7.75-7.82 (2H, m), 7.98 (1H, d, J = 9), 8.19-8.20 (2H, m) og 13.88 (1H, bs); MS (posES-FIA) 391.1155 M<+>; Renhet (HPLC kromsil Cl8) >88%.
EKSEMPEL 80
N-(4-Metoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid
(0.34 g, utbytte 61%). 'H NMR (CD3OD) 8 3.26-3.29 (8H, m), 3.76 (3H, s), 4.40 (2H, s), 6.93 (1H, d, J = 9), 7.08 (1H, dd, J = 9,3), 7.17 (1H, d, J = 3), 7.46-7.51 (3H, m), 7.52-7.57 (3H, m), 7.76 (2H, d, J = 9) og 7.86 (1H, d, J = 9); MS (posES-FIA) 461.1763 M<+>; Renhet (HPLC kromsil Cl 8) >90%.
EKSEMPEL 81
N-(2,4-Difluorbenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid (0.30 g, utbytte 64%). <*>H NMR (CD3OD) 8 3.30-3.80 (8H, m), 4.40 (2H, s), 6.66 (1H, d, J = 4), 7.04-7.15 (3H, m), 7.30 (1H, d, J = 3), 7.43-7.47 (3H, m), 7.2-7.56 (2H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J = 9) og 8.06.8.14 (1H, m); MS (posES-FIA) 467.1492 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 82
N-(4-Butoksybenzensulfonyl)-5-(4-benzyIpiperazin-l-yI)-indoI, hydroklorid
(0.30 g, utbytte 64%). 'H NMR (DMSO d6) 8 0.86 (3H, t, J = 7), 1.29-1.42 (2H, m), 1.55-1.69 (2H, m), 3.05-3.37 (6H, m), 3.60-3.70 (2H, m), 3.97 (2H, t, J = 6), 4.35 (2H, s), 6.70 (1H, d, J = 3), 7.02-7.15 (4H, m), 7.43-7.50 (3H, m), 7.65-7.71 (3H, m), 7.78-7.86 (3H, m) og 11.45 (1H, bs); MS (posES-FIA) 503.2236 M<+>; Renhet HPLC kromsil Cl 8) >95%.
EKSEMPEL 83
N-(3,4-Dimetoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid (0.36 g, utbytte 68%). 'H NMR (DMSO d6) 8 3.10.3.40 (6H, m), 3.65-3.85 (2H, m), 3.76 (6H, s), 4.35 (2H, s), 6.70 (1H, d, J = 4), 7.04-7.14 (3H, m), 7.34 (1H, d, J = 2), 7.42-7.47 (3H, m), 7.50 (1H, dd, J = 9, 2), 7.65-7.70 (2H, m), 7.73 (1H, d, J = 4), 7.83 (1H, d, J = 9) og 11.65 (1H, bs); MS (posES-FIA) 491.1875 M+; Renhet (HPLC kromsil C18)>98%.
EKSEMPEL 84
N-(Bifenyl-4-sulfonyI)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid
(0.35 g, utbytte 64%). 'H NMR (DMSO d6) 8 3.10-3.20 (4H, m), 3.30-3.40 (2H, m), 3.70-3.80 (2H, m), 4.36 (2H, s), 6.74 (1H, d, J = 4), 7.05-7.13 (2H, n), 7.40-7.50 (6H, m), 7.58-7.63 (2H, m), 7.63-7.68 (2H, m), 7.76 (1H, d, J = 4), 7.82-7.87 (3H, m), 7.98 (2H, d, J = 9) og 10.81 (1H, bs); MS (pos ES-FIA) 507.1981 M<+>; Renhet (HPLC kromsil C18) >98%.
EKSEMPEL 85
N-(Naftalen-2-sulfonyl)-5-(4-benzyIpiperazin-l-yl)-indol, hydroklorid
(0.40 g, utbytte 55%). <!>H NMR (DMSO d6) 8 3.05-3.35 (6H, m), 3.66 (2H, d, j = 12), 4.33 (2H, s), 6.71 (1H, d, J = 4), 6.99 (1H, dd, J = 9, 2), 7.10 (lH,d, J = 4), 7.41-7.45 83H, m), 7.58-7.75 (6H, m), 8.00 (1H, d, J = 4), 8.07 (1H, d, J = 8), 8.29 (1H, d, J = 9), 8.32 (1H, d, J = 7), 8.62 (1H, d, J = 9) og 11.53 (1H, bs); MS (posES-FIA) 481.1842 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 86
N-(4-Propylbenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid
(0.49 g, utbytte 63%). 'H NMR (DMSO d6) 8 0.81 (3H, t, J = 7), 1.44-1.56 (2H, m), 2.54 (2H, t, J = 8), 3.10.3.27 (6H, m), 3.28-3.38 (2H, m), 4.35 (2H, s), 6.70 (1H, d, J = 4), 7.05-7.09 (1H, m), 7.10-7.12 (1H, m), 7.37 (2H, d, J = 8), 7.43-7.48 (3H, m), 7.63-7.67 (2H, m), 7.69 (1H, d, J = 4), 7.77-7.84 (3H, m), og 11.37 (1H, bs); MS (posES-FIA) 473.2152 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 87
N-(3-FluorbenzensuIfonyI)-5-84-benzylpiperazin-l-yl)-indol, hydroklorid
(0.36 g, utbytte 70%). <*>H NMR (DMSO d6) 8 3.10-3.23 (2H, m), 3.26-3.40 (4H, m), 3.65-3.77 (2H, m), 4.37 (2H, s), 6.75 (1H, d, J = 4), 7.11 (1H, dd, J = 9, 2), 7.17 (1J, d, J =2), 7.40.7.45 (3H, m), 7.48-7.56 1H9, m), 7.58-7.65 (1H, m), 7.65-7.71 (2H, m), 7.73-7.78 (2H, m), 7.80-7.86 (2H, m) og 11.79 (1H, bs); MS (posES-FIA) 449.1595 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 88
N-(4-MetoksybenzensuIfonyl)-5-(piperazin-l-yl)-indol, hydroklorid N-(4-Metoksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol (0.25 g, 0.54 mmol) ble oppløst i DCM (4 ml), a-kloretylklorformat (0.150 g, 1.05 mmol) ble tilsatt og blandingen ble hensatt ved romtemperatur i 21 hvoretter den ble konsentrert. MeOH (10 ml) ble tilsatt og blandingen ble kjørt med tilbakeløp i 2 timer og deretter konsentrert til å gi produktet (0.22 g, kvantitativt utbytte). 'H NMR (MeOH d6) 8 3.39-3.47 (8H, m), 3.77 (3H, s), 6.64 (1H, d, J = 3), 6.94 (2H, d, J = 9), 7.15 (1H, dd, J = 9,2), 7.26 (1H, d, J = 2), 7.59 (1H, d, J = 4), 7.80 (2H, d, J = 9) og 7.90 (1H, d, J = 9); MS (posES-FIA) 371.1304 M+; Renhet (HPLC kromsil Cl8) >98%.
Eksemplene 89-95 ble fremstilt ved å benytte den samme prosedyren som i eksempel 88.
EKSEMPEL 89
N-(2,4-Difluorbenzensulfonyl)-5-(piperazin-l-yl)-indol, hydroklorid
(Isolert 0.20 g). 'H NMR (CDC13) 8 3.49-3.54 (4H, m), 3.57-3.62 (4H, m), 6.71 (1H, d, J = 4), 7.04-7.15 (2H, m), 7.28 (1H, dd, J = 9, 3), 7.51 (1H, d, J = 3), 7.62-7.65 (1H, m), 7.81 (1H, d, J = 9) og 8.08-8.16 (1H, m); MS (posES-FIA) 377.1012 M+; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 90
N-(4-ButoksybenzensulfonyI)-5-(piperazin-l-yl)-indol, hydroklorid
(Isolert 0.30 g). 'H NMR (DMSO d6) 8 0.84 (3H, t, J = 8), 1.28-1.39 (2H, m), 1.55-1.65 (2H, m), 3.22-3.30 (4H, m), 3.40-3.48 (4H, m), 3.95 (2H, t, J = 7), 6.73 (1H, d, J = 4), 7.00 (2H, d, J = 9), 7.19 (1H, d, J = 9), 7.29 (1H, bs), 7.71 (1H, d, J = 4), 7.84 (3H, d, J = 9) og 9.64 (1H, bs); MS (posES-FIA) 413.1770 M<+>, Renhet (HPLC kromsil C18)
>88%.
EKSEMPEL 91
N-(3,4-Dimetoksybenzensulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid
(Isolert 0.24 g). 'H NMR (DMSO d6) 8 3.28-3.36 (4H, m), 3.48-3.55 (4H, m), 3.75 (3H, s), 3.76 (3H, s), 6.76 (1H, d, J = 4), 7.05 (1H, d, J = 9), 7.23-7.44 (3H, m), 7.53 (1H, dd, J = 9, 3), 7.80 (1H, d, J = 4), 7.93 (1H, d, J = 9), og 9.81 (2H, bis); MS (posES-FIA) 401.1401 M<+>; Renhet (HPLC kromsil Cl 8) >98%.
EKSEMPEL 92
N-(Bifenyl-4-sulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid
(Isolert 0.21 g). 'H NMR (DMSO d6) 8 3.16-3.23 (4H, m), 3.27-3.32 (4H, m), 6.74 (1H, d, J = 4), 7.07-7.14 (2H, m), 7.39-7.49 (3H, m), 7.63-7.68 (2H, m), 7.75 (1H, d, J = 4), 7.82-7.87 (3H, m), 7.98 (2H, d, J = 9) og 9.00 (2H, bs); MS (posES-FIA) 417.1519 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 93
N-(NaftaIen-2-sulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid
(Isolert 0.25 g). <!>H NMR (DMSO d6) 8 3.15-3.25 (4H, m), 3.30-3.36 (4H, m), 6.73 (1H, d, J = 4), 7.05 (1H, dd, J = 9, 3), 7.17 (1H, d, J = 3), 7.61-7.74 (4H, m), 8.02 (1H, d, J = 4), 8.07 (1H, d, J = 8), 8.30 (1H, d, J = 8), 8.33 (1H, d, J = 8), 8.62 (1H, d, J = 9) og 9.46 (2H, bs); MS (posES-FIA) 391.1349 M<+>; Renhet (HPLC kromsil C18) >98%.
EKSEMPEL 94
N-(4-Propylbenzensulfonyl)-5-(piperazin-l-yl)-indol, dihydroklorid
(Isolert 0.24 g). <J>H NMR (DMSO d6) 8 0.80 (3H, t, J = 8), 1.44-1.55 (2H, m), 2.53 (2H, t, J = 8), 3.18-3.16 (4H, m), 3.36-3.42 (4H, m), 6.73 (1H, d, J = 4), 7.14 (1H, dd, J = 9, 2) , 7.21 (1H, d, J = 3), 7.36 (2H, d. J = 8), 7.71 (1H, d, J = 4), 7.79-7.85 (3H, m), 9.52 (2H, bs); MS (posES-FIA) 383.1679 M<+>; Renhet (HPLC kromsil C18) >98%.
EKSEMPEL 95
N-(3-FluorbenzensulfonyI)-5-(piperazin-l-yl)-indol, dihydroklorid
(Isolert 0.18 g). <!>H NMR (DMSO d6) 8 3.31-3.28 (4H, m), 3.32-3.43 (4H, m), 6.77 (1H, d, J = 4), 7.14 (1H, dd, J = 9, 3), 7.19 (1H, d, J = 2), 7.50-7.58 (1H, m), 7.59-7.66 (1H, m). 7.73-7.79 (2H, m), 7.80-7.87 (1H, m) og 9.53 (2H, bs); MS (posES-FIA) 359.1109 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 96
N-Benzensulfonyl-5-(piperazin-l-yl)-indol, dihydroklorid
l-Benzensulfonyl-5-brom-indol (0.336 g, 1 mmol), piperazin (0.516 g, 6 mmol), CSCO3 (0.456 g, 1.4 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (62 mg, 0.1 mmol) og xylen (10 ml) ble blandet og varmet til 120°C under røring i 181. Produktet ble isolert som hydrokloridsaltet (0.05 g). 'H NMR (CDC13) 8 3.00-3.16 (8H, m), 6.57 (1H, d, J = 3) , 6.99 (1H, s), 7.02 (1H, d, J = 3), 7.40 (2H, t, J = 8), 7.47-7.53 (2H, m) og 7.81-7.90 (3H, m); MS (posES-FIA) 341.1187 M<+>; Renhet (HPLC kromsil Cl8) >98%.
EKSEMPEL 98
Fremstilling av 3-substituert-l-arylsulfonylindol, hydroklorid.
(i) p-Fluor-sulfonylklorid, NaH, DMF.
EKSEMPEL 97 (Mellomprodukt)
3-(l-azabicyklo[2.2.2]okt-2-en-3-yl)-l H-indol, oksalat
Forbindelsen ble oppnådd ifølge prosedyren som er beskrevet i litteraturen ( Uli, V. O. Synthesis 1979, 136; Boettcher, H. ; Seyfried, C; Minck, K. O. ; Wolf, H. P. Ger. Ofgen.
( 1991), DE 90- 4009565). <*>H NMR (DMSO-d6) 8 11.48 (s, 1H), 7.75-7.,70 (m, 2H), 7.41 (d, J = 8 Hz, 1H), 7.20-7.05 (m, 2H), 6.92 (s, 1H), 3.34 (s, 1H, 3.26 (br, 2H), 2.84 (br, 2H), 1.88 (br, 2H), 1.63 (br, 2H).
EKSEMPEL 98
3-(l-Azabicyklo[2.2.2]okt-2-en-3-yl)-l-[(4-fluorfenyl)sulfonyl]-lH-indol Ved 0°C ble 3-(3-indolyl)-2,3-dihydrokinuklidin (179 mg, 0.80 mmol) tilsatt til en suspensjon av NaH (20 mg, 0.85 mmol) i DMF (1 ml) og rørt i 15 min. Deretter ble 4-fluorfenylsulfonylkloridet (174 mg, 0.90 mmol) tilsatt og den oppnådde løsningen ble rørt i 30 min ved 0°C og 3 t ved romtemperatur. DMF ble fordampet og det oppnådde faste stoffet ble kromatografert (Eluent CH2Cl2/MeOH, 90/10) til å gi 100 mg (32%) av den ønskede forbindelsen. <]>H NMR (270 MHz, DMSO-d6) 8 8.25-8.10 (m, 3H), 7.99 (d, J= 8 Hz, 1H), 7.83 (d, J= 8 Hz, 1H), 7.65-7.30 (m, 3H), 7.20-7.05 (m, 2H), 3.18 (br, 2H), 2.75 (br, 2H), 1.78 (br, 2H), 1.50 (br, 2H); MS (ESI+) for m/ z 383 (M+H)<+>.-
EKSEMPEL 99 (Mellomprodukt)
tert-Butyl 4-[2-jod-l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat En blanding av butylmagnesiumklorid (1 ml, 1 mmol, 2.0 M i eter) og di-isopropylamin (0.279 ml, 2 mmol) i tørr THF (5 ml) ble rørt i 41 under inert atmosfære ved romtemperatur. En løsning av tert-butyl 4-[l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat (220 mg, 0.5 mmol) i THF (2 ml) ble tilsatt langsomt og den oppnådde løsningen ble rørt i 21 ved romtemperatur. En løsning av jod (380 mg, 2.2 mmol) i THF (2 ml) ble tilsatt dråpevis og blandingen ble rørt over natten. Etter fordampning av løsningsmiddelet under vakuum ble resten behandlet med en vandig løsning av NH4CI (10 ml). Blandingen ble ekstrahert med CH2CI2 (3x10 ml) og de forenede organiske lagene ble tørket (MgSCv) og konsentrert under vakuum. Resten ble renset med kolonnekromatografi (SiCh) ved å benytte CH2CI2 som eluent til å gi 100 mg
(35%). <*>H NMR (500 MHz, CDC13) 8 8.05-7.80 (m, 3H), 7.60-7.35 (m, 3H), 7.19 (t, J= 8 Hz, 1H), 6.98 (s, 2H), 6.72 (d, 7= 8 Hz, 1H), 3.62 (m, 4H), 3.05 (m, 4H), 1.47 (m, 9H); MS (ESI+) for m/ z 568 (M+H)<+>.
EKSEMPEL 100
2-Jod-l-(fenylsulfonyl)-4-(l-piperazinyl)-lH-indol hydroklorid ICH2CI2 (1 ml) ble tert-butyl 4-[2-jod-l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat (25 mg, 0.044 mnol) og HC1 i eter (1 ml) tilsatt og ristet i 2 timer ved romtemperatur. Det oppnådde bunnfallet ble filtrert fra og vasket med eter hvilket ga 20 mg av den ønskede forbindelsen. <*>H NMR (270 MHz, DMSO-de) 8 9.02 (br, 1H), 7.90-7.80 (m, 3H), 7.75-7.55 (m, 3H), 7.32 (s, 1H), 7.22 (t, J= 8 Hz, 1H), 6.79 (d, J= 8 Hz, 1H), 3.35-3.10 (m, 8H); MS (ESI+) for m/ z 468 (M+H)<+>.
EKSEMPEL 101 (Mellomprodukt)
tert-Butyl 4-[2-fenyl-l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat tert-Butyl 4-[2-jod-l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat (40 mg,
0.07 mmol), fenylborsyre (12 mg, 0.1 mmol), Pd(PPh3) (2 mg, 0.002 mmol) og en 2 M vandig løsning av K2CO3 (0.075 ml) ble rørt i 3 dager ved 80°C i dimetoksyetan (2 ml). Etter fordampning av løsningsmiddelet ble råmaterialet renset med kolonnekromatografi (Si02) og dette førte til 30 mg av den ønskede forbindelsen (80%). <*>H NMR (270 MHz, DMSO-d6) 8 8.02 (d, J= 8 Hz, 1H), 7.55.7.20 (m, 11H), 6.78 (t, J= 8 Hz, 1H, 7.57 (s, 1H), 3.58 (m, 4H), 3.02 (m, 4H), 1.48 (m, 9H); MS (ESI+) for m/ z 518 (M+H)<+>.
EKSEMPEL 102
2-Fenyl-l-(fenylsulfonyl)-4-(l-piperazinyl)-lH-indol hydroklorid tert-Butyl 4-[2-fenyl-l-(fenylsulfonyl)-lH-indol-4-yl]-l-piperazinkarboksylat (30 mg, 0.058 mmol) ble oppløst i CH2C12 (1 ml) etterfulgt av tilsetning av HC1 i eter (1 ml). Reaksjonen ble ristet i 2 timer ved romtemperatur. Det oppnådde bunnfallet ble filtrert fra og vasket med eter, hvilket ga 20 mg av den ønskede forbindelsen (80%). <*>H NMR (270 MHz, CMSO-de) 8 9.02 (br, 1H), 7.90-7.80 (m, 3H), 7.75-7.55 (m, 3H), 7.32 (s, 1H), 7.22 (t, J= 8 Hz, 1H), 6.79 (d, J= 8 Hz, 1H), 3.35-3.10 (m, 8H). MS (ESI+) for m/z418(M+H)<+>.
EKSEMPEL 103 (Mellomprodukt)
4-Trifluormetansulfonyloksy-2-metyl-l-tetrabutyldimetylsilylindol 4-Hydroksy-2-metylindol (3.0 g, 20 mmol) ble oppløst i 30 ml DCM etterfulgt av tilsetning av trietylamin (4.2 ml). Løsningen ble avkjølt (isbad) og en løsning av trifluormetansulfonanhydrid (6.3 g, 22 mmol) i DCM (6 ml) ble tilsatt langsomt under røring. Etter 10 minutter ble løsningen vasket med vandig K2CO3, tørket (K2CO3) og løsningsmiddelet ble fordampet. Forbindelsen ble oppløst i THF (10 ml) og NaH (0.6 g av 80% suspensjon i olje) ble tilsatt. TBDMSC1 (3.3 g, 22 mmol) i THF (5 ml) ble tilsatt. Løsningen ble fortynnet med 20 ml av DCM, vasket med vandig NH4CI. Organiske fase ble tørket og fordampet. Forbindelsen ble renset med kromatografi (Si02 heksan/eter). Utbytte 5.7 g (75%): <*>H NMR (CDC13) 8 7.48 (d, J= 7.8 Hz, 1H), 7.10-6.96 (m, 2H), 6.44 (s, 1H), 2.50 (s, 3H), 0.96 (s, 9H), 0.64 (s, 6H); MS (ESI) 381.1
(M+H).
EKSEMPEL 104 (Mellomprodukt)
4-(N-Boc-piperazinyl)-2-metyl-l-tetrabutyldimetylsilylindoI 4-trifluormetansulfonyloksy-2-metyl-l-tetrabutyldimetylsilylindol (1.0 g, 2.6 mmol) og boc-piperazin (0.73 g, 3.9 mmol) ble reagert i henhold til metode 1 for å gi 0.75 g (67%) av et fast stoff: <!>H NMR (CDC13) 8 7.20 (d, J= 8.2 Hz, 1H), 6.96 (t, 1H), 6.55 (d, J= 7.4 Hz, 1H), 6.31 (s, 1H), 3.63 (pt, 4H), 3.11 (pt, 4H), 2.47 (s, 3H), 1.48 (s, 9H), 0.94 (s, 9H), 0.64 (s, 6H); MS (ESI) 417.4 (M+H).
EKSEMPEL 105
4-Piperazinyl-2-metyl-l-benzosulfonylindol trifluoracetat
4-(N-Boc-piperazinyl)-2-metyl-l-tetrabutyldimetylsilylindol (0.2 g, 0.48 mmol) ble oppløst i etylacetat (5 ml) etterfulgt av tilsetning av en løsning av natriumfluorid (0.1 g) i vann (1 ml). Blandingen ble rørt kraftig (50°C) i 2 timer. Den organiske fasen ble separert, tørket og fordampet. Råmaterialet ble oppløst i DCM (10 ml) etterfulgt av tilsetning av benzosulfonylklorid (0.1 g, 0.58 mmol) og vandig NaOH (0.5 ml, 50% vannløsning). Blandingen ble rørt kraftig i 11. Vann (5 ml) ble tilsatt, den organiske fasen ble separert, tørket og fordampet. Råmaterialet ble oppløst i DCM (10 ml) og trifluoreddiksyre (1 ml) ble tilsatt. Etter 3 t ble løsningsmiddel fordampet og forbindelsen ble krystallisert fra etanol. Utbytte 60 mg (54%): 'H NMR (CDC13) 8 7.83-7.77 (m, 3H), 7.59-7.56 (m, 1H), 7.50-7.46 (m, 2H), 7.19 (t, 1H), 6.81 (d, J= 7.8 Hz,
1H), 6.52 (s, 1H), 3.41 (pt, 4H), 3.30 (pt, 4H), 2.61 (s, 3H); <13>CNMR (CDC13) 8 143.7, 138.8,138.0,136.6,133.9,129.2,126.1,124.3,123.5,111.5,110.0,107.3,48.5,43.8, 14.6; MS (ESI) 356.4 (M+H).
EKSEMPEL 105
EKSEMPEL 106 (Mellomprodukt)
N-(t-Butyl-dimetylsilyl-4-(4-boc-homopiperazinyl)-indol
Tittelforbindelsen ble fremstilt ifølge eksempel 4.
'H NMR (D20) 8 9.37 (bs, 2H), NH; 7.95 (m, 2H); 7.73-7.56 (m, 4H); 7.44 (d, J = 8.2, 1H); 7.18 (t. J = 8.2, 1H); 6.84 (m, 1H); 6.65 (d, J = 7.9,1H); 3.65 (m, 2H); 3.46 (m, 2H); 3.31 (m, 2H); 3.19 (m, 2H); 2.13 (m, 2H). <13>D NMR (D20): 145.7,137.5,136.3, 135.2, 130.4, 127.3, 126.2,125.1,121.3,109.3,105.4,100.0, 50.8, 48.7, 46.6, 45.1, 25.6 MS (ESI) 356 (M+H).
EKSEMPEL 107 (Mellomprodukt)
l-Fenylsulfonyl-N-(t-butyl-dimetylsilyl-4-(4-boc-homopiperazinyI)-indol
'H NMR (CDCI3) 8 7.86 (m, 2H); 7.54-7.38 (m, 6H); 7.4 (t, J = 8.2,1H); 6.65-6.62 (m, 1H); 3.63-3.41 (m, 8H); 1.97 (m, 2H); 1.43 (s, 9H); MS (ESI) 456 (M+H).
EKSEMPEL 108
l-Fenylsulfonyl-4-(homopiperazinyl)-indol hydroklorid
•h NMR (CDCI3) 8: 7.24 (m, 2H); 7.09-7.07 (m, 6H); 7.01 (t, J = 8.1,1H); 6.53 (m, 1H; 3.69-3.28 (m, 8H); 2.06 (m, 2H); 1.42 (s, 9H); 0.91 (s, 9H); 0.56 (s, 6H). MS (ESI) 430
(M+H).
EKSEMPEL 108
Farmakologiske tester
Evnene hos en forbindelse ifølge oppfinnelsen til å binde 5HT6-reseptoren kan bestemmes ved å benytte in vivo og in vitro analyser som er kjent innenfor fagområdet. Den biolgiske aktiviteten av forbindelser fremstilt i eksemplene ble testet ved å benytte forskjellige tester.
5-HT6 reelt aktivitetsassay
Antagonister ved 5HT6-reseptoren ble karakteriser ved å måle hemming av 5-HT-indusert økning i cAMP i HEK 293-celler som uttrykker den humane 5-HT6-reseptoren (se Boess rn.fl. (1997) Neuropharmacology 36: 713-720). Oppsummert ble HEK293/5-HT6-celler sådd i polylysinbelagte 96-brønnsskåler ved en tetthet på 25 000/brønn og dyrket i DMEM (Dubecco's Modified Eagle Medium) (uten fenol-rødt) som inneholdt 5% dialysebehandlet fetalt bovint serum i 48 timer ved 37°C i en 5% C02-inkubator. Mediet ble deretter dratt ut og erstattet med 0.1 ml assaymedium (Hanks Balance saltoppløsning inneholdende 20 mM HEPES; 1.5 mM isobutylmetylxantin og 1 mg/ml bovint serumalbumin). Etter tilsetning av testsubstansene ble 50 ul oppløst i assaymediet, cellene ble inkubert i 10 min ved 37°C i 5% C02-inkubator. Mediet ble deretter dratt ut og cAMP-innholdet ble bestemt ved å benytte et radioaktivt cAMP-kit (Amersham Pharmacia Biotech, BIOTRAK RPA559). Potensen av antagonister ble kvantifisert ved å bestemme konsentrasjonen som forårsaket 50% hemming av 5-HT (ved [5-HT] = 8 ganger EC50) framkalt økning i cAMP, ved å benytte formelen KI=IC5o/(l+[5HT]/EC5o). Typisk var 5-HT6-reseptoraffinitetsverdiene (Kf) i området fra 0.1 nMtil2uM.
Metode for in vivo assay for reduksjon av matinntak
Dyr
Fete (ob/ob) mus velges ut da den primære dyremodellen for utvelging som denne mutant musen konsumerer høye mengder av mat, hvilket resulterer i et høyt signal til lydforhold. For videre å dokumentere og sammenligne effektivitetsdata blir også effekten av forbindelsene på matkonsumering studert i villtype (C57BL/6J) mus. Mengden av mat som konsumeres iløpet av 15 timer med infusjon av forbindelser registreres.
Hannmus (fete C57BL/6JBom-Lepob og magre villtype C75Bl/6JBom; Bomholtsgaard, Danmark) som var 8-9 uker med en gjennomsnittlig kroppsvekt på 50 g (fete) og 25 g (magre) benyttes i alle studiene. Dyrene holdes en og en i bur ved 23±1°C, 40-60% fuktighet og har fri tilgang til vann og standard laboratoriemat. 12/12-T lys/mørkesyklusen innstilles slik at lyset slukket kl 17:00. Dyrene tilpasses i minst en uke før studiestart.
Forbindelser
Testforbindelsene oppløses i løsningsmidler som er egnet for hver spesifikek forbindelse slik som cyklodekstrin, cyklodekstrin/metansulfonsyre, polyetylenglykol/metansulfonsyre, saltoppløsning. Nye løsninger lages for hvert studie. Doser på 30, 50 og 100 mg kg^dag"<1> benyttes. Renheten av testforbindelsene er av analytisk kvalitet.
Minipumpeimplantasjon
Dyrene veies ved starten av studiet og inndeles basert på kroppsvekt. Alzet osmotiske minipumper (Modell 200ID; infusjonshastighet 8 ul/t) benyttes og fylles i det alt
vesentlig som anbefalt i Alzefs tekniske informasjonsmanual (Alza Scientific Products, 1997; Teeuwes and Yam, 1976). Kontinuerlig subkutan infusjon med 24 timers varighet benyttes. Minipumpene fylles enten med forskjellige konsentrasjoner av testforbindelser som er oppløst i bindemiddel eller med kun bindemiddelløsning og holdes i
bindemiddel som er forvarmet til 37°C (tilnærmet 11). Minipumpene implanteres subkutant i nakke/ryggregionen under kortvirkende bedøvelse (metofan/enfluran). Denne kirurgiske prosedyren varer tilnærmet 5 minutter. Det tar omtrent 3 timer å oppnå stabil tilførsel av forbindelsen.
Matinntakmålinger
Vekten av matpelletsene måles kl 17:00 og kl 20:00 i to dager før (grunnlinje) og en dag etter implantasjonen av de osmotiske minipumpene. Innveiingen utføres med en computerassistert Mettler Toledo PR 5002 balanse. Det korrigeres for tilfeldig søling. Ved slutten av studiet avlives dyrene ved nakkevridning og det tas prøver fra hovedpulsåren for senere analyse av plasmalegemiddelkonsentrasjoner.
Bestemmelse av plasmakonsentrasjon
Plasmaprøveproteiner utfelles med metanol, sentrifugeres og supernatanten overføres til HPLC-glass og injiseres i væskekromatografi/massespektrometrisystemet. Massespektrometeret innstilles på elektrospraypositivion måte og flerreaksjons-registrering benyttes.
En lineær regresjonsanalyse av standardene som tvinges gjennom startpunktet benyttes for å kalkulere konsentrasjonene av de ukjente prøvene.
Statistisk evaluering
Matkonsumering i 15 timer måles i tre påfølgende dager og prosenten av grunnivåverdier utledes for hvert dyr fra dagen før og etter behandling. Verdiene uttrykkes som gjennomsnitt ± SD og ± SEM for åtte dyr pr dosegruppe. Statistisk evaluering utføres ved Kruskal-Wallis en-veis ANOVA ved å benytte prosentbasalverdier. Dersom statistisk signifikans oppnås ved nivået for p<0.05, utføres Mann-Whitney U-test for statistisk sammenligning mellom kontroll og behandlede grupper.
Claims (24)
1.
Forbindelse med formel (I):
der
Ar er
(1) fenyl,
(2) naftyl,
(3) tienyl, pyrazolyl, pyridyl, tetrahydrokinolyl, tetrahydroisokinolyl, benzotienyl, imidazolyl, benzoxadiazolyl, eller
(4) -R<9->fenyl: der hver av fenyl, naftyl og heterocyklisk ring uavhengig av hverandre eventuelt er substituert med halogen, Ci.6 alkyl, CF3, Ci.6 alkoksy, OCF3, COCF3, CN, N02 fenyloksy, fenyl, Ci.6 alkylsulfonyl, -Ci.6alkyl-NH-CO-fenyl; og R<9> er Ci-6 alkyl eller C2-6 alkenyl, der hver av disse eventuelt er substituert med fenyl;R<2> er H, fenyl, I eller Ci.6 alkyl; R<3> er H eller 3-(l -azabicyklo[2.2.2]okt-2-en)yl; R<4> er en heterocyklisk ring valgt fra gruppen bestående av:
hvori R6 ef H, Ci.6 alkyl eller benzyl; og R<5> er Heller
forutsatt at R<4> er H når R<5> er R<6->piperazinyl;
eller et farmasøytisk akseptabelt salt, hydrat eller stereoisomer derav.
2.
Forbindelse ifølge krav 1, der
Ar er
(1) fenyl,
(2) 1-naftyl eller 2-naftyl,
(3) tienyl, pyrazolyl, pyridyl, tetrahydrokinolyl, tetrahydroisokinolyl, benzotienyl, imidazolyl, benzoxadiazolyl, eller
(4) -R<9->fenyl;
der hver av fenyl, naftyl, og heterocyklisk ring uavhengig av hverandre eventuelt er substituert med F, Cl, Br, Ci-6 alkyl, CF3, C1.6 alkoksy, OCF3, fenyl eller C2-6 alkenyl; og R<9> er C1.2 alkyl;
R<2> er H, fenyl, I eller Ci.6 alkyl; •
R<4> er valgt fra gruppen bestående av:
R<5> er valgt fra H eller R<6->piperazinyl.
3.
Forbindelse ifølge krav 1, der Ar er fenyl, eventuelt substituert med F, Cl, Br, metyl, CF3, Cm alkoksy,OCF3, CN, N02, fenyloksy eller fenyl.
4.
Forbindelse ifølge krav 1, der Ar er 1-naftyl eller 2-naftyl, der hver av disse eventuelt kan være substituert med F, Cl, Br, metyl, CF3, Cm alkoksy, OCF3, CN, N02, fenyloksy, metylsulfonyl eller fenyl.
5.
Forbindelse ifølge krav 1, der Ar er en heterocyklisk gruppe valgt fra gruppen bestående av pyridyl, tienyl, imidazolyl, pyrazolyl, benzotienyl og benzoksadiazolyl, der hver av disse eventuelt kan være substituert med halogen, Ci-6 alkyl, CF3, Ci-6 alkoksyl, OCF3, CN, NO2, fenyloksy, fenyl, Ci-6 alkylsulfonyl, C2-6 alkenyl.
6.
Forbindelse ifølge krav 5, der Ar er en heterocyklisk ring valgt fra gruppen bestående av pyridyl, tienyl, imidazolyl, pyrazolyl, benzotienyl og benzoksadiazolyl, der hver av disse eventuelt kan være substituert med halogen eller C1.6 alkyl.
7.
Forbindelse ifølge krav 6, der Ar er 2-pyridyl, 3-pyridyl eller 4-pyridyl.
8.
Forbindelse ifølge krav 1, der Ar er -R<9->fenyl, der R<9> er Ci.3 alkyl eller C2-3 alkenyl, der hver av disse eventuelt kan være substituert med fenyl og der fenyl eventuelt er substituert med fenyl.
9.
Forbindelse ifølge et hvilket som helst av kravene 1 til 8, der hver av R<2> og R<3> er H.
10.
Forbindelse ifølge et hvilket som helst av kravene 1 til 9, der R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci.3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
11.
Forbindelse ifølge krav 1, der Ar er fenyl, eventuelt substituert med F, Cl, Br, metyl, CF3, Cm alkoksy, OCF3, CN, NO2, fenyloksy, fenyl eller metylsulfonyl; der hver av R<2 >og R<3> er H; og R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R6 er H, Ci_3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
12.
Forbindelse ifølge krav 1, der Ar er 1-naftyl eller 2-naftyl, der hver av disse eventuelt kan være substituert med F, Cl, Br, metyl, CF3, CM alkoksy, OCF3, CN, N02, fenyloksy, fenyl eller metylsulfonyl; hver av R<2> og R<3> er H; og og R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci-3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
13.
Forbindelse ifølge krav 1, der Ar er en heterocyklisk ring valgt fra gruppen bestående av pyridyl, tienyl, imidazolyl, pyrazolyl, benzotienyl og benzooksadiazolyl, der hver av disse eventuelt kan være substituert med halogener eller Cj-6 alkyl; der hver av R<2> og R<3 >er H; og R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci-3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
14.
Forbindelse ifølge krav 13, der Ar er 2-pyridyl, 3-pyridyl eller 4-pyridyl; hver av R<2> og R<3> er H; og R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci.3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl.
15.
Forbindelse ifølge krav 1, der Ar er -R<9->fenyl; hver av R<2> og R<3> er H; og R<4> er en heterosyklisk ring valgt fra gruppen bestående av
der R<6> er H, Ci-3 alkyl, eller benzyl;
R<5> er H eller R<6->piperazinyl, forutsatt at R<4> er H når R<5> er R<6->piperazinyl; R<9> er C1.3 alkyl eller C2-3 alkenyl, der hver av disse eventuelt kan være substituert med fenyl; og fenyl eventuelt er substituert med fenyl.
16.
Forbindelse ifølge krav 1, der forbindelsen er
1 -fenylsulfonyl-4-piperazinylindol hydroklorid, l-[(2,5-dimetoksyfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid,
1 -(mesitylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
1 -(1 -naftylsulfonyl)-4-) 1 -piperazinyl)-1 H-indol hydroklorid,
N,N-dimetyl-5 {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} -1 - naftalenaminhydroklorid
1 [(4-propoksyfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -[(2,5-diklor-3-tienyl)sulfonyl]-4-( 1 -piperazinyl-1 H-indol hydroklorid, 1 - [(4-metoksyfenyl)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 [(2,4-difluorfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
1 -([ 1,1' -bifenyl] -4-ylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 1 -[(3,4-dimetoksyfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 5-metyl-2-metoksy- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenyleter hydroklorid,
1- [(2,5-diklorfenyl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid,
1 - [(5 -klor-1,3 -dimetyl-1 H-pyrazol-4-yl)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid,
1 -[(3-klor-2-metylfenyl)sulfonyl]-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
2- klor-5-(4-{[4-(l-piperazinyl)-lH-indol-l-yl]sulfonyl}fenoksy)benzonitril hydroklorid,
4-brom-2- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenylmetyleter hydroklorid,
4-( 1 -piperazinyl)-1 -(3 -pyridylsulfonyl)-1 H-indol hydroklorid,
7- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} -2-(trifluoracetyl)-1,2,3,4-tetrahydroisokinolin hydroklorid,
metyl 2- {[4-( 1 -piperazinyl)-1 H-indol-1 -yl] sulfonyl} fenylsulfon hydroklorid,
1 - [(4-fluorfenyi)sulfonyl] -4-( 1 -piperazinyl)-1 H-indol hydroklorid, l-[(5-klor-3-metyl-l-benzotien-2-yl)sulfonyl]-4-(l-piperazinyl)-lH-indol hydroklorid,
4-(4-metyl-1 -piperazinyl)-1 -(4-metylbenzensulfonyl)-1 H-indol hydroklorid hydroklorid,
4-piperazino-N-(4-trifluormetyl)fenylsulfonyl)indol hydroklorid, 4-(3-metylpiperazin)-(N-(4-trifluormetyl)fenylsulfonyl)indol dihydroklorid,
4-(4-metyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-etyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-( 1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid, 4-(5-aza-indolizidinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-metyl-1 -homopiperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(3-metyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid, 4-(cw-3,5-dimetyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-(4-isopropyl-1 -piperazinyl)-1 -(2-metylbenzensulfonyl)-1 H-indol hydroklorid,
4-((lS,4S)-2-metyl-2,5-diazabicyklo[2.2.1]heptyl)-l-(2-metylbenzensulfonyl)-lH-indol hydroklorid,
4-(4-metyl-1 -homopiperazinyl)-1 -(benzensulfonyl)-1 H-indol
hydroklorid,
4-(ci s 3,5-dimetyl-1 -piperazinyl)-1 -(benzensulfonyl)-1 H-indol hydroklorid,
4-(4-etyl-1 -piperazinyl)-1 -(benzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-nitro-benzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-brom-benzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-klor-benzensulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-\-{ E 2-fenyl-etensulfonyl)-lH-indol hydroklorid, 4-piperazinyl-1 -(3 -trifluormetyl-benzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-cyanobenzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-klor-7-klor-2,1,3-benzoksadiazolsulfonyl)-1 H-indol hydroklorid,
4-piperazinyl-1 -(3 -cyanobenzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-fenoksybenzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-klorfenylmetansulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-metylfenylmetansulfonyl)-l H-indol hydroklorid, 4-piperazinyl-1 -(1,1 -difenyletansulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-1 -(4-trifluormetoksybenzensulfonyl)-1 H-indol hydroklorid, 4-piperazinyl-l-(5-[(benzoylamino)metyl]tiofen-2-sulfonyl)-lH-indol hydroklorid,
1 -[(N-metyl-1 H-imidazolyl-4-yl)sulfonyl]4-( 1 -piperazinyl)-1 H-indol hydroklorid,
N-benzensulfonyl5 -(4-metylpiperazin-1 -yl)-indol, N-(4-metylbenzensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, N-benzensulfonyl-5-(4-isopropylpiperazin-1 -yl)-indol, N-(4-metylbenzensulfonyl)-5-(4-isopropylpiperazin-1 -yl)-indol, N-(3,4-dimetoksybenzensulfonyl)-5-(4-propylpiperazin-1 -yl)-indol, hydroklorid,
N-(3-fluorbenzensulfonyl)-5-(4-propylpiperazin-l-yl)-indol, hydroklorid, N-(4-propylbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid, N-( 1 -naftalensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid, N-(bifenyl-4-sulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid,
N-(4-metoksybenzensulfonyl)-5-(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-(3,4-dimetoksybenzensulfonyl)-5 -(4-metylpiperazin-1 -yl)-indol, hydroklorid,
N-(2,4-difluorbenzensulfonyl)-5-(4-metylpiperazin-l-yl)-indol, hydroklorid,
N-(4-metoksybenzensulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(2,4-difluorbenzensulfonyl)-5-84-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(4-butoksybenzensulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(3,4-dimeloksybenzensulfonyl)-5-(4-benzylpiperazin-l-yl)-indol, hydroklorid,
N-(bifenyl-4-sulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid, N-(naftalen-2-sulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(4-propylbenzensulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid,
N-(3 -fluorbenzensulfonyl)-5-(4-benzylpiperazin-1 -yl)-indol, hydroklorid, N-(4-metoksybenzensulfonyl)-5 -(piperazin-1 -yl)-indol, hydroklorid, N-(2,4-difluorbenzensulfonyl)-5-piperazin-1 -yl)-indol, hydroklorid, N-(4-butoksybenzensulfonyl)-5-(piperazin-1 -yl)-indol, hydroklorid, N-(3,4-dimetoksybenzensulfonyl)-5-piperazin-1 -yl)-indol, dihydroklorid, N-(bifenyl-4-sulfonyl)-5-(piperazin-1 -yl)-indol, dihydroklorid, N-(naftalen-2-sulfonyl)-5-(piperazin-1 -yl)-indol, dihydroklorid, N-(4-propylbenzensulfonyl)-5-(piperazin-1 -yl)-indol, dihydroklorid,
N-(3 -fluorbenzensulfonyl)-5 -(piperazin-1 -yl)-indol, dihydroklorid, N-benzensulfonyl-5-(piperazin-l-yl)-indol, dihydroklorid,
3- (l-azabicyklo[2.2.2]okt-2-en-3-yl)-l-[(4-fluorfenyl)sulfonyl]-lH-indol, 2-j od-1 -(fenylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid, 2-fenyl-1 -(fenylsulfonyl)-4-( 1 -piperazinyl)-1 H-indol hydroklorid,
4- piperazinyl-2-metyl-l-benzosulfonylindol trifluoracetat, eller 1 -fenylsulfonyl-4-(homopiperazinyl)-indol hydroklorid.
17.
Forbindelse ifølge krav 1, der forbindelsen er l-(fenylsulfonyl)-4-(l-piperazinyl)-1H-indol.
18.
Forbindelse ifølge krav 1, der forbindelsen er l-[(2,5-dimetoksyfenyl)sulfonyl]-4-(l-piperazinyl)-1 H-indol.
19.
Forbindelse ifølge krav 1, der forbindelsen er 4-(l-piperazinyl)-l-(3-pyridylsulfonyl)-1 H-indol hydroklorid.
20.
Farmasøytisk sammensetning som omfatter en forbindelse iføle krav 1 og en farmasøytisk akseptabel bærer.
21.
Forbindelse ifølge et hvilket som helst av kravene 1 til 20 for bruk i terapi.
22.
Anvendelse av en forbindelse ifølge et hvilket som helst av kravene 1 til 20, til fremstilling av et medikament for å behandle eller forebygge en sykdom relatert til den serotoninrelaterte 5 -HT6-reseptoren.
23.
Anvendelse ifølge krav 22, der sykdommen er fedme.
24.
Anvendelse ifølge krav 22, der sykdommen er en CNS-forstyrrelse.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0003810A SE0003810D0 (sv) | 2000-10-20 | 2000-10-20 | Novel compounds their use and preparations |
US24311500P | 2000-10-25 | 2000-10-25 | |
PCT/SE2001/002319 WO2002032863A1 (en) | 2000-10-20 | 2001-10-19 | 2-, 3-, 4-, or 5-substituted-n1-(benzensulfonyl)indoles and their use in therapy |
Publications (3)
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NO20031589D0 NO20031589D0 (no) | 2003-04-08 |
NO20031589L NO20031589L (no) | 2003-05-28 |
NO325259B1 true NO325259B1 (no) | 2008-03-17 |
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NO20031589A NO325259B1 (no) | 2000-10-20 | 2003-04-08 | Substituerte N1-(benzensulfonyl) indoler, slike forbindelser for bruk i terapi, anvendelse av slike forbindelser samt farmasoytiske preparat inneholdende nevnte forbindelser. |
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US (2) | US7087750B2 (no) |
EP (1) | EP1326830A1 (no) |
KR (1) | KR100823908B1 (no) |
AU (2) | AU2001296193B2 (no) |
BR (1) | BR0114552A (no) |
CA (1) | CA2422717A1 (no) |
EA (1) | EA006132B1 (no) |
HK (1) | HK1084109A1 (no) |
IL (1) | IL154685A0 (no) |
MX (1) | MXPA03003397A (no) |
NO (1) | NO325259B1 (no) |
NZ (1) | NZ524675A (no) |
PL (1) | PL361887A1 (no) |
WO (1) | WO2002032863A1 (no) |
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-
2001
- 2001-10-19 WO PCT/SE2001/002319 patent/WO2002032863A1/en active IP Right Grant
- 2001-10-19 KR KR1020037005482A patent/KR100823908B1/ko not_active IP Right Cessation
- 2001-10-19 EA EA200300492A patent/EA006132B1/ru not_active IP Right Cessation
- 2001-10-19 AU AU2001296193A patent/AU2001296193B2/en not_active Ceased
- 2001-10-19 MX MXPA03003397A patent/MXPA03003397A/es active IP Right Grant
- 2001-10-19 EP EP01977043A patent/EP1326830A1/en not_active Withdrawn
- 2001-10-19 AU AU9619301A patent/AU9619301A/xx active Pending
- 2001-10-19 PL PL36188701A patent/PL361887A1/xx unknown
- 2001-10-19 CA CA002422717A patent/CA2422717A1/en not_active Abandoned
- 2001-10-19 BR BR0114552-5A patent/BR0114552A/pt not_active IP Right Cessation
- 2001-10-19 NZ NZ524675A patent/NZ524675A/en unknown
- 2001-10-19 IL IL15468501A patent/IL154685A0/xx unknown
- 2001-10-22 US US10/037,110 patent/US7087750B2/en not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
---|---|
NO20031589L (no) | 2003-05-28 |
AU9619301A (en) | 2002-04-29 |
CA2422717A1 (en) | 2002-04-25 |
EP1326830A1 (en) | 2003-07-16 |
US20050256106A1 (en) | 2005-11-17 |
US7087750B2 (en) | 2006-08-08 |
KR20030038825A (ko) | 2003-05-16 |
NZ524675A (en) | 2004-09-24 |
MXPA03003397A (es) | 2004-06-30 |
KR100823908B1 (ko) | 2008-04-21 |
US7524839B2 (en) | 2009-04-28 |
BR0114552A (pt) | 2003-07-01 |
HK1084109A1 (en) | 2006-07-21 |
US20020165251A1 (en) | 2002-11-07 |
IL154685A0 (en) | 2003-09-17 |
EA200300492A1 (ru) | 2003-10-30 |
PL361887A1 (en) | 2004-10-04 |
EA006132B1 (ru) | 2005-10-27 |
AU2001296193B2 (en) | 2006-04-27 |
WO2002032863A1 (en) | 2002-04-25 |
NO20031589D0 (no) | 2003-04-08 |
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