JP6465840B2 - エストロゲン受容体モジュレーターおよびその用途 - Google Patents
エストロゲン受容体モジュレーターおよびその用途 Download PDFInfo
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- JP6465840B2 JP6465840B2 JP2016149008A JP2016149008A JP6465840B2 JP 6465840 B2 JP6465840 B2 JP 6465840B2 JP 2016149008 A JP2016149008 A JP 2016149008A JP 2016149008 A JP2016149008 A JP 2016149008A JP 6465840 B2 JP6465840 B2 JP 6465840B2
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- Prior art keywords
- substituted
- unsubstituted
- phenyl
- chromene
- methyl
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- 239000002834 estrogen receptor modulator Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 321
- -1 4-((S) -2-((R) -3-methylpyrrolidin-1-yl) propoxy) phenyl Chemical group 0.000 claims description 193
- 150000003839 salts Chemical class 0.000 claims description 114
- 239000000243 solution Substances 0.000 claims description 98
- 239000008194 pharmaceutical composition Substances 0.000 claims description 42
- 229910052731 fluorine Inorganic materials 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 28
- 239000012453 solvate Substances 0.000 claims description 26
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 23
- 239000002775 capsule Substances 0.000 claims description 22
- 239000000725 suspension Substances 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 18
- 125000002393 azetidinyl group Chemical group 0.000 claims description 14
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 13
- 239000006185 dispersion Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 8
- 239000006187 pill Substances 0.000 claims description 8
- 239000000839 emulsion Substances 0.000 claims description 7
- 239000000499 gel Substances 0.000 claims description 6
- 238000010253 intravenous injection Methods 0.000 claims description 4
- 239000006210 lotion Substances 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
- 238000010254 subcutaneous injection Methods 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000007929 subcutaneous injection Substances 0.000 claims description 3
- 238000011200 topical administration Methods 0.000 claims description 3
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- JPFFAEPFVTWVBI-QMQXECRNSA-N (2r)-3-(3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound O([C@@H]1C2=CC=C(C=C2)OC[C@H](C)N2C[C@H](C)CC2)C2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1 JPFFAEPFVTWVBI-QMQXECRNSA-N 0.000 claims 1
- YKDMPXQGNUAFHO-QMQXECRNSA-N (2r)-3-(4-fluorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound O([C@@H]1C2=CC=C(C=C2)OC[C@H](C)N2C[C@H](C)CC2)C2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C=C1 YKDMPXQGNUAFHO-QMQXECRNSA-N 0.000 claims 1
- JPFFAEPFVTWVBI-WMUWJOOSSA-N (2s)-3-(3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound O([C@H]1C2=CC=C(C=C2)OC[C@H](C)N2C[C@H](C)CC2)C2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1 JPFFAEPFVTWVBI-WMUWJOOSSA-N 0.000 claims 1
- YKDMPXQGNUAFHO-WMUWJOOSSA-N (2s)-3-(4-fluorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound O([C@H]1C2=CC=C(C=C2)OC[C@H](C)N2C[C@H](C)CC2)C2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C=C1 YKDMPXQGNUAFHO-WMUWJOOSSA-N 0.000 claims 1
- NYAYKEFIXKTVIL-YZEIVILOSA-N 2-[2-fluoro-4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-3-(3-hydroxyphenyl)-4-methyl-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1F)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1 NYAYKEFIXKTVIL-YZEIVILOSA-N 0.000 claims 1
- JHYNJSFPCZLKON-JGZNSJETSA-N 2-[4-[(2s)-2-(3,3-dimethylpyrrolidin-1-yl)propoxy]phenyl]-3-(3-hydroxyphenyl)-4-methyl-2h-chromen-6-ol Chemical compound C([C@H](C)N1CC(C)(C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1 JHYNJSFPCZLKON-JGZNSJETSA-N 0.000 claims 1
- YSCUXLYCDQCOBS-UHFFFAOYSA-N 2-[4-[2-(3,3-dimethylpyrrolidin-1-yl)ethoxy]phenyl]-3-(3-hydroxyphenyl)-4-methyl-2h-chromen-6-ol Chemical compound O1C2=CC=C(O)C=C2C(C)=C(C=2C=C(O)C=CC=2)C1C(C=C1)=CC=C1OCCN1CCC(C)(C)C1 YSCUXLYCDQCOBS-UHFFFAOYSA-N 0.000 claims 1
- NAHHIXKSGGSPOL-UHFFFAOYSA-N 2h-chromen-6-ol Chemical compound O1CC=CC2=CC(O)=CC=C21 NAHHIXKSGGSPOL-UHFFFAOYSA-N 0.000 claims 1
- HFWPFAUEDRRQCT-GYMJABSESA-N 3-(2,4-difluoro-3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C(O)=C1F HFWPFAUEDRRQCT-GYMJABSESA-N 0.000 claims 1
- UNKBIANPWFKHCC-YZEIVILOSA-N 3-(2,4-difluorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C=C1F UNKBIANPWFKHCC-YZEIVILOSA-N 0.000 claims 1
- JVGKHOAHVDPFSG-YZEIVILOSA-N 3-(2-chloro-4-fluorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C=C1Cl JVGKHOAHVDPFSG-YZEIVILOSA-N 0.000 claims 1
- FTIVVYWRQPNPMX-YZEIVILOSA-N 3-(2-fluoro-3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1F FTIVVYWRQPNPMX-YZEIVILOSA-N 0.000 claims 1
- IESMOSFUAKOIHC-YZEIVILOSA-N 3-(2-fluoro-5-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC(O)=CC=C1F IESMOSFUAKOIHC-YZEIVILOSA-N 0.000 claims 1
- QZOKXAHOZAAOTG-GYMJABSESA-N 3-(3,4-difluoro-5-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC(O)=C(F)C(F)=C1 QZOKXAHOZAAOTG-GYMJABSESA-N 0.000 claims 1
- XYRTZDMPGSLLNO-YZEIVILOSA-N 3-(3,4-difluorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C(F)=C1 XYRTZDMPGSLLNO-YZEIVILOSA-N 0.000 claims 1
- CJJPACSUPGKACT-GYMJABSESA-N 3-(3,5-difluoro-4-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC(F)=C(O)C(F)=C1 CJJPACSUPGKACT-GYMJABSESA-N 0.000 claims 1
- OADJJQDRNJKXRD-YZEIVILOSA-N 3-(3-fluoro-4-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C(F)=C1 OADJJQDRNJKXRD-YZEIVILOSA-N 0.000 claims 1
- SXZPMPBHNMPCBI-YZEIVILOSA-N 3-(3-fluoro-5-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC(O)=CC(F)=C1 SXZPMPBHNMPCBI-YZEIVILOSA-N 0.000 claims 1
- GSKYCRNRCOSGPP-ZCIPHSPUSA-N 3-(3-hydroxy-2-methylphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC(O)=C1C GSKYCRNRCOSGPP-ZCIPHSPUSA-N 0.000 claims 1
- LLVQUBVAOXNDMT-AIECAEIUSA-N 3-(3-hydroxy-4-methylphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(C)C(O)=C1 LLVQUBVAOXNDMT-AIECAEIUSA-N 0.000 claims 1
- NIGKMMKMNGAIFH-MIBLMIDESA-N 3-(3-hydroxyphenyl)-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-4-(trifluoromethyl)-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C(F)(F)F)=C1C1=CC=CC(O)=C1 NIGKMMKMNGAIFH-MIBLMIDESA-N 0.000 claims 1
- DNWJNIUCMGAJQI-PGJZWCTDSA-N 3-(3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-7-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC(O)=CC=C2C(C)=C1C1=CC=CC(O)=C1 DNWJNIUCMGAJQI-PGJZWCTDSA-N 0.000 claims 1
- MTJMCYWOZVCWJG-COBFLCELSA-N 3-(3-hydroxyphenyl)-4-methyl-2-[4-[2-[(2r)-2-methylpyrrolidin-1-yl]ethoxy]phenyl]-2h-chromen-6-ol Chemical compound C[C@@H]1CCCN1CCOC1=CC=C(C2C(=C(C)C3=CC(O)=CC=C3O2)C=2C=C(O)C=CC=2)C=C1 MTJMCYWOZVCWJG-COBFLCELSA-N 0.000 claims 1
- SIPYPQLYQSNJNL-UEWHNOOISA-N 3-(3-hydroxyphenyl)-4-methyl-2-[4-[2-[(3r)-3-methylpiperidin-1-yl]ethoxy]phenyl]-2h-chromen-6-ol Chemical compound C1[C@H](C)CCCN1CCOC1=CC=C(C2C(=C(C)C3=CC(O)=CC=C3O2)C=2C=C(O)C=CC=2)C=C1 SIPYPQLYQSNJNL-UEWHNOOISA-N 0.000 claims 1
- GPURPDIEDCPRPM-KCHZNAQISA-N 3-(3-hydroxyphenyl)-4-methyl-2-[4-[2-[(3s)-3-methylpyrrolidin-1-yl]ethoxy]phenyl]-2h-chromen-6-ol Chemical compound C1[C@@H](C)CCN1CCOC1=CC=C(C2C(=C(C)C3=CC(O)=CC=C3O2)C=2C=C(O)C=CC=2)C=C1 GPURPDIEDCPRPM-KCHZNAQISA-N 0.000 claims 1
- ZXRWNCATOXLWCZ-PGJZWCTDSA-N 3-(4-chlorophenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(Cl)C=C1 ZXRWNCATOXLWCZ-PGJZWCTDSA-N 0.000 claims 1
- HRVVIPWTWJPNBO-YZEIVILOSA-N 3-(4-fluoro-3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(F)C(O)=C1 HRVVIPWTWJPNBO-YZEIVILOSA-N 0.000 claims 1
- OIQFCLKCRNYZIF-AIECAEIUSA-N 3-(4-hydroxy-2-methylphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1C OIQFCLKCRNYZIF-AIECAEIUSA-N 0.000 claims 1
- LHZULUDMKUWRMU-AIECAEIUSA-N 3-(4-hydroxy-3-methylphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C(C)=C1 LHZULUDMKUWRMU-AIECAEIUSA-N 0.000 claims 1
- VVFGKXXJOPKTPO-MIBLMIDESA-N 3-(4-hydroxyphenyl)-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-4-(trifluoromethyl)-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C(F)(F)F)=C1C1=CC=C(O)C=C1 VVFGKXXJOPKTPO-MIBLMIDESA-N 0.000 claims 1
- ZSEYQJFDZORYPF-PGJZWCTDSA-N 3-(4-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-7-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC(O)=CC=C2C(C)=C1C1=CC=C(O)C=C1 ZSEYQJFDZORYPF-PGJZWCTDSA-N 0.000 claims 1
- JAVWROGJKDGIHG-YZEIVILOSA-N 3-[3-hydroxy-4-(trifluoromethyl)phenyl]-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(C(F)(F)F)C(O)=C1 JAVWROGJKDGIHG-YZEIVILOSA-N 0.000 claims 1
- XXYYQWPLMSBMHJ-YZEIVILOSA-N 3-[4-hydroxy-3-(trifluoromethyl)phenyl]-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C(C(F)(F)F)=C1 XXYYQWPLMSBMHJ-YZEIVILOSA-N 0.000 claims 1
- MGYRMOBJZIUBQC-JDLBOKMSSA-N 4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-3-(4-methylsulfonylphenyl)-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=C(S(C)(=O)=O)C=C1 MGYRMOBJZIUBQC-JDLBOKMSSA-N 0.000 claims 1
- CSXDQUNPRHMXNG-SBCWPUQDSA-N 4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-3-phenyl-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC=C1 CSXDQUNPRHMXNG-SBCWPUQDSA-N 0.000 claims 1
- KHWLIAPHFDRPJN-UCZJRREFSA-N 4-methyl-3-(2-methylphenyl)-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C=C2C(C)=C1C1=CC=CC=C1C KHWLIAPHFDRPJN-UCZJRREFSA-N 0.000 claims 1
- YEHPLTVKBSCWAK-YZEIVILOSA-N 5-fluoro-3-(3-hydroxyphenyl)-4-methyl-2-[4-[(2s)-2-[(3r)-3-methylpyrrolidin-1-yl]propoxy]phenyl]-2h-chromen-6-ol Chemical compound C([C@H](C)N1C[C@H](C)CC1)OC(C=C1)=CC=C1C1OC2=CC=C(O)C(F)=C2C(C)=C1C1=CC=CC(O)=C1 YEHPLTVKBSCWAK-YZEIVILOSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 185
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
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- 238000005481 NMR spectroscopy Methods 0.000 description 98
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 91
- 229910052736 halogen Inorganic materials 0.000 description 82
- 150000002367 halogens Chemical class 0.000 description 82
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- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 76
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- 239000000543 intermediate Substances 0.000 description 51
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- 230000000694 effects Effects 0.000 description 47
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- 230000002829 reductive effect Effects 0.000 description 45
- 108010038795 estrogen receptors Proteins 0.000 description 44
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- 238000006243 chemical reaction Methods 0.000 description 42
- 241000124008 Mammalia Species 0.000 description 41
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- 125000006747 (C2-C10) heterocycloalkyl group Chemical group 0.000 description 34
- 125000000217 alkyl group Chemical group 0.000 description 33
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- 239000007858 starting material Substances 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 229940079593 drug Drugs 0.000 description 31
- 239000012267 brine Substances 0.000 description 30
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Description
本出願は、2010年6月10日に出願された、「ESTROGEN RECEPTOR MODULATORS AND USES THEREOF」と題する米国仮出願第61/253,531号の利益を主張するものであり、その全体が引用によって本明細書に組み込まれる。
R12は、
その薬学的に許容可能な塩、プロドラッグ、活性代謝物及び薬学的に許容可能な溶媒和物を含む、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)あるいは(XIII)の化合物は、エストロゲン受容体モジュレーターである。特異的な実施形態において、本明細書に記載の化合物は、エストロゲン受容体ディグレーダーである。特異的な実施形態において、本明細書に記載の化合物は、エストロゲン受容体アンタゴニストである。特異的な実施形態において、本明細書に記載されている化合物は、最小のエストロゲン受容体アゴニスト活性、あるいはエストロゲン受容体アゴニスト活性のないエストロゲン受容体ディグレーダーおよびエストロゲン受容体アンタゴニストである。
各R5は、H、ハロゲン、−CN、−OH、−OR9、−SR9、−S(=O)R10、−S(=O)2R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6フルオロアルコキシ、置換または非置換のC1−C6アルコキシ、および置換または非置換のC1−C6ヘテロアルキルから独立して選択され;各R6は、H、ハロゲン、−CN、−OH、−OR9、−SR9、−S(=O)R10、−S(=O)2R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6フルオロアルコキシ、置換または非置換のC1−C6アルコキシ、および置換または非置換のC1−C6ヘテロアルキルから独立して選択され;R7は、H又はC1−C4アルキルであり、各R9は、H、−C(=O)R10、−C(=O)OR10、−C(=O)NHR10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6ヘテロアルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6シクロアルキル、置換または非置換のC1−C6ヘテロシクロアルキル、置換又は非置換のアリール、置換又は非置換のヘテロアリール、−C1−C2アルキレン−(置換又は非置換のC3−C10シクロアルキル)、−C1−C2アルキレン(置換または非置換のC2−C10ヘテロシクロアルキル)、−C1−C2アルキレン(置換または非置換のアリール)、及び−C1−C2アルキレン(置換または非置換のヘテロアリール)から独立して選択され、又はR10は、置換又は非置換のC1−C6アルキル、置換又は非置換のC1−C6ヘテロアルキル、置換又は非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6シクロアルキル、置換または非置換のC1−C6ヘテロシクロアルキル、置換又は非置換のアリール、置換又は非置換のヘテロアリール、−C1−C2アルキレン−(置換または非置換のC3−C10シクロアルキル)、−C1−C2アルキレン−(置換又は非置換のC2−C10ヘテロシクロアルキル)、−C1−C2アルキレン−(置換又は非置換のアリール)、及び−C1−C2アルキレン−(置換または非置換のヘテロアリール)から独立して選択され;Yは−O−、−S−、あるいは−NR11−であり;R11は、H、−C(=O)R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキルまたは置換または非置換のC1−C6ヘテロアルキルであり;Xは、−O−、−S−、−CH2−、−NH−又は−N(C1−C6アルキル)−であり、mは、0、1、2、3、4又は5であり、nは、0、1、2、3又は4であり、pは、0、1、2、3又は4である。
幾つかの実施形態において、
R3は、H、ハロゲン、C1−C4アルキル、C3−C6シクロアルキル、またはC1−C4フルオロアルキルであり;
各R4は、H、ハロゲン、−CN、−OH、−OR9、−SR9、−S(=O)R10、−S(=O)2R10、−C(=O)R10、−C(=O)OH、−C(=O)OR10、−C(=O)NHR10、−C(=O)N(R10)2、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6フルオロアルコキシ、置換または非置換のC1−C6アルコキシ、および置換または非置換のC1−C6ヘテロアルキルから独立して選択され;
各R5は、H、ハロゲン、−CN、−OH、−OR9、−SR9、−S(=O)R10、−S(=O)2R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6フルオロアルコキシ、置換または非置換のC1−C6アルコキシ、および置換または非置換のC1−C6ヘテロアルキルから独立して選択され;
各R6は、H、ハロゲン、−CN、−OH、−OR9、−SR9、−S(=O)R10、−S(=O)2R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC1−C6フルオロアルコキシ、置換または非置換のC1−C6アルコキシ、および置換または非置換のC1−C6ヘテロアルキルから独立して選択され;
R7は、HまたはC1−C4アルキルであり;
各R9は、H、−C(=O)R10、−C(=O)OR10、−C(=O)NHR10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6ヘテロアルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC3−C10シクロアルキル、置換または非置換のC2−C10ヘテロシクロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、−C1−C2アルキレン−(置換または非置換のC3−C10シクロアルキル)、−C1−C2アルキレン−(置換または非置換のC2−C10ヘテロシクロアルキル)、−C1−C2アルキレン−(置換または非置換のアリール)、および−C1−C2アルキレン−(置換または非置換のヘテロアリール)から独立して選択され;
あるいは、各R10は、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6ヘテロアルキル、置換または非置換のC1−C6フルオロアルキル、置換または非置換のC3−C10シクロアルキル、置換または非置換のC2−C10ヘテロシクロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、−C1−C2アルキレン−(置換または非置換のC3−C10シクロアルキル)、−C1−C2アルキレン−(置換または非置換のC2−C10ヘテロシクロアルキル)、−C1−C2アルキレン−(置換または非置換のアリール)、および−C1−C2アルキレン−(置換または非置換のヘテロアリール)から独立して選択され;
R12は−L−NR2aR2bであり、
Lは置換または非置換のC1−C6アルキレンであり、ここでLが置換されると、その後LはR1で置換され、R1はF、C1−C4アルキルまたはC1−C4フルオロアルキルであり;
R2aは、HまたはR10であり;
R2bは、−C(=O)R10、−C(=O)OR10、−C(=O)NHR10、−S(=O)2R10、または、R10であり;または、
R2aとR2bは、置換または非置換の単環式ヘテロシクロアルキル、置換または非置換の二環式ヘテロシクロアルキル、置換または非置換の単環式ヘテロアリール、あるいは、置換または非置換の二環式ヘテロアリールを形成するために付けられているN原子と一緒に得られ;
Yは−O−、−S−、または−NR11−であり;R11は、H、−C(=O)R10、置換または非置換のC1−C6アルキル、置換または非置換のC1−C6フルオロアルキルまたは置換または非置換のC1−C6ヘテロアルキルであり;
Xは、−O−、−S−、−CH2−、−NH−、または−N(C1−C6アルキル)−であり:
mは、0、1、2、3、4または5であり;
nは、0、1、2または3であり、
pは、0、1、2、3または4である。
本明細書に記載される式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、または(XIII)の化合物は、標準合成技術を使用して、または当該技術分野で既知の方法を本明細書に記載の方法と組み合わせて使用することによって合成される。さらに、本明細書が提示する溶媒、温度、およびその他の反応条件は異なり得る。
1つの態様において、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)あるいは(XIII)の化合物は、1つ以上の立体中心を保有し、各立体中心はR配置またはS配置のいずれかに独立して存在する。本明細書に提示される化合物は、全てのジアステレオマー、エナンチオマー、およびエピマーの形態、ならびにそれらの適切な混合物も含む。本明細書に提供される化合物および方法は、すべてのシス、トランス、シン、アンチ、エントゲーゲン(E)、およびツザメン(Z)異性体、ならびにそれらの適切な混合物を含む。特定の実施形態において、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)および(XIII)の化合物は、化合物のラセミ混合物を光学活性な分割剤と反応させて、1組のジアステレオマー化合物(diastereoisomeric compounds)/塩を形成し、ジアステレオマーを分離させ、光学的に純粋なエナンチオマーを回復させることにより、それらの個々の立体異性体として調製する。いくつかの実施形態において、エナンチオマーの分離は、本明細書に記載の化合物の共有結合性ジアステレオマー誘導体を用いて行われる。別の実施形態において、ジアステレオマーは、溶解度の相違に基づく分離/分解技術によって分離される。他の実施形態において、立体異性体の分離は、クロマトグラフィーによって、またはジアステレオマー塩の形成によって実行され、並びに再結晶化、クロマトグラフィー、あるいはそれらの任意の組み合わせによる分離が実行される。Jean Jacques, Andre Collet, Samuel H. Wilen, ”Enantiomars, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981」参照。幾つかの実施形態において、立体異性体は立体選択性の合成によって得られる。
特に他に明記のない限り、明細書および請求項を含む、本出願に使用される以下の用語は、下記の定義を有する。明細書および添付の請求項に使用される、単数形「a」、「an」および「the」は、文脈がはっきりと特に指示していない限り、複数の指示対象を含むことを留意されたい。他に指示がない限り、質量分析、NMR、HPCL、タンパク質化学、生化学、組換えDNA技術、および薬理学の従来の方法が使用される。本出願において、「または」、あるいは「および」の使用は、特に他に明記のない限り、「および/または」を意味する。さらに、用語「含むこと(including)」、ならびに「含む(include)」、「含む(includes)」および「含まれる(included)」などの他の形態の使用は限定されない。本明細書で使用されるセクションの見出し(section headings)は、組織的な目的のみのためであり、記載される題目を限定するものとして解釈されるべきものではない。
適切な投与経路は、経口投与、静脈内投与、直腸投与、エアロゾル投与、非経口投与、経眼投与、経肺投与、経粘膜投与、経皮投与、膣内投与、経耳投与、経鼻投与、および、局所投与を含むが、これらに限定されない。加えて、ほんの一例として、非経口送達は、くも膜下腔内、直接脳室内、腹腔内、リンパ内、および、鼻腔内の注入だけでなく、筋肉内、皮下、静脈内、髄内の注入も含む。
いくつかの実施形態において、本明細書に記載の化合物は、医薬組成物に処方される。医薬組成物は、従来の様式で、活性化合物を薬学的に使用され得る調剤に加工する工程を促進させる、1以上の薬学的に許容可能な不活性成分を用いて処方される。適切な製剤は、選択される投与経路に依存する。本明細書に記載される医薬組成物の概要は、例えば、Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995);Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins1999)に見出され、そのような開示のため引用によって本明細書に組み込まれる。
1つの実施形態において、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)および(XIII)の化合物、あるいはその薬学的に許容可能な塩は、エストロゲン受容体活性の還元から利益を得る、哺乳動物中の疾患または疾病の処置用の薬の調製に使用される。そのような処置を必要とする哺乳動物において、本明細書に記載される疾患または疾病のいずれかを処置する方法は、前記哺乳動物に対して治療上効果的な量の、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)または(XIII)の少なくとも1つの化合物、あるいはその薬学的に許容可能な塩、あるいは薬学的に許容可能な塩、あるいは活性代謝物、プロドラッグ、あるいはその薬学的に許容可能な溶媒和物、の少なくとも1つを含む医薬組成物の投与に関与する。
特定の例において、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)または(XIII)の化合物、またはその薬学的に許容可能な塩の少なくとも1つを、1つ以上の他の治療薬と併用して投与することは適切である。
幾つかの実施形態において、エストロゲン受容体依存の疾病、エストロゲン受容体を媒介した疾病、又は癌を含む増殖の障害のような疾患の処置のための方法は、少なくとも1つの追加的な治療薬とともに、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)又は(XIII)、あるいは薬学的に許容可能なそれらの塩の化合物の、哺乳動物への投与を含んでいる。
本明細書中に記載の治療への適用において使用するために、キット及び製品も本明細書中に記載される。このようなキットは、運搬装置、包装、又は1又はそれ以上のバイアル、チューブ、及びその他同種のものを受け入れることができるように仕切られた容器を含むことができ、それぞれの容器は、本明細書中に記載される方法で使用される、個別の要素の1つを含んでいる。適切な容器としては、例えば、ボトル、バイアル、注射器、及び試験管が含まれる。容器は、任意の許容可能な素材から形成されており、例えば、ガラス又はプラスチックなどが含まれる。
これらの実施例は、例示目的でのみに提供され、本明細書中に記載の請求項の範囲を制限するものではない。
1H), 2.60 (m, 3H), 2.07 (m, 4H), 1.50−1.99 (m, 13H), 1.25 (m, 2H), 1.19 (d, 3H), 0.95 (d, 3H).
LCMS:472.6(M+H)+。
MCF7細胞を、10%のFCSを追加したRPMI 1640の中で維持した。転写アッセイは、250,000細胞/mLの密度で、10%のcharcoal stripped serumを追加したRPMI 1640中の96−ウェルの細胞培養プレートへ100μLの細胞を播種することにより実行し、一晩付着することを可能にした。細胞を、製造業者のプロトコルに従って、Lipofectin(Life Technologies)を使用して、一時的に形質移入した。3重の形質移入を、300ngの3X ERE−TK−Luc(レポーターベクター)、50ngのCMVpRL(正常化ベクター)、および130ngのpCMX(充填剤DNA)を使用して実行した。形質移入した細胞を一晩インキュベートし、その後、リガンドにより処理した。ERアゴニストアッセイのため、化合物を連続的に希釈し、charcoal stripped serumを追加したRPMI 1640を加えた50μLの化合物を、細胞に加えた。ERアンタゴニストアッセイのため、化合物を連続的に希釈し、charcoal stripped serumを追加した17β−エストラジオールを加えたRPMIを有する50μLの化合物を、細胞に加えた。アンタゴニストアッセイにおいて使用される最終の17β−エストラジオール濃度は、0.1nMであった。24時間のインキュベーションの後、培地を取り除き、細胞を、40μLの溶解バッファー(25mMのトリスリン酸塩、2mMのCDTA、10%のグリセロール、0.5%のTriton X−100、2mMのDTT)で溶解した。ホタルルシフェラーゼ活性を、40μLのルシフェラーゼバッファー(20mMのトリシン、0.1mMのEDTA、1.07mMの(MgCo3)4Mg(OH)2・5H2O、2.67mMのMgSO4、33.3mMのDTT、270μMの補酵素A、470μMのルシフェリン、530μMのATP)を追加した直後に測定した。レニラルシフェラーゼを、40μLのセレンテラジンバッファー(1.1MのNaCl、2.2mMのNa2EDTA、0.22MのKxPO4(pH5.1)、0.44mg/mLのBSA、1.3mMのNaN3、1.43μMのセレンテラジン、5.0にまで調節された最終的なpH)を追加した後に測定した。
MCF−7細胞を、10%のFBSおよび20mMのHEPESを含むRPMIにおいて、mL当たり20,000の細胞の濃度にまで調節した。16マイクロリットルの細胞懸濁液(320の細胞)を、384ウェルプレートの各ウェルに加え、細胞を一晩インキュベートして、細胞が付着することを可能にした。翌日、11点の各化合物の連続する片対数の希釈液16μLを、0.3乃至0.000003μMに及ぶ終末濃度にて、細胞に加えた。5日の化合物曝露の後、16μLのCellTiter−GLo(Promega, Madison WI)を細胞に加え、各ウェルの相対的な発光単位(RLU)を測定した。細胞のない32μLの培地に加えたCellTiter−GLoを使用して、バックグラウンド値を得た。各サンプルのパーセント生存率を以下のように測定した:(RLUサンプル−RLU バックグラウンド/RLU 未処置の細胞−RLUバックグラウンド)x100=%生存率。
MCF−7細胞を、10%のcharcoal stripped serumおよび20mMのHEPESを含むRPMIにおいて、mL当たり200,000の細胞の濃度に調節した。16マイクロリットルの細胞懸濁液(3200の細胞)を、ポリ−D−リジン384ウェルプレートの各ウェルに加え、細胞を一晩インキュベートして、細胞が付着することを可能した。翌日、11点の各化合物の連続する片対数の希釈液16μLを、0.3乃至0.000003μMに及ぶ終末濃度にて細胞に加えた。4または24時間後の化合物の追加時に、細胞を20分間固定した(PBS内での10%のホルマリン)。細胞を、PBS 0.1%のトリトンにおいて透過処理し、LICOR遮断バッファー(50μl/ウェル、90’)により遮断した。その後、ウェルを、LICOR遮断バッファー/0.1%のTween−20において1:100に希釈された、ER1D5(Santa Cruz Biotechnology)により4℃で一晩インキュベートした。Tweenを有するが抗体が無い遮断バッファーにより処理されたウェルを、バックグラウンド対照として使用した。ウェルを、0.1%のTween−20/PBSで洗浄し、その後、60分間、0.1%のTween−20および0.01%のSDSを含むLICOR遮断バッファーで希釈された、ヤギ抗マウスIRDye(商標)800CW(LICOR Inc;1:1000)およびDRAQ5 DNA色素(2mMのストック(stock)に関して1:2000)の中でインキュベートした。細胞を、0.1%のTween−20/PBSの中で洗浄した(50μl/ウェル、各5’)。プレートを、LICOR Odyssey赤外線画像システム上でスキャンした。800nmのチャネルおよび700nmのチャネル中の積分強度を、ERとDNAのレベルをそれぞれ決定するために測定した。パーセントERレベルを以下のように測定した:(積分強度800nmのサンプル/積分強度700nmのサンプル)/(積分強度800nmの未処置の細胞/積分強度700nmの未処置の細胞)x100=%ERレベル。
MCF−7細胞を、10%のcharcoal−stripped FBSおよび20mMのHEPESを含むRPMIにおいて、mL当たり200,000の細胞の濃度に調節した。16マイクロリットルの細胞懸濁液(3200の細胞)を、ポリ−D−リジン384ウェルプレートの各ウェルに加え、細胞を一晩インキュベートし、細胞が付着することを可能にした。翌日、11点の各化合物の連続する片対数の希釈16μLを、0.3乃至0.000003μMに及ぶ終末濃度にて、細胞に加えた。4または24時間後の化合物の追加にて、細胞を20分間固定した(PBSにおいて10%のホルマリン)。細胞を、PBS 0.1%のトリトンにおいて透過処理し、LICOR遮断バッファー(50μl/ウェル、90’)により遮断した。その後、ウェルを、LICOR遮断バッファー/0.1%のTween−20において1:1000に希釈された、SP1ウサギモノクローナルAb(Thermo Scientific)により、4℃で一晩インキュベートした。Tweenを有するが抗体が無い遮断バッファーにより処理されたウェルを、バックグラウンド対照として使用した。ウェルを0.1%のTween−20/PBSで洗浄し、その後、60分間、0.1%のTween−20と0.01%のSDSを含むLICOR遮断バッファーにおいて希釈された、ヤギ抗ウサギIRDye(商標)800CW(LICOR Inc.;1:1000)とDRAQ5 DNA色素(2mMのストックに関して1:2000)によりインキュベートした。細胞を、0.1%のTween−20/PBS中で洗浄した(50μl/ウェル、各々5’)。プレートを、LICOR Odyssey赤外線画像システム上でスキャンした。800nmのチャネルと700nmのチャネルにおける積分強度を、ERとDNAのレベルをそれぞれ決定するために測定した。パーセントERレベルを以下のように決定した:
T225中のサブ集密性(Subconfuent)イシカワ細胞を、5%のチャコールデキストランFBSと20mMのHEPESを含む、DMEM:Ham’s F−12 50:50フェノールレッド遊離塩基培地からなる、エストロゲン遊離塩基培地(EFBM)において24時間インキュベートする。細胞を翌日、mLにつき2.5×105の細胞の濃度、ウェルにつき16μL(ウェルにつき4000の細胞)で、明白な384ウェルプレートにおけるEFBM中で播種する。各化合物の12点の片対数の希釈をDMSO中で実行し、続いてEFBM中で希釈する。EFBM中の化合物の等量を、細胞を播種した直後に加え、細胞を3日間インキュベートする。細胞を5%のホルマリンにより固定し、PBSでリンスする。アルカリフォスファターゼ基質4−ニトロフェニルリン酸ジナトリウム塩六水和物(Alkaline Phosphatase substrate 4−Nitrophenyl phosphate disodium salt hexahydrate)を、2mMのMgCl2、1Mのジエタノールアミンを含み、pH9.0に調節された溶液に加える。基質溶液を細胞培養(ウェルにつき16μL)に加え、OD405を、1乃至30nMの濃度範囲にある17β−エストラジオールにより処置される細胞の405nmの波長での光電密度が、1.0乃至1.2の吸光度単位に達する時、重層プレート分光光度計で測定する。DMSO単独で処置される細胞は、バックグラウンド対照として機能する。サンプルを引いたバックグラウンドにおけるパーセント活性を以下のように測定する:%活性=17β−エストラジオールで処置された細胞x100のOD405サンプル/OD405max。
BG−1、細胞を、10%のFBSと20mMのHEPESを含むRPMIにおいて、mL当たり20,000の細胞の濃度に調節した。16マイクロリットルの細胞懸濁液(320の細胞)を、384ウェルプレートの各ウェルに加え、細胞を一晩インキュベートし、細胞が付着することを可能にした。翌日、11点の各化合物の連続する片対数の希釈液16μLを、0.3乃至0.000003μMに及ぶ終末濃度にて細胞に加えた。5日の化合物曝露の後、16μLのCellTiter−GLo(Promega,Madison WI)を細胞に加え、各ウェルの相対的な発光単位(RLU)を測定した。細胞の無い32μLの培地に加えられるCellTiter−Gloを使用し、バックグラウンド値を得た。各サンプルのパーセント生存率を以下のように測定した:(RLUサンプル−RLUバックグラウンド/RLU未処置の細胞−RLUバックグラウンド)x100=%生存率。A1847、SKOV3、SW626、A2780を含む、追加のER+卵巣癌細胞株における生存率効果を、実施例77に類似するアッセイにおいて描くことができる。
BG−1細胞を、10%のcharcoal−stripped FBSと20mMのHEPESを含むRPMIにおいて、mL当たり200,000の細胞の濃度に調節した。16マイクロリットルの細胞懸濁液(3200の細胞)を、ポリ−D−リジン384ウェルプレートの各ウェルに加え、細胞を一晩インキュベートし、細胞が付着することを可能にした。翌日、11点の各化合物の連続する片対数の希釈液16μLを、0.3乃至0.000003μMに及ぶ終末濃度にて、細胞に加えた。4または24時間後の化合物の追加にて、細胞を20分間固定した(PBSにおいて10%のホルマリン)。細胞を、PBS 0.1%のトリトンにおいて透過処理し、LICOR遮断バッファー(50μl/ウェル、90’)により遮断した。その後、ウェルを、LICOR遮断バッファー/0.1%のTween−20において1:100に希釈された、ER1D5(Santa Cruz Biotechnology)により4℃で一晩インキュベートした。Tweenを有するが抗体が無い遮断バッファーにより処理されたウェルを、バックグラウンド対照として使用した。ウェルを0.1%のTween−20/PBSで洗浄し、その後、60分間、0.1%のTween−20と0.01%のSDSを含むLICOR遮断バッファーにおいて希釈された、ヤギ抗マウスIRDye(商標)800CW(LICOR Inc.;1:1000)とDRAQ5 DNA色素(2mMのストックに関して1:2000)でインキュベートした。細胞を、0.1%のTween−20/PBS中で洗浄した(50μl/ウェル、各々5’)。プレートを、LICOR Odyssey赤外線画像システム上でスキャンした。800nmのチャネルと700nmのチャネルにおける積分強度を、ERとDNAのレベルをそれぞれ決定するために測定した。パーセントERレベルを以下のように決定した:
0.72mgの17−βエストラジオールを含む時間放出ペレット(time release pellets)を、nu/nuマウスへと皮下に移植した。MCF−7細胞を、5%のCO2、37℃で、10%のFBSを含むRPMIにおいて成長させた。細胞を沈降し、1X107細胞/mLにて、50%のRPMI(血清遊離)と50%のマトリゲルにおいて再懸濁した。MCF−7細胞を、ペレット移植の2乃至3日後に、右側腹部に皮下注射した(100μL/動物)。腫瘍容積(長さx幅2/2)を、隔週に監視した。腫瘍が〜200mm3動物の平均量に達したとき、動物を無作為化し、処置を始めた。動物を4週間毎日、ビヒクル又は試験化合物で処置した。腫瘍容積と体重を、研究の全体にわたって隔週で監視した。処置期間の終わりに、血漿と腫瘍のサンプルを、薬物動態学及び薬理学的な分析のためにそれぞれ採取した。
MCF−7腫瘍(平均腫瘍容積200mm3)を有するメスのnu/nuマウス(補足された17−βエストラジオールペレットを有する;0.72mg;60日の遅延放出)を、経口の経管栄養によってタモキシフェン(シトラート)により処置した。腫瘍容積(長さx幅2/2)と体重を、週に2回監視した。腫瘍容積が不変なままであった著しい抗腫瘍反応の後、明白な腫瘍成長を、処置のおよそ100日目に最初に観察した。処置の120日目に、タモキシフェンの投与量を増加した。急速な腫瘍の成長をタモキシフェン抵抗性と見なし、新しい宿主動物へのインビボの継代のために選択した。タモキシフェン抵抗性の腫瘍からの腫瘍断片(〜100mm3/動物)を、メスのnu/nuマウスの右側腹部へと皮下に移植した(17−βエストラジオールペレットを有する(0.72mg;60日の遅延放出))。継代された腫瘍を、毎週監視された一定のタモキシフェンの選択および腫瘍容積(長さx幅2/2)の下で維持した。腫瘍容積が〜150乃至250mm3に達した時、動物を処置グループ(平均腫瘍容積200mm3)へ無作為化し、タモキシフェンによる処置を終了した(タモキシフェンコントロールアーム(tamoxifen control arm)を除いて)。動物を4週間毎日、ビヒクルまたは試験化合物で処置した。腫瘍容積と体重を、研究の間週に2回監視した。処置期間の終わりに、血漿と腫瘍のサンプルを、薬物動態学及び薬理学的な分析のためにそれぞれ採取した。
時間放出ペレット(0.72mgの17−βエストラジオール/60日)を、メスのnu/nuマウスへ皮下に移植した。BG−1細胞を、5%のCO2、37℃で、10%のFBS、10mMのピルビン酸ナトリウム、10mMの非必須アミノ酸を含む、DMEM Ham’s F−12 50/50にて成長させた。細胞を沈降し、5X107細胞/mLで、50%のDMEM Ham’s F−12(血清遊離)と50%のマトリゲルにおいて再懸濁した。BG−1細胞を、ペレット移植の2乃至3日後、右側腹部上に皮下注射した(100μL/動物)。腫瘍容積(長さx幅2/2)を、隔週で監視した。腫瘍が〜250mm3の平均量に達したとき、動物を無作為化し、処置を始めた。動物を4週間毎日、ビヒクル又は試験化合物で処置した。腫瘍容積と体重を、研究の全体にわたって隔週で監視した。処置期間の終わりに、血漿と腫瘍のサンプルを、薬物動態学及び薬理学的な分析のためにそれぞれ採取した。
メスの未成熟のCD−IGSラット(到達時に生後21日)を3日間処置した。動物に、3日間毎日投薬した。ビヒクルまたは試験化合物を経管栄養によって経口投与し、15分後に、0.1mg/kgのエチニルエストラジオールの経口量を投与した。投薬の24時間後の4日目に、血漿を薬物動態学の分析のために集めた。血漿を収集した後すぐに、動物を安楽死させ、子宮を摘出して重さを量った。
メスの未成熟のCD−IGSラット(到達時に生後21日)を3日間処置した。動物に、3日間毎日投薬した。ビヒクルまたは試験化合物を経管栄養によって経口投与し、15分後に、ビヒクルの第2の経口量を投与した。投薬の24時間後の4日目に、血漿を薬物動態学の分析のために集めた。血漿を収集した後すぐに、動物を安楽死させ、子宮を摘出して重さを量った。
注入(皮下、静脈内)による投与に適している非経口の医薬組成物を調製するため、100mgの化合物または式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、又は(XIII)の化合物の水溶性の塩を、無菌水中で溶解し、その後、10mLの0.9%無菌食塩水と混合した。混合物を、注入による投与に適した投与ユニット剤形に組み込む。
経口送達のための医薬組成物を調製するために、水溶性の20%のプロピレングリコール溶液を調製する。これに、十分な量の式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、又は(XIII)の化合物、又はその薬学的に許容可能な塩を加え、20mg/mLの溶液を得る。
経口送達のための医薬組成物を調製するために、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、又は(XIII)の化合物、又はその薬学的に許容可能な塩を、デンプンと混合する。混合物を、経口投与に適した硬ゼラチンカプセルなどの経口投与ユニットに組み込む。
錠剤を、48重量%の式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、又は(XIII)の化合物、又はその薬学的に許容可能な塩、45重量%の微結晶性セルロース、5重量%の低置換ヒドロキシプロピルセルロース、および2重量%のステアリン酸マグネシウムを混合することによって調製する。錠剤を直接の圧縮によって調製する。圧縮錠剤の全重量を、250乃至500mgに維持する。
製薬の局所ゲル組成物を調製するために、式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(X)、(XI)、(XII)、又は(XIII)の化合物、又はその薬学的に許容可能な塩を、ヒドロキシプロピルセルロース、プロピレングリコール、イソプロピルミリステートおよび精製されたアルコールUSPと混合する。結果として生じるゲル混合物を、その後、局所投与に適切な容器(チューブなど)に組み込む。
Claims (12)
- 式(VI)の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物であって:
ここで、
R1が、H又は−CH3であり;
R3が、−CH3又は−CF3であり;
各R4が独立して、F、Cl、Br、−OH、−S(=O)2CH3 、−CH3 、−C≡CH、又は−CF 3 であり;
各R5が、H、F、Cl、−CH3及び−CF3から独立して選択され;
各R6が、Hであり;
以下の式が、アゼチジニル又はピロリジニルであり;
各R8が、F又は−CH 3 から独立して選択され;
各R9が、Hであり;
Yが、−O−であり;
Xが、−O−であり;
mが、0、1、2又は3であり;
nが、0又は1であり;
pが、0又は1であり;
tが、1又は2であることを特徴とする、式(VI)の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。 -
-
- 式(VI)の化合物が、式(VIII)の構造を有することを特徴とする、請求項1乃至3のいずれか1つに記載の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。
- 式(VI)の化合物が、式(IX)の構造を有することを特徴とする、請求項1乃至3のいずれか1つに記載の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。
- 式(VI)の化合物が、式(X)の構造
各R8が、F又は−CH 3 から独立して選択されることを特徴とする、請求項1または2に記載の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。 -
R8が−CH3であることを特徴とする、請求項1乃至5のいずれか1つに記載の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。 - R1が、H又は−CH3であり、
R3が、−CH3であり、
R4が−OHであり、
R9がHであり、
Xが−O−であり、
Yが−O−であり、
nが0であり、
mが1であることを特徴とする、請求項1乃至7のいずれか1つに記載の化合物、あるいは、その薬学的に許容可能な塩または溶媒和物。 - 3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
(S)−3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
(R)−3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−(2−((R)−3−メチルピペリジン−1−イル)エトキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((R)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−(2−((S)−3−メチルピロリジン−1−イル)エトキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((S)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((R)−2−((S)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
2−(4−((S)−2−(3,3−ジメチルピロリジン−1−イル)プロポキシ)フェニル)−3−(3−ヒドロキシフェニル)−4−メチル−2H−クローメン−6−ol;
2−(4−(2−(3,3−ジメチルピロリジン−1−イル)エトキシ)フェニル)−3−(3−ヒドロキシフェニル)−4−メチル−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−(2−((R)−2−メチルピロリジン−1−イル)エトキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−2−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((S)−2−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−7−ol;
3−(4−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−7−ol;
4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−3−フェニル−2H−クローメン−6−ol;
3−(4−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
(S)−3−(4−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
(R)−3−(4−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−フルオロ−4−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
2−(2−フルオロ−4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−3−(3−ヒドロキシフェニル)−4−メチル−2H−クローメン−6−ol;
3−(3−ヒドロキシ−4−メチルフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−ヒドロキシ−2−メチルフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−ヒドロキシ−2−メチルフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−ヒドロキシ−3−メチルフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3−フルオロ−5−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−クロロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(2−フルオロ−4−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3,4−ジフルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3,5−ジフルオロ−4−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(2,4−ジフルオロ−3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(3,4−ジフルオロ−5−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(2−クロロ−4−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(2,4−ジフルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−ブロモフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−3−(o−トリル)−2H−クローメン−6−ol;
3−(4−フルオロ−3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−エチニルフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−3−(4−(メチルスルホニル)フェニル)―2H−クローメン−6−ol;
3−(2−フルオロ−3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
5−フルオロ−3−(3−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(2−フルオロ−5−ヒドロキシフェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−フルオロフェニル)−4−メチル−2−(4−((S)−2−((R)−2−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
2−(4−((S)−2−((R)−3−フルオロピロリジン−1−イル)プロポキシ)フェニル)−3−(3−ヒドロキシフェニル)−4−メチル−2H−クローメン−6−ol;
3−(4−ヒドロキシフェニル)−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−4−(トリフルオロメチル)−2H−クローメン−6−ol;
3−(3−ヒドロキシフェニル)−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−4−(トリフルオロメチル)−2H−クローメン−6−ol;
3−(3−ヒドロキシ−4−(トリフルオロメチル)フェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−ol;
3−(4−ヒドロキシ−3−(トリフルオロメチル)フェニル)−4−メチル−2−(4−((S)−2−((R)−3−メチルピロリジン−1−イル)プロポキシ)フェニル)−2H−クローメン−6−olである化合物、
又は、その薬学的に許容可能な塩。 - 請求項1乃至9のいずれか1つに記載の化合物、又はその薬学的に許容可能な塩を含む医薬組成物。
- 前記医薬組成物が、静脈注射、皮下注射、経口投与、又は局所投与のために処方されることを特徴とする、請求項10に記載の医薬組成物。
- 前記医薬組成物が、錠剤、丸剤、カプセル剤、液体、懸濁液、ゲル、分散剤、溶液、乳濁液、軟膏、又はローション剤であることを特徴とする、請求項10に記載の医薬組成物。
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