JP5150481B2 - ドーパミンd3受容体のモジュレーターとしての3−(1,2,4−トリアゾール−3−イルアルキル)アザビシクロ(3.1.0)ヘキサン誘導体 - Google Patents
ドーパミンd3受容体のモジュレーターとしての3−(1,2,4−トリアゾール−3−イルアルキル)アザビシクロ(3.1.0)ヘキサン誘導体 Download PDFInfo
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- JP5150481B2 JP5150481B2 JP2008505840A JP2008505840A JP5150481B2 JP 5150481 B2 JP5150481 B2 JP 5150481B2 JP 2008505840 A JP2008505840 A JP 2008505840A JP 2008505840 A JP2008505840 A JP 2008505840A JP 5150481 B2 JP5150481 B2 JP 5150481B2
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- JP
- Japan
- Prior art keywords
- methyl
- phenyl
- triazol
- azabicyclo
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical class C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 title 1
- 102000004073 Dopamine D3 Receptors Human genes 0.000 title 1
- 108090000525 Dopamine D3 Receptors Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 317
- -1 4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl Chemical group 0.000 claims description 205
- 150000003839 salts Chemical class 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 44
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 125000003545 alkoxy group Chemical group 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 12
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000002541 furyl group Chemical group 0.000 claims description 10
- 125000002971 oxazolyl group Chemical group 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
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- JCRCAKXQXKRHFN-NZQKXSOJSA-N (1s,5r)-3-[4-[4-methyl-5-(oxan-4-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C2CCOCC2)C)=CC=C(C(F)(F)F)C=C1 JCRCAKXQXKRHFN-NZQKXSOJSA-N 0.000 claims description 3
- SNTNNYRQVPBAGA-YADARESESA-N (1s,5r)-3-[4-[5-(2-fluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C(=CC=CC=2)F)C)=CC=C(C(F)(F)F)C=C1 SNTNNYRQVPBAGA-YADARESESA-N 0.000 claims description 3
- OBSHSKYKHZUDTO-NZQKXSOJSA-N (1s,5r)-3-[4,4-difluoro-4-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCC(F)(F)C2=NN=C(N2C)C=2C=CC=CC=2)=CC=C(C(F)(F)F)C=C1 OBSHSKYKHZUDTO-NZQKXSOJSA-N 0.000 claims description 2
- LLPXGYPYTGKDGE-QFBILLFUSA-N (1s,5r)-3-[4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound CN1C(SC)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 LLPXGYPYTGKDGE-QFBILLFUSA-N 0.000 claims description 2
- WQHTXCOSDYNVSA-XUZZJYLKSA-N (1s,5r)-3-[4-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=CC=CC=2)C)=CC=C(C(F)(F)F)C=C1 WQHTXCOSDYNVSA-XUZZJYLKSA-N 0.000 claims description 2
- ZQBZAKXVTILNKH-SIKLNZKXSA-N (1s,5r)-3-[4-(4-methyl-5-pyridazin-4-yl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=NN=CC=2)C)=CC=C(C(F)(F)F)C=C1 ZQBZAKXVTILNKH-SIKLNZKXSA-N 0.000 claims description 2
- HFZOTTQLIACSJC-SIKLNZKXSA-N (1s,5r)-3-[4-(4-methyl-5-thiophen-3-yl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C2=CSC=C2)C)=CC=C(C(F)(F)F)C=C1 HFZOTTQLIACSJC-SIKLNZKXSA-N 0.000 claims description 2
- ZBCYESWVOMJSMP-PGRDOPGGSA-N (1s,5r)-3-[4-(5-tert-butyl-4-methyl-1,2,4-triazol-3-yl)butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound N1=C(C(C)(C)C)N(C)C(CCCCN2C[C@]3(C[C@H]3C2)C=2C=CC(=CC=2)C(F)(F)F)=N1 ZBCYESWVOMJSMP-PGRDOPGGSA-N 0.000 claims description 2
- DQHYTUYOSZYPNQ-GBXCKJPGSA-N (1s,5r)-3-[4-[4-methyl-5-(1,3,5-trimethylpyrazol-4-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound CC1=NN(C)C(C)=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 DQHYTUYOSZYPNQ-GBXCKJPGSA-N 0.000 claims description 2
- IJRJXQCRKUIOGO-WMZHIEFXSA-N (1s,5r)-3-[4-[4-methyl-5-(1-methylpyrrol-2-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound CN1C=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 IJRJXQCRKUIOGO-WMZHIEFXSA-N 0.000 claims description 2
- DGUUGENNPMRMNY-GBXCKJPGSA-N (1s,5r)-3-[4-[4-methyl-5-(2-methylpyridin-3-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound CC1=NC=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 DGUUGENNPMRMNY-GBXCKJPGSA-N 0.000 claims description 2
- ZXEBGAXOSAZAFX-WMZHIEFXSA-N (1s,5r)-3-[4-[4-methyl-5-(5-methylpyrazin-2-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1=NC(C)=CN=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 ZXEBGAXOSAZAFX-WMZHIEFXSA-N 0.000 claims description 2
- XNMKSNLYJQYQSZ-XUZZJYLKSA-N (1s,5r)-3-[4-[4-methyl-5-(6-methylpyridin-3-yl)-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1=NC(C)=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 XNMKSNLYJQYQSZ-XUZZJYLKSA-N 0.000 claims description 2
- GUTVLFHYHYLZGQ-YADARESESA-N (1s,5r)-3-[4-[4-methyl-5-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound CC1=NC(C(F)(F)F)=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 GUTVLFHYHYLZGQ-YADARESESA-N 0.000 claims description 2
- UJJCCBQJZZQOLL-GBXCKJPGSA-N (1s,5r)-3-[4-[4-methyl-5-[4-(trifluoromethoxy)phenyl]-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=CC(OC(F)(F)F)=CC=2)C)=CC=C(C(F)(F)F)C=C1 UJJCCBQJZZQOLL-GBXCKJPGSA-N 0.000 claims description 2
- LFQNQCSXHHXWLY-MHECFPHRSA-N (1s,5r)-3-[4-[5-(2,4-dichlorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C(=CC(Cl)=CC=2)Cl)C)=CC=C(C(F)(F)F)C=C1 LFQNQCSXHHXWLY-MHECFPHRSA-N 0.000 claims description 2
- JXDMXCIIXXRIOF-MHECFPHRSA-N (1s,5r)-3-[4-[5-(2,4-difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C(=CC(F)=CC=2)F)C)=CC=C(C(F)(F)F)C=C1 JXDMXCIIXXRIOF-MHECFPHRSA-N 0.000 claims description 2
- DZLQIDIUGLSERH-YADARESESA-N (1s,5r)-3-[4-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C(=CC=CC=2)Cl)C)=CC=C(C(F)(F)F)C=C1 DZLQIDIUGLSERH-YADARESESA-N 0.000 claims description 2
- NOLGPBVMBXXESK-NBGIEHNGSA-N (1s,5r)-3-[4-[5-(2-methoxyphenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound COC1=CC=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 NOLGPBVMBXXESK-NBGIEHNGSA-N 0.000 claims description 2
- URNYYQLYOGWFLX-YADARESESA-N (1s,5r)-3-[4-[5-(3,4-difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=C(F)C(F)=CC=2)C)=CC=C(C(F)(F)F)C=C1 URNYYQLYOGWFLX-YADARESESA-N 0.000 claims description 2
- VZUGNXNOOUAYKD-YADARESESA-N (1s,5r)-3-[4-[5-(3,5-difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=C(F)C=C(F)C=2)C)=CC=C(C(F)(F)F)C=C1 VZUGNXNOOUAYKD-YADARESESA-N 0.000 claims description 2
- VHKZDBHIAWSABJ-GBXCKJPGSA-N (1s,5r)-3-[4-[5-(3-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=C(Cl)C=CC=2)C)=CC=C(C(F)(F)F)C=C1 VHKZDBHIAWSABJ-GBXCKJPGSA-N 0.000 claims description 2
- JRKBBSUEINBXIB-GBXCKJPGSA-N (1s,5r)-3-[4-[5-(3-fluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=C(F)C=CC=2)C)=CC=C(C(F)(F)F)C=C1 JRKBBSUEINBXIB-GBXCKJPGSA-N 0.000 claims description 2
- UOHXMCSXIKMKPF-SQJMNOBHSA-N (1s,5r)-3-[4-[5-(3-methoxyphenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound COC1=CC=CC(C=2N(C(CCCCN3C[C@]4(C[C@H]4C3)C=3C=CC(=CC=3)C(F)(F)F)=NN=2)C)=C1 UOHXMCSXIKMKPF-SQJMNOBHSA-N 0.000 claims description 2
- LYYUOPGYPGZNPY-GBXCKJPGSA-N (1s,5r)-3-[4-[5-(4-fluorophenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCC=2N(C(=NN=2)C=2C=CC(F)=CC=2)C)=CC=C(C(F)(F)F)C=C1 LYYUOPGYPGZNPY-GBXCKJPGSA-N 0.000 claims description 2
- ZNYZRQCCNZZLSD-SQJMNOBHSA-N (1s,5r)-3-[4-[5-(4-methoxyphenyl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1=CC(OC)=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 ZNYZRQCCNZZLSD-SQJMNOBHSA-N 0.000 claims description 2
- SSGMCIQDEXKAQQ-GBXCKJPGSA-N (1s,5r)-3-[4-[5-(6-methoxypyridin-3-yl)-4-methyl-1,2,4-triazol-3-yl]butyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1=NC(OC)=CC=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 SSGMCIQDEXKAQQ-GBXCKJPGSA-N 0.000 claims description 2
- XYTALYCALRXGKS-BKMJKUGQSA-N (1s,5r)-3-[4-methyl-4-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCC(C)(C)C2=NN=C(N2C)C=2C=CC=CC=2)=CC=C(C(F)(F)F)C=C1 XYTALYCALRXGKS-BKMJKUGQSA-N 0.000 claims description 2
- JDUMSLXKOLEYPP-WIOPSUGQSA-N (1s,5r)-3-[5-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCCC=2N(C(=NN=2)C=2C=CC=CC=2)C)=CC=C(C(F)(F)F)C=C1 JDUMSLXKOLEYPP-WIOPSUGQSA-N 0.000 claims description 2
- GSTSMTVBYVSNTA-GBXCKJPGSA-N (1s,5r)-3-[5-[4-methyl-5-(5-methylpyrazin-2-yl)-1,2,4-triazol-3-yl]pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1=NC(C)=CN=C1C(N1C)=NN=C1CCCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 GSTSMTVBYVSNTA-GBXCKJPGSA-N 0.000 claims description 2
- WMPMDKLVQYNARP-UQBPGWFLSA-N (1s,5r)-3-[5-[5-(2,4-difluorophenyl)-4-methyl-1,2,4-triazol-3-yl]pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCCC=2N(C(=NN=2)C=2C(=CC(F)=CC=2)F)C)=CC=C(C(F)(F)F)C=C1 WMPMDKLVQYNARP-UQBPGWFLSA-N 0.000 claims description 2
- NBNPHFSVDRKHTO-NBGIEHNGSA-N (1s,5r)-3-[5-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound C1([C@]23C[C@H]2CN(C3)CCCCCC=2N(C(=NN=2)C=2C(=CC=CC=2)Cl)C)=CC=C(C(F)(F)F)C=C1 NBNPHFSVDRKHTO-NBGIEHNGSA-N 0.000 claims description 2
- QSAMSXVFTCTEQI-BKMJKUGQSA-N (1s,5r)-3-[5-[5-(3-methoxyphenyl)-4-methyl-1,2,4-triazol-3-yl]pentyl]-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane Chemical compound COC1=CC=CC(C=2N(C(CCCCCN3C[C@]4(C[C@H]4C3)C=3C=CC(=CC=3)C(F)(F)F)=NN=2)C)=C1 QSAMSXVFTCTEQI-BKMJKUGQSA-N 0.000 claims description 2
- YXAKPCYFWUAWSP-WMZHIEFXSA-N 2,4-dimethyl-5-[4-methyl-5-[4-[(1s,5r)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexan-3-yl]butyl]-1,2,4-triazol-3-yl]-1,3-oxazole Chemical compound O1C(C)=NC(C)=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 YXAKPCYFWUAWSP-WMZHIEFXSA-N 0.000 claims description 2
- PMKDOWZCFSONRX-WMZHIEFXSA-N 2,4-dimethyl-5-[4-methyl-5-[4-[(1s,5r)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexan-3-yl]butyl]-1,2,4-triazol-3-yl]-1,3-thiazole Chemical compound S1C(C)=NC(C)=C1C(N1C)=NN=C1CCCCN1C[C@@]2(C=3C=CC(=CC=3)C(F)(F)F)C[C@H]2C1 PMKDOWZCFSONRX-WMZHIEFXSA-N 0.000 claims description 2
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000000411 transmission spectrum Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000725 trifluoropropyl group Chemical group [H]C([H])(*)C([H])([H])C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001845 vibrational spectrum Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- 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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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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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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- A61P25/34—Tobacco-abuse
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- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
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- Plural Heterocyclic Compounds (AREA)
Description
Gは、フェニル、ピリジル、ベンゾチアゾリルおよびインダゾリルからなる群から選択され;
pは、0〜5の整数であり;
R1は、独立して、ハロゲン、ヒドロキシ、シアノ、C1−4アルキル、ハロC1−4アルキル、C1−4アルコキシ、ハロC1−4アルコキシ、C1−4アルカノイルおよびSF5からなる群から選択されるか;または、基R5に相当し;
各R2は、独立して、水素、フッ素またはC1−4アルキルであり;
nは、2、3、4または5であり;
R3は、C1−4アルキルであり;
R4は、水素、またはC1−4アルキル基、ベンジル基、フェニル基、ヘテロシクリル基、5−または6−員の芳香族複素環基、または8−ないし11−員の二環式基であり、いずれの基も、ハロゲン、シアノ、C1−4アルキル、ハロC1−4アルキル、C1−4アルコキシ、ハロC1−4アルコキシ、C1−4アルカノイルおよびSF5からなる群から選択される1、2、3または4個の置換基で置換されていてもよく;またはR4は、−SR6基であり;
R5は、イソオキサゾリル、−CH2−N−ピロリル、1,1−ジオキシド−2−イソチアゾリジニル、チエニル、チアゾリル、ピリジルおよび2−ピロリジノニルからなる群から選択され、かかる基は、ハロゲン、シアノ、C1−4アルキル、ハロC1−4アルキル、C1−4アルコキシおよびC1−4アルカノイルからなる群から選択される1または2個の置換基によって置換されていてもよく;
R6は、C1−4アルキルまたは−CH2C3−4シクロアルキルであり;
R1が塩素であって、pが1である場合、かかるR1は、分子の残部に結合した連結部に対してオルト位で存在することはなく;また、R1がR5に相当する場合、pは1である]
で示される化合物またはその医薬上許容される塩を提供する。
の化合物が提供される。
式(IA):
で示される化合物またはその医薬上許容される塩が提供される。
一の具体例において、pは1または2である。
別の具体例において、pは0である。
一の具体例において、nは3または4である。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
で示される化合物またはその医薬上許容される塩が提供される。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
1)全ての可能な構造を定義付ける。
2)これらの構造のスペクトルを予測する。
3)予測したスペクトルを実験的スペクトルと比較する。
正しい構造は、実験に従うスペクトルを与え、正しくない構造は、実験と一致しないスペクトルを与えるであろう。
アブイニシオOR帰属の場合、Dalton Quantum Chemistry Programが用いられた。
で示される化合物またはその医薬上許容される塩の(1S,5R)配置に富む立体化学異性体が提供される。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
で示される化合物またはその医薬上許容される塩の(1S,5R)配置に富む立体化学異性体が提供される。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
で示される化合物またはその医薬上許容される塩の(1S,5R)配置または(1R,5R)配置に富む立体化学異性体が提供される。
一の具体例において、nは3または4である。
一の具体例において、R1はハロゲンまたはトリフルオロメチルである。
(1S,5R)−1−[2−フルオロ−4−(トリフルオロメチル)フェニル]−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[6−(トリフルオロメチル)−3−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(4−ピリダジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(2−メチル−3−ピリジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(6−メチル−3−ピリジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(5−メチル−2−ピラジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジメチル−1,3−オキサゾール−5−イル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[5−(トリフルオロメチル)−2−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(2−メチル−1,3−チアゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−{4−[5−(3,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[6−(トリフルオロメチル)−3−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(テトラヒドロ−2H−ピラン−4−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[5−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ペンチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[4−メチル−5−(5−メチル−2−ピラジニル)−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[4−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジクロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(4−メチル−1,3−チアゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジメチル−1,3−チアゾール−5−イル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(フェニルメチル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(1,1−ジメチルエチル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(4−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[2−メチル−6−(トリフルオロメチル)−3−ピリジニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[3−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[2−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
3−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]ベンゾニトリル;
2−メチル−5−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]キノリン;
(1S,5R)−3−{4−[4−メチル−5−(1,3,5−トリメチル−1H−ピラゾール−4−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
4−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]ベンゾニトリル;
(1S,5R)−3−[4−メチル−4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ペンチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4,4−ジフルオロ−4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(3−チエニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(1−メチル−1H−ピロール−2−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(4−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[6−(メチルオキシ)−3−ピリジニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3,5−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[4−メチル−5−(4−メチル−1,3−オキサゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(5−{4−メチル−5−[3−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ペンチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(2−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(2,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(メチルチオ)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{5−[(シクロプロピルメチル)チオ]−4−メチル−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4−(4−メチル−5−{4−[(トリフルオロメチル)オキシ]フェニル}−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
およびその医薬上許容される塩を包含する。
(a)式(II):
で示される化合物を式(III):
で示される化合物と反応させるか;または
(b)式(II):
で示される化合物を式(XIII):
で示される化合物と反応させるか;または
(c)pが1または2である式(I)の化合物の場合、式(IV):
で示される化合物を化合物R1−Y1[式中、Yが基Mのとき、Y1はハロゲンであり、またはYがハロゲンもしくはパーフルオロアルキルスルホニルオキシ基である場合、Y1は上記の基M、または適当な遷移金属(例えば、Pd)の存在下、適当な塩基(例えば、Cs2CO3)によって活性化されることのできる水素である]と反応させる工程を含み、工程(a)または(b)の後、
(i)いずれかの保護基を除去し;および/または
(ii)塩を形成させ;および/または
(iii)式(I)の化合物またはその塩を式(I)の別の化合物またはその塩に変換する工程を含んでもよい。
工程(a’)は、アニリン(VII)のジアゾ化、次いで、マレイミドとの反応によって、3−アリールマレイミド(VIII)を得ることを示し;
工程(b’)は、(VIII)のシクロプロパン化により、二環式イミド(IX)を得ることを示し;
工程(c’)は、イミド(IX)の還元により、式(II)の化合物を得ることを示す]
R1、pおよびGは、式(I)における定義通りであり、R14Oは、適当なアルコキシ基であり、PGは、適当な保護基であり、Yは、ハロゲン、例えば、臭素、またはスルホニルオキシ基、例えば、トリフルオロメチルスルホニルオキシであってもよく、
工程(a’’)は、(2,5−ジヒドロ−1H−ピロール−3−イル)ボロネート(X)と芳香族ハロゲンまたはスルホニルオキシ誘導体(XI)のカップリング反応を示し;
工程(b’’)は、(XII)のシクロプロパン化、次いで、所望により、脱保護することによって、二環式アミン(II)を得ることを示す。]
(i)1以上のR1のアルコキシ(例えば、メトキシ)からヒドロキシへの変換、
(ii)1以上のR1のヒドロキシからスルホニルオキシ、例えば、アルキルスルホニルオキシまたはハロアルキルスルホニルオキシ、例えば、メタンスルホニルオキシまたはアルキルスルホニルオキシまたはトリフルオロメタンスルホニルオキシへの変換、
(iii)1以上のR1のハロゲンまたはペルフルオロアルキルスルホニルオキシからシアノへの変換;
およびその後、所望により、式(I)の塩の形成を含む。
Ki=IC50/(1+L/KD)
[式中、L=放射性リガンド、KD=受容体に対する放射性リガンドのアフィニティー]
によって計算されるKi値として報告される(Cheng and Prusoff,Biochem.Pharmacol.22:3099,1973)。
本発明の化合物で治療されうる他の病態は、下記に定義されるような強迫(OC)スペクトル障害を包含する。
式(I)の化合物は、性的機能不全、例えば、早漏の治療に有用でありうる。
式(I)の化合物は、認識障害の治療に有用でありうる。
サブタイプ妄想型(295.30)、解体型(295.10)、緊張型(295.20)、鑑別不能(undifferentiated)型(295.90)および残遺型(295.60)を包含する統合失調症;統合失調症様障害(295.40);サブタイプ双極型および抑鬱型を包含する統合失調性感情障害(295.70);サブタイプ恋愛(Erotomanic)型、誇大(Gradiose)型、嫉妬(Jealous)型、迫害(Persecutory)型、身体(Somatic)型、混合(Mixed)型および不特定(Unspecified)型を包含する妄想障害(297.1);簡単な精神障害(298.8);共通の精神障害(297.3);妄想を伴うサブタイプおよび幻覚を伴うサブタイプを包含する一般的健康状態に起因する精神障害;妄想を伴う(293.81)および幻覚を伴う(293.82)サブタイプを包含する物質誘導性精神障害;および不特定の精神障害(298.9)を包含する。
物質依存、物質渇望および物質濫用などの物質使用障害;物質中毒、物質離脱、物質誘導性せん妄、物質誘導性持続性認知症、物質誘導性持続性健忘障害、物質誘導性精神障害、物質誘導性気分障害、物質誘導性不安障害、物質誘導性性的機能不全、物質誘導性睡眠障害および幻覚剤持続性知覚障害(フラッシュバック)などの物質誘導性障害;アルコール依存(303.90)、アルコール濫用(305.00)、アルコール中毒(303.00)、アルコール離脱(291.81)、アルコール中毒せん妄、アルコール離脱せん妄、アルコール誘導性持続性認知症、アルコール誘導性持続性健忘障害、アルコール誘導性精神障害、アルコール誘導性気分障害、アルコール誘導性不安障害、アルコール誘導性性的機能不全、アルコール誘導性睡眠障害および不特定のアルコール関連障害(291.9)などのアルコール関連障害;アンフェタミン依存(304.40)、アンフェタミン濫用(305.70)、アンフェタミン中毒(292.89)、アンフェタミン離脱(292.0)、アンフェタミン中毒せん妄、アンフェタミン誘導性精神障害、アンフェタミン誘導性気分障害、アンフェタミン誘導性不安障害、アンフェタミン誘導性性的機能不全、アンフェタミン誘導性睡眠障害および不特定のアンフェタミン関連障害(292.9)などのアンフェタミン(またはアンフェタミン様)関連障害;カフェイン中毒(305.90)、カフェイン誘導性不安障害、カフェイン誘導性睡眠障害および不特定のカフェイン関連障害(292.9)などのカフェイン関連障害;大麻依存(304.30)、大麻濫用(305.20)、大麻中毒(292.89)、大麻中毒せん妄、大麻誘導性精神障害、大麻誘導性不安障害および不特定の大麻関連障害(292.9)などの大麻関連障害;コカイン依存(304.20)、コカイン濫用(305.60)、コカイン中毒(292.89)、コカイン離脱(292.0)、コカイン中毒せん妄、コカイン誘導性精神障害、コカイン誘導性気分障害、コカイン誘導性不安障害、コカイン誘導性性的機能不全、コカイン誘導性睡眠障害および不特定コカイン関連障害(292.9)などのコカイン関連障害;幻覚剤依存(304.50)、幻覚剤濫用(305.30)、幻覚剤中毒(292.89)、幻覚剤持続性知覚障害(フラッシュバック)(292.89)、幻覚剤中毒せん妄、幻覚剤誘導性精神障害、幻覚剤誘導性気分障害、幻覚剤誘導性不安障害および不特定の幻覚剤関連障害(292.9)などの幻覚剤関連障害;吸入剤依存(304.60)、吸入剤濫用(305.90)、吸入剤中毒(292.89)、吸入剤中毒せん妄、吸入剤誘導性持続性認知症、吸入剤誘導性精神障害、吸入剤誘導性気分障害、吸入剤誘導性不安障害および不特定吸入剤関連障害(292.9)などの吸入剤関連障害;ニコチン依存(305.1)、ニコチン離脱(292.0)および不特定のニコチン関連障害(292.9)などのニコチン関連障害;オピオイド依存(304.00)、オピオイド濫用(305.50)、オピオイド中毒(292.89)、オピオイド離脱(292.0)、オピオイド中毒せん妄、オピオイド誘導性精神障害、オピオイド誘導性気分障害、オピオイド誘導性性的機能不全、オピオイド誘導性睡眠障害および不特定オピオイド関連障害(292.9)などのオピオイド関連障害;フェンシクリジン依存(304.60)、フェンシクリジン濫用(305.90)、フェンシクリジン中毒(292.89)、フェンシクリジン中毒せん妄、フェンシクリジン誘導性精神障害、フェンシクリジン誘導性気分障害、フェンシクリジン誘導性不安障害および不特定のフェンシクリジン関連障害(292.9)などのフェンシクリジン(またはフェンシクリジン様)関連障害;鎮静剤、催眠剤または不安緩解剤依存(304.10)、鎮静剤、催眠剤または不安緩解剤濫用(305.40)、鎮静剤、催眠剤または不安緩解剤中毒(292.89)、鎮静剤、催眠剤または不安緩解剤離脱(292.0)、鎮静剤、催眠剤または不安緩解剤中毒せん妄、鎮静剤、催眠剤または不安緩解剤離脱せん妄、鎮静剤、催眠剤または不安緩解剤持続性認知症、鎮静剤、催眠剤または不安緩解剤持続性健忘障害、鎮静剤、催眠剤または不安緩解剤誘導性精神障害、鎮静剤、催眠剤または不安緩解剤誘導性気分障害、鎮静剤、催眠剤または不安緩解剤不安障害、鎮静剤、催眠剤または不安緩解剤誘導性性的機能不全、鎮静剤、催眠剤または不安緩解剤誘導性睡眠障害および不特定の鎮静剤、催眠剤または不安緩解剤関連障害(292.9)などの鎮静剤、催眠剤または不安緩解剤関連障害;多物質依存(304.80)などの多物質関連障害;およびアナボリックステロイド、硝酸塩吸入剤および亜酸化窒素などの他の(または未知の)物質関連障害を包含する物質関連障害を包含する。
強迫障害(300.3)、身体醜形障害(300.7)およびハイパーコンドリアシス(hyperchondriasis)(300.7)を包含する身体表現性障害、病的飢餓(307.51)、拒食症(307.1)、他に分類されない摂食障害(307.50)、例えば、過食、他に分類されない衝動調節障害[間欠性爆発性障害(312.34)、強迫性購買またはショッピング、反復性自傷、咬爪癖、心因性擦創、窃盗癖(312.32)、病的賭博(312.31)、抜毛癖(312.39)およびインターネット中毒を包含する]、性的倒錯(302.70)および非倒錯性性的中毒、シデナム(Sydeham)舞踏病、斜頚、自閉障害(299.0)、強迫性買い溜め、およびトゥーレット症候群(307.23)を包含する運動障害を包含する。
また、哺乳動物における活性な治療物質として有用な、例えば、本明細書に記載の病態のいずれかの治療において有用な式(I)の化合物またはその医薬上許容される塩が提供される。
医薬における使用のために、本発明の化合物は、通常、標準的な医薬組成物として投与される。したがって、本発明は、さらなる態様において、式(I)の化合物またはその医薬上(すなわち、生理学上)許容される塩および医薬上(すなわち、生理学上)許容される担体を含んでなる医薬組成物を提供する。該医薬組成物は、本明細書中に記載の病態のいずれかの治療において有用であることができる。
経口投与時に活性な式(I)の化合物およびその塩は、液体または固体、例えば、シロップ、懸濁液またはエマルジョン、錠剤、カプセルおよびロゼンジとして処方することができる。
錠剤形態の組成物は、固形処方の調製にルーチンに使用されるいずれか適当な医薬担体を用いて調製することができる。かかる担体の例には、ステアリン酸マグネシウム、デンプン、ラクトース、シュークロースおよびセルロースが挙げられる。
典型的な非経口組成物は、滅菌水性担体または非経口的に許容される油、例えば、ポリエチレングリコール、ポリビニルピロリドン、レシチン、落花生油、またはゴマ油中における該化合物またはその塩の溶液または懸濁液からなる。別法では、該溶液を凍結乾燥し、次いで、投与直前に適当な溶媒で復元することができる。
経直腸投与用組成物は、好都合には、ココア脂のような通常の坐剤基剤を含有する坐剤の形態である。
経皮投与に適当な組成物は、軟膏、ゲルおよびばんそこうを包含する。
経口投与のための各投薬単位は、例えば、1〜250mg(非経口投与の場合、例えば0.1〜25mgを含有する)の式(I)の化合物または遊離の塩基として計算されたその塩を含有する。
本発明の医薬上許容される化合物は、通常、例えば、式(I)の化合物または遊離の塩基として計算されたその塩の1mg〜500mg、例えば10mg〜400mg、例えば、10〜250mgの経口投与量、または0.1mg〜100mg、例えば0.1mg〜50mg、例えば、1〜25mgの静脈内、皮下または筋内投与量で、該化合物を一日に1〜4回投与する一日の投与計画(成人患者用)において投与されるであろう。適当には、該化合物は、連続的治療の期間、例えば、1週間以上投与されるであろう。
本発明の化合物の機能的強度および固有の活性は、下記のGTPγSシンチレーション近接アッセイ(GTPγS−SPA)によって測定できる。該研究に使用される細胞は、チャイニーズハムスター卵巣(CHO)細胞である。
細胞系統
CHO D2
CHO D3
化合物は、2つの択一的プロトコールにしたがって試験されうる。
10−6M ロイペプチン(Sigma L2884)−5000xストック=バッファー中5mg/ml
25μg/mlバシトラシン(Sigma B0125)−1000xストック=バッファー中25mg/ml
1mM PMSF−1000xストック=100%エタノール中17mg/ml
2x10−6Mペプステイン(Pepstain)A−1000xストック=100%DMSO中2mM
fKi=IC50/1+([A]/EC50)
[式中:[A]は、アッセイ中におけるアゴニスト5−HTの濃度であり、EC50は、同じ実験において得られた5−HT EC50値であり、fpKiは、−logfKiとして定義される]
を用いて、「アンタゴニスト様式」実験によって得られたIC50から計算される。
10−4M ロイペプチン(Sigma L2884)−5000xストック=バッファー中5mg/ml
25μg/mlバシトラシン(Sigma B0125)−1000xストック=バッファー中25mg/ml
1mM PMSF−1000xストック=100%エタノール中17mg/ml
2x10−6Mペプステイン(Pepstain)A−1000xストック=100%DMSO中2mM
fKi=IC50/1+([A]/EC50)
[式中:[A]は、アッセイ中におけるアゴニスト キネロランの濃度であり、EC50は、同じ実験において得られたキネロランEC50値であり、fpKiは、−logfKiとして定義される]
を用いて、「アンタゴニスト様式」実験によって得られたIC50から計算される。
上記に列挙された本発明の化合物は、30より大きいD2を超える選択性を有する。
全ての温度は、℃を示す。赤外線スペクトルは、FT−IR装置で測定した。化合物は、陽電子スプレー(ES+)イオン化様式において作動される質量分析計中に、アセトニトリル中に溶解した試料を直接注入することによって分析された。プロトン磁気共鳴(1H−NMR)スペクトルは、400MHzで記録され、化学シフトは、内部標準として使用されるMe4Siからのppm低磁場(d)において報告され、シングレット(s)、ブロード・シングレット(bs)、ダブレット(d)、ダブレットのダブレット(dd)、トリプレット(t)、カルテット(q)またはマルチプレット(m)として割り当てられる。
NMR (1H, CDCl3):δ5.75 (m, 1H), 5.05 (m, 2H), 4.25 (s, 3H), 2.75 (t, 2H), 2.1 (dd, 2H), 1.85 (m, 2H). MS (m/z): 128[MH]+.
NMR (1H, MeOD): δ5.75 (m, 1H), 4.97 (m, 2H), 2.95 (s, 3H), 2.75 (s, 3H), 2.43 (m, 2H), 2.08 (m, 2H), 1.65 (m, 2H). MS (m/z): 141[MH]+.
NMR (1H, CDCl3): δ9.65 (s, 1H), 9.4 (d, 1H), 7.98 (d, 1H), 4.0 (s, 3H).
MS (m/z): 139[MH]+
NMR (1H, DMSO): δ9.5 (s, 1H), 9.4 (d, 1H), 7.98 (d, 1H), NH および NH2 は観察されず。 MS (m/z): 139[MH]+.
MS (m/z): 152[MH]+.
MS (m/z): 152[MH]+.
MS (m/z): 153[MH]+.
MS (m/z): 459[MH]+.
MS (m/z): 158.1[MH]+.
MS (m/z): 145[MH]+.
NMR (1H, CDCl3):δ7.6 (m, 2H), 7.5 (m, 3H), 5.92 (m, 1H), 5.03 (m, 2H), 3.52 (s, 3H), 2.8 (t, 2H), 2.2(dd, 2H), 1.95 (m, 2H). MS (m/z): 228[MH]+.
MS (m/z): 230[MH]+.
MS (m/z): 243[MH]+.
MS (m/z): 242[MH]+.
MS (m/z): 243[MH]+.
MS (m/z): 247[MH]+.
MS (m/z): 249.1[MH]+.
MS (m/z): 264 [MH]+
MS (m/z): 145[MH]+.
NMR (1H, CDCl3):δ9.8 (s, 1H), 7.6 (bm, 2H), 7.5 (bm, 3H), 5.52 (bm, 1H), 5.28 (bm, 2H), 3.6 (s, 3H), 2.85 (bm, 2H), 2.7 (bm, 2H), 2.15 (bm, 2H). MS (m/z): 230[MH]+.
MS (m/z): 232[MH]+.
MS (m/z): 244[MH]+.
MS (m/z): 244[MH]+.
MS (m/z):245[MH]+.
MS (m/z): 249[MH]+.
MS (m/z): 251.1[MH]+.
MS (m/z): 266[MH]+.
MS (m/z): 238[MH]+.
溶媒を真空下で蒸発させ、残渣を水に溶解し、DCMで抽出した。有機層をNa2SO4で乾燥させ、濃縮し、フラッシュクロマトグラフィーによって精製して、標題化合物を淡黄色油として得た(127mg)。
MS (m/z): 246[MH]+.
MS (m/z): 262[MH]+.
MS (m/z): 324[MH]+.
MS (m/z): 339[MH]+.
MS (m/z): 204 [MH]+.
MS (m/z): 172 [MH]+.
MS (m/z): 158 [MH]+.
MS (m/z): 249 [MH]+.
MS (m/z): 263 [MH]+.
MS (m/z): 242 [MH]+.
MS (m/z): 258 [MH]+.
MS (m/z): 296 [MH]+.
MS (m/z): 262 [MH]+.
MS (m/z): 245 [MH]+.
MS (m/z): 251 [MH]+.
MS (m/z): 264 [MH]+.
MS (m/z): 260 [MH]+.
MS (m/z): 297 [MH]+.
MS (m/z): 264 [MH]+.
MS (m/z): 247 [MH]+.
MS (m/z): 243 [MH]+.
MS (m/z): 208[MH]+.
MS (m/z): 210[MH]+.
MS (m/z): 280[MH]+
MS (m/z): 358[MH]+.
MS (m/z): 311[MH]+.
MS (m/z): 313[MH]+.
MS (m/z): 258[MH]+.
MS (m/z): 260[MH]+.
MS (m/z): 258[MH]+.
MS (m/z): 260[MH]+.
MS (m/z): 262[MH]+.
MS (m/z): 264[MH]+.
MS (m/z): 253[MH]+.
MS (m/z): 255[MH]+.
MS (m/z): 293[MH]+.
MS (m/z): 295[MH]+.
MS (m/z): 260[MH]+.
MS (m/z): 262[MH]+.
MS (m/z): 253[MH]+.
MS (m/z): 255[MH]+.
MS (m/z): 242[MH]+.
MS (m/z): 260[MH]+.
MS (m/z): 258[MH]+.
MS (m/z): 264[MH]+.
MS (m/z): 266[MH]+.
MS (m/z): 251[MH]+.
MS (m/z): 329 [MH]+.
MS (m/z): 251[MH]+.
MS (m/z): 354 [MH]+.
MS (m/z): 280 [MH]+.
MS (m/z): 358 [MH]+.
MS (m/z): 262 [MH]+.
MS (m/z): 264 [MH]+.
NMR (1H, CDCl3):δ8.12 (m, 1H), 7.55 (m, 1H), 7.33 (m, 1H), 3.88 (s, 3H).
MS (m/z): 143 [MH]+.
MS (m/z): 234 [MH]+.
MS (m/z): 236 [MH]+.
MS (m/z): 264 [MH]+.
MS (m/z): 266 [MH]+.
MS (m/z): 173 [MH]+.
MS (m/z): 264 [MH]+.
MS (m/z): 266 [MH]+.
MS (m/z): 140 [MH]+.
MS (m/z): 231 [MH]+.
MS (m/z): 233 [MH]+.
MS (m/z): 168 [MH]+.
MS (m/z): 259 [MH]+.
MS (m/z): 261 [MH]+.
MS (m/z): 246 [MH]+.
MS (m/z): 248 [MH]+.
MS (m/z): 246 [MH]+.
MS (m/z): 248 [MH]+.
MS (m/z): 282 [MH]+.
MS (m/z): 360 [MH]+.
NMR (1H, DMSO-D6): 6.2 (bs, 1H), 3.3 (m, 2H), 3.15 (m, 4H), 2.95 (d, 2H), 2.35 (t, 2H), 2.2 (m, 1H), 1.95 (t, 2H), 1.75 (d, 2H), 1.35 (m, 2H). MS (m/z): 266 [MH]+.
NMR (1H, CDCl3): 3.7 (t, 2H), 3.5 (sb, 3H), 2.8 (m, 2H), 2.7 (m, 3H), 1.9 (m, 2H), 1.7 (m, 2H). MS (m/z): 202 [MH]+.
NMR (1H, CDCl3): 3.7 (t, 2H), 3.5 (s, 3H), 3.1 (d, 2H), 2.8 (d, 2H), 2.7 (m, 1H), 1.9 (m, 2H), 1.7 (m, 2H), 1.15 (m, 1H), 0.6 (m, 2H), 0.25 (sb, 2H). MS (m/z): 242 [MH]+.
NMR (1H, CDCl3): 9.8 (s, 1H), 3.45 (s, 3H), 2.8 (t, 2H), 2.7 (m, 5H), 2.1 (m, 2H). MS (m/z): 200 [MH]+.
MS (m/z): 312[MH]+.
MS (m/z): 314[MH]+.
NMR (1H, CDCl3): 7.73-7.70 (m, 2H), 7.67-7.60 (m, 4H), 7.57-7.52 (m, 2H), 4.1 (bd, 1H), 3.89 (bm, 1H), 3.62 (bm, 1H), 3.72 (s, 3H), 3.38 (t, 2H), 3..0 (t, 2H), 2.41 (m, 1H), 1.97 (m, 4H), 1.48 (m, 1H), 1.37 (m, 1H). MS (m/z): 459[MH]+.
NMR (1H, CD3OD): 8.701(s, 1H), 7.99 (d, 1H), 7.81 (d, 1H), 7.61 (t, 2H), 7.6 (d, 3H), 4.16 (bd, 1H), 3.86 (bd, 1H), 3.79 (db, 1H), 3.71 (bd, 1H), 3.68 (s, 3H), 3.38 (t, 2H), 2.97 (t, 2H), 2.46 (m, 1H), 1.97 (m, 4H), 1.48 (d, 2H). MS (m/z): 442[MH]+.
NMR (1H, CD3OD): 7.58 (t, 2H), 7.57 (d, 2H), 7.52 (t, 1H), 7.51 (d, 2H), 7.41 (d, 2H), 4.03 (bs, 1H), 3.74 (bs, 1H), 3.7-3.55 (bm, 2H), 3.59 (s, 3H), 3.27 (t, 2H), 2.88 (t, 2H), 2.25 (m, 1H), 1.87 (bm, 4H), 1.34 (t, 1H), 1.29 (bt, 1H). MS (m/z): 441[MH]+.
NMR (1H, CD3OD): 9.67 (s, 1H), 9.51 (d, 1H), 8.23 (dd, 1H), 7.67 (d, 2H), 7.51 (d, 2H), 4.17 (d, 1H), 3.9 (s, 3H), 3.89 (d, 1H), 3.71 (d, 1H), 3.67 (d, 1H), 3.39 (bt, 2H), 3.12 (bt, 2H), 2.34 (bm, 1H), 1.99 (bs, 4H), 1.51 (bm, 1H), 1.36 (bm, 1H). MS (m/z): 443[MH]+.
NMR (1H, CD3OD): 8.68 (dd, 1H), 7.95 (dd, 1H), 7.68 (d, 2H), 7.54 (dd, 1H), 7.52 (d, 2H), 4.17 (m, 1H), 3.90 (m, 1H), 3.70 (m, 2H), 3.49 (s, 3H), 3.39 (t, 2H), 2.99 (t, 2H), 2.49 (s, 3H), 2.35 (m, 1H),1.97 (m, 4H), 1.42 (m, 2H). MS (m/z): 456[MH]+.
NMR (1H, CD3OD): 8.83 (s, 1H), 8.24 (d, 1H), 7.69 (d, 1H), 7.67 (d, 2H), 7.51 (d, 2H), 4.16 (m, 1H), 3.88 (m, 1H), 3.74 (s, 3H), 3.71 (m, 2H), 3.38 (m, 2H), 3.01 (t, 2H), 2.71 (s, 3H), 2.35 (m, 1H),1.97 (m, 4H), 1.47 (m, 1H), 1.38 (m, 1H). MS (m/z): 456[MH]+.
NMR (1H, CD3OD): 9.17(m, 1H), 8.69 (m, 1H), 7.66 (d, 2H), 7.51 (d, 2H), 4.19 (m, 1H), 4.07 (m, 3H), 3.88 (m, 1H), 3.67 (m, 2H), 3.39 (m, 2H), 3.08 (m, 2H), 2.66 (m, 3H), 2.35 (m, 1H),1.96 (m, 4H), 1.49 (m, 1H), 1.34 (m, 1H). MS (m/z): 457MH]+.
NMR (1H, CDCl3): 7.66 (d, 2H), 7.49 (d, 2H), 4.05 (m, 1H), 3.76 (m, 1H), 3.74 (s, 3H), 3.60 (m, 2H), 3.29 (m, 2H), 2.94 (t, 2H), 2.53 (s, 3H), 2.34 (s, 3H), 2.28 (m, 1H), 1.92 (m, 4H), 1.46 (m, 1H), 1.32 (m, 1H). MS (m/z): 460[MH]+.
NMR (1H, メタノール-d4):δ8.80 (s, 1H), 8.07 (dd, 1H), 7.80 (m, 3H), 7.72 (m, 2H), 7.43 (d, 1H), 4.20 (d, 1H), 4.08 (d, 1H), 3.91 (d, 1H), 3.85 (s, 3H), 3.62 (m, 1H), 3.42 (m, 2H), 3.14 (m, 2H), 2.52 (m, 1H), 2.03 (m, 4H), 1.67 (m, 2H). MS (m/z): 442 [MH]+.
NMR (1H, DMSO-d6):δ10.52 (bs, 1H), 8.13 (s, 1H), 7.71 (d, 2H), 7.50 (d, 2H), 4.05 (m, 1H), 3.71 (s, 3H), 3.62 (m, 4H), 3.50 (m, 2H), 3.25 (m, 2H), 2.83 (t, 2H), 2.30 (m, 1H), 1.84 (m, 2H), 1.76 (m, 3H), 1.19 (m, 1H). MS (m/z): 462.0 [MH]+.
NMR (1H, DMSO): 10.6 (bs, 1H), 8.72 (s, 1H), 7.99 (d, 1H), 7.89 (d, 1H), 7.80 (td, 1H), 7.64 (dd, 1H), 7.56 (bm, 1H), 4.08 (bd, 1H), 3.73 (bd, 1H), 3.68 (bd, 1H), 3.61 (s, 3H), 3.52 (bd, 1H), 3.24 (t, 2H), 2.83 (t, 2H), 2.4 (m, 1H), 1.86 (m, 2H), 1.78 (m, 3H), 1.3 (bt, 1H). MS (m/z): 478[MH]+.
NMR (1H, DMSO): 10.59 (bs, 1H), 7.81 (m, 1H), 7.71 (d, 2H), 7.65 (m, 1H), 7.57 (m, 1H), 7.50 (d, 2H), 4.06 (d, 1H), 3.74 (d, 1H), 3.62 (m, 3H), 3.43 (m, 2H), 3.25 (m, 2H), 2.84 (m, 2H), 2.30 (m, 1H), 1.84 (m, 5H), 1.19 (m, 1H). MS (m/z): 477[MH]+.
NMR (1H, DMSO): 10.69 (bs, 1H), 7.70 (d, 2H), 7.48 (d, 2H), 4.02 (bs, 1H), 3.92 (d, 2H), 3.66 (m, 4H), 3.47 (m, 2H), 3.35 (m, 5H), 2.84 (m, 2H), 2.29 (m, 1H), 1.78 (m, 9H), 1.21 (m, 1H). MS (m/z): 449[MH]+.
NMR (1H, CD3OD): 7.69 (m, 4H), 7.56 (m, 3H), 7.49 (d, 2H), 4.03 (d, 1H), 3.70 (d, 1H), 3.61 (m, 1H), 3.61 (s, 3H), 3.49 (m, 1H), 3.17 (m, 2H), 2.82 (t, 2H), 2.28 (m, 1H), 1.77 (m, 6H), 1.44 (m, 1H), 1.18 (m, 1H). MS (m/z): 455[MH]+.
NMR (1H, CD3OD): 9.14(m, 1H), 8.66 (m, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 4.17 (d, 1H), 3.99 (m, 3H), 3.85 (d, 1H), 3.64 (m, 2H), 3.30 (m, 2H), 2.94 (t, 2H), 2.64 (m, 3H), 2.34 (bs, 1H),1.88 (m, 4H), 1.55 (m, 2H), 1.42 (m, 1H), 1.35 (m, 1H). MS (m/z): 455[MH]+.
MS (m/z): 471 [MH]+.
MS (m/z): 509 [MH]+.
NMR(1H, DMSO-D6):δ=1.19 (m, 1H), 1.73 (m, 1H), 1.79 (m, 2H), 1.89 (m, 2H), 2.29 (m, 1H), 2.85 (m, 2H), 3.26 (m, 2H), 3.42 (m, 2H), 3.63 (m, 4H), 3.71 (d, 1H), 4.02 (d, 1H), 7.49 (d, 2H), 7.63 (m, 3H), 7.70 (d, 2H), 7.76 (bs, 1H), 10.51 (bs, 1H).
MS (m/z): 475 [MH]+.
MS (m/z): 459 [MH]+.
NMR (1H, DMSO-D6) δ=1.20 (m, 1H), 1.69 (m, 1H), 1.83 (m, 4H), 2.29 (m, 1H), 2.40 (s, 3H), 2.82 (t, 2H), 3.24 (m, 2H), 3.41 (m, 1H), 3.49 (s, 3H), 3.63 (m, 1H), 3.71 (m, 1H), 4.05 (m, 1H), 7.49 (d, 2H), 7.70 (d, 2H), 9.27 (s, 1H), 10.38 (bs, 1 H).
MS (m/z): 462 [MH]+.
NMR (1H, DMSO-D6)δ=1.19 (m, 1H), 1.70 (m, 1H), 1.83 (m, 4H), 2.29 (m, 1H), 2.30 (s, 3H), 2.68 (s, 3H), 2.81 (t, 2H), 3.24 (m, 2H), 3.49 (s, 3H), 3.50 (m, 1H), 3.62 (m, 1H), 3.71 (m, 1H), 4.05 (m, 1H), 7.50 (d, 2H), 7.70 (d, 2H), 10.47 (bs, 1H).
MS (m/z): 476 [MH]+.
MS (m/z): 455 [MH]+.
1H NMR (500 MHz, CD3OD)δ ppm 7.67 (d, 2 H), 7.51 (d, 2 H) , 4.00 - 4.23 (m, 1 H), 3.91 (s, 3 H), 3.91 (s, 3 H), 3.91 (s, 3 H), 3.54 - 3.80 (m, 2 H), 3.34 - 3.42 (m, 2 H), 2.95 - 3.05 (m, 2 H), 2.28 - 2.42 (m, 1 H), 1.85 - 2.07 (m, 4 H), 1.48 - 1.59 (m, 10 H), 1.28 - 1.42 (m, 1 H). MS (m/z): 421[MH]+.
1H NMR (500 MHz, CD3OD): ppm 7.75 (d, 2 H), 7.67 (d, 4 H), 7.51 (d, 2 H), 4.16 (d, 1 H), 3.88 (d, 1 H), 3.76 (s, 3 H), 3.60 - 3.73 (m, 2 H), 3.27 - 3.42 (m, 2 H), 3.00 (t, 2 H), 2.28 - 2.40 (m, 1 H), 1.82 - 2.02 (m, 4 H), 1.56 - 1.66 (m, 2 H) , 1.47 - 1.55 (m, 1 H), 1.31 - 1.40 (m, 1 H). MS: 489 [MH]+
NMR (DMSO-d6) ppm 1.15 - 1.25 (m, 1 H) 1.67 - 1.73 (m, 1 H) 1.72 - 1.95 (m, 4 H) 2.23 - 2.35 (m, 1 H) 2.52 (s, 3 H) 2.78 - 2.94 (m, 2 H) 3.14 - 3.49 (m, 2 H) 3.43 (s, 3 H) 3.47 - 3.56 (m, 1 H) 3.59 - 3.68 (m, 1 H) 3.73 (d, 1 H) 4.07 (d, 1 H) 7.49 (d, 2 H) 7.70 (d, 2 H) 7.91 (d, 1 H) 8.13 (d, 1 H) 10.38 (br. s., 1 H). MS (m/z): 525 [MH]+.
NMR (1H, メタノール-d4) ppm 1.32 - 1.43 (m, 1 H) 1.42 - 1.51 (m, 1 H) 1.89 - 2.05 (m, 4 H) 2.30 - 2.41 (m, 1 H) 2.97 - 3.06 (m, 2 H) 3.35 - 3.43 (m, 2 H) 3.60 - 3.79 (m, 2 H) 3.74 (s, 3 H) 3.79 - 3.98 (m, 1 H) 3.89 (s, 3 H) 4.03 - 4.28 (m, 1 H) 7.18 - 7.30 (m, 3 H) 7.48 - 7.60 (m, 3 H) 7.67 (d, 2 H).MS (m/z): 471 [MH]+
NMR (1H, メタノール-d4) ppm 1.33 - 1.44 (m, 1 H) 1.44 - 1.53 (m, 1 H) 1.88 - 2.08 (m, 4 H) 2.30 - 2.42 (m, 1 H) 2.94 - 3.07 (m, 2 H) 3.35 - 3.43 (m, 2 H) 3.56 (s, 3 H) 3.63 - 3.79 (m, 2 H) 3.80 - 3.91 (m, 1 H) 3.90 (s, 3 H) 4.01 - 4.27 (m, 1 H) 7.19 (t, 1 H) 7.27 (d, 1 H) 7.48 (d, 1 H) 7.53 (d, 2 H) 7.63 - 7.72 (m, 3 H). MS (m/z): 471 [MH]+.
NMR (1H, CDCl3): ppm 1.47 - 2.03 (m, 7 H) 2.47 - 2.69 (m, 4 H) 2.77 - 2.92 (m, 2 H) 3.09 - 3.23 (m, 1 H) 3.35 - 3.47 (m, 1 H) 3.65 (s, 3 H) 7.23 (d, 2 H) 7.54 (d, 2 H) 7.67 (t, 1 H) 7.81 (d, 1 H) 7.90 - 7.99 (m, 2 H), acid proton not detected.
MS (m/z): 466[MH]+.
NMR (1H, CD3OD) ppm 1.35 - 1.54 (m, 2 H) 1.92 - 2.11 (m, 4 H) 2.29 - 2.45 (m, 1 H) 2.84 (s, 3 H) 3.03 (t, 2 H) 3.41 (t, 2 H) 3.53 (s, 3 H) 3.61 - 3.83 (m, 2 H) 3.81 - 4.00 (m, 1 H) 4.07 - 4.28 (m, 1 H) 7.53 (d, 2 H) 7.64 (d, 1 H) 7.68 (d, 2 H) 7.84 (d, 1 H) 8.02 (t, 1 H) 8.25 (d, 1 H) 8.32 (d, 1 H). MS (m/z): 506 [MH]+
NMR (1H, CD3OD) ppm 1.34 - 1.44 (m, 1 H) 1.42 - 1.53 (m, 1 H) 1.92 - 2.04 (m, 4 H) 2.17 (s, 3 H) 2.26 (s, 3 H) 2.32 - 2.38 (m, 1 H) 2.99 (t, 2 H) 3.39 (t, 2 H) 3.57 (s, 3 H) 3.64 - 3.79 (m, 2 H) 3.80 - 3.91 (m, 1 H) 3.82 (s, 3 H) 4.04 - 4.25 (m, 1 H) 7.52 (d, 2 H) 7.67 (d, 2 H). MS (m/z): 473 [MH]+.
NMR (1H, CD3OD) ppm 1.23 - 1.42 (m, 2 H) 1.76 - 1.96 (m, 4 H) 2.20 - 2.30 (m, 1 H) 2.88 (t, 2 H) 3.27 (t, 2 H) 3.49 - 3.70 (m, 2 H) 3.61 (s, 3 H) 3.70 - 3.84 (m, 1 H) 3.96 - 4.18 (m, 1 H) 7.41 (d, 2 H) 7.57 (d, 2 H) 7.79 (d, 2 H) 7.86 (d, 2 H).
MS (m/z): 466 [MH]+.
NMR (1H, CD3OD) ppm 1.26 - 1.35 (m, 1 H) 1.51 - 1.61 (m, 1 H) 1.61 (s, 6 H) 1.74 - 1.88 (m, 2 H) 1.92 - 2.02 (m, 2 H) 2.24 - 2.38 (m, 1 H) 3.23 - 3.36 (m, 2 H) 3.57 - 3.65 (m, 1 H) 3.65 - 3.74 (m, 1 H) 3.78 - 3.89 (m, 1 H) 3.92 (s, 3 H) 4.07 - 4.20 (m, 1 H) 7.45 - 7.55 (m, 2 H) 7.63 - 7.74 (m, 5 H) 7.74 - 7.82 (m, 2 H). MS (m/z): 469 [MH]+.
NMR (1H, CD3OD) ppm 1.17 - 1.32 (m, 1 H) 1.55 - 1.69 (m, 1 H) 2.02 - 2.21 (m, 2 H) 2.26 - 2.35 (m, 1 H) 2.58 - 2.77 (m, 2 H) 3.23 - 3.43 (m, 2 H) 3.50 - 3.61 (m, 1 H) 3.64 - 3.73 (m, 1 H) 3.74 - 3.83 (m, 1 H) 3.79 (s, 3 H) 4.11 (dd, 1 H) 7.49 (d, 2 H) 7.57 - 7.65 (m, 3 H) 7.70 (d, 2 H) 7.75 (d, 2 H) 10.31 (br. s., 1 H). MS (m/z): 477 [MH]+.
NMR (1H, DMSO-D6):δ=1.16-1.31 (m, 1H), 1.65-1.76 (m, 1H), 1.74-2.00 (m, 4H), 2.24-2.40 (m, 1H), 2.85 (t, 2H), 3.20-3.34 (m, 2H), 3.46-3.59 (m, 1H), 3.57-3.83 (m, 2H), 3.64 (s, 3H), 3.97-4.22 (m, 1H), 7.42 (td, 1H), 7.48-7.68 (m, 3H), 7.52-7.59 (m, 2H), 7.73 (d, 2H), 10.40 (bs, 1H). MS (m/z): 459 [MH]+.
NMR (1H, DMSO-D6)δ=1.09-1.30 (m, 1H), 1.60-1.70 (m, 1H), 1.72-1.93 (m, 4H), 2.26-2.34 (m, 1H), 2.75-2.87 (m, 2H), 3.19-3.38 (m, 2H), 3.37 (s, 3H), 3.46-3.56 (m, 1H), 3.58-3.67 (m, 1H), 3.68-3.78 (m, 1H), 3.94-4.14 (m, 1H), 7.42-7.54 (m, 4H), 7.57-7.65 (m, 1H), 7.64-7.76 (m, 3H), 10.26 (bs, 1H). MS (m/z): 475 [MH]+.
NMR (1H, DMSO-D6)δ=1.10-1.25 (m, 1H), 1.6 -1.95 (m, 5H), 2.22-2.33 (m, 1H), 2.89 (t, 2H), 3.16-3.29 (m, 2H), 3.29-3.84 (m, 3H), 3.74 (s, 3H), 3.96-4.08 (m, 1H), 7.49 (d, 2H), 7.57 (d, 1H), 7.69 (d, 2H), 7.80-7.87 (m, 1H), 8.21 (s, 1H), 10.79 (bs, 1 H). MS (m/z): 447 [MH]+.
NMR (1H, DMSO-D6):δ=1.16-1.27 (m, 1H), 1.65-1.71 (m, 1H), 1.75-1.97 (m, 4H), 2.26-2.34 (m, 1H), 2.81 (t, 2H), 3.15-3.32 (m, 2H), 3.44 (s, 3H), 3.46-3.58 (m, 1H), 3.57-3.67 (m, 1H), 3.74 (d, 1H), 4.04 (d, 1H), 7.30 (dt, 1H), 7.49 (d, 2H), 7.54 (dd, 1H), 7.61-7.69 (m, 1H), 7.71 (d, 2H), 10.37 (bs, 1H). MS (m/z): 477 [MH]+.
NMR (1H, DMSO-D6)δ=1.16-1.24 (m, 1H), 1.69-1.77 (m, 1H), 1.75-1.94 (m, 4H), 2.25-2.34 (m, 1H), 2.86 (t, 2H), 3.14-3.32 (m, 2H), 3.52-3.67 (m, 2H), 3.60 (s, 3H), 3.66-3.77 (m, 1H), 3.74 (s, 3H), 3.97-4.13 (m, 1H), 6.22 (t, 1H), 6.55 (d, 1H), 7.02-7.08 (m, 1H), 7.49 (d, 2H), 7.70 (d, 2H), 10.53 (bs, 1H). MS (m/z): 444 [MH]+.
NMR (1H, DMSO-D6):δ=1.15-1.23 (m, 1H), 1.68-1.75 (m, 1H), 1.74-1.91 (m, 4H), 2.25-2.34 (m, 1H), 2.80 (t, 2H), 3.19-3.28 (m, 2H), 3.46-3.57 (m, 1H), 3.57-3.67 (m, 1H), 3.59 (s, 3H), 3.65-3.81 (m, 1H), 3.95-4.10 (m, 1H), 7.40 (t, 2H), 7.49 (d, 2H), 7.64-7.78 (m, 4H), 10.50 (bs, 1H). MS (m/z): 459 [MH]+.
NMR (1H, DMSO-D6, 標題化合物の遊離塩基):δ=8.41 (s, 1H), 7.88 (d, 1H), 7.55 (d, 2H), 7.23 (d, 2H), 7.89 (d, 1H), 4.02 (s, 3H), 3.62 (s, 3H), 3.40 (d, 1H), 3.15 (d, 1H), 2.82 (t, 2H), 2.68-2.47 (m, 4H), 1.98-1.60 (m, 4H), 1.52 (m, 1H), 0.85 (m, 2H). MS (m/z): 472 [MH]+.
NMR (1H, DMSO-D6):δ=1.16-1.24 (m, 1H), 1.61-1.69 (m, 1H), 1.72-1.93 (m, 4H), 2.25-2.34 (m, 1H), 2.82 (t, 2H), 3.17-3.30 (m, 2H), 3.44-3.56 (m, 1H), 3.59-3.68 (m, 1H), 3.64 (s, 3H), 3.67-3.79 (m, 1H), 3.97-4.15 (m, 1H), 7.40-7.53 (m, 5H), 7.71 (d, 2H), 10.33 (bs, 1H). MS (m/z): 477 [MH]+.
NMR (1H, CD3OD) ppm 1.11 - 1.26 (m, 1 H) 1.35 - 1.47 (m, 1 H) 1.48 - 1.62 (m, 2 H) 1.76 - 1.97 (m, 4 H) 2.25 - 2.37 (m, 1 H) 2.43 (s, 3 H) 2.91 (t, 2 H) 3.22 - 3.32 (m, 2 H) 3.54 - 3.72 (m, 3 H) 3.75 (s, 3 H) 3.83 (d, 1 H) 7.50 (d, 2 H) 7.66 (d, 2 H) 8.35 (s, 1 H). MS (m/z): 460 [MH]+.
NMR (1H, DMSO-d6) ppm 1.16 - 1.24 (m, 1 H) 1.28 - 1.37 (m, 1 H) 1.38 - 1.51 (m, 2 H) 1.74 - 1.85 (m, 4 H) 2.20 - 2.33 (m, 1 H) 2.79 (t, 2 H) 3.11 - 3.25 (m, 2 H) 3.45 - 3.56 (m, 1 H) 3.59 (s, 3 H) 3.59 - 3.67 (m, 1 H) 3.67 - 3.78 (m, 1 H) 3.82 (s, 3 H) 4.08 (d, 1 H) 7.10 (dd, 1 H) 7.19 (d, 1 H) 7.22 (d, 1 H) 7.46 - 7.53 (m, 3 H) 7.69 (d, 2 H) 10.40 (br. s., 1 H). MS (m/z): 485 [MH]+.
NMR (1H, DMSO-d6) ppm 1.33 - 1.41 (m, 1 H) 1.39 - 1.48 (m, 1 H) 1.50 - 1.63 (m, 2 H) 1.79 - 1.91 (m, 2 H) 1.91 - 2.01 (m, 2 H) 2.36 (br. s., 1 H) 2.97 (t, 2 H) 3.25 - 3.37 (m, 2 H) 3.51 (s, 3 H) 3.61 - 3.67 (m, 1 H) 3.68 - 3.76 (m, 1 H) 3.78 - 3.95 (m, 1 H) 4.07 - 4.22 (m, 1 H) 7.47 - 7.53 (m, 2 H) 7.54 - 7.59 (m, 2 H) 7.63 - 7.71 (m, 4 H) H), 酸プロトンは検出されず。 MS (m/z): 489 [MH]+.
NMR (1H, DMSO-d6):δ=1.17-1.27 (m, 1H), 1.44 (t, 2H), 1.59-1.66 (m, 1H), 1.70-1.83 (m, 4H), 2.25-2.33 (m, 1H), 2.79 (t, 2H), 3.12-3.27 (m, 2H), 3.43 (s, 3H), 3.46-3.55 (m, 1H), 3.58-3.67 (m, 1H), 3.66-3.78 (m, 1H), 3.93-4.13 (m, 1H), 7.30 (td, 1H), 7.48 (d, 2H), 7.50-7.57 (m, 1H), 7.60-7.67 (m, 1H), 7.70 (d, 2H), 10.18 (bs, 1H).
MS (m/z): 491 [MH]+.
MS (m/z): 411 [MH]+ .
NMR (1H, CD3OD): 7.67 (d, 2H), 7.50 (d, 2H), 4.15 (m, 1H), 3.86(m, 1H), 3.73 (s, 3H), 3.67 (m, 2H), 3.37 (m, 2H), 3.24 (d, 2H), 3.04 (m, 2H), 2.33 (m, 1 H), 1.93 (m, 4H), 1.53 (m, 1H), 1.35 (m, 1H), 1.21 (m, 1H), 0.66 (m, 2H), 0.36 (m, 2H)
MS (m/z): 242 [MH]+.
NMR (1H, DMSO-d6) ppm 1.17 - 1.28 (m, 1 H) 1.56 - 1.64 (m, 1 H) 1.72 - 1.92 (m, 4 H) 2.27 - 2.34 (m, 1 H) 2.83 (t, 2 H) 3.19 - 3.33 (m, 2 H) 3.45 - 3.58 (m, 1 H) 3.58 - 3.67 (m, 1 H) 3.61 (s, 3 H) 3.69 - 3.79 (m, 1 H) 4.07 (d, 1 H) 7.50 (d, 2 H) 7.56 (d, 2 H) 7.71 (d, 2 H) 7.83 (d, 2 H) 10.15 (br. s., 1 H). MS (m/z): 525 [MH]+.
本発明は、本明細書中に記載される特別の基の全ての組み合わせを包含すると理解されるべきである。
該記載および請求の範囲が一部を形成する出願は、いずれの後の出願に関しても優先権の基礎として使用することができる。かかる後の出願の請求の範囲は、本明細書中に記載されるいずれの特徴または特徴の組み合わせに向けられたものであってもよい。それらは、生産物、組成物、方法または使用のクレームの形態を取ってもよく、例示として、限定するものではないが、添付の請求の範囲を包含しうる。
Claims (9)
- 式(I):
Gは、フェニルおよびピリジルからなる群から選択され;
pは、0〜5の整数であり;
R1は、独立して、ハロゲンおよびハロC1−4アルキルからなる群から選択され;
各R2は、独立して、水素、フッ素またはC1−4アルキルであり;
nは、2、3、4または5であり;
R3は、C1−4アルキルであり;
R4は、フェニル、キノリニル、ピラニル、ピリジニル、ピラゾリル、ピリミジル、ピリダジニル、ピラジニル、フラニル、チエニル、オキサゾリル、イソオキサゾリル、チアゾリル、トリアゾリル、ベンジル基、t−ブチル基、チオメチルシクロプロピル、またはチオメチルであり、いずれの基も、ハロゲン、シアノ、C1−4アルキル、ハロC1−4アルキル、C1−4アルコキシ、ハロC1−4アルコキシ、C1−4アルカノイルおよびSF5からなる群から選択される1、2、3または4個の置換基で置換されていてもよく;
R1が塩素であって、pが1である場合、かかるR1は、分子の残部に結合した連結部に対してオルト位で存在することはない]
で示される化合物またはその医薬上許容される塩。 - R1がハロゲンまたはトリフルオロメチルである請求項1または2記載の化合物またはその医薬上許容される塩。
- R2が水素である請求項1〜3のいずれか1項記載の化合物またはその医薬上許容される塩。
- 両方のR2が同時にメチルまたはフッ素である請求項1〜3のいずれか1項記載の化合物またはその医薬上許容される塩。
- nが3または4である請求項1〜5のいずれか1項記載の化合物またはその医薬上許容される塩。
- R3がメチルである請求項1〜6のいずれか1項記載の化合物またはその医薬上許容される塩。
- (1S,5R)−1−[2−フルオロ−4−(トリフルオロメチル)フェニル]−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[6−(トリフルオロメチル)−3−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(4−ピリダジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(2−メチル−3−ピリジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(6−メチル−3−ピリジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(5−メチル−2−ピラジニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジメチル−1,3−オキサゾール−5−イル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−[4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[5−(トリフルオロメチル)−2−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(2−メチル−1,3−チアゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1R,5S/1S,5R)−3−{4−[5−(3,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[6−(トリフルオロメチル)−3−ピリジニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(テトラヒドロ−2H−ピラン−4−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[5−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ペンチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[4−メチル−5−(5−メチル−2−ピラジニル)−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[4−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジクロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(4−メチル−1,3−チアゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジメチル−1,3−チアゾール−5−イル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(フェニルメチル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(1,1−ジメチルエチル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(4−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[2−メチル−6−(トリフルオロメチル)−3−ピリジニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[3−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[2−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
3−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]ベンゾニトリル;
2−メチル−5−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]キノリン;
(1S,5R)−3−{4−[4−メチル−5−(1,3,5−トリメチル−1H−ピラゾール−4−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
4−[4−メチル−5−(4−{(1S,5R)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサ−3−イル}ブチル)−4H−1,2,4−トリアゾール−3−イル]ベンゾニトリル;
(1S,5R)−3−[4−メチル−4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ペンチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4,4−ジフルオロ−4−(4−メチル−5−フェニル−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(3−チエニル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(2,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(1−メチル−1H−ピロール−2−イル)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(4−フルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{4−メチル−5−[6−(メチルオキシ)−3−ピリジニル]−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[5−(3,5−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[4−メチル−5−(4−メチル−1,3−オキサゾール−5−イル)−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(5−{4−メチル−5−[3−(メチルオキシ)フェニル]−4H−1,2,4−トリアゾール−3−イル}ペンチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(2−クロロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{5−[5−(2,4−ジフルオロフェニル)−4−メチル−4H−1,2,4−トリアゾール−3−イル]ペンチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−{4−[4−メチル−5−(メチルチオ)−4H−1,2,4−トリアゾール−3−イル]ブチル}−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−(4−{5−[(シクロプロピルメチル)チオ]−4−メチル−4H−1,2,4−トリアゾール−3−イル}ブチル)−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
(1S,5R)−3−[4−(4−メチル−5−{4−[(トリフルオロメチル)オキシ]フェニル}−4H−1,2,4−トリアゾール−3−イル)ブチル]−1−[4−(トリフルオロメチル)フェニル]−3−アザビシクロ[3.1.0]ヘキサン;
またはその医薬上許容される塩である請求項1記載の化合物。 - (a)式(II):
で示される化合物を式(III):
で示される化合物と反応させるか;または
(b)式(II):
で示される化合物を式(XIII):
で示される化合物と反応させる工程を含み、
その後、工程(a)または(b)の後、
(i)いずれかの保護基を除去し;および/または
(ii)塩を形成させ;および/または
(iii)式(I)の化合物またはその塩を式(I)の別の化合物またはその塩に変換する工程を含んでもよい、請求項1記載の化合物の製法。
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GBGB0507602.1A GB0507602D0 (en) | 2005-04-14 | 2005-04-14 | Compounds |
GB0507602.1 | 2005-04-14 | ||
PCT/EP2006/003554 WO2006108701A1 (en) | 2005-04-14 | 2006-04-12 | 3- (1,2,4-triazol-3ylalkyl) azabriclo (3.1.0) hexane derivatives as modulators of dopamine d3 receptors |
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JP2008535886A JP2008535886A (ja) | 2008-09-04 |
JP5150481B2 true JP5150481B2 (ja) | 2013-02-20 |
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Country Status (5)
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US (1) | US7947683B2 (ja) |
EP (1) | EP1869017A1 (ja) |
JP (1) | JP5150481B2 (ja) |
GB (1) | GB0507602D0 (ja) |
WO (1) | WO2006108701A1 (ja) |
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PT2060570E (pt) * | 2004-02-23 | 2012-05-07 | Glaxo Group Ltd | Derivados de azabiciclo(3.1.0)-hexano úteis como moduladores dos receptores d3 da dopamina |
US20070043100A1 (en) | 2005-08-16 | 2007-02-22 | Hagen Eric J | Novel polymorphs of azabicyclohexane |
GB0507601D0 (en) * | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
ATE484502T1 (de) * | 2005-06-14 | 2010-10-15 | Glaxo Group Ltd | Neue verbindungen |
GB0512099D0 (en) * | 2005-06-14 | 2005-07-20 | Glaxo Group Ltd | Compounds |
KR20170005888A (ko) | 2005-07-27 | 2017-01-16 | 뉴로반스, 인크. | 신규 1-아릴-3-아자바이사이클로[3.1.0]헥산:제조 방법 및 신경 정신 질환 치료를 위한 용도 |
GB0517175D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
GB0517191D0 (en) | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
EP1919908B1 (en) * | 2005-08-22 | 2010-11-10 | Glaxo Group Limited | Triazole derivatives as modulators of dopamine d3 receptors |
GB0517187D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
GB0517193D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
US8163927B2 (en) | 2006-04-03 | 2012-04-24 | Glaxo Group Limited | Azabicyclo [3.1.0] hexane derivatives as modulators of dopamine D3 receptors |
BRPI0709660A2 (pt) * | 2006-04-03 | 2011-07-19 | Glaxo Group Limided | derivados de azabiciclo [3,1,0] hexila como moduladores dos receptores de dopamina d3 |
WO2007113260A1 (en) * | 2006-04-03 | 2007-10-11 | Glaxo Group Limited | Azabicyclo [3. 1. o] hexyl derivatives as modulators of dopamine d3 receptors |
US20080045725A1 (en) | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
US8138377B2 (en) | 2006-11-07 | 2012-03-20 | Dov Pharmaceutical, Inc. | Arylbicyclo[3.1.0]hexylamines and methods and compositions for their preparation and use |
US9133159B2 (en) | 2007-06-06 | 2015-09-15 | Neurovance, Inc. | 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
WO2008153937A2 (en) * | 2007-06-06 | 2008-12-18 | Dov Pharmaceutical, Inc. | Novel 1- heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
GB0719235D0 (en) | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
GB0719234D0 (en) | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
JP2009256247A (ja) * | 2008-04-17 | 2009-11-05 | Sumitomo Seika Chem Co Ltd | チアゾール類の製造方法 |
MY154000A (en) * | 2008-09-22 | 2015-04-30 | Cayman Chem Co | Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases |
CN102803224A (zh) | 2009-06-26 | 2012-11-28 | 万能药生物有限公司 | 新的氮杂双环己烷类化合物 |
KR101723832B1 (ko) * | 2015-09-16 | 2017-04-06 | (주)국전약품 | 에틸-4-메틸-5-티아졸카복실레이트의 제조방법 |
CN105483749B (zh) * | 2015-11-27 | 2017-11-24 | 北京工业大学 | 3‑胺基‑2‑硫氰基‑α,β‑不饱和羰基类化合物的成对电合成方法 |
WO2019146740A1 (ja) | 2018-01-26 | 2019-08-01 | 塩野義製薬株式会社 | ドーパミンd3受容体拮抗作用を有する環式化合物 |
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IL65843A (en) * | 1977-08-11 | 1986-12-31 | American Cyanamid Co | Pharmaceutical compositions for the treatment of depression containing 3-aza-bicyclo(3.1.0)hexane derivatives and certain novel compounds of this type |
US4435419A (en) * | 1981-07-01 | 1984-03-06 | American Cyanamid Company | Method of treating depression using azabicyclohexanes |
DE4341403A1 (de) * | 1993-12-04 | 1995-06-08 | Basf Ag | N-substituierte 3-Azabicycloalkan-Derivate, ihre Herstellung und Verwendung |
AR022229A1 (es) * | 1999-01-12 | 2002-09-04 | Abbott Gmbh & Co Kg | Compuestos de triazol, composicion farmaceutica que los comprende y uso de los mismos para preparar dicha composicion |
ATE382617T1 (de) * | 2000-11-14 | 2008-01-15 | Smithkline Beecham Plc | Tetrahydrobenzazepin-derivate zur verwendung als dopamin-d3-rezeptor-modulatoren (antipsychotische mittel) |
PT2060570E (pt) * | 2004-02-23 | 2012-05-07 | Glaxo Group Ltd | Derivados de azabiciclo(3.1.0)-hexano úteis como moduladores dos receptores d3 da dopamina |
GB0507601D0 (en) * | 2005-04-14 | 2005-05-18 | Glaxo Group Ltd | Compounds |
GB0507680D0 (en) * | 2005-04-15 | 2005-05-25 | Glaxo Group Ltd | Compounds |
ATE484502T1 (de) * | 2005-06-14 | 2010-10-15 | Glaxo Group Ltd | Neue verbindungen |
GB0512099D0 (en) * | 2005-06-14 | 2005-07-20 | Glaxo Group Ltd | Compounds |
GB0517175D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
EP1919908B1 (en) * | 2005-08-22 | 2010-11-10 | Glaxo Group Limited | Triazole derivatives as modulators of dopamine d3 receptors |
GB0517191D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
GB0517193D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Novel use |
GB0517187D0 (en) * | 2005-08-22 | 2005-09-28 | Glaxo Group Ltd | Compounds |
BRPI0709660A2 (pt) * | 2006-04-03 | 2011-07-19 | Glaxo Group Limided | derivados de azabiciclo [3,1,0] hexila como moduladores dos receptores de dopamina d3 |
GB0616574D0 (en) * | 2006-08-21 | 2006-09-27 | Glaxo Group Ltd | Compounds |
EP1921073A1 (en) * | 2006-11-10 | 2008-05-14 | Laboratorios del Dr. Esteve S.A. | 1,2,4-Triazole derivatives as sigma receptor inhibitors |
-
2005
- 2005-04-14 GB GBGB0507602.1A patent/GB0507602D0/en not_active Ceased
-
2006
- 2006-04-12 WO PCT/EP2006/003554 patent/WO2006108701A1/en not_active Application Discontinuation
- 2006-04-12 US US11/911,027 patent/US7947683B2/en not_active Expired - Fee Related
- 2006-04-12 EP EP06724411A patent/EP1869017A1/en not_active Withdrawn
- 2006-04-12 JP JP2008505840A patent/JP5150481B2/ja not_active Expired - Fee Related
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GB0507602D0 (en) | 2005-05-18 |
JP2008535886A (ja) | 2008-09-04 |
US20090124629A1 (en) | 2009-05-14 |
WO2006108701A1 (en) | 2006-10-19 |
US7947683B2 (en) | 2011-05-24 |
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