JP5847830B2 - オレキシン受容体拮抗薬として有用なラクタム誘導体 - Google Patents
オレキシン受容体拮抗薬として有用なラクタム誘導体 Download PDFInfo
- Publication number
- JP5847830B2 JP5847830B2 JP2013538312A JP2013538312A JP5847830B2 JP 5847830 B2 JP5847830 B2 JP 5847830B2 JP 2013538312 A JP2013538312 A JP 2013538312A JP 2013538312 A JP2013538312 A JP 2013538312A JP 5847830 B2 JP5847830 B2 JP 5847830B2
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- JP
- Japan
- Prior art keywords
- dimethoxyphenyl
- benzyl
- methyl
- piperidin
- pyrrolidin
- 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.)
- Expired - Fee Related
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- 150000003951 lactams Chemical class 0.000 title description 37
- 229940123730 Orexin receptor antagonist Drugs 0.000 title description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 437
- -1 phenyloxy Chemical group 0.000 claims description 387
- 229910052757 nitrogen Inorganic materials 0.000 claims description 239
- 125000001424 substituent group Chemical group 0.000 claims description 165
- 150000001875 compounds Chemical class 0.000 claims description 135
- 125000003118 aryl group Chemical group 0.000 claims description 114
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000001072 heteroaryl group Chemical group 0.000 claims description 80
- 229920006395 saturated elastomer Polymers 0.000 claims description 73
- 150000002367 halogens Chemical group 0.000 claims description 70
- 229910052736 halogen Chemical group 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 64
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 52
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 52
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 49
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 125000001624 naphthyl group Chemical group 0.000 claims description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 claims description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000002619 bicyclic group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 208000020016 psychiatric disease Diseases 0.000 claims description 11
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 208000019116 sleep disease Diseases 0.000 claims description 8
- 208000010877 cognitive disease Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 206010012335 Dependence Diseases 0.000 claims description 6
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- 208000025966 Neurological disease Diseases 0.000 claims description 6
- 235000005686 eating Nutrition 0.000 claims description 6
- 230000007937 eating Effects 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- 230000003340 mental effect Effects 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 230000035622 drinking Effects 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- YYSWFDUHMSXIJH-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-1-[[3-(2-methyl-1,3-thiazol-4-yl)phenyl]methyl]pyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(C=CC=2)C=2N=C(C)SC=2)C(=O)CC1 YYSWFDUHMSXIJH-UHFFFAOYSA-N 0.000 claims description 4
- PLXRFUMPYLQAFR-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-3,3-difluoro-1-[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=CC(OC(F)(F)F)=CC=2)C(=O)C(F)(F)C1 PLXRFUMPYLQAFR-UHFFFAOYSA-N 0.000 claims description 4
- APXVOQGYSIFTDK-UHFFFAOYSA-N 6-(2,6-dimethoxyphenyl)-1-[(3-phenylphenyl)methyl]piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(C=CC=2)C=2C=CC=CC=2)C(=O)CCC1 APXVOQGYSIFTDK-UHFFFAOYSA-N 0.000 claims description 4
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 4
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 claims description 4
- DBVGSXHWGMFERG-UHFFFAOYSA-N 5-(2,6-dimethoxyphenyl)-4-[[4-(trifluoromethoxy)phenyl]methyl]morpholin-3-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=CC(OC(F)(F)F)=CC=2)C(=O)COC1 DBVGSXHWGMFERG-UHFFFAOYSA-N 0.000 claims description 3
- 229920001774 Perfluoroether Polymers 0.000 claims description 3
- 229910052770 Uranium Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- ADMREWYBXXZUMI-LJQANCHMSA-N (6r)-6-(2,6-dimethoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1[C@@H]1N(CC=2N=C3C=CC=CC3=CC=2)C(=O)CCC1 ADMREWYBXXZUMI-LJQANCHMSA-N 0.000 claims description 2
- ADMREWYBXXZUMI-IBGZPJMESA-N (6s)-6-(2,6-dimethoxyphenyl)-1-(quinolin-2-ylmethyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1[C@H]1N(CC=2N=C3C=CC=CC3=CC=2)C(=O)CCC1 ADMREWYBXXZUMI-IBGZPJMESA-N 0.000 claims description 2
- OCTOQPZKGOMKKM-UHFFFAOYSA-N 1-(1-benzofuran-2-ylmethyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2OC3=CC=CC=C3C=2)C(=O)CCC1 OCTOQPZKGOMKKM-UHFFFAOYSA-N 0.000 claims description 2
- OICORZNDSGZRFF-UHFFFAOYSA-N 1-(1-benzothiophen-5-ylmethyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C=CSC3=CC=2)C(=O)CCC1 OICORZNDSGZRFF-UHFFFAOYSA-N 0.000 claims description 2
- XUPSRCQFRXDXIL-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-3,3-difluoro-5-(2-fluoro-6-methoxyphenyl)pyrrolidin-2-one Chemical compound COC1=CC=CC(F)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(F)(F)C1 XUPSRCQFRXDXIL-UHFFFAOYSA-N 0.000 claims description 2
- KZHOUIVIZGUISG-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2,4-dimethoxypyridin-3-yl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=NC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(C)C1 KZHOUIVIZGUISG-UHFFFAOYSA-N 0.000 claims description 2
- YEGSYMNMIHXAMS-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2,6-dimethoxyphenyl)-3,3-difluoropyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(F)(F)C1 YEGSYMNMIHXAMS-UHFFFAOYSA-N 0.000 claims description 2
- PEAXRVOYMYUBCP-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(C)C1 PEAXRVOYMYUBCP-UHFFFAOYSA-N 0.000 claims description 2
- FHPANOIZEGWXAC-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)CC1 FHPANOIZEGWXAC-UHFFFAOYSA-N 0.000 claims description 2
- XJZTXMOXMDLNSA-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2-ethoxy-6-fluorophenyl)-3-methylpyrrolidin-2-one Chemical compound CCOC1=CC=CC(F)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(C)C1 XJZTXMOXMDLNSA-UHFFFAOYSA-N 0.000 claims description 2
- NZJJLLAOHLKKIZ-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-5-(2-fluoro-6-methoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(F)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)C(C)C1 NZJJLLAOHLKKIZ-UHFFFAOYSA-N 0.000 claims description 2
- JVILZWKBBUPTPP-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-6-(2,4-dimethoxypyridin-3-yl)piperidin-2-one Chemical compound COC1=CC=NC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)CCC1 JVILZWKBBUPTPP-UHFFFAOYSA-N 0.000 claims description 2
- ALXXSSTULXRROK-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)CCC1 ALXXSSTULXRROK-UHFFFAOYSA-N 0.000 claims description 2
- RZIWRUCHHJWXCX-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-6-(3,5-dimethoxypyridin-4-yl)piperidin-2-one Chemical compound COC1=CN=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)CCC1 RZIWRUCHHJWXCX-UHFFFAOYSA-N 0.000 claims description 2
- PLSLMYBUUIRIHB-UHFFFAOYSA-N 1-(dibenzofuran-2-ylmethyl)-7-(2,6-dimethoxyphenyl)azepan-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4OC3=CC=2)C(=O)CCCC1 PLSLMYBUUIRIHB-UHFFFAOYSA-N 0.000 claims description 2
- SXJVXFFSXZNQAN-UHFFFAOYSA-N 1-(dibenzothiophen-2-ylmethyl)-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3C4=CC=CC=C4SC3=CC=2)C(=O)C(C)C1 SXJVXFFSXZNQAN-UHFFFAOYSA-N 0.000 claims description 2
- ZVAPJUVMCPUKOM-UHFFFAOYSA-N 1-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C3OC(F)(F)OC3=CC=2)C(=O)CCC1 ZVAPJUVMCPUKOM-UHFFFAOYSA-N 0.000 claims description 2
- ZCYAKVORBGSGNZ-UHFFFAOYSA-N 1-[(2-chloro-5-pyridin-2-ylphenyl)methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C(=CC=C(C=2)C=2N=CC=CC=2)Cl)C(=O)CCC1 ZCYAKVORBGSGNZ-UHFFFAOYSA-N 0.000 claims description 2
- ZJYAAFGKMJOGRF-UHFFFAOYSA-N 1-[(3-chloro-5-pyridin-2-ylphenyl)methyl]-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(C=C(Cl)C=2)C=2N=CC=CC=2)C(=O)C(C)C1 ZJYAAFGKMJOGRF-UHFFFAOYSA-N 0.000 claims description 2
- YOXFIJCSNYXNHO-UHFFFAOYSA-N 1-[(3-chloro-5-pyridin-2-ylphenyl)methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(C=C(Cl)C=2)C=2N=CC=CC=2)C(=O)CCC1 YOXFIJCSNYXNHO-UHFFFAOYSA-N 0.000 claims description 2
- MNPWTNLMGSASDH-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=CC(Cl)=CC=2)C(=O)CCC1 MNPWTNLMGSASDH-UHFFFAOYSA-N 0.000 claims description 2
- HMIGQZCCCBMNIM-UHFFFAOYSA-N 1-[1-[5-chloro-6-(difluoromethoxy)pyridin-3-yl]ethyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(C(C)C=2C=C(Cl)C(OC(F)F)=NC=2)C(=O)CCC1 HMIGQZCCCBMNIM-UHFFFAOYSA-N 0.000 claims description 2
- KYSCRMHLIVJYBV-UHFFFAOYSA-N 1-[[3-(2,2-difluoroethoxy)phenyl]methyl]-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(OCC(F)F)C=CC=2)C(=O)C(C)C1 KYSCRMHLIVJYBV-UHFFFAOYSA-N 0.000 claims description 2
- AEGWGVROKVYKOO-UHFFFAOYSA-N 1-[[3-(2-methyl-1,3-thiazol-4-yl)phenyl]methyl]-5-(2-phenylphenyl)pyrrolidin-2-one Chemical compound S1C(C)=NC(C=2C=C(CN3C(CCC3C=3C(=CC=CC=3)C=3C=CC=CC=3)=O)C=CC=2)=C1 AEGWGVROKVYKOO-UHFFFAOYSA-N 0.000 claims description 2
- APJABJVOEWIGOA-UHFFFAOYSA-N 1-[[3-(4-chloro-1,3-thiazol-2-yl)phenyl]methyl]-5-(2,4-dimethoxypyridin-3-yl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=NC(OC)=C1C1N(CC=2C=C(C=CC=2)C=2SC=C(Cl)N=2)C(=O)C(C)C1 APJABJVOEWIGOA-UHFFFAOYSA-N 0.000 claims description 2
- WRGYINVCPYAEMS-UHFFFAOYSA-N 1-[[3-(4-chloro-1,3-thiazol-2-yl)phenyl]methyl]-5-(2-ethoxy-6-fluorophenyl)-3-methylpyrrolidin-2-one Chemical compound CCOC1=CC=CC(F)=C1C1N(CC=2C=C(C=CC=2)C=2SC=C(Cl)N=2)C(=O)C(C)C1 WRGYINVCPYAEMS-UHFFFAOYSA-N 0.000 claims description 2
- XLRJGGDGKILWEN-UHFFFAOYSA-N 1-[[3-(4-chloro-1,3-thiazol-2-yl)phenyl]methyl]-5-(2-fluoro-6-methoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(F)=C1C1N(CC=2C=C(C=CC=2)C=2SC=C(Cl)N=2)C(=O)C(C)C1 XLRJGGDGKILWEN-UHFFFAOYSA-N 0.000 claims description 2
- KVUGNCAMECQIRX-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(OC(F)F)C=CC=2)C(=O)C(C)C1 KVUGNCAMECQIRX-UHFFFAOYSA-N 0.000 claims description 2
- QBJBEALOLFIXNB-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-5-(2-ethoxy-6-fluorophenyl)-3-methylpyrrolidin-2-one Chemical compound CCOC1=CC=CC(F)=C1C1N(CC=2C=C(OC(F)F)C=CC=2)C(=O)C(C)C1 QBJBEALOLFIXNB-UHFFFAOYSA-N 0.000 claims description 2
- NARHBIYXYMDLPF-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(OC(F)F)C=CC=2)C(=O)CCC1 NARHBIYXYMDLPF-UHFFFAOYSA-N 0.000 claims description 2
- GFQGXIOHOSSFLL-UHFFFAOYSA-N 1-[[3-chloro-4-(difluoromethoxy)phenyl]methyl]-5-(2,6-dimethoxyphenyl)-3-methylpyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(Cl)C(OC(F)F)=CC=2)C(=O)C(C)C1 GFQGXIOHOSSFLL-UHFFFAOYSA-N 0.000 claims description 2
- VYCRLUGMYIJYFL-UHFFFAOYSA-N 1-[[3-chloro-4-(difluoromethoxy)phenyl]methyl]-5-(2-ethoxy-6-fluorophenyl)-3-methylpyrrolidin-2-one Chemical compound CCOC1=CC=CC(F)=C1C1N(CC=2C=C(Cl)C(OC(F)F)=CC=2)C(=O)C(C)C1 VYCRLUGMYIJYFL-UHFFFAOYSA-N 0.000 claims description 2
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- SFFPOJXQDRAKDL-UHFFFAOYSA-N 1-[[4-(cyclopropylmethoxy)phenyl]methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=CC(OCC3CC3)=CC=2)C(=O)CCC1 SFFPOJXQDRAKDL-UHFFFAOYSA-N 0.000 claims description 2
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- HJECQBRQQKEBMC-UHFFFAOYSA-N 1-[[4-(trifluoromethoxy)phenyl]methyl]-6-(2,4,6-trimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC(OC)=CC(OC)=C1C1N(CC=2C=CC(OC(F)(F)F)=CC=2)C(=O)CCC1 HJECQBRQQKEBMC-UHFFFAOYSA-N 0.000 claims description 2
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- OMGGLDITIJYJNZ-UHFFFAOYSA-N 1-[[5-chloro-6-(difluoromethoxy)pyridin-3-yl]methyl]-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(Cl)C(OC(F)F)=NC=2)C(=O)CC1 OMGGLDITIJYJNZ-UHFFFAOYSA-N 0.000 claims description 2
- CKHQMMOXQOHIAU-UHFFFAOYSA-N 1-[[5-chloro-6-(difluoromethoxy)pyridin-3-yl]methyl]-6-(2,6-dimethoxyphenyl)piperidin-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(Cl)C(OC(F)F)=NC=2)C(=O)CCC1 CKHQMMOXQOHIAU-UHFFFAOYSA-N 0.000 claims description 2
- OWJWDXDGABGHJK-UHFFFAOYSA-N 1-[[5-chloro-6-(difluoromethoxy)pyridin-3-yl]methyl]-7-(2,6-dimethoxyphenyl)azepan-2-one Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=C(Cl)C(OC(F)F)=NC=2)C(=O)CCCC1 OWJWDXDGABGHJK-UHFFFAOYSA-N 0.000 claims description 2
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- NZSFTRSYJIFQBH-UHFFFAOYSA-N [4-(difluoromethoxy)pyridin-2-yl]methanol Chemical compound OCC1=CC(OC(F)F)=CC=N1 NZSFTRSYJIFQBH-UHFFFAOYSA-N 0.000 description 2
- VZBZNHKSOYUKMG-UHFFFAOYSA-N [5-chloro-6-(difluoromethoxy)pyridin-3-yl]methanol Chemical compound OCC1=CN=C(OC(F)F)C(Cl)=C1 VZBZNHKSOYUKMG-UHFFFAOYSA-N 0.000 description 2
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- XCYVPSNADNRFPM-UHFFFAOYSA-N [6-(difluoromethoxy)pyridin-2-yl]methanol Chemical compound OCC1=CC=CC(OC(F)F)=N1 XCYVPSNADNRFPM-UHFFFAOYSA-N 0.000 description 2
- YZZNTAXNTQWXQP-UHFFFAOYSA-N [6-(difluoromethoxy)pyridin-3-yl]methanol Chemical compound OCC1=CC=C(OC(F)F)N=C1 YZZNTAXNTQWXQP-UHFFFAOYSA-N 0.000 description 2
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
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- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- QFGXAEFJJINHAI-UHFFFAOYSA-N dibenzothiophene-2-carbaldehyde Chemical compound C1=CC=C2C3=CC(C=O)=CC=C3SC2=C1 QFGXAEFJJINHAI-UHFFFAOYSA-N 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Natural products CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 2
- AALCMHQSZBRNHY-UHFFFAOYSA-N ethyl 2-(2,6-dimethoxyphenyl)-2-[[4-(trifluoromethoxy)phenyl]methylamino]acetate Chemical compound COC=1C=CC=C(OC)C=1C(C(=O)OCC)NCC1=CC=C(OC(F)(F)F)C=C1 AALCMHQSZBRNHY-UHFFFAOYSA-N 0.000 description 2
- OPKSSMREKMTWAL-UHFFFAOYSA-N ethyl 2-(2,6-dimethoxyphenyl)-4,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidine-3-carboxylate Chemical compound O=C1C(=O)C(C(=O)OCC)C(C=2C(=CC=CC=2OC)OC)N1CC1=CC=C(OC(F)(F)F)C=C1 OPKSSMREKMTWAL-UHFFFAOYSA-N 0.000 description 2
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- CDKZIXFZCIEWTP-UHFFFAOYSA-N ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate Chemical compound CCOC(=O)C(C)CC(N)C1=C(F)C=CC=C1OCC CDKZIXFZCIEWTP-UHFFFAOYSA-N 0.000 description 2
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- FEKFXYRBNANTDE-UHFFFAOYSA-N ethyl 6-(tert-butylsulfinylamino)-6-(2,6-dimethoxyphenyl)hexanoate Chemical compound CCOC(=O)CCCCC(NS(=O)C(C)(C)C)C1=C(OC)C=CC=C1OC FEKFXYRBNANTDE-UHFFFAOYSA-N 0.000 description 2
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- 239000012634 fragment Substances 0.000 description 2
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 2
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- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
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- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 2
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
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- 230000014759 maintenance of location Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000003818 metabolic dysfunction Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- KRONQPLREOSAER-UHFFFAOYSA-N methyl 2-(4-methyl-1,3-thiazol-2-yl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2SC=C(C)N=2)=C1 KRONQPLREOSAER-UHFFFAOYSA-N 0.000 description 2
- LSIMUOASCLPFQN-UHFFFAOYSA-N methyl 2-(5-methyl-1,3-thiazol-2-yl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2SC(C)=CN=2)=C1 LSIMUOASCLPFQN-UHFFFAOYSA-N 0.000 description 2
- YQZJQGVVANWHLX-UHFFFAOYSA-N methyl 2-(difluoromethoxy)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(OC(F)F)=C1 YQZJQGVVANWHLX-UHFFFAOYSA-N 0.000 description 2
- BTDLOJXTXLEZRT-UHFFFAOYSA-N methyl 2-chloro-5-pyridin-2-ylbenzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(C=2N=CC=CC=2)=C1 BTDLOJXTXLEZRT-UHFFFAOYSA-N 0.000 description 2
- MSNFOUCVUZMALD-UHFFFAOYSA-N methyl 2-methyl-1,3-benzothiazole-5-carboxylate Chemical compound COC(=O)C1=CC=C2SC(C)=NC2=C1 MSNFOUCVUZMALD-UHFFFAOYSA-N 0.000 description 2
- YKDLQQWJZYJXKD-UHFFFAOYSA-N methyl 2-phenoxy-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1=CSC(OC=2C=CC=CC=2)=N1 YKDLQQWJZYJXKD-UHFFFAOYSA-N 0.000 description 2
- LEYRXQSMZUXPHE-UHFFFAOYSA-N methyl 2-pyrazol-1-ylpyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(N2N=CC=C2)=C1 LEYRXQSMZUXPHE-UHFFFAOYSA-N 0.000 description 2
- SHNLPSIFBMTXDB-UHFFFAOYSA-N methyl 2-pyridin-2-ylpyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C=2N=CC=CC=2)=C1 SHNLPSIFBMTXDB-UHFFFAOYSA-N 0.000 description 2
- SJSMPDRHSQNTKC-UHFFFAOYSA-N methyl 3-chloro-5-pyridin-2-ylbenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(C=2N=CC=CC=2)=C1 SJSMPDRHSQNTKC-UHFFFAOYSA-N 0.000 description 2
- DEDDVJYIFRNDRK-UHFFFAOYSA-N methyl 4-(difluoromethoxy)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC(OC(F)F)=CC=N1 DEDDVJYIFRNDRK-UHFFFAOYSA-N 0.000 description 2
- OBATZCGETGNQEY-UHFFFAOYSA-N methyl 4-(tert-butylsulfinylamino)-4-(2,6-dimethoxyphenyl)butanoate Chemical compound COC(=O)CCC(NS(=O)C(C)(C)C)C1=C(OC)C=CC=C1OC OBATZCGETGNQEY-UHFFFAOYSA-N 0.000 description 2
- VFMUWVLBGWRPPP-UHFFFAOYSA-N methyl 4-(tert-butylsulfinylamino)-4-(2-phenylphenyl)butanoate Chemical compound COC(=O)CCC(NS(=O)C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 VFMUWVLBGWRPPP-UHFFFAOYSA-N 0.000 description 2
- HTLLWFJNIRKIJO-UHFFFAOYSA-N methyl 4-amino-4-(2-phenylphenyl)butanoate Chemical compound COC(=O)CCC(N)C1=CC=CC=C1C1=CC=CC=C1 HTLLWFJNIRKIJO-UHFFFAOYSA-N 0.000 description 2
- QCPCORWMMFZMIQ-UHFFFAOYSA-N methyl 4-oxo-1h-pyridine-2-carboxylate Chemical compound COC(=O)C1=CC(O)=CC=N1 QCPCORWMMFZMIQ-UHFFFAOYSA-N 0.000 description 2
- DGBNPXOYPZVAHU-UHFFFAOYSA-N methyl 5-(2,6-dimethoxyphenyl)-3,3-dimethyl-5-oxopentanoate Chemical compound COC(=O)CC(C)(C)CC(=O)C1=C(OC)C=CC=C1OC DGBNPXOYPZVAHU-UHFFFAOYSA-N 0.000 description 2
- DIUISNHQBFQVFQ-UHFFFAOYSA-N methyl 5-(2,6-dimethoxyphenyl)-3-methyl-5-oxopentanoate Chemical compound COC(=O)CC(C)CC(=O)C1=C(OC)C=CC=C1OC DIUISNHQBFQVFQ-UHFFFAOYSA-N 0.000 description 2
- ACAQLBYYHMQXQW-UHFFFAOYSA-N methyl 5-(2,6-dimethoxyphenyl)-5-(quinolin-3-ylmethylamino)pentanoate Chemical compound C=1N=C2C=CC=CC2=CC=1CNC(CCCC(=O)OC)C1=C(OC)C=CC=C1OC ACAQLBYYHMQXQW-UHFFFAOYSA-N 0.000 description 2
- OCIRFWWKOVYGEN-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(2,3-dihydro-1,4-benzodioxin-5-yl)pentanoate Chemical compound O1CCOC2=C1C=CC=C2C(NS(=O)C(C)(C)C)CCCC(=O)OC OCIRFWWKOVYGEN-UHFFFAOYSA-N 0.000 description 2
- REDFZRZCWQEPHR-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(2,4-dimethoxypyridin-3-yl)pentanoate Chemical compound COC(=O)CCCC(NS(=O)C(C)(C)C)C1=C(OC)C=CN=C1OC REDFZRZCWQEPHR-UHFFFAOYSA-N 0.000 description 2
- BWKYAXLNBMFIOS-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(2,6-dimethoxyphenyl)pentanoate Chemical compound COC(=O)CCCC(NS(=O)C(C)(C)C)C1=C(OC)C=CC=C1OC BWKYAXLNBMFIOS-UHFFFAOYSA-N 0.000 description 2
- UNHLAJRNEUSMLG-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(2-phenylphenyl)pentanoate Chemical compound COC(=O)CCCC(NS(=O)C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 UNHLAJRNEUSMLG-UHFFFAOYSA-N 0.000 description 2
- WRIBGKHWYZBWOD-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(3,5-dimethoxypyridin-4-yl)pentanoate Chemical compound COC(=O)CCCC(NS(=O)C(C)(C)C)C1=C(OC)C=NC=C1OC WRIBGKHWYZBWOD-UHFFFAOYSA-N 0.000 description 2
- QFXFJVIOXCWMCX-UHFFFAOYSA-N methyl 5-(tert-butylsulfinylamino)-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate Chemical compound COC(=O)CCCC(NS(=O)C(C)(C)C)C1=C(OC)N=CN=C1OC QFXFJVIOXCWMCX-UHFFFAOYSA-N 0.000 description 2
- OCDABRUVMXCZAS-UHFFFAOYSA-N methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate Chemical compound COC(=O)CCCC(N)C1=C(OC)C=CN=C1OC OCDABRUVMXCZAS-UHFFFAOYSA-N 0.000 description 2
- XXGROQOASIUDSH-UHFFFAOYSA-N methyl 5-amino-5-(2-methoxynaphthalen-1-yl)pentanoate Chemical compound C1=CC=C2C(C(N)CCCC(=O)OC)=C(OC)C=CC2=C1 XXGROQOASIUDSH-UHFFFAOYSA-N 0.000 description 2
- BCMGDPIRDGXMBH-UHFFFAOYSA-N methyl 5-amino-5-(2-phenylphenyl)pentanoate Chemical compound COC(=O)CCCC(N)C1=CC=CC=C1C1=CC=CC=C1 BCMGDPIRDGXMBH-UHFFFAOYSA-N 0.000 description 2
- YWSBJHZQAXWUEG-UHFFFAOYSA-N methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate Chemical compound COC(=O)CCCC(N)C1=C(OC)C=NC=C1OC YWSBJHZQAXWUEG-UHFFFAOYSA-N 0.000 description 2
- XGUCLTNCHVUKGN-UHFFFAOYSA-N methyl 5-chloro-6-(difluoromethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(OC(F)F)C(Cl)=C1 XGUCLTNCHVUKGN-UHFFFAOYSA-N 0.000 description 2
- NVEWDXZTSKXQJB-UHFFFAOYSA-N methyl 5-chloro-6-oxo-1h-pyridine-3-carboxylate Chemical compound COC(=O)C1=CNC(=O)C(Cl)=C1 NVEWDXZTSKXQJB-UHFFFAOYSA-N 0.000 description 2
- WGXOSLDTCWYDFN-UHFFFAOYSA-N methyl 5-oxo-5-(2,4,6-trimethoxyphenyl)pentanoate Chemical compound COC(=O)CCCC(=O)C1=C(OC)C=C(OC)C=C1OC WGXOSLDTCWYDFN-UHFFFAOYSA-N 0.000 description 2
- YBTZROCKNUIONO-UHFFFAOYSA-N methyl 5-oxopentanoate Chemical compound COC(=O)CCCC=O YBTZROCKNUIONO-UHFFFAOYSA-N 0.000 description 2
- LRPHDKSHVUDHNF-UHFFFAOYSA-N methyl 6-(1,3-thiazol-2-yl)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(C=2SC=CN=2)=N1 LRPHDKSHVUDHNF-UHFFFAOYSA-N 0.000 description 2
- BJMNOUHMXFCJPB-UHFFFAOYSA-N methyl 6-(difluoromethoxy)pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(OC(F)F)=N1 BJMNOUHMXFCJPB-UHFFFAOYSA-N 0.000 description 2
- LFIBWARSZWWCFE-UHFFFAOYSA-N methyl 6-(difluoromethoxy)pyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(OC(F)F)N=C1 LFIBWARSZWWCFE-UHFFFAOYSA-N 0.000 description 2
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- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- JKCUTYHCGWGNTF-UHFFFAOYSA-N ethyl 2-(2-fluoro-6-methoxyphenyl)-4,5-dioxo-1-[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidine-3-carboxylate Chemical compound O=C1C(=O)C(C(=O)OCC)C(C=2C(=CC=CC=2F)OC)N1CC1=CC=C(OC(F)(F)F)C=C1 JKCUTYHCGWGNTF-UHFFFAOYSA-N 0.000 description 1
- LKRRWYZRWNSFBL-UHFFFAOYSA-N ethyl 4-(tert-butylsulfinylamino)-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate Chemical compound CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)C1=C(F)C=CC=C1OC LKRRWYZRWNSFBL-UHFFFAOYSA-N 0.000 description 1
- VKJYHSJJJZKQOL-UHFFFAOYSA-N ethyl 4-amino-2-methyl-4-(2-phenylphenyl)butanoate Chemical compound CCOC(=O)C(C)CC(N)C1=CC=CC=C1C1=CC=CC=C1 VKJYHSJJJZKQOL-UHFFFAOYSA-N 0.000 description 1
- FTJATNSAFIFEDU-UHFFFAOYSA-N ethyl hept-6-enoate Chemical compound CCOC(=O)CCCCC=C FTJATNSAFIFEDU-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000008713 feedback mechanism Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
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- 238000000799 fluorescence microscopy Methods 0.000 description 1
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- 239000011874 heated mixture Substances 0.000 description 1
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- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YOWKNNKTQWCYNC-UHFFFAOYSA-N methyl 2-bromo-1,3-thiazole-4-carboxylate Chemical compound COC(=O)C1=CSC(Br)=N1 YOWKNNKTQWCYNC-UHFFFAOYSA-N 0.000 description 1
- KKOUHTMLFUAAGG-UHFFFAOYSA-N methyl 2-chloropyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(Cl)=C1 KKOUHTMLFUAAGG-UHFFFAOYSA-N 0.000 description 1
- DATHOCDTDDUESC-UHFFFAOYSA-N methyl 2-oxo-1h-pyridine-4-carboxylate Chemical compound COC(=O)C=1C=CNC(=O)C=1 DATHOCDTDDUESC-UHFFFAOYSA-N 0.000 description 1
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- IFOUTYPZEIPAOH-UHFFFAOYSA-N methyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate Chemical compound COC(=O)C(C)CC(N)C1=C(OC)C=CC=C1OC IFOUTYPZEIPAOH-UHFFFAOYSA-N 0.000 description 1
- SRXOJMOGPYFZKC-UHFFFAOYSA-N methyl 4-chloro-4-oxobutanoate Chemical compound COC(=O)CCC(Cl)=O SRXOJMOGPYFZKC-UHFFFAOYSA-N 0.000 description 1
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- DGXFSAJLICGEKF-UHFFFAOYSA-N tert-butyl 3-(2,6-dimethoxyphenyl)-2,5-dioxo-4-[[4-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate Chemical compound COC1=CC=CC(OC)=C1C1C(=O)N(C(=O)OC(C)(C)C)CC(=O)N1CC1=CC=C(OC(F)(F)F)C=C1 DGXFSAJLICGEKF-UHFFFAOYSA-N 0.000 description 1
- SFCSDBVVQFAEQD-UHFFFAOYSA-N tert-butyl 3-(2,6-dimethoxyphenyl)-5-oxo-4-[[4-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate Chemical compound COC1=CC=CC(OC)=C1C1N(CC=2C=CC(OC(F)(F)F)=CC=2)C(=O)CN(C(=O)OC(C)(C)C)C1 SFCSDBVVQFAEQD-UHFFFAOYSA-N 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
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- 238000005809 transesterification reaction Methods 0.000 description 1
- WUOFQGMXQCSPPV-UHFFFAOYSA-N tributyl(1,3-thiazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CS1 WUOFQGMXQCSPPV-UHFFFAOYSA-N 0.000 description 1
- YYQKQPYPLADFMK-UHFFFAOYSA-N tributyl(1,3-thiazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CSC=N1 YYQKQPYPLADFMK-UHFFFAOYSA-N 0.000 description 1
- GOWNSHUNTJWVOM-UHFFFAOYSA-N tributyl(1,3-thiazol-5-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=CS1 GOWNSHUNTJWVOM-UHFFFAOYSA-N 0.000 description 1
- PZPGNMUMILSRSX-UHFFFAOYSA-N tributyl-(4-methyl-1,3-thiazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC(C)=CS1 PZPGNMUMILSRSX-UHFFFAOYSA-N 0.000 description 1
- HDWHGDDNMJOCCU-UHFFFAOYSA-N trimethyl(pyridin-2-yl)stannane Chemical compound C[Sn](C)(C)C1=CC=CC=N1 HDWHGDDNMJOCCU-UHFFFAOYSA-N 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Landscapes
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pyrrole Compounds (AREA)
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| IBPCT/IB2010/055105 | 2010-11-10 | ||
| IB2010055105 | 2010-11-10 | ||
| PCT/IB2011/054993 WO2012063207A1 (en) | 2010-11-10 | 2011-11-09 | Lactam derivatives useful as orexin receptor antagonists |
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| WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
| LT2855453T (lt) | 2012-06-04 | 2017-02-27 | Actelion Pharmaceuticals Ltd. | Benzimidazolo prolino dariniai |
| HUE042374T2 (hu) | 2012-06-13 | 2019-06-28 | Incyte Holdings Corp | Szubsztituált triciklusos vegyületek mint FGFR inhibitorok |
| NZ704171A (en) | 2012-07-19 | 2017-10-27 | Cayman Chemical Co Inc | Difluorolactam compositions for ep4-mediated osteo related diseases and conditions |
| US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
| EP3763367A1 (en) | 2012-12-06 | 2021-01-13 | Celgene Quanticel Research, Inc. | Pyridine-pyrazole derivatives as histone demethylase inhibitors |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| US9914725B2 (en) | 2013-03-15 | 2018-03-13 | Cayman Chemical Company, Inc. | Methods of synthesizing a difluorolactam analog |
| EA201591793A1 (ru) | 2013-03-15 | 2016-01-29 | Кайман Кемикал Компани, Инк. | Лактамные соединения в качестве селективных агонистов ep4-рецепторов для применения при лечении опосредованных ep4 заболеваний и состояний |
| US9676712B2 (en) | 2013-03-15 | 2017-06-13 | Cayman Chemical Company, Inc. | Lactam compounds as EP4 receptor-selective agonists for use in the treatment of EP4-mediated diseases and conditions |
| KR102469849B1 (ko) | 2013-04-19 | 2022-11-23 | 인사이트 홀딩스 코포레이션 | Fgfr 저해제로서 이환식 헤테로사이클 |
| CN104133004A (zh) * | 2013-05-03 | 2014-11-05 | 上海美迪西生物医药有限公司 | 血浆样品中2,3-吲哚醌的浓度的测定方法 |
| CA2910398A1 (en) | 2013-07-19 | 2015-01-22 | Cayman Chemical Company, Inc. | Methods, systems, and compositions for promoting bone growth |
| PT3077389T (pt) | 2013-12-03 | 2017-12-15 | Idorsia Pharmaceuticals Ltd | Forma cristalina de (s)-(2-(6-cloro-7-metil-1hbenzo[d]imidazol-2-il)-2-metilpirrolidin-1-il)(5-metoxi-2-(2h-1,2,3-triazol-2-il)fenil)metanona e a sua utilização como como antagonistas do receptor de orexina |
| UA119151C2 (uk) | 2013-12-03 | 2019-05-10 | Ідорсія Фармасьютікалз Лтд | КРИСТАЛІЧНА СОЛЬОВА ФОРМА (S)-(2-(6-ХЛОР-7-МЕТИЛ-1H-БЕНЗО[d]ІМІДАЗОЛ-2-ІЛ)-2-МЕТИЛПІРОЛІДИН-1-ІЛ)(5-МЕТОКСИ-2-(2H-1,2,3-ТРИАЗОЛ-2-ІЛ)ФЕНІЛ)МЕТАНОНУ ЯК АНТАГОНІСТ ОРЕКСИНОВОГО РЕЦЕПТОРА |
| SI3077391T1 (sl) | 2013-12-04 | 2018-11-30 | Idorsia Pharmaceuticals Ltd | Uporaba benzimidazol-prolinskih derivatov |
| WO2015088864A1 (en) * | 2013-12-09 | 2015-06-18 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-3-ester-4-ether orexin receptor antagonists |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| AU2016219822B2 (en) | 2015-02-20 | 2020-07-09 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
| CA3027500A1 (en) * | 2016-06-21 | 2017-12-28 | X4 Pharmaceuticals, Inc. | Cxcr4 inhibitors and uses thereof |
| EP3808748A1 (en) | 2016-06-21 | 2021-04-21 | X4 Pharmaceuticals, Inc. | Substituted piperidines as cxcr4-inhibitors |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
| US11434201B2 (en) * | 2017-08-02 | 2022-09-06 | Vertex Pharmaceuticals Incorporated | Processes for preparing pyrrolidine compounds |
| EP4309737A3 (en) | 2018-05-04 | 2024-03-27 | Incyte Corporation | Solid forms of an fgfr inhibitor and processes for preparing the same |
| EP3788046B1 (en) | 2018-05-04 | 2025-12-10 | Incyte Corporation | Salts of an fgfr inhibitor |
| US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
| US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| CN110563565A (zh) * | 2019-09-02 | 2019-12-13 | 南通大学 | 一种3-溴-6-氟-2-甲氧基苯甲醛的合成方法 |
| US12122767B2 (en) | 2019-10-01 | 2024-10-22 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| WO2021076602A1 (en) | 2019-10-14 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| JP7720840B2 (ja) | 2019-12-04 | 2025-08-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
| KR20220131900A (ko) | 2019-12-04 | 2022-09-29 | 인사이트 코포레이션 | Fgfr 억제제의 유도체 |
| US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| CA3215903A1 (en) | 2021-04-12 | 2022-10-20 | Incyte Corporation | Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent |
| WO2022261159A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| EP4352059A1 (en) | 2021-06-09 | 2024-04-17 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| CN114456184B (zh) * | 2022-02-21 | 2023-08-22 | 南华大学附属第一医院 | 一种3-芳基异喹啉衍生物及其制备与应用 |
| CN115047127B (zh) * | 2022-04-25 | 2024-03-08 | 中国检验检疫科学研究院 | 一种利用挥发性代谢组学技术鉴别nfc和fc橙汁的方法 |
| TW202409023A (zh) | 2022-07-14 | 2024-03-01 | 美商富曼西公司 | 除草苯并𠯤 |
| WO2025111184A1 (en) | 2023-11-21 | 2025-05-30 | Fmc Corporation | Substituted tetrahydroquinoline and tetrahydroquinoxaline herbicides |
| WO2025224168A1 (en) | 2024-04-24 | 2025-10-30 | Idorsia Pharmaceuticals Ltd | Aryl sulfone and sulfanone derivatives as orexin receptor modulators |
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| GB0115862D0 (en) * | 2001-06-28 | 2001-08-22 | Smithkline Beecham Plc | Compounds |
| EP1537089A4 (en) * | 2002-07-23 | 2008-04-16 | Cytokinetics Inc | CONNECTIONS, COMPOSITIONS AND PROCEDURES |
| HRP20150371T1 (hr) | 2004-03-01 | 2015-05-08 | Actelion Pharmaceuticals Ltd. | Supstituirani derivati 1,2,3,4-tetrahidroizokinolina |
| EP1888563A1 (en) * | 2005-05-23 | 2008-02-20 | Merck & Co., Inc. | Proline bis-amide orexin receptor antagonists |
| AU2007226203A1 (en) | 2006-03-15 | 2007-09-20 | Actelion Pharmaceuticals Ltd | Tetrahydroisoquinoline derivatives to enhance memory function |
| PL2069332T3 (pl) * | 2006-08-15 | 2011-07-29 | Actelion Pharmaceuticals Ltd | Związki azetydynowe jako antagoniści receptorów oreksynowych |
| EP2079690B1 (en) * | 2006-09-29 | 2010-09-15 | Actelion Pharmaceuticals Ltd. | 3-aza-bicyclo[3.1.0]hexane derivatives |
| CL2008000836A1 (es) * | 2007-03-26 | 2008-11-07 | Actelion Pharmaceuticals Ltd | Compuestos derivados de tiazolidina, antagonistas del receptor de orexina; composicion farmaceutica que los comprende; y su uso en el tratamiento de neurosis emocional, depresion grave, trastornos psicoticos, alzheimer, parkinson, dolor, entre otras. |
| EA201070091A1 (ru) * | 2007-07-03 | 2010-06-30 | Глэксо Груп Лимитед | Производные пиперидина, пригодные в качестве антагонистов рецептора орексина |
| CA2694993A1 (en) * | 2007-08-15 | 2009-02-19 | Actelion Pharmaceuticals Ltd | 1,2-diamido-ethylene derivatives |
| EP2207778A2 (en) * | 2007-09-24 | 2010-07-21 | Actelion Pharmaceuticals Ltd. | Pyrrolidines and piperidines as orexin receptor antagonists |
| PE20091010A1 (es) | 2007-10-10 | 2009-08-08 | Actelion Pharmaceuticals Ltd | Derivados de tetrahidroquinolina |
| CA2722347A1 (en) * | 2008-04-30 | 2009-11-05 | Actelion Pharmaceuticals Ltd | Piperidine and pyrrolidine compounds |
| JP2011522878A (ja) * | 2008-06-11 | 2011-08-04 | アクテリオン ファーマシューティカルズ リミテッド | オレキシン受容体拮抗薬としてのテトラゾール化合物 |
| CA2739919A1 (en) * | 2008-10-21 | 2010-04-29 | Merck Sharp & Dohme Corp. | 2,4-disubstituted pyrrolidine orexin receptor antagonists |
| US20120088759A1 (en) | 2009-05-12 | 2012-04-12 | Hamed Aissaoui | Thiazolidin-4-one and [1,3]-thiazinan-4-one compounds as orexin receptor antagonists |
| JP5612080B2 (ja) | 2009-05-12 | 2014-10-22 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | 新規なオキサゾリジノン誘導体 |
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2011
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- 2011-11-09 CA CA2815179A patent/CA2815179A1/en not_active Abandoned
- 2011-11-09 EP EP11820868.5A patent/EP2638008B1/en not_active Not-in-force
- 2011-11-09 US US13/884,741 patent/US9242970B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012063207A1 (en) | 2012-05-18 |
| CN103201261A (zh) | 2013-07-10 |
| US9242970B2 (en) | 2016-01-26 |
| US20130237525A1 (en) | 2013-09-12 |
| EP2638008A1 (en) | 2013-09-18 |
| JP2013545744A (ja) | 2013-12-26 |
| EP2638008B1 (en) | 2015-07-01 |
| CA2815179A1 (en) | 2012-05-18 |
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