JP5827943B2 - ピリド［４，３−ｂ］インドールおよびその使用方法 - Google Patents
ピリド［４，３−ｂ］インドールおよびその使用方法 Download PDFInfo
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- JP5827943B2 JP5827943B2 JP2012508752A JP2012508752A JP5827943B2 JP 5827943 B2 JP5827943 B2 JP 5827943B2 JP 2012508752 A JP2012508752 A JP 2012508752A JP 2012508752 A JP2012508752 A JP 2012508752A JP 5827943 B2 JP5827943 B2 JP 5827943B2
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- Prior art keywords
- substituted
- methyl
- unsubstituted
- pyrido
- alkyl
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- 238000000034 method Methods 0.000 title description 70
- RDMFHRSPDKWERA-UHFFFAOYSA-N 5H-Pyrido[4,3-b]indole Chemical compound C1=NC=C2C3=CC=CC=C3NC2=C1 RDMFHRSPDKWERA-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 461
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- -1 aminocarbonylamino, aminocarbonyloxy, aminosulfonyl Chemical group 0.000 claims description 148
- 125000001072 heteroaryl group Chemical group 0.000 claims description 126
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 125
- 150000003839 salts Chemical class 0.000 claims description 118
- 125000003118 aryl group Chemical group 0.000 claims description 90
- 125000005843 halogen group Chemical group 0.000 claims description 72
- 208000024891 symptom Diseases 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 65
- 239000012453 solvate Substances 0.000 claims description 61
- 208000010877 cognitive disease Diseases 0.000 claims description 58
- 125000004076 pyridyl group Chemical group 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 102000000543 Histamine Receptors Human genes 0.000 claims description 53
- 108010002059 Histamine Receptors Proteins 0.000 claims description 53
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 49
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 208000028698 Cognitive impairment Diseases 0.000 claims description 37
- 125000003107 substituted aryl group Chemical group 0.000 claims description 35
- 125000004442 acylamino group Chemical group 0.000 claims description 29
- 125000005102 carbonylalkoxy group Chemical group 0.000 claims description 29
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 28
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 28
- 125000004104 aryloxy group Chemical group 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 24
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000000304 alkynyl group Chemical group 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 21
- 125000005589 carbonylalkylenealkoxy group Chemical group 0.000 claims description 21
- 125000004001 thioalkyl group Chemical group 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 150000003573 thiols Chemical class 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 14
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 10
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 10
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 8
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
- 230000019771 cognition Effects 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 5
- PXSYMVMGRYBTRY-UHFFFAOYSA-N 2,8-dimethyl-5-[(2-phenyl-1,3-dioxolan-2-yl)methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC1(C=2C=CC=CC=2)OCCO1 PXSYMVMGRYBTRY-UHFFFAOYSA-N 0.000 claims description 4
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
- NCKQTYFVEMJDIE-UHFFFAOYSA-N ethyl 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(4-fluorophenyl)butanoate Chemical compound C1=2CCN(C)CC=2C2=CC(C)=CC=C2N1CC(CC(=O)OCC)C1=CC=C(F)C=C1 NCKQTYFVEMJDIE-UHFFFAOYSA-N 0.000 claims description 4
- KSHIBYPIOGCPDH-UHFFFAOYSA-N 2,8-dimethyl-5-[(2-pyridin-3-yl-1,3-dioxolan-2-yl)methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC1(C=2C=NC=CC=2)OCCO1 KSHIBYPIOGCPDH-UHFFFAOYSA-N 0.000 claims description 3
- SDDGVYKUUGHLJD-UHFFFAOYSA-N 2-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-1-(4-fluorophenyl)-1-phenylethanol Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(O)(C=1C=CC(F)=CC=1)C1=CC=CC=C1 SDDGVYKUUGHLJD-UHFFFAOYSA-N 0.000 claims description 3
- CMBIIHJHLILBSO-UHFFFAOYSA-N 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(4-fluorophenyl)-n-methylbutanamide Chemical compound C1=2CCN(C)CC=2C2=CC(C)=CC=C2N1CC(CC(=O)NC)C1=CC=C(F)C=C1 CMBIIHJHLILBSO-UHFFFAOYSA-N 0.000 claims description 3
- WPRCVURQRSQRDQ-UHFFFAOYSA-N 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(4-fluorophenyl)butanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(CC(O)=O)C1=CC=C(F)C=C1 WPRCVURQRSQRDQ-UHFFFAOYSA-N 0.000 claims description 3
- WIFQQALACNYNTA-UHFFFAOYSA-N 5-[[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]methyl]-2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC1(C=2C=CC(F)=CC=2)OCCO1 WIFQQALACNYNTA-UHFFFAOYSA-N 0.000 claims description 3
- NXUKGYHIRFZZSE-UHFFFAOYSA-N 8-chloro-2-methyl-5-[[2-(2-methylpyridin-4-yl)-1,3-dioxolan-2-yl]methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC1(C=2C=C(C)N=CC=2)OCCO1 NXUKGYHIRFZZSE-UHFFFAOYSA-N 0.000 claims description 3
- XNSPQXHRNZQWTD-UHFFFAOYSA-N 8-chloro-2-methyl-5-[[2-(6-methylpyridin-3-yl)-1,3-dioxolan-2-yl]methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC1(C=2C=NC(C)=CC=2)OCCO1 XNSPQXHRNZQWTD-UHFFFAOYSA-N 0.000 claims description 3
- VAVLJFSBBMYFKS-UHFFFAOYSA-N 8-chloro-5-[[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]methyl]-2-methyl-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC1(C=2C=CC(Cl)=CC=2)OCCO1 VAVLJFSBBMYFKS-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- CEHPIEPEGHHJJZ-UHFFFAOYSA-N 2,8-dimethyl-5-[(2-pyrimidin-4-yl-1,3-dioxolan-2-yl)methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC1(C=2N=CN=CC=2)OCCO1 CEHPIEPEGHHJJZ-UHFFFAOYSA-N 0.000 claims description 2
- CRBBHOGWBDLVRA-UHFFFAOYSA-N 2-methyl-5-[(2-pyridin-4-yl-1,3-dioxolan-2-yl)methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC=CC=C1N2CC1(C=2C=CN=CC=2)OCCO1 CRBBHOGWBDLVRA-UHFFFAOYSA-N 0.000 claims description 2
- QXTAYFISWQSPRT-UHFFFAOYSA-N 3-(2,4-difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)butanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(CC(O)=O)C1=CC=C(F)C=C1F QXTAYFISWQSPRT-UHFFFAOYSA-N 0.000 claims description 2
- WXTVXXFBPXVBTO-UHFFFAOYSA-N 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(2-fluorophenyl)-n-methylbutanamide Chemical compound C1=2CCN(C)CC=2C2=CC(C)=CC=C2N1CC(CC(=O)NC)C1=CC=CC=C1F WXTVXXFBPXVBTO-UHFFFAOYSA-N 0.000 claims description 2
- OPMKRVRPBZAAMY-UHFFFAOYSA-N 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(2-fluorophenyl)butanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(CC(O)=O)C1=CC=CC=C1F OPMKRVRPBZAAMY-UHFFFAOYSA-N 0.000 claims description 2
- HFYNOYFHGWDKRQ-UHFFFAOYSA-N 4-(8-chloro-2-methyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(4-chlorophenyl)butanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC(CC(O)=O)C1=CC=C(Cl)C=C1 HFYNOYFHGWDKRQ-UHFFFAOYSA-N 0.000 claims description 2
- QNTGEWKKHKULDO-UHFFFAOYSA-N 4-(8-chloro-2-methyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-(4-methoxyphenyl)butanoic acid Chemical compound C1=CC(OC)=CC=C1C(CC(O)=O)CN1C2=CC=C(Cl)C=C2C2=C1CCN(C)C2 QNTGEWKKHKULDO-UHFFFAOYSA-N 0.000 claims description 2
- ZHAOCYAINPJTBG-UHFFFAOYSA-N 4-(8-chloro-2-methyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-pyrimidin-4-ylbutanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC(CC(O)=O)C1=CC=NC=N1 ZHAOCYAINPJTBG-UHFFFAOYSA-N 0.000 claims description 2
- WDTMBTSDKCPDBW-UHFFFAOYSA-N 8-chloro-2-methyl-5-[2-(3-methylpyridin-4-yl)butyl]-3,4-dihydro-1H-pyrido[4,3-b]indole Chemical compound CCC(CN1C2=C(CN(C)CC2)C2=CC(Cl)=CC=C12)C1=C(C)C=NC=C1 WDTMBTSDKCPDBW-UHFFFAOYSA-N 0.000 claims description 2
- FQGQMNNNLBPFDH-UHFFFAOYSA-N 8-chloro-2-methyl-5-[[2-(3-methylpyridin-4-yl)-1,3-dioxolan-2-yl]methyl]-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC1(C=2C(=CN=CC=2)C)OCCO1 FQGQMNNNLBPFDH-UHFFFAOYSA-N 0.000 claims description 2
- VPCVVOOGNDRGFN-UHFFFAOYSA-N 8-chloro-5-[[2-(2-chlorophenyl)-1,3-dioxolan-2-yl]methyl]-2-methyl-3,4-dihydro-1h-pyrido[4,3-b]indole Chemical compound C1N(C)CCC2=C1C1=CC(Cl)=CC=C1N2CC1(C=2C(=CC=CC=2)Cl)OCCO1 VPCVVOOGNDRGFN-UHFFFAOYSA-N 0.000 claims description 2
- MQTGBDFTUKTJSY-UHFFFAOYSA-N CCC(CN1C2=C(CN(CC2)C)C3=C1C=CC(=C3)Cl)C4=CN=C(C=C4)C Chemical compound CCC(CN1C2=C(CN(CC2)C)C3=C1C=CC(=C3)Cl)C4=CN=C(C=C4)C MQTGBDFTUKTJSY-UHFFFAOYSA-N 0.000 claims description 2
- DQBINRGWLUXRHX-UHFFFAOYSA-N CCC(CN1C2=C(CN(CC2)CC)C3=C1C=CC(=C3)C)C4=CC(=NC=C4)C Chemical compound CCC(CN1C2=C(CN(CC2)CC)C3=C1C=CC(=C3)C)C4=CC(=NC=C4)C DQBINRGWLUXRHX-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims 2
- HEWRNYREUNAAIV-UHFFFAOYSA-N 2-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-1-phenyl-1-pyridin-4-ylethanol Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(O)(C=1C=CN=CC=1)C1=CC=CC=C1 HEWRNYREUNAAIV-UHFFFAOYSA-N 0.000 claims 1
- OUNFKARXQGDBIP-UHFFFAOYSA-N 4-(2,8-dimethyl-3,4-dihydro-1h-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-ylbutanoic acid Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CC(CC(O)=O)C1=CC=NC=C1 OUNFKARXQGDBIP-UHFFFAOYSA-N 0.000 claims 1
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Landscapes
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1135/NUM/2009 | 2009-04-29 | ||
| IN1135MU2009 | 2009-04-29 | ||
| US18125909P | 2009-05-26 | 2009-05-26 | |
| US61/181,259 | 2009-05-26 | ||
| PCT/US2010/033055 WO2011019417A1 (en) | 2009-04-29 | 2010-04-29 | Pyrido [4, 3-b] indoles and methods of use |
Publications (3)
| Publication Number | Publication Date |
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| JP2012525431A JP2012525431A (ja) | 2012-10-22 |
| JP2012525431A5 JP2012525431A5 (enExample) | 2013-06-27 |
| JP5827943B2 true JP5827943B2 (ja) | 2015-12-02 |
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| RU2544856C2 (ru) * | 2008-01-25 | 2015-03-20 | Сергей Олегович Бачурин | НОВЫЕ ПРОИЗВОДНЫЕ 2,3,4,5-ТЕТРАГИДРО-1-ПИРИДО[4,3-b]ИНДОЛА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ |
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| TWI450900B (zh) | 2008-03-24 | 2014-09-01 | Medivation Technologies Inc | 橋聯雜環化合物及使用方法 |
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| CN102316732B (zh) | 2008-10-31 | 2015-04-01 | 梅迪维新技术公司 | 氮杂*并[4,5-b]吲哚以及使用方法 |
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| US9962368B2 (en) | 2009-01-09 | 2018-05-08 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
| CA2748813C (en) | 2009-01-09 | 2018-07-10 | Board Of Regents Of The University Of Texas System | Pro-neurogenic compounds |
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| US20120172377A1 (en) | 2012-07-05 |
| CN102480956A (zh) | 2012-05-30 |
| CN102480956B (zh) | 2015-04-08 |
| WO2011019417A8 (en) | 2011-12-15 |
| JP2012525431A (ja) | 2012-10-22 |
| EP2424366B1 (en) | 2016-02-17 |
| EP2424366A1 (en) | 2012-03-07 |
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