JP7001682B2 - 置換１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２（３Ｈ）－オン及びＧＬＵＮ２Ｂ受容体調節因子としてのそれらの使用 - Google Patents

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Publication number

JP7001682B2

JP7001682B2 JP2019518219A JP2019518219A JP7001682B2 JP 7001682 B2 JP7001682 B2 JP 7001682B2 JP 2019518219 A JP2019518219 A JP 2019518219A JP 2019518219 A JP2019518219 A JP 2019518219A JP 7001682 B2 JP7001682 B2 JP 7001682B2

Authority

JP

Japan

Prior art keywords

methyl

imidazole

pyridin

phenyl

oxo

Prior art date

2016-10-06

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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• RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims description 310
• FPGGLMIYNLQOID-UHFFFAOYSA-N 3h-pyridin-2-one Chemical compound O=C1CC=CC=N1 FPGGLMIYNLQOID-UHFFFAOYSA-N 0.000 title claims description 22
• 238000006467 substitution reaction Methods 0.000 title description 6
• 108010054200 NR2B NMDA receptor Proteins 0.000 title 1
• -1 N (CH 3 ) 2 Chemical group 0.000 claims description 911
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 598
• 150000001875 compounds Chemical class 0.000 claims description 448
• 125000000217 alkyl group Chemical group 0.000 claims description 133
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 125
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 105
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 92
• 150000003839 salts Chemical class 0.000 claims description 89
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 84
• 150000002460 imidazoles Chemical class 0.000 claims description 79
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 69
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 63
• 208000035475 disorder Diseases 0.000 claims description 54
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
• 239000012453 solvate Substances 0.000 claims description 52
• 239000002904 solvent Substances 0.000 claims description 50
• 150000001204 N-oxides Chemical class 0.000 claims description 49
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 44
• 206010015037 epilepsy Diseases 0.000 claims description 42
• 125000004076 pyridyl group Chemical group 0.000 claims description 40
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 38
• 238000011282 treatment Methods 0.000 claims description 35
• 125000001544 thienyl group Chemical group 0.000 claims description 33
• 201000010099 disease Diseases 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 26
• 125000003566 oxetanyl group Chemical group 0.000 claims description 24
• 229910052731 fluorine Inorganic materials 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 108010038912 Retinoid X Receptors Proteins 0.000 claims description 21
• 208000002193 Pain Diseases 0.000 claims description 20
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 20
• 125000003386 piperidinyl group Chemical group 0.000 claims description 19
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 125000002393 azetidinyl group Chemical group 0.000 claims description 17
• 229910052801 chlorine Inorganic materials 0.000 claims description 17
• 125000000335 thiazolyl group Chemical group 0.000 claims description 17
• 230000000694 effects Effects 0.000 claims description 15
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 14
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 14
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
• 230000001404 mediated effect Effects 0.000 claims description 14
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 13
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 13
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
• 125000001188 haloalkyl group Chemical group 0.000 claims description 12
• 230000000155 isotopic effect Effects 0.000 claims description 12
• 125000002757 morpholinyl group Chemical group 0.000 claims description 12
• 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 11
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
• 208000012661 Dyskinesia Diseases 0.000 claims description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
• 208000020925 Bipolar disease Diseases 0.000 claims description 9
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 9
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 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 8
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 7
• 208000020706 Autistic disease Diseases 0.000 claims description 7
• 208000006011 Stroke Diseases 0.000 claims description 7
• 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 claims description 7
• 208000024714 major depressive disease Diseases 0.000 claims description 7
• 230000004770 neurodegeneration Effects 0.000 claims description 7
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 7
• 125000001425 triazolyl group Chemical group 0.000 claims description 7
• 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 6
• 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 6
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
• 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 6
• 206010003805 Autism Diseases 0.000 claims description 6
• WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 6
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
• UDSAJFSYJMHNFI-UHFFFAOYSA-N 2,6-diazaspiro[3.3]heptane Chemical compound C1NCC11CNC1 UDSAJFSYJMHNFI-UHFFFAOYSA-N 0.000 claims description 5
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 5
• 230000036407 pain Effects 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 208000024827 Alzheimer disease Diseases 0.000 claims description 4
• 208000027534 Emotional disease Diseases 0.000 claims description 4
• 208000023105 Huntington disease Diseases 0.000 claims description 4
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 4
• 230000007812 deficiency Effects 0.000 claims description 4
• 201000000980 schizophrenia Diseases 0.000 claims description 4
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
• 208000018737 Parkinson disease Diseases 0.000 claims description 3
• 230000002490 cerebral effect Effects 0.000 claims description 3
• 206010014599 encephalitis Diseases 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• WGSXKYXKAARAKD-UHFFFAOYSA-N 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene Chemical group FC1=CC(N=C=O)=CC(C(F)(F)F)=C1 WGSXKYXKAARAKD-UHFFFAOYSA-N 0.000 claims description 2
• 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
• DDUPXXNVHYDBLY-UHFFFAOYSA-N 3-methyl-1-[(1-methylpyrazol-4-yl)methyl]-6-(5-methylthiophen-2-yl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC(=CC=1)C)CC=1C=NN(C=1)C)=O DDUPXXNVHYDBLY-UHFFFAOYSA-N 0.000 claims description 2
• NEDSMCXQFAFVFO-UHFFFAOYSA-N 3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-6-(5-methylthiophen-2-yl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC(=CC=1)C)CC1=NC(=NO1)C)=O NEDSMCXQFAFVFO-UHFFFAOYSA-N 0.000 claims description 2
• KWXUGFQJZZGRGS-UHFFFAOYSA-N 3-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-6-(5-methylthiophen-2-yl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC(=CC=1)C)CC1=NOC(=C1)C)=O KWXUGFQJZZGRGS-UHFFFAOYSA-N 0.000 claims description 2
• GLKFKNUELBYIAG-UHFFFAOYSA-N 3-methyl-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-6-(5-methylthiophen-2-yl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC(=CC=1)C)CC=1OC(=NN=1)C)=O GLKFKNUELBYIAG-UHFFFAOYSA-N 0.000 claims description 2
• GZRRGDYNZLPZOQ-UHFFFAOYSA-N 3-methyl-6-(5-methylthiophen-2-yl)-1-(thiadiazol-4-ylmethyl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC(=CC=1)C)CC=1N=NSC=1)=O GZRRGDYNZLPZOQ-UHFFFAOYSA-N 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• WSFBQRMKQICRJG-UHFFFAOYSA-N CC(C=C(C=C1)C2=CC=CC(CN3C=CN(C)C3)=N2)=C1F Chemical compound CC(C=C(C=C1)C2=CC=CC(CN3C=CN(C)C3)=N2)=C1F WSFBQRMKQICRJG-UHFFFAOYSA-N 0.000 claims description 2
• HDQZEPMLLOUWAL-UHFFFAOYSA-N CCOC(C=CC=C1)=C1C(C(CN1C=CNC1)=C1)=CC=C1OC Chemical compound CCOC(C=CC=C1)=C1C(C(CN1C=CNC1)=C1)=CC=C1OC HDQZEPMLLOUWAL-UHFFFAOYSA-N 0.000 claims description 2
• YQPAPNTUJQGUKR-UHFFFAOYSA-N CCOC(C=CC=C1)=C1C1=CC(F)=CC=C1CN1C=CNC1 Chemical compound CCOC(C=CC=C1)=C1C1=CC(F)=CC=C1CN1C=CNC1 YQPAPNTUJQGUKR-UHFFFAOYSA-N 0.000 claims description 2
• OOWVRTNUBVCCQV-UHFFFAOYSA-N CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(C(F)F)=C3F)N=C2)C1 Chemical compound CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(C(F)F)=C3F)N=C2)C1 OOWVRTNUBVCCQV-UHFFFAOYSA-N 0.000 claims description 2
• ZQQWPZPGAZTGDJ-UHFFFAOYSA-N CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(OC(F)F)=C3Cl)N=C2)C1 Chemical compound CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(OC(F)F)=C3Cl)N=C2)C1 ZQQWPZPGAZTGDJ-UHFFFAOYSA-N 0.000 claims description 2
• IPOQOLGVOUQJSD-UHFFFAOYSA-N CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(OC(F)F)=C3F)N=C2)C1 Chemical compound CN1C=CN(CC2=CC(F)=C(C(C=C3)=CC(OC(F)F)=C3F)N=C2)C1 IPOQOLGVOUQJSD-UHFFFAOYSA-N 0.000 claims description 2
• AATTXPOEAJTHHM-UHFFFAOYSA-N CN1C=CN(CC2=CC=C(C(C=C3)=CC(C(F)F)=C3F)N=N2)C1 Chemical compound CN1C=CN(CC2=CC=C(C(C=C3)=CC(C(F)F)=C3F)N=N2)C1 AATTXPOEAJTHHM-UHFFFAOYSA-N 0.000 claims description 2
• UYFUMTOBIHPKNH-UHFFFAOYSA-N CN1C=CN(CC2=CC=C(C(C=C3)=CC(OC(F)F)=C3Cl)N=N2)C1 Chemical compound CN1C=CN(CC2=CC=C(C(C=C3)=CC(OC(F)F)=C3Cl)N=N2)C1 UYFUMTOBIHPKNH-UHFFFAOYSA-N 0.000 claims description 2
• XSSQWYPJKMYVHD-UHFFFAOYSA-N CN1C=CN(CC2=CC=C(C(C=C3)=CC(OC(F)F)=C3F)N=N2)C1 Chemical compound CN1C=CN(CC2=CC=C(C(C=C3)=CC(OC(F)F)=C3F)N=N2)C1 XSSQWYPJKMYVHD-UHFFFAOYSA-N 0.000 claims description 2
• OBDPRFBMRLOHDB-UHFFFAOYSA-N CN1C=CN(CC2=NC=NC(C3=CC(F)=CC=C3)=C2)C1 Chemical compound CN1C=CN(CC2=NC=NC(C3=CC(F)=CC=C3)=C2)C1 OBDPRFBMRLOHDB-UHFFFAOYSA-N 0.000 claims description 2
• ZXPZOEJFFLCKJS-UHFFFAOYSA-N COC1=CC=C(C(C2)OCCN2C(CN2C=CNC2)=O)C=C1 Chemical compound COC1=CC=C(C(C2)OCCN2C(CN2C=CNC2)=O)C=C1 ZXPZOEJFFLCKJS-UHFFFAOYSA-N 0.000 claims description 2
• 208000028698 Cognitive impairment Diseases 0.000 claims description 2
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• 208000020358 Learning disease Diseases 0.000 claims description 2
• 208000026139 Memory disease Diseases 0.000 claims description 2
• 208000019695 Migraine disease Diseases 0.000 claims description 2
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
• 208000037581 Persistent Infection Diseases 0.000 claims description 2
• 201000009916 Postpartum depression Diseases 0.000 claims description 2
• 208000029560 autism spectrum disease Diseases 0.000 claims description 2
• PBIUUJCEMUAWJJ-UHFFFAOYSA-N azetidine-3-carbonitrile Chemical compound N#CC1CNC1 PBIUUJCEMUAWJJ-UHFFFAOYSA-N 0.000 claims description 2
• 208000010877 cognitive disease Diseases 0.000 claims description 2
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 230000001419 dependent effect Effects 0.000 claims description 2
• 201000003723 learning disability Diseases 0.000 claims description 2
• 206010027599 migraine Diseases 0.000 claims description 2
• 230000003387 muscular Effects 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
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• 208000020431 spinal cord injury Diseases 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 11
• 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 2
• 102000034527 Retinoid X Receptors Human genes 0.000 claims 2
• DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
• CPDQEVFLGVBHTQ-UHFFFAOYSA-N 3-methyl-1-[(2-methylpyrimidin-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C1=CC(=CC=C1)C(F)(F)F)CC1=NC(=NC=C1)C)=O CPDQEVFLGVBHTQ-UHFFFAOYSA-N 0.000 claims 1
• SQPXLYVIPJMWAG-UHFFFAOYSA-N 3-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-6-(4-methylthiophen-2-yl)imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C=1SC=C(C=1)C)CC1=NOC(=C1)C)=O SQPXLYVIPJMWAG-UHFFFAOYSA-N 0.000 claims 1
• BWRBBWDKLYUBJM-UHFFFAOYSA-N 3-methyl-1-[(5-methyl-1,2-oxazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]imidazo[4,5-b]pyridin-2-one Chemical compound CN1C(N(C=2C1=NC=C(C=2)C1=CC(=CC=C1)C(F)(F)F)CC1=NOC(=C1)C)=O BWRBBWDKLYUBJM-UHFFFAOYSA-N 0.000 claims 1
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 1
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