CN112805063B - 作为gabaa a5受体调节剂的双环衍生物 - Google Patents
作为gabaa a5受体调节剂的双环衍生物 Download PDFInfo
- Publication number
- CN112805063B CN112805063B CN201980063431.3A CN201980063431A CN112805063B CN 112805063 B CN112805063 B CN 112805063B CN 201980063431 A CN201980063431 A CN 201980063431A CN 112805063 B CN112805063 B CN 112805063B
- Authority
- CN
- China
- Prior art keywords
- methyl
- fluorophenyl
- methoxy
- tetrahydro
- triazol
- 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.)
- Active
Links
- 125000002619 bicyclic group Chemical group 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 173
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 144
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 77
- 238000000034 method Methods 0.000 claims abstract description 53
- 238000011282 treatment Methods 0.000 claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 36
- 239000004480 active ingredient Substances 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 95
- 201000010099 disease Diseases 0.000 claims description 60
- 208000010877 cognitive disease Diseases 0.000 claims description 55
- -1 2- { [3- (4-fluorophenyl) -5-methyl-1, 2-oxazol-4-yl ] methoxy } -5,6,7, 8-tetrahydro-1, 6-naphthyridin-6-yl Chemical group 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 208000035475 disorder Diseases 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 201000000980 schizophrenia Diseases 0.000 claims description 25
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 24
- 208000024891 symptom Diseases 0.000 claims description 24
- 206010012289 Dementia Diseases 0.000 claims description 21
- 208000024827 Alzheimer disease Diseases 0.000 claims description 20
- 238000011321 prophylaxis Methods 0.000 claims description 19
- 208000024714 major depressive disease Diseases 0.000 claims description 18
- 206010027175 memory impairment Diseases 0.000 claims description 17
- 208000028698 Cognitive impairment Diseases 0.000 claims description 16
- 201000010374 Down Syndrome Diseases 0.000 claims description 16
- 230000006999 cognitive decline Effects 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 15
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 15
- 208000037820 vascular cognitive impairment Diseases 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 210000003169 central nervous system Anatomy 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 13
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 208000019022 Mood disease Diseases 0.000 claims description 11
- 239000002475 cognitive enhancer Substances 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- 208000027626 Neurocognitive disease Diseases 0.000 claims description 9
- 230000037410 cognitive enhancement Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 208000026139 Memory disease Diseases 0.000 claims description 8
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 230000007278 cognition impairment Effects 0.000 claims description 8
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 208000027520 Somatoform disease Diseases 0.000 claims description 7
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
- 206010044688 Trisomy 21 Diseases 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 7
- 208000027753 pain disease Diseases 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- YBJCDTIWNDBNTM-UHFFFAOYSA-N 1-methylsulfonylethane Chemical compound CCS(C)(=O)=O YBJCDTIWNDBNTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 229940016409 methylsulfonylmethane Drugs 0.000 claims description 6
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 6
- OHPFIURCPBDDFH-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-N-(1-methyl-5-oxopyrrolidin-3-yl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)NC1CN(C(C1)=O)C)C OHPFIURCPBDDFH-UHFFFAOYSA-N 0.000 claims description 3
- FVRQRXRVKLGUHG-UHFFFAOYSA-N C1=C(F)C=CC(C=2C(=C(ON=2)C)COC2=NC3=C(C=C2)CN(C(=O)C)CC3)=C1 Chemical compound C1=C(F)C=CC(C=2C(=C(ON=2)C)COC2=NC3=C(C=C2)CN(C(=O)C)CC3)=C1 FVRQRXRVKLGUHG-UHFFFAOYSA-N 0.000 claims description 3
- DDRXKTPRVSLWJP-UHFFFAOYSA-N (1,1-dioxothian-4-yl)-[2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone Chemical compound CC1=C(C(=NO1)C2=CC=C(C=C2)F)COC3=NC4=C(CN(CC4)C(=O)C5CCS(=O)(=O)CC5)C=C3 DDRXKTPRVSLWJP-UHFFFAOYSA-N 0.000 claims description 2
- IETUCUOGOZWGJB-UHFFFAOYSA-N (3-chlorophenyl)-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone Chemical compound ClC=1C=C(C(=O)N2CC=3C=CC(=NC=3CC2)OCC2=C(N=NN2C2=CC=C(C=C2)F)C)C=CC=1 IETUCUOGOZWGJB-UHFFFAOYSA-N 0.000 claims description 2
- SLMHAZCGGGWHRX-HXUWFJFHSA-N (5R)-5-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-methylpyrrolidin-2-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)[C@H]1CCC(N1C)=O)C SLMHAZCGGGWHRX-HXUWFJFHSA-N 0.000 claims description 2
- SLMHAZCGGGWHRX-FQEVSTJZSA-N (5S)-5-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-methylpyrrolidin-2-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)[C@@H]1CCC(N1C)=O)C SLMHAZCGGGWHRX-FQEVSTJZSA-N 0.000 claims description 2
- QVZBIXVWFBZNIS-UHFFFAOYSA-N 1-[2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(C)=O)C QVZBIXVWFBZNIS-UHFFFAOYSA-N 0.000 claims description 2
- KHWRDWIIDJAFHQ-UHFFFAOYSA-N 1-[2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-2-methoxyethanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(COC)=O)C KHWRDWIIDJAFHQ-UHFFFAOYSA-N 0.000 claims description 2
- JTUIPEJYCSUDQQ-UHFFFAOYSA-N 1-[2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(C)=O)C JTUIPEJYCSUDQQ-UHFFFAOYSA-N 0.000 claims description 2
- QISFVWCTFGVVSH-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=CC=C2C(=N1)CN(C2)C(C)=O)C QISFVWCTFGVVSH-UHFFFAOYSA-N 0.000 claims description 2
- DBCZYWJNMCGCKR-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-2,2-dimethylpropan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(C(C)(C)C)=O)C DBCZYWJNMCGCKR-UHFFFAOYSA-N 0.000 claims description 2
- ATKOTHLPBKBASC-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-2-methylpropan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(C(C)C)=O)C ATKOTHLPBKBASC-UHFFFAOYSA-N 0.000 claims description 2
- BAFQGTJJFBRHCA-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-3-methylbutan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(CC(C)C)=O)C BAFQGTJJFBRHCA-UHFFFAOYSA-N 0.000 claims description 2
- IGANKKXNZYWZFN-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(C)=O)C IGANKKXNZYWZFN-UHFFFAOYSA-N 0.000 claims description 2
- KUNZDYIIZBFFIE-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]propan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(CC)=O)C KUNZDYIIZBFFIE-UHFFFAOYSA-N 0.000 claims description 2
- PIABAEATXPVRNL-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-6,8-dihydro-5H-1,7-naphthyridin-7-yl]ethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CN(CCC=2C=C1)C(C)=O)C PIABAEATXPVRNL-UHFFFAOYSA-N 0.000 claims description 2
- SWXWAFWNZQBDGH-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-2-methylpropan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(C(C)C)=O)C SWXWAFWNZQBDGH-UHFFFAOYSA-N 0.000 claims description 2
- SKQKKNRYYXFJQN-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]ethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(C)=O)C SKQKKNRYYXFJQN-UHFFFAOYSA-N 0.000 claims description 2
- TWPMNPAALDJMPK-UHFFFAOYSA-N 1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]propan-1-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(CC)=O)C TWPMNPAALDJMPK-UHFFFAOYSA-N 0.000 claims description 2
- VLQZKWVCWZLURG-UHFFFAOYSA-N 1-[2-[[5-(4-chlorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound ClC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(C)=O)C VLQZKWVCWZLURG-UHFFFAOYSA-N 0.000 claims description 2
- UAVWCBFZNAQLCB-UHFFFAOYSA-N 1-[2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-2-methylpropan-1-one Chemical compound FC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(C(C)C)=O)C UAVWCBFZNAQLCB-UHFFFAOYSA-N 0.000 claims description 2
- CCPWUXXPRTWCKO-UHFFFAOYSA-N 1-[2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound FC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(C)=O)C CCPWUXXPRTWCKO-UHFFFAOYSA-N 0.000 claims description 2
- HSGRHLUXHXTARS-UHFFFAOYSA-N 1-[2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]propan-1-one Chemical compound FC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(CC)=O)C HSGRHLUXHXTARS-UHFFFAOYSA-N 0.000 claims description 2
- FZYMSCLXDBCKOR-UHFFFAOYSA-N 1-ethyl-4-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]pyrrolidin-2-one Chemical compound C(C)N1C(CC(C1)C(=O)N1CC=2C=CC(=NC=2CC1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C)=O FZYMSCLXDBCKOR-UHFFFAOYSA-N 0.000 claims description 2
- WUHASFQSYJWPQZ-UHFFFAOYSA-N 2,2-difluoro-1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound CC1=C(N(N=N1)C2=CC=C(C=C2)F)COC3=NC4=C(CN(C4)C(=O)C(F)F)C=C3 WUHASFQSYJWPQZ-UHFFFAOYSA-N 0.000 claims description 2
- NHAVPZBYCXDYLA-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N,N-dimethyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N(C)C)C NHAVPZBYCXDYLA-UHFFFAOYSA-N 0.000 claims description 2
- ZUGSNHSKYZRTGC-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-N-(oxolan-3-yl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)NC1COCC1)C ZUGSNHSKYZRTGC-UHFFFAOYSA-N 0.000 claims description 2
- COUPFRKMXMSVIF-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-N,N-dimethyl-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N(C)C)C COUPFRKMXMSVIF-UHFFFAOYSA-N 0.000 claims description 2
- BFBQNXDBCFYSQA-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-N-(oxolan-3-yl)-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)NC1COCC1)C BFBQNXDBCFYSQA-UHFFFAOYSA-N 0.000 claims description 2
- VJZODEQRIGYXDS-UHFFFAOYSA-N 2-fluoro-1-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound FCC(=O)N1CC2=NC(=CC=C2C1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C VJZODEQRIGYXDS-UHFFFAOYSA-N 0.000 claims description 2
- QLKWIZYDNATRKP-UHFFFAOYSA-N 2-fluoro-1-[2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]ethanone Chemical compound FCC(=O)N1CC2=NC(=CC=C2C1)OCC1=C(N=NN1C)C1=CC=C(C=C1)F QLKWIZYDNATRKP-UHFFFAOYSA-N 0.000 claims description 2
- SLOOXBXYFZZFMA-UHFFFAOYSA-N 4-[2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-methylpyrrolidin-2-one Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1CC(N(C1)C)=O)C SLOOXBXYFZZFMA-UHFFFAOYSA-N 0.000 claims description 2
- CEPWICKCWXPROW-UHFFFAOYSA-N 4-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-methylpyrrolidin-2-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1CC(N(C1)C)=O)C CEPWICKCWXPROW-UHFFFAOYSA-N 0.000 claims description 2
- BOXIMVULKPABHC-UHFFFAOYSA-N 4-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-propan-2-ylpyrrolidin-2-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1CC(N(C1)C(C)C)=O)C BOXIMVULKPABHC-UHFFFAOYSA-N 0.000 claims description 2
- YLVWLVGKOYHREW-UHFFFAOYSA-N 5-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carbonyl]-1-methylpiperidin-2-one Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1CCC(N(C1)C)=O)C YLVWLVGKOYHREW-UHFFFAOYSA-N 0.000 claims description 2
- DVVPHPORYSWGRG-UHFFFAOYSA-N CC1=C(COC2=NC(CCN(C3)C(CCS(C)(=O)=O)=O)=C3C=C2)C(C(C=C2)=CC=C2F)=NO1 Chemical compound CC1=C(COC2=NC(CCN(C3)C(CCS(C)(=O)=O)=O)=C3C=C2)C(C(C=C2)=CC=C2F)=NO1 DVVPHPORYSWGRG-UHFFFAOYSA-N 0.000 claims description 2
- LVNXXOSTQHOUEJ-UHFFFAOYSA-N [2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(oxolan-3-yl)methanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1COCC1)C LVNXXOSTQHOUEJ-UHFFFAOYSA-N 0.000 claims description 2
- LVNXXOSTQHOUEJ-KRWDZBQOSA-N [2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-[(3S)-oxolan-3-yl]methanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)[C@@H]1COCC1)C LVNXXOSTQHOUEJ-KRWDZBQOSA-N 0.000 claims description 2
- QOLCYFCYKXOVDP-UHFFFAOYSA-N [2-[[3-(4-chlorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyridin-4-ylmethanone Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=CC=NC=C1)C QOLCYFCYKXOVDP-UHFFFAOYSA-N 0.000 claims description 2
- UMFHAUNGEIGDID-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(1,2-oxazol-5-yl)methanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=CC=NO1)C UMFHAUNGEIGDID-UHFFFAOYSA-N 0.000 claims description 2
- CVLHGIGSEPDOGG-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(1-methylpyrrol-3-yl)methanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=CN(C=C1)C)C CVLHGIGSEPDOGG-UHFFFAOYSA-N 0.000 claims description 2
- HZJHBUSRGUYMRE-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(5-methyl-1,2-oxazol-3-yl)methanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=NOC(=C1)C)C HZJHBUSRGUYMRE-UHFFFAOYSA-N 0.000 claims description 2
- VELCIJHTXAIRCT-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(oxolan-2-yl)methanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1OCCC1)C VELCIJHTXAIRCT-UHFFFAOYSA-N 0.000 claims description 2
- CTWBYWXKUNSXJJ-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(oxolan-3-yl)methanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1COCC1)C CTWBYWXKUNSXJJ-UHFFFAOYSA-N 0.000 claims description 2
- AWASMZLLTPEXPS-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-morpholin-4-ylmethanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N1CCOCC1)C AWASMZLLTPEXPS-UHFFFAOYSA-N 0.000 claims description 2
- VUEKKKDGNCPLAN-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-piperidin-1-ylmethanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N1CCCCC1)C VUEKKKDGNCPLAN-UHFFFAOYSA-N 0.000 claims description 2
- AGPCPYSTRMOJMO-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyrrolidin-1-ylmethanone Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N1CCCC1)C AGPCPYSTRMOJMO-UHFFFAOYSA-N 0.000 claims description 2
- PVWSTPYWRSVTTD-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-(oxolan-2-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(=O)C1OCCC1)C PVWSTPYWRSVTTD-UHFFFAOYSA-N 0.000 claims description 2
- HODZKNGPLLFLEY-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-(oxolan-3-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(=O)C1COCC1)C HODZKNGPLLFLEY-UHFFFAOYSA-N 0.000 claims description 2
- JMBJGBOSZSCOSY-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-pyridin-2-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(=O)C1=NC=CC=C1)C JMBJGBOSZSCOSY-UHFFFAOYSA-N 0.000 claims description 2
- LYERYHQKKTTXPJ-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-pyridin-3-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(=O)C=1C=NC=CC=1)C LYERYHQKKTTXPJ-UHFFFAOYSA-N 0.000 claims description 2
- QIFLJIOWZAZIIX-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-pyridin-4-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=CC=C2C(=N1)CN(C2)C(=O)C1=CC=NC=C1)C QIFLJIOWZAZIIX-UHFFFAOYSA-N 0.000 claims description 2
- MLETTWUUFMGHTC-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(1,2-oxazol-5-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=CC=NO1)C MLETTWUUFMGHTC-UHFFFAOYSA-N 0.000 claims description 2
- DHWHRGLMCKSQLB-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(3-methyloxolan-3-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1(COCC1)C)C DHWHRGLMCKSQLB-UHFFFAOYSA-N 0.000 claims description 2
- YUAOYTWLTIJARC-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(4-methoxycyclohexyl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1CCC(CC1)OC)C YUAOYTWLTIJARC-UHFFFAOYSA-N 0.000 claims description 2
- JQPBMFRJWHTYAJ-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(oxolan-2-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1OCCC1)C JQPBMFRJWHTYAJ-UHFFFAOYSA-N 0.000 claims description 2
- GKHTZTAJUUJEEH-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-(oxolan-3-yl)methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1COCC1)C GKHTZTAJUUJEEH-UHFFFAOYSA-N 0.000 claims description 2
- GKHTZTAJUUJEEH-QGZVFWFLSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-[(3R)-oxolan-3-yl]methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)[C@H]1COCC1)C GKHTZTAJUUJEEH-QGZVFWFLSA-N 0.000 claims description 2
- GKHTZTAJUUJEEH-KRWDZBQOSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-[(3S)-oxolan-3-yl]methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)[C@@H]1COCC1)C GKHTZTAJUUJEEH-KRWDZBQOSA-N 0.000 claims description 2
- NWEBPWVAXYWDGK-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-[6-(trifluoromethyl)pyridin-3-yl]methanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C=1C=NC(=CC=1)C(F)(F)F)C NWEBPWVAXYWDGK-UHFFFAOYSA-N 0.000 claims description 2
- XJHYZHZZPXZOCX-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-morpholin-4-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N1CCOCC1)C XJHYZHZZPXZOCX-UHFFFAOYSA-N 0.000 claims description 2
- HVGDXPCVNBSDFM-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyridin-2-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=NC=CC=C1)C HVGDXPCVNBSDFM-UHFFFAOYSA-N 0.000 claims description 2
- PJXOAZCULMRGCB-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyridin-3-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C=1C=NC=CC=1)C PJXOAZCULMRGCB-UHFFFAOYSA-N 0.000 claims description 2
- YTPKQJIHOHUSEH-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyridin-4-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)C1=CC=NC=C1)C YTPKQJIHOHUSEH-UHFFFAOYSA-N 0.000 claims description 2
- UISCMIPGGLCWDH-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]-pyrrolidin-1-ylmethanone Chemical compound FC1=CC=C(C=C1)N1N=NC(=C1COC1=NC=2CCN(CC=2C=C1)C(=O)N1CCCC1)C UISCMIPGGLCWDH-UHFFFAOYSA-N 0.000 claims description 2
- LCNUIOCHHIHEGG-UHFFFAOYSA-N [2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-(oxolan-2-yl)methanone Chemical compound FC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(=O)C1OCCC1)C LCNUIOCHHIHEGG-UHFFFAOYSA-N 0.000 claims description 2
- SRXYGKVOSMLHKS-UHFFFAOYSA-N [2-[[5-(4-fluorophenyl)-3-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]-(oxolan-3-yl)methanone Chemical compound FC1=CC=C(C=C1)C=1N=NN(C=1COC1=CC=C2C(=N1)CN(C2)C(=O)C1COCC1)C SRXYGKVOSMLHKS-UHFFFAOYSA-N 0.000 claims description 2
- BORXJKWROXINDS-UHFFFAOYSA-N cyclobutyl-[2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone Chemical compound C1(CCC1)C(=O)N1CC=2C=CC(=NC=2CC1)OCC=1C(=NOC=1C)C1=CC=C(C=C1)F BORXJKWROXINDS-UHFFFAOYSA-N 0.000 claims description 2
- DHJZJURRLBOQQH-UHFFFAOYSA-N cyclobutyl-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]methanone Chemical compound C1(CCC1)C(=O)N1CC2=NC(=CC=C2C1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C DHJZJURRLBOQQH-UHFFFAOYSA-N 0.000 claims description 2
- ZDRPDEFDVKGPFQ-UHFFFAOYSA-N cyclopropyl-[2-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone Chemical compound C1(CC1)C(=O)N1CC=2C=CC(=NC=2CC1)OCC=1C(=NOC=1C)C1=CC=C(C=C1)F ZDRPDEFDVKGPFQ-UHFFFAOYSA-N 0.000 claims description 2
- KHRSGSQJKGEFHK-UHFFFAOYSA-N cyclopropyl-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-5,7-dihydropyrrolo[3,4-b]pyridin-6-yl]methanone Chemical compound C1(CC1)C(=O)N1CC2=NC(=CC=C2C1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C KHRSGSQJKGEFHK-UHFFFAOYSA-N 0.000 claims description 2
- OZVXGPJLSRNTCH-UHFFFAOYSA-N cyclopropyl-[2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridin-6-yl]methanone Chemical compound C1(CC1)C(=O)N1CC=2C=CC(=NC=2CC1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C OZVXGPJLSRNTCH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 abstract description 67
- 229940126662 negative allosteric modulator Drugs 0.000 abstract description 11
- 229940002612 prodrug Drugs 0.000 abstract description 9
- 239000000651 prodrug Substances 0.000 abstract description 9
- 239000012453 solvate Substances 0.000 abstract description 9
- 239000002207 metabolite Substances 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 6
- 102000005962 receptors Human genes 0.000 description 69
- 108020003175 receptors Proteins 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- 239000000556 agonist Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 230000000694 effects Effects 0.000 description 22
- 150000002431 hydrogen Chemical group 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 125000002837 carbocyclic group Chemical group 0.000 description 17
- 239000005557 antagonist Substances 0.000 description 16
- 125000002950 monocyclic group Chemical group 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 230000027455 binding Effects 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 241000124008 Mammalia Species 0.000 description 10
- 208000006011 Stroke Diseases 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 208000011580 syndromic disease Diseases 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 208000020925 Bipolar disease Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000003623 enhancer Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 201000004810 Vascular dementia Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 229940044551 receptor antagonist Drugs 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 208000023105 Huntington disease Diseases 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000003281 allosteric effect Effects 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000006266 etherification reaction Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 5
- 229920002401 polyacrylamide Polymers 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 208000011117 substance-related disease Diseases 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 4
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 201000002832 Lewy body dementia Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 4
- 229940049706 benzodiazepine Drugs 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000003920 cognitive function Effects 0.000 description 4
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000015654 memory Effects 0.000 description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 208000012672 seasonal affective disease Diseases 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 230000002739 subcortical effect Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- VSWBSWWIRNCQIJ-GJZGRUSLSA-N (R,R)-asenapine Chemical compound O1C2=CC=CC=C2[C@@H]2CN(C)C[C@H]2C2=CC(Cl)=CC=C21 VSWBSWWIRNCQIJ-GJZGRUSLSA-N 0.000 description 3
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 3
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000017194 Affective disease Diseases 0.000 description 3
- 208000007848 Alcoholism Diseases 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010013654 Drug abuse Diseases 0.000 description 3
- 206010016845 Foetal alcohol syndrome Diseases 0.000 description 3
- 201000011240 Frontotemporal dementia Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 206010065390 Inflammatory pain Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000283984 Rodentia Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 201000007930 alcohol dependence Diseases 0.000 description 3
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 230000000949 anxiolytic effect Effects 0.000 description 3
- 229960004372 aripiprazole Drugs 0.000 description 3
- 229960005245 asenapine Drugs 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 239000012148 binding buffer Substances 0.000 description 3
- 239000004044 bronchoconstricting agent Substances 0.000 description 3
- 230000003435 bronchoconstrictive effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960004170 clozapine Drugs 0.000 description 3
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 3
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 239000003596 drug target Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 208000026934 fetal alcohol spectrum disease Diseases 0.000 description 3
- 201000007794 fetal alcohol syndrome Diseases 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 229960003878 haloperidol Drugs 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 229960003162 iloperidone Drugs 0.000 description 3
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- XJGVXQDUIWGIRW-UHFFFAOYSA-N loxapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 XJGVXQDUIWGIRW-UHFFFAOYSA-N 0.000 description 3
- 229960001432 lurasidone Drugs 0.000 description 3
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 description 3
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 229960005017 olanzapine Drugs 0.000 description 3
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 229960001057 paliperidone Drugs 0.000 description 3
- 239000004031 partial agonist Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 125000001484 phenothiazinyl group Chemical class C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 3
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 3
- 229960003634 pimozide Drugs 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229960004431 quetiapine Drugs 0.000 description 3
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000002287 radioligand Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229960001534 risperidone Drugs 0.000 description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229960004940 sulpiride Drugs 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 150000005075 thioxanthenes Chemical class 0.000 description 3
- 229960000607 ziprasidone Drugs 0.000 description 3
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 3
- NZMJFRXKGUCYNP-UHFFFAOYSA-N α5ia Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N=NN(C)C=4)C4=CC=CC=C4C3=NN=2)=N1 NZMJFRXKGUCYNP-UHFFFAOYSA-N 0.000 description 3
- OCKIPDMKGPYYJS-ZDUSSCGKSA-N (3r)-spiro[1-azabicyclo[2.2.2]octane-3,2'-3h-furo[2,3-b]pyridine] Chemical compound C1N(CC2)CCC2[C@]21OC1=NC=CC=C1C2 OCKIPDMKGPYYJS-ZDUSSCGKSA-N 0.000 description 2
- VMAKIACTLSBBIY-BOPFTXTBSA-N (z)-3-(4-chloroanilino)-n-(4-chlorophenyl)-2-(3-methyl-1,2-oxazol-5-yl)prop-2-enamide Chemical compound O1N=C(C)C=C1C(\C(=O)NC=1C=CC(Cl)=CC=1)=C\NC1=CC=C(Cl)C=C1 VMAKIACTLSBBIY-BOPFTXTBSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 2
- AUEKAKHRRYWONI-UHFFFAOYSA-N 1-(4,4-diphenylbutyl)piperidine Chemical class C1CCCCN1CCCC(C=1C=CC=CC=1)C1=CC=CC=C1 AUEKAKHRRYWONI-UHFFFAOYSA-N 0.000 description 2
- CEIIEALEIHQDBX-UHFFFAOYSA-N 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methyl-3-isoxazolyl)urea Chemical compound C1=C(Cl)C(OC)=CC(OC)=C1NC(=O)NC1=NOC(C)=C1 CEIIEALEIHQDBX-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- KFRQROSRKSVROW-UHFFFAOYSA-N 2,1,3-benzoxadiazol-5-yl(morpholin-4-yl)methanone Chemical compound C1=CC2=NON=C2C=C1C(=O)N1CCOCC1 KFRQROSRKSVROW-UHFFFAOYSA-N 0.000 description 2
- YBAWYTYNMZWMMJ-UHFFFAOYSA-N 2-(6-fluoro-1h-indol-3-yl)-n-[[3-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]ethanamine Chemical compound FC(F)C(F)(F)COC1=CC=CC(CNCCC=2C3=CC=C(F)C=C3NC=2)=C1 YBAWYTYNMZWMMJ-UHFFFAOYSA-N 0.000 description 2
- DUHUCHOQIDJXAT-OLVMNOGESA-N 3-hydroxy-(3-α,5-α)-Pregnane-11,20-dione Chemical compound C([C@@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1=O DUHUCHOQIDJXAT-OLVMNOGESA-N 0.000 description 2
- NUNXCMWVHVCBMM-UHFFFAOYSA-N 4-(bromomethyl)-3-(4-fluorophenyl)-5-methyl-1,2-oxazole Chemical compound Cc1onc(c1CBr)-c1ccc(F)cc1 NUNXCMWVHVCBMM-UHFFFAOYSA-N 0.000 description 2
- GXYZREDEYDFJPT-ZMBIFBSDSA-N 4-cyano-n-[(2r)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propyl]-n-pyridin-2-ylbenzamide;hydrochloride Chemical compound Cl.C([C@@H](C)N1CCN(CC1)C=1C=2OCCOC=2C=CC=1)N(C=1N=CC=CC=1)C(=O)C1=CC=C(C#N)C=C1 GXYZREDEYDFJPT-ZMBIFBSDSA-N 0.000 description 2
- 229940124801 5-HT6 antagonist Drugs 0.000 description 2
- OJBLXSPBJMGZDN-UHFFFAOYSA-N 5-[3-(difluoromethyl)-4-fluorophenyl]-3-[(2-methylimidazol-1-yl)methyl]pyridazine;dihydrochloride Chemical compound Cl.Cl.CC1=NC=CN1CC1=CC(C=2C=C(C(F)=CC=2)C(F)F)=CN=N1 OJBLXSPBJMGZDN-UHFFFAOYSA-N 0.000 description 2
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 2
- GRQVZNMSXFEEHD-UHFFFAOYSA-N 6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-n-methylpyridine-3-carboxamide;hydrochloride Chemical compound Cl.N1=CC(C(=O)NC)=CC=C1OC1=CC=C(CCN(CC2)C3CCC3)C2=C1 GRQVZNMSXFEEHD-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QZDCYUCETTWCMO-CDFKWJNJSA-N C1C2C[C@H]3C[N@](C2)CC1[C@H]3Oc1nnc(s1)-c1ccccc1 Chemical compound C1C2C[C@H]3C[N@](C2)CC1[C@H]3Oc1nnc(s1)-c1ccccc1 QZDCYUCETTWCMO-CDFKWJNJSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 2
- 208000024254 Delusional disease Diseases 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000038624 GSKs Human genes 0.000 description 2
- 108091007911 GSKs Proteins 0.000 description 2
- ZXRVKCBLGJOCEE-UHFFFAOYSA-N Gaboxadol Chemical compound C1NCCC2=C1ONC2=O ZXRVKCBLGJOCEE-UHFFFAOYSA-N 0.000 description 2
- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 229940115480 Histamine H3 receptor antagonist Drugs 0.000 description 2
- 229940122931 Histamine H3 receptor inverse agonist Drugs 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- LHXOCOHMBFOVJS-OAHLLOKOSA-N Ladostigil Chemical compound CCN(C)C(=O)OC1=CC=C2CC[C@@H](NCC#C)C2=C1 LHXOCOHMBFOVJS-OAHLLOKOSA-N 0.000 description 2
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 2
- 206010024419 Libido decreased Diseases 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- 102000014649 NMDA glutamate receptor activity proteins Human genes 0.000 description 2
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 2
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 description 2
- 208000014060 Niemann-Pick disease Diseases 0.000 description 2
- 102000002512 Orexin Human genes 0.000 description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 2
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 201000009916 Postpartum depression Diseases 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 229960003305 alfaxalone Drugs 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 description 2
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000003693 atypical antipsychotic agent Substances 0.000 description 2
- 229940127236 atypical antipsychotics Drugs 0.000 description 2
- 125000003828 azulenyl group Chemical group 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 239000002439 beta secretase inhibitor Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- KVLLHLWBPNCVNR-SKCUWOTOSA-N capromorelin Chemical compound C([C@@]12CN(CCC1=NN(C2=O)C)C(=O)[C@@H](COCC=1C=CC=CC=1)NC(=O)C(C)(C)N)C1=CC=CC=C1 KVLLHLWBPNCVNR-SKCUWOTOSA-N 0.000 description 2
- 229950004826 capromorelin Drugs 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- WKDNQONLGXOZRG-BOPKNSRXSA-N chembl3261045 Chemical compound C1CC(OC)CCC11[C@@]2(N=C(N)C(C)=N2)C2=CC(C=3C=C(C=NC=3)C#CC)=CC=C2C1 WKDNQONLGXOZRG-BOPKNSRXSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000000064 cholinergic agonist Substances 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960003530 donepezil Drugs 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 2
- 229960003337 entacapone Drugs 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- 229950004346 gaboxadol Drugs 0.000 description 2
- 229960003980 galantamine Drugs 0.000 description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 2
- 239000003540 gamma secretase inhibitor Substances 0.000 description 2
- 229950006567 ganaxolone Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 2
- 229960001410 hydromorphone Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 150000005624 indolones Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- BQDUNOMMYOKHEP-UHFFFAOYSA-N l-838,417 Chemical compound CN1N=CN=C1COC(C(=C1)C(C)(C)C)=NN2C1=NN=C2C1=CC(F)=CC=C1F BQDUNOMMYOKHEP-UHFFFAOYSA-N 0.000 description 2
- 229960002623 lacosamide Drugs 0.000 description 2
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229950008812 ladostigil Drugs 0.000 description 2
- 230000013016 learning Effects 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 229960003406 levorphanol Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 102000004311 liver X receptors Human genes 0.000 description 2
- 108090000865 liver X receptors Proteins 0.000 description 2
- 210000005265 lung cell Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- 229960004640 memantine Drugs 0.000 description 2
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 2
- 230000009245 menopause Effects 0.000 description 2
- 229960001797 methadone Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- SSRDSYXGYPJKRR-ZDUSSCGKSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-chloro-1-benzothiophene-2-carboxamide Chemical compound C1N(CC2)CCC2[C@H]1NC(=O)C1=CC(C=CC=C2Cl)=C2S1 SSRDSYXGYPJKRR-ZDUSSCGKSA-N 0.000 description 2
- AMKVXSZCKVJAGH-UHFFFAOYSA-N naratriptan Chemical compound C12=CC(CCS(=O)(=O)NC)=CC=C2NC=C1C1CCN(C)CC1 AMKVXSZCKVJAGH-UHFFFAOYSA-N 0.000 description 2
- 229960005254 naratriptan Drugs 0.000 description 2
- OGZQTTHDGQBLBT-UHFFFAOYSA-N neramexane Chemical compound CC1(C)CC(C)(C)CC(C)(N)C1 OGZQTTHDGQBLBT-UHFFFAOYSA-N 0.000 description 2
- 229950004543 neramexane Drugs 0.000 description 2
- 230000002981 neuropathic effect Effects 0.000 description 2
- DLWSRGHNJVLJAH-UHFFFAOYSA-N nitroflurbiprofen Chemical compound FC1=CC(C(C(=O)OCCCCO[N+]([O-])=O)C)=CC=C1C1=CC=CC=C1 DLWSRGHNJVLJAH-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 108060005714 orexin Proteins 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- 229960005118 oxymorphone Drugs 0.000 description 2
- 208000002851 paranoid schizophrenia Diseases 0.000 description 2
- 239000006201 parenteral dosage form Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 2
- 229960005301 pentazocine Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 229940126027 positive allosteric modulator Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- YRVIKLBSVVNSHF-JTQLQIEISA-N pozanicline Chemical compound CC1=NC=CC=C1OC[C@H]1NCCC1 YRVIKLBSVVNSHF-JTQLQIEISA-N 0.000 description 2
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 2
- 229960003089 pramipexole Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 229960004136 rivastigmine Drugs 0.000 description 2
- ULFRLSNUDGIQQP-UHFFFAOYSA-N rizatriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CN1C=NC=N1 ULFRLSNUDGIQQP-UHFFFAOYSA-N 0.000 description 2
- 229960000425 rizatriptan Drugs 0.000 description 2
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 2
- 229960001879 ropinirole Drugs 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- LPZHKCVGWZFNDC-UHFFFAOYSA-N tert-butyl 2-chloro-7,8-dihydro-5h-1,6-naphthyridine-6-carboxylate Chemical compound ClC1=CC=C2CN(C(=O)OC(C)(C)C)CCC2=N1 LPZHKCVGWZFNDC-UHFFFAOYSA-N 0.000 description 2
- SYYLNESTCFDFBW-UHFFFAOYSA-N tert-butyl 2-oxo-1,5,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate Chemical compound N1C(=O)C=CC2=C1CCN(C(=O)OC(C)(C)C)C2 SYYLNESTCFDFBW-UHFFFAOYSA-N 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 229960001918 tiagabine Drugs 0.000 description 2
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 2
- QKIWQBLNTSQOLY-UHFFFAOYSA-N tpa-023 Chemical compound CCN1N=CN=C1COC(C(=C1)C(C)(C)C)=NN2C1=NN=C2C1=CC=CC=C1F QKIWQBLNTSQOLY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009529 traumatic brain injury Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 2
- 229960001360 zolmitriptan Drugs 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- GLHHFOSVBQQNAW-GDYXXZBVSA-N (2r)-2-[[(3r)-3-(1,3-benzodioxol-5-yl)-3-[(6-methoxynaphthalen-2-yl)sulfonylamino]propanoyl]amino]-3-[4-[[(2s,6r)-2,6-dimethylpiperidin-1-yl]methyl]phenyl]-n-methyl-n-propan-2-ylpropanamide;hydrochloride Chemical compound Cl.C([C@@H](NC(=O)C[C@@H](NS(=O)(=O)C1=CC2=CC=C(C=C2C=C1)OC)C=1C=C2OCOC2=CC=1)C(=O)N(C)C(C)C)C(C=C1)=CC=C1CN1[C@@H](C)CCC[C@H]1C GLHHFOSVBQQNAW-GDYXXZBVSA-N 0.000 description 1
- DNISEZBAYYIQFB-PHDIDXHHSA-N (2r,3r)-2,3-diacetyloxybutanedioic acid Chemical compound CC(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(C)=O DNISEZBAYYIQFB-PHDIDXHHSA-N 0.000 description 1
- SSNHGLKFJISNTR-DYSNNVSPSA-N (6ar,10ar)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1.C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 SSNHGLKFJISNTR-DYSNNVSPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ATBXNGWEESVROU-UHFFFAOYSA-N 1,2,3,3a-tetrahydropyrrolo[3,2-b]pyrrole Chemical compound N1=CC=C2NCCC21 ATBXNGWEESVROU-UHFFFAOYSA-N 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 1
- FNQJDLTXOVEEFB-UHFFFAOYSA-N 1,2,3-benzothiadiazole Chemical class C1=CC=C2SN=NC2=C1 FNQJDLTXOVEEFB-UHFFFAOYSA-N 0.000 description 1
- SLLFVLKNXABYGI-UHFFFAOYSA-N 1,2,3-benzoxadiazole Chemical class C1=CC=C2ON=NC2=C1 SLLFVLKNXABYGI-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical class C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- 150000000183 1,3-benzoxazoles Chemical class 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 description 1
- IJDXSTIWUARVEK-UHFFFAOYSA-N 1,4-dioxaspiro[4.4]nonane Chemical compound C1CCCC21OCCO2 IJDXSTIWUARVEK-UHFFFAOYSA-N 0.000 description 1
- WENISBCJPGSITQ-UHFFFAOYSA-N 1-azatricyclo[3.3.1.13,7]decane Chemical compound C1C(C2)CC3CC1CN2C3 WENISBCJPGSITQ-UHFFFAOYSA-N 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- JFVMNDINHUZJDN-UHFFFAOYSA-N 1-oxaspiro[4.4]nonan-2-one Chemical compound O1C(=O)CCC11CCCC1 JFVMNDINHUZJDN-UHFFFAOYSA-N 0.000 description 1
- RNXNMGPFJLESKN-UHFFFAOYSA-N 1-oxaspiro[4.5]decane Chemical compound C1CCOC21CCCCC2 RNXNMGPFJLESKN-UHFFFAOYSA-N 0.000 description 1
- ZHKJHQBOAJQXQR-UHFFFAOYSA-N 1H-azirine Chemical compound N1C=C1 ZHKJHQBOAJQXQR-UHFFFAOYSA-N 0.000 description 1
- MFJCPDOGFAYSTF-UHFFFAOYSA-N 1H-isochromene Chemical compound C1=CC=C2COC=CC2=C1 MFJCPDOGFAYSTF-UHFFFAOYSA-N 0.000 description 1
- APXRHPDHORGIEB-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidine Chemical class N1=CN=C2C=NNC2=C1 APXRHPDHORGIEB-UHFFFAOYSA-N 0.000 description 1
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- NKUNFNVAHJNALA-QGZVFWFLSA-N 2-[(2s)-2-(4-fluorophenyl)morpholin-4-yl]-3-methyl-6-pyrimidin-4-ylpyrimidin-4-one Chemical compound C=1C(=O)N(C)C(N2C[C@@H](OCC2)C=2C=CC(F)=CC=2)=NC=1C1=CC=NC=N1 NKUNFNVAHJNALA-QGZVFWFLSA-N 0.000 description 1
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical class C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- FRACHJCOMOVESL-UHFFFAOYSA-N 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine;hydrochloride Chemical compound Cl.C1NCCC2=NC(Cl)=CC=C21 FRACHJCOMOVESL-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- RECARUFTCUAFPV-UHFFFAOYSA-N 2-oxa-7-azaspiro[3.5]nonane Chemical compound C1OCC11CCNCC1 RECARUFTCUAFPV-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 description 1
- BQUTUDOHXKHNJX-UHFFFAOYSA-N 3-(4-fluorophenyl)-5-methyl-4-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yloxymethyl)-1,2-oxazole Chemical compound FC1=CC=C(C=C1)C1=NOC(=C1COC1=NC=2CCNCC=2C=C1)C BQUTUDOHXKHNJX-UHFFFAOYSA-N 0.000 description 1
- INGJMHPGMVUEKY-UHFFFAOYSA-N 3-(cyclopropylmethyl)-6-fluoro-7-methyl-N-[5-(1-methylimidazol-4-yl)pyridin-2-yl]benzimidazol-5-amine Chemical compound C1(CC1)CN1C=NC2=C1C=C(C(=C2C)F)NC2=NC=C(C=C2)C=2N=CN(C2)C INGJMHPGMVUEKY-UHFFFAOYSA-N 0.000 description 1
- QYSYOGCIDRANAR-UHFFFAOYSA-N 3-[3-tert-butyl-2-[(2-methyl-1,2,4-triazol-3-yl)methoxy]pyrazolo[1,5-d][1,2,4]triazin-7-yl]-5-methyl-1,2-oxazole Chemical compound O1C(C)=CC(C=2N3N=C(OCC=4N(N=CN=4)C)C(=C3C=NN=2)C(C)(C)C)=N1 QYSYOGCIDRANAR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RBSPCALDSNXWEP-UHFFFAOYSA-N 3-fluoro-5-[3-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-5-yl]benzonitrile Chemical compound N1=CC(F)=CC=C1C1=NOC(C=2C=C(C=C(F)C=2)C#N)=N1 RBSPCALDSNXWEP-UHFFFAOYSA-N 0.000 description 1
- WBYJZPAHGAGMQX-UHFFFAOYSA-N 4-amino-1-methylpyrrolidin-2-one Chemical compound CN1CC(N)CC1=O WBYJZPAHGAGMQX-UHFFFAOYSA-N 0.000 description 1
- NRPQELCNMADTOZ-OAQYLSRUSA-N 4-cyano-n-[(2r)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propyl]-n-pyridin-2-ylbenzamide Chemical compound C([C@@H](C)N1CCN(CC1)C=1C=2OCCOC=2C=CC=1)N(C=1N=CC=CC=1)C(=O)C1=CC=C(C#N)C=C1 NRPQELCNMADTOZ-OAQYLSRUSA-N 0.000 description 1
- ROUCOZSGXKNGNA-UHFFFAOYSA-N 5-(bromomethyl)-1-(4-fluorophenyl)-4-methyltriazole Chemical compound BrCC1=C(N=NN1C1=CC=C(C=C1)F)C ROUCOZSGXKNGNA-UHFFFAOYSA-N 0.000 description 1
- YYPQQTDJMQWGFE-UHFFFAOYSA-N 5-(bromomethyl)-4-(4-chlorophenyl)-1-methyltriazole Chemical compound CN1C(=C(N=N1)C2=CC=C(C=C2)Cl)CBr YYPQQTDJMQWGFE-UHFFFAOYSA-N 0.000 description 1
- IDIHDKRVMNYVON-UHFFFAOYSA-N 5-(bromomethyl)-4-(4-fluorophenyl)-1-methyltriazole Chemical compound C1=C(C=CC(=C1)C=1N=NN(C=1CBr)C)F IDIHDKRVMNYVON-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- VLYSFRDQDDZUCK-UHFFFAOYSA-N 6-oxaspiro[3.4]octane Chemical compound C1CCC11COCC1 VLYSFRDQDDZUCK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 1
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical compound C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 description 1
- POOPWPIOIMBTOH-UHFFFAOYSA-N 8-oxa-3-azabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1O2 POOPWPIOIMBTOH-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 1
- 108091007504 ADAM10 Proteins 0.000 description 1
- BLTVBQXJFVRPFK-UHFFFAOYSA-N AZD1080 Chemical compound OC=1NC2=CC=C(C#N)C=C2C=1C(N=C1)=CC=C1CN1CCOCC1 BLTVBQXJFVRPFK-UHFFFAOYSA-N 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 101150051188 Adora2a gene Proteins 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 230000007134 Aβ oligomerisation Effects 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- TYDVEODKTPMZSM-UHFFFAOYSA-N C1=C(C=CC(=C1)N1C(=C(N=N1)C)CBr)Cl Chemical compound C1=C(C=CC(=C1)N1C(=C(N=N1)C)CBr)Cl TYDVEODKTPMZSM-UHFFFAOYSA-N 0.000 description 1
- GJTMABFGSMCZPU-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C=C2)=C1N=C2OCC1=C(C)ON=C1C(C=C1)=CC=C1F)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C=C2)=C1N=C2OCC1=C(C)ON=C1C(C=C1)=CC=C1F)=O GJTMABFGSMCZPU-UHFFFAOYSA-N 0.000 description 1
- RZZPDXZPRHQOCG-OJAKKHQRSA-O CDP-choline(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC[N+](C)(C)C)O[C@H]1N1C(=O)N=C(N)C=C1 RZZPDXZPRHQOCG-OJAKKHQRSA-O 0.000 description 1
- 208000011597 CGF1 Diseases 0.000 description 1
- 101100495314 Caenorhabditis elegans cdk-5 gene Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 1
- 208000016270 Corticobasal syndrome Diseases 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine group Chemical group N[C@H](CCCCN)C(=O)O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- GRJMIMFTPGNXIC-UHFFFAOYSA-N Dialin Natural products C1=C(OC)C(OC)=CC=C1C1C2=CC(OC)=C(OC)C=C2C=C(C)C1C GRJMIMFTPGNXIC-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 102100039673 Disintegrin and metalloproteinase domain-containing protein 10 Human genes 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 240000002989 Euphorbia neriifolia Species 0.000 description 1
- 101150096839 Fcmr gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241001272567 Hominoidea Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001125071 Homo sapiens Neuromedin-K receptor Proteins 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229940124786 LRRK2 inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229940124761 MMP inhibitor Drugs 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 description 1
- 102100036837 Metabotropic glutamate receptor 2 Human genes 0.000 description 1
- 102100038357 Metabotropic glutamate receptor 5 Human genes 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010027603 Migraine headaches Diseases 0.000 description 1
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- WOPJUQQSVPZRIB-UHFFFAOYSA-N N-(2-chlorophenyl)-2-[[3-(4-fluorophenyl)-5-methyltriazol-4-yl]methoxy]-7,8-dihydro-5H-1,6-naphthyridine-6-carboxamide Chemical compound ClC1=C(C=CC=C1)NC(=O)N1CC=2C=CC(=NC=2CC1)OCC1=C(N=NN1C1=CC=C(C=C1)F)C WOPJUQQSVPZRIB-UHFFFAOYSA-N 0.000 description 1
- 229940124635 NMED-160 Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000004404 Neurofibroma Diseases 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 102100029409 Neuromedin-K receptor Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- GMPZPHGHNDMRKL-RZDIXWSQSA-N O([C@H]1CC[C@@H](CC1)C1=NN=C2CN(CC3=CC(Cl)=CC=C3N21)C)C1=CC=CC=N1 Chemical compound O([C@H]1CC[C@@H](CC1)C1=NN=C2CN(CC3=CC(Cl)=CC=C3N21)C)C1=CC=CC=N1 GMPZPHGHNDMRKL-RZDIXWSQSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229940076380 PDE9 inhibitor Drugs 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 201000010769 Prader-Willi syndrome Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 206010037407 Pulmonary hypoplasia Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 102100033929 Sodium-dependent noradrenaline transporter Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 102100037346 Substance-P receptor Human genes 0.000 description 1
- 208000011963 Substance-induced psychotic disease Diseases 0.000 description 1
- 231100000393 Substance-induced psychotic disorder Toxicity 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000003691 T-Type Calcium Channels Human genes 0.000 description 1
- 108090000030 T-Type Calcium Channels Proteins 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 210000001766 X chromosome Anatomy 0.000 description 1
- CWHVJODFJFPXRZ-UHFFFAOYSA-N [3-(4-chlorophenyl)-5-methyltriazol-4-yl]methanol Chemical compound ClC1=CC=C(C=C1)N1N=NC(=C1CO)C CWHVJODFJFPXRZ-UHFFFAOYSA-N 0.000 description 1
- YTPVTPNVCHCMAT-UHFFFAOYSA-N [3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methanol Chemical compound OCC1=C(C)ON=C1C1=CC=C(F)C=C1 YTPVTPNVCHCMAT-UHFFFAOYSA-N 0.000 description 1
- PAPVCDWYFVTHQZ-UHFFFAOYSA-N [3-(4-fluorophenyl)-5-methyltriazol-4-yl]methanol Chemical compound OCC1=C(C)N=NN1C1=CC=C(F)C=C1 PAPVCDWYFVTHQZ-UHFFFAOYSA-N 0.000 description 1
- YZJVGQMWOSAMQG-UHFFFAOYSA-N [5-(4-chlorophenyl)-3-methyltriazol-4-yl]methanol Chemical compound ClC1=CC=C(C=C1)C=1N=NN(C=1CO)C YZJVGQMWOSAMQG-UHFFFAOYSA-N 0.000 description 1
- YWCDGGGUOPYQCY-UHFFFAOYSA-N [5-(4-fluorophenyl)-3-methyltriazol-4-yl]methanol Chemical compound CN1N=NC(C=2C=CC(F)=CC=2)=C1CO YWCDGGGUOPYQCY-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000001251 acridines Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229940121359 adenosine receptor antagonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 230000008856 allosteric binding Effects 0.000 description 1
- 229940125516 allosteric modulator Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 229940070164 balovaptan Drugs 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 150000001565 benzotriazoles Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 210000004781 brain capillary Anatomy 0.000 description 1
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 1
- 229960001210 brexpiprazole Drugs 0.000 description 1
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 description 1
- 229960004064 bumetanide Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000000609 carbazolyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- KPWSJANDNDDRMB-QAQDUYKDSA-N cariprazine Chemical compound C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-QAQDUYKDSA-N 0.000 description 1
- 229960005123 cariprazine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000037411 cognitive enhancing Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- ZXIJMRYMVAMXQP-UHFFFAOYSA-N cycloheptene Chemical compound C1CCC=CCC1 ZXIJMRYMVAMXQP-UHFFFAOYSA-N 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- IQQBRKLVEALROM-UHFFFAOYSA-N drinabant Chemical compound C=1C(F)=CC(F)=CC=1N(S(=O)(=O)C)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 IQQBRKLVEALROM-UHFFFAOYSA-N 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- OPQRBXUBWHDHPQ-UHFFFAOYSA-N etazolate Chemical compound CCOC(=O)C1=CN=C2N(CC)N=CC2=C1NN=C(C)C OPQRBXUBWHDHPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000009454 functional inhibition Effects 0.000 description 1
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- AFJRYPJIKHMNGL-UHFFFAOYSA-N gtpl4299 Chemical compound C1N2N=CN=C2C2=CC(Br)=CC=C2N2C=NC(C(F)F)=C21 AFJRYPJIKHMNGL-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- YKYOQIXTECBVBB-AWEZNQCLSA-N l-655,708 Chemical compound O=C1C2=CC(OC)=CC=C2N2C=NC(C(=O)OCC)=C2[C@@H]2CCCN21 YKYOQIXTECBVBB-AWEZNQCLSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 230000008449 language Effects 0.000 description 1
- 229950007396 lecozotan Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960000423 loxapine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960004938 molindone Drugs 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- YHYKUSGACIYRML-KRWDZBQOSA-N n-[3-[(5r)-3-amino-2,5-dimethyl-1,1-dioxo-6h-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide Chemical compound C1S(=O)(=O)N(C)C(N)=N[C@]1(C)C1=CC(NC(=O)C=2N=CC(F)=CC=2)=CC=C1F YHYKUSGACIYRML-KRWDZBQOSA-N 0.000 description 1
- YUTIXVXZQIQWGY-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=CC=C2SC(NC(=O)C)=NC2=C1OC(N=CN=1)=CC=1C1=CC=C(C(F)(F)F)C=C1 YUTIXVXZQIQWGY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000008284 neuronal mechanism Effects 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940124643 non-selective drug Drugs 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001354 painful effect Effects 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229960002957 praziquantel Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SCHKZZSVELPJKU-UHFFFAOYSA-N prx-03140 Chemical compound O=C1N(C(C)C)C=2SC=CC=2C(O)=C1C(=O)NCCCN1CCCCC1 SCHKZZSVELPJKU-UHFFFAOYSA-N 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- FXIDXTIMKAEBGY-UHFFFAOYSA-N pwz-029 Chemical compound C1N(C)C(=O)C2=CC(Cl)=CC=C2N2C=NC(COC)=C21 FXIDXTIMKAEBGY-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000849 selective androgen receptor modulator Substances 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 1
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000004039 social cognition Effects 0.000 description 1
- 239000003195 sodium channel blocking agent Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- WPGQCIFKYNDOET-UHFFFAOYSA-N spiro[1h-2-benzofuran-3,2'-oxane] Chemical compound C12=CC=CC=C2COC21CCCCO2 WPGQCIFKYNDOET-UHFFFAOYSA-N 0.000 description 1
- MXXGFDQBAJVZQC-UHFFFAOYSA-N spiro[cyclobutane-1,3'-indole] Chemical compound C1CC2(C1)C=NC1=C2C=CC=C1 MXXGFDQBAJVZQC-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FANKTZOGLUPXMH-UHFFFAOYSA-N tert-butyl 2-phenylmethoxy-7,8-dihydro-5H-1,6-naphthyridine-6-carboxylate Chemical compound C(C1=CC=CC=C1)OC1=NC=2CCN(CC=2C=C1)C(=O)OC(C)(C)C FANKTZOGLUPXMH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- QGHREAKMXXNCOA-UHFFFAOYSA-N thiophanate-methyl Chemical compound COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC QGHREAKMXXNCOA-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009478 tonic inhibition Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000008523 triazolopyridines Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000006004 trihaloethyl group Chemical group 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 229950003000 verubecestat Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- WJJYZXPHLSLMGE-UHFFFAOYSA-N xaliproden Chemical compound FC(F)(F)C1=CC=CC(C=2CCN(CCC=3C=C4C=CC=CC4=CC=3)CC=2)=C1 WJJYZXPHLSLMGE-UHFFFAOYSA-N 0.000 description 1
- 229960004664 xaliproden Drugs 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- 229960002811 ziconotide Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
-
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供式(I)的化合物和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型,其对γ‑氨基丁酸A受体亚单元α5具有亲和性及选择性且充当为GABAAα5负向别构调节剂,由此有用于治疗或预防与GABAAα5受体相关的疾病,提供其制备方法、包含它们单独或与一种或多种其他活性成分组合的药物组合物及它们作为药物的用途。
Description
【技术领域】
本发明提供对γ-氨基丁酸A受体亚单元α5(GABAAα5)具有亲和性及选择性且充当为GABAAα5负向别构调节剂(GABAAα5NAM)的式(I)的化合物,由此有用于治疗或预防与GABAAα5受体相关的疾病,提供其制备方法、包含它们的药物组合物及它们作为药物的用途。
【背景技术】
γ-氨基丁酸(GABA)为中枢神经系统中主要的抑制性神经传导物。对GABA敏感的受体分为两个主要家族:配体门控GABAA受体及G蛋白偶合GABAB受体。
配体门控GABAA受体调整哺乳动物脑中的大多数抑制性神经传导。受体由形成配体门控Cl--信道的多种亚单元(α1-6、β1-3、γ1-3、δ、ε、π、θ、ρ1-3)(Olsen和Sieghart的Pharmacol Rev 2008,60:243-260)的五聚体装配所组成。亚单元在脑中的分布具有发育及区域上的不同。此高变异性导致抑制性神经元机制的广泛变化且对特定的治疗性干预提供可能性(Fritschy和的J Comp Neurol 1995,359:154-194)。GABAA受体的生理学角色及药理学概况极力地取决于亚单元构成。对遗传修饰型小鼠的研究证实受体亚单元组成(尤其关于α亚型)很大程度上决定作用在苯并二氮平敏感性别构调节位点(BDZ位点)上的化合物的药理性(Rudolph和Knoflach的Nat Rev Drug Discov 2011,10:685-697)。广泛分布的含α1的受体调整镇静和健忘效应,而含α2和α3的受体负责抗焦虑、抗惊厥和肌肉松弛效应(Sieghart和Sperk的Curr Top Med Chem 2002,2:795-816;Whiting等人的DrugDiscov Today 2003,8:445-450)。含α5亚单元的受体(α5GABAARs)优先表达在啮齿动物和灵长类动物二者的海马中且被认为与认知功能有牵连(Wisden等人的J Neurosci 1992,12:1040-1062;Quirck等人的Neuropharmacol 1996,35:1331-1335;Sur等人的Brain Res1999,822:265-270)。
这些含α5的受体主要为突触外受体且调整持续性抑制作用(tonic inhibition)(Caraiscos等人的Proc Natl Acad Sci USA2004,101:3662-3667)。它们对海马及皮层主要神经元的兴奋性的抑制效应可解释α5GABAAR在认知、学习和记忆方面的显著效应及它们在各种包括下列障碍方面的潜在治疗效用:中风、认知损害、精神分裂症、失智相关病症或与社会认知受损相关的疾病(Soh和Lynch的Curr Drug Targets 2015,16:735-746)。
作用在BDZ-位点上的早期调节剂为具有抗焦虑、镇静、麻醉或抗惊厥效力的GABA增强剂或具有认知增强效应的部分阻断剂(或者称为反向激动剂或负向别构调节剂(NAM))的非选择性化合物。GABAA受体激动剂及强化剂已作为临床实施中的有效药物特征化(Foster和Kemp的Curr Opin Pharmacol 2006,6:7-17),而NAM迄今仅在动物行为实验中及很少的人体研究中做过测试(Soh和Lynch的Curr Drug Targets 2015;16:735-746)。结果显示有利的活性,然而非选择性作用在许多GABAA受体亚型上的药物导致非所期望的CNS副作用,如镇静、健忘、药物滥用、焦虑、激动或惊厥。因此,GABA研究倾向于设计选择性靶向特异性GABAA受体亚型(它们之中的α5GABAAR)的新药物(的Adv Pharmacol 2015,72:1-36)。
α5亚单元的缺失揭露了含α5的受体在神经可塑性(Martin等人的J Neurosci2010,30:5269-5282)及高频率神经网络振荡(Glykis等人的J Neurosci 2008 28:1421-1426)中的角色,从根本上涉及注意力、讯息处理和记忆的过程。在遗传上或药理上降低的α5亚单元功能导致啮齿动物模式的认知能力的显著改善(和Rudolph的F1000Research,2017 6[F1000 Faculty Rev]:101)。体外及体内实验二者皆显示GABAAα5的负向别构调节为治疗或预防其各种病理学病症或症状的有前途的策略。α5GABAAR的选择性反向激动剂,即NGD97-1(Bednar等人的Clin Pharmacol Ther 75,2004 75:P30)、α5IA(WO 02/06285A1;Dawson等人的J Pharmacol Exp Ther 2006,316:1335-1345;Braudeau等人的J Psychopharmacol 2011,25:1030-1042)、L-655,708(Quirck等人的Neuropharmacol1996,35:1331-1335;Atack等人的Neuropharmacology 2006,51:1023-102)、α5IA-II(WO98/50385A1;Collinson等人的Psychopharmacology 2006;188:619-628)、MRK-016(WO 99/67245A1;Atack等人的J Pharmacol Exp Ther.2009,331:470-484)、HT-2678(Gupta等人的241st ACS National Meeting,Anaheim,CA,March 27-31,2011,MEDI 17)、PWZ-029(WO2007/018660 A2;Savic等人的Brain Res 2008;1208:150-159;Biawat,Thesis at TheUniversity of Wisconsin-Milwaukee,August 2014)、TB-21007(Chambers等人的J MedChem2003,46:2227-2240)、ONO-8590580(Higashino等人的XXIV InternationalSymposium on Medicinal Chemistry,Manchester,UK-August 29,2016,Abstract P280;Kawaharada等人的J Pharm Exp Ther 2018,366:58-65)、RO4938581(Ballard等人的Psychopharmacology 2009,202(1-3):207-223)、RO4882224(Knust等人的Bioorg MedChem Lett.2009,19:5940-5944)、巴米沙尼(basmisanil)(WO 2009/071476 A1;WO 2012/059482 A1;Hipp等人的Neuropsychiatric Electrophysiology 2016,2(Suppl 1):A20)及选择性α5GABAAR竞争阻断剂S44819(Gacsályi等人的Neuropharmacology 2017,125:30-38)在临床前研究中如预期般证明有效缓解认知损害而不具有促生焦虑、促惊厥或运动性副作用。α5IA的认知改善效应是在早期的试验性研究中在健康的志愿者中证实(Nutt等人的Neuropharmacology 2007,53:810-820)。另外,巴米沙尼(以RG1662或RO5186582编号)(在与精神分裂症相关性认知损害(NCT02953639)的临床开发中的α5选择性化合物)导致唐氏综合征患者中显著增加的高频率γ震荡的EEG活动,表明对认知功能的潜在促进效应(Bolognani等人的67th Annu Meet Am Acad Neurol Washington,DC,April 23,2015,Abst P6.273)。迄今未曾报导临床测试的α5阻断剂α5IA、S44819或巴米沙尼的CNS副作用(Atack等人的Pharmacol Therap2010,125:11-26;Darmani等人的J Neurosci 2016,36:12312-12320;Wandel等人的Eur Neuropsychopharmacol 2015 25(Suppl2):S259)。以临床前数据及临床发现为基础,可预测α5-亚单元选择性负向调节剂的有利的临床概况。
与非选择性药物相比,由于α5GABAAR的特定功能及分隔式CNS表达概况,终究使负向调节其功能的选择性及温和干预可具有治疗利益。
因此,对α5GABAAR、GABAAα5NAM分别具有高亲和性及选择性的化合物可单独或与一种或多种其他活性成分组合用于治疗或预防中枢神经系统障碍,其中疾病的症状和/或综合征的一可能与GABAAα5受体相关。这些障碍包括但不限于神经认知障碍(Collinson等人的J Neurosci 2002,22:5572-5580),诸如阿尔茨海默疾病(AD)(Kwakowsky等人的JNeurochem 2018,145:374-392;Solas等人的Curr Pharm Des 2015;21:4960-4971;Wu等人的Nat Commun2014,4159)、前驱性AD和轻度认知损害(Maubach的Curr Drug Targets CNSNeurol Disord 2003,2:233-239)、血管性认知损害和血管性痴呆(Gacsályi等人的Eur JPharmacol 2018,834:118-125)、额颞叶退化,包括额颞叶型痴呆、进行性核上神经麻痹症和皮质基底核综合征(Murley和Rowe的Brain 2018,5:1263-1285)、路易氏体(Lewy body)型痴呆(Khundakar等人的Acta Neuropathol Commun2016,4:66)、年龄相关性记忆损害和认知衰退(Koh等人的Neuropharmacology 2013,64:142-152)、与脑癌相关性认知损害,包括但不限于髓母细胞瘤(medulloblastoma)(Sengupta等人的CNS Oncol 2014,3:245-247)、手术后痴呆(Cheng等人的J Neurosci 2006,26:3713-3720)、发炎诱导性痴呆(Wang等人的Cell Rep 2012,2:488-496)、与疾病相关性认知损害,包括但不限于偏头痛和紧张性头痛(Russo等人的Am J Hum Genet 2005,76:327-333)、多发性硬化症(Stefano和Giorgio的Brain 2015,138:2467-2468)、帕金森氏症(Blaszczyk,Front Neurosci 2016,10:269-277)、癫痫(Schipper等人的Mol Neurobiol 2016,53:5252-5265)、注意力不足过动症和成人注意力不足(Bollmann等人的Transl Psychiatry 2015,8:e589;Edden等人的Arch Gen Psychiatry 2014,69:750-753)或其他CNS疾病,包括但不限于创伤后压力障碍(Lu等人的Neuronal Plast 2017,2017:5715816)、精神分裂症(Guidotti等人的Psychopharmacology2005,180:191-205)、与精神分裂症相关性阳性、阴性和/或认知症状(Asai等人的Schizophrenia Res 2008,99:333-340;Gill等人的Neuropsychopharmacology 2011,36:1903-1911;Hauser等人的Mol Psychiatry 2005,10:201-207;Redrobe等人的Psychopharmacology2012,221:451-468)、双相障碍(Otani等人的Neurosci Lett 2005,381:108-113)、泛自闭症障碍(ASD)(Mendez等人的Neuropharmacology 2013,68:195-201)、X染色体易裂症(Curia等人的Cereb Cortex2009,19:1515-1520)、普瑞德-威利(Prader-Willi)综合征(Bittel等人的J Med Genet2003,40:568-574)、唐氏综合征(Braudeau等人的J Psychopharmacol 2011,25:1030-1042;Martinez-Cue等人的J Neurosci 2013,33:953-966)、亨廷顿氏(Huntington)舞蹈症(Du等人的Front Mol Neurosci.2017,10:198)、第I型神经纤维瘤(Ribeiro等人的Cortex2015,64:194-208)、睡眠障碍(Mesbah-Oskui等人的Neurotoxicol Teratol 2017,61:115-122)、酒精中毒(Stephens等人的Eur J Pharmacol 2005,526:240-250)、胎儿酒精综合征(Toso等人的Am J Obstet Gynecol 2006,195:522-527)、情感障碍(Carreno等人的Int JNeuropsychopharmacol 2017,20:504-509;Choudary等人的Proc Natl Acad Sci USA2005,102:15653-15658;Fischell等人的Neuropsychopharmacology 2015;40:2499-2509)、精神病障碍(Wearne等人的Neuropharmacology 2016,111:107-118)、物质诱导性精神病障碍(Neugebauer等人的Behav Brain Res 2018,342:11-18)、焦虑障碍(Behlke等人的Neuropsychopharmacology 2016,41:2492-2501;Botta等人的Nat Neuroscience 2015,18:1493-1500)、恐惧相关障碍(Botta等人的Nat Neuroscience 2015,18:1493-1500;Crestani等人的Proc Natl Acad Sci USA 2002,99:8980-8985)、压力障碍(Fischell等人的Neuropsychopharmacology 2015;40:2499-2509)、行为或药物成瘾(Mick等人的AddictBiol 2017,22:1601-1609)、中风(Clarkson等人的Nature 2010,468:305-309;Lake等人的J Cereb Blood Flow Metab 2015,35:1601-1609)、神经病性疼痛(Xiao等人的Proc NatlAcad Sci USA 2002,99:8360-8365)和发炎性疼痛(Bravo-Hernández等人的Eur JPharmacol.2014,734:91-97;Munro等人的Neuropharmacology 2011,61:121-132)。调节α5GABAAR还可有利于治疗疾病和病症,包括但不限于支气管收缩疾病,诸如但不限于气喘、慢性阻塞性肺部疾病和肺支气管发育不全(Gallos等人的Am J Physiol Lung Cell MolPhysiol 2015,308:L931-942;Mizuta等人的Am J Physiol Lung Cell Mol Physiol2008,294:L1206-1216)。特别期望能够调节α5GABAAR的化合物为治疗神经认知障碍、阿尔茨海默疾病和精神分裂症的有用的候选物。
作用在GABAA受体的α5亚单元上的许多结构上不同的化合物为本技术中已知(Guerrini等人的Expert Opin Ther Patents 2013,23(7):843-866),包括异噁唑(例如WO2009/071464 A1、WO 2009/071477 A1、WO 2010/097368 A1、WO 2010/112475 A1、WO 2010/127978 A1)和三唑衍生物(例如WO 2012/062687 A1、WO 2014/001281 A1)。
作为NR1 H4(类法尼醇(farnesoid)X或FXR)受体激动剂的特定的异噁唑和三唑衍生物说明于例如WO 2017/133521 A1、WO 2013/007387 A1、WO 2008/157270 A1或WO 2007/140174 A2中。而且,作为LXR(肝X受体)调节剂的四氢异喹啉衍生物揭示于例如WO 2007/047991 A1中。
尽管有许多GABAAα5受体的研究及调节剂,但是仍对提供可用于治疗或预防与GABAAα5受体相关的疾病的化合物有持续不满足的需求。
【发明内容】
本发明提供式(I)的化合物
其中,
A代表
基团、/>基团或/>基团,
R1为氢或卤素,
n和m各自独立地为1或2,
R2为氢;任选地且独立地经一个或多个卤素、C1-4烷氧基、-S(O)2-C1-4烷基或R3取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基,
和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。
本发明提供如上文定义的式(I)的化合物,其用于治疗或预防与GABAAα5受体相关的疾病。
本发明提供如上文定义的式(I)的化合物的用途,其用于制造用于治疗或预防与GABAAα5受体相关的疾病的药物。
本发明提供用于治疗或预防与GABAAα5受体相关的疾病的方法,其包含对此治疗或预防有需要的个体(包括人类)给予有效量的至少一种如上文定义的式(I)的化合物。
本发明提供如上文定义的式(I)的化合物与一种或多种其他活性成分的组合用途,其用于治疗或预防与GABAAα5受体相关的疾病。
本发明提供含有如上文定义的式(I)的化合物作为活性成分的药物组合物。
本发明提供包含如上文定义的式(I)的化合物与一种或多种其他活性成分的组合的药物(组合药物组合物)。
本发明提供含有单独或与一种或多种其他活性成分组合的如上文定义的式(I)的化合物作为活性成分的药物组合物,其用于治疗或预防与GABAAα5受体相关的疾病。
本发明提供用于制造如上文定义的式(I)的化合物的方法。
本发明还提供含有单独或与一种或多种其他活性成分组合的如上文定义的式(I)的化合物的药物组合物的化学或药物制剂。
【具体实施方式】
本发明提供对含有γ-氨基丁酸A受体的α5亚单元(GABAAα5受体)具有亲和性及选择性且充当为GABAAα5受体负向别构调节剂的式(I)的化合物,由此有用于治疗或预防与GABAAα5受体相关的疾病,提供其制备方法、包含它们单独或与一种或多种其他活性成分组合的药物组合物及它们作为药物的用途。
本发明关于式(I)的化合物
其中
A代表
基团、/>基团或/>基团,
R1为氢或卤素,
n和m各自独立地为1或2,
R2为氢;任选地且独立地经一个或多个卤素、C1-4烷氧基、-S(O)2-C1-4烷基或R3取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基,
和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。
除非另有其他定义,否则本文所使用的所有技术及科学术语具有与本领域普通技术人员共同理解的相同意义。尽管类似或等同于那些本文所述的方法及材料可用于本发明的实施或测试,但是在下文说明适合的方法及材料。
所使用的命名是基于IUPAC系统命名,除非另有其他指示。
出现在结构的碳、氧、硫或氮原子上的任何开放价数在本文表示氢的存在,除非另有其他指示。
本文所使用的通用术语的定义于下文说明,无论所讨论的术语是否单独或与其他群组组合呈现。
“任选的”或“任选地”意指随后说明的事件或状况可能但未必会发生,且该说明包括事件或状况发生的事例及不发生的事例。
术语“取代基”表示置换母体分子上的氢原子的一个原子或一组原子。
术语“经取代”表示指定的基团携有一个或多个取代基。
当指示取代基的数目时,则术语“一个或多个”是指一个取代基至最高可能数目的取代基的范围,即以取代基置换一个氢至最多置换所有的氢。优选一、二或三个取代基在给出的原子上(尤其为碳原子上)。
在任何基团可携带多个取代基且提供多种可能的取代基的情况下,取代基是经独立地选择且未必为相同的。
术语“未经取代”意指指定的基团未携有任何取代基。
术语“任选地经取代”意指指定的基团的任何原子未经取代或经一个或多个独立地选自可能的取代基群组的取代基取代。当指示取代基的数目时,则术语“一个或多个”意指一个取代基至最高可能数目的取代基,即以取代基置换一个氢至最多置换所有的氢。可能的取代基包括但不限于C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基、氧代基及类似者。
单独或与其他基团组合的术语“C1-4烷基”是指直链或支链、单个或多个支链烃基且由1至4个碳原子所组成。实例包括但不限于甲基、乙基、丙基、异丙基(i-propyl)(异丙基(isopropyl))、正丁基、2-丁基(仲丁基)或叔丁基(t-butyl)(叔丁基(tert-butyl))。优选的烷基为C1-3烷基。
单独或与其他基团组合的术语“C1-4烷氧基”是指-O-C1-4烷基,其中C1-4烷基是如上文所定义。实例包括但不限于甲氧基、乙氧基、异丙氧基、正丙氧基或叔丁氧基。优选的烷氧基为C1-3烷氧基。
单独或与其他基团组合的术语“-S(O)2-C1-4烷基”是指经-S(O)2-取代的C1-4烷基,其中C1-4烷基是如上文所定义。实例包括但不限于甲基磺酰基、乙基磺酰基、异丙基磺酰基、正丙基磺酰基、仲丁基磺酰基或叔丁基磺酰基。优选的磺酰基为-S(O)2-C1-3烷基。
单独或与其他基团组合的术语“卤素”、“卤代(halo)”或“卤化物”是指氟(fluoro)(氟(fluorine))、氯(chloro)(氯(chlorine))、溴(bromo)(溴(bromine))或碘(iodo)(碘(iodine)),优选为氟(氟)、氯(氯)或溴(溴)。优选的卤素为氟和氯。
单独或与其他基团组合的术语“卤代C1-4烷基”是指在该C1-4烷基的任何碳原子上经一个或多个相同或不同的卤素取代的如上文定义的C1-4烷基,以及包括邻近和原始的卤取代。术语“全卤烷基”是指其中所有的氢原子经相同或不同的卤素原子置换的C1-4烷基。实例包括但不限于单卤-、二卤-或三卤-甲基、-乙基或-丙基,例如3,3,3-三氟丙基、2-氟乙基、2,2,2-三氟乙基、氟甲基或三氟甲基。优选的卤烷基为卤代C1-3烷基。
单独或与其他基团组合的术语“碳环”是指包含3至14个碳环原子的单价单环或双环、稠合或桥连、饱和、单-或双-不饱和或芳族环系统。术语“环烷基”是指包含3至10个碳环原子的单价单环或双环、稠合或桥连、饱和碳环基团。实例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、环辛烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷或金刚烷及类似者。优选的环烷基为单环。优选的单环状环烷基为3至6元。术语“环烯基”是指包含3至10个碳环原子的单价单环或双环、稠合或桥连、单-或双-不饱和碳环基团。实例包括环丁烯、环戊烯、环戊二烯、环己烯、环己二烯、环庚烯、十氢萘及类似者。优选的环烯基为单环。优选的单环状环烯基为4至6元。术语“芳基”是指包含6至14个碳环原子的单价、单-或双环芳族碳环基团。双环芳基包含至少一个芳族碳环基团。实例包括苯基、二氢茚、茚、萘基、二氢萘(dialin)、四氢萘、蒽基、薁基(azulenyl)、二氢茚基及类似者。优选的芳基为6至10元。优选的芳基为单环。优选的单环芳基为苯基。
单独或与其他基团组合的术语“杂环”是指包含1、2、3或4个独立地选自N、O及S的环杂原子,其余环原子为碳的3至10个环原子的单价饱和或部分不饱和单环、双环、稠合、桥连或螺环系统。优选的杂环为单环。单环杂环的实例为氮丙啶、2H-氮并环(azirine)、环氧乙烷、硫杂丙环、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、氮杂环丁烷-2-酮、吡咯烷、吡咯烷酮、吡咯啉、吡唑烷、咪唑啉、吡唑啉、四氢呋喃、二氢呋喃、二氧杂环戊烷(dioxolane)、四氢噻吩、噁唑烷、二氢噁唑、异噁唑烷、氧硫杂环戊烷、环丁砜、噻唑烷、噻唑烷二酮、琥珀酰亚胺、噁唑烷酮、尿囊素、哌啶、哌啶酮、哌嗪、四氢吡喃、四氢硫代吡喃、二氢吡喃、四氢吡啶、二噁烷、硫杂环己烷(thiane)、二硫杂环己烷、1,1-二氧代基硫杂环己烷、吗啉、硫代吗啉、1,1-二氧代基硫代吗啉、氮杂环庚烷、二氮杂环庚烷、高哌嗪、氧氮杂环庚烷基及类似者。优选的单环杂环为4至6元。优选的单环杂环为饱和的。双环、稠合、桥连或螺杂环的实例为双稠吡咯烷(pyrrolizidine)、二氢吡咯并吡咯、四氢吡咯并吡咯、呋喃并吡咯、噻吩并吡咯、吲哚啉、吲哚、异吲哚、苯并异噻唑酮、十氢异喹啉、十氢喹啉、四氢喹啉、二氢喹啉、二氢异喹啉、色烯、异色烯、苯并噁嗪、奎宁环、氮杂金刚烷、螺[环丁烷-1,3’-吲哚]、1-氧杂螺[4.5]癸烷、1,6-氧杂螺[3.4]辛烷、8-氮杂-双环[3.2.1]辛烷、8-氧杂-3-氮杂-双环[3.2.1]辛烷、四氢-螺[异苯并呋喃-1,2’-吡喃]、1-氧杂螺[4.4]壬烷-2-酮、2-氧杂-7-氮杂螺[3.5]壬烷、1,4-二氧杂-7-氮杂螺[4.4]壬烷、1,3-二氮杂螺[4.4]壬-2-烯-4-酮、9-氮杂-双环[3.3.1]壬烷、3-氧杂-9-氮杂双环[3.3.1]壬烷、3-硫杂-9-氮杂-双环[3.3.1]壬烷、1,4-二硫杂-7-氮杂螺[4.4]壬烷、8-氮杂螺[4.5]癸烷-7,9-二酮、1,3,8-三氮杂螺[4.5]癸烷-4-酮及类似者。
单独或与其他基团组合的术语“杂芳基”是指包含1、2、3或4个独立地选自N、O及S的杂原子,其余环原子为碳的5至12个环原子的单价、杂环芳族、单-或双环状环系统。双环杂芳基包含至少一个芳族环。杂芳基的实例为吡咯、呋喃、噻吩、咪唑、噁唑、异噁唑、噻唑、异噻唑、三唑、四唑、噁二唑、噻二唑、四唑、吡啶、吡嗪、吡唑、哒嗪、嘧啶、三嗪、氮杂、二氮杂/>、苯并呋喃、苯并噻吩、吲哚、异吲哚、异苯并呋喃、苯并咪唑、苯并噁唑、苯并异噁唑、苯并噻唑、苯并异噻唑、苯并噁二唑、苯并噻二唑、苯并三唑、嘌呤、喹啉、异喹啉、喹唑啉、喹噁啉、咔唑或吖啶。优选的杂芳基为5至10元。优选的杂芳基为单环。优选的单环杂芳基为5或6元。
术语“本发明的化合物(compound(s)of this invention)”,“本发明的化合物(compound(s)of the present invention)”或“如上文定义的式(I)的化合物”是指式(I)的化合物和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。而且,如下文所定义的A、R1-R7、n和m的实施方式的任何组合为式(I)的化合物的优选群组。
术语“盐”是指药学上可接受的盐和/或药学上不可接受的盐。
术语“药学上可接受的盐”是指保留式(I)的化合物的生物学效力和性质且可用适合的无毒性有机酸或无机酸或有机碱或无机碱形成的常规的酸加成盐或碱加成盐。酸加成盐的实例包括衍生自无机酸的盐,诸如但不限于衍生自盐酸、氢溴酸、氢碘酸、硫酸、胺磺酸、磷酸、硝酸和过氯酸的盐,及衍生自各种有机酸的盐,诸如但不限于衍生自乙酸、丙酸、苯甲酸、乙醇酸、苯基乙酸、水杨酸、丙二酸、马来酸、油酸、双羟萘酸、棕榈酸、苯磺酸、甲苯磺酸、甲烷磺酸、草酸、酒石酸、琥珀酸、柠檬酸、苹果酸、乳酸、谷氨酸、富马酸及类似者的盐。碱加成盐的实例为衍生自氢氧化铵、氢氧化钾、氢氧化钠和氢氧化四级铵(诸如氢氧化四甲铵)的盐。这些盐时常展现比用于它们制备的化合物更有利的溶解性质且因此更适合用于制备各种药物调配物。
“药学上不可接受的盐”对式(I)的化合物的纯化或分离可能优选且因此也在本发明的范围内。
术语“前药”是指根据本发明的式(I)的化合物的衍生物,其本身不具有治疗效应,但是含有在体外化学或代谢降解(生物转化)后变成负责治疗效应的“生物活性代谢物”的这些基团。与本发明的式(I)的化合物相关联的这些分解基团(特别为那些适合于前药的基团)为本技术中已知且也可应用于本发明的化合物(Rautio等人的Nature Reviews-DrugDiscovery 2008,7:255-270)。
式(I)的化合物可以各种几何异构体形式存在。另外,特定的式(I)的化合物可含有一个或多个不对称中心,因此以立体异构体形式及非对映异构体形式存在。术语“立体异构体”表示具有相同的分子连接性及键多重性,但其原子的空间排列不同的化合物。所有这些化合物(诸如顺式异构体、反式异构体、非对映异构体混合物、消旋体、对映异构体的非消旋性混合物、实质上纯的对映异构体和纯的对映异构体)在本发明的范围内。实质上纯的对映异构体含有至多5wt%,优选为2wt%,最优选为1wt%的相应的相反的对映异构体。
光学异构体可通过已知的方法分解消旋性混合物而制得,例如通过使用光学活性酸或碱以形成非对映异构体盐或通过形成共价非对映异构体。适合的酸包括例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、二甲苯酰基酒石酸和樟脑磺酸。非对映异构体混合物可基于它们物理和/或化学差异而分离成个别的非对映异构体,该分离是通过那些本领域技术人员已知的方法,诸如色谱法或分段结晶。接着光学活性碱或酸从经分离的非对映异构体盐释放。分离光学异构体的各种方法包括通过衍化而任选地使用的手性色谱法(例如手性HPLC柱),以达到最大的对映异构体分离为目标。适当的手性HPLC柱为Diacel柱,诸如CHIRALPAK或CHIRALCEL柱,其可依要求常规地选择。在适用的情况下,也可使用通过衍化而进行的酶催化分离。式(I)的光学活性化合物也可使用光学活性起始材料及使用手性合成法而无需消旋化反应条件来制备。
式(I)的化合物可以各种多晶型形式存在。如本技术中已知,多晶型性为化合物以一种以上的结晶形式(即多晶型形式)结晶的能力。特定化合物的多晶型形式可以相同的化学式或组成定义,而它们的化学结构不同,如两种不同的化学化合物的结晶结构。
式(I)的化合物及其盐也可以溶剂合物或水合物存在,它们也在本发明的范围内。术语“溶剂合物”是指溶剂与溶质的非共价化学计量或非化学计量组合。术语“水合物”是指水与溶质的非共价化学计量或非化学计量组合。
本发明提供包含至少一种如上文定义的式(I)的化合物作为活性成分的药物组合物。
本发明提供包含如上文定义的式(I)的化合物与一种或多种其他活性成分的组合的药物组合物。药物组合物可包含一起呈单一剂型或单独的至少一种本发明的化合物及一种或多种其他活性成分。组合的组合物可同时、分开或依序给予。
术语“药物组合物”(或“组合物”)是指欲给予有其需要的个体(例如人类)的包含治疗有效量的活性成分与药学上可接受的赋形剂的混合物或溶液。
本发明还关于药物组合物的化学及药物制剂。
本发明的药物组合物可调配成各种药物调配物,诸如但不限于固体经口剂型,诸如片剂(例如颊内、舌下、泡腾、可咀嚼、经口可分散)、胶囊、丸剂、药丸、可经口分散膜、粒剂、粉剂;液体调配物,诸如溶液、乳液、悬浮液、糖浆、酏剂、滴剂;肠胃外剂型、诸如静脉内注射液、肌内注射液、皮下注射液;其他形式的药、诸如眼滴剂、半固体眼用制剂、半固体皮肤制剂(诸如软膏、乳膏、糊剂)、透皮治疗系统、栓剂、直肠胶囊、直肠溶液、乳液和悬浮液等。
本发明的药物组合物可以各种方式给予,诸如但不限于经口、直肠、粘液、透皮或经肠给予;肠胃外给予、包括肌内、皮下、静脉内、髓内注射以及关节内、鞘内、直接心室内、腹膜内、鼻内或眼内注射和眼滴剂。
可选择地,化合物可经局部而不经全身给予,例如经常以调节释放型调配物直接注射化合物至肾脏或心脏。另外,药物可以靶向载体系统给予,例如在组织特异性抗体囊封的脂质体内。脂质体选择性地转移活性剂至靶器官供其吸收。
药物组合物可以各种方式及各种药物形式给予。本发明的化合物可以单独或与药学上可接受的赋形剂组合的单一或多个剂量给予。达成适当的治疗效应所需的剂量可广泛地改变,且总是必须适合于有关疾病的程度、欲治疗的患者的状况与体重和对活性成分的敏感性、剂量方案的方式及每日治疗次数的个人需求。
对于简单给予,优选的是药物组合物是由含有欲给予一次或少量多次或一半、三分之一、四分之一的活性成分量的剂量单位所组成。这些剂量单位为例如具备有一半或四分之一凹痕的片剂,有助于片剂分成一半或四分之一,以便于权衡所需的活性成分量。
含有根据本发明的活性成分的药物组合物通常每一剂量单位含有0.01至500mg活性成分。在各调配物中的活性成分量当然也有可能超过上述的上限或下限。
本发明还关于用于儿科应用的药物组合物,诸如但不限于溶液、糖浆、酏剂、悬浮液、用于制备悬浮液的粉剂、可分散或泡腾片剂、可咀嚼片剂、可经口分散片剂、片剂或包膜片剂、经口起泡粉剂或粒剂、胶囊。
本发明的药物组合物可以本身已知的方法制备,诸如常规的混合、溶解、乳化、悬浮、微囊化、冷冻干燥、挤出和球形化、层压、包薄膜、造粒、囊化、制糖锭或压制。
本发明的药物组合物可以常规方式使用一种或多种促进活性成分并入药学上可接受的药物形式中的生理上(或药学上)可接受的赋形剂调配。术语“生理上或药学上可接受的赋形剂”表示用于调配药物产品的任何成分,其不具有治疗活性且无毒性。适当的调配是取决于所选择的给予模式。可使用本技术中熟知的技术及赋形剂中任一者。
可应用于制备的赋形剂可选自下列类别,诸如但不限于片剂和胶囊的填充剂、片剂和胶囊的粘合剂、修饰型药物释放剂、崩解剂、助流剂、润滑剂、甜味剂、掩味剂、调味剂、包膜材料、界面活性剂、稳定剂、防腐剂或抗氧化剂、缓冲剂、复合剂、润湿剂或乳化剂、用于调节渗透压的盐、冻干赋形剂、微囊化剂、软膏材料、穿透增强剂、增溶剂、溶剂、栓剂材料、悬浮剂。适合的药物赋形剂可为例如:淀粉、微晶纤维素、滑石、葡萄糖、乳糖、明胶、二氧化硅、滑石、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、纤维素衍生物、氯化钠、甘油、丙二醇、水、乙醇及类似者。
本发明的另一实施方式关于特定的粘合剂的用途,其可改善活性成分的溶解度、溶出度、渗透性、吸收性或生物利用率,诸如但不限于亲水性聚合物、热熔融挤出赋形剂、界面活性剂、缓冲剂、复合剂、乳化剂、冻干赋形剂、崩解剂、微囊化剂、渗透促进剂、增溶剂、共溶剂、悬浮剂。
上文所述的赋形剂及各种制备方法仅为代表性实例。也可使用技术中已知的其他材料及方法技术。
术语“其他活性成分”是指治疗剂,包括但不限于乙酰胆碱酶抑制剂(诸如加兰他敏(galantamine)、卡巴拉汀(rivastigmine)、多奈哌齐(donepezil)、他可林(tacrine)、苯丝瑞林(phenserine)、拉多替吉(ladostigil)和ABT-089);NMDA受体激动剂或拮抗剂(诸如美金刚(memantine)、奈拉美生(neramexane)、EVT101和AZD4282);抗类淀粉蛋白抗体,包括抗类淀粉蛋白人源化单株抗体(诸如巴匹珠单抗(bapineuzumab)、ACCOOl、CAD 106、AZD3102、H12A11V1);β-分泌酶抑制剂(诸如凡鲁拜司他(verubecestat)和AZD3293)或γ-分泌酶抑制剂(诸如LY450139和TAK 070)或调节剂;tau磷酸化抑制剂;ApoE4构形调节剂;p25/CDK5抑制剂;NK1/NK3受体拮抗剂;COX-2抑制剂(诸如塞来昔布(celecoxib)、罗非昔布(rofecoxib)、伐地昔布(valdecoxib)、406381和644784);LRRK2抑制剂;HMG-CoA还原酶抑制剂;NSAID(诸如布洛芬(ibuprofen));维生素E;甘氨酸转运抑制剂;甘氨酸位点拮抗剂(诸如拉考沙胺(lacosamide));LXRβ激动剂;雄性素受体调节剂;Αβ寡聚物形成阻断剂;NR2B拮抗剂、抗发炎化合物(诸如(R)-氟吡洛芬(flurbiprofen)、硝基氟吡洛芬(nitroflurbiprofen)、ND-1251、VP-025、HT-0712和EHT-202);PPARγ激动剂(诸如吡格列酮(pioglitazone)和罗格列酮(rosiglitazone));CB-1受体拮抗剂或反向激动剂(诸如AVE1625);CB-2激动剂(诸如842166和SAB378);VR-1拮抗剂(诸如AMG517、705498、782443、PAC20030、VI 14380和A425619);缓激肽Bl受体拮抗剂(诸如SSR240612和NVPSAA164);钠通道阻断剂和拮抗剂(诸如VX409和SPI860);NOS抑制剂(诸如SD6010和274150);抗生素;生长激素促分泌素(诸如伊布莫仑(ibutamoren)、伊布莫仑甲磺酸盐和卡莫瑞林(capromorelin));钾通道开放剂;AMPA激动剂或AMPA调节剂(诸如CX-717、LY 451395、LY404187和S-18986);GSK3抑制剂(诸如AZD1080、SAR502250和CEP16805);神经元α7nAChR激动剂或PAM(诸如ABT-126、AZD0328、EVP-6124、AVL-3288或PNU-120596);MARK配体;M1或M4 mAChR激动剂或PAM;mGluR2拮抗剂或NAM或PAM;mGluR5拮抗剂(诸如AZD9272);α激动剂;ADAM-10配体;镇静剂、安眠药、抗焦虑药、抗精神病药、环吡咯酮、咪唑并吡啶、吡唑并嘧啶、轻量镇定剂、褪黑激素激动剂和拮抗剂、褪黑激素剂;食欲素(orexin)拮抗剂和激动剂;前动力蛋白激动剂和拮抗剂;T型钙通道拮抗剂;三唑并吡啶、苯并二氮平、巴比妥酸盐(barbiturate);5-HT1A拮抗剂(诸如来考左坦(lecozotan));5-HT2拮抗剂;5-HT4激动剂(诸如PRX-03140);5-HT6拮抗剂(诸如GSK 742467、SGS-518、FK-962、SL-65.0155、SRA-333和沙利罗登(xaliproden));组织胺H3受体拮抗剂和反向激动剂(诸如S38093、ABT-834、ABT829、GSK 189254和CEP16795);PDE4抑制剂(诸如HT0712);PDE9抑制剂(诸如BI40936);PDE10抑制剂;HDAC抑制剂;KCNQ拮抗剂;GABAA传讯增强剂(诸如L-838,417、TPA-023、阿法沙龙(alphaxalone)、加那梭龙(ganaxolone)、加波沙朵(gaboxadol)、替加宾(tiagabine)、维加巴汀(vigabatrine)、布米他奈(bumetadine))和阻断剂(诸如S44819)、GABAB传讯增强剂(诸如贝可芬(baclofen))、V1a受体拮抗剂(诸如巴洛维坦(balovaptan));MAO-B抑制剂;多巴胺转运抑制剂;降肾上腺素转运抑制剂;D2激动剂和部分激动剂;抗胆碱能药(诸如比培立汀(biperiden));COMT抑制剂(诸如恩他卡朋(entacapone));A2a腺苷受体拮抗剂;胆碱能激动剂;选自神经弛缓剂的酚噻嗪(phenothiazine)、噻吨(thioxanthene)(诸如氯丙硫蒽(chlorprothixene)和替沃噻吨(thiothixene))、杂环二苯并氮平(诸如氯氮平(clozapine))、丁酸酚酮(诸如氟哌啶醇(haloperidol))、二苯基丁基哌啶(诸如匹莫齐特(pimozide))和吲哚酮(诸如莫利多酮(molindolone))分类的化合物;洛沙平(loxapine)、舒必利(sulpiride);非典型抗精神病药(诸如阿立哌唑(aripiprazole)、阿塞那平(asenapine)、普瑞斯哌唑(brexpiprazole)、卡利拉秦(cariprazine)、伊洛哌酮(iloperidone)、鲁拉西酮(lurasidone)、奥氮平(olanzapine)、帕潘立酮(paliperidone)、喹硫平(quetiapine)、利培酮(risperidone)和齐拉西酮(ziprasidone));左旋多巴(levodopa);钙通道阻断剂(诸如齐考诺肽(ziconotide)和NMED160);MMP抑制剂;血栓溶解剂;类鸦片止痛药(诸如可待因(codeine)、芬太尼(fentanyl)、氢吗啡酮(hydromorphone)、左啡诺(levorphanol)、得美乐(meperidine)、美沙酮(methadone)、吗啡(morphine)、羟考酮(oxycodone)、羟吗啡酮(oxymorphone)、戊唑辛(pentazocine)、丙氧芬(propoxyphene));普拉克索(pramipexole);罗匹尼诺(ropinirole);嗜中性球抑制因子;SSRI或SSNRI;三环抗忧虑药;降肾上腺素调节剂;锂;丙戊酸盐;加巴喷丁(gabapentin);普瑞巴林(pregabalin);利扎曲普坦(rizatriptan);佐米曲普坦(zolmitriptan);那拉曲坦(naratriptan)和舒马曲坦(sumatriptan)或影响受体或酶的其他药物,其使本发明的化合物的效力、安全性、方便性增加或使本发明的化合物的不良副作用或毒性降低。
在一个实施方式中,其他活性成分是指乙酰胆碱酶抑制剂(诸如加兰他敏、卡巴拉汀、多奈哌齐、他可林、苯丝瑞林(phenserine)、拉多替吉和ABT-089);NMDA受体激动剂或拮抗剂(诸如美金刚、奈拉美生、EVT101和AZD4282);抗类淀粉蛋白抗体,包括抗类淀粉蛋白人源化单株抗体(诸如巴匹珠单抗、ACCOOl、CAD 106、AZD3102、H12A11V1);β-分泌酶抑制剂(诸如凡鲁拜司他和AZD3293)或γ-分泌酶抑制剂(诸如LY450139和TAK 070)或调节剂;tau磷酸化抑制剂;ApoE4构形调节剂;甘氨酸转运抑制剂;AMPA激动剂或AMPA调节剂(诸如CX-717、LY 451395、LY404187和S-18986);神经元α7nAChR激动剂或PAM(诸如ABT-126、AZD0328、EVP-6124、AVL-3288或PNU-120596);5-HT6拮抗剂(诸如GSK 742467、SGS-518、FK-962、SL-65.0155、SRA-333和沙利罗登);组织胺H3受体拮抗剂和反向激动剂(诸如S38093、ABT-834、ABT 829、GSK 189254和CEP16795);GABAA传讯增强剂(诸如L-838,417、TPA-023、阿法沙龙、加那梭龙、加波沙朵、替加宾、维加巴汀、布米他奈)和阻断剂(诸如S44819)、GABAB传讯增强剂(诸如贝可芬)、V1a受体拮抗剂(诸如巴洛维坦);D2部分激动剂;胆碱能激动剂;选自镇神剂的酚噻嗪、噻吨(诸如氯丙硫蒽和替沃噻吨)、杂环二苯并氮平(诸如氯氮平)、丁酸酚酮(诸如氟哌啶醇)、二苯基丁基哌啶(诸如匹莫齐特)和吲哚酮(诸如莫利多酮)分类的化合物;洛沙平、舒必利;或非典型抗精神病药(诸如阿立哌唑、阿塞那平、普瑞斯哌唑、卡利拉秦、伊洛哌酮、鲁拉西酮、奥氮平、帕潘立酮、喹硫平、利培酮和齐拉西酮)。
术语“调节剂”是指与靶受体相互作用的分子,其中相互作用可为例如促效、拮抗或反向促效。
术语“抑制剂”是指与特定配体竞争的分子、降低或防止特定配体与特定受体结合的分子、或降低或防止特定蛋白质的功能抑制的分子。
术语“激动剂”是指对受体结合位点具有亲和性且增强经受体调整的反应的活性的化合物。“完全激动剂”实现完全反应的效应,“部分激动剂”实现少于完全活化的效应,甚至在占据总受体群时。
术语“反向激动剂”是指通过结合至相同的激动剂结合位点而产生与激动剂相反的效应,或通过结合在不同的别构结合位点上而降低激动剂效应的化合物。
术语“拮抗剂”是指减少或防止另一化合物或受体位点作用或减弱激动剂效应的化合物。“竞争性拮抗剂”是结合至与激动剂相同的位点但不活化该位点,因此阻断激动剂的作用。“非竞争性拮抗剂”是结合至受体上的别构位点以防止受体活化。“可逆性拮抗剂”与受体的结合为非共价(可洗出),而“不可逆性拮抗剂”的结合为共价(不可洗出)。
术语“别构调节剂”是指在不同于激动剂结合位点的位点上与受体结合的化合物,即结合至别构位点,其中通过诱导受体的构形变化以改变受体对内源性配体或激动剂的亲和性和/或活性。“正向别构调节剂”或“PAM”是增加亲和性,而“负向别构调节剂”或“NAM”是降低亲和性,由此间接降低受体的活性。如上文定义的式(I)的化合物为结合至选择对GABAAα5受体具有反向促效性的苯并二氮平结合位点的负向别构调节剂。
术语“抑制常数”(Ki)是指特定的抑制剂对受体的绝对结合亲和性。其是使用竞争结合测定法测量且等于若没有竞争配体存在时特定的抑制剂将会占据一半受体的情况下的浓度。Ki值可以对数方式转换成pKi值(-logKi),其中越高的值表示以指数方式越大的效力。
术语“次最大有效浓度”是指获得最大特定效应的10%所需的特定化合物的浓度。
术语“功能选择性”是指特定化合物在不同的受体亚型上不同的调节程度。在本发明中,若化合物是通过降低超过20%的GABA效应,同时影响少于10%的其他GABAA受体亚型而充当为GABAAα5受体上的反向激动剂,则化合物具有特定的功能选择性。
术语“病症”、“缺失”、“不足”、“失能”、“障碍”、“疾病”或“疾病状态”可交换使用以表示任何疾病、病症、症状、综合征、障碍或适应症。
术语“与GABAAα5受体相关的疾病”是指中枢神经系统的疾病、病症或障碍,其中疾病的症状和/或综合征中的一者可与GABAAα5受体相关。这些疾病包括但不限于神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍或其他疾病。
术语“认知”是指个体(优选为哺乳动物,更优选为人类)用于组织讯息的过程,包括获取讯息(感知)、选择(注意)、表示(理解)及保留(记忆)讯息,且使用其指导行为(动作输出的论据及协调)。改善认知功能的干预可针对这些核心机能中的任一者。
在一个实施方式中,如上文定义的式(I)的化合物是用作为认知增强剂。术语“认知增强剂”是指认知功能的改善,特别为社会认知、整体注意力(complex attention)、执行功能、知觉动作功能、语言或学习和记忆的改善。认知增强为以一些方式改善次系统,而不是修复已损坏的某些障碍或补救特定的功能障碍的干预。
与GABAAα5受体相关的疾病可显示彼此为共病。共病表示与患者中的另一病症同时存在但与其无关的医学病症,或在患者中引起的医学病症是由同一患者中的另一病症引起或在其他方面与该另一病症相关。然而,在精神疾病、心理疾病或心智健康疾病中,共病不一定暗示有多种疾病存在,而是可反映出吾等目前无法提供说明所有症状的单一诊断。
术语“神经退化性障碍”包括但不限于阿尔茨海默疾病(AD)、亨廷顿氏舞蹈症(HD)、帕金森氏症(PD)或肌萎缩性侧索硬化症(ALS)。
术语“神经认知障碍”包括但不限于认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆(或其不同的形式,诸如在阿尔茨海默疾病、尼曼匹克症(NiemannPick-disease)、帕金森氏症或亨廷顿氏舞蹈症中的痴呆,痴呆合并路易氏体(DLB)、额颞叶型痴呆、血管性痴呆(VaD)、皮质下痴呆、混合型血管与皮质下痴呆、多发性梗塞型痴呆、手术后痴呆或发炎诱导性痴呆)、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害(包括但不限于髓母细胞瘤)、唐氏综合征(DS)的认知衰退或重度抑郁症(MDD)的认知功能障碍。
术语“精神分裂症”包括但不限于不同形式的精神分裂症,与精神分裂症、准精神分裂症及妄想症相关性阳性、阴性和/或认知症状。
术语“疼痛障碍”包括但不限于致痛性、神经性或发炎性疼痛。
术语“情感障碍”包括但不限于忧郁相关障碍(诸如重度抑郁症(MDD)、低落性情感障碍、循环性情感障碍、季节性情感障碍/季节性抑郁症、创伤性脑损伤后抑郁症(TBI)、产后抑郁症、经前情绪低落症、与绝经期相关性抑郁症状、药物滥用/戒断后抑郁症、双相障碍、缓解型双相障碍或双相障碍的抑郁症发作)、双相障碍、物质(酒精或药物)诱导或待分类的情感障碍(MD-NOS)。
术语“其他疾病”包括但不限于注意力不足过动症和成人注意力不足、其他压力相关病症、中风、第I型神经纤维瘤、多发性硬化症、急性脑膜炎、酒精中毒、胎儿酒精综合征或支气管收缩疾病(诸如气喘、慢性阻塞性肺部疾病和肺支气管发育不全)。
在一个实施方式中,与GABAAα5受体相关的疾病是指阿尔茨海默疾病(AD)、亨廷顿氏舞蹈症(HD)、帕金森氏症、肌萎缩性侧索硬化症(ALS)、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆或其不同形式(诸如在阿尔茨海默疾病、尼曼匹克症、帕金森氏症或亨廷顿氏舞蹈症中的痴呆,痴呆合并路易氏体(DLB)、额颞叶型痴呆、血管性痴呆(VaD)、皮质下痴呆、混合型血管与皮质下痴呆、多发性梗塞型痴呆、手术后痴呆或发炎诱导性痴呆)、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害(包括但不限于髓母细胞瘤)、唐氏综合征(DS)的认知衰退、重度抑郁症(MDD)的认知功能障碍;不同形式的精神分裂症、与精神分裂症、准精神分裂症及妄想症相关性阳性、阴性和/或认知症状;致痛性、神经性或发炎性疼痛;抑郁症相关障碍(诸如重度抑郁症(MDD)、低落性情感障碍、循环性情感障碍、季节性情感障碍/季节性抑郁症、创伤性脑损伤后抑郁症(TBI)、产后抑郁症、经前情绪低落症、与绝经期相关性抑郁症状、药物滥用/戒断后抑郁症、双相障碍、缓解型双相障碍或双相障碍的抑郁症发作)、双相障碍、物质(酒精或药物)诱导或待分类的情感障碍(MD-NOS);注意力不足过动症和成人注意力不足、其他压力相关病症、中风、第I型神经纤维瘤、多发性硬化症、急性脑膜炎、酒精中毒、胎儿酒精综合征或支气管收缩疾病(诸如气喘、慢性阻塞性肺部疾病和肺支气管发育不全)。
在一个实施方式中,与GABAAα5受体相关的疾病是指阿尔茨海默疾病(AD)、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征(DS)的认知衰退、重度抑郁症(MDD)的认知功能障碍或精神分裂症。
本发明提供治疗或预防与GABAAα5受体相关的疾病或用于认知增强的方法,其包含对此治疗或预防有需要的个体(优选为哺乳动物,更优选为人类)给予治疗有效量的单独或与至少一种药学上可接受的赋形剂呈药物调配物形式的如上文定义的式(I)的化合物。
本发明提供治疗或预防与GABAAα5受体相关的疾病或用于认知增强的方法,其包含对此治疗或预防有需要的个体(优选为哺乳动物,更优选为人类)给予治疗有效量的与一种或多种其他活性成分组合的如上文定义的式(I)的化合物。
本发明提供治疗或预防神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍或其他疾病或其症状和/或综合征中的至少一者或用于认知增强的方法,其中疾病的症状和/或综合征中的一者可与患有该疾病的个体(优选为哺乳动物,更优选为人类)中的GABAAα5受体相关。此治疗方法包含对此治疗或预防有需要的个体(优选为哺乳动物,更优选为人类)给予治疗有效量的如上文定义的式(I)的化合物。治疗方法可包括对此治疗有需要的个体(优选为哺乳动物,更优选为人类)给予治疗有效量的药物组合物,其包含如上文定义的式(I)的化合物。
本发明提供治疗或预防患有下列疾病的个体(优选为哺乳动物,更优选为人类)中的阿尔茨海默疾病(AD)、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征(DS)的认知衰退、重度抑郁症(MDD)的认知功能障碍或精神分裂症或其症状和/或综合征中的至少一者或用于认知增强的方法。
本发明提供如上文定义的式(I)的化合物,其用于治疗或预防与GABAAα5受体相关的疾病或用作为认知增强剂。
本发明提供与一种或多种其他活性成分组合的如上文定义的式(I)的化合物,其用于治疗或预防与GABAAα5受体相关的疾病或用作为认知增强剂。
本发明提供如上文定义的式(I)的化合物,其用于治疗或预防神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍或其他疾病或其症状和/或综合征中的至少一者或用作为认知增强剂。
本发明提供如上文定义的式(I)的化合物,其用于治疗或预防阿尔茨海默疾病(AD)、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征(DS)的认知衰退、重度抑郁症(MDD)的认知功能障碍或精神分裂症或其症状和/或综合征中的至少一者或用作为认知增强剂。
本发明提供如上文定义的式(I)的化合物的用途,其用于制造用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强剂。
本发明提供如上文定义的式(I)的化合物与一种或多种其他活性成分组合的用途,其用于制造用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强剂。
本发明提供如上文定义的式(I)的化合物的用途,其用于制造用于治疗或预防神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍或其他疾病或其症状和/或综合征中的至少一者或用于认知增强剂。
本发明提供如上文定义的式(I)的化合物的用途,其用于制造用于治疗或预防阿尔茨海默疾病(AD)、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害(MCI)、血管性认知损害(VCI)、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征(DS)的认知衰退、重度抑郁症(MDD)的认知功能障碍或精神分裂症或其症状和/或综合征中的至少一者或用于认知增强剂。
本发明还关于包含如上文定义的式(I)的化合物的药物组合物,其用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强。
本发明还关于包含如上文定义的式(I)的化合物与一种或多种其他活性成分的药物组合物,其用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强。
术语“治疗”是指使已患有疾病或经诊断患有疾病的患者或个体缓解特定的病理学病症、消除或减轻病症的一种或多种症状,减缓或消除疾病状态的进展及预防或延迟病理学病症的复发。“预防(prevention)”(或预防(prophylaxis)或延迟疾病作用)通常是通过如同给予已发展出疾病或病症的患者相同或类似的方式给予药物来执行。
术语“治疗有效量”是指与未接受此量的相应个体相比而导致疾病、疾病状态或副作用的治疗、治愈、预防或改善且降低疾病或病理学病症的进展的活性成分量。该术语也包括增强正常的生理学功能的有效量。用于治疗的如上文定义的式(I)的化合物以及其任何药学上可接受的盐可作为未加工化学物以治疗有效量给予。另外,活性成分是作为药物调配物生效。如上文定义的式(I)的化合物确切的治疗有效量是取决于许多因素而定,包括但不限于个体(患者)的年龄和体重、需要治疗的疾病的精确类型和其严重性、药品的本性及给予途径。
术语“个体”是指脊椎动物。在特定的实施方式中,脊椎动物为哺乳动物。哺乳动物包括人类、非人类灵长类动物(诸如黑猩猩和其他猿与猴种类)、农场动物(诸如牛,马,绵羊,山羊和猪)、家畜(诸如兔子,狗和猫)、实验室动物(包括啮齿类动物,例如大鼠,小鼠和天竺鼠)。在特定的实施方式中,哺乳动物为人类。术语个体不表示特别的年龄或性别。
在一个实施方式中,本发明关于式(I’)的化合物
其中
R1至R7、n和m是如上文式(I)的化合物所定义,
A代表
基团、/>基团或/>基团,
其中任何环A的位置“a1”是连接至位置“a2”,且其中任何环A的位置“b1”是连接至位置“b2”。
在一个实施方式中,本发明关于式(I-a)的化合物
其中
R1为氢或卤素,
n和m各自独立地为1或2,
R2为氢;任选地且独立地经一个或多个卤素、C1-4烷氧基、-S(O)2-C1-4烷基或R3取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基,
和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。
在一个实施方式中,本发明关于式(I-b)的化合物
其中
R1为氢或卤素,
n和m各自独立地为1或2,
R2为氢;任选地且独立地经一个或多个卤素、C1-4烷氧基、-S(O)2-C1-4烷基或R3取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基,
和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。
在一个实施方式中,本发明关于式(I-c)的化合物
其中
R1为氢或卤素,
n和m各自独立地为1或2,
R2为氢;任选地且独立地经一个或多个卤素、C1-4烷氧基、-S(O)2-C1-4烷基或R3取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基,
和/或其盐和/或其几何异构体和/或其立体异构体和/或其对映异构体和/或其消旋体和/或其非对映异构体和/或其生物活性代谢物和/或其前药和/或其溶剂合物和/或其水合物和/或其多晶型。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为氢。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为氟、氯或溴。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为氢。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为卤代C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为C1-4烷氧基C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为甲氧基甲基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为C1-4烷基-S(O)2-C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为甲基磺酰基甲烷或乙基磺酰基甲烷。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为经任选地取代的碳环、杂环或杂芳基取代的C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4和R5为氢。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4和R5为C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4为氢,R5为C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4为氢,R5为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4为C1-4烷基,R5为C1-4烷基或任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4和R5与它们连接的N一起形成任选地经取代的杂环。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为NR4R5,且R4为氢,R5为任选地经取代的杂环,或R4和R5与它们连接的N一起形成任选地经取代的单环杂环。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为任选地经取代的C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中R2为经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代的C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中任选地经取代的碳环、杂环或杂芳基选自包含环丙基、环丁烷、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉的群组。
在一个实施方式中,本发明关于式(I)的化合物,其中n为1,及m为2。
在一个实施方式中,本发明关于式(I)的化合物,其中n为2,及m为1。
在一个实施方式中,本发明关于式(I)的化合物,其中n和m为1。
在一个实施方式中,本发明关于式(I)的化合物,其中n为2,及m为2。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为卤素,n和m各自独立地为1或2,且R2为C1-4烷氧基C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为卤素,n和m各自独立地为1或2,且R2为C1-4烷基-S(O)2-C1-4烷基。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为卤素,n和m各自独立地为1或2,且R2为NR4R5。
在一个实施方式中,本发明关于式(I)的化合物,其中R1为卤素,n和m各自独立地为1或2,且R2为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟、溴或氯,
R2为C1-3烷基、C1-4烷氧基C1-3烷基、C1-3烷基-S(O)2-C1-3烷基、NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7,及
R6和R7为C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟或氯,
R2为C1-4烷氧基C1-3烷基、甲基磺酰基甲烷、乙基磺酰基甲烷、NR4R5或R6,
R4和R5各自独立地为氢、C1-3烷基或R7,及
R6和R7为选自包含下列者的群组的碳环、杂环或杂芳基:环丙基、环丁烷、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为卤素,
n为1,及m为2,
R2为任选地且独立地经C1-4烷氧基、-S(O)2-C1-4烷基取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟、氯或溴,
n为1,及m为2,
R2为C1-3烷基、C1-4烷氧基C1-3烷基、C1-3烷基-S(O)2-C1-3烷基、NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7,及
R6和R7为C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟或氯,
n为1,及m为2,
R2为C1-4烷氧基C1-3烷基、甲基磺酰基甲烷、乙基磺酰基甲烷、NR4R5或R6,
R4和R5各自独立地为氢、C1-3烷基或R7,及
R6和R7为选自包含下列者的群组的碳环、杂环或杂芳基:环丙基、环丁烷、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为卤素,
n为2,及m为1,
R2为任选地且独立地经C1-4烷氧基、-S(O)2-C1-4烷基取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R3、R6和R7为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟、溴或氯,
n为2,及m为1,
R2为C1-3烷基、C1-4烷氧基C1-3烷基、C1-3烷基-S(O)2-C1-3烷基、NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7,及
R6和R7为C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟或氯,
n为2,及m为1,
R2为C1-4烷氧基C1-3烷基、甲基磺酰基甲烷、乙基磺酰基甲烷、NR4R5或R6,
R4和R5各自独立地为氢、C1-3烷基或R7,及
R6和R7为选自包含下列者的群组的碳环、杂环或杂芳基:环丙基、环丁烷、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为卤素,
n和m为1,
R2为任选地且独立地经C1-4烷氧基、-S(O)2-C1-4烷基取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R6和R7为任选地经取代的碳环、杂环或杂芳基。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟、氯或溴,
n和m为1,
R2为C1-3烷基、C1-4烷氧基C1-3烷基、C1-3烷基-S(O)2-C1-3烷基、NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7,及
R6和R7为C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为氟或氯,
n和m为1,
R2为C1-4烷氧基C1-3烷基、甲基磺酰基甲烷、乙基磺酰基甲烷、NR4R5或R6,
R4和R5各自独立地为氢、C1-3烷基或R7,及
R6和R7为选自包含下列者的群组的碳环、杂环或杂芳基:环丙基、环丁烷、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
在一个实施方式中,本发明关于式(I)的化合物,其中
R1为卤素,
n和m为2,
R2为任选地且独立地经C1-4烷氧基、-S(O)2-C1-4烷基取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7;或R4和R5与它们连接的N一起形成任选地经取代的杂环,及
R6和R7为任选地经取代的碳环、杂环或杂芳基。
如上文定义的A、R1至R7、n和m的实施方式的任何组合为式(I)的化合物的优选群组。
在一个实施方式中,本发明关于选自由下列所组成的群组的如上文定义的式(I)的化合物:
1-[2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-7,8-二氢-1,6-萘啶-6(5H)-基]乙酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(1,2-噁唑-5-羰基)-5,6,7,8-四氢-1,6-萘啶,
6-环丁烷羰基-2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
6-环丙烷羰基-2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
4-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1λ6-硫杂环己烷-1,1-二酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环戊烷-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲烷磺酰基乙-1-酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(5-甲基-1,2-噁唑-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(1-甲基-1H-吡咯-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2,2,2-三氟-1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
4-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3R)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3S)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
6-环丙烷羰基-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(1,2-噁唑-5-羰基)-5,6,7,8-四氢-1,6-萘啶,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲基丙-1-酮,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1λ6-硫杂环己烷-1,1-二酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)丙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
6-(3-氯苯甲酰基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(3-甲基氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,7-萘啶-7-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(4-甲氧基环己烷羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[6-(三氟甲基)吡啶-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3S)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
(5S)-5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
(5R)-5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲氧基乙-1-酮,
1-乙基-4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)吡咯烷-2-酮,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-(丙-2-基)吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)乙-1-酮,
5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基哌啶-2-酮,
环丙基(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)甲酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-3-甲烷磺酰基丙-1-酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲烷磺酰基乙-1-酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
2,2,2-三氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)丙-1-酮,
2,2-二氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
2-氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环己烷-4-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-3-甲基丁-1-酮,
5-[({6-环丁烷羰基-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基}氧基)甲基]-1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲基丙-1-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2,2-二甲基丙-1-酮,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环戊烷-2-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环戊烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环己烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
3-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
2-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[4-(4-氯苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)丙-1-酮,
2-氟-1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环戊烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲基丙-1-酮,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环戊烷-2-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环己烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N-(1-甲基-5-氧代基吡咯烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N,N-二甲基-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡咯烷-1-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N-(氧杂环戊烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
N-(2-氯苯基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吗啉-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
N-(4-氯苯基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(吗啉-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-N,N-二甲基-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(吡咯烷-1-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(哌啶-1-羰基)-5,6,7,8-四氢-1,6-萘啶,及
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-N-(氧杂环戊烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺。
已使用下列缩写说明式(I)的化合物的通用合成、生物测定、中间体及实施例:
BOC=叔丁氧基羰基
Boc2O=二碳酸二-叔丁酯
DCM=二氯甲烷
PBr3=三溴化磷
TFA=三氟乙酸
DIPEA=N-乙基-N-(丙-2-基)丙-2-胺
BzOH=苯甲醇
18-冠-6=1,4,7,10,13,16-六氧杂环十八烷
Pd/C=钯/碳
AcCN=乙腈
三光气=碳酸双(三氯甲基)酯
Tris=2-氨基-2-(羟甲基)丙-1,3-二醇
TLC=薄层色谱法
盐水=盐(通常为氯化钠)的高浓缩溶液
本发明还关于式(I)的化合物的合成。制备本发明的化合物的许多方法例证于下列的流程及实施例中。起始材料是可购得或根据本技术中已知或如本文例证的程序制得。
式(III)的中间体的合成显示于流程1中,其中A和R1是如上文式(I)所述的实施方式中任一者所定义。
根据流程1,将式(II)的化合物在适合的溶剂中(诸如二氯甲烷)与溴化剂(诸如PBr3)反应以得到式(III)的中间体。式(II)的羟基衍生物为本技术中已知(例如WO 2013/057123 A1、WO 2012/062623 A1)或可以常规的方法合成。
流程1
上述反应所需的试剂及详细的方法步骤在中间体中列出。
式(I)的化合物可根据流程2合成,其中A、R1、R2、n和m是如上文式(I)所述的实施方式中任一者所定义。
根据流程2,保护可商购获得的式(IV)的双环胺衍生物以提供式(V)的N-BOC胺。反应可在BOC酐的存在下于二氯甲烷中使用碱(诸如三乙胺)进行。以苯甲醇处理式(V)的氯衍生物得到式(VI)的苯甲醚衍生物,随后式(VI)的苯甲醚的钯催化裂解获得所期望的式(VII)的羟基衍生物。在式(VII)的醇与式(III)的中间体之间的醚化可在K2CO3的存在下于乙腈中完成以形成式(VIII)的醚衍生物。使用酸(诸如以氯化氢饱和的乙酸乙酯或在二氯甲烷中的TFA)去保护式(VIII)的醚衍生物以提供最终的式(IX)的中间体。最后,式(IX)的胺衍生物可在碱(Et3N)的存在下以式(X)的R2COCl酰化;或当R2=NR4R5时,式(IX)的胺衍生物可在碱(DIPEA)的存在下使用三光气与式(XI)的HNR4R5反应以形成式(I)的化合物。式(X)的酰基氯及式(XI)的胺可购得或可以常规的方法制得,其中R2的定义与上文式(I)所述者相同。
流程2
上文反应所需的试剂及详细的方法步骤在实施例中列出。
本发明的式(I)的化合物中的各自的活性数据是以下文所述的方法于体外测定。
生物实施例1:结合测定法
受体结合测定法所使用的GABAAα5β3γ2蛋白质是源自于表达人类重组GABAAα5β3γ2受体的HEK细胞(Millipore CYL3073)产生的膜。细胞是根据供货商(Millipor)提供的用法说明储存及于内部培养。将细胞沉淀物在10倍改良型Krebs Henseleit缓冲液(膜制备缓冲液)中:20mM Tris、120mM NaCl、100mM KCl、25mM CaCl2及25mM MgCl2 pH=7.4于4℃下使用Ultra Turrax(Janke&Kunkel)以最大速度经15秒均质化。将均质物在4℃下以40,000g离心30分钟。将上清液弃置,且将所得沉淀物在膜制备缓冲液中洗涤。将沉淀物再悬浮于膜制备缓冲液中且将1.4mL安瓿的等分试样储存在-70℃下直到使用。
受体结合测定法是以96孔格式的深孔盘中执行。将用于各96孔盘的一个安瓿的膜均质物解冻,且在结合缓冲液(50mM Tris pH=7.4、100mM KCl)中稀释且以200μL分配至各孔中。放射性配体[3H]Ro151788(Perkin Elmer:NET757250UC)在结合缓冲液中制备且以50μL体积添加至各孔中以得到0.5nM的最终浓度。添加额外50μL适合浓度的试验化合物。最终检测体积为300μL。培育是在4℃下进行60分钟。以10μM未经标记的地西泮(diazepam)用于非特异性结合。在培育后,将样品在GF/BTM上使用过滤垫收获器(Filtermate Harvester)(Perkin Elmer)过滤且以5x1 mL结合缓冲液洗涤。将盘在40℃经1小时干燥且将40μL Microscint(Perkin Elmer)闪烁混合液添加至各孔中。在Microbeta(Perkin Elmer)中读取盘。
特异性放射性配体结合(SB)经定义为总结合(Tot)与非特异性结合(NSB)之间的差异。结果是以关注的化合物存在下获得的特异性结合抑制百分比表示。
使用最少六种药物浓度以一式三份用于IC50及Ki测定。IC50值(即给出50%的特异性结合抑制的化合物浓度)是使用Origin 7.5软件从浓度-位移曲线以S型拟合计算。Ki值(即抑制常数)是使用Cheng-Prusoff公式Ki=IC50/[1+(L/KD)]计算,其中[L]为放射性配体浓度及KD为针对受体的经标记的配体的亲和性。KD是从饱和分析测定。
本发明的化合物在上述测定法中测定,且发现全部对GABAAα5受体具有高亲和性(Ki<200nM)。优选为具有Ki<50nM的化合物。
表1显示用上述结合测定法获得的代表性hGABAAα5Ki试验结果:
生物实施例2:功能测定法
在使用QPatch自动化膜片钳系统的功能测定法中,使用表达GABAAα1β3γ2及GABAAα5β3γ2受体的人类HEK293细胞株。
将稳定地表达人类重组GABAAα1β3γ2受体次单元(Millipore,CYL3073)或人类重组GABAAα5β3γ2受体次单元(Millipore,CYL3053)的HEK293细胞株系在10%FBS(Gibco)补充的DMEM中培养,每周传递两次且培养在事先以聚-d-赖氨酸涂布的培养皿上。
在培养后2至4天,从细胞进行自动化全细胞膜片钳纪录。细胞使用胰蛋白酶/EDTA(Sigma)处理(在37℃下于0.25%的胰蛋白酶中2分钟)而分离,而后在离心(125G,3min,2x)后,接着再悬浮于含有12.5mM HEPES、1×青霉素-链霉素-两性霉素(SigmaMix)及大豆胰蛋白酶抑制剂(Sigma,0.04mg/ml)的无血清为主培养基(Gibco,CHO-S-SFM-II)中。
将细胞悬浮液以及细胞外溶液(130mM NaCl、5mM KCl、5.1mM HEPES、4.9mMHEPES-Na、10mM CaCl2、2mM MgCl2、10mM葡萄糖和0.1%的DMSO,pH=7.35至7.4)与细胞内溶液(80mM KCl、50mM KF、36mM KOH、10mM EGTA、10mM HEPES、1.75mM MgCl2、0.5mM CaCl2、4mMNa2ATP、14mM磷肌酸、50U/ml肌酸-磷酸激酶、0.3mM GTP、pH=7.25至7.3)在室温下以单一细胞模式添加至QPatch-HTX自动化膜片钳系统(Sophion)中。在-80mV的保持电位下激发内向电流,通过先在浓度匹配的DMSO(0.1或0.3%)对照溶液中五次,接着在试验化合物的存在下四次,最后再在对照溶液中三次(洗出)以2至4-min间隔次最大有效浓度(1μM)3-s长施用对照激动剂GABA。在实验结束时,施用100μM GABA,使GABA反应饱和且评定对照GABA施用的效力。电流信号是在100Hz下经低通量滤过且以1kHz取样率纪录。
百分比调节通过比较在试验化合物的存在与不存在下经GABA激发的峰电流幅度来计算。
本发明的化合物是以10μM在上述的测定法中测试,且发现全部对α5亚型具有超越α1亚型的GABAAα5负向别构调节子活性及选择性。优选的化合物在α5亚型具有少于-20%的功能性效力。
表2显示用上述测定法获得的代表性hGABAAα5和hGABAAα1功能性效力试验结果:
本发明将以下列的中间体及实施例进一步例证而非限制本发明的范围于此。本领域技术人员可从以上说明及从中间体和实施例确定本发明的基本特征且可以不脱离其本质和范围而实现特定的改变及调整,使本发明适应于多种应用及条件。因此,本发明不限于下列的示例性实施例,而是以所附的权利要求决定其范围。
式(I)的化合物通常可根据本领域技术人员的一般常识和/或以操作实施例和/或中间体所述的方法制备。溶剂、温度、压力及其他反应条件可由本领域技术人员容易地选择。起始材料在可商购获得和/或可由本领域技术人员根据文献程序容易地制备。在化合物制备期间可使用组合技术,例如在中间体适合于使用这些方法的情况下。
中间体1
4-(溴甲基)-3-(4-氟苯基)-5-甲基-1,2-噁唑
将4.98g(24.0mmol)[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲醇(WO 2013/057123 A1,Hoffmann-La Roche)溶解在80mL无水二氯甲烷中且将9.76g(3.39mL,36.1mmol)三溴化磷逐滴添加至搅拌溶液中。将反应混合物在室温下搅拌1小时且倒入50mL碳酸氢钠饱和溶液中。将混合物再搅拌10分钟且将相分离。将有机相以水洗涤,经无水硫酸钠干燥且蒸发,以提供作为黄棕色固体的5.89g(97%)的标题化合物。MS(ESI)m/z:269.9[M+H]+。
中间体2
5-(溴甲基)-1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑
类似于中间体1,将[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲醇(WO 2012/062623 A1,Hoffmann-La Roche)转化成标题化合物(114mg,87%),其是以透明油获得。化合物在静置时不稳定且缓慢地分解;因此其是在醚化反应步骤中原位产生。
中间体3
5-(溴甲基)-1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑
类似于中间体1,将[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲醇(WO 2012/062623 A1,Hoffmann-La Roche)转化成标题化合物(210mg,81.7%),其是以透明油获得。化合物在静置时不稳定且缓慢地分解;因此其是在醚化反应步骤中原位产生。
中间体4
5-(溴甲基)-4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑
类似于中间体1,将[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲醇(WO 2012/062623 A1,Hoffmann-La Roche)转化成标题化合物(55mg,73%),其是以透明油获得。化合物在静置时不稳定且缓慢地分解;因此其是在醚化反应步骤中原位产生。
中间体5
5-(溴甲基)-4-(4-氯苯基)-1-甲基-1H-1,2,3-三唑
类似于中间体1,将[4-(4-氯苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲醇(WO 2012/062623 A1,Hoffmann-La Roche)转化成标题化合物(120mg,85%),其是以透明油获得。化合物在静置时不稳定且缓慢地分解;因此其是在醚化反应步骤中原位产生。
实施例1
1-[2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-7,8-二氢-1,6-萘啶-6(5H)-基]乙酮
a.:2-氯-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(WO2013/079452A1,Hoffmann-La Roche)
将10mL DCM中的14.2g(65.0mmol)的二碳酸二-叔丁酯的溶液经由加料漏斗在15min内逐滴添加至150mL的DCM中的可商购获得的10.0g(59.3mmol)的2-氯-5,6,7,8-四氢-1,6-萘啶盐酸盐及6.6g(9.0mL,65.0mmol)三乙胺的浆液中。将所得溶液在室温下搅拌2小时且使用TLC(1:1的环己烷-乙酸乙酯作为洗脱剂)监测。在完成时,将反应混合物浓缩。将残余物溶解在50mL的乙酸乙酯中,且以30mL水、30mL盐水洗涤三次且经MgSO4干燥。在减压下蒸发溶剂,以得到作为灰白色固体的标题化合物。产量:15.4g(97%)。MS(ESI)m/z:269.1[M+H]+。
b.:2-(苯甲基氧基)-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯(WO2016/107832A1,Hoffmann-La Roche)
将9.4g(167.4mmol)的固体氢氧化钾添加至150mL的甲苯中的15.0g(55.8mmol)的2-氯-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯的冰冷却溶液中,随后搅拌30分钟且接着逐滴添加在150mL甲苯中的8.7mL(83.7mmol)苯甲醇的溶液。接着添加1.5g(5.58mmol)的固体18-冠-6且将反应混合物在130℃下搅拌隔夜。在冷却后,过滤无机物且将过滤物在减压下浓缩,以提供残余物,将其在硅胶上以快速色谱法纯化(10:1的环己烷-乙酸乙酯作为洗脱剂)。获得作为白色固体的标题化合物。产量:10.5g(55.4%)。MS(ESI)m/z:341.1[M+H]+。
c.:2-氧代基-1,5,7,8-四氢-1,6-萘啶-6(2H)-羧酸叔丁酯(WO2016/107832A1,Hoffmann-La Roche)
将500mL乙酸乙酯及150mL的甲醇中的4.0g(11.7mmol)的2-(苯甲基氧基)-7,8-二氢-1,6-萘啶-6(5H)-羧酸叔丁酯的溶液在氮氛围下搅拌,直到混合物变成透明溶液。添加Pd/C触媒(10%w/w,200mg)且将氢气起泡通过反应混合物3.5小时。在完成后,以TLC(10:1的氯仿-甲醇作为洗脱剂)监测,滤除触媒且将过滤物在减压下浓缩,以得到粗制产物。在从二乙醚再结晶后,分离出作为白色固体的标题化合物。产量:2.6g(89.0%)。MS(ESI)m/z:251.1[M+H]+。
d.:2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羧酸叔丁酯
将9.10g(33.7mmol)的4-(溴甲基)-3-(4-氟苯基)-5-甲基-1,2-噁唑及8.43g(33.7mmol)的2-氧代基-1,5,7,8-四氢-1,6-萘啶-6(2H)-羧酸叔丁酯溶解在100mL无水乙腈中。接着将9.31g(67.4mmol)的无水碳酸钾添加至溶液中且将悬浮液在回流下搅拌5小时。以TLC(DCM:MeOH=20:1作为洗脱剂,硅胶板)追踪转化率。在反应完成后,将混合物过滤且蒸发,以得到15.6g的油状粗制产物,将其以快速柱色谱法(硅胶,洗脱剂:DCM:MeOH,0至5%的梯度)进一步纯化。产量:11.6g(77%)玻璃状固体。MS(ESI)m/z:440.3[M+H]+。
e.:2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶
将11.5g(26.2mmol)的2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羧酸叔丁酯溶解在200mL的乙酸乙酯中。将以氯化氢饱和的180mL的乙酸乙酯逐滴添加至溶液中。将反应混合物在室温下搅拌15分钟。将所形成的白色沉淀物滤出,以少部分的乙酸乙酯洗涤且在真空干燥器中干燥,以得到10.2g的白色结晶固体。MS(ESI)m/z:340.2[M+H]+。使用粗制化合物而无纯化。
f.:1-[2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-7,8-二氢-1,6-萘啶-6(5H)-基]乙酮
将7.63g(22.5mmol)的2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶溶解在100mL的无水二氯甲烷中。将6.83g(9.4mL,67.4mmol)的无水三乙胺以一份添加至溶液中,且将反应混合物以冰水浴冷却。将20mL无水二氯甲烷中的1.60mL(1.76g,22.5mmol)乙酰氯溶液在10分钟期间内逐滴添加至搅拌的反应混合物中。移除冷却浴,且容许混合物温热至室温。以TLC(DCM:MeOH=10:1或环己烷:EtOAc=1:3作为洗脱剂,硅胶板)检查转化率。将反应混合物以碳酸氢钠饱和溶液及水洗涤,经无水硫酸钠干燥且蒸发。获得10.4g残余物,将其以快速柱色谱法纯化(硅胶,洗脱剂:环己烷:EtOAc 40至80%的梯度)。产量:6.28g(64%),与标题化合物相同的白色无定形固体。MS(ESI)m/z:404.1[M+Na]+。
表3显示根据流程2合成的化合物:
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
/>
实施例75
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N-(1-甲基-5-氧代基吡咯烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺
将704mg(0.95mL,5.45mmol)的N,N-二异丙基乙胺以一份添加至30mL的无水二氯甲烷中的284mg(2.49mmol)的4-氨基-1-甲基吡咯烷-2-酮的溶液中,且将反应混合物以冰水浴冷却,接着添加一份296mg(0.998mmol)的碳酸双(三氯甲基)酯。将因此获得的溶液搅拌30分钟,接着将10mL的无水二氯甲烷中的757mg(2.23mmol)的2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶在5分钟期间内逐滴添加至搅拌的反应混合物中。移除冷却浴,且容许混合物温热至室温及搅拌8小时。将反应混合物以碳酸氢钠饱和溶液及水洗涤,经无水硫酸钠干燥且蒸发。将获得的残余物以快速柱色谱法纯化(硅胶,洗脱剂:100%的DCM→80%的DCM:20%的MeOH(35min))。产量:338mg(32%),与标题化合物相同的白色无定形固体。MS(ESI)m/z:480.2[M+H]+。
表4表示根据实施例75合成的化合物:
/>
药物制剂实施例
下列的调配物实施例说明本发明的代表性药物组合物。然而,本发明不限于下列的药物组合物。
A)固体口服剂型
I.片剂
II.口腔分散膜
B)液体口服剂型
III.口服悬浮液
IV.糖浆
C)肠胃外剂型
V.静脉内注射液
D)其他剂型
VI.栓剂
VII.眼滴剂
VIII.鼻滴剂或喷雾剂
/>
Claims (15)
1.一种式(I)的化合物
其中
A代表
基团、/>基团或/>基团,
R1为卤素,
n为1和m为2,或n为2和m为1,或n和m为1,
R2为任选地且独立地经一个或多个卤素、C1-4烷氧基或-S(O)2-C1-4烷基取代的C1-4烷基;NR4R5或R6,
R4和R5各自独立地为氢、C1-4烷基或R7,及
R6和R7为C3-6环烷基、C6-10芳基、包含1或2个独立地选自N、O及S的环杂原子的C4-6杂环或包含1或2个独立地选自N及O的环杂原子的C5-6杂芳基,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代,
和/或其盐。
2.如权利要求1的化合物,其中
R1为氟、溴或氯,
R2为C1-3烷基、C1-4烷氧基C1-3烷基、C1-3烷基-S(O)2-C1-3烷基、NR4R5或R6。
3.如权利要求2的化合物,其中
R1为氟或氯,
R2为C1-4烷氧基C1-3烷基、甲基磺酰基甲烷、乙基磺酰基甲烷、NR4R5或R6,
R4和R5各自独立地为氢、C1-3烷基或R7,及
R6和R7为环丙基、环丁基、环己烷、苯基、氧杂环丁烷、四氢呋喃、四氢吡喃、硫杂环己烷、吡咯烷、哌啶、吡啶、异噁唑、吡咯和吗啉,任选地经C1-4烷基、C1-4烷氧基、卤素、卤代C1-4烷基、卤代C1-4烷氧基、羟基或氧代基取代。
4.如权利要求1的化合物,其选自由下列所组成的群组:
1-[2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-7,8-二氢-1,6-萘啶-6(5H)-基]乙酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(1,2-噁唑-5-羰基)-5,6,7,8-四氢-1,6-萘啶,
6-环丁烷羰基-2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
6-环丙烷羰基-2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
4-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1λ6-硫杂环己烷-1,1-二酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环戊烷-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲烷磺酰基乙-1-酮,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(5-甲基-1,2-噁唑-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(1-甲基-1H-吡咯-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2,2,2-三氟-1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
4-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3R)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3S)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
6-环丙烷羰基-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(1,2-噁唑-5-羰基)-5,6,7,8-四氢-1,6-萘啶,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲基丙-1-酮,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1λ6-硫杂环己烷-1,1-二酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)丙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-2-羰基)-5,6,7,8-四氢-1,6-萘啶,
6-(3-氯苯甲酰基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(3-甲基氧杂环戊烷-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(氧杂环己烷-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,7-萘啶-7-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(4-甲氧基环己烷羰基)-5,6,7,8-四氢-1,6-萘啶,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)乙-1-酮,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[6-(三氟甲基)吡啶-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-[(3S)-氧杂环戊烷-3-羰基]-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡啶-3-羰基)-5,6,7,8-四氢-1,6-萘啶,
(5S)-5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
(5R)-5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基吡咯烷-2-酮,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-2-甲氧基乙-1-酮,
1-乙基-4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)吡咯烷-2-酮,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-(丙-2-基)吡咯烷-2-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)乙-1-酮,
5-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-羰基)-1-甲基哌啶-2-酮,
环丙基(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)甲酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-基)-3-甲烷磺酰基丙-1-酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲烷磺酰基乙-1-酮,
1-(2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
2,2,2-三氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)丙-1-酮,
2,2-二氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
2-氟-1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环己烷-4-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-3-甲基丁-1-酮,
5-[({6-环丁烷羰基-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基}氧基)甲基]-1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲基丙-1-酮,
1-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2,2-二甲基丙-1-酮,
1-(2-{[1-(4-氯苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环戊烷-2-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环戊烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(4-氟苯基)-4-甲基-5-({[6-(氧杂环己烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
4-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
3-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
2-(2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-羰基)吡啶,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[4-(4-氯苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)丙-1-酮,
2-氟-1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,7-二氢-6H-吡咯并[3,4-b]吡啶-6-基)乙酮,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环戊烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
1-(2-{[4-(4-氟苯基)-1-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5H,6H,7H-吡咯并[3,4-b]吡啶-6-基)-2-甲基丙-1-酮,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环戊烷-2-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
4-(4-氟苯基)-1-甲基-5-({[6-(氧杂环己烷-3-羰基)-5H,6H,7H-吡咯并[3,4-b]吡啶-2-基]氧基}甲基)-1H-1,2,3-三唑,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N-(1-甲基-5-氧代基吡咯烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N,N-二甲基-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吡咯烷-1-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-N-(氧杂环戊烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
N-(2-氯苯基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-6-(吗啉-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
N-(4-氯苯基)-2-{[1-(4-氟苯基)-4-甲基-1H-1,2,3-三唑-5-基]甲氧基}-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(吗啉-4-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-N,N-二甲基-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(吡咯烷-1-羰基)-5,6,7,8-四氢-1,6-萘啶,
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-6-(哌啶-1-羰基)-5,6,7,8-四氢-1,6-萘啶,及
2-{[3-(4-氟苯基)-5-甲基-1,2-噁唑-4-基]甲氧基}-N-(氧杂环戊烷-3-基)-5,6,7,8-四氢-1,6-萘啶-6-甲酰胺。
5.如权利要求1至4中任一项的化合物在制备药物中的用途,所述药物用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强。
6.如权利要求5的用途,其中与该GABAAα5受体相关的该疾病选自由下列所组成的群组:神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍及其他疾病。
7.如权利要求6的用途,其中与该GABAAα5受体相关的该疾病选自由下列所组成的群组:阿尔茨海默疾病、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害、血管性认知损害、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征的认知衰退、重度抑郁症的认知功能障碍及精神分裂症。
8.如权利要求1至4中任一项的化合物与一种或多种其他活性成分组合在制备药物中的用途,所述药物用于治疗或预防与GABAAα5受体相关的疾病或用于认知增强。
9.一种药物组合物,其包含作为活性成分的至少一种如权利要求1至4中任一项的化合物及至少一种药学上可接受的赋形剂。
10.如权利要求9的药物组合物,其中该组合物进一步包含一种或多种其他活性成分。
11.如权利要求9至10中任一项的药物组合物,其用于治疗或预防与GABAAα5受体相关的疾病或作为认知增强剂。
12.如权利要求11的药物组合物,其中与该GABAAα5受体相关的该疾病选自由下列所组成的群组:神经退化性障碍、神经认知障碍、精神分裂症、情感障碍、疼痛障碍、物质相关与成瘾障碍及其他疾病。
13.如权利要求12的药物组合物,其中与该GABAAα5受体相关的该疾病选自由下列所组成的群组:阿尔茨海默疾病、认知缺失障碍、记忆缺失、年龄相关性记忆损害或认知衰退、痴呆、轻度认知损害、血管性认知损害、中风后发生的CNS症状、与脑癌相关性认知损害、唐氏综合征的认知衰退、重度抑郁症的认知功能障碍及精神分裂症。
14.一种式(III)的化合物
其中
A代表
基团,/>基团,或/>基团,
R1为卤素。
15.一种式(IX)的化合物
其中
A代表
基团,/>基团,或/>基团,R1为卤素,
n和m各自独立地为1或2。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU1800333A HU231223B1 (hu) | 2018-09-28 | 2018-09-28 | GABAA A5 receptor modulátor hatású biciklusos vegyületek |
HUP1800333 | 2018-09-28 | ||
PCT/IB2019/058208 WO2020065597A1 (en) | 2018-09-28 | 2019-09-27 | Bicyclic derivatives as gabaa α5 receptor modulators |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112805063A CN112805063A (zh) | 2021-05-14 |
CN112805063B true CN112805063B (zh) | 2024-02-23 |
Family
ID=89992765
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980063431.3A Active CN112805063B (zh) | 2018-09-28 | 2019-09-27 | 作为gabaa a5受体调节剂的双环衍生物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US20210386718A1 (zh) |
EP (1) | EP3856342A1 (zh) |
JP (1) | JP7480128B2 (zh) |
KR (1) | KR20210086631A (zh) |
CN (1) | CN112805063B (zh) |
AR (1) | AR116549A1 (zh) |
AU (1) | AU2019346147A1 (zh) |
BR (1) | BR112021005837A2 (zh) |
CA (1) | CA3113072A1 (zh) |
EA (1) | EA202190857A1 (zh) |
HU (1) | HU231223B1 (zh) |
MX (1) | MX2021003670A (zh) |
TW (1) | TW202035403A (zh) |
WO (1) | WO2020065597A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021191837A1 (en) * | 2020-03-26 | 2021-09-30 | Richter Gedeon Nyrt. | 1,3-dihydro-2h-pyrrolo[3,4-c]pyridine derivatives as gabaa α5 receptor modulators |
TW202202495A (zh) * | 2020-03-26 | 2022-01-16 | 匈牙利商羅特格登公司 | 作為gamma-胺基丁酸A受體次單元alpha 5受體調節劑之㖠啶及吡啶并〔3,4-c〕嗒𠯤衍生物 |
HUP2100338A1 (hu) * | 2021-09-29 | 2023-04-28 | Richter Gedeon Nyrt | GABAA ALFA5 receptor modulátor hatású biciklusos aminszármazékok |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101883769A (zh) * | 2007-12-04 | 2010-11-10 | 弗·哈夫曼-拉罗切有限公司 | 异噁唑-吡嗪衍生物 |
CN102300863A (zh) * | 2009-02-25 | 2011-12-28 | 弗·哈夫曼-拉罗切有限公司 | 具有乙基和乙烯基连接体的异*唑/邻-吡啶衍生物 |
CN103221402A (zh) * | 2010-11-09 | 2013-07-24 | 霍夫曼-拉罗奇有限公司 | 三唑衍生物及其用于神经障碍的用途 |
WO2014001278A1 (en) * | 2012-06-26 | 2014-01-03 | Aniona Aps | A phenyl triazole derivative and its use for modulating the gabaa receptor complex |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998050385A1 (en) | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
GB9813576D0 (en) | 1998-06-24 | 1998-08-19 | Merck Sharp & Dohme | Therapeutic agents |
GB0017518D0 (en) | 2000-07-17 | 2000-08-30 | Merck Sharp & Dohme | Therapeutic agents |
JP4148672B2 (ja) | 2000-11-17 | 2008-09-10 | 武田薬品工業株式会社 | イソオキサゾール誘導体 |
JP2003261545A (ja) | 2001-12-28 | 2003-09-19 | Takeda Chem Ind Ltd | 神経栄養因子産生・分泌促進剤 |
CA2607226A1 (en) | 2005-05-16 | 2007-02-15 | Wisys Technology Foundation, Inc. | Gabaergic agents to treat memory deficits |
US7790745B2 (en) | 2005-10-21 | 2010-09-07 | Bristol-Myers Squibb Company | Tetrahydroisoquinoline LXR Modulators |
ATE460403T1 (de) | 2006-05-24 | 2010-03-15 | Lilly Co Eli | Verbindungen und verfahren zur modulierung von fx-rezeptoren |
MX2009013624A (es) | 2007-06-13 | 2010-04-27 | Glaxosmithkline Llc | Agonistas de receptor farnesoide x. |
BRPI0820112B8 (pt) | 2007-12-04 | 2021-05-25 | Hoffmann La Roche | derivados de isoxazol-piridina, seu uso e processos de preparação e medicamento |
US7943619B2 (en) | 2007-12-04 | 2011-05-17 | Hoffmann-La Roche Inc. | Isoxazolo-pyridazine derivatives |
US8222246B2 (en) | 2009-04-02 | 2012-07-17 | Hoffmann-La Roche Inc. | Substituted isoxazoles |
CA2760746C (en) | 2009-05-05 | 2017-07-11 | F. Hoffmann-La Roche Ag | Isoxazole-pyrazole derivatives |
ES2430223T3 (es) | 2009-05-07 | 2013-11-19 | F. Hoffmann-La Roche Ag | Derivados de isoxazol-piridina como moduladores de GABA |
GB2474120B (en) | 2009-10-01 | 2011-12-21 | Amira Pharmaceuticals Inc | Compounds as Lysophosphatidic acid receptor antagonists |
GB201016088D0 (en) | 2010-09-24 | 2010-11-10 | Phase Focus Ltd | Improvements in imaging |
MY164595A (en) | 2010-11-05 | 2018-01-30 | Hoffmann La Roche | Use of active pharmaceutical compounds for the treatment of central nervous system conditions |
CN103189370B (zh) | 2010-11-09 | 2015-07-08 | 霍夫曼-拉罗奇有限公司 | 作为gaba受体用配体的三唑衍生物 |
UY33726A (es) | 2010-11-15 | 2012-06-29 | Abbott Lab | Inhibidores de nampt y rock |
EP2545964A1 (en) | 2011-07-13 | 2013-01-16 | Phenex Pharmaceuticals AG | Novel FXR (NR1H4) binding and activity modulating compounds |
US8604062B2 (en) | 2011-10-20 | 2013-12-10 | Hoffman-La Roche Inc. | Process for the preparation of isoxazolyl-methoxy nicotinic acids |
JP6224097B2 (ja) | 2012-06-26 | 2017-11-01 | サニオナ・エイピイエス | フェニルトリアゾール誘導体及びgabaa受受容体複合体を調節するための該フェニルトリアゾール誘導体の使用 |
WO2017133521A1 (zh) | 2016-02-01 | 2017-08-10 | 山东轩竹医药科技有限公司 | Fxr受体激动剂 |
KR102564643B1 (ko) | 2016-12-08 | 2023-08-08 | 에프. 호프만-라 로슈 아게 | Gaba a 알파5 pam으로서 신규한 이소옥사졸릴 에터 유도체 |
-
2018
- 2018-09-28 HU HU1800333A patent/HU231223B1/hu unknown
-
2019
- 2019-09-27 JP JP2021516369A patent/JP7480128B2/ja active Active
- 2019-09-27 CN CN201980063431.3A patent/CN112805063B/zh active Active
- 2019-09-27 US US17/279,654 patent/US20210386718A1/en active Pending
- 2019-09-27 EP EP19779613.9A patent/EP3856342A1/en active Pending
- 2019-09-27 MX MX2021003670A patent/MX2021003670A/es unknown
- 2019-09-27 BR BR112021005837-0A patent/BR112021005837A2/pt unknown
- 2019-09-27 TW TW108135172A patent/TW202035403A/zh unknown
- 2019-09-27 WO PCT/IB2019/058208 patent/WO2020065597A1/en unknown
- 2019-09-27 CA CA3113072A patent/CA3113072A1/en active Pending
- 2019-09-27 AU AU2019346147A patent/AU2019346147A1/en active Pending
- 2019-09-27 AR ARP190102762A patent/AR116549A1/es unknown
- 2019-09-27 EA EA202190857A patent/EA202190857A1/ru unknown
- 2019-09-27 KR KR1020217012783A patent/KR20210086631A/ko not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101883769A (zh) * | 2007-12-04 | 2010-11-10 | 弗·哈夫曼-拉罗切有限公司 | 异噁唑-吡嗪衍生物 |
CN102300863A (zh) * | 2009-02-25 | 2011-12-28 | 弗·哈夫曼-拉罗切有限公司 | 具有乙基和乙烯基连接体的异*唑/邻-吡啶衍生物 |
CN103221402A (zh) * | 2010-11-09 | 2013-07-24 | 霍夫曼-拉罗奇有限公司 | 三唑衍生物及其用于神经障碍的用途 |
WO2014001278A1 (en) * | 2012-06-26 | 2014-01-03 | Aniona Aps | A phenyl triazole derivative and its use for modulating the gabaa receptor complex |
Also Published As
Publication number | Publication date |
---|---|
HUP1800333A2 (hu) | 2020-04-28 |
HU231223B1 (hu) | 2022-01-28 |
AU2019346147A1 (en) | 2021-05-20 |
JP2022502366A (ja) | 2022-01-11 |
MX2021003670A (es) | 2021-08-19 |
KR20210086631A (ko) | 2021-07-08 |
BR112021005837A2 (pt) | 2021-07-27 |
EP3856342A1 (en) | 2021-08-04 |
US20210386718A1 (en) | 2021-12-16 |
CN112805063A (zh) | 2021-05-14 |
AR116549A1 (es) | 2021-05-19 |
EA202190857A1 (ru) | 2021-06-23 |
TW202035403A (zh) | 2020-10-01 |
WO2020065597A1 (en) | 2020-04-02 |
JP7480128B2 (ja) | 2024-05-09 |
CA3113072A1 (en) | 2020-04-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4709849B2 (ja) | アルツハイマー病治療のためのグリシントランスポーターi(glyt−1)インヒビターとしての二環式及び三環式置換フェニルメタノン類 | |
CN112805063B (zh) | 作为gabaa a5受体调节剂的双环衍生物 | |
RU2470931C2 (ru) | Производные оксадиазола и их применение в качестве потенцирующих средств метаботропных глутаматных рецепторов-842 | |
JP2002030084A (ja) | 1−アザビシクロアルカン化合物およびその医薬用途 | |
US20210330650A1 (en) | Spirochromane derivatives | |
TW202017904A (zh) | 經取代之(吖)吲哚衍生物 | |
US20240067637A1 (en) | NAPHTHYRIDINE AND PYRIDO[3,4-c]PYRIDAZINE DERIVATIVES AS GABAA ALPHA 5 RECEPTOR MODULATORS | |
JP2017507144A (ja) | スピロオキサゾロン | |
EA045543B1 (ru) | БИЦИКЛИЧЕСКИЕ ПРОИЗВОДНЫЕ КАК МОДУЛЯТОРЫ α5 РЕЦЕПТОРОВ GABAA | |
TWI428342B (zh) | 新穎二氫-唑并苯并二氮雜酮化合物、其製備方法及含其之醫藥組合物 | |
US9926332B2 (en) | Dihydro-oxazinobenzodiazepine compounds, a process for their preparation and pharmaceutical compositions containing them | |
WO2021191837A1 (en) | 1,3-dihydro-2h-pyrrolo[3,4-c]pyridine derivatives as gabaa α5 receptor modulators | |
TW202330518A (zh) | 作為GABAA α5受體調節劑之雙環胺衍生物 | |
WO2016171181A1 (ja) | 2位置換縮合ピラゾール誘導体 | |
OA19571A (en) | Triazolobenzazepines as vasopressin V1a receptor antagonists. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |