TWI616445B - 新穎環丙苯并呋喃基吡啶并吡二酮類 - Google Patents
新穎環丙苯并呋喃基吡啶并吡二酮類 Download PDFInfo
- Publication number
- TWI616445B TWI616445B TW105103193A TW105103193A TWI616445B TW I616445 B TWI616445 B TW I616445B TW 105103193 A TW105103193 A TW 105103193A TW 105103193 A TW105103193 A TW 105103193A TW I616445 B TWI616445 B TW I616445B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- dihydro
- benzofuran
- dione
- mmol
- Prior art date
Links
- QVLZENOJNCBARC-UHFFFAOYSA-N 6-(2H-cyclopropa[g][1]benzofuran-2-yl)pyrido[2,3-b]pyrazine-2,3-dione Chemical class O1C(C=C2C1=C1C(C=C2)=C1)C=1C=CC=2C(=NC(C(N=2)=O)=O)N=1 QVLZENOJNCBARC-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- -1 4-methyl-1H-imidazol-1-yl Chemical group 0.000 claims description 183
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 133
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 59
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 56
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 48
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims description 29
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 7
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 6
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 50
- 239000013067 intermediate product Substances 0.000 abstract description 19
- 238000010189 synthetic method Methods 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 112
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 91
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 83
- 239000000203 mixture Substances 0.000 description 83
- 125000001424 substituent group Chemical group 0.000 description 79
- 239000000047 product Substances 0.000 description 77
- 238000005481 NMR spectroscopy Methods 0.000 description 76
- 238000003786 synthesis reaction Methods 0.000 description 74
- 230000015572 biosynthetic process Effects 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 63
- 239000011541 reaction mixture Substances 0.000 description 63
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 57
- 229910052736 halogen Inorganic materials 0.000 description 56
- 150000002367 halogens Chemical class 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 53
- 239000002904 solvent Substances 0.000 description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- 125000001072 heteroaryl group Chemical group 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 44
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 43
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 42
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000002585 base Substances 0.000 description 39
- 229910052799 carbon Inorganic materials 0.000 description 39
- 229910052757 nitrogen Inorganic materials 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
- 125000005842 heteroatom Chemical group 0.000 description 35
- 239000007787 solid Substances 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000002253 acid Substances 0.000 description 30
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 29
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 229910052938 sodium sulfate Inorganic materials 0.000 description 28
- 235000011152 sodium sulphate Nutrition 0.000 description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 27
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 26
- 229910052717 sulfur Inorganic materials 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 239000011593 sulfur Substances 0.000 description 25
- 239000003921 oil Substances 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 150000001412 amines Chemical class 0.000 description 23
- 150000001721 carbon Chemical group 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 239000011780 sodium chloride Substances 0.000 description 23
- 208000024827 Alzheimer disease Diseases 0.000 description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 17
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 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 16
- 239000000543 intermediate Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000007795 chemical reaction product Substances 0.000 description 15
- 229910052760 oxygen Inorganic materials 0.000 description 15
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000001569 carbon dioxide Substances 0.000 description 13
- 229910002092 carbon dioxide Inorganic materials 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000001301 oxygen Substances 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
- 125000006413 ring segment Chemical group 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 11
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 11
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000002883 imidazolyl group Chemical group 0.000 description 11
- 238000004808 supercritical fluid chromatography Methods 0.000 description 11
- 235000019000 fluorine Nutrition 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000000908 ammonium hydroxide Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 150000007524 organic acids Chemical class 0.000 description 9
- 235000005985 organic acids Nutrition 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 8
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 208000012902 Nervous system disease Diseases 0.000 description 7
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 208000020016 psychiatric disease Diseases 0.000 description 7
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 7
- 125000001425 triazolyl group Chemical group 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 208000025966 Neurological disease Diseases 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 150000001409 amidines Chemical class 0.000 description 6
- 150000001414 amino alcohols Chemical class 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 239000007937 lozenge Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 229940076279 serotonin Drugs 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 229940124648 γ-Secretase Modulator Drugs 0.000 description 6
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- INJOMKTZOLKMBF-UHFFFAOYSA-N Guanfacine Chemical compound NC(=N)NC(=O)CC1=C(Cl)C=CC=C1Cl INJOMKTZOLKMBF-UHFFFAOYSA-N 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 150000001602 bicycloalkyls Chemical group 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 125000002971 oxazolyl group Chemical group 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 125000000335 thiazolyl group Chemical group 0.000 description 5
- YCYMCMYLORLIJX-SNVBAGLBSA-N (2r)-2-propyloctanoic acid Chemical compound CCCCCC[C@H](C(O)=O)CCC YCYMCMYLORLIJX-SNVBAGLBSA-N 0.000 description 4
- VHNYOQKVZQVBLC-RTCGXNAVSA-N (4r,7e,9as)-7-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]-4-(3,4,5-trifluorophenyl)-1,3,4,8,9,9a-hexahydropyrido[2,1-c][1,4]oxazin-6-one Chemical compound C1([C@@H]2COC[C@@H]3CC\C(C(N32)=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC(F)=C(F)C(F)=C1 VHNYOQKVZQVBLC-RTCGXNAVSA-N 0.000 description 4
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 4
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 4
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 4
- MHNSPTUQQIYJOT-SJDTYFKWSA-N Doxepin Hydrochloride Chemical compound Cl.C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 MHNSPTUQQIYJOT-SJDTYFKWSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 108010025020 Nerve Growth Factor Proteins 0.000 description 4
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 4
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 4
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000001786 isothiazolyl group Chemical group 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 230000000626 neurodegenerative effect Effects 0.000 description 4
- 150000002825 nitriles Chemical group 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 4
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 3
- CEMAWMOMDPGJMB-UHFFFAOYSA-N (+-)-Oxprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1OCC=C CEMAWMOMDPGJMB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- MXUNKHLAEDCYJL-UHFFFAOYSA-N 5-(hydroxymethyl)-3-(3-methylphenyl)-1,3-oxazolidin-2-one Chemical compound CC1=CC=CC(N2C(OC(CO)C2)=O)=C1 MXUNKHLAEDCYJL-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 3
- 238000006964 Chan-Lam coupling reaction Methods 0.000 description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 208000030814 Eating disease Diseases 0.000 description 3
- VWLHWLSRQJQWRG-UHFFFAOYSA-O Edrophonum Chemical compound CC[N+](C)(C)C1=CC=CC(O)=C1 VWLHWLSRQJQWRG-UHFFFAOYSA-O 0.000 description 3
- 208000019454 Feeding and Eating disease 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
- 239000007821 HATU Substances 0.000 description 3
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 108010005716 Interferon beta-1a Proteins 0.000 description 3
- 108010005714 Interferon beta-1b Proteins 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- NZDMFGKECODQRY-UHFFFAOYSA-N Maprotiline hydrochloride Chemical compound Cl.C12=CC=CC=C2C2(CCCNC)C3=CC=CC=C3C1CC2 NZDMFGKECODQRY-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 3
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 3
- UEQUQVLFIPOEMF-UHFFFAOYSA-N Mianserin Chemical compound C1C2=CC=CC=C2N2CCN(C)CC2C2=CC=CC=C21 UEQUQVLFIPOEMF-UHFFFAOYSA-N 0.000 description 3
- 208000007101 Muscle Cramp Diseases 0.000 description 3
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 3
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 description 3
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 3
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000005392 Spasm Diseases 0.000 description 3
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 3
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 3
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
- XXRMYXBSBOVVBH-UHFFFAOYSA-N bethanechol chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(N)=O XXRMYXBSBOVVBH-UHFFFAOYSA-N 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229960001058 bupropion Drugs 0.000 description 3
- 229960004484 carbachol Drugs 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 3
- 229960001076 chlorpromazine Drugs 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
- 208000010877 cognitive disease Diseases 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- DWLTUUXCVGVRAV-XWRHUKJGSA-N davunetide Chemical compound N([C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O DWLTUUXCVGVRAV-XWRHUKJGSA-N 0.000 description 3
- 108010042566 davunetide Proteins 0.000 description 3
- CURUTKGFNZGFSE-UHFFFAOYSA-N dicyclomine Chemical compound C1CCCCC1C1(C(=O)OCCN(CC)CC)CCCCC1 CURUTKGFNZGFSE-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 235000014632 disordered eating Nutrition 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 3
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 3
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 206010013663 drug dependence Diseases 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- YKASHPSKFYVZRC-UHFFFAOYSA-M furan-2-ylmethyl(trimethyl)azanium;iodide Chemical compound [I-].C[N+](C)(C)CC1=CC=CO1 YKASHPSKFYVZRC-UHFFFAOYSA-M 0.000 description 3
- QORVDGQLPPAFRS-XPSHAMGMSA-N galantamine hydrobromide Chemical compound Br.O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 QORVDGQLPPAFRS-XPSHAMGMSA-N 0.000 description 3
- 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 3
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 3
- 229960002491 ibudilast Drugs 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- YQZBAXDVDZTKEQ-UHFFFAOYSA-N loxapine succinate Chemical compound [H+].[H+].[O-]C(=O)CCC([O-])=O.C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 YQZBAXDVDZTKEQ-UHFFFAOYSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 3
- 229960002508 pindolol Drugs 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 description 3
- 235000011009 potassium phosphates Nutrition 0.000 description 3
- IBALRBWGSVJPAP-HEHNFIMWSA-N progabide Chemical compound C=1C(F)=CC=C(O)C=1C(=N/CCCC(=O)N)/C1=CC=C(Cl)C=C1 IBALRBWGSVJPAP-HEHNFIMWSA-N 0.000 description 3
- 229960002752 progabide Drugs 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 229960003770 reboxetine Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 3
- 208000019116 sleep disease Diseases 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 3
- CAKQUTGYRBUKKS-UHFFFAOYSA-N trimethylphosphanium;iodide Chemical compound [I-].C[PH+](C)C CAKQUTGYRBUKKS-UHFFFAOYSA-N 0.000 description 3
- 229960000744 vinpocetine Drugs 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 3
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 3
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 2
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 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 2
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 2
- ZERWDZDNDJBYKA-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O ZERWDZDNDJBYKA-UHFFFAOYSA-N 0.000 description 2
- GMBQZIIUCVWOCD-UQHLGXRBSA-N (25R)-5beta-spirostan-3beta-ol Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)C[C@H]4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 GMBQZIIUCVWOCD-UQHLGXRBSA-N 0.000 description 2
- CGTZMJIMMUNLQD-STYNFMPRSA-N (2r)-2-[(r)-(2-ethoxyphenoxy)-phenylmethyl]morpholine;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CGTZMJIMMUNLQD-STYNFMPRSA-N 0.000 description 2
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- 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 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- WGQCGOMSKOHLMD-UHFFFAOYSA-N 2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-3,4-dihydro-1h-pyrido[4,3-b]indole;hydrochloride Chemical compound Cl.C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 WGQCGOMSKOHLMD-UHFFFAOYSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 description 2
- OQDPVLVUJFGPGQ-UHFFFAOYSA-N 2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine Chemical compound C=1C=C2OCOC2=CC=1CN(CC1)CCN1C1=NC=CC=N1 OQDPVLVUJFGPGQ-UHFFFAOYSA-N 0.000 description 2
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 2
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- AZEXWHKOMMASPA-UHFFFAOYSA-N 2-{[4-(1-methyl-4-pyridin-4-yl-1h-pyrazol-3-yl)phenoxy]methyl}quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(C)C=C1C1=CC=NC=C1 AZEXWHKOMMASPA-UHFFFAOYSA-N 0.000 description 2
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 description 2
- NOIIUHRQUVNIDD-UHFFFAOYSA-N 3-[[oxo(pyridin-4-yl)methyl]hydrazo]-N-(phenylmethyl)propanamide Chemical compound C=1C=CC=CC=1CNC(=O)CCNNC(=O)C1=CC=NC=C1 NOIIUHRQUVNIDD-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 2
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-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
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 2
- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OVCDSSHSILBFBN-UHFFFAOYSA-N Amodiaquine Chemical compound C1=C(O)C(CN(CC)CC)=CC(NC=2C3=CC=C(Cl)C=C3N=CC=2)=C1 OVCDSSHSILBFBN-UHFFFAOYSA-N 0.000 description 2
- 108010001779 Ancrod Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- RZZPDXZPRHQOCG-OJAKKHQRSA-M 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-M 0.000 description 2
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- 208000028698 Cognitive impairment Diseases 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- 201000010374 Down Syndrome Diseases 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 description 2
- 108010072051 Glatiramer Acetate Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 101000652482 Homo sapiens TBC1 domain family member 8 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 2
- 206010020710 Hyperphagia Diseases 0.000 description 2
- 208000030990 Impulse-control disease Diseases 0.000 description 2
- NYMGNSNKLVNMIA-UHFFFAOYSA-N Iproniazid Chemical compound CC(C)NNC(=O)C1=CC=NC=C1 NYMGNSNKLVNMIA-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- WXFIGDLSSYIKKV-RCOVLWMOSA-N L-Metaraminol Chemical compound C[C@H](N)[C@H](O)C1=CC=CC(O)=C1 WXFIGDLSSYIKKV-RCOVLWMOSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- RLJFTICUTYVZDG-UHFFFAOYSA-N Methiothepine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2CC1N1CCN(C)CC1 RLJFTICUTYVZDG-UHFFFAOYSA-N 0.000 description 2
- RGHAZVBIOOEVQX-UHFFFAOYSA-N Metoprolol succinate Chemical compound OC(=O)CCC(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 RGHAZVBIOOEVQX-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- KLPWJLBORRMFGK-UHFFFAOYSA-N Molindone Chemical compound O=C1C=2C(CC)=C(C)NC=2CCC1CN1CCOCC1 KLPWJLBORRMFGK-UHFFFAOYSA-N 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- 208000019022 Mood disease Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JNNOSTQEZICQQP-UHFFFAOYSA-N N-desmethylclozapine Chemical compound N=1C2=CC(Cl)=CC=C2NC2=CC=CC=C2C=1N1CCNCC1 JNNOSTQEZICQQP-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 102000007072 Nerve Growth Factors Human genes 0.000 description 2
- 102000004230 Neurotrophin 3 Human genes 0.000 description 2
- 108090000742 Neurotrophin 3 Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 2
- 244000131316 Panax pseudoginseng Species 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- DPWPWRLQFGFJFI-UHFFFAOYSA-N Pargyline Chemical compound C#CCN(C)CC1=CC=CC=C1 DPWPWRLQFGFJFI-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 206010063493 Premature ageing Diseases 0.000 description 2
- 208000032038 Premature aging Diseases 0.000 description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N Pyridoxal phosphate Natural products CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-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
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 102100030302 TBC1 domain family member 8 Human genes 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 2
- GFBKORZTTCHDGY-UWVJOHFNSA-N Thiothixene Chemical compound C12=CC(S(=O)(=O)N(C)C)=CC=C2SC2=CC=CC=C2\C1=C\CCN1CCN(C)CC1 GFBKORZTTCHDGY-UWVJOHFNSA-N 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 206010044688 Trisomy 21 Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- RNJCXDJXPXWMDK-UHFFFAOYSA-N [AlH3].COCCO[Na] Chemical compound [AlH3].COCCO[Na] RNJCXDJXPXWMDK-UHFFFAOYSA-N 0.000 description 2
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 2
- HUJHNGIBRDLRBE-UHFFFAOYSA-N [O].C1=CC=C2OC=CC2=C1 Chemical group [O].C1=CC=C2OC=CC2=C1 HUJHNGIBRDLRBE-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 2
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 2
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 229960001444 amodiaquine Drugs 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- HJJPJSXJAXAIPN-UHFFFAOYSA-N arecoline Chemical compound COC(=O)C1=CCCN(C)C1 HJJPJSXJAXAIPN-UHFFFAOYSA-N 0.000 description 2
- YFGHCGITMMYXAQ-LJQANCHMSA-N armodafinil Chemical compound C=1C=CC=CC=1C([S@](=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-LJQANCHMSA-N 0.000 description 2
- GVTLDPJNRVMCAL-UHFFFAOYSA-N arofylline Chemical compound C1=2N=CNC=2C(=O)N(CCC)C(=O)N1C1=CC=C(Cl)C=C1 GVTLDPJNRVMCAL-UHFFFAOYSA-N 0.000 description 2
- 159000000032 aromatic acids Chemical class 0.000 description 2
- 229940009098 aspartate Drugs 0.000 description 2
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 2
- 229960002430 atomoxetine Drugs 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- XJURALZPEJKKOV-CQSZACIVSA-N bay 38-7271 Chemical compound C([C@H](CC1=2)CO)C1=CC=CC=2OC1=CC=CC(OS(=O)(=O)CCCC(F)(F)F)=C1 XJURALZPEJKKOV-CQSZACIVSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- CPFJLLXFNPCTDW-BWSPSPBFSA-N benzatropine mesylate Chemical compound CS([O-])(=O)=O.O([C@H]1C[C@H]2CC[C@@H](C1)[NH+]2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 CPFJLLXFNPCTDW-BWSPSPBFSA-N 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N but-2-ene Chemical compound CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 229960004596 cabergoline Drugs 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 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 2
- 229960005123 cariprazine Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229960001284 citicoline Drugs 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(i) oxide Chemical compound [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000013480 data collection Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical group CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 description 2
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 2
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical compound CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 2
- 229960005426 doxepin Drugs 0.000 description 2
- 229960000394 droperidol Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 2
- 229950009041 edaravone Drugs 0.000 description 2
- 229950004685 eprodisate Drugs 0.000 description 2
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 2
- AQNDDEOPVVGCPG-UHFFFAOYSA-N esmolol Chemical compound COC(=O)CCC1=CC=C(OCC(O)CNC(C)C)C=C1 AQNDDEOPVVGCPG-UHFFFAOYSA-N 0.000 description 2
- XBLBDYCZFZESPN-UHFFFAOYSA-J ethene;platinum(2+);tetrachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Pt+2].[Pt+2].C=C.C=C XBLBDYCZFZESPN-UHFFFAOYSA-J 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 229960001938 fencamfamin Drugs 0.000 description 2
- IKFBPFGUINLYQI-UHFFFAOYSA-N fencamfamin Chemical compound CCNC1C(C2)CCC2C1C1=CC=CC=C1 IKFBPFGUINLYQI-UHFFFAOYSA-N 0.000 description 2
- 229960001582 fenfluramine Drugs 0.000 description 2
- LZPBLUATTGKZBH-UHFFFAOYSA-L fenoprofen calcium Chemical compound O.O.[Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 LZPBLUATTGKZBH-UHFFFAOYSA-L 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229960000556 fingolimod Drugs 0.000 description 2
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 229960001258 fluphenazine hydrochloride Drugs 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 229960003883 furosemide Drugs 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 229960002048 guanfacine Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical compound C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 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 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 229940111894 intuniv Drugs 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- GKWPCEFFIHSJOE-UHFFFAOYSA-N laquinimod Chemical compound OC=1C2=C(Cl)C=CC=C2N(C)C(=O)C=1C(=O)N(CC)C1=CC=CC=C1 GKWPCEFFIHSJOE-UHFFFAOYSA-N 0.000 description 2
- 229960004294 lercanidipine Drugs 0.000 description 2
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 description 2
- 229960003907 linezolid Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 description 2
- 229960000423 loxapine Drugs 0.000 description 2
- 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 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229960001962 mefloquine Drugs 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 229960004640 memantine Drugs 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- DOZYTHNHLLSNIK-JOKMOOFLSA-M mycophenolate sodium Chemical compound [Na+].OC1=C(C\C=C(/C)CCC([O-])=O)C(OC)=C(C)C2=C1C(=O)OC2 DOZYTHNHLLSNIK-JOKMOOFLSA-M 0.000 description 2
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 2
- OKFDRAHPFKMAJH-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-(methanesulfonamido)dibenzofuran-1-carboxamide Chemical compound C=12C3=CC(NS(=O)(=O)C)=CC=C3OC2=C(OC(F)F)C=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl OKFDRAHPFKMAJH-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- 229940032018 neurotrophin 3 Drugs 0.000 description 2
- 229960003057 nialamide Drugs 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960005366 nilvadipine Drugs 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- QVYRGXJJSLMXQH-UHFFFAOYSA-N orphenadrine Chemical compound C=1C=CC=C(C)C=1C(OCCN(C)C)C1=CC=CC=C1 QVYRGXJJSLMXQH-UHFFFAOYSA-N 0.000 description 2
- 235000020830 overeating Nutrition 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 229960005434 oxybutynin Drugs 0.000 description 2
- 229960001057 paliperidone Drugs 0.000 description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 2
- 229960002296 paroxetine Drugs 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229960005198 perampanel Drugs 0.000 description 2
- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- HZOTZTANVBDFOF-PBCQUBLHSA-N physostigmine salicylate Chemical compound OC(=O)C1=CC=CC=C1O.C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C HZOTZTANVBDFOF-PBCQUBLHSA-N 0.000 description 2
- 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 2
- 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 2
- 229960004310 piribedil Drugs 0.000 description 2
- 229960003651 pitolisant Drugs 0.000 description 2
- NNACHAUCXXVJSP-UHFFFAOYSA-N pitolisant Chemical compound C1=CC(Cl)=CC=C1CCCOCCCN1CCCCC1 NNACHAUCXXVJSP-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- MICLTPPSCUXHJT-UHFFFAOYSA-M potassium;4-[3-(6-oxo-3h-purin-9-yl)propanoylamino]benzoate Chemical compound [K+].C1=CC(C(=O)[O-])=CC=C1NC(=O)CCN1C(NC=NC2=O)=C2N=C1 MICLTPPSCUXHJT-UHFFFAOYSA-M 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- VJZLQIPZNBPASX-OJJGEMKLSA-L prednisolone sodium phosphate Chemical compound [Na+].[Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 VJZLQIPZNBPASX-OJJGEMKLSA-L 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- WIKYUJGCLQQFNW-UHFFFAOYSA-N prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 2
- MGNVWUDMMXZUDI-UHFFFAOYSA-N propane-1,3-disulfonic acid Chemical compound OS(=O)(=O)CCCS(O)(=O)=O MGNVWUDMMXZUDI-UHFFFAOYSA-N 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 2
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 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 2
- 229960004641 rituximab Drugs 0.000 description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 2
- 229960002586 roflumilast Drugs 0.000 description 2
- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 description 2
- IQWCBYSUUOFOMF-QTLFRQQHSA-N sabcomeline Chemical compound C1CC2[C@@H](C(/C#N)=N/OC)CN1CC2 IQWCBYSUUOFOMF-QTLFRQQHSA-N 0.000 description 2
- 229950000425 sabcomeline Drugs 0.000 description 2
- 229950002652 safinamide Drugs 0.000 description 2
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- CDAISMWEOUEBRE-CDRYSYESSA-N scyllo-inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O CDAISMWEOUEBRE-CDRYSYESSA-N 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 229960003946 selegiline Drugs 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229940118176 surmontil Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960001685 tacrine 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
- 229940095064 tartrate Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229960002784 thioridazine Drugs 0.000 description 2
- 229960005138 tianeptine Drugs 0.000 description 2
- QAXBVGVYDCAVLV-UHFFFAOYSA-N tiletamine Chemical compound C=1C=CSC=1C1(NCC)CCCCC1=O QAXBVGVYDCAVLV-UHFFFAOYSA-N 0.000 description 2
- 229940034744 timoptic Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 2
- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 2
- 229960002309 toloxatone Drugs 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 229960002324 trifluoperazine Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YDGHCKHAXOUQOS-BTJKTKAUSA-N trimipramine maleate Chemical compound [O-]C(=O)\C=C/C([O-])=O.C1CC2=CC=CC=C2[NH+](CC(C[NH+](C)C)C)C2=CC=CC=C21 YDGHCKHAXOUQOS-BTJKTKAUSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- MDYOLVRUBBJPFM-UHFFFAOYSA-N tropolone Chemical compound OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 description 2
- 229960000438 udenafil Drugs 0.000 description 2
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- NAUWTFJOPJWYOT-UHFFFAOYSA-N vanoxerine Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)OCCN1CCN(CCCC=2C=CC=CC=2)CC1 NAUWTFJOPJWYOT-UHFFFAOYSA-N 0.000 description 2
- 229960002381 vardenafil Drugs 0.000 description 2
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 2
- 229960004751 varenicline Drugs 0.000 description 2
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
- 235000012431 wafers Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 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 2
- 229960002911 zonisamide Drugs 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- MMAYTCMMKJYIAM-RUGRQLENSA-N (-)-voacangine Chemical compound C([C@H]1C[C@@H]([C@H]2[C@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=C(OC)C=C12 MMAYTCMMKJYIAM-RUGRQLENSA-N 0.000 description 1
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 description 1
- TWUSDDMONZULSC-QMTHXVAHSA-N (1s,2r)-2-(tert-butylamino)-1-(2,5-dimethoxyphenyl)propan-1-ol Chemical compound COC1=CC=C(OC)C([C@H](O)[C@@H](C)NC(C)(C)C)=C1 TWUSDDMONZULSC-QMTHXVAHSA-N 0.000 description 1
- VNWTVKHKDANUMG-UHFFFAOYSA-N (2,2-dimethyl-1,3-dioxol-4-yl)methanol Chemical compound CC1(C)OC=C(CO)O1 VNWTVKHKDANUMG-UHFFFAOYSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- YWPHCCPCQOJSGZ-LLVKDONJSA-N (2r)-2-[(2-ethoxyphenoxy)methyl]morpholine Chemical compound CCOC1=CC=CC=C1OC[C@@H]1OCCNC1 YWPHCCPCQOJSGZ-LLVKDONJSA-N 0.000 description 1
- TWHNMSJGYKMTRB-KXYUELECSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-methylphenol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 TWHNMSJGYKMTRB-KXYUELECSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- XTBQNQMNFXNGLR-MKSBGGEFSA-N (2s)-1-(2-ethylphenoxy)-3-[[(1s)-1,2,3,4-tetrahydronaphthalen-1-yl]amino]propan-2-ol;oxalic acid Chemical compound OC(=O)C(O)=O.CCC1=CC=CC=C1OC[C@@H](O)CN[C@@H]1C2=CC=CC=C2CCC1 XTBQNQMNFXNGLR-MKSBGGEFSA-N 0.000 description 1
- BHVJEDVPEXXDDP-LPCSYZHESA-N (2s)-1-(4-amino-2,3,5-trimethylphenoxy)-3-[4-[4-[(4-fluorophenyl)methyl]phenyl]piperazin-1-yl]propan-2-ol;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CC1=C(N)C(C)=CC(OC[C@@H](O)CN2CCN(CC2)C=2C=CC(CC=3C=CC(F)=CC=3)=CC=2)=C1C BHVJEDVPEXXDDP-LPCSYZHESA-N 0.000 description 1
- VHKVKWTWHZUFIA-DGOKBZBKSA-N (2s)-1-phenylpropan-2-amine;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioic acid Chemical compound C[C@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O VHKVKWTWHZUFIA-DGOKBZBKSA-N 0.000 description 1
- IHHXIUAEPKVVII-APFIOPMWSA-N (2s)-2,6-diaminohexanoic acid;(2r)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-APFIOPMWSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- NRNSHPCDKHOUOE-SNVBAGLBSA-N (2s)-2-amino-2-[(3,4-dihydroxyphenyl)methyl]-3-fluoropropanoic acid Chemical compound FC[C@@](N)(C(O)=O)CC1=CC=C(O)C(O)=C1 NRNSHPCDKHOUOE-SNVBAGLBSA-N 0.000 description 1
- PHOZOHFUXHPOCK-QMMMGPOBSA-N (2s)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)[C@H](CC)SC11CCN(C)CC1 PHOZOHFUXHPOCK-QMMMGPOBSA-N 0.000 description 1
- OOBHFESNSZDWIU-GXSJLCMTSA-N (2s,3s)-3-methyl-2-phenylmorpholine Chemical compound C[C@@H]1NCCO[C@H]1C1=CC=CC=C1 OOBHFESNSZDWIU-GXSJLCMTSA-N 0.000 description 1
- PUOAETJYKQITMO-LANLRWRYSA-N (3e)-1-[(1s)-1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C1([C@H](C)N2CCC\C(C2=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC=C(F)C=C1 PUOAETJYKQITMO-LANLRWRYSA-N 0.000 description 1
- 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 1
- JQQWDYJWDCIVKQ-QUCCMNQESA-N (3r,4s)-3-(4-benzyl-4-hydroxypiperidin-1-yl)-3,4-dihydro-2h-chromene-4,7-diol Chemical compound C1CN([C@H]2[C@H](C3=CC=C(O)C=C3OC2)O)CCC1(O)CC1=CC=CC=C1 JQQWDYJWDCIVKQ-QUCCMNQESA-N 0.000 description 1
- CTVQNEVLCGSTKL-CXUHLZMHSA-N (4-chlorophenyl) 5-[(e)-methoxyiminomethyl]-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1C(/C=N/OC)=CCCN1C(=O)OC1=CC=C(Cl)C=C1 CTVQNEVLCGSTKL-CXUHLZMHSA-N 0.000 description 1
- LBJYPLZODCWHKE-GOSISDBHSA-N (4r)-4-cyclopropyl-8-fluoro-5-[6-(trifluoromethyl)pyridin-3-yl]sulfonyl-1,4-dihydropyrazolo[4,3-c]quinoline Chemical compound C1([C@H]2N(C3=CC=C(C=C3C=3NN=CC=32)F)S(=O)(=O)C=2C=NC(=CC=2)C(F)(F)F)CC1 LBJYPLZODCWHKE-GOSISDBHSA-N 0.000 description 1
- DQNMZSIJHFEYTM-LEWJYISDSA-N (4s,5r)-3-[3-(azepan-1-yl)propyl]-4-(2-methylpropyl)-5-phenyl-1,3-oxazolidin-2-one Chemical compound O([C@@H]([C@@H]1CC(C)C)C=2C=CC=CC=2)C(=O)N1CCCN1CCCCCC1 DQNMZSIJHFEYTM-LEWJYISDSA-N 0.000 description 1
- GOTMKOSCLKVOGG-OAHLLOKOSA-N (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol Chemical compound C1([C@@H]2C3=CC(O)=C(Cl)C=C3CCN(C2)C)=CC=CC=C1 GOTMKOSCLKVOGG-OAHLLOKOSA-N 0.000 description 1
- DMJWENQHWZZWDF-PKOBYXMFSA-N (6aS,13bR)-11-chloro-7-methyl-5,6,6a,8,9,13b-hexahydronaphtho[1,2-a][3]benzazepin-12-ol Chemical compound CN1CCC2=CC(Cl)=C(O)C=C2[C@H]2C3=CC=CC=C3CC[C@H]12 DMJWENQHWZZWDF-PKOBYXMFSA-N 0.000 description 1
- BGOQGUHWXBGXJW-YOEHRIQHSA-N (6as,12br)-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine-10,11-diol Chemical compound N1CC2=CC=CC=C2[C@@H]2[C@@H]1CCC1=C2C=C(O)C(O)=C1 BGOQGUHWXBGXJW-YOEHRIQHSA-N 0.000 description 1
- FNKBVTBXFLSTPB-LBPRGKRZSA-N (7s)-7-(dipropylamino)-4-fluoro-5,6,7,8-tetrahydronaphthalen-1-ol Chemical compound C1=CC(O)=C2C[C@@H](N(CCC)CCC)CCC2=C1F FNKBVTBXFLSTPB-LBPRGKRZSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical class C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-M (R)-lactate Chemical compound C[C@@H](O)C([O-])=O JVTAAEKCZFNVCJ-UWTATZPHSA-M 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-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
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- GMDCDXMAFMEDAG-CHHFXETESA-N (S,S)-asenapine maleate Chemical compound OC(=O)\C=C/C(O)=O.O1C2=CC=CC=C2[C@H]2CN(C)C[C@@H]2C2=CC(Cl)=CC=C21 GMDCDXMAFMEDAG-CHHFXETESA-N 0.000 description 1
- BRIPGNJWPCKDQZ-WXXKFALUSA-N (e)-but-2-enedioic acid;1-[4-(2-methoxyethyl)phenoxy]-3-(propan-2-ylamino)propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1.COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 BRIPGNJWPCKDQZ-WXXKFALUSA-N 0.000 description 1
- GEOCVSMCLVIOEV-BTJKTKAUSA-N (z)-but-2-enedioic acid;2-methyl-4-phenyl-3,4-dihydro-1h-isoquinolin-8-amine Chemical compound OC(=O)\C=C/C(O)=O.C12=CC=CC(N)=C2CN(C)CC1C1=CC=CC=C1 GEOCVSMCLVIOEV-BTJKTKAUSA-N 0.000 description 1
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- BEQLOSVHRBTANS-UHFFFAOYSA-N 1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluoro-8-iodododecane Chemical compound CCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F BEQLOSVHRBTANS-UHFFFAOYSA-N 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- MVXGSLGVWBVZCA-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(1-phenylpropan-2-ylamino)ethyl]purine-2,6-dione;hydrochloride Chemical compound Cl.C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCNC(C)CC1=CC=CC=C1 MVXGSLGVWBVZCA-UHFFFAOYSA-N 0.000 description 1
- WSTAITCRSVOCTK-UHFFFAOYSA-N 1,4-diazabicyclo[2.2.2]octane;trimethylalumane Chemical compound C[Al](C)C.C[Al](C)C.C1CN2CCN1CC2 WSTAITCRSVOCTK-UHFFFAOYSA-N 0.000 description 1
- JENANTGGBLOTIB-UHFFFAOYSA-N 1,5-diphenylpentan-3-one Chemical compound C=1C=CC=CC=1CCC(=O)CCC1=CC=CC=C1 JENANTGGBLOTIB-UHFFFAOYSA-N 0.000 description 1
- JPHHGFNKNXDZSD-BVDKZHGWSA-N 1-(2-chlorophenyl)-6-[(2s)-3,3,3-trifluoro-2-methylpropyl]-5,7a-dihydro-3ah-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound O=C1NC(C[C@H](C)C(F)(F)F)=NC2C1C=NN2C1=CC=CC=C1Cl JPHHGFNKNXDZSD-BVDKZHGWSA-N 0.000 description 1
- JOTGRACNXIDMSG-UHFFFAOYSA-N 1-(phenylmethoxymethoxy)-2-prop-1-ynyl-4-(trifluoromethoxy)benzene Chemical compound C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1)OC(F)(F)F)C#CC JOTGRACNXIDMSG-UHFFFAOYSA-N 0.000 description 1
- QEMSVZNTSXPFJA-HNAYVOBHSA-N 1-[(1s,2s)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl]-4-phenylpiperidin-4-ol Chemical compound C1([C@H](O)[C@H](C)N2CCC(O)(CC2)C=2C=CC=CC=2)=CC=C(O)C=C1 QEMSVZNTSXPFJA-HNAYVOBHSA-N 0.000 description 1
- UVSWWUWQVAQPJR-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine Chemical compound C1=C(OC)C(OC)=CC=C1CCN1CCN(CCCC=2C=CC=CC=2)CC1 UVSWWUWQVAQPJR-UHFFFAOYSA-N 0.000 description 1
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 1
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 description 1
- MLBHFBKZUPLWBD-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]-2-propanamine Chemical compound CC(N)CC1=CC=CC(C(F)(F)F)=C1 MLBHFBKZUPLWBD-UHFFFAOYSA-N 0.000 description 1
- YFRBKEVUUCQYOW-UHFFFAOYSA-N 1-[6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]pyridin-3-yl]pyrrolidin-2-one Chemical compound O=C1CCCN1C(C=N1)=CC=C1OC1=CC=C(CCN(CC2)C3CCC3)C2=C1 YFRBKEVUUCQYOW-UHFFFAOYSA-N 0.000 description 1
- JQSAYKKFZOSZGJ-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCN(C(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 JQSAYKKFZOSZGJ-UHFFFAOYSA-N 0.000 description 1
- GODZNYBQGNSJJN-UHFFFAOYSA-N 1-aminoethane-1,2-diol Chemical compound NC(O)CO GODZNYBQGNSJJN-UHFFFAOYSA-N 0.000 description 1
- NYNOBRTYKCVRJN-UHFFFAOYSA-N 1-benzyl-5-bromopyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(Br)=CN1CC1=CC=CC=C1 NYNOBRTYKCVRJN-UHFFFAOYSA-N 0.000 description 1
- KZMHSGBETSENAT-UHFFFAOYSA-N 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene Chemical compound FC1=CC(OC(F)(F)F)=CC=C1Br KZMHSGBETSENAT-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical compound CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- GLEJBCISKQNDJI-UHFFFAOYSA-N 1-fluoro-2-(phenylmethoxymethoxy)-3-prop-1-ynyl-5-(trifluoromethoxy)benzene Chemical compound C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1C#CC)OC(F)(F)F)F GLEJBCISKQNDJI-UHFFFAOYSA-N 0.000 description 1
- NGOBGSJYWNMQDY-UHFFFAOYSA-N 1-fluoro-3-iodo-2-(phenylmethoxymethoxy)-5-(trifluoromethoxy)benzene Chemical compound C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1I)OC(F)(F)F)F NGOBGSJYWNMQDY-UHFFFAOYSA-N 0.000 description 1
- JWAWEQBUZOGIBZ-UHFFFAOYSA-N 1-methyltriazole Chemical compound CN1C=CN=N1 JWAWEQBUZOGIBZ-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- VPXVPJQOPRBXPO-UHFFFAOYSA-N 2,5-bis[6-[ethyl-[(2-methoxyphenyl)methyl]amino]hexylamino]cyclohexa-2,5-diene-1,4-dione Chemical compound C=1C=CC=C(OC)C=1CN(CC)CCCCCCNC(C(C=1)=O)=CC(=O)C=1NCCCCCCN(CC)CC1=CC=CC=C1OC VPXVPJQOPRBXPO-UHFFFAOYSA-N 0.000 description 1
- VWGJUXTWIWCQGL-UHFFFAOYSA-M 2-(2-cyclopentyl-2-hydroxy-2-thiophen-2-ylacetyl)oxyethyl-diethyl-methylazanium;bromide Chemical compound [Br-].C=1C=CSC=1C(O)(C(=O)OCC[N+](C)(CC)CC)C1CCCC1 VWGJUXTWIWCQGL-UHFFFAOYSA-M 0.000 description 1
- LZYVYVIQKXALAF-UHFFFAOYSA-N 2-(4-nitrophenoxy)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=C([N+]([O-])=O)C=C1 LZYVYVIQKXALAF-UHFFFAOYSA-N 0.000 description 1
- OBHWTRBRRFQGRJ-UHFFFAOYSA-N 2-(7-imidazol-1-yl-6-nitro-2,3-dioxo-4h-quinoxalin-1-yl)acetic acid;hydrate Chemical compound O.[O-][N+](=O)C=1C=C2NC(=O)C(=O)N(CC(=O)O)C2=CC=1N1C=CN=C1 OBHWTRBRRFQGRJ-UHFFFAOYSA-N 0.000 description 1
- HJOCKFVCMLCPTP-UHFFFAOYSA-N 2-[(2-ethoxyphenoxy)methyl]morpholine;hydron;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCC1OCCNC1 HJOCKFVCMLCPTP-UHFFFAOYSA-N 0.000 description 1
- RATZLMXRALDSJW-CYBMUJFWSA-N 2-[(2r)-2-ethyl-3h-1-benzofuran-2-yl]-4,5-dihydro-1h-imidazole Chemical compound C1([C@@]2(OC3=CC=CC=C3C2)CC)=NCCN1 RATZLMXRALDSJW-CYBMUJFWSA-N 0.000 description 1
- FTGBVHPWUIHWRH-UHFFFAOYSA-N 2-[2-[2-[2-[carboxymethyl-[2-(2-octoxyethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(2-octoxyethoxy)-2-oxoethyl]anilino]acetic acid Chemical compound CCCCCCCCOCCOC(=O)CN(CC(O)=O)C1=CC=CC=C1OCCOC1=CC=CC=C1N(CC(O)=O)CC(=O)OCCOCCCCCCCC FTGBVHPWUIHWRH-UHFFFAOYSA-N 0.000 description 1
- UEBBYLJZCHTLEG-UTKZUKDTSA-N 2-[[(1r,2s)-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl]methyl-methylamino]acetic acid Chemical compound C1([C@@H]2C3=CC=C(C=C3CC[C@@H]2CN(C)CC(O)=O)OC)=CC=CC=C1 UEBBYLJZCHTLEG-UTKZUKDTSA-N 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- WKAVKKUXZAWHDM-UHFFFAOYSA-N 2-acetamidopentanedioic acid;2-(dimethylamino)ethanol Chemical compound CN(C)CCO.CC(=O)NC(C(O)=O)CCC(O)=O WKAVKKUXZAWHDM-UHFFFAOYSA-N 0.000 description 1
- DUGMCDWNXXFHDE-VZYDHVRKSA-N 2-amino-2-methyl-n-[(2r)-1-(1-methylsulfonylspiro[2h-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC2(C3=CC=CC=C3N(C2)S(C)(=O)=O)CC1)OCC1=CC=CC=C1 DUGMCDWNXXFHDE-VZYDHVRKSA-N 0.000 description 1
- UCYXPWDIMHOZKA-UHFFFAOYSA-N 2-bromo-4-(difluoromethoxy)-5-fluorophenol Chemical compound BrC1=C(C=C(C(=C1)OC(F)F)F)O UCYXPWDIMHOZKA-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- PFEFZNARVCCVLN-UHFFFAOYSA-N 2-fluoro-4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1F PFEFZNARVCCVLN-UHFFFAOYSA-N 0.000 description 1
- WHCIRBAVGCODKE-UHFFFAOYSA-N 2-fluoro-6-iodo-4-(trifluoromethoxy)phenol Chemical compound FC1=C(C(=CC(=C1)OC(F)(F)F)I)O WHCIRBAVGCODKE-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- VKEBWWSHSNUJMC-UHFFFAOYSA-N 2-iodo-1-(phenylmethoxymethoxy)-4-(trifluoromethoxy)benzene Chemical compound C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1)OC(F)(F)F)I VKEBWWSHSNUJMC-UHFFFAOYSA-N 0.000 description 1
- WOCGRJGJXZXHSA-UHFFFAOYSA-N 2-iodo-4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1I WOCGRJGJXZXHSA-UHFFFAOYSA-N 0.000 description 1
- MRDCXUYQUSFQKF-UHFFFAOYSA-N 2-iodo-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1I MRDCXUYQUSFQKF-UHFFFAOYSA-N 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- IAOXOGSROBNNPI-UHFFFAOYSA-N 2-methyl-3-(phenylmethoxymethyl)-5-(trifluoromethoxy)-1-benzofuran Chemical compound C(C1=CC=CC=C1)OCC1=C(OC2=C1C=C(C=C2)OC(F)(F)F)C IAOXOGSROBNNPI-UHFFFAOYSA-N 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HLLNAMJBYIOZGY-UHFFFAOYSA-N 3,4-dihydro-2h-quinolizine Chemical compound C1=CC=CN2CCCC=C21 HLLNAMJBYIOZGY-UHFFFAOYSA-N 0.000 description 1
- WAOQONBSWFLFPE-VIFPVBQESA-N 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide Chemical compound CCN1CCC[C@H]1CNC(=O)C1=C(O)C(Cl)=CC(Cl)=C1OC WAOQONBSWFLFPE-VIFPVBQESA-N 0.000 description 1
- HYHNPUGUPISSQO-FYWRMAATSA-N 3-(2-chlorophenyl)-2-[(e)-2-[6-(diethylaminomethyl)pyridin-2-yl]ethenyl]-6-fluoroquinazolin-4-one Chemical compound CCN(CC)CC1=CC=CC(\C=C\C=2N(C(=O)C3=CC(F)=CC=C3N=2)C=2C(=CC=CC=2)Cl)=N1 HYHNPUGUPISSQO-FYWRMAATSA-N 0.000 description 1
- IOSAAWHGJUZBOG-UHFFFAOYSA-N 3-(6-amino-9h-purin-9-yl)nonan-2-ol Chemical compound N1=CN=C2N(C(C(C)O)CCCCCC)C=NC2=C1N IOSAAWHGJUZBOG-UHFFFAOYSA-N 0.000 description 1
- MHNSPTUQQIYJOT-UHFFFAOYSA-N 3-(6h-benzo[c][1]benzoxepin-11-ylidene)propyl-dimethylazanium;chloride Chemical compound Cl.C1OC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 MHNSPTUQQIYJOT-UHFFFAOYSA-N 0.000 description 1
- KSAUCBGUWGWPDL-UHFFFAOYSA-N 3-(benzenesulfonyl)-5,7-dimethyl-2-methylsulfanylpyrazolo[1,5-a]pyrimidine Chemical compound CSC1=NN2C(C)=CC(C)=NC2=C1S(=O)(=O)C1=CC=CC=C1 KSAUCBGUWGWPDL-UHFFFAOYSA-N 0.000 description 1
- OFKWWALNMPEOSZ-UHFFFAOYSA-N 3-(hydrazinylmethyl)phenol Chemical compound NNCC1=CC=CC(O)=C1 OFKWWALNMPEOSZ-UHFFFAOYSA-N 0.000 description 1
- WVORWODYFYSTJU-UHFFFAOYSA-N 3-[2-iodo-4-(trifluoromethyl)phenoxy]propane-1,2-diol Chemical compound IC1=C(OCC(CO)O)C=CC(=C1)C(F)(F)F WVORWODYFYSTJU-UHFFFAOYSA-N 0.000 description 1
- KJNNWYBAOPXVJY-UHFFFAOYSA-N 3-[4-[2-butyl-1-[4-(4-chlorophenoxy)phenyl]imidazol-4-yl]phenoxy]-n,n-diethylpropan-1-amine Chemical compound CCCCC1=NC(C=2C=CC(OCCCN(CC)CC)=CC=2)=CN1C(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 KJNNWYBAOPXVJY-UHFFFAOYSA-N 0.000 description 1
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
- WOUMHLGSMDVJHS-UHFFFAOYSA-L 3-benzyl-1-[6-(3-benzyl-1-azoniabicyclo[2.2.2]octan-1-yl)hexyl]-1-azoniabicyclo[2.2.2]octane;dichloride Chemical compound [Cl-].[Cl-].C1CC(C(CC=2C=CC=CC=2)C2)CC[N+]12CCCCCC[N+](CC1)(C2)CCC1C2CC1=CC=CC=C1 WOUMHLGSMDVJHS-UHFFFAOYSA-L 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- KQFQPAJCFHNHKB-UHFFFAOYSA-N 3-chloro-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C(Cl)=C1 KQFQPAJCFHNHKB-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- SWVNNWWBKBALGG-UHFFFAOYSA-N 3-cyclopropyl-1-benzofuran-2-ol Chemical compound Oc1oc2ccccc2c1C1CC1 SWVNNWWBKBALGG-UHFFFAOYSA-N 0.000 description 1
- UTFSPWRTXCDUIJ-UHFFFAOYSA-N 3-fluoro-4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C(F)=C1 UTFSPWRTXCDUIJ-UHFFFAOYSA-N 0.000 description 1
- XTLJKHBPNDOAGE-UHFFFAOYSA-N 3-fluoro-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C(F)=C1 XTLJKHBPNDOAGE-UHFFFAOYSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- LBSRZVRITCRLIU-UHFFFAOYSA-N 3-o-ethyl 5-o-(2-piperidin-1-ylethyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCCCC2)C1C1=CC=CC([N+]([O-])=O)=C1 LBSRZVRITCRLIU-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- YYWZKGZIIKPPJZ-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]heptan-4-ol Chemical compound C1C2C(C)(C)C1CCC2(O)C YYWZKGZIIKPPJZ-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- SZSHJTJCJOWMHM-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-methyl-6-(5-piperidin-1-ylpentoxy)pyrimidine Chemical compound C=1C(C=2C=CC(F)=CC=2)=NC(C)=NC=1OCCCCCN1CCCCC1 SZSHJTJCJOWMHM-UHFFFAOYSA-N 0.000 description 1
- KYGXQIJIJIWLGF-UHFFFAOYSA-N 4-(difluoromethoxy)-3-fluorophenol Chemical compound OC1=CC=C(OC(F)F)C(F)=C1 KYGXQIJIJIWLGF-UHFFFAOYSA-N 0.000 description 1
- WDRJNKMAZMEYOF-UHFFFAOYSA-N 4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1 WDRJNKMAZMEYOF-UHFFFAOYSA-N 0.000 description 1
- UTUUPXBCDMQYRR-HSZRJFAPSA-N 4-[(2r)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine Chemical compound COC1=CC=C([C@H](CC=2C=CN=CC=2)C=2C=CC=CC=2)C=C1OC1CCCC1 UTUUPXBCDMQYRR-HSZRJFAPSA-N 0.000 description 1
- IPHACPSYWWYGQN-UHFFFAOYSA-N 4-[(6-methoxy-3,8-dimethyl-2h-pyrazolo[3,4-b]quinolin-4-yl)methyl]-1,4-oxazepane Chemical compound C=12C=C(OC)C=C(C)C2=NC2=NNC(C)=C2C=1CN1CCCOCC1 IPHACPSYWWYGQN-UHFFFAOYSA-N 0.000 description 1
- JSEWHEILACKEJH-UHFFFAOYSA-N 4-[[2-iodo-4-(trifluoromethyl)phenoxy]methyl]-2,2-dimethyl-1,3-dioxolane Chemical compound IC1=C(OCC2OC(OC2)(C)C)C=CC(=C1)C(F)(F)F JSEWHEILACKEJH-UHFFFAOYSA-N 0.000 description 1
- DOMDQZCKLBEOTD-UHFFFAOYSA-N 4-bromo-1-(difluoromethoxy)-2-fluorobenzene Chemical compound FC(F)OC1=CC=C(Br)C=C1F DOMDQZCKLBEOTD-UHFFFAOYSA-N 0.000 description 1
- RYVOZMPTISNBDB-UHFFFAOYSA-N 4-bromo-2-fluorophenol Chemical compound OC1=CC=C(Br)C=C1F RYVOZMPTISNBDB-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
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- QNWOSJAGFSUDFE-UHFFFAOYSA-N 5-(aminooxymethyl)-2-bromophenol Chemical compound NOCC1=CC=C(Br)C(O)=C1 QNWOSJAGFSUDFE-UHFFFAOYSA-N 0.000 description 1
- DGWKVXVCPCPOAK-UHFFFAOYSA-N 5-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-n-methylpyrazine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CN=C1OC1=CC=C(CCN(CC2)C3CCC3)C2=C1 DGWKVXVCPCPOAK-UHFFFAOYSA-N 0.000 description 1
- JCPWIGCGJUGLJQ-OGFXRTJISA-N 5-[[(2r)-azetidin-2-yl]methoxy]-2-chloropyridine;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.C1=NC(Cl)=CC=C1OC[C@@H]1NCC1 JCPWIGCGJUGLJQ-OGFXRTJISA-N 0.000 description 1
- YJMYSLFFZJUXOA-UHFFFAOYSA-N 5-bromo-3-[3-(4-chlorophenyl)propoxy]-4-(pyridin-3-ylmethylamino)-1h-pyridazin-6-one Chemical compound C1=CC(Cl)=CC=C1CCCOC1=NNC(=O)C(Br)=C1NCC1=CC=CN=C1 YJMYSLFFZJUXOA-UHFFFAOYSA-N 0.000 description 1
- FMWHTGBMLAHATK-UHFFFAOYSA-N 5-chloro-2-iodo-4-(trifluoromethyl)phenol Chemical compound ClC=1C(=CC(=C(C=1)O)I)C(F)(F)F FMWHTGBMLAHATK-UHFFFAOYSA-N 0.000 description 1
- HVGBXJSDXCPLCB-UHFFFAOYSA-N 5-fluoro-2-iodo-4-(trifluoromethoxy)phenol Chemical compound FC=1C(=CC(=C(C=1)O)I)OC(F)(F)F HVGBXJSDXCPLCB-UHFFFAOYSA-N 0.000 description 1
- VRCWSYYXUCKEED-UHFFFAOYSA-N 6-Hydroxypicolinic acid Chemical compound OC(=O)C1=CC=CC(=O)N1 VRCWSYYXUCKEED-UHFFFAOYSA-N 0.000 description 1
- FCBQJNCAKZSIAH-UHFFFAOYSA-N 6-[2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethylsulfinyl]-3h-1,3-benzoxazol-2-one Chemical compound C1=CC(F)=CC=C1CC1CCN(CCS(=O)C=2C=C3OC(=O)NC3=CC=2)CC1 FCBQJNCAKZSIAH-UHFFFAOYSA-N 0.000 description 1
- RFRMMZAKBNXNHE-UHFFFAOYSA-N 6-[4,6-dihydroxy-5-(2-hydroxyethoxy)-2-(hydroxymethyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-(2-hydroxypropoxy)oxane-3,4-diol Chemical compound CC(O)COC1C(O)C(O)C(CO)OC1OC1C(O)C(OCCO)C(O)OC1CO RFRMMZAKBNXNHE-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- YVPUUUDAZYFFQT-UHFFFAOYSA-N 7-(4-methylpiperazin-1-yl)-3h-1,3-benzoxazol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC2=C1OC(=O)N2 YVPUUUDAZYFFQT-UHFFFAOYSA-N 0.000 description 1
- VJPXJCQAEYLZCE-UHFFFAOYSA-M 7-bromo-5-pyridin-2-yl-1,3-dihydro-1,4-benzodiazepin-2-one;methyl-di(propan-2-yl)-[2-(9h-xanthene-9-carbonyloxy)ethyl]azanium;bromide Chemical compound [Br-].C12=CC(Br)=CC=C2NC(=O)CN=C1C1=CC=CC=N1.C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 VJPXJCQAEYLZCE-UHFFFAOYSA-M 0.000 description 1
- NTAKOCCPYVBVRS-UHFFFAOYSA-N 7-fluoro-2-methyl-3-(phenylmethoxymethyl)-5-(trifluoromethoxy)-1-benzofuran Chemical compound C(C1=CC=CC=C1)OCC1=C(OC2=C1C=C(C=C2F)OC(F)(F)F)C NTAKOCCPYVBVRS-UHFFFAOYSA-N 0.000 description 1
- XFTVOHWWEQGXLS-UHFFFAOYSA-N 8-bromo-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol Chemical compound C1N(C)CCC2=CC(Br)=C(O)C=C2C1C1=CC=CC=C1 XFTVOHWWEQGXLS-UHFFFAOYSA-N 0.000 description 1
- CFHDISFPIIFJTI-UHFFFAOYSA-N 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepin-2-ol Chemical compound C1CN(C)CCN1C1=NC2=CC=C(O)C=C2OC2=CC=C(Cl)C=C12 CFHDISFPIIFJTI-UHFFFAOYSA-N 0.000 description 1
- MKJIEFSOBYUXJB-UHFFFAOYSA-N 9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2CC(CC(C)C)C(=O)CC2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-UHFFFAOYSA-N 0.000 description 1
- NEEKVKZFYBQFGT-BTJKTKAUSA-N 9-amino-1,2,3,4-tetrahydroacridin-1-ol;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.C1=CC=C2C(N)=C(C(O)CCC3)C3=NC2=C1 NEEKVKZFYBQFGT-BTJKTKAUSA-N 0.000 description 1
- HJWHHQIVUHOBQN-UHFFFAOYSA-N 9-chloro-5-phenyl-3-prop-2-enyl-1,2,4,5-tetrahydro-3-benzazepine-7,8-diol Chemical compound C1N(CC=C)CCC=2C(Cl)=C(O)C(O)=CC=2C1C1=CC=CC=C1 HJWHHQIVUHOBQN-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 108010005094 Advanced Glycation End Products Proteins 0.000 description 1
- 241000673185 Aeolus Species 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000029197 Amphetamine-Related disease Diseases 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- XUHBBTKJWIBQMY-MHZLTWQESA-N Anatibant Chemical compound O=C([C@@H]1CCCN1S(=O)(=O)C=1C=CC(Cl)=C(C=1Cl)COC1=CC=CC2=C(C)C=C(N=C21)C)NCCCNC(=O)C1=CC=C(C(N)=N)C=C1 XUHBBTKJWIBQMY-MHZLTWQESA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 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 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- XEAOPVUAMONVLA-QGZVFWFLSA-N Avagacestat Chemical compound C=1C=C(Cl)C=CC=1S(=O)(=O)N([C@H](CCC(F)(F)F)C(=O)N)CC(C(=C1)F)=CC=C1C=1N=CON=1 XEAOPVUAMONVLA-QGZVFWFLSA-N 0.000 description 1
- 102100021257 Beta-secretase 1 Human genes 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 1
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- ZFCIBZSXKFCIDL-UHFFFAOYSA-N C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1)OC(F)(F)F)C#CC[Si](C)(C)C Chemical compound C(C1=CC=CC=C1)OCOC1=C(C=C(C=C1)OC(F)(F)F)C#CC[Si](C)(C)C ZFCIBZSXKFCIDL-UHFFFAOYSA-N 0.000 description 1
- 108010081642 CA 074 methyl ester Proteins 0.000 description 1
- FIZNMGPSUFXXAE-UHFFFAOYSA-N CN(C)C.CN(C)C.C(C1)N2CCN1CC2 Chemical compound CN(C)C.CN(C)C.C(C1)N2CCN1CC2 FIZNMGPSUFXXAE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 101000898643 Candida albicans Vacuolar aspartic protease Proteins 0.000 description 1
- 101000898783 Candida tropicalis Candidapepsin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 102100028892 Cardiotrophin-1 Human genes 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- PCLITLDOTJTVDJ-UHFFFAOYSA-N Chlormethiazole Chemical compound CC=1N=CSC=1CCCl PCLITLDOTJTVDJ-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 1
- 208000022497 Cocaine-Related disease Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 101000898784 Cryphonectria parasitica Endothiapepsin Proteins 0.000 description 1
- 244000304337 Cuminum cyminum Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- DSCFFEYYQKSRSV-KLJZZCKASA-N D-pinitol Chemical compound CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]1O DSCFFEYYQKSRSV-KLJZZCKASA-N 0.000 description 1
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 description 1
- HCMCKZWEUHDBNH-IGPVODHVSA-N Dactylorhin B Natural products O=C(OCc1ccc(O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)cc1)[C@@H](O)[C@](O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1)([C@H](CC)C)C(=O)OCc1ccc(O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)cc1 HCMCKZWEUHDBNH-IGPVODHVSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- WUFQLZTXIWKION-UHFFFAOYSA-N Deoxypeganine Chemical compound C1C2=CC=CC=C2N=C2N1CCC2 WUFQLZTXIWKION-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 108010057987 Desmodus rotundus salivary plasminogen activator alpha 1 Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000012848 Dextrorphan Substances 0.000 description 1
- PQUCIEFHOVEZAU-UHFFFAOYSA-N Diammonium sulfite Chemical compound [NH4+].[NH4+].[O-]S([O-])=O PQUCIEFHOVEZAU-UHFFFAOYSA-N 0.000 description 1
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 1
- ZWRLWJAFBLTMSQ-UHFFFAOYSA-N Docosa-7,10,14-triensaeure Natural products C1C(C)=C2CC(C)(C)CC2C(O)C2=COC=C21 ZWRLWJAFBLTMSQ-UHFFFAOYSA-N 0.000 description 1
- 229940121891 Dopamine receptor antagonist Drugs 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000014094 Dystonic disease Diseases 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
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NLPRAJRHRHZCQQ-UHFFFAOYSA-N Epibatidine Natural products C1=NC(Cl)=CC=C1C1C(N2)CCC2C1 NLPRAJRHRHZCQQ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- SGSAZIKXWZLPEA-UHFFFAOYSA-N FC(C=1C=CC2=C(C(=CO2)CO)C1)(F)F Chemical compound FC(C=1C=CC2=C(C(=CO2)CO)C1)(F)F SGSAZIKXWZLPEA-UHFFFAOYSA-N 0.000 description 1
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 208000001914 Fragile X syndrome Diseases 0.000 description 1
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 239000009429 Ginkgo biloba extract Substances 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- XYZZKVRWGOWVGO-UHFFFAOYSA-N Glycerol-phosphate Chemical compound OP(O)(O)=O.OCC(O)CO XYZZKVRWGOWVGO-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 description 1
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100021496 Insulin-degrading enzyme Human genes 0.000 description 1
- 108090000828 Insulysin Proteins 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 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
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- DAQAKHDKYAWHCG-UHFFFAOYSA-N Lactacystin Natural products CC(=O)NC(C(O)=O)CSC(=O)C1(C(O)C(C)C)NC(=O)C(C)C1O DAQAKHDKYAWHCG-UHFFFAOYSA-N 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
- 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 1
- 241000219739 Lens Species 0.000 description 1
- 235000014647 Lens culinaris subsp culinaris Nutrition 0.000 description 1
- 244000043158 Lens esculenta Species 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 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 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 108010016230 MBP-8298 Proteins 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- JUOSGGQXEBBCJB-UHFFFAOYSA-N Metanicotine Natural products CNCCC=CC1=CC=CN=C1 JUOSGGQXEBBCJB-UHFFFAOYSA-N 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000019430 Motor disease Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 208000029578 Muscle disease Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 102000047918 Myelin Basic Human genes 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- 244000270834 Myristica fragrans Species 0.000 description 1
- 235000009421 Myristica fragrans Nutrition 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- ONXPDKGXOOORHB-BYPYZUCNSA-N N(5)-methyl-L-glutamine Chemical compound CNC(=O)CC[C@H](N)C(O)=O ONXPDKGXOOORHB-BYPYZUCNSA-N 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- YLXDSYKOBKBWJQ-LBPRGKRZSA-N N-[2-[(8S)-2,6,7,8-tetrahydro-1H-cyclopenta[e]benzofuran-8-yl]ethyl]propanamide Chemical compound C1=C2OCCC2=C2[C@H](CCNC(=O)CC)CCC2=C1 YLXDSYKOBKBWJQ-LBPRGKRZSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- QSQQPMHPCBLLGX-UHFFFAOYSA-N N-methyl-4-[2-(phenylmethyl)phenoxy]-1-butanamine Chemical compound CNCCCCOC1=CC=CC=C1CC1=CC=CC=C1 QSQQPMHPCBLLGX-UHFFFAOYSA-N 0.000 description 1
- RVNBZZUIXFEKDS-UHFFFAOYSA-N N1CCNCC1.C(CCC)C1=CC=CC=C1 Chemical compound N1CCNCC1.C(CCC)C1=CC=CC=C1 RVNBZZUIXFEKDS-UHFFFAOYSA-N 0.000 description 1
- SJDOMIRMMUGQQK-UHFFFAOYSA-N NAN 190 Chemical compound COC1=CC=CC=C1N1CCN(CCCCN2C(C3=CC=CC=C3C2=O)=O)CC1 SJDOMIRMMUGQQK-UHFFFAOYSA-N 0.000 description 1
- OJNSNSZTGUACNI-IBFUIWIBSA-N N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 Chemical compound N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 OJNSNSZTGUACNI-IBFUIWIBSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 208000018526 Narcotic-Related disease Diseases 0.000 description 1
- 102100028782 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- YSEXMKHXIOCEJA-FVFQAYNVSA-N Nicergoline Chemical compound C([C@@H]1C[C@]2([C@H](N(C)C1)CC=1C3=C2C=CC=C3N(C)C=1)OC)OC(=O)C1=CN=CC(Br)=C1 YSEXMKHXIOCEJA-FVFQAYNVSA-N 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 208000010577 Niemann-Pick disease type C Diseases 0.000 description 1
- UPMRZALMHVUCIN-UHFFFAOYSA-N Nitecapone Chemical compound CC(=O)C(C(C)=O)=CC1=CC(O)=C(O)C([N+]([O-])=O)=C1 UPMRZALMHVUCIN-UHFFFAOYSA-N 0.000 description 1
- UUFAJPMQSFXDFR-LLVKDONJSA-N Norselegiline Chemical compound C#CCN[C@H](C)CC1=CC=CC=C1 UUFAJPMQSFXDFR-LLVKDONJSA-N 0.000 description 1
- DITOENWBJBNZSL-UHFFFAOYSA-N O-methyl-hippeastrine Natural products C1=C2C3C4N(C)CCC4=CC(OC)C3OC(=O)C2=CC2=C1OCO2 DITOENWBJBNZSL-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 description 1
- 229940076380 PDE9 inhibitor Drugs 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 206010034158 Pathological gambling Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- BDABGOLMYNHHTR-UHFFFAOYSA-N Perzinfotel Chemical compound OP(O)(=O)CCN1CCCNC2=C1C(=O)C2=O BDABGOLMYNHHTR-UHFFFAOYSA-N 0.000 description 1
- MFOCDFTXLCYLKU-CMPLNLGQSA-N Phendimetrazine Chemical compound O1CCN(C)[C@@H](C)[C@@H]1C1=CC=CC=C1 MFOCDFTXLCYLKU-CMPLNLGQSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 206010034912 Phobia Diseases 0.000 description 1
- 229940122233 Phosphodiesterase 8B inhibitor Drugs 0.000 description 1
- 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 description 1
- 229940122353 Phosphodiesterase 11 inhibitor Drugs 0.000 description 1
- 229940121828 Phosphodiesterase 2 inhibitor Drugs 0.000 description 1
- 229940123263 Phosphodiesterase 3 inhibitor Drugs 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 229940123304 Phosphodiesterase 7 inhibitor Drugs 0.000 description 1
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 201000009916 Postpartum depression Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010050254 Presenilins Proteins 0.000 description 1
- 102000015499 Presenilins Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- VVWYOYDLCMFIEM-UHFFFAOYSA-N Propantheline Chemical compound C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 VVWYOYDLCMFIEM-UHFFFAOYSA-N 0.000 description 1
- XLBIBBZXLMYSFF-UHFFFAOYSA-M Propantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 XLBIBBZXLMYSFF-UHFFFAOYSA-M 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- RVOLLAQWKVFTGE-UHFFFAOYSA-N Pyridostigmine Chemical compound CN(C)C(=O)OC1=CC=C[N+](C)=C1 RVOLLAQWKVFTGE-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 101000933133 Rhizopus niveus Rhizopuspepsin-1 Proteins 0.000 description 1
- 101000910082 Rhizopus niveus Rhizopuspepsin-2 Proteins 0.000 description 1
- 101000910079 Rhizopus niveus Rhizopuspepsin-3 Proteins 0.000 description 1
- 101000910086 Rhizopus niveus Rhizopuspepsin-4 Proteins 0.000 description 1
- 101000910088 Rhizopus niveus Rhizopuspepsin-5 Proteins 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 1
- 101000898773 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Saccharopepsin Proteins 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 238000006932 Simmons-Smith cyclopropanation reaction Methods 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- JACAAXNEHGBPOQ-LLVKDONJSA-N Talampanel Chemical compound C([C@H](N(N=1)C(C)=O)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(N)C=C1 JACAAXNEHGBPOQ-LLVKDONJSA-N 0.000 description 1
- JOAHPSVPXZTVEP-YXJHDRRASA-N Terguride Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=CNC3=C1 JOAHPSVPXZTVEP-YXJHDRRASA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 208000025569 Tobacco Use disease Diseases 0.000 description 1
- DHCOPPHTVOXDKU-UHFFFAOYSA-N Tofimilast Chemical compound C1CN2C(C=3SC=CC=3)=NN=C2C2=C1C(CC)=NN2C1CCCC1 DHCOPPHTVOXDKU-UHFFFAOYSA-N 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000016620 Tourette disease Diseases 0.000 description 1
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 1
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical group C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000007930 Type C Niemann-Pick Disease Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- VOXIUXZAOFEFBL-UHFFFAOYSA-N Voacangin Natural products CCC1CC2CN3CC1C(C2)(OC(=O)C)c4[nH]c5ccc(OC)cc5c4C3 VOXIUXZAOFEFBL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- WVHBEIJGAINUBW-UHFFFAOYSA-N Xaliproden hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(C=2CCN(CCC=3C=C4C=CC=CC4=CC=3)CC=2)=C1 WVHBEIJGAINUBW-UHFFFAOYSA-N 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- BYPMJBXPNZMNQD-PZJWPPBQSA-N Zicronapine Chemical compound C1C(C)(C)N(C)CCN1[C@H]1C2=CC(Cl)=CC=C2[C@H](C=2C=CC=CC=2)C1 BYPMJBXPNZMNQD-PZJWPPBQSA-N 0.000 description 1
- BKPRVQDIOGQWTG-ICOOEGOYSA-N [(1s,2r)-2-phenylcyclopropyl]azanium;[(1r,2s)-2-phenylcyclopropyl]azanium;sulfate Chemical compound [O-]S([O-])(=O)=O.[NH3+][C@H]1C[C@@H]1C1=CC=CC=C1.[NH3+][C@@H]1C[C@H]1C1=CC=CC=C1 BKPRVQDIOGQWTG-ICOOEGOYSA-N 0.000 description 1
- PBHFNBQPZCRWQP-AZUAARDMSA-N [(3aS,8bR)-3,4,8b-trimethyl-2,3a-dihydro-1H-pyrrolo[2,3-b]indol-7-yl] N-phenylcarbamate Chemical compound CN([C@H]1[C@](C2=C3)(C)CCN1C)C2=CC=C3OC(=O)NC1=CC=CC=C1 PBHFNBQPZCRWQP-AZUAARDMSA-N 0.000 description 1
- JGAGHIIOCADQOV-CTNGQTDRSA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n-(2-methylphenyl)carbamate Chemical compound CN([C@@H]1[C@@](C2=C3)(C)CCN1C)C2=CC=C3OC(=O)NC1=CC=CC=C1C JGAGHIIOCADQOV-CTNGQTDRSA-N 0.000 description 1
- PBHFNBQPZCRWQP-QUCCMNQESA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n-phenylcarbamate Chemical compound CN([C@@H]1[C@@](C2=C3)(C)CCN1C)C2=CC=C3OC(=O)NC1=CC=CC=C1 PBHFNBQPZCRWQP-QUCCMNQESA-N 0.000 description 1
- ZIGIADNCAWZUAB-CTNGQTDRSA-N [(3ar,8bs)-8b-methyl-2,3,3a,4-tetrahydro-1h-pyrrolo[2,3-b]indol-7-yl] n-(4-propan-2-ylphenyl)carbamate Chemical compound C1=CC(C(C)C)=CC=C1NC(=O)OC1=CC=C(N[C@@H]2[C@@]3(C)CCN2)C3=C1 ZIGIADNCAWZUAB-CTNGQTDRSA-N 0.000 description 1
- ZOBDWFRKFSPCRB-UNMCSNQZSA-N [(4as,9as)-2,4a,9-trimethyl-4,9a-dihydro-3h-oxazino[6,5-b]indol-6-yl] n-(2-ethylphenyl)carbamate Chemical compound CCC1=CC=CC=C1NC(=O)OC1=CC=C(N(C)[C@@H]2[C@@]3(C)CCN(C)O2)C3=C1 ZOBDWFRKFSPCRB-UNMCSNQZSA-N 0.000 description 1
- FZSPJBYOKQPKCD-VIFPVBQESA-N [1-(4-chlorophenyl)-2-methylpropan-2-yl] (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)CC1=CC=C(Cl)C=C1 FZSPJBYOKQPKCD-VIFPVBQESA-N 0.000 description 1
- YQMMVZVQAHYXFZ-UHFFFAOYSA-N [2-fluoro-4-(trifluoromethoxy)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(OC(F)(F)F)C=C1F YQMMVZVQAHYXFZ-UHFFFAOYSA-N 0.000 description 1
- JCZIKWXOUOGQPY-UHFFFAOYSA-N [2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-yl]methanol Chemical compound CC=1OC2=C(C=1CO)C=C(C=C2)OC(F)(F)F JCZIKWXOUOGQPY-UHFFFAOYSA-N 0.000 description 1
- YUUGYIUSCYNSQR-LBPRGKRZSA-N [4-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]-[5-methylsulfonyl-2-[(2s)-1,1,1-trifluoropropan-2-yl]oxyphenyl]methanone Chemical compound FC(F)(F)[C@H](C)OC1=CC=C(S(C)(=O)=O)C=C1C(=O)N1CCN(C=2C(=CC(=CN=2)C(F)(F)F)F)CC1 YUUGYIUSCYNSQR-LBPRGKRZSA-N 0.000 description 1
- HXRNADMHJBXZGO-UHFFFAOYSA-N [5-chloro-2-(4-methoxyphenyl)-1-benzofuran-3-yl]-[4-[3-(diethylamino)propoxy]phenyl]methanone Chemical compound C1=CC(OCCCN(CC)CC)=CC=C1C(=O)C1=C(C=2C=CC(OC)=CC=2)OC2=CC=C(Cl)C=C12 HXRNADMHJBXZGO-UHFFFAOYSA-N 0.000 description 1
- LTQDJZBXTIDLCG-UHFFFAOYSA-N [7-fluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-yl]methanol Chemical compound FC1=CC(=CC=2C(=C(OC=21)C)CO)OC(F)(F)F LTQDJZBXTIDLCG-UHFFFAOYSA-N 0.000 description 1
- NVFKVXLXRHMGPY-UHFFFAOYSA-N [N].C(CCC)(=O)OC1=CC=CC=C1 Chemical compound [N].C(CCC)(=O)OC1=CC=CC=C1 NVFKVXLXRHMGPY-UHFFFAOYSA-N 0.000 description 1
- AFCGFAGUEYAMAO-UHFFFAOYSA-N acamprosate Chemical compound CC(=O)NCCCS(O)(=O)=O AFCGFAGUEYAMAO-UHFFFAOYSA-N 0.000 description 1
- 229960004047 acamprosate Drugs 0.000 description 1
- BUVGWDNTAWHSKI-UHFFFAOYSA-L acamprosate calcium Chemical compound [Ca+2].CC(=O)NCCCS([O-])(=O)=O.CC(=O)NCCCS([O-])(=O)=O BUVGWDNTAWHSKI-UHFFFAOYSA-L 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- KTUFKADDDORSSI-UHFFFAOYSA-N acebutolol hydrochloride Chemical compound Cl.CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 KTUFKADDDORSSI-UHFFFAOYSA-N 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000026345 acute stress disease Diseases 0.000 description 1
- 229940092980 adalat Drugs 0.000 description 1
- 229940047812 adderall Drugs 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 150000001279 adipic acids Chemical class 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- CGNMLOKEMNBUAI-UHFFFAOYSA-N adrafinil Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)NO)C1=CC=CC=C1 CGNMLOKEMNBUAI-UHFFFAOYSA-N 0.000 description 1
- 229960002820 adrafinil Drugs 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 229940013181 advil Drugs 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229960003225 alaproclate Drugs 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical class O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229940060515 aleve Drugs 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 1
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 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
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- OMHBPUNFVFNHJK-UHFFFAOYSA-P ambenonium Chemical compound C=1C=CC=C(Cl)C=1C[N+](CC)(CC)CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl OMHBPUNFVFNHJK-UHFFFAOYSA-P 0.000 description 1
- 229960000451 ambenonium Drugs 0.000 description 1
- DXUUXWKFVDVHIK-UHFFFAOYSA-N ambenonium chloride Chemical compound [Cl-].[Cl-].C=1C=CC=C(Cl)C=1C[N+](CC)(CC)CCNC(=O)C(=O)NCC[N+](CC)(CC)CC1=CC=CC=C1Cl DXUUXWKFVDVHIK-UHFFFAOYSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 229960000959 amineptine Drugs 0.000 description 1
- VDPUXONTAVMIKZ-UHFFFAOYSA-N amineptine hydrochloride Chemical compound [Cl-].C1CC2=CC=CC=C2C([NH2+]CCCCCCC(=O)O)C2=CC=CC=C21 VDPUXONTAVMIKZ-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003036 amisulpride Drugs 0.000 description 1
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960002519 amoxapine Drugs 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 229940052327 amphetamine aspartate Drugs 0.000 description 1
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 1
- 229940008238 amphetamine sulfate Drugs 0.000 description 1
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 1
- 229940025141 anafranil Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 229960001694 anagrelide Drugs 0.000 description 1
- 229940072359 anaprox Drugs 0.000 description 1
- 229950004248 anatibant Drugs 0.000 description 1
- 229960004233 ancrod Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960000793 aniracetam Drugs 0.000 description 1
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 229940089918 ansaid Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 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
- 229940070343 apokyn Drugs 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 229960001164 apremilast Drugs 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
- BFNCJMURTMZBTE-UHFFFAOYSA-N aptiganel Chemical compound CCC1=CC=CC(N(C)C(N)=NC=2C3=CC=CC=C3C=CC=2)=C1 BFNCJMURTMZBTE-UHFFFAOYSA-N 0.000 description 1
- 229950001180 aptiganel Drugs 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
- 229960004823 armodafinil Drugs 0.000 description 1
- 229950009746 arofylline Drugs 0.000 description 1
- 229950005776 arundic acid Drugs 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 description 1
- 239000001168 astaxanthin Substances 0.000 description 1
- 229940022405 astaxanthin Drugs 0.000 description 1
- 235000013793 astaxanthin Nutrition 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
- 229940022802 atropen Drugs 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 description 1
- 229960000307 avanafil Drugs 0.000 description 1
- 229940003504 avonex Drugs 0.000 description 1
- GDCXBZMWKSBSJG-UHFFFAOYSA-N azane;4-methylbenzenesulfonic acid Chemical compound [NH4+].CC1=CC=C(S([O-])(=O)=O)C=C1 GDCXBZMWKSBSJG-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229940031774 azilect Drugs 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- MYTWFJKBZGMYCS-NQIIRXRSSA-N bay 60-7550 Chemical compound C1=C(OC)C(OC)=CC=C1CC(NN12)=NC(=O)C1=C(C)N=C2[C@H]([C@@H](C)O)CCCC1=CC=CC=C1 MYTWFJKBZGMYCS-NQIIRXRSSA-N 0.000 description 1
- JPYQFYIEOUVJDU-UHFFFAOYSA-N beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 description 1
- 229960005200 beclamide Drugs 0.000 description 1
- IALVDLPLCLFBCF-CHWSQXEVSA-N befloxatone Chemical compound O=C1O[C@@H](COC)CN1C1=CC=C(OCC[C@@H](O)C(F)(F)F)C=C1 IALVDLPLCLFBCF-CHWSQXEVSA-N 0.000 description 1
- 229950000017 befloxatone Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940088007 benadryl Drugs 0.000 description 1
- 229940090012 bentyl Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229960002837 benzphetamine Drugs 0.000 description 1
- ANFSNXAXVLRZCG-RSAXXLAASA-N benzphetamine hydrochloride Chemical compound [Cl-].C([C@H](C)[NH+](C)CC=1C=CC=CC=1)C1=CC=CC=C1 ANFSNXAXVLRZCG-RSAXXLAASA-N 0.000 description 1
- 229940024774 benztropine mesylate Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000002439 beta secretase inhibitor Substances 0.000 description 1
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 1
- 229940099231 betapace Drugs 0.000 description 1
- 229940021459 betaseron Drugs 0.000 description 1
- 229960002123 bethanechol chloride Drugs 0.000 description 1
- 229950010365 bicifadine Drugs 0.000 description 1
- OFYVIGTWSQPCLF-NWDGAFQWSA-N bicifadine Chemical compound C1=CC(C)=CC=C1[C@@]1(CNC2)[C@H]2C1 OFYVIGTWSQPCLF-NWDGAFQWSA-N 0.000 description 1
- LASLVGACQUUOEB-UHFFFAOYSA-N bicyclo[1.1.0]butane Chemical compound C1C2CC21 LASLVGACQUUOEB-UHFFFAOYSA-N 0.000 description 1
- MKCBRYIXFFGIKN-UHFFFAOYSA-N bicyclo[1.1.1]pentane Chemical compound C1C2CC1C2 MKCBRYIXFFGIKN-UHFFFAOYSA-N 0.000 description 1
- YZLCEXRVQZNGEK-UHFFFAOYSA-N bicyclo[2.2.0]hexane Chemical compound C1CC2CCC21 YZLCEXRVQZNGEK-UHFFFAOYSA-N 0.000 description 1
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical compound C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 description 1
- 229960004933 bifemelane Drugs 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- KGCBATGZRGGGQG-KQHOVRMTSA-N bis[[4-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyphenyl]methyl] (2R,3S)-3-hydroxy-2-(2-methylpropyl)-2-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxybutanedioate Chemical compound O([C@](CC(C)C)([C@H](O)C(=O)OCC=1C=CC(O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=1)C(=O)OCC=1C=CC(O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O KGCBATGZRGGGQG-KQHOVRMTSA-N 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- OXKRFEWMSWPKKV-RXVVDRJESA-N bradanicline Chemical compound C([C@@H]1N2CCC(CC2)[C@@H]1NC(=O)C=1OC2=CC=CC=C2C=1)C1=CC=CN=C1 OXKRFEWMSWPKKV-RXVVDRJESA-N 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 208000009973 brain hypoxia - ischemia Diseases 0.000 description 1
- 229950006941 brasofensine Drugs 0.000 description 1
- NRLIFEGHTNUYFL-QJDHNRDASA-N brasofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2/C=N/OC)=CC=C(Cl)C(Cl)=C1 NRLIFEGHTNUYFL-QJDHNRDASA-N 0.000 description 1
- 229940097683 brevibloc Drugs 0.000 description 1
- 229950000394 brocresine Drugs 0.000 description 1
- 229950004068 brofaromine Drugs 0.000 description 1
- WZXHSWVDAYOFPE-UHFFFAOYSA-N brofaromine Chemical compound C=1C2=CC(OC)=CC(Br)=C2OC=1C1CCNCC1 WZXHSWVDAYOFPE-UHFFFAOYSA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- JMSRBKPMLUGHCR-UHFFFAOYSA-N bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229960004301 butriptyline Drugs 0.000 description 1
- ALELTFCQZDXAMQ-UHFFFAOYSA-N butriptyline Chemical compound C1CC2=CC=CC=C2C(CC(C)CN(C)C)C2=CC=CC=C21 ALELTFCQZDXAMQ-UHFFFAOYSA-N 0.000 description 1
- LUERRSICNAPHLV-UHFFFAOYSA-N butyl-[2,3,4,5-tetramethyl-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CCCCPC1=C(C)C(C)=C(C)C(C)=C1C1=C(C(C)C)C=C(C(C)C)C=C1C(C)C LUERRSICNAPHLV-UHFFFAOYSA-N 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229940088033 calan Drugs 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940058898 campral Drugs 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940057922 carbatrol Drugs 0.000 description 1
- QTAOMKOIBXZKND-PPHPATTJSA-N carbidopa Chemical compound O.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 QTAOMKOIBXZKND-PPHPATTJSA-N 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229940097611 cardene Drugs 0.000 description 1
- 108010041776 cardiotrophin 1 Proteins 0.000 description 1
- 229940088029 cardizem Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940063628 catapres Drugs 0.000 description 1
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 1
- 150000001768 cations Chemical class 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
- 229940047493 celexa Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 229940029783 cerebyx Drugs 0.000 description 1
- WUTYZMFRCNBCHQ-PSASIEDQSA-N cevimeline Chemical compound C1S[C@H](C)O[C@]21C(CC1)CCN1C2 WUTYZMFRCNBCHQ-PSASIEDQSA-N 0.000 description 1
- 229960001314 cevimeline Drugs 0.000 description 1
- RCTCWZRPYFBGLQ-KVBIMOIYSA-N chembl2105639 Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 RCTCWZRPYFBGLQ-KVBIMOIYSA-N 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 229950001653 cilomilast Drugs 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 description 1
- 229960001653 citalopram Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- 229960004414 clomethiazole Drugs 0.000 description 1
- 229960004606 clomipramine Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 201000006145 cocaine dependence Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940097480 cogentin Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 108010002212 colostrinine Proteins 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940003372 compro Drugs 0.000 description 1
- 229960003155 condoliase Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229940038717 copaxone Drugs 0.000 description 1
- 229940097488 corgard Drugs 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- UVKZSORBKUEBAZ-UHFFFAOYSA-N cyclizine Chemical compound C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UVKZSORBKUEBAZ-UHFFFAOYSA-N 0.000 description 1
- 229960003564 cyclizine Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical compound CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- ACQBHJXEAYTHCY-UHFFFAOYSA-N cyclopropyl-[4-[3-(1H-imidazol-5-yl)propoxy]phenyl]methanone Chemical compound C=1C=C(OCCCC=2NC=NC=2)C=CC=1C(=O)C1CC1 ACQBHJXEAYTHCY-UHFFFAOYSA-N 0.000 description 1
- 229940029644 cymbalta Drugs 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 229950008614 davunetide Drugs 0.000 description 1
- 229940098357 daytrana Drugs 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940027008 deltasone Drugs 0.000 description 1
- MUGNLPWYHGOJEG-UHFFFAOYSA-N delucemine Chemical compound C=1C=CC(F)=CC=1C(CCNC)C1=CC=CC(F)=C1 MUGNLPWYHGOJEG-UHFFFAOYSA-N 0.000 description 1
- 229950006926 delucemine Drugs 0.000 description 1
- RWZVPVOZTJJMNU-UHFFFAOYSA-N demarcarium Chemical compound C=1C=CC([N+](C)(C)C)=CC=1OC(=O)N(C)CCCCCCCCCCN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 RWZVPVOZTJJMNU-UHFFFAOYSA-N 0.000 description 1
- 229940075922 depacon Drugs 0.000 description 1
- 229940089052 depakene Drugs 0.000 description 1
- 229940075925 depakote Drugs 0.000 description 1
- 229940003382 depo-medrol Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229950001282 desmoteplase Drugs 0.000 description 1
- 229940099340 desoxyn Drugs 0.000 description 1
- 229960001623 desvenlafaxine Drugs 0.000 description 1
- 229940076405 detrol Drugs 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- SSQJFGMEZBFMNV-PMACEKPBSA-N dexanabinol Chemical compound C1C(CO)=CC[C@@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@H]21 SSQJFGMEZBFMNV-PMACEKPBSA-N 0.000 description 1
- 229940099242 dexedrine Drugs 0.000 description 1
- 229950010249 dexefaroxan Drugs 0.000 description 1
- 229960001042 dexmethylphenidate Drugs 0.000 description 1
- DUGOZIWVEXMGBE-CHWSQXEVSA-N dexmethylphenidate Chemical compound C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 DUGOZIWVEXMGBE-CHWSQXEVSA-N 0.000 description 1
- 229940052370 dextroamphetamine saccharate Drugs 0.000 description 1
- 229940119751 dextroamphetamine sulfate Drugs 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- JAQUASYNZVUNQP-PVAVHDDUSA-N dextrorphan Chemical compound C1C2=CC=C(O)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 JAQUASYNZVUNQP-PVAVHDDUSA-N 0.000 description 1
- 229950006878 dextrorphan Drugs 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 1
- 229960004515 diclofenac potassium Drugs 0.000 description 1
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 1
- 229960001193 diclofenac sodium Drugs 0.000 description 1
- GUBNMFJOJGDCEL-UHFFFAOYSA-N dicyclomine hydrochloride Chemical compound [Cl-].C1CCCCC1C1(C(=O)OCC[NH+](CC)CC)CCCCC1 GUBNMFJOJGDCEL-UHFFFAOYSA-N 0.000 description 1
- 229960002777 dicycloverine Drugs 0.000 description 1
- 229940120144 didrex Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 229960000616 diflunisal Drugs 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- PBUNVLRHZGSROC-VTIMJTGVSA-N dihydro-alpha-ergocryptine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1 PBUNVLRHZGSROC-VTIMJTGVSA-N 0.000 description 1
- 229960002032 dihydroergocryptine Drugs 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
- 229960004419 dimethyl fumarate Drugs 0.000 description 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 1
- XQKRYBXCYCKQLL-UHFFFAOYSA-N dimethylaminomethanol Chemical compound CN(C)CO XQKRYBXCYCKQLL-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- XLZOVRYBVCMCGL-BPNVQINPSA-L disodium;4-[(z)-[tert-butyl(oxido)azaniumylidene]methyl]benzene-1,3-disulfonate Chemical compound [Na+].[Na+].CC(C)(C)[N+](\[O-])=C\C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O XLZOVRYBVCMCGL-BPNVQINPSA-L 0.000 description 1
- DKGJFKPIUSHDIT-UHFFFAOYSA-L disodium;propane-1,3-disulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CCCS([O-])(=O)=O DKGJFKPIUSHDIT-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229950009055 disufenton Drugs 0.000 description 1
- 229940099170 ditropan Drugs 0.000 description 1
- 229940028937 divalproex sodium Drugs 0.000 description 1
- LBOJYSIDWZQNJS-CVEARBPZSA-N dizocilpine Chemical compound C12=CC=CC=C2[C@]2(C)C3=CC=CC=C3C[C@H]1N2 LBOJYSIDWZQNJS-CVEARBPZSA-N 0.000 description 1
- 229950004794 dizocilpine Drugs 0.000 description 1
- 229940110377 dl- arginine Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940072701 dolobid Drugs 0.000 description 1
- 229940072340 dolophine Drugs 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Natural products O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 1
- 229960003135 donepezil hydrochloride Drugs 0.000 description 1
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000000221 dopamine uptake inhibitor Substances 0.000 description 1
- HWXIGFIVGWUZAO-UHFFFAOYSA-N doxofylline Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CC1OCCO1 HWXIGFIVGWUZAO-UHFFFAOYSA-N 0.000 description 1
- 229960004483 doxofylline Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 235000005686 eating Nutrition 0.000 description 1
- 229950009714 ecopipam Drugs 0.000 description 1
- 229960003748 edrophonium Drugs 0.000 description 1
- 229940098766 effexor Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 229940011681 elavil Drugs 0.000 description 1
- 229940084238 eldepryl Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 229940071670 emsam Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 229950002995 enecadin Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229940072357 enlon Drugs 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 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 1
- 229960003337 entacapone Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- NLPRAJRHRHZCQQ-IVZWLZJFSA-N epibatidine Chemical compound C1=NC(Cl)=CC=C1[C@@H]1[C@H](N2)CC[C@H]2C1 NLPRAJRHRHZCQQ-IVZWLZJFSA-N 0.000 description 1
- 229960003367 ersofermin Drugs 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- 229960003745 esmolol Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- LRLPHWSABSQPOE-UHFFFAOYSA-N ethyl 5-(difluoromethoxy)-6-fluoro-2-methyl-1-benzofuran-3-carboxylate Chemical compound FC(OC=1C(=CC2=C(C(=C(O2)C)C(=O)OCC)C=1)F)F LRLPHWSABSQPOE-UHFFFAOYSA-N 0.000 description 1
- UDJDCMQTPZXZKX-UHFFFAOYSA-N ethyl 6-chloro-2-methyl-5-(trifluoromethyl)-1-benzofuran-3-carboxylate Chemical compound ClC1=CC2=C(C(=C(O2)C)C(=O)OCC)C=C1C(F)(F)F UDJDCMQTPZXZKX-UHFFFAOYSA-N 0.000 description 1
- HTRJWERNQSHARK-UHFFFAOYSA-N ethyl 6-fluoro-2-methyl-5-(trifluoromethoxy)-1-benzofuran-3-carboxylate Chemical compound FC1=CC2=C(C(=C(O2)C)C(=O)OCC)C=C1OC(F)(F)F HTRJWERNQSHARK-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229940108366 exelon Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 231100000040 eye damage Toxicity 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 1
- RZTAMFZIAATZDJ-UHFFFAOYSA-N felodipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-UHFFFAOYSA-N 0.000 description 1
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 description 1
- 229950003930 femoxetine Drugs 0.000 description 1
- 229940032465 fenethylline Drugs 0.000 description 1
- TVURRHSHRRELCG-UHFFFAOYSA-N fenoldopam Chemical compound C1=CC(O)=CC=C1C1C2=CC(O)=C(O)C(Cl)=C2CCNC1 TVURRHSHRRELCG-UHFFFAOYSA-N 0.000 description 1
- 229960002724 fenoldopam Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960002419 flupentixol Drugs 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 229960001374 fluphenazine decanoate Drugs 0.000 description 1
- VIQCGTZFEYDQMR-UHFFFAOYSA-N fluphenazine decanoate Chemical compound C1CN(CCOC(=O)CCCCCCCCC)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 VIQCGTZFEYDQMR-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940053650 focalin Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- ZZBSPTCNZDTZBR-QGXZNONUSA-N formobactin Chemical compound N([C@@H](CCCCN(O)C=O)C(=O)OC(CCCCCCCCC)C(C)(C)C(=O)NC1C(N(O)CCCC1)=O)C(=O)C(=C(O1)C)N=C1C1=CC=CC=C1O ZZBSPTCNZDTZBR-QGXZNONUSA-N 0.000 description 1
- 229960000693 fosphenytoin Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- QUAGBPHWBBENAF-UHFFFAOYSA-M furan-2-ylmethyl(trimethyl)azanium 4-methylbenzenesulfonate Chemical compound C[N+](C)(C)CC1=CC=CO1.CC1=CC=C(S([O-])(=O)=O)C=C1 QUAGBPHWBBENAF-UHFFFAOYSA-M 0.000 description 1
- HEDXEAAVEOJUCR-UHFFFAOYSA-N furtrethonium Chemical compound C[N+](C)(C)CC1=CC=CO1 HEDXEAAVEOJUCR-UHFFFAOYSA-N 0.000 description 1
- 229950008234 furtrethonium Drugs 0.000 description 1
- 229950008907 furtrethonium iodide Drugs 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 229960002024 galantamine hydrobromide Drugs 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- 229940009600 gammagard Drugs 0.000 description 1
- 229950000264 ganstigmine Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- WZBNEZWCNKUOSM-VOTSOKGWSA-N gavestinel Chemical compound OC(=O)C=1NC2=CC(Cl)=CC(Cl)=C2C=1\C=C\C(=O)NC1=CC=CC=C1 WZBNEZWCNKUOSM-VOTSOKGWSA-N 0.000 description 1
- 229950005000 gavestinel Drugs 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 229940003380 geodon Drugs 0.000 description 1
- 229940068052 ginkgo biloba extract Drugs 0.000 description 1
- 235000020686 ginkgo biloba extract Nutrition 0.000 description 1
- 229960003776 glatiramer acetate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000003823 glutamate receptor agonist Substances 0.000 description 1
- 229940015042 glycopyrrolate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- MHLPKAGDPWUOOT-UHFFFAOYSA-N housane Chemical compound C1CC2CC21 MHLPKAGDPWUOOT-UHFFFAOYSA-N 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NIBOMXUDFLRHRV-UHFFFAOYSA-N hydron;8-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-8-azaspiro[4.5]decane-7,9-dione;dichloride Chemical compound Cl.Cl.COC1=CC=CC=C1N1CCN(CCN2C(CC3(CCCC3)CC2=O)=O)CC1 NIBOMXUDFLRHRV-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229930005342 hyoscyamine Natural products 0.000 description 1
- 229960003210 hyoscyamine Drugs 0.000 description 1
- HSIBGVUMFOSJPD-CFDPKNGZSA-N ibogaine Chemical compound N1([C@@H]2[C@H]3C[C@H](C1)C[C@@H]2CC)CCC1=C3NC2=CC=C(OC)C=C12 HSIBGVUMFOSJPD-CFDPKNGZSA-N 0.000 description 1
- OLOCMRXSJQJJPL-UHFFFAOYSA-N ibogaine Natural products CCC1CC2CC3C1N(C2)C=Cc4c3[nH]c5ccc(OC)cc45 OLOCMRXSJQJJPL-UHFFFAOYSA-N 0.000 description 1
- AREITJMUSRHSBK-UHFFFAOYSA-N ibogamine Natural products CCC1CC2C3CC1CN2CCc4c3[nH]c5ccccc45 AREITJMUSRHSBK-UHFFFAOYSA-N 0.000 description 1
- 229940076716 ibutamoren mesylate Drugs 0.000 description 1
- 229960004135 idebenone Drugs 0.000 description 1
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 description 1
- 229960003162 iloperidone Drugs 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960002102 imipramine hydrochloride Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 1
- 229950002473 indalpine Drugs 0.000 description 1
- SADQVAVFGNTEOD-UHFFFAOYSA-N indalpine Chemical compound C=1NC2=CC=CC=C2C=1CCC1CCNCC1 SADQVAVFGNTEOD-UHFFFAOYSA-N 0.000 description 1
- MNLULKBKWKTZPE-UHFFFAOYSA-N indantadol Chemical compound C1=CC=C2CC(NCC(=O)N)CC2=C1 MNLULKBKWKTZPE-UHFFFAOYSA-N 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229940095990 inderal Drugs 0.000 description 1
- 230000000053 inderal effect Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229960004461 interferon beta-1a Drugs 0.000 description 1
- 229960003161 interferon beta-1b Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 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
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229950010499 ipenoxazone Drugs 0.000 description 1
- GGECDTUJZOXAAR-UHFFFAOYSA-N iproclozide Chemical compound CC(C)NNC(=O)COC1=CC=C(Cl)C=C1 GGECDTUJZOXAAR-UHFFFAOYSA-N 0.000 description 1
- 229960002589 iproclozide Drugs 0.000 description 1
- 229940070023 iproniazide Drugs 0.000 description 1
- 229950011153 irdabisant Drugs 0.000 description 1
- XUKROCVZGZNGSI-CQSZACIVSA-N irdabisant Chemical compound C[C@@H]1CCCN1CCCOC1=CC=C(C2=NNC(=O)C=C2)C=C1 XUKROCVZGZNGSI-CQSZACIVSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- RPCVIAXDAUMJJP-PZBABLGHSA-N ispronicline Chemical compound CN[C@@H](C)C\C=C\C1=CN=CC(OC(C)C)=C1 RPCVIAXDAUMJJP-PZBABLGHSA-N 0.000 description 1
- 229950001646 ispronicline Drugs 0.000 description 1
- 229950005937 itameline Drugs 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- PTKHFRNHJULJKT-UHFFFAOYSA-N jnj-5207852 Chemical compound C1CCCCN1CCCOC(C=C1)=CC=C1CN1CCCCC1 PTKHFRNHJULJKT-UHFFFAOYSA-N 0.000 description 1
- 229940102367 kemstro Drugs 0.000 description 1
- 229940039412 ketalar Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229960001632 labetalol Drugs 0.000 description 1
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 description 1
- DAQAKHDKYAWHCG-RWTHQLGUSA-N lactacystin Chemical compound CC(=O)N[C@H](C(O)=O)CSC(=O)[C@]1([C@@H](O)C(C)C)NC(=O)[C@H](C)[C@@H]1O DAQAKHDKYAWHCG-RWTHQLGUSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229950008812 ladostigil Drugs 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960004577 laquinimod Drugs 0.000 description 1
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 1
- 229940036674 latuda Drugs 0.000 description 1
- 229950007396 lecozotan Drugs 0.000 description 1
- 229940063725 leukeran Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 229940097443 levitra Drugs 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 229960003406 levorphanol Drugs 0.000 description 1
- 229940054157 lexapro Drugs 0.000 description 1
- HTDFEXRUDGWNHA-UHFFFAOYSA-N lifarizine Chemical compound CC=1NC(C=2C=CC(C)=CC=2)=NC=1CN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 HTDFEXRUDGWNHA-UHFFFAOYSA-N 0.000 description 1
- 229950003413 lifarizine Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940063721 lioresal Drugs 0.000 description 1
- 229940002661 lipitor Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960001451 lisdexamfetamine Drugs 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 229960002813 lofepramine Drugs 0.000 description 1
- SAPNXPWPAUFAJU-UHFFFAOYSA-N lofepramine Chemical compound C12=CC=CC=C2CCC2=CC=CC=C2N1CCCN(C)CC(=O)C1=CC=C(Cl)C=C1 SAPNXPWPAUFAJU-UHFFFAOYSA-N 0.000 description 1
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 1
- 229960005209 lofexidine Drugs 0.000 description 1
- 229950007692 lomerizine Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940089504 lopressor Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229940089527 loxitane Drugs 0.000 description 1
- 229960001432 lurasidone Drugs 0.000 description 1
- STIRHCNEGQQBOY-QEYWKRMJSA-N ly-235,959 Chemical compound C1[C@@H](CP(O)(O)=O)CC[C@H]2CN[C@H](C(=O)O)C[C@H]21 STIRHCNEGQQBOY-QEYWKRMJSA-N 0.000 description 1
- 229940009697 lyrica Drugs 0.000 description 1
- MRSJBSHLMOBYSH-UHFFFAOYSA-N m-Nisoldipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 MRSJBSHLMOBYSH-UHFFFAOYSA-N 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- UGVOBAHBYOONQU-UHFFFAOYSA-I manganese(3+) (20Z)-5,10,15-tris(1-ethylpyridin-1-ium-2-yl)-20-(1-ethylpyridin-2-ylidene)porphyrin-22-ide pentachloride Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Mn+3].CC[N+]1=CC=CC=C1C(C1=CC=C([N-]1)C(C=1[N+](=CC=CC=1)CC)=C1C=CC(=N1)C(C=1[N+](=CC=CC=1)CC)=C1C=CC([N-]1)=C1C=2[N+](=CC=CC=2)CC)=C2N=C1C=C2 UGVOBAHBYOONQU-UHFFFAOYSA-I 0.000 description 1
- 229960004090 maprotiline Drugs 0.000 description 1
- QSLMDECMDJKHMQ-GSXCWMCISA-N maprotiline Chemical compound C12=CC=CC=C2[C@@]2(CCCNC)C3=CC=CC=C3[C@@H]1CC2 QSLMDECMDJKHMQ-GSXCWMCISA-N 0.000 description 1
- 229940110127 marplan Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940064748 medrol Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- DAHIQPJTGIHDGO-IAGOWNOFSA-N mesembrine Chemical compound C1=C(OC)C(OC)=CC=C1[C@]1(CCC(=O)C2)[C@@H]2N(C)CC1 DAHIQPJTGIHDGO-IAGOWNOFSA-N 0.000 description 1
- DAHIQPJTGIHDGO-UHFFFAOYSA-N mesembrine Natural products C1=C(OC)C(OC)=CC=C1C1(CCC(=O)C2)C2N(C)CC1 DAHIQPJTGIHDGO-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229960003663 metaraminol Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960001252 methamphetamine Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- XGWSRLSPWIEMLQ-YTFOTSKYSA-N methyl n-({(2s,3s)-3-[(propylamino)carbonyl]oxiran-2-yl}carbonyl)-l-isoleucyl-l-prolinate Chemical compound CCCNC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@H](C(=O)OC)CCC1 XGWSRLSPWIEMLQ-YTFOTSKYSA-N 0.000 description 1
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001293 methylprednisolone acetate Drugs 0.000 description 1
- 229960000334 methylprednisolone sodium succinate Drugs 0.000 description 1
- 229950006793 metitepine Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960000939 metoprolol succinate Drugs 0.000 description 1
- 229960001300 metoprolol tartrate Drugs 0.000 description 1
- 229960001952 metrifonate Drugs 0.000 description 1
- 229960003955 mianserin Drugs 0.000 description 1
- 229950005726 mibampator Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 108010068982 microplasmin Proteins 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 229960000600 milnacipran Drugs 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940088319 miostat Drugs 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940028394 moban Drugs 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- 229960001165 modafinil Drugs 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229960004938 molindone Drugs 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 229940072709 motrin Drugs 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 229940083410 myfortic Drugs 0.000 description 1
- 229940103801 mytelase Drugs 0.000 description 1
- ATKZKAYWARYLBW-UHFFFAOYSA-N n-(3,5-dichloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide Chemical compound COC1=CC=C(S(=O)(=O)NC=2C(=C(Cl)C=C(Cl)C=2)OC)C=C1N1CCNCC1 ATKZKAYWARYLBW-UHFFFAOYSA-N 0.000 description 1
- ULRDYYKSPCRXAJ-KRWDZBQOSA-N n-[(2r)-2-[4-[4-[2-(methanesulfonamido)ethyl]phenyl]phenyl]propyl]propane-2-sulfonamide Chemical compound C1=CC([C@@H](C)CNS(=O)(=O)C(C)C)=CC=C1C1=CC=C(CCNS(C)(=O)=O)C=C1 ULRDYYKSPCRXAJ-KRWDZBQOSA-N 0.000 description 1
- HNWIZDPHFDXSOR-BSSYVKIHSA-N n-[(2s)-2-amino-3-[[(2s)-1-[[(2s)-3-cyclohexyl-1-[[(2s,3r)-3-hydroxy-4-oxo-1-phenyl-4-[3-(2h-tetrazol-5-yl)anilino]butan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-oxopropyl]-5-fluoro-2,4-dioxo-1h-pyrimidine-6-carboxamide Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)[C@@H](O)C(=O)NC=1C=C(C=CC=1)C1=NNN=N1)NC(=O)C=1NC(=O)NC(=O)C=1F HNWIZDPHFDXSOR-BSSYVKIHSA-N 0.000 description 1
- QXQSUBKWSHMXDP-INIZCTEOSA-N n-[(2s)-5-(6-fluoropyridin-3-yl)-2,3-dihydro-1h-inden-2-yl]propane-2-sulfonamide Chemical compound C([C@@H](CC1=C2)NS(=O)(=O)C(C)C)C1=CC=C2C1=CC=C(F)N=C1 QXQSUBKWSHMXDP-INIZCTEOSA-N 0.000 description 1
- 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 1
- CMRLNEYJEPELSM-BTQNPOSSSA-N n-[(3s)-1-azabicyclo[2.2.2]octan-3-yl]-1h-indazole-3-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C(N[C@H]3C4CCN(CC4)C3)=O)=NNC2=C1 CMRLNEYJEPELSM-BTQNPOSSSA-N 0.000 description 1
- TTYKUKSFWHEBLI-DLBZAZTESA-N n-[(3s,4s)-4-[4-(5-cyanothiophen-2-yl)phenoxy]oxolan-3-yl]propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)N[C@H]1COC[C@H]1OC1=CC=C(C=2SC(=CC=2)C#N)C=C1 TTYKUKSFWHEBLI-DLBZAZTESA-N 0.000 description 1
- PILCQJJJAFRKHO-UHFFFAOYSA-N n-[1-(5-chloro-2,3-dimethoxyphenyl)ethyl]-2-methylsulfonyl-5-piperazin-1-ylaniline;hydrochloride Chemical compound Cl.COC1=CC(Cl)=CC(C(C)NC=2C(=CC=C(C=2)N2CCNCC2)S(C)(=O)=O)=C1OC PILCQJJJAFRKHO-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
- CVFSMSTXULJISA-UHFFFAOYSA-N n-ethyl-2-phenylbicyclo[2.2.1]heptan-3-amine;hydrochloride Chemical compound Cl.CCNC1C(C2)CCC2C1C1=CC=CC=C1 CVFSMSTXULJISA-UHFFFAOYSA-N 0.000 description 1
- SXMBKHYDZOCBMT-UHFFFAOYSA-N n-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide Chemical compound C1C(C(=O)NCC)CC1(F)C(C=C1F)=CC=C1CN1CCCC1 SXMBKHYDZOCBMT-UHFFFAOYSA-N 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
- OVTCHWSLKGENKP-GHXNOFRVSA-N n-tert-butyl-1-(2,4-disulfophenyl)methanimine oxide Chemical compound CC(C)(C)[N+](\[O-])=C\C1=CC=C(S(O)(=O)=O)C=C1S(O)(=O)=O OVTCHWSLKGENKP-GHXNOFRVSA-N 0.000 description 1
- 229960004255 nadolol Drugs 0.000 description 1
- 229940089466 nalfon Drugs 0.000 description 1
- 229940033872 namenda Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940090008 naprosyn Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 229960003940 naproxen sodium Drugs 0.000 description 1
- 229940087524 nardil Drugs 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 229940105623 neo-synephrine Drugs 0.000 description 1
- 238000009099 neoadjuvant therapy Methods 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- OGZQTTHDGQBLBT-UHFFFAOYSA-N neramexane Chemical compound CC1(C)CC(C)(C)CC(C)(N)C1 OGZQTTHDGQBLBT-UHFFFAOYSA-N 0.000 description 1
- 229950004543 neramexane Drugs 0.000 description 1
- 229940020452 neupro Drugs 0.000 description 1
- 210000001178 neural stem cell Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960003642 nicergoline Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- UIAGMCDKSXEBJQ-UHFFFAOYSA-N nimodipine Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-UHFFFAOYSA-N 0.000 description 1
- 229940072101 nimotop Drugs 0.000 description 1
- 229950008980 nitecapone Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 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 1
- 229960001073 nomifensine Drugs 0.000 description 1
- 229960002498 nomifensine maleate Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic 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
- 229940079063 norflex Drugs 0.000 description 1
- 229940087480 norpramin Drugs 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 229940036132 norvasc Drugs 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000001702 nutmeg Substances 0.000 description 1
- 229940117152 nuvigil Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950000175 oglemilast Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 description 1
- 229950005421 olprinone Drugs 0.000 description 1
- 229940003740 omnipred Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940109739 orap Drugs 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 229960003941 orphenadrine Drugs 0.000 description 1
- AZHVQJLDOFKHPZ-UHFFFAOYSA-N oxathiazine Chemical compound O1SN=CC=C1 AZHVQJLDOFKHPZ-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960001227 oxiracetam Drugs 0.000 description 1
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 1
- 229960004570 oxprenolol Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 1
- 229940055692 pamelor Drugs 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 229940026768 parcopa Drugs 0.000 description 1
- 229950010798 pardoprunox Drugs 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 229960001779 pargyline Drugs 0.000 description 1
- 229940000596 parlodel Drugs 0.000 description 1
- 229940087824 parnate Drugs 0.000 description 1
- 229950010649 parogrelil Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 description 1
- 229960000761 pemoline Drugs 0.000 description 1
- NRNCYVBFPDDJNE-UHFFFAOYSA-N pemoline Chemical compound O1C(N)=NC(=O)C1C1=CC=CC=C1 NRNCYVBFPDDJNE-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229960003293 penthienate Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- UWCVGPLTGZWHGS-ZORIOUSZSA-N pergolide mesylate Chemical compound CS(O)(=O)=O.C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 UWCVGPLTGZWHGS-ZORIOUSZSA-N 0.000 description 1
- 229940088507 permax Drugs 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 229950006454 perzinfotel Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229960000436 phendimetrazine Drugs 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- 229960003209 phenmetrazine Drugs 0.000 description 1
- OQUKIQWCVTZJAF-UHFFFAOYSA-N phenol;sulfuric acid Chemical compound OS(O)(=O)=O.OC1=CC=CC=C1 OQUKIQWCVTZJAF-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 229940052794 phenytek Drugs 0.000 description 1
- 229960002790 phenytoin sodium Drugs 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 229910000064 phosphane Inorganic materials 0.000 description 1
- 150000003002 phosphanes Chemical class 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 239000002606 phosphodiesterase VII inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960001697 physostigmine Drugs 0.000 description 1
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 1
- 229960002516 physostigmine salicylate Drugs 0.000 description 1
- URMTUEWUIGOJBW-UHFFFAOYSA-N piclozotan Chemical compound ClC1=COC2=CC=CC=C2C(=O)N1CCCCN(CC=1)CCC=1C1=CC=CC=N1 URMTUEWUIGOJBW-UHFFFAOYSA-N 0.000 description 1
- 229950002181 piclozotan Drugs 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229960003300 pimavanserin Drugs 0.000 description 1
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 1
- 229960002164 pimobendan Drugs 0.000 description 1
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 description 1
- 229960003634 pimozide Drugs 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229960000753 pipradrol Drugs 0.000 description 1
- XSWHNYGMWWVAIE-UHFFFAOYSA-N pipradrol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CCCCN1 XSWHNYGMWWVAIE-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical compound CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- 229940072689 plaquenil Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229950003486 ponezumab Drugs 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 208000028173 post-traumatic stress disease Diseases 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- YRVIKLBSVVNSHF-JTQLQIEISA-N pozanicline Chemical compound CC1=NC=CC=C1OC[C@H]1NCCC1 YRVIKLBSVVNSHF-JTQLQIEISA-N 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940063161 pred forte Drugs 0.000 description 1
- 229940063162 pred mild Drugs 0.000 description 1
- 229960002943 prednisolone sodium phosphate Drugs 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 239000013630 prepared media Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 1
- 229940014148 pristiq Drugs 0.000 description 1
- 229940099209 probanthine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229940089949 procardia Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003111 prochlorperazine Drugs 0.000 description 1
- TURAMGVWNUTQKH-UHFFFAOYSA-N propa-1,2-dien-1-one Chemical compound C=C=C=O TURAMGVWNUTQKH-UHFFFAOYSA-N 0.000 description 1
- 229960000697 propantheline Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940117394 provigil Drugs 0.000 description 1
- 229940035613 prozac Drugs 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
- 229940117820 purinethol Drugs 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N pyridine-3-amine Natural products NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 1
- 229960002290 pyridostigmine Drugs 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- FTSUPYGMFAPCFZ-ZWNOBZJWSA-N quinpirole Chemical compound C([C@H]1CCCN([C@@H]1C1)CCC)C2=C1C=NN2 FTSUPYGMFAPCFZ-ZWNOBZJWSA-N 0.000 description 1
- 229950001037 quinpirole Drugs 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 229950001518 raclopride Drugs 0.000 description 1
- 229960001150 ramelteon Drugs 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- 229940051845 razadyne Drugs 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940038850 rebif Drugs 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229940080693 reglan Drugs 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229940113775 requip Drugs 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 229960003312 retigabine Drugs 0.000 description 1
- 229940039245 revatio Drugs 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229940061969 rheumatrex Drugs 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- JUQLTPCYUFPYKE-UHFFFAOYSA-N ritanserin Chemical compound CC=1N=C2SC=CN2C(=O)C=1CCN(CC1)CCC1=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 JUQLTPCYUFPYKE-UHFFFAOYSA-N 0.000 description 1
- 229950009626 ritanserin Drugs 0.000 description 1
- JUOSGGQXEBBCJB-GORDUTHDSA-N rivanicline Chemical compound CNCC\C=C\C1=CC=CN=C1 JUOSGGQXEBBCJB-GORDUTHDSA-N 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- MQTUXRKNJYPMCG-CYBMUJFWSA-N robalzotan Chemical compound C1CCC1N([C@H]1COC=2C(F)=CC=C(C=2C1)C(=O)N)C1CCC1 MQTUXRKNJYPMCG-CYBMUJFWSA-N 0.000 description 1
- 229940106905 robinul Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- 229960003179 rotigotine Drugs 0.000 description 1
- 229940063635 salagen Drugs 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229940042084 saphris Drugs 0.000 description 1
- HKFMQJUJWSFOLY-OAQYLSRUSA-N sarizotan Chemical compound C1=CC(F)=CC=C1C1=CN=CC(CNC[C@@H]2OC3=CC=CC=C3CC2)=C1 HKFMQJUJWSFOLY-OAQYLSRUSA-N 0.000 description 1
- 229950007903 sarizotan Drugs 0.000 description 1
- OLWRVVHPJFLNPW-UHFFFAOYSA-N sb-277,011-a Chemical compound C1=CC=C2C(C(NC3CCC(CCN4CC5=CC=C(C=C5CC4)C#N)CC3)=O)=CC=NC2=C1 OLWRVVHPJFLNPW-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- CXYRUNPLKGGUJF-RAFJPFSSSA-M scopolamine methobromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 CXYRUNPLKGGUJF-RAFJPFSSSA-M 0.000 description 1
- 208000012672 seasonal affective disease Diseases 0.000 description 1
- 229940082552 sectral Drugs 0.000 description 1
- 229960003678 selegiline hydrochloride Drugs 0.000 description 1
- 229940035004 seroquel Drugs 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- BLFQGGGGFNSJKA-XHXSRVRCSA-N sertraline hydrochloride Chemical compound Cl.C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 BLFQGGGGFNSJKA-XHXSRVRCSA-N 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229940001089 sinemet Drugs 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- CBXWGGFGZDVPNV-UHFFFAOYSA-N so4-so4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- QHJLLDJTVQAFAN-UHFFFAOYSA-M sodium meclofenamate monohydrate Chemical compound O.[Na+].CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C([O-])=O)=C1Cl QHJLLDJTVQAFAN-UHFFFAOYSA-M 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229950007874 solanezumab Drugs 0.000 description 1
- 229940087854 solu-medrol Drugs 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940012488 strattera Drugs 0.000 description 1
- 238000012916 structural analysis Methods 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
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 1
- 229950004608 talampanel Drugs 0.000 description 1
- 229950005628 tarenflurbil Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940000238 tasmar Drugs 0.000 description 1
- 229940090016 tegretol Drugs 0.000 description 1
- 229940065385 tenex Drugs 0.000 description 1
- 229940108485 tenormin Drugs 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- VCVWXKKWDOJNIT-ZOMKSWQUSA-N tesofensine Chemical compound C1([C@H]2C[C@@H]3CC[C@@H](N3C)[C@@H]2COCC)=CC=C(Cl)C(Cl)=C1 VCVWXKKWDOJNIT-ZOMKSWQUSA-N 0.000 description 1
- 229950009970 tesofensine Drugs 0.000 description 1
- 229950002896 tetomilast Drugs 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- PMJIHLSCWIDGMD-UHFFFAOYSA-N tideglusib Chemical compound O=C1SN(C=2C3=CC=CC=C3C=CC=2)C(=O)N1CC1=CC=CC=C1 PMJIHLSCWIDGMD-UHFFFAOYSA-N 0.000 description 1
- 229960004523 tiletamine Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- 229960000488 tizanidine Drugs 0.000 description 1
- 229950003899 tofimilast Drugs 0.000 description 1
- 229940041597 tofranil Drugs 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 229940035305 topamax Drugs 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229960003570 tramiprosate Drugs 0.000 description 1
- 229940108522 trandate Drugs 0.000 description 1
- 229940035321 transderm scop Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229950005135 traxoprodil Drugs 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 description 1
- 229940111528 trexall Drugs 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 229960001032 trihexyphenidyl Drugs 0.000 description 1
- QDWJJTJNXAKQKD-UHFFFAOYSA-N trihexyphenidyl hydrochloride Chemical compound Cl.C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 QDWJJTJNXAKQKD-UHFFFAOYSA-N 0.000 description 1
- ULYLMHUHFUQKOE-UHFFFAOYSA-N trimethyl(prop-2-ynyl)silane Chemical compound C[Si](C)(C)CC#C ULYLMHUHFUQKOE-UHFFFAOYSA-N 0.000 description 1
- YWWDBCBWQNCYNR-UHFFFAOYSA-O trimethylphosphanium Chemical compound C[PH+](C)C YWWDBCBWQNCYNR-UHFFFAOYSA-O 0.000 description 1
- WRZANXPBEAYOPX-UHFFFAOYSA-N trimethylphosphanium diiodide Chemical compound [I-].[I-].C[PH+](C)C.C[PH+](C)C WRZANXPBEAYOPX-UHFFFAOYSA-N 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940079023 tysabri Drugs 0.000 description 1
- 229940089541 uniphyl Drugs 0.000 description 1
- 229940045137 urecholine Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- NPTIPEQJIDTVKR-STQMWFEESA-N vabicaserin Chemical compound C1CNCC2=CC=CC3=C2N1C[C@@H]1CCC[C@@H]13 NPTIPEQJIDTVKR-STQMWFEESA-N 0.000 description 1
- 229950009968 vabicaserin Drugs 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229950007136 vanoxerine Drugs 0.000 description 1
- 108010084171 vanutide cridificar Proteins 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229950001843 velnacrine Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- RNOBTWYQAWEZHH-JGVFFNPUSA-N vi5lr1eu47 Chemical compound C12=CC(C(F)(F)F)=CC=C2[C@]2([H])CNC[C@@]1([H])C2 RNOBTWYQAWEZHH-JGVFFNPUSA-N 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- 229960003740 vilazodone Drugs 0.000 description 1
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 description 1
- 229960001255 viloxazine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 229940063670 visken Drugs 0.000 description 1
- CKWXDLJHOHJWOX-UHFFFAOYSA-N voacangine hydroxyindolenine Natural products CCC1CC2N3CCC4(O)C(=Nc5ccc(OC)cc45)C2(CC1C3)C(=O)OC CKWXDLJHOHJWOX-UHFFFAOYSA-N 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 229940013007 vyvanse Drugs 0.000 description 1
- 229940009065 wellbutrin Drugs 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229960004664 xaliproden Drugs 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
- 239000008434 yi-zhi Substances 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
- 229940000119 zanaflex Drugs 0.000 description 1
- REZGGXNDEMKIQB-UHFFFAOYSA-N zaprinast Chemical compound CCCOC1=CC=CC=C1C1=NC(=O)C2=NNNC2=N1 REZGGXNDEMKIQB-UHFFFAOYSA-N 0.000 description 1
- 229950005371 zaprinast Drugs 0.000 description 1
- 229940068543 zelapar 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
- 229950009086 zicronapine Drugs 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- 229940020965 zoloft Drugs 0.000 description 1
- 229940083488 zonalon Drugs 0.000 description 1
- 229950007059 zonampanel Drugs 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
- XZVHHLNLLVICFA-SNVBAGLBSA-N α-difluoromethyl-dopa Chemical compound FC(F)[C@](C(O)=O)(N)CC1=CC=C(O)C(O)=C1 XZVHHLNLLVICFA-SNVBAGLBSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本發明揭示化合物及該等化合物之醫藥上可接受之鹽,其中該等化合物具有式I結構,
其中X、R1、R2a、R2b、R4a、R4b、R5a、R5b、R6、R7、R10、R11、及y係如說明書中所定義。本文亦揭示對應醫藥組合物、治療方法、合成方法、及中間產物。
Description
本發明係關於適用於治療神經退化性及/或神經病症(諸如阿茲海默氏症(Alzheimer's disease))等等之新穎式I環丙苯并呋喃基吡啶并吡二酮類化合物。
癡呆起因於多種不同病理過程。導致癡呆之最常見病理過程係阿茲海默氏症(AD)、腦澱粉樣血管病(CM)及朊病毒介導之疾病(參見,例如Haan等人,Clin.Neurol.Neurosurg.1990,92(4):305-310;Glenner等人,J.Neurol.Sci.1989,94:1-28)。AD影響幾乎半數之全部超過85歲之人類(美國人口之最快速增長部分)。因此,預期到2050年美國AD患者數量從約400萬增加至約1400萬。
本發明係關於用於治療神經退化性及/或神經病症(諸如阿茲海默氏症及唐氏症候群)之γ-分泌酶調節劑群組(參見Ann.Rep.Med.Chem.2007,Olsen等人,42:27-47)。
本發明係關於如式I描述之γ-分泌酶調節劑:
或其醫藥上可接受之鹽,其中:X係含有1至3個雜原子之(5-至14-員)雜芳基;R1(若化學上容許)係選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;R2a及R2b(若化學上容許)在每次出現時,係獨立地選自由氫、鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R2a及R2b連同其連接之碳原子一起形成(C3-C8)環烷基或(4-至10-員)雜環烷基,其中該(C3-C8)環烷基及該(4-至10-員)雜環烷基係視情況經一至三個R8取代;
R4a及R4b(若化學上容許)係各者獨立地選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R4a及R4b連同其連接之碳原子一起形成(C3-C8)環烷基,其中該(C3-C8)環烷基係視情況經一至三個R8取代;R5a及R5b在每次出現時係獨立地選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R5a及R5b連同其連接之碳原子一起形成(C3-C8)環烷基,其中該(C3-C8)環烷基係視情況經一至三個R8取代;R6及R7係各獨立選自由氫、鹵素、氰基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4及-OR9組成之群;但R6及R7不均係羥基;R8在每次出現時係獨立地選自由氰基、鹵素、羥基、-SF5、硝
基、視情況經取代之(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、及視情況經取代之(C1-C6)烷氧基(C1-C6)烷基組成之群;R9係選自由氫及視情況經取代之(C1-C6)烷基組成之群;y係選自1、2、3或4之整數;環B係視情況經一至三個R10取代;其中各個R10係獨立地選自由鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或兩個R10取代基與其連接之碳原子一起形成視情況經取代之(C3-C8)環烷基;環D係視情況經一至四個R11取代,其中各個R11係獨立地選自由鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、視情況經取代之(4-至6-員)雜環烷基;-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;及R4及R5在每次出現時各獨立地選自氫或視情況經取代之(C1-C6)烷基;限制條件為該化合物不為7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮。
本發明化合物包括如本文描述之實例2-22、C22、C33、C40及C44或其醫藥上可接受之鹽。
本文亦提供包括醫藥有效量之一或多種本文描述之化合物及其一
醫藥上可接受之媒劑、載劑或賦形劑的組合物。
式I化合物係γ-分泌酶調節劑。γ-分泌酶在產生與阿茲海默氏症相關聯之澱粉樣β蛋白質(Aβ)斑方面具有重要作用。由此,據信式I化合物可用於治療各種與Aβ產生有關之神經退化性及/或神經病症。
從描述本發明之說明書及隨附申請專利範圍,本發明之其他特徵及優點將顯而易見。
此文檔中之標題僅用於由讀者炔速查閱。其不應被理解為以任何方式限制本發明或申請專利範圍。
定義及示例
如本說明書(包括申請專利範圍)全篇使用,除非另作特定說明,以下術語具有下文定義之含義。複數及單數應處理為可互換的,而非指定數量。
術語「(C1-C6)烷基」指含有1至6個碳原子的直鏈或分支鏈飽和烴基取代基(即,藉由移除氫獲自烴之取代基)。此等取代基之實例包括甲基、乙基、丙基(包括正丙基及異丙基)、丁基(包括正丁基、異丁基、第二丁基及第三丁基)、戊基及己基。
如本文使用術語「視情況經取代之(C1-C6)烷基」指如上文定義之(C1-C6)烷基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。例如,(C1-C6)烷基部分可經一或多個鹵素原子取代以形成「鹵代(C1-C6)烷基」。鹵代(C1-C6)烷基之代表實例包
括(但不限於)氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、五氟乙基、等等。
術語「(C1-C3)烷基」指含有1至3個碳原子的直鏈或分支鏈飽和烴基取代基(即,藉由移除氫獲自烴之取代基)。此等取代基之實例包括甲基、乙基、及丙基(包括正丙基及異丙基)。
術語「(C2-C6)烯基」指具有2至6個碳原子且具有至少一個碳-碳雙鍵的脂族烴,包括具有至少一個碳-碳雙鍵的直鏈及分支鏈基團。代表實例包括(但不限於)乙烯基、1-丙烯基、2-丙烯基(烯丙基)、異丙烯基、2-甲基-1-丙烯基、1-丁烯基及2-丁烯基。當本發明化合物含有(C2-C6)烯基時,該化合物可呈純E(異側)形式、純Z(同側)形式、或任何其混合物存在。
術語「視情況經取代之(C2-C6)烯基」指如上文定義之(C2-C6)烯基,其中一或多個氫原子係由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
術語「(C2-C6)炔基」指具有2至6個碳原子及具有至少一個碳-碳三鍵的脂族烴,包括具有至少一個碳-碳三鍵的直鏈或分支鏈基團。炔基之代表實例包括(但不限於)乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基、及1-丁炔基。
術語「視情況經取代之(C2-C6)炔基」指如上文定義之(C2-C6)炔基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視
情況經取代之(C1-C6)烷基。
術語「鹵素」指氟(可表示為-F)、氯(可表示為-Cl)、溴(可表示為-Br)、或碘(可表示為-I)。
如本文使用術語「(C1-C6)烷氧基」意指經由氧原子連接至母分子部分的如上文定義之(C1-C6)烷基。實例包括(但不限於)甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、第三-丁氧基、戊氧基、及己氧基。
如本文使用術語「視情況經取代之(C1-C6)烷氧基」指如上文定義之(C1-C6)烷氧基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。例如,(C1-C6)烷氧基可經一或多個鹵素原子取代以形成「鹵代(C1-C6)烷氧基」。鹵代(C1-C6)烷氧基之代表實例包括(但不限於)氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基、及五氟乙氧基等等。
如本文使用術語「(C1-C6)烷氧基(C1-C6)烷基」意指經由如上文定義之(C1-C6)烷基連接至母分子部分的如上文定義之(C1-C6)烷氧基。實例包括(但不限於)甲氧基甲基、甲氧基乙基等等。
如本文使用術語「視情況經取代之(C1-C6)烷氧基(C1-C6)烷基」意指如上文定義之(C1-C6)烷氧基(C1-C6)烷基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
如本文使用,術語「硫(C1-C6)烷基」意指經由硫原子連接至母分子部分的如上文定義之(C1-C6)烷基。硫(C1-C6)烷基之代表實例包括(但不限於)硫甲基、硫乙基、硫(第三丁基)、及硫己基。
如本文使用,術語「視情況經取代之硫(C1-C6)烷基」指如上文定義之硫(C1-C6)烷基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
術語「(C3-C8)環烷基」指藉由從具有3至8個碳原子之飽和碳環分子移除氫獲得之碳環取代基。「(C3-C6)環烷基」指藉由從具有3至6個碳原子之飽和碳環分子移除氫獲得之碳環取代基。「(C3-C8)環烷基」可係單環,其實例包括環丙基、環丁基、環戊基、環己基、環庚基、及環辛基。或者,環烷基可含有超過一個環,諸如(C4-C8)雙環烷基。術語「(C4-C8)雙環烷基」指含有4至8個碳原子之雙環系統。該雙環烷基可係稠合,諸如雙環[1.1.0]丁烷、雙環[2.1.0]戊烷、雙環[2.2.0]己烷、雙環[3.1.0]己烷、雙環[3.2.0]庚烷及雙環[3.3.0]辛烷。術語「雙環烷基」亦包括橋接雙環烷基系統諸如但不限於雙環[2.2.1]庚烷及雙環[1.1.1]戊烷。
術語「視情況經取代之(C3-C8)環烷基」指如上文定義(C3-C8)之環烷基,其中一或多個氫原子由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
術語「(C6-C10)芳基」指含有6至10個碳原子之由一個環或兩個稠
合環組成之芳族取代基。此等芳族取代基之實例包括(但不限於)苯基及萘基。(C6-C10)芳基亦可包括視情況稠合至如本文定義之(C3-C6)環烷基環的苯基及萘基取代基(例如,雙環[4.2.0]辛-1,3,5三烯基)或稠合至(5-至6-員)雜環烷基環的苯基及萘基取代基(例如二氫苯并呋喃基、苯并間二氧雜環戊烯基、及氧異吲哚啉基),其中具有此稠合芳基作為取代基之基團係連接至芳基之碳原子。當該芳基係苯基時,本文亦將其稱為「視情況經取代之苯基」。
術語「視情況經取代之(C6-C10)芳基」指如上文定義之(C6-C10)芳基,其中一或多個氫原子由選自由鹵素、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
如本文使用,術語「雜環烷基」指如上文定義之環烷基,其中該等環碳原子之至少一者由選自氮、氧或硫之雜原子置換。「(4-至10-員)雜環烷基」指含有共4至10個環原子的如上文定義之雜環烷基取代基,其中該等環原子之至少一者係選自氧、氮、或硫之雜原子。雜環烷基可係具有至多10個總成員之單環。或者,如上文定義之雜環烷基可包括2或3個稠合在一起之環,其中至少一個此環含有作為環原子之雜原子(即,氮、氧或硫)。在具有雜環烷基取代基之基團中,當該雜原子係具有適當價數之氮時,連接至基團的雜環烷基取代基之環原子可係至少一個雜原子,或其可係環碳原子,其中該環碳原子可係在與該至少一個雜原子相同之環中或其中該環碳原子可在與該至少一個雜原子不同之環中。相似地,若該雜環烷基取代基繼而經基團或取代基取代,則當該雜原子係具有適當價數之氮時,該基團或取代基可連接至該至少一雜原子,或其可連接至環碳原子,其中該環碳原子可
係在與該至少一雜原子相同之環中或其中該環碳原子可係在與該至少一雜原子不同之環中。
「雜環烷基」定義中亦包括的是稠合至(C6-C10)芳族環或(5-至10-員)雜芳族環的雜環烷基。當此稠合雜環烷基經一或多個取代基取代時,除非另作說明,否則該一或多個取代基係各連接至該雜環烷基之雜原子(當該雜原子係具有適當價數之氮時)或至該雜環烷基之碳原子。雜環烷基環之實例包括(但不限於)四氫吖唉基、二氫呋喃基、二氫噻吩基、四氫噻吩基、四氫呋喃基、四氫三基、四氫吡唑基、四氫噁基、四氫嘧啶基、八氫苯并呋喃基、八氫苯并咪唑基、八氫苯并噻唑基、咪唑啶基、吡咯啶基、哌啶基、哌基、噁唑啶基、噻唑啶基、吡唑啶基、硫嗎啉基、四氫吡喃基、四氫噻基、四氫噻二基、四氫噁唑基、嗎啉基、氧雜環丁烷基、四氫二基、噁基、噁噻基、奎寧環基、絪基、異絪基、二氫苯并噁基、吲哚啉基、異吲哚啉基、二氫苯并呋喃基、四氫喹啉基、異氧鉻基、二氫-1H-異吲哚基、2-氮雜二環[2.2.1]庚酮基、3-氮雜二環[3.1.0]己基、3-氮雜二環[4.1.0]庚基等等。雜環烷基環之額外實例包括四氫呋喃-2-基、四氫呋喃-3-基、咪唑啶-1-基、咪唑啶-2-基、咪唑啶-4-基、吡咯啶-1-基、吡咯啶-2-基、吡咯啶-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、哌-1-基、哌-2-基、1,3-噁唑啶-3-基、1,4-氧氮雜環庚烷-4-基、異噻唑啶基、1,3-噻唑啶-3-基、1,2-吡唑啶-2-基、1,2-四氫噻-2-基、1,3-噻-3-基、1,2-四氫二-2-基、1,3-四氫二-1-基、1,4-噁-4-基、噁唑啶酮基、2-側氧基-哌啶基(例如,2-側氧基-哌啶-1-基)、等等。
術語「視情況經取代之雜環烷基」(例如,視情況經取代之(4-至6-員)雜環烷基)指如上文定義之雜環烷基,其中一或多個氫原子(在化學上容許的情況下)由選自由鹵素、側氧基、氰基、羥基、-SF5、硝
基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。
術語「(5-至14-員)雜芳基」指具有5至14個環原子之雜芳環,其中環原子之至少一者係雜原子(即,氧、氮、或硫),剩餘環原子獨立選自由碳、氧、氮、及硫組成之群。「(5-至6-員)雜芳基」指具有5至6個環原子之雜芳環,其中環原子之至少一者係雜原子(即,氧、氮、或硫),剩餘環原子獨立選自由碳、氧、氮、及硫組成之群。「(6-員)雜芳基」指具有6個環原子之雜芳環。「(5-員)雜芳基」指具有5個環原子之雜芳環,其中至少環原子之一係雜原子。雜芳基可由單一環或2或3個稠合環組成。雜芳基之實例包括(但不限於)6-員環取代基諸如吡啶基、吡基、嘧啶基及噠基;5-員雜芳基諸如三唑基、咪唑基、呋喃基、異噁唑基、異噻唑基、1,2,3-、1,2,4-、1,2,5-或1,3,4-噁二唑基、噁唑基、噻吩基、噻唑基、及吡唑基;6/5-員稠合環取代基諸如吲哚基、吲唑基、苯并呋喃基、苯咪唑基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、異苯并硫呋喃基、苯并硫呋喃基、苯異噁唑基、苯并噁唑基、呋喃并吡啶基、嘌呤基、咪唑吡啶基、吡咯并吡啶基、吡唑并吡啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基、吡咯并吡啶基、吡唑并吡啶基、噻吩并吡啶基、三唑并嘧啶基、三唑并吡啶基(例如,[1,2,4]三唑并[1,5-a]吡啶-2-基)、及鄰胺苯甲基;及6/6-員稠合環取代基諸如喹啉基、異喹啉基、噌啉基、喹唑啉基、氧代絪烯基、及1,4-苯并噁基。在具有雜芳基取代基之基團中,當該雜原子係具有適當價數之氮時,連接至該基團之雜芳基取代基之環原子可係至少一個雜原子,或其可係環碳原子,其中該環碳原子可係在與該至少一個雜原子相同之環中或其中該環碳原子可係在與該至少一
個雜原子不同之環中。相似地,若該雜芳基取代基繼而經基團或取代基取代,當該雜原子係具有適當價數之氮時該基團或取代基可連接至該至少一雜原子或其可連接至環碳原子,其中該環碳原子可係在與該至少一雜原子相同之環中,或其中該環碳原子可在與該至少一雜原子不同之環上。
應瞭解該「(5-至14-員)雜芳基」可視情況稠合至(C3-C8)環烷基,或至如本文定義之(4-至10-員)雜環烷基。具有此稠合雜芳基為取代基之基團係連接至該雜芳基之芳族碳或當該雜原子係具有適當價數之氮時連接至該雜芳基之雜原子。此稠合雜芳基可經至多四個取代基取代;除非另作說明,否則該取代基各連接至該雜芳基之芳族碳或當該雜原子係具有適當價數之氮時連接至該雜芳基之雜原子。
術語「視情況經取代之(5-至14-員)雜芳基」、「視情況經取代之(5-至6-員)雜芳基」及「視情況經取代之(5-至6-員)含氮雜芳基」指如上文定義之(5-至14-員)雜芳基、(5-至6-員)雜芳基、及(5-至6-員)含氮雜芳基,其中一或多個氫原子(在化學上容許的情況下)由選自由鹵素、側氧基、氰基、羥基、-SF5、硝基、-N(R4)(R5)、-N(R4)(C(=O)R5)、-N(R4)C(=O)-OR5、-C(=O)-N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4、及(C3-C8)環烷基組成之群的取代基置換,其中R4及R5各獨立地係氫或視情況經取代之(C1-C6)烷基。該取代基可於任何適當碳原子連接至雜芳基部分或當該雜原子係具有適當價數之氮時連接至雜原子。
術語「氫」指氫取代基,及可表示為-H。
術語「羥基(hydroxy)」或「羥基(hydroxyl)」指-OH。當與另一術語(等)結合使用時,詞頭「羥基」指該詞頭連接之取代基係經一或多個羥基取代基取代。具有一或多個羥基取代基連接至其的碳之化合物包括,例如,醇、烯醇及苯酚。
術語「氰基」(亦稱為「腈」)意指-CN,其亦可表示為:
術語「側氧基」意指=O基團。
若將取代基描述為「經取代」,非氫取代基係代替該取代基之碳或氮上之氫取代基。因此,例如,經取代之烷基取代基係其中至少一個非氫取代基係在烷基取代基上之氫取代基位置上的烷基取代基。出於闡明目的,單氟烷基係經一個氟取代基取代的烷基,及二氟烷基係經兩個氟取代基取代的烷基。應瞭解若在取代基上具有超過一個取代基,各個非氫取代基可係相同或不同(除非另作說明)。
若將取代基描述作為「視情況經取代」,則該取代基可係(1)未經取代,或(2)經取代。若將取代基之碳描述為視情況經一或多個取代基清單取代,則在碳上一或多個該氫(至存在任何的一定程度)可分開及/或一起由獨立選擇之可選取代基取代。若將取代基之氮描述為視情況經一或多個取代基清單取代,則在氮上一或多個氫(至存在任何的一定程度)可各者由獨立選擇之可選取代基置換。作為又一實例,當可選取代基存在時,例如,R10或R11,彼等取代基係在本說明書中指出,及當不存在時,該可選取代基連接之原子(即,C或N)可具有必要數量連接之氫。
此說明書可互換地使用術語「取代基」、「自由基」及「基團」。
若將該取代基描述為視情況經至多特定數量非氫取代基取代,該取代基可係(1)未經取代;或(2)由至多特定數量非氫取代基或由至多最大數量在該取代基上可取代位置取代(無論哪一者更小)。由此,例如,若將取代基描述為視情況經至多3個非氫取代基取代之雜芳基,則任何具有小於3個可取代位置之雜芳基可視情況經至多僅與該
雜芳基所具有可取代位置相同之非氫取代基取代。為了闡明,四唑基(僅具有一個可取代位置)可視情況經至多一個非氫取代基取代。為進一步闡明,若胺基氮描述如視情況經至多2個非氫取代基取代,則若該胺基氮係一級氮該氮可視情況經至多2個非氫取代基取代,而若該胺基氮係二級氮該胺基氮可視情況經至多僅1個非氫取代基取代。
若將取代基描述為「獨立地選擇」自一群組,則獨立於另一者選擇各個取代基。各取代基由此可係與其他取代基相同或不同。
如本文使用,除非說明,否則取代基之連接點可係取代基之任何適宜位置。
當與取代基之鍵顯示為穿過在環中連接兩個原子之鍵時,則此取代基可鍵接至在可取代之環中任何形成環之原子。
「患者」指溫血動物,諸如,例如,豬、牛、雞、馬、天竺鼠、小鼠、大鼠、沙鼠、貓、兔、夠、猴子、黑猩猩及人類。
除非另作說明,否則如本文使用之「治療(treating)」或「治療(treat)」意指逆轉、緩和、抑制此等術語適用之疾病或病症或一或多個此等疾病或病症之症狀的進程或預防此等術語適用之疾病或病症或一或多個此等疾病或病症之症狀。除非另作說明,否則如本文使用之術語「治療(treatment)」指治療行為,「治療(treating)」係緊接上文定義。術語「治療(treating)」亦包括個體之佐劑及新佐劑治療。
「醫藥上可接受」表明物質或組合物必須係與包括調配物之其他成分及/或待使用其治療之哺乳動物化學或毒物學上相容。
「異構體」意指如下文定義之「立體異構體」及「幾何異構體」。
「立體異構體」指具有一或多個對掌性中心之化合物,其可各自以R或S構形存在。立體異構體包括全部非對映異構體、對映異構體及差向異構體以及消旋異構體及其混合物。
「幾何異構體」指以順式、反式、抗、同向(E)及異向(Z)形式以及其混合物存在之化合物。
如本文使用術語「式I」、「式II」及「式III」後文稱為「本發明化合物」。亦將此等術語定義為包括式I至III化合物全部形式,包括其水合物、溶劑合物、異構體、晶體及非晶形式、同型體、多晶型物、及代謝產物。例如,式I至III化合物、或其醫藥上可接受之鹽可以非溶劑合物及與醫藥可接受溶劑諸如水、乙醇及等等之溶劑合物形式存在。當該溶劑或水緊密結合時,該錯合物具有不依賴濕度之良好定義之化學計量。然而,當該溶劑或水為弱結合時,如在通道溶劑合物及吸濕化合物中,該水/溶劑含量可取決於濕度及乾燥條件。在此等情形下,非化學計量可係常態。一般而言,出於本發明之目的認為溶劑合物形式等效於非溶劑合物形式。
本發明化合物可作為包合物或其他錯合物存在。包括在本發明範圍內的係錯合物諸如包合物、藥物-主體包含錯合物,其中該藥物及主體以化學計量或非化學計量含量存在。亦包括含有二或多個有機及/或無機組分之本發明化合物之錯合物,其可呈化學計量或非化學計量量。所得錯合物可係離子化、部分離子化、或非離子化。對於此等錯合物之評審,參見Haleblian的J.Pharm.Sci.,64(8),1269-1288(1975年8月)。
本發明化合物可作為幾何異構體存在。本發明化合物可具有一或多個不對稱中心,由此作為二、或多個立體異構形式存在。本發明包括本發明化合物之全部個別立體異構體及幾何異構體及其混合物。個別對映體可藉由解析、對掌性層析、或其他為熟習此項技術者熟知之方法,或藉由在合成中使用相關對映反應物或試劑獲得。
本發明化合物之碳-碳鍵在本文可使用實線()、實心楔()、或點楔()描繪。描繪與不對稱碳原子之鍵使用實線意
在表明包括於此碳原子處全部可能之立體異構體(例如,特定對映體、消旋混合物等等)。描繪不對稱碳原子之鍵使用實心或點楔意在表明存在顯示之立體異構體。當存在於消旋化合物中時,實心或點楔用以限定相對立體化學,而非絕對立體化學。使用(+/-)標記具有此等表明之相對立體化學之消旋化合物。例如,除非另作說明,否則希望本發明化合物可作為立體異構體存在,該立體異構體包括順式及反式異構體、光學異構體諸如R及S對映體、非對映體、幾何異構體、旋轉異構體、構形異構體、阻轉異構體、及其混合物。本發明化合物可顯示超過一種類型異構現象,並由其混合物(諸如消旋體或非對映體對)組成。亦包括其中抗衡離子係光學活性之酸加成鹽或鹼加成鹽,例如,D-乳酸鹽或L-離胺酸,或消旋,例如,DL-酒石酸鹽或DL-精胺酸。
當任何消旋體結晶時,二種不同類型晶體係可能。第一類型係上文提及之消旋化合物(正消旋),其中產生含有兩種等莫耳量對映體之一種均相形式之晶體。第二種類型係消旋混合物或聚結,其中產生等莫耳量之兩種晶體形式,各者包括單一對映體。
本發明亦包括全部醫藥上可接受之同位素標記化合物,除一或多個原子由具有相同原子數量但不同於自然界主導之原子質量或質量數的原子質量或質量數的原子置換外,其係與在式I至III中引述之彼等相同。適宜包括於本發明化合物中之同位素實例包括(但不限於)氫同位素,諸如2H、3H;碳同位素,諸如11C、13C、及14C;氯同位素,諸如36Cl;氟同位素,諸如18F;碘同位素,諸如123I及125I;氮同位素,諸如13N及15N;氧同位素,諸如15O、17O、及18O;磷同位素,諸如32P;及硫同位素,諸如35S。本發明之某些同位素標記化合物(例如併入放射性同位素之彼等)可用於藥物及/或受質組織分配研究(例如,分析)。鑑於併入便利性及已有的偵測方式,放射性同位素氚(即3H)及
碳-14(即14C)可特別用於此目的。經較重同位素(諸如氘(即2H))之取代可提供源自更大代謝穩定性的一些治療優點,例如活體內半衰期增加或劑量需求降低及因此,可係在一些環境下較佳。經正子發射同位素(諸如11C、18F、15O及13N)之取代可用於正子發射斷層掃描(PET)研究以檢查受質受體佔用情況。通常,可藉由熟習此項技術者已知的習知技術或藉由與彼等隨附反應圖及/或實例及製法中所述者類似的方法,藉由使用適當同位素標記反應試劑代替先前使用的非標記反應試劑來製備本發明之同位素標記化合物。本發明之醫藥上可接受之溶劑合物包括彼等其中結晶溶劑可經同位素取代者,例如D2O、丙酮-d6、DMSO-d6。本發明化合物以及在下文描述之實例1至22中例示之化合物包括此等化合物之同位素標記形式,諸如但不限於氘化及氚化同位素及上文討論之全部其他同位素。
本發明化合物可以衍生自無機或有機酸之鹽形式使用。取決於特定化合物,化合物之鹽可能因該鹽之一或多種物理性質而有利,諸如於不同溫度及濕度中增強的醫藥穩定性、或於水或油中之理想溶解度。在一些情形中,化合物鹽亦可有助於分離、純化、及/或溶解該化合物。
在意圖將鹽投與患者之情況下(例如與用於活體外情況相反),該鹽較佳係醫藥上可接受的。術語「醫藥上可接受之鹽」指藉由本發明化合物與酸(其陰離子一般認為適宜人類吸收)、或鹼(其陽離子一般認為適宜人類吸收)結合製備之鹽。由於與母體化合物相比其較高水溶性,醫藥上可接受之鹽係特別可用作本發明方法之產物。
當可能時,本發明化合物之適宜醫藥可接受之酸加成鹽包括衍生自無機酸,諸如鹽酸、氫溴酸、氫氟酸、硼酸、氟硼酸、磷酸、偏磷酸、硝酸、碳酸、磺酸及硫酸,及有機酸諸如乙酸、苯磺酸、苯甲酸、檸檬酸、乙磺酸、富馬酸、葡萄糖酸、乙醇酸、異硫磺酸、乳
酸、乳糖酸、馬來酸、蘋果酸、甲磺酸、三氟甲磺酸、琥珀酸、甲苯磺酸、酒石酸及三氟乙酸之彼等。適宜有機酸一般包括(但不限於)脂族酸、環脂族酸、芳族酸、芳脂族酸、雜環酸、羧酸、及有機酸之磺酸類別。
適宜有機酸之特定實例包括(但不限於)乙酸鹽、三氟乙酸鹽、甲酸鹽、丙酸鹽、琥珀酸鹽、乙醇酸鹽、葡萄醣酸鹽、二葡萄醣酸鹽、乳酸鹽、蘋果酸鹽、酒石酸鹽、檸檬酸鹽、抗壞血酸鹽、尿甘酸鹽、馬來酸鹽、富馬酸鹽、丙酮酸鹽、天冬胺酸鹽、麩胺酸鹽、苯甲酸鹽、鄰胺基苯甲酸鹽、硬脂酸鹽、水楊酸鹽、對羥基苯甲酸鹽、苯基乙酸鹽、杏仁酸鹽、恩貝酸鹽(雙羥萘酸鹽)、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、泛酸鹽、甲苯磺酸鹽、2-羥基乙磺酸鹽、磺胺酸鹽(sufanilate)、環己胺基磺酸鹽、β-羥基丁酸鹽、半乳糖二酸鹽、半乳糖醛酸鹽、己二酸鹽、藻酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊丙酸鹽、十二烷基硫酸鹽、糖庚酸鹽、甘油磷酸鹽、庚酸鹽、己酸鹽、煙鹼酸鹽、2-萘磺酸鹽、草酸鹽、撲酸鹽、果膠酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、硫氰酸鹽、及十一烷酸鹽。
此外,若本發明化合物具有酸部分,則其適宜醫藥上可接受之鹽可包括鹼金屬鹽(例如,鈉或鉀鹽)、鹼土金屬鹽(例如鈣或鎂鹽);及經適宜有機配位體形成之鹽,例如第四銨鹽。在另一實施例中,鹼鹽係由形成無毒性鹽之鹼形成,包括鋁、精胺酸、雙苄苄基乙二胺、膽鹼、二乙胺、二醇胺、甘胺酸、離胺酸、葡甲胺(N-甲基葡萄胺)、乙醇胺、緩血酸胺及鋅鹽。
有機鹽可自諸如以下之第二、第三或第四胺鹽製得:緩血酸胺、二乙胺、N,N'-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、葡甲胺及普魯卡因(procaine)。鹼性含氮基團可經諸如以下之試劑四級胺化:低碳數烷基(C1-C6)鹵化物(例如,甲基、乙基、丙
基、及丁基氯化物、溴化物、及碘化物)、二烷基硫酸鹽(例如,二甲基、二乙基、二丁基、及二戊基硫酸鹽)、長鏈鹵化物(例如,癸基、月桂基、肉豆蔻基、及硬脂基氯化物、溴化物、及碘化物)、芳基烷基鹵化物(例如,苄基及苯乙基溴化物)、及其他。
在一實施例中,亦可形成酸及鹼之半鹽,例如,半硫酸鹽及半鈣鹽。
亦在本發明之範圍內的是所謂之本發明之化合物之「前藥」。由此,當投與人體中或上時,本身具有微量或不具有醫藥活性之本發明化合物的某些衍生物可轉化為具有期望活性之本發明化合物(例如,藉由水解)。此等衍生物稱為「前藥」。關於前藥使用之其他資訊可發現於「Pro-drugs as Novel Delivery Systems,第14卷,ACS Symposium Series(T.Higuchi及V.Stella)及「Bioreversible Carriers in Drug Design」Pergamon Press,1987(E.B.Roche編,美國製藥協會(American Pharmaceutical Association))。本發明之前藥可如(例如)由使用熟習此項技術者熟知作為「前部分」(例如如在H.Bundgaard之「Design of Prodrugs」(Elsevier,1985)中描述)的特定部分替代存在於本發明化合物中之適當官能團來製備。
本發明亦包括含有保護基之本發明化合物。熟習此項技術者應瞭解,本發明化合物亦可使用某些用於純化或儲存之保護基製備並可在投與患者前移除。此官能團之保護及脫除保護係描述於「Protective Groups in Organic Chemistry」,由J.F.W.McOmie編著,Plenum Press(1973)及「Protective Groups in Organic Synthesis」,第三版,T.W.Greene與P.G.M.Wuts,Wiley-Interscience(1999)中。
通常,投與以有效治療本文描述病症之含量之本發明化合物。可藉由任何適宜途徑以適宜此途徑之醫藥組合物形式及有效用於預期
治療之量投與本發明化合物。熟習此項技術者使用醫學技術熟悉之臨床前及臨床途徑容易確定治療醫學病症進程所需之化合物之治療上有效劑量。本文使用之術語「治療上有效量」指在某種程度上將緩解待治療疾病之一或多個症狀所投與化合物量。
化合物
如上所描繪之式I化合物具有由3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮表示之稠合雙環核心。在該核心左側,吡啶酮環係經R6、R7取代,及(5-至14-員)雜芳基部分由X表示,其中X係進一步經R1取代;及在該核心右側,吡酮環係經R4a、R4b、R5a、R5b及由以下結構表示之側鏈環丙苯并呋喃基部分取代:
在某些實施例中,在如上描繪之式I中,R1、R2a、R2b、R4a、R4b、R5a、R5b、R6、R7、R10、R11、及y係如上文定義;及X由以下表示:Xi)含有1至3個雜原子之(5-至6-員)雜芳基;Xii)含有1至3個雜原子之(6-員)雜芳基;或Xiii)含有1至3個雜原子之(5-員)雜芳基。
在某些其他實施例中,該(5-至6-員)雜芳基係選自由三唑基、咪唑基、呋喃基、噻吩基、吡唑基、異噻唑基、噻唑基、異噁唑基、噁唑基、吡啶基、嘧啶基、吡基、及噠基組成之群。
在某些實施例中,該(6-員)雜芳基係選自由吡啶基、嘧啶基、吡基、及噠基組成之群。
在某些其他實施例中,該(5-員)雜芳基係選自由三唑基、咪唑基、呋喃基、噻吩基、吡唑基、異噻唑基、噻唑基、異噁唑基及噁唑基組成之群。
在某些其他實施例中,X係(5-員)雜芳基,其中該雜芳基係咪唑基。
在某些其他實施例中,X係(5-員)雜芳基,其中該雜芳基係三唑基。
在某些其他實施例中,在如上描繪之式I中,X係由如緊接上文描述之實施例之一表示,其中:R1(若化學上容許)係選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;R2a及R2b(若化學上容許)在每次出現時係獨立地選自由氫、鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R2a及R2b連同其連接之碳原子一起形成(C3-C8)環烷基或(4-至10-員)雜環烷基,其中該(C3-C8)環烷基及(4-至10-員)雜環烷基係視情況經一至三個R8取
代;R4a及R4b(若化學上容許)係各者獨立地選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R4a及R4b連同其連接之碳原子一起形成(C3-C8)環烷基,其中該(C3-C8)環烷基係視情況經一至三個R8取代;R5a及R5b在每次出現時係獨立地選自由氫、鹵素、氰基、羥基、側氧基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或R5a及R5b連同其連接之碳原子一起形成(C3-C8)環烷基,其中該(C3-C8)環烷基係視情況經一至三個R8取代;R6及R7係各獨立選自由氫、鹵素、氰基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C1-C6)烷氧基(C1-C6)烷基、視情況經取代之(C3-C8)環烷基、視情況經取代之苯基、-N(R4)(R5)、、N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、-C(=O)-OR4及-OR9組成之群;但R6及R7不均係羥基;
R8在每次出現時係獨立地選自由氰基、鹵素、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、及視情況經取代之(C1-C6)烷氧基(C1-C6)烷基組成之群;R9係選自由氫及視情況經取代之(C1-C6)烷基組成之群;y係選自1、2、3或4之整數;環B係視情況經一至三個R10取代;其中各個R10係獨立地選自由鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;或兩個R10取代基與其連接之碳原子一起形成視情況經取代之(C3-C8)環烷基;環D係視情況經一至四個R11取代,其中各個R11係獨立地選自由鹵素、氰基、羥基、-SF5、硝基、視情況經取代之(C1-C6)烷基、視情況經取代之(C2-C6)烯基、視情況經取代之(C2-C6)炔基、視情況經取代之硫(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之(C3-C8)環烷基、視情況經取代之(4-至6-員)雜環烷基;-N(R4)(R5)、-N(R4)(C=(O)R5)、-C(=O)N(R4)(R5)、-O-C(=O)N(R4)(R5)、-C(=O)-R4、及-C(=O)-OR4組成之群;及R4及R5在每次出現時各者獨立地選自氫或視情況經取代之(C1-C6)烷基;限制條件為該化合物不為7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮。
在某些其他實施例中,在如上描繪之式I中,X係選自由三唑基、咪唑基、呋喃基、噻吩基、吡唑基、異噻唑基、噻唑基、異噁唑
基、及噁唑基組成之群的(5-員)雜芳基,其中:R1係選自由氫、鹵素、氰基、羥基、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基組成之群;其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基、或-SF5之取代基取代;R2a及R2b係各獨立選自氫、鹵素、氰基、羥基或視情況經取代之(C1-C6)烷基;R4a、R4b、R5a及R5b係各獨立選自由氫、鹵素、氰基、羥基、側氧基、-SF5、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基組成之群,其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基或-SF5之取代基取代;R6及R7係各獨立選自由氫、氰基、鹵素、-SF5、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基組成之群,其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基或-SF5之取代基取代;y係1;環B係視情況經一至兩個R10取代,其中各個R10係獨立地選自鹵素、氰基、羥基、-SF5、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基,其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基或-SF5之取代基取代;及環D係視情況經一至三個R11取代,其中各個R11係獨立地選自由鹵素、氰基、羥基、視情況經取代之(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、-SF5、-N(R4)(R5)、硝基、及視情況經取代之(C3-C8)環烷基組成之群,其中該(C1-C6)烷基、(C1-C6)烷氧基、及(C3-C8)環烷基係視情況經一至三個獨立選自鹵素、氰基、羥基、-SF5、及視情況經取代之(C1-C6)烷基之取代基取代,其中R4及R5係各獨立選自氫或
視情況經取代之(C1-C6)烷基;限制條件為該化合物不為7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮。
在某些實施例中,在如緊接上文描述之式I中:R1係視情況經取代之(C1-C6)烷基,其中該(C1-C6)烷基係經一至三個選自鹵素、側氧基、氰基、羥基、或-SF5之取代基取代;及R2a、R2b、R4a、R4b、R5a及R5b各獨立地係i)氫;或ii)視情況經取代之(C1-C6)烷基,其中該(C1-C6)烷基係經一至三個選自鹵素、側氧基、氰基、羥基、或-SF5之取代基取代。
在某些其他實施例中,R1係甲基;及R2a、R2b、R4a、R4b、R5a及R5b各獨立地係氫。
在某些其他實施例中,R1係甲基;R2a、R2b、R5a及R5b各獨立地係氫;及R4a及R4b之一係氫及另一者係甲基。
在另一實施例中,R1係甲基;R2a及R2b之一係氫及另一者係甲基;及R4a、R4b、R5a及R5b各獨立地係氫。
為進一步闡明本發明化合物,其中X係(5-員)雜芳環及該(5-員)雜芳基環係咪唑基或三唑基,下文描述以下亞屬:如下文描繪之式II係如上描繪之式I之子集,其中X係其中該雜芳基係咪唑基之(5-員)雜芳基,R1係(C1-C6)烷基,其中該(C1-C6)烷基係甲基,R6及R7各係氫,y係1,及該環丙苯并呋喃基部分係經由該環丙苯并呋喃基部分之苯甲基位置連接;
在某些實施例中,在如上描繪之式II或其醫藥上可接受之鹽中:R1係選自由氫、鹵素、氰基、羥基、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基組成之群;其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基、或-SF5之取代基取代;R2a、R2b、R4a、R4b、R5a及R5b各獨立選自氫、鹵素、氰基、羥基或視情況經取代之(C1-C6)烷基;環B係視情況經一至兩個R10取代,其中各R10係獨立地選自鹵素或視情況經取代之(C1-C6)烷基;及環D係視情況經一至三個R11取代,其中各R11係獨立地選自鹵素、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基;限制條件為該化合物不為7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮。
在某些實施例中,式II係如緊接上文描述:R1係選自由氫、鹵素、氰基、羥基、(C1-C6)烷基、及(C1-C6)烷氧基組成之群;其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三
個氟原子取代。
R2a、R2b、R4a、R4b、R5a及R5b各獨立選自氫或(C1-C6)烷基,其中(C1-C6)烷基係甲基;環B係視情況經一至兩個R10取代,其中各Rl0係選自:i)鹵素,選自氟或氯,或ii)(C1-C6)烷基,其中(C1-C6)烷基係甲基;且環D係視情況經一至三個R11取代,其中各R11係選自:i)鹵素,選自氟或氯;ii)視情況經取代之(C1-C6)烷基,其中該(C1-C6)烷基係甲基及該甲基係視情況經一至三個氟取代(例如,氟甲基、二氟甲基、或三氟甲基);及iii)視情況經取代之(C1-C6)烷氧基,其中該(C1-C6)烷氧基係甲氧基及該甲氧基係視情況經一至三個氟取代(例如,氟甲氧基,二氟甲氧基、或三氟甲氧基)。
在任何上文提及之式II之實施例中,R1係(C1-C6)烷基,其中該烷基係甲基。在某些實施例中,當R1係甲基時,式I之R1-X部分係4-甲基-1H-咪唑-1-基。
如下文描繪之式III係如上描繪之式I之子集,其中X係(5-員)雜芳基,其中該雜芳基係三唑基,R1係(C1-C6)烷基,其中該(C1-C6)烷基係甲基,R6及R7各係氫,y係1,及該環丙苯并呋喃基部分係經由該環丙苯并呋喃基部分之苯甲基位置連接:
在某些實施例中,在如上描繪之式III或其醫藥上可接受之鹽中:R1係選自由氫、鹵素、氰基、羥基、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基組成之群;其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個選自鹵素、側氧基、氰基、羥基或-SF5之取代基取代;R2a、R2b、R4a、R4b、R5a及R5b係各獨立選自氫、鹵素、氰基、羥基或視情況經取代之(C1-C6)烷基;環B係視情況經一至兩個R10取代,其中各R10係獨立地選自鹵素或視情況經取代之(C1-C6)烷基;且環D係視情況經一至三個R11取代,其中各R11係獨立地選自鹵素、視情況經取代之(C1-C6)烷基、及視情況經取代之(C1-C6)烷氧基。
在某些實施例中,式III係如緊接上文描述:R1係選自由氫、鹵素、氰基、羥基、(C1-C6)烷基、及(C1-C6)烷氧基組成之群;其中該(C1-C6)烷基及(C1-C6)烷氧基係視情況經一至三個氟原子取代;
R2a、R2b、R4a、R4b、R5a及R5b係各獨立選自氫或(C1-C6)烷基,其中該(C1-C6)烷基係甲基;環B係視情況經一至兩個R10取代,其中各R10係選自:i)鹵素,選自氟或氯,或ii)(C1-C6)烷基,其中該(C1-C6)烷基係甲基;且環D係視情況經一至三個R11取代,其中各R11係選自:i)鹵素,選自氟或氯;ii)視情況經取代之(C1-C6)烷基,其中該(C1-C6)烷基係甲基及該甲基係視情況經一至三個氟取代(例如,氟甲基、二氟甲基、或三氟甲基);及iii)視情況經取代之(C1-C6)烷氧基,其中該(C1-C6)烷氧基係甲氧基及該甲氧基係視情況經一至三個氟取代(例如,氟甲氧基、二氟甲氧基、或三氟甲氧基)。
在任何上文提及之式III實施例中,R1係(C1-C6)烷基,其中該烷基係甲基。在某些實施例中,其中R1係甲基,該R1-X部分係3-甲基-1H-1,2,4-三唑-1-基。
在某些其他實施例中,本發明化合物係選自由下列組成之群:7-(4-甲基-1H-咪唑-1-基)-2-{[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;
2-{[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-
2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-[4-(羥甲基)-1H-咪唑-1-基]-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙
[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;及2-{[(1aR,6bR)-3-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;或其醫藥上可接受的鹽。
在另一實施例中,選擇之本發明化合物,或其醫藥上可接受之鹽可用於治療神經退化性及神經疾病,包括阿茲海默氏症或尼曼匹克(Niemann-Pick)症C型。
在某些實施例中,選擇之本發明化合物可用於減少有需要個體之澱粉樣β(Aβ)蛋白質的產生。
在某些實施例中,選擇之本發明化合物可用於治療患者之阿茲海默氏症或尼曼匹克症C型,該方法包括投與治療上有效量之本發明化合物或其醫藥上可接受之鹽給有需要之患者。
在某些實施例中,本發明係關於包括選擇之本發明化合物、或其醫藥上可接受之鹽及醫藥上可接受之賦形劑的醫藥組合物。
在某些實施例中,本發明係關於一種減少有需要個體之澱粉樣
β(Aβ)蛋白質之產生的方法,該方法包括投與該個體治療上有效量之式I、式II或式III化合物,或其醫藥上可接受之鹽。
在某些其他實施例中,本發明係關於一種治療有需要個體之阿茲海默氏症的方法,該方法包括投與該個體治療上有效量之式I、式II或式III化合物,或其醫藥上可接受之鹽。
藥物學
阿茲海默氏症(AD)研究表明,該疾病與在大腦中各種形狀及尺寸斑積聚有關。有關AD之原發斑係由澱粉樣β肽(Aβ)構成。當澱粉樣前驅蛋白(APP)經歷藉由天冬胺醯基蛋白酶β-及γ-分泌酶之連續蛋白質水解時產生Aβ(Haas等人,「Trafficking and proteolytic processing of APP」。Cold Spring Harbor Perspeet.Med.,2011)。γ-分泌酶係由至少四種不同整合蛋白質組成之大型錯合物,其中一者係早衰蛋白質及已識別為保護催化之天冬胺酸鹽之催化組分(De Strooper,Bart等人,「Presenilins and γ-Secretase:Structure,Function,and Role in Alzheimer’s Disease」。Cold Spring Harbor Perspect.Med.2012;2:a006304)。首先發現早衰蛋白質1及2為導致早發性阿茲海默氏症的錯義突變位點。隨後發現編碼之多通路膜蛋白為導致產生獲自澱粉樣蛋白前驅體之澱粉樣β蛋白質的羧基末端之γ-分泌酶、包膜天冬胺醯基蛋白酶錯合物之催化組分(De Strooper,Bart等人;2012)。因此,靶向用於藥物發現之γ-分泌酶錯合物已成為阿茲海默氏症研究的主要焦點。
據信本發明化合物係γ-分泌酶調節劑,其調節γ-分泌酶錯合物使得較長病原Aβ肽(即Aβ42)減少及較短Aβ類(即Aβ37及/或Aβ38)增加。γ-分泌酶調節劑可用於治療哺乳動物(較佳地人類)之涉及γ-分泌酶錯合物之中樞神經系統症狀或疾病,諸如尼曼匹克症C型;神經疾病(諸如偏頭痛;癲癇;阿茲海默氏症、帕金森病;腦損傷;中風;腦血管
疾病(包括腦動脈硬化、腦澱粉樣血管病、遺傳性腦出血、及大腦缺氧缺血));認知障礙(包括失憶、老年性癡呆、HIV-有關癡呆、阿茲海默氏症、亨廷頓氏病、路易體性癡呆、血管性癡呆、藥物-有關癡呆、肌震顫、肌張力障礙、譫妄、皮克氏病、克雅氏病、HIV病、妥瑞氏症候群、癲癇症、及輕度認知障礙);遲延性運動障礙;肌肉痙攣及有關肌肉痙攣或變弱之疾病(包括顫動);精神不全(包括痙攣、唐氏症候群及脆X症候群);睡眠障礙(包括嗜睡、近日節律睡眠障礙、失眠症、類睡症、及睡眠不足)及精神疾病諸如焦慮(包括急性應激障礙、廣泛性焦慮症、社交焦慮症、驚恐性障礙、創傷後應激障礙、廣場恐怖症、及強制性障礙);人為性疾病(包括急性幻覺性躁狂);衝動控制障礙(包括強迫性賭博及間歇性爆發障礙);情感障礙(包括雙相情感I障礙、雙相情感II障礙、躁狂症、混合情感狀態、重度抑鬱、慢性抑鬱、季節性抑鬱、神經病性抑鬱、經前症候群(PMS)、經前焦慮障礙(PDD)、及產後抑鬱);神經運動性障礙、精神障礙(包括神經分裂症、分裂情感障礙、精神分裂、及妄想性障礙);藥物依賴(包括麻醉藥依賴、酒精中毒、安非他明依賴、可卡因成癮、尼古丁依賴、及戒藥症候群);進食障礙(包括厭食症、貪食症、暴飲暴食症、過食症、肥胖症、強迫進食障礙及食冰癖);性功能障礙;尿失禁;神經損傷障礙(包括眼睛損傷、視網膜病變或眼黃斑變性;耳鳴、聽力障礙與聽力損失;腦水腫)及兒科精神疾病(包括注意力缺乏症、注意力缺乏/多動症、行為障礙、及自閉症),包括投與該哺乳動物治療上有效量之本發明化合物,或其醫藥上可接受之鹽。
在某些實施例中,本發明化合物可用於治療哺乳動物(較佳地人類)之神經疾病(諸如偏頭痛;癲癇症;阿茲海默氏症;帕金森病;尼曼匹克症C型;腦損傷;中風;腦血管疾病;認知障礙;睡眠障礙)或精神疾病(諸如焦慮;人為性疾病;衝動控制障礙;情感障礙;精神
運動性障礙;精神障礙;藥物依賴;進食障礙;及兒科精神障礙),包括投與該哺乳動物治療上有效量本發明化合物或其醫藥上可接受之鹽。
本發明化合物亦可用於提高記憶力(短期及長期)及學習能力。
目前,Diagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR)第四版文本修訂(2000年,美國精神病學協會(American Psychiatric Association),華盛頓D.C.)提供一種用於識別眾多本文描述疾病之診斷工具。熟習此項技術者將瞭解本文描述疾病(包括彼等在DMS-IV中描述者)存在替代命名法、疾病分類學、及分類系統,及該等術語及分類系統隨著醫學科學之進步而演進。
調配物
本發明化合物可經口投與。經口投與可包括吞嚥,使得該化合物進入胃腸道,或可採用經頰或舌下投與,由此該化合物直接從嘴進入血液。
在另一實施例中,本發明化合物亦可直接投與至血液、肌肉、或內部器官中。非經腸投與之適宜途徑包括靜脈內、動脈內、腹膜內、鞘內、胃內、尿道內、胸骨內、顱內、肌內及皮下。非經腸投與之適宜裝置包括針(包括微型針)注射器、無針注射器及輸注技術。
在另一實施例中,本發明化合物亦可局部投與至皮膚或黏膜,即,皮膚或經皮。在另一實施例中,本發明化合物亦可經鼻投與或藉由吸入。在另一實施例中,本發明化合物可經直腸或陰道投與。在另一實施例中,本發明化合物亦可直接投與至眼睛或耳朵。
化合物及/或含有該化合物之組合物的劑量方案係基於各種因素,包括患者之類型、年齡、體重、性別及醫學情況;症狀嚴重性;投與途徑;及採用之特定化合物之活性。由此劑量方案可廣泛變化。約0.01mg至約100mg/千克體重/天之數量級劑量程度可用於治療上文
指出之症狀。在一實施例中,本發明化合物之總日劑量(一次或分次劑量投與)通常係約0.01至約100mg/kg。在另一實施例中,本發明化合物之總日劑量係約0.1至約50mg/kg,及在另一實施例中,約0.5至約30mg/kg(即,mg本發明化合物/kg體重)。在一實施例中,用劑係0.01至10mg/kg/天。在另一實施例中,用劑係0.1至1.0mg/kg/天。劑量單位組合物可包含其構成日劑量之此等含量或其約數。在眾多實例中,投與該化合物在一天中可重複數次(通常不超過4次)。若需要,每天多次劑量通常可用於增加總日劑量。
用於經口投與之該等組合物較佳係呈包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、75.0、100、125、150、175、200、250、及500毫克活性成分之錠劑形式提供以針對患者之症狀性調整劑量。藥劑通常含有約0.01mg至約500mg活性成分,或在另一實施例中,約1mg至約100mg活性成分。在固定速度輸注期間,靜脈內劑量可從約0.1至約10mg/kg/分鐘變化。
本發明適宜個體包括哺乳類個體。本發明哺乳動物包括(但不限於)犬、貓、牛、山羊、馬、綿羊、豬、齧齒動物、兔類動物、靈長類等等,及包括子宮內哺乳動物。在一實施例中,人類係適宜個體。人類個體可係任一性別或於任何成長階段。
在另一實施例中,本發明包括一或多種本發明化合物在製備用於治療本文指出之症狀之藥劑方面的用途。
為治療上文提及之症狀,可投與化合物本身之本發明化合物。或者,由於其與母體化合物相比之更大水溶性,醫藥上可接受之鹽係適宜用於醫學應用。
在另一實施例中,本發明包括醫藥組合物。此等醫藥組合物包括以醫藥上可接受之載劑呈現之本發明化合物。該載劑可係固體、液體、或二者,及可與該化合物調配為單位劑量組合物,例如,錠劑,
其可含有0.05重量%至95重量%活性化合物。本發明化合物可與作為可靶向之藥物載劑的適宜聚合物偶合。亦可存在其他醫藥活性物質。
可藉由任何適宜途徑投與本發明化合物,較佳地以適合此途徑之醫藥組合物之形式,並以有效用於預期治療之劑量。(例如)可經口、經直腸、非經腸、或局部投與該活性化合物及組合物。
固體劑型之經口投與可係(例如)以離散單位存在,諸如硬或軟膠囊、藥片、藥丸、口含錠、或錠劑,各者含有預定含量之至少一種本發明化合物。在另一實施例中,經口投與可係以粉劑或顆粒劑形式。在另一實施例中,口服劑型係舌下,諸如例如口含錠。在此等固體劑型中,本發明化合物一般與一或多種佐劑結合。此等膠囊或錠劑可含有可控制釋放之調配物。在膠囊、錠劑、及藥片之情形下,該等劑型亦可包括緩衝劑或可經腸溶包衣製備。
在另一實施例中,經口投與可係以液體劑型。用於經口投與之液體劑型包括(例如)含有通常用於此項技術之惰性稀釋劑(即水)的醫藥上可接受之乳液、溶液、懸浮液、糖漿、及酏劑。此等組合物亦可包括佐劑,諸如濕潤、乳化、懸浮、矯味(例如甜味)、及/或香味劑。
在另一實施例中,本發明包括非經腸劑型。「非經腸投與」包括(例如)皮下注射、靜脈內注射、腹膜內注射、肌肉內注射、胸骨內注射、及輸注。可根據已知技術使用適宜分散、濕潤、及/或懸浮劑調配可注射製劑(即,無菌可注射水性或油性懸浮液)。
在另一實施例中,本發明包括局部劑型。「局部投與」包括(例如)經皮投與(諸如經由經皮貼片或離子導入裝置)、眼內投與、或鼻內或吸入投與。用於局部投與之組合物亦包括(例如)局部用凝膠、噴霧劑、軟膏、及乳膏。局部調配物可包括增強活性成分透過皮膚或其他受影響區域吸收或滲入的化合物。當本發明化合物藉由經皮裝置投與時,可使用儲液器及多孔膜類型或固體基質種類之貼片完成投與。用
於此目的之典型調配物包括凝膠、水凝膠、洗劑、溶液、乳膏、軟膏、散粉、敷料、泡沫劑、膜、皮膚貼片、晶片、植入物、海綿、纖維、繃帶及微乳液。亦可使用脂質體。典型載劑包括醇、水、礦物油、液體石蠟、白礦脂、甘油、聚乙二醇及丙二醇。穿透增強劑可併入,參見,例如,Finnin及Morgan,J.Pharm.Sci.,88(10),955-958(1999)。
適宜局部投與至眼睛之調配物包括(例如)其中本發明化合物溶於或懸浮在適宜載劑中的滴眼液。適宜用於經眼或耳投與的典型調配物可係以在等滲、經pH調整、無菌鹽水中之微粒化懸浮液或溶液液滴形式。適宜經眼及耳投與之其他調配物包括軟膏、生物可降解(例如,可吸收凝膠海綿、膠原蛋白)及不可生物降解(例如,聚矽氧)植入物、晶片、透鏡及微粒或囊狀系統,諸如微脂粒或脂質體。聚合物諸如交聯聚丙烯酸、聚乙烯醇、玻尿酸、纖維素聚合物(例如,羥丙基甲基纖維素、羥乙基纖維素、或甲基纖維素)、或雜多醣聚合物(例如結冷膠)可與防腐劑(諸如氯化苄二甲烴銨)一起併入。此等調配物亦可藉由離子導入法遞送。
對於鼻內投與或藉由吸入投與而言,本發明之活性化合物係方便地以從由患者壓出或抽出的泵噴霧容器的溶液或懸浮液形式遞送或作為使用適宜推進劑從加壓容器或噴霧器的氣溶膠噴霧呈現。適宜用於鼻內投與之調配物係通常從乾燥粉末吸入器以乾燥粉末形式(單獨;作為混合物,例如與乳糖之乾燥摻合物;或作為混合組分粒子,例如,與磷脂(諸如卵磷脂)混合)投與或作為來自加壓容器、泵、噴霧、霧化器(較佳係使用電液動力學之霧化器以產生細霧)或噴霧器(使用或不使用適宜推進劑(諸如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷))的氣溶膠噴霧。對於鼻內使用而言,該粉末可包括生物黏附劑,例如,甲殼素或環糊精。
在另一實施例中,本發明包括直腸劑型。此直腸劑型可係呈(例如)栓劑之形式。可可黃油係傳統栓劑基質,但若適當可使用各種替代物。
亦可使用在醫藥技術中已知之其他載劑材料及投與模式。可藉由任何熟知藥學技術(諸如有效調配及投與程序)來製備本發明醫藥組合物。上文有關有效調配及投與程序之考量係在此項技術中熟知並描述於標準教科書中。藥物調配係在(例如)Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania,1975;Liberman等人編,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;及Kibbe等人編,Handbook of Pharmaceutical Excipients(第3版),美國醫藥協會,華盛頓,1999中討論。
本發明化合物亦可單獨或與其他治療劑組合用於治療各種症狀或疾病狀態。本發明化合物及其他治療劑可同時(以相同劑型或分開劑型)或順序投與。例示性治療劑可係(例如)代謝型麩胺酸受體促效劑。
「組合」投與二或多種化合物意指在存在一者改變另一者生物功效下時間上足夠緊湊地投與兩種化合物。該二或多種化合物可同時、合併或順序投與。此外,可藉由在投與前混合該等化合物或藉由於相同時間點但不同解剖部位或藉由不同投與途徑投與該等化合物來進行同時投與。
片語「合併投與」、「輔助投與」、「同時投與」及「同時地投與」意指組合投與該等化合物。
本發明包括由本發明化合物提供的γ-分泌酶調節劑化合物及一或多種額外醫藥活性劑之組合之用途。若投與活性劑之組合,則其可以分開劑型或單一劑型之組合順序或同時投與。由此,本發明亦包括含
有一定量下列之醫藥組合物:(a)包括本發明化合物或該化合物之醫藥上可接受之鹽的第一試劑;(b)第二醫藥活性劑;及(c)醫藥上可接受之載劑、媒劑或稀釋劑。
可根據待治療之疾病、病症、或症狀選擇各種醫藥活性劑以與本發明化合物結合使用。可與本發明組合物組合使用之醫藥活性劑包括不作限制之以下各者:(i)乙醯膽鹼酯酶抑制劑,諸如鹽酸多奈哌齊(donepezil hydrochloride)(ARICEPT、MEMAC)、水楊酸毒扁豆鹼(physostigmine salicylate)(ANTILIRIUM)、硫酸毒扁豆鹼(ESERINE)、美曲膦脂(metrifonate)、新斯的明(neostigmine)、更斯的明(ganstigmine)、吡啶斯的明(pyridostigmine)(MESTINON)、阿伯農(ambenonium)(MYTELASE)、得瑪卡(demarcarium)、Debio 9902(亦稱為ZT-1;Debiopharm)、雷斯替明(rivastigmine)(EXELON)、拉多替吉(ladostigil)、NP-0361、氫溴酸加蘭他敏(galantamine hydrobromide)(RAZADYNE、RIMINYL、NIVALIN)、他克林(tacrine)(COGNEX)、托塞啶(tolserine)、馬來酸維吖啶(velnacrine maleate)、美莫喹恩(memoquin)、石杉鹼A(HUP-A;NeuroHitech)、苯羥基丙胺酸(phenserine)、騰喜龍(edrophonium)(ENLON、TENSILON)、及INM-176;(ii)澱粉樣-β(或其片段),諸如共軛至泛HLA DR-結合抗原決定基之Aß1-15(PADRE)、ACC-001(Elan/Wyeth)、ACI-01、ACI-24、AN-1792、Affitope AD-01、CAD106、及V-950;(iii)澱粉樣-β(或其片段)之抗體,諸如坡那珠單抗(ponezumab)、松蘭珠單抗(solanezumab)、八平珠單抗(bapineuzumab)(亦稱為AAB-001)、AAB-002(Wyeth/Elan)、ACI-01-Ab7、BAN-2401、靜脈內Ig(GAMMAGARD)、LY2062430(人源化m266;Lilly)、R1450
(Roche)、ACU-5A5、huC091,及彼等在國際專利公開案第WO04/032868號、第WO05/025616號、第WO06/036291號、第WO06/069081號、第WO06/118959號、美國專利公開案第US2003/0073655號、第US2004/0192898號、第US2005/0048049號、第US2005/0019328號、歐洲專利公開案第EP0994728號及第1257584號,及美國專利第5,750,349號中所揭示者;(iv)澱粉樣-減少或抑制劑(包括彼等減少澱粉樣產生、累積及纖維化者)諸如地美本(dimebon)、達伐替(davunetide)、依普沙特(eprodisate)、亮丙瑞林(leuprolide)、SK-PC-B70M、塞來考昔(celecoxib)、洛伐他汀(lovastatin)、阿那索斯(anapsos)、奧拉西坦(oxiracetam)、普拉西坦(pramiracetam)、伐尼克蘭(varenicline)、尼麥角林(nicergoline)、初乳肽(colostrinin)、雙諾色林(bisnorcymserine)(亦稱為BNC)、NIC5-15(Humanetics)、E-2012(Eisai)、吡格列酮(pioglitazone)、氯碘羥喹(clioquinol)(亦稱為PBT1)、PBT2(Prana Biotechnology)、氟比洛芬(flurbiprofen)(ANSAID,FROBEN)及其R-對映體他熱氟比(tarenflurbil)(FLURIZAN)、硝基氟比洛芬(nitroflurbiprofen)、非諾洛芬(fenoprofen)(FENOPRON、NALFON)、布洛芬(ibuprofen)(ADVIL、MOTRIN、NUROFEN)、布洛芬離胺酸、甲芬那酸(meclofenamic acid)、甲芬那酸鈉(MECLOMEN)、吲哚美辛(indomethacin)(INDOCIN)、雙氯芬酸鈉(VOLTAREN)、雙氯芬酸鉀、舒林酸(sulindac)(CLINORIL)、硫化舒林酸、二氟尼柳(diflunisal)(DOLOBID)、萘普生(naproxen)(NAPROSYN)、萘普生鈉(ANAPROX,ALEVE)、ARC031(Archer Pharmaceuticals)、CAD-106(Cytos)、LY450139(Lilly)、胰島素降解酶(亦稱為胰島素酶)、銀杏葉提取物EGb-761(ROKAN,TEBONIN)、曲米沙特(tramiprosate)
(CEREBRIL,ALZHEMED)、依羅沙特(eprodisate)(FIBRILLEX,KIACTA)、化合物W(3,5-雙(4-硝基苯氧基)苯甲酸)、NGX-96992、腦啡肽酶(neprilysin)(亦稱為中性肽鏈內切酶(NEP))、鯊肌醇(scyllo-inositol)(亦稱為青蟹肌醇(scyllitol))、阿伐他汀(atorvastatin)(LIPITOR)、辛伐他汀(simvastatin)(ZOCOR)、KLVFF-(EEX)3、SKF-74652、甲磺酸伊布莫侖(ibutamoren mesylate)、BACE抑制劑諸如ASP-1702、SCH-745966、JNJ-715754、AMG-0683、AZ-12304146、BMS-782450、GSK-188909、NB-533、E2609及TTP-854;γ-分泌酶調節劑諸如ELND-007;及RAGE(晚期糖基化終產物受體)抑制劑,諸如TTP488(Transtech)及TTP4000(Transtech),及在美國專利第7,285,293號中所揭示之包括PTI-777之彼等;(v)α-腎上腺素能受體促效劑,諸如胍法辛(guanfacine)(INTUNIV、TENEX)、可尼丁(clonidine)(CATAPRES)、阿拉明(metaraminol)(ARAMINE)、甲基多巴(methyldopa)(ALDOMET、DOPAMET、NOVOMEDOPA)、替紮尼定(tizanidine)(ZANAFLEX)、苯腎上腺素(phenylephrine)(亦稱為新星奈佛林(neosynephrine))、甲氧胺、西拉唑啉(cirazoline)、胍法辛(guanfacine)(INTUNIV)、洛非西定(lofexidine)、甲苯噻、莫達非尼(modafinil)(PROVIGIL)、阿屈非尼(adrafinil)、及阿莫非尼(armodafinil)(NUVIGIL);(vi)β-腎上腺素能受體阻斷劑(β阻斷劑),諸如卡替洛爾(carteolol)、艾司洛尓(esmolol)(BREVIBLOC)、拉貝洛爾(labetalol)(NORMODYNE、TRANDATE)、氧烯洛爾(oxprenolol)(LARACOR,TRASACOR)、心得樂(pindolol)(VISKEN)、普萘洛爾(propanolol)(INDERAL)、索他洛爾(sotalol)(BETAPACE,SOTALEX,SOTACOR)、噻嗎咯爾(timolol)(BLOCADREN、
TIMOPTIC)、醋丁洛爾(acebutolol)(SECTRAL、PRENT)、納多洛爾(nadolol)(CORGARD)、酒石酸美托洛爾(metoprolol tartrate)(LOPRESSOR)、琥珀酸美托洛爾(metoprolol succinate)(TOPROL-XL)、阿替洛爾(atenolol)(TENORMIN)、布托沙明(butoxamine)、及SR 59230A(Sanofi);(vii)抗膽鹼能劑,諸如阿米曲替林(amitriptyline)(ELAVIL、ENDEP)、布替林(butriptyline)、甲磺酸苯紮托品(benztropine mesylate)(COGENTIN)、三己芬迪(trihexyphenidyl)(ARTANE)、苯海拉明(diphenhydramine)(BENADRYL)、鄰甲苯海明(orphenadrine)(NORFLEX)、莨菪鹼(hyoscyamine)、阿托品(atropine)(ATROPEN)、東莨菪鹼(scopolamine)(TRANSDERM-SCOP)、甲基溴化東莨菪鹼(scopolamine methylbromide)(PARMINE)、雙環維林(dicycloverine)(BENTYL、BYCLOMINE、DIBENT、DILOMINE)、托特羅定(tolterodine)(DETROL)、奧昔布寧(oxybutynin)(DITROPAN、LYRINEL XL、OXYTROL)、溴化環戊噻吩(penthienate bromide)、丙胺太林(propantheline)(PRO-BANTHINE)、賽克利嗪(cyclizine)、鹽酸托法尼(imipramine hydrochloride)(TOFRANIL)、馬來酸丙咪嗪(imipramine maleate)(SURMONTIL)、洛非帕明(lofepramine)、地昔帕明(desipramine)(NORPRAMIN)、多塞平(doxepin)(SINEQUAN,ZONALON)、三甲丙咪嗪(trimipramine)(SURMONTIL)、及胃長寧(glycopyrrolate)(ROBINUL);(vii)抗驚厥劑,諸如卡馬西平(carbamazepine)(TEGRETOL,CARBATROL)、奧卡西平(oxcarbazepine)(TRILEPTAL)、苯妥英鈉(phenytoin sodium)(PHENYTEK)、磷苯妥英(fosphenytoin)(CEREBYX,PRODILANTIN)、α-正丙基戊酸鈉二聚物
(divalproex sodium)(DEPAKOTE)、加巴噴丁(gabapentin)(NEURONTIN)、普加巴林(pregabalin)(LYRICA)、topirimate(TOPAMAX)、丙戊酸(valproic acid)(DEPAKENE)、丙戊酸鈉(DEPACON)、1-苄基-5-溴尿嘧啶、普羅加胺(progabide)、貝克拉胺(beclamide)、唑尼沙胺(zonisamide)(TRERIEF、EXCEGRAN)、CP-465022、瑞替加濱(retigabine)、他侖帕奈(talampanel)、及普裡米酮(primidone)(MYSOLINE);(ix)抗精神病藥,諸如魯拉西酮(lurasidone)(LATUDA亦稱為SM-13496;Dainippon Sumitomo)、阿立哌唑(aripiprazole)(ABILIFY)、氯丙嗪(chlorpromazine)(THORAZINE)、氟哌啶醇(haloperidol)(HALDOL)、伊洛培酮(iloperidone)(FANAPTA)、癸酸三氟噻噸(flupentixol decanoate)(DEPIXOL,FLUANXOL)、血安平(reserpine)(SERPLAN)、匹莫齊特(pimozide)(ORAP)、癸酸氟非那嗪(fluphenazine decanoate)、鹽酸氟奮乃靜(fluphenazine hydrochloride)、丙氯拉嗪(prochlorperazine)(COMPRO)、氯氧平(asenapine)(SAPHRIS)、洛沙平(loxapine)(LOXITANE)、嗎茚酮(molindone)(MOBAN)、羥哌氯丙嗪(perphenazine)、硫利噠嗪(thioridazine)、甲哌硫丙硫蒽(thiothixine)、三氟啦嗪(trifluoperazine)(STELAZINE)、雷美爾通(ramelteon)、氯氮平(clozapine)(CLOZARIL)、去甲氯氮平(norclozapine)(ACP-104)、利培酮(risperidone)(RISPERDAL)、帕利哌酮(paliperidone)(INVEGA)、美哌隆(melperone)、奧蘭紮平(olanzapine)(ZYPREXA)、奎硫平(quetiapine)(SEROQUEL)、他奈坦(talnetant)、阿米舒必利(amisulpride)、齊拉西酮(ziprasidone)(GEODON)、布南色林(blonanserin)(LONASEN)、及ACP-103(Acadia Pharmaceuticals);(x)鈣離子通道阻斷劑,諸如洛美利嗪(lomerizine)、齊考諾肽
(ziconotide)、尼伐地平(nilvadipine)(ESCOR,NIVADIL)、地帕地平(diperdipine)、阿莫地平(amlodipine)(NORVASC,ISTIN,AMLODIN)、非洛地平(felodipine)(PLENDIL)、尼卡地平(nicardipine)(CARDENE)、利心平(nifedipine)(ADALAT、PROCARDIA)、MEM 1003及其母體化合物尼莫地平(nimodipine)(NIMOTOP)、尼索地平(nisoldipine)(SULAR)、尼群地平(nitrendipine)、拉西地平(lacidipine)(LACIPIL,MOTENS)、樂卡地平(lercanidipine)(ZANIDIP)、利法裡嗪(lifarizine)、地爾硫(diltiazem)(CARDIZEM)、異搏定(verapamil)(CALAN,VERELAN)、AR-R18565(AstraZeneca)、及尼卡丁(enecadin);(xi)兒茶酚對甲基轉移酶(COMT)抑制劑,諸如硝替卡朋(nitecapone)、托卡朋(tolcapone)(TASMAR)、恩他卡朋(entacapone)(COMTAN)、及托酚酮(tropolone);(xii)中樞神經系統刺激劑,諸如托莫西汀(atomoxetine)、瑞波西汀(reboxetine)、壯陽鹼(yohimbine)、咖啡因(caffeine)、苯甲嗎啉(phenmetrazine)、苯甲曲秦(phendimetrazine)、苯異妥英(pemoline)、芬坎法明(fencamfamine)(GLUCOENERGAN,REACTIVAN)、芬乙茶鹼(fenethylline)(CAPTAGON)、哌苯甲醇(pipradol)(MERETRAN)、地阿諾(deanol)(亦稱為二甲基胺基甲醇)、利他林(methylphenidate)(DAYTRANA)、鹽酸哌甲酯(methylphenidate hydrochloride)(RITALIN)、右哌甲酯(dexmethylphenidate)(FOCALIN)、安非他明(amphetamine)(單獨或與其他CNS刺激物結合,例如ADDERALL(天冬胺酸安非他明、硫酸安非他明、糖酸右旋安非他明、及硫酸右旋安非他明))、硫酸右旋安非他明(DEXEDRINE,DEXTROSTAT)、甲基苯丙胺(methamphetamine)(DESOXYN)、賴非他明(lisdexamfetamine)(VYVANSE)、及苄非他明(benzphetamine)(DIDREX);
(xiii)皮質類固醇,諸如普賴鬆(prednisone)(STERAPRED,DELTASONE)、強的松(prednisolone)(PRELONE)、強的松乙酸鹽(OMNIPRED、PRED MILD、PRED FORTE)、強的松磷酸鈉(ORAPRED ODT)、甲基強的松(MEDROL);甲基強的松乙酸鹽(DEPO-MEDROL)及甲基強的松琥珀酸鈉(A-METHAPRED,SOLU-MEDROL);(xiv)多巴胺受體促效劑,諸如阿樸嗎啡(apomorphine)(APOKYN)、溴麥角隱亭(bromocriptine)(PARLODEL)、卡麥角林(cabergoline)(DOSTINEX)、二氫西丁(dihydrexidine)、二氫麥角隱亭(dihydroergocryptine)、非諾多泮(fenoldopam)(CORLOPAM)、麥角乙脲(lisuride)(DOPERGIN)、特他洛爾培高利特(terguride spergolide)(PERMAX)、吡貝地爾(piribedil)(TRIVASTAL,TRASTAL)、普拉克索(pramipexole)(MIRAPEX)、喹吡羅(quinpirole)、羅匹尼祿(ropinirole)(REQUIP)、羅替戈汀(rotigotine)(NEUPRO)、SKF-82958(GlaxoSmithKline)、卡利拉嗪(cariprazine)、帕多盧諾(pardoprunox)及沙立佐坦(sarizotan);(xv)多巴胺受體抗拮劑,諸如氯丙嗪、氟奮乃靜(fluphenazine)、易寧優(haloperidol)、洛克塞平(loxapine)、理思必妥(risperidone)、硫利噠嗪(thioridazine)、替沃噸(thiothixene)、三氟拉(trifluoperazine)、四苯喹嗪(tetrabenazine)(NITOMAN、XENAZINE)、7-羥基氯氧平、氟哌利多(droperidol)(INAPSINE、DRIDOL、DROPLETAN)、多潘立酮(domperidone)(MOTILIUM)、L-741742、L-745870、奎丙靈(raclopride)、SB-277011A、SCH-23390、依考匹泮(ecopipam)、SKF-83566、及甲氧氯普胺(metoclopramide)(REGLAN);(xvi)多巴胺再吸收抑制劑,諸如安非他酮(bupropion)、沙芬醯胺(safinamide)、馬來酸諾米芬新(nomifensine maleate)(MERITAL)、伐
諾司林(vanoxerine)(亦稱為GBR-12909)及其癸酸酯DBL-583、及阿米庚酸(amineptine);(xvii)γ-胺丁酸(GABA)受體促效劑,諸如巴氯芬(baclofen)(LIORESAL、KEMSTRO)、絲洛芬(siclofen)、戊巴比妥(pentobarbital)(NEMBUTAL)、普羅加胺(progabide)(GABRENE)、及氯美噻唑(clomethiazole);(xviii)組織胺3(H3)拮抗劑,諸如環丙沙芬(ciproxifan)、鹽酸替洛利(tiprolisant)、S-38093、依達雙沙(irdabisant)、匹托利沙(pitolisant)、GSK-239512、GSK-207040、JNJ-5207852、JNJ-17216498、HPP-404、SAR-110894、反-N-乙基-3-氟-3-[3-氟-4-(吡咯烷-1-基甲基)苯基]環丁烷甲醯胺(PF-3654746及彼等揭示於美國專利公開案第US2005-0043354號、第US2005-0267095號、第US2005-0256135號、第US2008-0096955號、第US2007-1079175號、及第US2008-0176925號;國際專利公開案第WO2006/136924號、第WO2007/063385號、第WO2007/069053號、第WO2007/088450號、第WO2007/099423號、第WO2007/105053號、第WO2007/138431號、及第WO2007/088462號;及美國專利第7,115,600號中者);(xix)免疫調節劑,諸如醋酸格拉替美(glatiramer acetate)(亦稱為共聚體-1;COPAXONE)、MBP-8298(合成髓鞘鹼性蛋白肽)、富馬酸二甲酯、芬戈莫德(fingolimod)(亦稱為FTY720)、羅喹美克(roquinimex)(LINOMIDE)、拉喹莫德(laquinimod)(亦稱為ABR-215062及SAIK-MS)、ABT-874(人類抗-IL-12抗體;Abbott)、利妥昔單抗(rituximab)(RITUXAN)、阿侖單抗(alemtuzumab)(CAMPATH)、達克珠單抗(daclizumab)(ZENAPAX)、及那他珠單抗(natalizumab)(TYSABRI);(xx)免疫抑制劑,諸如胺甲蝶呤(methotrexate)(TREXALL
RHEUMATREX)、米托蒽醌(mitoxantrone)(NOVANTRONE)、嗎替麥考酚酯(mycophenolate mofetil)(CELLCEPT)、黴酚酸鈉(mycophenolate sodium)(MYFORTIC)、硫唑嘌呤(azathioprine)(AZASAN、IMURAN)、巰基嘌呤(mercaptopurine)(PURI-NETHOL)、環磷醯胺(NEOSAR,CYTOXAN)、苯丁酸氮芥(chlorambucil)(LEUKERAN)、克拉屈濱(cladribine)(LEUSTATIN,MYLINAX)、甲胎蛋白(alpha-fetoprotein)、依那西普(etanercept)(ENBREL)、及4-(苄氧基)-5-[(5-十一烷基-2H-吡咯-2-亞甲基)甲基]-1H,1'H-2,2'-二吡咯(亦稱為PNU-156804);(xxi)干擾素,包括干擾素β-1a(AVONEX,REBIF)及干擾素β-1b(BETASERON、BETAFERON);(xxii)左旋多巴(或其甲酯或乙酯),單獨或與DOPA脫羧酶抑制劑(例如,卡比多巴(carbidopa)(SINEMET,CARBILEV,PARCOPA)、苄絲肼(benserazide)(MADOPAR)、α-甲基多巴、單氟甲基多巴、二氟甲基多巴、溴克立辛(brocresine)、或m-羥基苄基肼)組合;(xxiii)N-甲基-D-天冬胺酸(NMDA)受體拮抗劑,諸如美金剛(memantine)(NAMENDA,AXURA,EBIXA)、金剛烷胺(amantadine)(SYMMETREL)、阿坎酸(acamprosate)(CAMPRAL)、貝生羅地(besonprodil)、克他命(ketamine)(KETALAR)、德蘆西明(delucemine)、地塞比諾(dexanabinol)、右依法克生(dexefaroxan)、右美沙芬(dextromethorphan)、去甲右美沙芬(dextrorphan)、曲索羅地(traxoprodil)、CP-283097、荷美坦(himantane)、依達他多(idantadol)、伊培沙宗(ipenoxazone)、L-701252(Merck)、蘭西明(lancicemine)、左嗎啡(levorphanol)(DROMORAN)、LY-233536及LY-235959(均Lilly)、美沙酮(methadone)(DOLOPHINE)、奈拉美生(neramexane)、培净福太(perzinfotel)、苯環己哌啶(phencyclidine)、
噻奈普汀(tianeptine)(STABLON)、地佐環平(dizocilpine)(亦稱為MK-801)、EAB-318(Wyeth)、伊菠加因(ibogaine)、老刺木鹼(voacangine)、替來他明(tiletamine)、瑞魯左樂(riluzole)(RILUTEK)、阿替加奈(aptiganel)(CERES0TAT)、加維斯替奈(gavestinel)、及瑞馬西胺(remacimide);(xxiv)單胺氧化酶(MAO)抑制劑,諸如司來吉蘭(selegiline)(EMSAM)、鹽酸司來吉蘭(塞利吉林)(L-deprenyl、ELDEPRYL、ZELAPAR)、去甲基司來吉蘭、溴法羅明(brofaromine)、苯乙肼(phenelzine)(NARDIL)、反苯環丙胺(tranylcypromine)(PARNATE)、嗎氯貝胺(moclobemide)(AURORIX,MANERIX)、貝氟沙通(befloxatone)、沙芬醯胺(safinamide)、異噁唑醯肼(isocarboxazid)(MARPLAN)、煙肼醯胺(nialamide)(NIAMID)、雷沙吉蘭(rasagiline)(AZILECT)、異煙醯異丙肼(iproniazid)(MARSILID,IPROZID,IPRONID)、CHF-3381(Chiesi Farmaceutici)、異丙氯肼(iproclozide)、托洛沙酮(toloxatone)(HUMORYL、PERENUM)、二苯美侖(bifemelane)、脫氧瓦絲素(desoxypeganine)、去氫駱駝蓬鹼(harmine)(亦稱為駱駝蓬鹼(telepathine)或巴那特林(banasterine))、二氫駱駝蓬鹼(harmaline)、利奈唑胺(linezolid)(ZYVOX,ZYVOXID)、及巴吉林(pargyline)(EUDATIN、SUPIRDYL);(xxv)蠅蕈鹼受體(特別是M1亞型)促效劑,諸如西維美林(cevimeline)、左乙拉西坦(levetiracetam)、氯貝膽鹼(bethanechol chloride)(DUVOID,URECHOLINE)、伊他美林(itameline)、毛果芸香鹼(pilocarpine)(SALAGEN)、NGX267、檳榔鹼(arecoline)、L-687306(Merck)、L-689660(Merck)、呋索碘銨(furtrethonium iodide)(FURAMON,FURANOL)、苯磺酸呋索銨(furtrethonium benzensul-fonate)、對甲苯磺酸呋索銨(furtrethonium p-toluenesulfonate)、McN-
A-343、氧化震顫素(oxotremorine)、沙可美林(sabcomeline)、AC-90222(Acadia Pharmaceuticals)、及卡巴可(carbachol)(CARBASTAT,MIOSTAT,CARBOPTIC);(xxvi)神經保護藥物,諸如伯舒替尼(bosutinib)、硫酸軟骨素酶(condoliase)、愛莫克爾(airmoclomol)、拉莫三嗪(lamotrigine)、吡侖帕萘(perampanel)、茴拉西坦(aniracetam)、迷那普明(minaprime)、2,3,4,9-四氫-1H-咔唑-3-酮肟、去氨普酶(desmoteplase)、阿那替巴(anatibant)、蝦青素(astaxanthin)、神經肽NAP(例如AL-108及AL-208;均獲自Allon Therapeutics)、神經斯妥(neurostrol)、派拉朋耐(perampenel)、異丙克蘭(ispronicline)、雙(4-β-D-葡萄哌喃糖基氧苄基)-2-β-D-葡萄哌喃糖基-2-異丁基酒石酸鹽(亦稱為達羅林素B(dactylorhin B)或DHB)、氟美巴汀(formobactin)、紮利羅登(xaliproden)(XAPRILA)、乳胞素(lactacystin)、鹽酸二美伯林(dimeboline hydrochloride)(DIMEBON)、地舒芬通(disufenton)(CEROVIVE)、阿倫酸(arundic acid)(ONO-2506,PROGLIA,CEREACT)、胞磷膽鹼(citicoline)(亦稱為胞嘧啶核苷5’-二磷酸膽鹼)、依達拉奉(edaravone)(RADICUT)、AEOL-10113及AEOL-10150(均獲自Aeolus Pharmaceuticals)、AGY-94806(亦稱為SA-450及Msc-1)、粒細胞群落刺激因子(亦稱為AX-200)、BAY-38-7271(亦稱為KN-387271;Bayer AG)、安克洛酶(ancrod)(VIPRINEX,ARWIN)、DP-b99(D-Pharm Ltd)、HF-0220(17-ß-羥基表雄酮(epiandrosterone);Newron Pharmaceuticals)、HF-0420(亦稱為寡托品(oligotropin))、5'-磷酸吡哆醛(亦稱為MC-1)、微纖維蛋白溶酶、S-18986、吡氯佐坦(piclozotan)、NP031112、他克莫司(tacrolimus)、L-絲胺醯基-L-甲硫胺醯基-L-丙胺醯基-L-離胺醯基-L-麩胺醯基-甘胺醯基-L-纈胺酸、AC-184897(Acadia Pharmaceuticals)、ADNF-14(National Institutes of
Health)、乙烯二薁基硝酮(stilbazulenyl nitrone)、SUN-N8075(Daiichi Suntory Biomedical Research)、及唑南帕奈(zonampanel);(xxvii)菸鹼受體促效劑,諸如地棘蛙素(epibatidine)、安非他酮(bupropion)、CP-601927、伐尼克蘭(varenicline)、ABT-089(Abbott)、ABT-594、AZD-0328(AstraZeneca)、EVP-6124、R3487(亦稱為MEM3454;Roche/Memory Pharmaceuticals)、R4996(亦稱為MEM63908;Roche/Memory Pharmaceuticals)、TC-4959及TC-5619(均獲自Targacept)、及RJR-2403;(xxviii)去甲腎上腺素(降腎上腺素)再吸收抑制劑,諸如阿托西汀(atomoxetine)(STRATTERA)、多塞平(doxepin)(APONAL,ADAPIN,SINEQUAN)、去甲替林(nortriptyline)(AVENTYL,PAMELOR,NORTRILEN)、阿莫沙平(amoxapine)(ASENDIN,DEMOLOX,MOXIDIL)、瑞波西汀(reboxetine)(EDRONAX,VESTRA)、維洛沙嗪(viloxazine)(VIVALAN)、麥普替林(maprotiline)(DEPRILEPT、LUDIOMIL、PSYMION)、安非他酮(bupropion)(WELLBUTRIN)、及雷達法辛(radaxafine);(xxix)磷酸二酯酶(PDE)抑制劑,包括(但不限於),(a)PDE1抑制劑(例如長春西汀(vinpocetine)(CAVINTON、CERACTIN、INTELECTOL)及揭示於美國專利第6,235,742號中者),(b)PDE2抑制劑(例如赤-9-(2-羥基-3-壬基)腺嘌呤(EHNA),BAY 60-7550,及揭示於美國專利第6,174,884號中者),(c)PDE3抑制劑(例如阿那格雷(anagrelide)、西洛他唑(cilostazol)、米立農(milrinone)、奧普力農(olprinone)、帕羅格列(parogrelil)、及匹莫苯丹(pimobendan)),(d)PDE4抑制劑(例如,阿普司特(apremilast)、異丁司特(ibudilast)、羅氟司特(roflumilast)、咯利普蘭(rolipram)、Ro 20-1724、異丁司特(ibudilast)(KETAS)、吡拉米司特(piclamilast)(亦稱為RP73401)、
CDP840、西洛司特(cilomilast)(ARIFLO)、羅氟司特(roflumilast)、替普司特(tofimilast)、格力司特(oglemilast)(亦稱為GRC 3886)、替托司特(tetomilast)(亦稱為OPC-6535)、力瑞司特(lirimifast)、茶鹼(theophylline)(UNIPHYL,THEOLAIR)、阿羅茶鹼(arofylline)(亦稱為LAS-31025)、多索茶鹼(doxofylline)、RPR-122818、或松葉菊鹼(mesembrine)),及(e)PDE5抑制劑(例如,西地那非(sildenafil)(VIAGRA、REVATIO)、他達拉非(tadalafil)(CIALIS)、伐地那非(vardenafil)(LEVITRA、VIVANZA)、烏地那非(udenafil)、阿伐那非(avanafil)、阿斯達莫(dipyridamole)(PERSANTINE)、E-4010、E-4021、E-8010、紮普司特(zaprinast)、西地那非(iodenafil)、米羅那非(mirodenafil)、DA-8159、及彼等揭示於國際專利申請案WO2002/020521、WO2005/049616、WO2006/120552、WO2006/126081、WO2006/126082、WO2006/126083、及WO2007/122466中者),(f)PDE7抑制劑;(g)PDE8抑制劑;(h)PDE9抑制劑(例如,BAY73-6691(Bayer AG)及彼等揭示於美國專利公開案第US2003/0195205號、第US2004/0220186號、第US2006/0111372號、第US2006/0106035號、及第USSN 12/118,062號(2008年5月9日申請)中者),(i)PDE10抑制劑諸如2-({4-[1-甲基-4-(吡啶-4-基)-1H-吡唑-3-基]苯氧基}甲基)喹啉(PF-2545920)、及SCH-1518291,及(j)PDE11抑制劑;(xxx)喹啉類,諸如奎寧(包括其鹽酸鹽、二鹽酸鹽、硫酸鹽、亞硫酸鹽及葡萄糖酸鹽)、氯喹、甲氯喹、羥基氯喹(PLAQUENIL)、甲氟喹(LARIAM)、及胺二喹(CAMOQUIN,FLAVOQUINE);(xxxi)β-分泌酶抑制劑,諸如ASP-1702、SCH-745966、JNJ-715754、AMG-0683、AZ-12304146、BMS-782450、GSK-188909、NB-533、LY-2886721、E-2609、HPP-854、(+)-酒石酸苯丁胺
(POSIPHEN)、LSN-2434074(亦稱為LY-2434074)、KMI-574、SCH-745966、Ac-rER(N 2-乙醯基-D-精胺醯基-L-精胺酸)、洛伐他汀(loxistatin)(亦稱為E64d)、及CA074Me;(xxxii)γ-分泌酶抑制劑及調節劑,諸如BMS-708163(Avagacest)、WO20060430064(Merck)、DSP8658(Dainippon)、ITI-009、L-685458(Merck)、ELAN-G、ELAN-Z、4-氯-N-[2-乙基-1(S)-(羥甲基)丁基]苯磺醯胺;(xxxiii)血清素(5-羥色胺)1A(5-HT1A)受體拮抗劑,諸如螺旋哌丁苯(spiperone)、左吲哚洛爾(levo-pindolol)、BMY 7378、NAD-299、S(-)-UH-301、NAN 190、來考佐坦(lecozotan);(xxxiv)血清素(5-羥色胺)2C(5-HT2c)受體促效劑,諸如戊卡色林(vabicaserin)及紮卡那平(zicronapine);(xxxv)血清素(5-羥色胺)4(5-HT4)受體促效劑,諸如PRX-03140(Epix);(xxxvi)血清素(5-羥色胺)6(5-HT6)受體促效劑,諸如A-964324、AVI-101、AVN-211、米安舍林(mianserin)(TORVOL,BOLVIDON,NORVAL)、美賽西平(methiothepin)(亦稱為甲替平(metitepine))、利坦色林(ritanserin)、ALX-1161、ALX-1175、MS-245、LY-483518(亦稱為SGS518;Lilly)、MS-245、Ro 04-6790、Ro 43-68544、Ro 63-0563、Ro 65-7199、Ro 65-7674、SB-399885、SB-214111、SB-258510、SB-271046、SB-357134、SB-699929、SB-271046、SB-742457(GlaxoSmithKline)、Lu AE58054(Lundbeck A/S)、及PRX-07034(Epix);(xxxvii)血清素(5-HT)再吸收抑制劑,諸如阿拉丙酯(alaproclate)、西酞普蘭(citalopram)(CELEXA,CIPRAMIL)、依他普侖(escitalopram)(LEXAPRO、CIPRALEX)、氯丙咪嗪(clomipramine)
(ANAFRANIL)、度洛西汀(duloxetine)(CYMBALTA)、非莫西汀(femoxetine)(MALEXIL)、苯氟拉明(fenfluramine)(PONDIMIN)、諾苯氟拉明(norfenfluramine)、氟西汀(fluoxetine)(PROZAC)、氟伏沙明(fluvoxamine)(LUVOX)、吲達品(indalpine)、米那普侖(milnacipran)(IXEL)、帕羅西汀(paroxetine)(PAXIL,SEROXAT)、舍曲林(sertraline)(ZOLOFT,LUSTRAL)、曲唑酮(trazodone)(DESYREL,MOLIPAXIN)、文拉法新(venlafaxine)(EFFEXOR)、齊美利定(zimelidine)(NORMUD,ZELMID)、比西發定(bicifadine)、去甲文拉法辛(desvenlafaxine)(PRISTIQ)、布索芬新(brasofensine)、維拉佐酮(vilazodone)、卡利拉嗪(cariprazine)、神經幹細胞及特索芬辛(tesofensine);(xxxviii)營養素,諸如神經生長因子(NGF)、鹼性纖維母細胞生長因子(bFGF;ERSOFERMIN)、神經營養素-3(NT-3)、心肌營養素-1、腦源性神經營養素(BDNF)、神經胚素、鎳紋蛋白、及膠源性神經營養素(GDNF),及刺激營養素產生之試劑,諸如丙戊茶鹼(propentofylline)、艾地苯醌(idebenone)、PYM50028(COGANE;Phytopharm)及AIT-082(NEOTROFIN);(xxxix)甘胺酸轉運蛋白-1抑制劑,諸如帕利伏汀(paliflutine)、ORG-25935、JNJ-17305600、及ORG-26041;(xl)AMPA-型穀胺酸受體調節劑,諸如吡侖帕奈(perampanel)、米巴帕他(mibampator)、瑟盧雷帕(selurampanel)、GSK-729327、及N-{(3S,4S)-4-[4-(5-氰基噻吩-2-基)苯氧基]四氫呋喃-3-基}丙烷-2-磺醯胺;等等。
本發明進一步包括適宜用於進行上文描述之治療方法的套組。在一實施例中,該套組含有充分進行本發明方法量的包括一或多個本
發明化合物之第一劑型及劑量之容器。
在另一實施例中,本發明套組包括一或多個本發明化合物。
可藉由下文描述之方法連同在有機化學技術中熟知之合成方法、或為熟習此項技術者熟知之改良及衍生來製備本發明化合物或其醫藥上可接受之鹽。本文使用之起始材料係市售或可藉由在此項技術中熟知之常規方法(諸如彼等揭示於標準參考書諸如Compendium of Organic Synthetic Methods,第I至XII卷(由Wiley-Interscience出版)之方法)製備。較佳方法包括(但不限於)下文描述之彼等。
在任何以下合成順序期間,必需及/或期望保護在任何相關分子上之敏感或反應性基團。此可藉由習知保護基方式(諸如彼等描述於T.W.Greene,Protective Groups in Organic Chemistry,John Wiley & Sons,1981;T.W.Greene與P.G.M.Wuts,Protective Groups in Organic Chemistry,John Wiley & Sons,1991;及T.W.Greene與P.G.M.Wuts,Protective Groups in Organic Chemistry,John Wiley & Sons,1999,其以引用的方式併入本文中)達成。
可根據本文下文討論之反應圖製備本發明化合物或其醫藥上可接受之鹽。除非另作說明,否則在反應圖中之取代基係如上文定義。可藉由為一般技術之化學專家熟知之標準程序達成產物分離及純化。
熟習此項技術者應瞭解,用於反應圖、方法及實例之各種符號、上標及下標係出於表示習慣及/或反映其引入此反應圖之目的使用,及並非意在在隨附申請專利範圍中必須對應該符號、上標或下標。反應圖係表示用於合成本發明化合物之方法。其並非以任何方式限制本發明之範圍。
當用於合成本發明化合物之中間產物時併入鹼性中心時,其適宜酸加成鹽可用於合成途徑。此等適宜加成鹽包括(但不限於)彼等衍
生自無機酸,諸如鹽酸、氫溴酸、氫氟酸、氫碘酸、硼酸、氟硼酸、磷酸、硝酸、碳酸、及硫酸,及有機酸諸如乙酸、苯磺酸、苯甲酸、乙磺酸、富馬酸、乳酸、馬來酸、甲磺酸、三氟甲磺酸、琥珀酸、甲苯磺酸、及三氟乙酸者。適宜之有機酸一般包括(但不限於)脂族酸、環脂族酸、芳族酸、芳脂族酸、雜環酸、羧酸、及有機酸之磺酸類別。
適宜有機酸之特定實例包括(但不限於)乙酸鹽、三氟乙酸鹽、甲酸鹽、丙酸鹽、琥珀酸鹽、乳酸鹽、馬來酸鹽、富馬酸鹽、苯甲酸鹽、對羥基苯甲酸鹽、苯基乙酸鹽、杏仁酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、己二酸鹽、丁酸鹽、樟腦酸鹽、環戊丙酸鹽、十二烷基硫酸鹽、庚酸鹽、己酸鹽、煙鹼酸鹽、2-萘磺酸鹽、草酸鹽、3-苯基丙酸鹽、特戊酸鹽、及十一烷酸鹽。
此外,若用於製備本發明化合物之中間產物具有酸部分,其適宜鹽可用於合成。此等鹽包括鹼金屬鹽(例如,鋰、鈉或鉀鹽)、鹼土金屬鹽(例如鈣或鎂鹽);及經適宜有機配位體(諸如胺或第四銨陽離子)形成之鹽。此等酸性中間產物之有機鹽可由第一、第二或第三胺諸如甲胺、二乙胺、二乙二胺或三甲胺製備。可藉由第三胺與試劑諸如低碳數烷基(C1-C6)鹵化物(例如,甲基、乙基、丙基、及丁基氯化物、溴化物、及碘化物)、二烷基硫酸鹽(例如,二甲基、二乙基、二丁基、及二戊基硫酸鹽)、芳基烷基鹵化物(例如,苄基及苯乙基溴化物)、及其他來製備第四胺。
上文反應圖1闡明用於製備式I描繪之化合物的一合成順序。在如圖描繪之合成的初始步驟中,在存在酸諸如鹽酸水溶液時加熱式1.1化合物之適當酯(其中R1通常係(C1-C6)烷基,諸如甲基、乙基、第三丁基及等等)以獲得對應式1.2之吡啶酮酸。在此初始步驟期間,式1.1之R1-X、R6及R7取代基應由在終產物中期望之相同部分或其經保護之變型表示。例如,可採用反應反應圖1製備實例1之終產物,其中R1由甲基表示,X係由咪唑基表示,且式1.1之R6及R7各由氫表示。
接著,式1.2之酸中間產物經歷與式1.3之胺基醇使用適當醯胺偶合劑諸如HATU[六氟磷酸O-(7-偶氮苯并三唑-1-基)-N,N,N',N'-四甲基銪]之醯胺偶合並原位環化反應。該反應在存在適宜鹼諸如N,N-二異丙基乙胺時且在溶劑諸如二氯甲烷中或N,N-二甲基甲醯胺中進行。在此步驟期間,式1.3之y應由如在終產物中期望之整數表示,及該A、R2a、R2b、R4a、R4b、R5a、R5b取代基應由如在終產物中期望之相同部分或其經保護之變型表示。例如,可採用反應圖1製備實例1之終產物,其中R2a、R2b、R4a、R4b、R5a及R5b各係氫,y係1,及A表示5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基。
反應圖2闡明用於製備式I化合物之另一合成順序。使用為熟習此項技術者熟知之眾多還原胺化方案之一,式2.1之氯醛與式2.2之胺的反應獲得式2.3之氯烷胺。例如,此反應可藉由使用還原劑諸如三乙醯氧基硼氫化鈉在適宜溶劑諸如甲醇中進行。在此步驟期間,式2.2之胺之y應由如在終產物中期望之整數表示。式2.1之R5a及R5b取代基及式2.2胺之A、R2a、及R2b取代基亦應由如在終產物中期望之相同部分或其經保護之變型表示。
在純化後,可分離所得式2.3之氯烷胺並作為其鹽酸鹽儲存。可隨後藉由在溶劑諸如二氯甲烷中用適宜醯胺偶合劑(諸如BOP-Cl[雙(2-氧-3-噁唑烷基)膦醯氯]、T3P[2,4,6-三丙基-1,3,5,2,4,6-三氧三磷雜環己烷2,4,6-三氧化物]或HATU(較佳HATU))處理式2.3之氯烷胺、式1.2之酸(反應圖1)、及鹼諸如N,N-二異丙基乙胺之混合物來製備式I之最終化合物。在此步驟期間,式1.2之R1-X、R6及R7取代基應由如在終產物中期望之相同部分或其經保護之變型表示。
反應圖3表示熟習此項技術者可容易設想及開發之用於製備式1.3胺基醇之若干合成順序。例如,式1.3之胺基醇可藉由使用為熟習此項技術者熟知之眾多程序之一進行式3.1之酮與式2.2之胺之還原胺化反應來製備。
另一方法包括式3.2之醛與式2.2之胺之還原胺化反應,接著藉由使用適宜程序(包括經甲醇氯化氫或氟化四丁銨處理)移除第三丁基(二甲基)甲矽烷基(TBS)保護基。
用於合成式1.3之胺基醇之另一方法包括式3.3之胺與式3.4之鹵化物或甲磺酸鹽之烷基化。
又一方法包括式2.2之胺與式3.5之溴醇之烷基化。合成各種式2.2之胺之方法以及製備式1.3胺基醇之替代方法係在實例部分中例示。
採用此等揭示內容結合在此項技術中普遍熟知的技術,熟習此項技術者可進一步概括彼等合成以容許獲得各種式2.2之胺及式1.3之胺基醇,包括(但不限於)變型(其中y由在終產物中期望之整數表示,及A、R2a、R2b、R4a、R4b、R5a、及R5b取代基由如在終產物中期望之相同部分或其經保護之變型表示)。
反應圖4闡明用於製備式1.1化合物(其中R1-X=4-甲基咪唑-1-基或3-甲基三唑-1-基)之一合成順序。使用N-溴代琥珀醯亞胺(NBS)在溶劑諸如DMSO與水之混合物中溴化式4.1之3-胺基吡啶化合物。在此初始步驟期間,R6及R7取代基由如在終產物中期望之相同部分或其經保護之變型表示。隨後使用甲醇鈉在適宜溶劑諸如1,4-二噁烷中加熱所得式4.2之中間產物以獲得式4.3之甲氧基化合物。隨後使用乙酸酐與甲酸之混合物處理式4.3之中間產物以獲得式4.4之甲醯胺,其在存在碘化鉀及鹼諸如碳酸銫時在適宜溶劑諸如N,N-二甲基甲醯胺中經氯丙酮烷基化。隨後在存在NH4OAc下於乙酸中加熱所得式4.5之中間產物以提供式4.6之咪唑衍生物。最終,可藉由使式4.6之中間產物經羰基化/酯化反應製備式1.1之化合物。可藉由加熱式4.6之溴化物與鹼諸如三乙胺在適當醇溶劑(「ROH」)(其中R通常係(C1-C6)烷基諸如甲基或乙基)中之溶液在CO氛圍下在存在適宜鈀觸媒諸如Pd(dppf)Cl2二氯甲烷{[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀(II),二氯甲烷錯合物}時進行此轉化以獲得式1.1之酯。
A)鈴木(Suzuki)偶合:R1X-B(OH)2,「Pd」,鹼
B)CH-活化:「Pd」,5-員雜芳基,諸如
提供式1.1化合物,其中R1-X-係
C)Chan-Lam偶合:Cu2O或Cu(OAc)2,5-員雜芳基諸如
提供式1.1化合物其中R1-X-係
D)鈴木偶合:R1X-Br,「Pd」,鹼
其中X=5-至6-員雜芳基環
反應圖5描繪用於製備式1.1之化合物之替代合成順序。在第一步驟中,使用氧化劑諸如mCPBA[3-氯過氧苯甲酸]在適宜溶劑諸如二氯乙烷中氧化式5.1之吡啶基衍生物以獲得對應式5.2之N-氧化物。在此
初始步驟期間,式5.1之R6及R7取代基由如在終產物中期望之相同部分或其經保護之變型表示。隨後在存在TMSCN[三甲基甲矽烷基氰化物]及鹼諸如三乙胺時在溶劑諸如乙腈中加熱式5.2之N-氧化物以獲得式5.3之腈中間產物。可隨後由式5.3在兩步驟中藉由使式5.3經甲醇鈉在溶劑諸如THF中,接著經適當醇溶劑(「ROH」)(其中R通常係(C1-C6)烷基諸如甲基、乙基及等等)及酸諸如鹽酸處理,製備對應酯。式5.5之酯係容許引入各種雜環R1-X之多種中間產物。例如,式5.5可使用熟習此項技術者熟知之方法[參見Tetrahedron 2002,58,9633-9695]經與雜芳基硼酸之鈴木偶合。或者,可使用直接芳基化途徑[參見D.Lapointe等人,J.Org.Chem. 2011,76,749-759,及其中參考]將式5.5化合物偶合至雜環X。例如,可藉由在存在適宜鈀觸媒諸如氯化烯丙基鈀二聚體及鹼諸如碳酸鉀時在溶劑諸如1,4-二噁烷中加熱將式5.5化合物偶合至2-甲基-1,3-噁唑[式5.7,其中R1=Me]以獲得式1.1之中間產物,其中R1-X=2-甲基-1,3-噁唑-5-基。
或者,可使用與二硼試劑諸如5,5,5',5'-四甲基-2,2'-二-1,3,2-二氧雜硼烷在存在乙酸鉀與鈀觸媒諸如Pd(dppf)Cl2˙二氯甲烷時在溶劑諸如1,4-二噁烷中鈀催化交叉偶合,將式5.5化合物轉化為對應式5.6之硼酸鹽。所得式5.6之硼酸鹽中間產物可繼而經與雜芳基鹵化物之鈴木偶合以獲得式1.1之終產物。用於引入雜環X之另一方法包括使用Chan-Lam偶合[參見Tetrahedron Lett. 2003,44,3863-3865及Synthesis 2008,5,795-799]。例如,可藉由與適宜銅源諸如氧化銅(I)或乙酸銅(II)在溶劑諸如甲醇中在存在空氣時加熱,將式5.6之硼酸鹽偶合至式5.8之經取代咪唑或至式5.9之經取代三唑以獲得式1.1之中間產物,其中X=咪唑-1-基或三唑-1-基。
A)鈴木偶合:R1X-B(OH)2,「Pd」,鹼
B)CH-活化:「Pd」,5-員雜芳基諸如
提供式I化合物,其中R1-X-係
C)Chan-Lam偶合:Cu2O或Cu(OAc)2,5-員雜芳基諸如
提供式I化合物其中R1-X-係
D)鈴木偶合:R1X-Br,「Pd」,鹼
其中X=5-至6-員雜芳環
E)「Pd」,及雜芳基諸如或
提供式I化合物,其中R1-X-係或
反應圖6闡明用於製備式I化合物之另一組合成順序。在酸諸如鹽酸中加熱式6.1之中間產物獲得式6.2之吡啶酮酸中間產物。在此初始
步驟期間,式6.1之R6及R7取代基由如在終產物中期望之相同部分或其經保護之變型表示。接著,式6.2之酸可經使用在反應圖1中描述之化學與式1.3之胺基醇(反應圖1)偶合/環化反應以獲得式6.3之中間產物。在此步驟期間,式1.3之y應由在終產物中期望之整數表示,及R2a、R2b、R4a、R4b、R5a,、R5b、R10及R11取代基應由在終產物中期望之相同部分或其經保護之變型表示。
式6.3中間產物之替代合成包括在溶劑諸如N,N-二甲基甲醯胺中加熱式6.2之中間產物、二溴乙烷、及鹼諸如碳酸銫之混合物以獲得式6.4之內酯。在此初始步驟期間,式6.1之R6及R7取代基由在終產物中期望之相同部分或其經保護之變型表示。所得式6.3之中間產物可隨後經與式2.2之胺(反應圖2)的醯胺化反應。可使用若干不同條件進行此轉化。例如,可在存在鹼諸如1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(TBD)時在溶劑諸如N,N-二甲基甲醯胺中加熱式6.2之內酯與式2.2之胺,接著添加三氟乙酸乙酯以獲得式6.3之內醯胺,其中R4a=R4b=R5a=R5b=H。在醯胺化步驟期間,式2.2之y應由在終產物中期望之整數表示。
可隨後使用在反應圖5中討論之策略直接由式6.3或經由式6.5之硼酸鹽形成最終化合物式I。或者,其中雜環X係經由C-N鍵連接至吡啶酮環之式I化合物可藉由鈀催化交叉偶合形成。例如,可藉由在存在鈀觸媒諸如參(二苄叉丙酮)二鈀(0)及適宜配位體諸如二-第三丁基[3,4,5,6-四甲基-2',4',6'-三(丙-2-基)聯苯-2-基]磷烷及鹼諸如磷酸鉀時在溶劑諸如甲苯中加熱以將式6.6之三唑偶合至式6.3,獲得式I之最終化合物,其中X=1,2,4-三唑-1-基。
反應圖7闡明用於製備式I化合物之另一合成順序,其中R4a=R4b=R5a=R5b=H。該方法包括在溶劑諸如N,N-二甲基甲醯胺中加熱式1.2化合物(反應圖1)、二溴乙烷、及鹼諸如碳酸銫之混合物以獲得式7.1之內酯中間產物。在此初始步驟期間,該式1.2之R1-X、R6及R7取代基由在終產物中期望之相同部分或其經保護之變型表示。式7.1之內酯可隨後在存在試劑諸如DIBAL(氫化二異丁銨)或雙(三甲基鋁)-1,4-二氮雜雙環[2.2.2]辛烷加合物時在溶劑諸如THF中與式2.2之胺反應(獲自反應圖2)以獲得式7.2之醯胺醇。在此步驟期間,式2.2之y應由在終產物中期望之整數表示,及R2a、R2b、R10及R11取代基應由在終產物中期望之相同部分或其經保護之變型表示。式7.2之中間產物可在存在鹼諸如三乙胺時在溶劑諸如THF中與甲磺醯氯反應,接著經鹼諸如1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(TBD)處理以獲得式I化合物(其中R4a=R4b=R5a=R5b=H)。或者,該閉環可以逐步方式進行:首先藉由經亞硫醯氯處理將式7.2之醇轉化為對應氯化物,接著使用適宜鹼諸如雙(三甲基甲矽烷基)醯胺鋰使醯胺NH去質子化以獲得式I
最終化合物。或者,內醯胺7.1與胺2.2在N,N-二甲基甲醯胺中之溶液可經1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(TBD)在N,N-二甲基甲醯胺中處理以形成中間產物7.2,其可隨後在相同罐中經由添加三氟乙酸乙酯直接轉化為式I。
可在一步驟中由對應式I化合物(其中X係咪唑基及R1係甲基)製備式I化合物(其中X係咪唑基及R1係羥甲基)。可經由經獲自適宜物種諸如猴子之微粒體在存在氯化鎂與煙鹼醯胺腺嘌呤二核苷酸磷酸酯(NADPH)時在適宜緩衝液諸如磷酸鉀(pH 7.4)中培育,進行此轉化。
可設想若干獲得式2.2中間產物(其中R2a=R2b=H,R10=甲基,y=1,R10連接至鄰近苯并呋喃氧原子之第四碳原子,及胺甲基取代基連接至苄基位置)之途徑。一途徑從使用適宜鹵化劑諸如N-溴代琥珀醯亞胺(NBS)或N-碘代琥珀醯亞胺(NIS)溴化或碘化式9.1苯酚開始。在此步驟期間,R11取代基應由在終產物中期望之相同部分或其經保護之變型表示。所得式9.2之苯酚中間產物隨後與苄基氯甲醚在存在適宜鹼諸如碳酸鉀時且在溶劑諸如乙腈中反應以獲得式9.3之中間產物。此化合物隨後經使用銅源諸如碘化銅(I)及鈀觸媒諸如二氯雙(三苯基膦)鈀(II)在三乙胺中與三甲基(丙-2-炔-1-基)矽烷之索諾格席拉(Sonogashira)偶合。隨後使用氟化物源諸如四-N-氟化丁銨(TBAF)在溶劑諸如四氫呋喃中移除三甲基甲矽烷基保護基以獲得式9.5之中間產物。隨後在存在鉑觸媒諸如二-μ-氯-二氯雙(伸乙基)二鉑(III)時在溶劑諸如甲苯中加熱此化合物以獲得苯并呋喃中間產物9.6。隨後經由氫解使用碳載氫氧化鈀在環己烯中移除苄基保護基。苯并呋喃2,3-雙鍵之環丙基化可在許多條件(諸如西蒙斯史密斯(Simmons-Smith)反應)下進行。例如,在適宜溶劑諸如二氯甲烷中經二乙基鋅及二碘甲烷處理式9.7之中間產物以獲得式9.8之環丙基苯并呋喃醇中間產物。可隨後使用為熟習此項技術者熟知之若干程序,將式9.8中間產物中之第一醇轉化為對應第一胺。例如,此官能團互相轉化可經由與鄰苯二甲
醯亞胺之光延(Mitsunobu)反應,接著使用試劑諸如單水合肼在溶劑諸如二氯甲烷及甲醇中脫除保護基達成以獲得期望式2.2之胺。
反應圖10顯示式2.2中間產物(其中R2a=R2b=H,y=1,R10連接至鄰近苯并呋喃氧原子之第四碳原子,及該胺甲基取代基連接至苄基位置)之替代合成途徑。在此途徑中,式9.2之苯酚在存在鹼諸如碳酸鉀時在溶劑諸如乙腈中經1,4-加成為式10.1之炔衍生物。在此步驟期間,R10及R11取代基應由在終產物期望之相同部分或其經保護之變型表示。所得式10.2化合物隨後使用適宜鈀觸媒諸如雙(三-第三丁基膦)鈀(0)在存在鹼諸如三乙胺時在溶劑諸如乙腈中經分子內赫克(Heck)反應。隨後使用碘化三甲基氧化鋶在二甲基亞碸中在存在鹼諸如第三丁醇鉀時環丙基化所得式10.3之苯并呋喃中間產物。立即使用適宜鹼諸如氫氧化鉀或第三丁醇鉀將該酯水解為式10.4之對應酸。在該順序中最終步驟包括將式10.4之羧酸轉化為式2.2之胺。此官能團相互轉化可在若干為熟習此項技術者熟知之不同條件下進行。例如,酸10.4與氫氧化銨之醯胺偶合及偶合劑諸如1,1'-羰基二咪唑遞送式10.5之第一醯
胺,其隨後使用適宜還原劑諸如雙(2-甲氧基乙氧基)氫化鋁在溶劑諸如甲苯中將其還原。
下文闡明各種本發明化合物之合成。可單獨或與在此項技術中一般已知之技術組合使用在此等實例中闡明之方法來製備在本發明範圍內之其他化合物。
實驗一般在惰性氛圍(氮氣或氬氣)下進行,特別當其中採用對氧氣-或水分-敏感之試劑或中間產物時。一般使用市售溶劑及試劑且未經進一步純化。若適當可採用無水溶劑,一般為來自Acros Organics之AcroSeal®產品或來自EMD Chemicals之DriSolv®產品。在其他情形下,市售溶劑經過具有4Å分子篩之管柱,直至達成以下針對水之QC標準:a)對於二氯甲烷、甲苯、N,N-二甲基甲醯胺及四氫呋喃而言<100ppm;b)對於甲醇、乙醇、1,4-二噁烷及二異丙胺而言<180ppm。對於非常敏感的反應,溶劑進一步經金屬鈉、氫化鈣或分子篩處理,並在即將使用前才蒸餾。在進行進一步反應或提交用於生物測試前,一般在真空下乾燥產物。由液相層析-質譜法(LCMS)、大氣壓化學電離法(APCI)或氣相層析-質譜法(GCMS)儀表記錄質譜資料。核磁共振(NMR)化學位移資料係以參考所採用之氘化溶劑之殘峰的百萬分率(ppm,δ)表示。在一些實例中,進行對掌分離法,以分離某些本發明化合物之對映體(在一些實例中,根據其洗脫順序將分離之對映體命名為ENT-1及ENT-2)。在一些實例中,使用偏光計測量對映體之旋光度。根據其觀察到之旋光度數據(或其比旋光度數據),將順時針方向旋轉之對映體命名為(+)-對映體及逆時針方向旋轉之對映體命名為(-)-對映體。藉由鄰近該結構出現之(+/-)來表示消旋化合物;在此等情形下,所指示之立體化學表示該化合物取代基之相對(而非絕對)組態。
一般藉由LCMS來追蹤該經由可檢測中間產物進行之反應,並讓其進行至完全轉化後才添加下一種試劑。在其他實例或方法中之合成參考程序中,反應條件(反應時間及溫度)可變化。一般而言,藉由薄層層析法或質譜法追蹤反應,並在適當時進行處理。純化法可能隨實驗之間而變化:一般而言,選擇用於洗脫劑/梯度之溶劑及溶劑比以提供適當Rfs或滯留時間。
7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(1)
(實例1之化合物先前於2014年4月1日申請之美國臨時專利申請案第61/973,436號中作為實例19揭示。雖然此化合物並不包括於本申請案之申請專利範圍內,但本文例示以提供額外合成方法論)。
步驟1:合成4-{[2-碘-4-(三氟甲基)苯氧基]甲基}-2,2-二甲基-1,3-二氧雜環戊烷(C1)。
以逐滴方式將偶氮二甲酸二異丙酯(8.2mL,42mmol)緩慢添加
至含(2,2-二甲基-1,3-二氧雜環戊-4-基)甲醇(5.5g,42mmol)及三苯基膦(10.9g,42mmol)之四氫呋喃(80mL)0℃溶液中。將2-碘-4-(三氟甲基)苯酚(8.0g,28mmol)緩慢添加至0℃反應混合物中,其隨後容許於室溫攪拌6小時。在真空中移除溶劑後,將該殘留物分配在水與乙酸乙酯間,並用水洗滌該有機層,經硫酸鈉乾燥,過濾並在減壓下濃縮。矽膠層析(洗脫劑:10%乙酸乙酯於己烷中)獲得呈淺黃色液體之產物。產率:6.5g,16mmol,57%。1H NMR(400MHz,CDCl3)δ 8.02(br s,1H),7.58(br d,J=8.6Hz,1H),6.88(d,J=8.6Hz,1H),4.48-4.56(m,1H),4.23(dd,J=8.4,6.2Hz,1H),4.18(dd,ABX圖案的一半,J=9.5,4.2Hz,1H),4.04-4.11(m,2H),1.49(s,3H),1.42(s,3H)。
步驟2. 合成3-[2-碘-4-(三氟甲基)苯氧基]丙烷-1,2-二醇(C2)。
於室溫攪拌含C1(6.5g,16mmol)之乙酸(3.2mL,56mmol)及水(0.29mL,16mmol)溶液18小時,屆時在減壓下將其濃縮。使用戊烷洗滌該殘留物,及所得固體不經進一步純化即可用於下一步驟。產率:5.25g,14.5mmol,91%。GCMS m/z 362[M+]。1H NMR(400MHz,CDCl3)δ 8.01-8.04(m,1H),7.60(br d,J=8.6Hz,1H),6.89(d,J=8.6Hz,1H),4.13-4.23(m,3H),3.83-3.97(m,2H),2.71(d,J=4.5Hz,1H),2.05(dd,J=6.2,6.0Hz,1H)。
步驟3. 合成1-{[第三丁基(二甲基)甲矽烷基]氧基}-3-[2-碘-4-(三氟甲基)苯氧基]丙-2-醇(C3)。
在含C2(5.25g,14.5mmol)之N,N-二甲基甲醯胺(50mL)溶液中添加咪唑(1.1g,16mmol),接著緩慢添加第三丁基(二甲基)氯化甲矽烷(2.4g,16mmol)。在於室溫6小時後,使用冰水稀釋該反應混合物並隨後經乙酸乙酯萃取。已合併之有機層經硫酸鈉乾燥,過濾並在真空中濃縮。矽膠層析(洗脫劑:5%乙酸乙酯於己烷中)獲得呈淺黃色液體之產物。產率:4.12g,8.65mmol,60%。NMR(400MHz,CDCl3)
δ 8.01-8.03(m,1H),7.58(br d,J=8.6Hz,1H),6.88(d,J=8.6Hz,1H),4.05-4.17(m,3H),3.84-3.92(m,2H),2.58(d,J=5.8Hz,1H),0.91(s,9H),0.10(s,3H),0.09(s,3H)。
步驟4:合成1-{[第三丁基(二甲基)甲矽烷基]氧基}-3-[2-碘-4-(三氟甲基)苯氧基]丙-2-酮(C4)。
將戴斯-馬丁(Dess-Martin)高碘烷[1,1,1-參(乙醯氧)-1,1-二氫-1,2-苯并碘氧雜環戊-3-(1H)-酮;11.0g,25.9mmol]添加至含C3(4.12g,8.65mmol)之二氯甲烷(40mL)0℃溶液中,及攪拌該反應混合物14小時。通過經矽藻土墊過濾移除過量氧化劑;使用水稀釋該濾液並經二氯甲烷萃取。在真空中濃縮已合併之有機層,該粗產物不經額外純化即可用於一下步驟。產率:3.7g,7.8mmol,90%。1H NMR(400MHz,CDCl3)δ 8.05-8.07(m,1H),7.57(br d,J=8.6Hz,1H),6.70(d,J=8.6Hz,1H),4.94(s,2H),4.59(s,2H),0.96(s,9H),0.15(s,6H)。
步驟5. 合成3-({[第三丁基(二甲基)甲矽烷基]氧基}甲基)-5-(三氟甲基)-2,3-二氫-1-苯并呋喃-3-醇(C5)。
將甲基鋰(1.6M溶液於乙醚中,9.2mL,15mmol)緩慢添加至含C4(3.5g,7.4mmol)之四氫呋喃(30mL)-78℃溶液中,並於此溫度攪拌該反應混合物5小時。隨後緩慢添加氯化銨水溶液,並使用乙酸乙酯萃取所得混合物。已合併之有機層經硫酸鈉乾燥、過濾、並在真空中濃縮以獲得可直接用於下一步驟之粗產物(2.1g)。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.62-7.65(m,1H),7.51-7.55(m,1H),6.91(d,J=8.6Hz,1H),4.49(s,2H),3.84(AB四重峰,J AB=9.8Hz,△υAB=11.3Hz,2H),0.94(s,9H),0.12(s,3H),0.10(s,3H)。
步驟6. 合成[5-(三氟甲基)-1-苯并呋喃-3-基]甲醇(C6)。
將對甲苯磺酸(10%,11mL)水溶液緩慢添加至含C5(獲自先前步驟;2.1g,6.0mmol)之丙酮(20mL)溶液中,及容許將該反應混合
物於室溫攪拌14小時。經由在真空中濃縮移除丙酮,及使用乙酸乙酯萃取該含水殘留物。已合併之有機層經硫酸鈉乾燥,過濾,及在減壓下濃縮;矽膠層析(洗脫劑:5%乙酸乙酯於己烷中)獲得呈淺黃色液體之產物(435mg)。亦分離出者係C6之經第三丁基(二甲基)甲矽烷基保護之衍生物,此以相似方式經歷對甲苯磺酸,獲得額外150mg產物。總產率:在兩步驟中585mg,2.71mmol,37%。1H NMR(400MHz,CDCl3)δ 8.00(br s,1H),7.73(br s,1H),7.56-7.63(m,2H),4.90(br d,J=5.3Hz,2H),1.68(t,J=5.6Hz,1H)。
步驟7. 合成[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲醇(C7)。
在含C6(100mg,0.46mmol)之二氯甲烷(10mL)0℃溶液中添加二碘甲烷(744mg,2.78mmol),接著於相同溫度緩慢添加二乙基鋅(1M溶液於己烷中,1.39mL,1.39mmol)。容許將該反應混合物緩慢加熱至室溫,屆時將其攪拌3小時。隨後經由添加飽和硫代硫酸鈉溶液將其淬冷,並經二氯甲烷萃取;已合併之有機層經飽和氯化鈉水溶液洗滌,經硫酸鈉乾燥,過濾,並在真空中濃縮。矽膠層析(梯度:0%至30%乙酸乙酯於己烷中)獲得呈黃色油之產物。產率:50mg,0.22mmol,48%。GCMS m/z 230[M+]。1H NMR(400MHz,DMSO-d 6 )δ 7.75-7.78(m,1H),7.47(br d,J=8.3Hz,1H),7.00(d,J=8.8Hz,1H),4.98(dd,J=5.9,5.4Hz,1H),4.93(dd,J=5.5,1.8Hz,1H),3.93(dd,ABX圖案的一半,J=11.8,5.9Hz,1H),3.73(dd,ABX圖案的一半,J=11.9,5.3Hz,1H),1.26(dd,J=6.2,5.8Hz,1H),0.40(dd,J=6.5,1.8Hz,1H)。
步驟8. 合成[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲磺酸甲酯(C8)。
將三乙胺(0.27mL,1.9mmol)及甲磺醯氯(61μL,0.79mmol)添
加至含C7(150mg,0.65mmol)之二氯甲烷(10mL)0℃溶液中,並容許將該反應混合物緩慢加熱至室溫。在將其攪拌6小時後,經由添加飽和碳酸鈉氫水溶液淬冷該反應混合物,並經二氯甲烷萃取。使用飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮以獲得產物(120mg)。此物質直接用於下一步驟。
步驟9. 合成1-[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲胺(C9)。
在含C8(獲自先前步驟;120mg,0.39mmol)之甲醇(1mL)0℃溶液中添加甲醇氨(5mL)並於70℃在密閉管中加熱該反應混合物16小時。隨後將其蒸發至乾燥;該殘留物與水混合並經乙酸乙酯萃取。使用飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。在矽膠上層析(洗脫劑:10%甲醇於二氯甲烷中)獲得呈淺黃色膠之產物。產率:在兩步驟50mg,0.22mmol,34%。
步驟10. 合成1-(2-羥乙基)-5-(4-甲基-1H-咪唑-1-基)-6-氧-N-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-1,6-二氫吡啶-2-甲醯胺(C11)。
在含C9(115mg,0.502mmol)之四氫呋喃(1L)溶液中添加雙(三甲基銨)-1,4-二氮雜二環[2.2.2]辛烷加合物(270mg,1.05mmol)。將該反應混合物加熱至40℃持續45分鐘,屆時將其使用7-(4-甲基-1H-咪唑-1-基)-3,4-二氫吡啶并[2,1-c][1,4]噁-1,6-二酮(C10,其可經由C.W.amEnde等人,PCT Int.Appl.,WO 2012131539,2012年10月4日之方法製備)(120mg,0.49mmol)並加熱至65℃持續5小時。經由添加1M氫氧化鈉水溶液淬冷該反應,及所得漿液經水稀釋並經5%甲醇於二氯甲烷中萃取;使用飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。經含10%乙酸乙酯之己烷研磨獲得不經額外純化即可用於下一步驟之呈灰白色固體之產物(100mg)。
LCMS m/z 475.0[M+H]+。
步驟11. 合成1-(2-氯代乙基)-5-(4-甲基-1H-咪唑-1-基)-6-氧-N-{[5--(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-1,6-二氫吡啶-2-甲醯胺(C12)。
在含C11(獲自先前步驟;100mg,0.21mmol)之二氯甲烷(10mL)-10℃溶液中添加三乙胺(90μL,0.65mmol),接著逐滴添加甲磺醯氯(70mg,0.61mmol)。隨後容許將該反應混合物加熱至室溫並攪拌2小時,屆時將其使用二氯甲烷稀釋,經碳酸氫鈉水溶液及飽和氯化鈉水溶液洗滌,經硫酸鈉乾燥,過濾,並在真空中蒸發。獲得不經額外純化即可用於下一步驟之呈黏性棕色固體之產物(100mg)。
步驟12. 合成7-(4-甲基-1H-咪唑-1-基)-2-{[5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(1)。
在含C12(獲自先前步驟;100mg,0.20mmol)之四氫呋喃(10mL)溶液中添加1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(99mg,0.71mmol)及容許於室溫攪拌該反應混合物16小時。添加冰水,及在減壓下將該混合物蒸發至乾燥;該殘留物經水稀釋並使用乙酸乙酯萃取。已合併之有機層經飽和氯化鈉水溶液洗滌,經硫酸鈉乾燥,過濾,並在真空中濃縮。反相HPLC(管柱:YMC-Actus Triart C18,5μm;流動相A:20mM碳酸氫銨於水中;流動相B:乙腈;梯度:10%至55% B)獲得呈灰白色固體之產物。產率:在三步內18mg,39μmol,8%。LCMS m/z 457.0[M+H]+。1H NMR(400MHz,CDCl3)δ 8.20(s,1H),7.62-7.65(m,1H),7.43(d,J=7.6Hz,1H),7.40-7.45(m,1H),7.24-7.3(m,1H,假設;部分由溶劑峰掩蓋),7.09-7.13(m,1H),6.91(d,J=8.6Hz,1H),4.90-4.94(m,1H),4.86(d,J=14.7Hz,1H),4.26-4.35(m,1H),4.11-4.20(m,1H),3.54-3.64(m,2H),3.43(d,J=14.8Hz,
1H),2.28(s,3H),1.25(dd,J=6.7,5.8Hz,1H),0.62(dd,J=7,2Hz,1H)。
7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(2)及7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(3)
步驟1. 合成2-碘-4-(三氟甲氧基)苯酚(C13)。
將4-(三氟甲氧基)苯酚(4.0mL,31mmol)添加至含N-碘代琥珀醯亞胺(95%,6.95g,29.3mmol)之乙酸(2.0mL,35mmol)懸浮液中,
並將該混合物攪拌5分鐘。引入硫酸(98%,0.5mL,9mmol),並於室溫持續攪拌48小時,屆時將該反應混合物倒入水(100mL)中並使用乙醚萃取。已合併之有機層經水洗滌,使用1M硫代硫酸鈉水溶液洗滌兩次,經脫色碳處理,並經硫酸鎂乾燥。在通過矽藻土墊及矽膠過濾該混合物後,在真空中濃縮該濾液以獲得呈油之產物(13.2g)。藉由1H NMR分析,此產物含有大量乙酸乙酯。校正乙酸乙酯之產量:8.5g,28mmol,96%。1H NMR(400MHz,CDCl3)δ 7.54(br d,J=2.6Hz,1H),7.15(br dd,J=8.9,2.6Hz,1H),6.99(d,J=8.9Hz,1H)。
步驟2. 合成1-[(苄氧基)甲氧基]-2-碘-4-(三氟甲氧基)苯(C14)。
使用碳酸鉀(8.46g,61.2mmol),接著苄基氯甲醚(6.38mL,45.9mmol)處理含C13(9.30g,30.6mmol)之乙腈(100mL)溶液。容許於室溫攪拌該反應混合物過夜,屆時將其分配在水與乙醚間。已合併之有機層經水洗滌,經硫酸鎂乾燥,過濾,並在真空中濃縮;經由矽膠層析法(梯度:0%至5%乙酸乙酯於庚烷中)純化獲得呈油之產物。產率:10.8g,25.5mmol,83%。1H NMR(400MHz,CDCl3)δ 7.67(br d,J=2.2Hz,1H),7.30-7.40(m,5H),7.19(br dd,ABX圖案的一半,J=9,2Hz,1H),7.14(d,AB四重峰的一半,J=9.0Hz,1H),5.35(s,2H),4.76(s,2H)。
步驟3. 合成(3-{2-[(苄氧基)甲氧基]-5-(三氟甲氧基)苯基}丙-2-炔-1-基)(三甲基)矽烷(C15)。
攪拌含C14(2.80g,6.60mmol)、碘化銅(I)(254mg,1.33mmol)及二氯雙(三苯基膦)鈀(II)(99%,468mg,0.660mmol)之三乙胺(20mL)之混合物5分鐘,屆時添加三甲基(丙-2-炔-1-基)矽烷(80%,1.85mL,9.9mmol)並將該反應混合物加熱至50℃。在5小時後,將其冷卻至室溫並分配在乙醚與飽和氯化銨水溶液間。使用1M鹽酸水溶液洗滌有機層,經硫酸鎂乾燥,過濾,並在真空中濃縮。獲得不經額外純
化即可使用之呈稠油之產物。產率:2.69g,6.58mmol,定量。GCMS m/z 408.2[M+]。
步驟4. 合成1-[(苄氧基)甲氧基]-2-(丙-1-炔-1-基)-4-(三氟甲氧基)苯(C16)。
將氟化四丁銨(1M溶液於四氫呋喃中;10mL,10mmol)添加至含C15(2.60g,6.36mmol)之四氫呋喃(25mL)溶液中及於室溫攪拌該反應混合物。在2小時後,將其分配在水與乙醚間;使用水洗滌有機層,經硫酸鎂乾燥,過濾,並在減壓下濃縮。矽膠層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得呈油之產物。產率:1.99g,5.92mmol,93%。1H NMR(400MHz,CDCl3)δ 7.29-7.40(m,5H),7.24-7.27(m,1H,假設;部分由溶劑峰掩蓋),7.17(d,AB四重峰的一半,J=9.0Hz,1H),7.08(br d,AB四重峰的一半,J=9Hz,1H),5.36(s,2H),4.78(s,2H),2.12(s,3H)。
步驟5. 合成3-[(苄氧基)甲基]-2-甲基-5-(三氟甲氧基)-1-苯并呋喃(C17)。
化合物C16(1.99g,5.92mmol)及二-mu-氯-二氯雙(伸乙基)二鉑(II)(蔡斯(Zeise’s)二聚體,190mg,0.32mmol)在甲苯(20mL)中合併並加熱至35℃持續3小時。在將該反應混合物冷卻至室溫後,矽膠層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得固體產物。產率:1.50g,4.46mmol,75%。1H NMR(400MHz,CDCl3)δ 7.29-7.42(m,7H),7.09(br d,J=8.8Hz,1H),4.61(s,2H),4.57(s,2H),2.44(s,3H)。
步驟6. 合成[2-甲基-5-(三氟甲氧基)-1-苯并呋喃-3-基]甲醇(C18)。
含C17(1.80g,5.35mmol)之乙醇(25mL)溶液經碳載氫氧化鈀(20%,1.0g)處理。添加環己烯(6mL,60mmol),及於回流加熱該反應混合物5小時,屆時將其冷卻並使用額外碳載氫氧化鈀(1.0g)及環
己烯(6mL,60mmol)處理。在於回流加熱過夜後,使用矽藻土過濾該反應混合物,並在真空中濃縮該濾液。矽膠層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得呈白色固體之產物。產率:787mg,3.20mmol,60%。GCMS m/z 246.1[M+]。1H NMR(400MHz,CDCl3)δ 7.47(br s,1H),7.38(d,J=8.8Hz,1H),7.10(br d,J=8.8Hz,1H),4.77(s,2H),2.48(s,3H)。
步驟7. 合成[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲醇(C19)。
在冰浴中冷卻二乙基鋅(1.0M溶液於己烷中;10.4mL,10.4mmol),使用二氯甲烷(10mL)稀釋,並經含二碘甲烷(1.67mL,20.7mmol)之二氯甲烷(2mL)處理。5分鐘後,添加含C18(510mg,2.07mmol)之二氯甲烷(10mL)溶液,並於0℃攪拌5分鐘。隨後容許將該反應混合物加熱至室溫並攪拌4小時,屆時將其使用飽和氯化銨水溶液淬冷。使用乙醚萃取該混合物,且已合併之有機層經硫酸鎂乾燥,過濾,在真空中濃縮,並經由矽膠層析(梯度:5%至30%乙酸乙酯於庚烷中)純化。獲得呈固體之產物。產率:500mg,1.9mmol,92%。GCMS m/z 260.1[M+]。1H NMR(400MHz,CDCl3)δ 7.26-7.30(m,1H,假設;大部分由溶劑峰掩蓋),6.98(br d,J=8.8Hz,1H),6.79(d,J=8.7Hz,1H),4.14(d,J=12.1Hz,1H),3.87(d,J=12.0Hz,1H),1.76(s,3H),1.07(d,J=6.2Hz,1H),0.62(d,J=6.2Hz,1H)。
步驟8. 合成2-{[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-1H-異吲哚-1,3(2H)-二酮(C20)。
將1H-異吲哚-1,3(2H)-二酮(1.64g,11.1mmol)及三苯基膦(2.89g,11.0mmol)添加至含C19(2.40g,9.22mmol)之四氫呋喃(50mL)溶液中。逐滴添加偶氮二甲酸二異丙酯(95%,2.07mL,10.2mmol),並容許於室溫攪拌該反應混合物2小時。隨後將其分配在乙醚與飽和
氯化鈉水溶液間,及該有機層經硫酸鎂乾燥,過濾,並在真空中濃縮。矽膠層析(梯度:5%至50%乙酸乙酯於庚烷中)獲得呈稠油之產物。產率:1.6g,4.1mmol,44%。LCMS m/z 389.8[M+H]+。1H NMR(400MHz,CDCl3)δ 7.86-7.90(m,2H),7.73-7.77(m,2H),7.61-7.65(m,1H),6.94(br d,J=8.7Hz,1H),6.75(d,J=8.7Hz,1H),4.24(d,J=15.2Hz,1H),3.98(d,J=15.3Hz,1H),1.92(s,3H),1.12(d,J=6.3Hz,1H),0.52(d,J=6.3Hz,1H)。
步驟9. 合成1-[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲胺(C21)。
將單水合肼(2.0mL,41mmol)添加至含C20(1.6g,4.1mmol)之二氯甲烷(10mL)及甲醇(10mL)溶液中。於室溫攪拌該反應混合物過夜,屆時將其分配在1M氫氧化鈉水溶液與乙醚間。使用乙醚萃取該水層,及已合併之有機層經硫酸鈉乾燥,過濾,並在減壓下濃縮,獲得呈稠油之產物。產率:1.0g,3.9mmol,95%。1H NMR(400MHz,CDCl3)δ 7.20-7.24(m,1H),6.97(br d,J=8.7Hz,1H),6.78(d,J=8.7Hz,1H),3.39(d,J=14.2Hz,1H),2.86(d,J=14.0Hz,1H),1.75(s,3H),0.95(d,J=6.2Hz,1H),0.55(d,J=6.2Hz,1H)。
步驟10. 7-(4-甲基-1H-咪唑-1-基)-2-{[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(C22)之合成。
將1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(97%,830mg,5.78mmol)添加至C21(1.00g,3.86mmol)及C10(1.26g,5.14mmol)於N,N-二甲基甲醯胺(4mL)中之溶液中。在室溫3小時後,使用三氟乙酸乙酯(1.1mL,9.2mmol)處理該反應混合物並容許攪拌過夜。添加氫氧化鈉水溶液(1M,6mL,6mmol),且於室溫攪拌該混合物15分鐘。經由過濾收集固體,使用水及乙醚沖洗,並與甲苯共沸3次,獲
得呈灰白色固體之產物。產率:1.68g,3.45mmol,89%。LCMS m/z 487.4[M+H]+。1H NMR(400MHz,CDCl3),特徵峰:δ 8.21(s,1H),7.45(d,J=7.7Hz,1H),7.11-7.14(m,1H),6.98(br d,J=9Hz,1H),6.81(d,J=8.7Hz,1H),5.05(d,J=15.2Hz,1H),4.23(ddd,ABXY圖案之一半,J=14,8,4Hz,1H),4.15(ddd,ABXY圖案之一半,J=14,7,4Hz,1H),3.56(ddd,ABXY圖案之一半,J=13,7,4Hz,1H),3.46(ddd,ABXY圖案之一半,J=13,8,4Hz,1H),3.18(d,J=15.2Hz,1H),2.29(s,3H),1.84(s,3H),1.00(d,J=6.5Hz,1H),0.68(d,J=6.4Hz,1H)。
步驟11. 7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(2)及7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(3)之分離。
化合物C22(1.68g,3.45mmol)經由超臨界液體層析法(管柱:Chiral Technologies Chiralpak AD-H,5μm;流動相:30%[0.2%氫氧化銨於甲醇中]於二氧化碳中)分離為其組分對映體。隨後將各對映體溶於乙酸乙酯(10mL)中,經過注射過濾器,並在真空中濃縮。首先洗脫之對映體經乙醚研磨,獲得呈固體之3。第二洗脫之對映體從乙酸乙酯/庚烷中再結晶,獲得呈固體之2。
3:產率:435mg,0.894mmol,26%。LCMS m/z 487.4[M+H]+。1H NMR(400MHz,CD3OD)δ 8.28(br s,1H),7.77(d,J=7.8Hz,1H),7.28-7.32(m,2H),7.28(d,J=7.8Hz,1H),6.96-7.01(m,1H),6.83(d,J=8,7Hz,1H),4.93(d,J=15.1Hz,1H),4.13-4.25(m,2H),3.72(ddd,J=13,6,5Hz,1H),3.50(ddd,J=13,8,5Hz,1H),3.39(d,J=15.2Hz,1H),2.23(d,J=0.9Hz,3H),1.85(s,3H),1.14(d,J=6.4
Hz,1H),0.57(d,J=6.5Hz,1H)。
2:產率:447mg,0.919mmol,27%。LCMS m/z 487.4[M+H]+。1H NMR(400MHz,CD3OD)δ 8.28(br s,1H),7.77(d,J=7.8Hz,1H),7.28-7.32(m,2H),7.28(d,J=7.8Hz,1H),6.96-7.01(m,1H),6.83(d,J=8.8Hz,1H),4.93(d,J=15.1Hz,1H),4.13-4.25(m,2H),3.72(ddd,J=13,6,5Hz,1H),3.50(ddd,J=13,8,5Hz,1H),3.39(d,J=15.2Hz,1H),2.23(d,J=0.8Hz,3H),1.85(s,3H),1.14(d,J=6.4Hz,1H),0.57(d,J=6.4Hz,1H)。使化合物2經歷建立其絕對立體化學之X-射線結構分析(參見下文)。化合物2與其對映體3相比係更有效(參見表7);在此等實例之分離的全部對映體中觀察到此效能差異,及用於以使用2及3直接類推來確定全部情形之絕對立體化學。
在Bruker APEX繞射儀上於室溫進行資料收集。資料收集由ω及φ掃描組成。
藉由直接方法使用SHELX軟體套裝在空間群P1中解析此結構。隨後藉由滿陣最小平方法精煉該結構。發現全部非氫原子及使用各向異性位移參數精煉。
在不對稱單元中兩種分子之構形係輕微與彼此不同。兩種分子均具有相同立體化學。
將全部氫原子置於計算位置且容許在其載體原子上。最終精煉包括全部氫原子之各向同性位移參數。
使用PLATON(Spek 2010)進行使用似真方法(Hooft 2008)分析絕對結構。結果表明絕對結構已經校正。該方法計算校正結構係100.0%之概率。Hooft參數記錄為0.07,其中esd為0.06。
最終R-指數係5%。最終差異傅里葉揭示無丟失或誤置電子密度。
相關晶體、資料收集、及精煉資訊匯總在表1中。原子坐標、鍵長、鍵角度、及位移參數在表2至5中列出。
軟體及參考
SHELXTL,版本5.1,Bruker AXS,1997。
PLATON,A.L.Spek,J.Appl.Cryst. 2003,36,7-13。
MERCURY,C.F.Macrae、P.R.Edington、P.McCabe、E.Pidcock、G.P.Shields、R.Taylor、M.Towler及J.van de Streek,J.Appl.Cryst. 2006,39,453-457。
OLEX2,O.V.Dolomanov、L.J.Bourhis、R.J.Gildea、J.A.K.Howard及H.Puschmann,J.Appl.Cryst. 2009,42,339-341。
R.W.W.Hooft、L.H.Straver及A.L.Spek,J.Appl.Cryst. 2008,41,96-103。
H.D.Flack,Acta Cryst. 1983,A39,867-881。
2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(4)及2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(5)
步驟1. 合成[2-氟-4-(三氟甲氧基)苯基]硼酸(C23)。
將硼酸三丙-2-基酯(43.6g,232mmol)添加至4-溴-3-氟苯基三氟甲醚(50.0g,193mmol)之甲苯(400mL)與四氫呋喃(100mL)溶液中,
並將該混合物冷卻至-78℃。隨後於維持該反應溫度低於-60℃之速度逐滴添加正丁鋰(2.5M溶液;92.7mL,232mmol),及於-70℃攪拌該反應混合物4小時。在將該反應混合物加熱至-20℃後,經由添加鹽酸水溶液(2M,200mL)將其淬冷,並隨後於室溫(20℃)攪拌40分鐘。水層經乙酸乙酯(3 x 50mL)萃取,及已合併之有機層經飽和氯化鈉水溶液(100mL)洗滌,經硫酸鈉乾燥,過濾,及在真空中濃縮以獲得可直接用於下一步驟之呈白色固體之產物(43g)。
步驟2. 合成2-氟-4-(三氟甲氧基)苯酚(C24)。
在含C23(獲自先前步驟;43g,193mmol)之二氯甲烷(300mL)20℃溶液中添加過氧化氫(30%溶液,99mL,1.0mol),及於20℃攪拌該反應混合物2小時。隨後將其分配在水(200mL)與二氯甲烷(200mL)間;經二氯甲烷(2 x 100mL)萃取水層,及已合併之有機層經飽和氯化鈉水溶液(200mL)洗滌,經硫酸鈉乾燥,過濾,並在減壓下濃縮。矽膠層析(洗脫劑:10%乙酸乙酯於石油醚中)獲得呈黃色油之產物(30g,藉由1H NMR分析由1:0.3莫耳比之產物與乙酸乙酯構成)。校正產率:在2步驟內26g,130mol,67%。LCMS m/z 195.0[M-H+]。1H NMR(400MHz,CDCl3),僅產物峰:δ 6.98-7.05(m,2H),6.94(br d,AB四重峰的一半,J=9Hz,1H)5.54(br d,J=3.3Hz,1H)。
步驟3. 合成2-氟-6-碘-4-(三氟甲氧基)苯酚(C25)。
於25℃攪拌含C24(9.5g,48mmol)及N-碘代琥珀醯亞胺(12g,53mmol)之N,N-二甲基甲醯胺(50mL)混合物4小時,屆時將其經水(300mL)稀釋並經第三丁基甲醚(3 x 100mL)萃取。已合併之有機層按順序經飽和含水亞硫酸氫鈉溶液(50mL)及飽和氯化鈉水溶液(50mL)洗滌,經硫酸鈉乾燥,過濾,並在真空中濃縮。在矽膠上層析(梯度:0%至20%乙酸乙酯於石油醚中)獲得呈黃色油之產物。產率:12.0g,37.3mmol,78%。LCMS m/z 320.9[M-H+]。1H NMR(400
MHz,CDCl3)δ 7.40(br s,1H),7.06(dd,J=10.2,2.0Hz,1H),5.78(br s,1H)。
步驟4. 合成2-[(苄氧基)甲氧基]-1-氟-3-碘-5-(三氟甲氧基)苯(C26)。
將苄基氯甲醚(7.66g,48.9mmol)添加至含C25(10.5g,32.6mmol)及碳酸鉀(9.01g,65.2mmol)之乙腈(100mL)混合物中,及於25℃攪拌所得懸浮液2小時。隨後使用水(400mL)稀釋該反應混合物並經二氯甲烷(3 x 200mL)萃取;已合併之有機層經硫酸鈉乾燥,過濾,並在真空中濃縮。矽膠層析(梯度:0%至20%乙酸乙酯於石油醚中)獲得呈無色油之產物。產率:12.3g,27.8mmol,85%。1H NMR(400MHz,CDCl3)δ 7.46-7.51(m,1H),7.30-7.41(m,5H),7.06(ddq,J=10.9,2.8,0.7Hz,1H),5.33(s,2H),4.93(s,2H)。
步驟5. 合成2-[(苄氧基)甲氧基]-1-氟-3-(丙-1-炔-1-基)-5-(三氟甲氧基)苯(C27)。
含C26(12.0g,27.1mmol)、丁-2-酸(4.56g,54.2mmol)、及碳酸銫(13.3g,40.8mmol)之甲苯(200mL)混合物經烯丙基氯化鈀二聚體(497mg,1.36mmol)及4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(785mg,1.36mmol)處理。經氮氣脫氣該反應混合物兩次,屆時將其加熱至80℃持續16小時,隨後經矽藻土過濾。在真空中濃縮該濾液並藉由矽膠層析法(梯度:0%至30%乙酸乙酯於石油醚中)純化,獲得呈黃色油之產物。產率:9.2g,26mmol,96%。1H NMR(400MHz,CDCl3)δ 7.30-7.40(m,5H),7.05-7.09(m,1H),6.96(br dd,J=10.7,2.6Hz,1H),5.35(s,2H),4.91(s,2H),2.07(s,3H)。
步驟6. 合成3-[(苄氧基)甲基]-7-氟-2-甲基-5-(三氟甲氧基)-1-苯并呋喃(C28)。
將二-mu-氯-二氯雙(亞乙基)二鉑(II)(840mg,1.43mmol)添加至
含C27(9.2g,26mmol)之甲苯(200mL)溶液中;於35℃攪拌該反應混合物16小時,隨後容許於25℃靜置2天。在真空中濃縮該反應混合物,及該殘留物經由矽膠層析法(梯度:0%至20%乙酸乙酯於石油醚中)純化以獲得呈黃色油之產物。產率:6.5g,18mmol,69%。1H NMR(400MHz,CDCl3)δ 7.30-7.41(m,5H),7.19-7.23(m,1H),6.91(br d,J=10.5Hz,1H),4.59(s,2H),4.56(s,2H),2.46(s,3H)。
步驟7. 合成[7-氟-2-甲基-5-(三氟甲氧基)-1-苯并呋喃-3-基]甲醇(C29)。
在含C28(3.0g,8.5mmol)之乙醇(150mL)溶液中添加碳載氫氧化鈀(300mg),及使用氫氣脫氣該反應混合物三次。在50psi氫氣下於60℃攪拌所得黑色懸浮液16小時,屆時通過矽藻土將其過濾。該濾液在真空中濃縮,該殘留物與獲自第二反應(在3.0g C28上進行,8.5mmol)之物質合併並經矽膠上層析(梯度:0%至50%乙酸乙酯於石油醚中),獲得呈白色固體之產物。產率:3.60g,13.6mmol,80%。1H NMR(400MHz,CDCl3)δ 7.28-7.31(m,1H),6.92(br d,J=10.7Hz,1H),4.77(br s,2H),2.52(s,3H)。
步驟8. 合成[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲醇(C30)。
將二碘甲烷(43.8g,164mmol)及二乙基鋅(1M溶液在甲苯中,81.8mmol,81.8mL)添加至含C29(2.70g,10.2mmol)之甲苯(200mL)溶液中,並於30℃攪拌該反應混合物16小時。隨後於0℃將其逐滴添加至水(200mL)中;攪拌所得混合物10分鐘,屆時將其通過矽藻土過濾。水層經乙酸乙酯(3 x 100mL)萃取,及該已合併之有機層經飽和氯化鈉水溶液(100mL)洗滌,經硫酸鈉乾燥,過濾,並在減壓下濃縮。在矽膠上層析(梯度:0%至30%乙酸乙酯於石油醚中)獲得呈黃色油之產物。產率:2.0g,7.2mmol,71%。LCMS m/z 261.0
[M-OH]+。1H NMR(400MHz,CDCl3)δ 7.10-7.12(m,1H),6.85(br d,J=10.5Hz,1H),4.12(d,J=12.0Hz,1H),3.87(d,J=12.0Hz,1H),1.80(s,3H),1.14(d,J=6.5Hz,1H),0.70(d,J=6.5Hz,1H)。
步驟9. 合成2-{[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-1H-異吲哚-1,3(2H)-二酮(C31)。
將偶氮二甲酸二異丙酯(640mg,3.16mmol)逐滴添加至含C30(800mg,2.88mmol)、1H-異吲哚-1,3(2H)-二酮(465mg,3.16mmol)及三苯基膦(830mg,3.16mmol)之四氫呋喃(60mL)混合物中。於25℃攪拌該反應混合物20小時,屆時將其在真空中濃縮。矽膠層析(梯度:0%至20%乙酸乙酯於石油醚中)獲得呈無色油之產物。產率:880mg,2.16mmol,75%。1H NMR(400MHz,CDCl3)δ 7.86-7.91(m,2H),7.73-7.78(m,2H),7.46-7.49(m,1H),6.81(br d,J=10.3Hz,1H),4.24(d,J=15.2Hz,1H),3.97(d,J=15.3Hz,1H),1.96(s,3H),1.19(d,J=6.6Hz,1H),0.61(d,J=6.8Hz,1H)。
步驟10. 合成1-[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲胺(C32)。
在含C31(500mg,1.2mmol)之甲醇(30mL)溶液中添加單水合肼(50%水溶液,5mL,50mmol),及於25℃攪拌該反應混合物16小時。在真空中移除溶劑後,使用二氯甲烷(5mL)稀釋該殘留物並過濾;在減壓下濃縮該濾液以獲得呈無色油之產物。產量:300mg,1.1mmol,92%。1H NMR(400MHz,DMSO-d 6 )δ 7.39-7.43(m,1H),7.21(br d,J=10.9Hz,1H),3.15(d,J=13.8Hz,1H),2.80(d,J=13.9Hz,1H),1.71(s,3H),1.17(d,J=6.3Hz,1H),0.50(d,J=6.3Hz,1H)。
步驟11. 合成2-{[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(C33)。
將1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(191mg,1.37mmol)添加至含C10(252mg,1.03mmol)及C32(190mg,0.685mmol)之N,N-二甲基甲醯胺(5mL)懸浮液中,並於25℃攪拌該反應混合物30分鐘。隨後歷時5分鐘於25℃逐滴添加三氟乙酸乙酯(386mg,2.72mmol),屆時於60℃攪拌該反應混合物1小時,冷卻,並與衍生自第二反應(在42.2mg C32上進行,0.152mmol)之相似物質合併。使用氫氧化鈉水溶液(1M,5mL)及飽和氯化鈉水溶液(5mL)稀釋該混合物,並經二氯甲烷(3 x 5mL)萃取。已合併之有機層經硫酸鈉乾燥,過濾,並在真空中濃縮。經由矽膠層析法(梯度:0%至10%甲醇於二氯甲烷中)純化獲得呈黃色膠之消旋產物。產率:180mg,0.357mmol,43%。LCMS m/z 505.2[M+H]+。1H NMR(400MHz,CDCl3)δ 8.22(br s,1H),7.45(d,J=7.6Hz,1H),7.29(d,J=7.8Hz,1H),7.12(br s,1H),7.04-7.08(m,1H),6.85(br d,J=10Hz,1H),5.06(d,J=15.2Hz,1H),4.23(dd,J=5.9,5.6Hz,2H),3.57(ddd,ABXY圖案之一半,J=13,6,5Hz,1H),3.48(ddd,ABXY圖案之一半,J=13,6,6Hz,1H),3.16(d,J=15.2Hz,1H),2.28(d,J=1Hz,3H),1.89(s,3H),1.07(d,J=6.8Hz,1H),0.76(d,J=6.6Hz,1H)。
步驟12. 2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(4)及2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(5)之分離。
將消旋體C33(160mg,0.32mmol)使用超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD,10μm;流動相:30%(含0.1%氫氧化銨之甲醇)在二氧化碳中]分離為其組分對映體。該第二洗脫之
對映體係4,分離為白色固體。產率:71mg,0.14μmol,44%。LCMS m/z 505.1[M+H]+。滯留時間:7.68分鐘(管柱:Chiral Technologies Chiralpak AD-H,4.6 x 250mm,5μm;流動相A:二氧化碳;流動相B:含有0.05%二乙胺之甲醇;梯度:5%至40% B;流速:2.5mL/分鐘)。1H NMR(400MHz,CDCl3)δ 8.22(br s,1H),7.45(d,J=7.8Hz,1H),7.29(d,J=7.8Hz,1H),7.12(br s,1H),7.05-7.08(m,1H),6.85(br d,J=10.2Hz,1H),5.05(d,J=15.2Hz,1H),4.23(dd,J=6.2,5.5Hz,2H),3.57(ddd,ABXY圖案之一半,J=13,5.5,5.5Hz,1H),3.48(ddd,ABXY圖案之一半,J=13,6,6Hz,1H),3.17(d,J=15.3Hz,1H),2.28(br s,3H),1.89(s,3H),1.07(d,J=6.8Hz,1H),0.76(d,J=6.6Hz,1H)。
亦獲得呈白色固體之首先洗脫之對映體5。產率:73mg,0.14μmol,44%。LCMS m/z 505.2[M+H]+。滯留時間:6.42分鐘,使用如上文針對4記錄之彼等的相同分析條件。1H NMR(400MHz,CDCl3)δ 8.21(br s,1H),7.45(d,J=7.8Hz,1H),7.29(d,J=7.8Hz,1H),7.12(br s,1H),7.04-7.08(m,1H),6.85(br d,J=10.4Hz,1H),5.06(d,J=15.3Hz,1H),4.23(dd,J=6.0,5.6Hz,2H),3.57(ddd,ABXY圖案之一半,J=13,5.5,5.5Hz,1H),3.48(ddd,ABXY圖案之一半,J=13,6,6Hz,1H),3.16(d,J=15.3Hz,1H),2.28(d,J=0.8Hz,3H),1.89(s,3H),1.07(d,J=6.8Hz,1H),0.76(d,J=6.8Hz,1H)。
2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(6)及2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基7甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(7)
步驟1. 合成5-氟-2-碘-4-(三氟甲氧基)苯酚(C34)。
於室溫攪拌含3-氟-4-(三氟甲氧基)苯酚(7.0g,36mmol)及N-碘代琥珀醯亞胺(95%,8.45g,35.7mmol)之乙酸(10mL)混合物5分鐘及隨後經濃硫酸(18M,0.58mL,10.4mmol)處理。在攪拌該反應過夜後,將其分配在水與乙醚間。使用水及2M硫代硫酸鈉水溶液洗滌有機層,經活性碳處理,並經硫酸鎂乾燥。通過矽藻土墊及矽膠過濾該混合物,且在真空中濃縮該濾液,獲得呈油之產物(11.0g),該產物藉由1H NMR分析含有兩莫耳當量乙酸。針對乙酸校正之產率:8.0
g,25mmol,70%。GCMS m/z 322.0[M+]。1H NMR(400MHz,CDCl3)δ 7.60(br d,J=8.1Hz,1H),6.88(d,J=10.9Hz,1H)。
步驟2. 合成(2E)-3-[5-氟-2-碘-4-(三氟甲氧基)苯氧基]丁-2-酸乙酯(C35)。
於回流下加熱含C34[獲自先前步驟;11.0g(針對乙酸校正:8.0g,25mmol)]、丁-2-酸乙酯(4.0mL,34mmol)及碳酸鉀(18.0g,130mmol)之乙腈(100mL)混合物6小時,隨後容許於室溫攪拌過夜。在將該反應混合物分配在水與乙醚間後,使用水及飽和氯化鈉水溶液洗滌有機層,經硫酸鎂乾燥,過濾,並在真空中濃縮。在矽膠上層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得呈油之產物。產率:8.60g,19.8mmol,79%。GCMS m/z 434.1[M+]。1H NMR(400MHz,CDCl3)δ 7.78(br d,J=8.0Hz,1H),6.98(d,J=10.0Hz,1H),4.78(s,1H),4.13(q,J=7.1Hz,2H),2.53(s,3H),1.25(t,J=7.1Hz,3H)。
步驟3. 合成6-氟-2-甲基-5-(三氟甲氧基)-1-苯并呋喃-3-甲酸乙酯(C36)。
將氮氣流鼓泡通過含C35(250mg,0.57mmol)之乙腈(5mL)溶液持續10分鐘,屆時將二乙胺(0.40mL,2.9mmol)添加至該溶液,接著添加雙(三-第三丁基膦)鈀(0)(14.9mg,29.2μmol)。將該反應混合物加熱至90℃持續20小時,冷卻至室溫,並分配在乙醚與水間。使用水洗滌有機層,經硫酸鎂乾燥,過濾,並在減壓下濃縮;矽膠層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得白色固體產物。產率:148mg,0.483mmol,84%。1H NMR(400MHz,CDCl3)δ 7.91(dq,J=7.7,1.1Hz,1H),7.30(d,J=9.3Hz,1H),4.43(q,J=7.1Hz,2H),2.78(s,3H),1.45(t,J=7.1Hz,3H)。
步驟4. 合成4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-甲酸(C37)。
使用第三丁醇鉀(645mg,5.75mmol)處理含碘化三甲基氧化鋶(98%,1.35g,6.01mmol)之二甲基亞碸(10mL)懸浮液並於室溫攪拌30分鐘。添加含C36(1.60g,5.22mmol)之二甲基亞碸(5mL)溶液及四氫呋喃(2mL);攪拌該反應混合物2小時,屆時將其經額外碘化三甲基氧化鋶(98%,300mg,1.3mmol)及第三丁醇鉀(130mg,1.16mmol)處理。30分鐘後,添加氫氧化鉀(85%,700mg,11mmol),並持續攪拌2小時。將水(10mL)添加至該反應混合物,隨後經由添加1M鹽酸水溶液調節至pH 4至5。使用乙酸乙酯(3 x 50mL)萃取該混合物,及使用水及飽和氯化鈉水溶液洗滌該已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。所得稠油經庚烷(100mL)處理,在減壓下濃縮,溶於乙醚,使用水洗滌兩次,經硫酸鈉乾燥,過濾,並在真空中濃縮。獲得固體產物。產率:1.40g,4.79mmol,92%。1H NMR(400MHz,CD3OD)δ 7.57(br d,J=7.9Hz,1H),6.83(d,J=10.4Hz,1H),1.98(d,J=6.2Hz,1H),1.83(s,3H),0.92(d,J=6.3Hz,1H)。
步驟5. 合成4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-甲醯胺(C38)。
將1,1'-羰基二咪唑(266mg,1.64mmol)添加C37(400mg,1.37mmol)之四氫呋喃(10mL)溶液中,及於室溫攪拌該反應混合物30分鐘。添加濃縮之氫氧化銨溶液(0.7mL),及持續攪拌1小時,屆時將該反應混合物分配在水與乙醚間。使用水洗滌有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮,獲得呈膏狀固體之產物。產率:390mg,1.34mmol,98%。GCMS m/z 291.2[M+]。1H NMR(400MHz,DMSO-d 6 )δ 7.50(br d,J=7.9Hz,1H),7.41(br s,1H),7.31(br s,1H),7.15(d,J=10.9Hz,1H),1.96(d,J=6.6Hz,1H),1.65(s,3H),0.75(d,J=6.6Hz,1H)。
步驟6. 合成1-[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙
[b][1]苯并呋喃-6b-基]甲胺(C39)。
將雙(2-甲氧基乙氧基)氫化鈉鋁(3.3M溶液在甲苯中;7.0mL,23mmol)添加至含C38(1.70g,5.84mmol)之甲苯(30mL)溶液中。於室溫攪拌該反應混合物2小時,屆時將其在冰浴中冷卻並使用氫氧化鈉水溶液(1M,30mL)淬冷。所得混合物經乙醚萃取;使用飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,並在真空中濃縮。矽膠層析(梯度:0%至5%甲醇於二氯甲烷中)獲得呈稠油之產物。產率:1.2g,4.3mmol,74%。GCMS m/z 260.2[M-NH3]+。1H NMR(400MHz,CDCl3)δ 7.25-7.31(m,1H,假設;部分由溶劑峰掩蓋),6.66(d,J=10.2Hz,1H),3,34(d,J=14.0Hz,1H),2.87(d,J=14.0Hz,1H),1.75(s,3H),0.95(d,J=6.3Hz,1H),0.56(d,J=6.3Hz,1H)。
步驟7. 合成2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(C40)。
使用在實例2及3中針對由C21合成C22描述之方法進行C39至產物之轉化。獲得呈白色固體之產物。產率:560mg,1.11mmol,97%。LCMS m/z 505.1[M+H]+。1H NMR(400MHz,CDCl3)δ 8.22(d,J=1.2Hz,1H),7.45(d,J=7.7Hz,1H),7.24-7.31(m,2H,假設;部分由溶劑峰遮蓋),7.11-7.14(m,1H),6.68(d,J=10.0Hz,1H),5.06(d,J=15.1Hz,1H),4.26(ddd,ABXY圖案之一半,J=14.2,6.3,4.7Hz,1H),4.20(ddd,ABXY圖案之一半,J=14.3,8.0,4.4Hz,1H),3.56(ddd,ABXY圖案之一半,J=13.2,6.3,4.5Hz,1H),3.46(ddd,ABXY圖案之一半,J=13.2,7.9,4.5Hz,1H),3.12(d,J=15.2Hz,1H),2.29(br s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.68(d,J=6.6Hz,1H)。
步驟8. 2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二
氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(6)及2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(7)之分離。
經由超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD-H,5μm;流動相:30%(0.2%氫氧化銨於甲醇中)於二氧化碳中]進行分離C40(560mg,1.1mmol)成其組分對映體。隨後將各對映體溶於乙酸乙酯(15mL)中,過濾,並在真空中濃縮;懸浮於乙醚中,接著過濾,獲得產物,均為固體。化合物6係第二洗脫之對映體。產率:160mg,0.317mg,28%。LCMS m/z 505.1[M+H]+。1H NMR(400MHz,CDCl3)δ 8.22(s,1H),7.45(d,J=7.7Hz,1H),7.26-7.31(m,2H,假設;部分由溶劑峰遮蓋),7.13(br s,1H),6.68(d,J=10.0Hz,1H),5.06(d,J=15.2Hz,1H),4.26(ddd,ABXY圖案之一半,J=14,6,5Hz,1H),4.20(ddd,ABXY圖案之一半,J=14,8,4Hz,1H),3.56(ddd,ABXY圖案之一半,J=13,6,5Hz,1H),3.46(ddd,ABXY圖案之一半,J=13,8,5Hz,1H),3.12(d,J=15.2Hz,1H),2.29(s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.68(d,J=6.6Hz,1H)。
化合物7為首先洗脫之對映體。產率:180mg,0.357mmol,31%。LCMS m/z 505.2[M+H]+。1H NMR(400MHz,CDCl3)δ 8.22(s,1H),7.45(d,J=7.7Hz,1H),7.26-7.31(m,2H,假設;部分由溶劑峰遮蓋),7.13(br s,1H),6.68(d,J=10.0Hz,1H),5.06(d,J=15.2Hz,1H),4.26(ddd,ABXY圖案之一半,J=14.5,6,5Hz,1H),4.20(ddd,ABXY圖案之一半,J=14.3,7.8,4.3Hz,1H),3.56(ddd,ABXY圖案之一半,J=13,6,4.5Hz,1H),3.46(ddd,ABXY圖案之一半,J=13,8,5Hz,1H),3.12(d,J=15.1Hz,1H),2.29(s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.68(d,J=6.6Hz,1H)。
2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(8)及2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(9)
步驟1. 合成5-溴-6-氧-1,6-二氫吡啶-2-甲酸(C41)。
將溴(115g,720mmol)逐滴添加至含6-側氧基-1,6-二氫吡啶-2-甲酸(25g,180mmol)之乙酸(400mL)懸浮液中。將該反應混合物加熱至80℃持續16小時,屆時在減壓下將其濃縮至乾燥。該殘留物經第三丁基甲醚研磨(200mL)並過濾;使用第三丁基甲醚(3 x 100mL)洗滌該濾餅以獲得呈灰色固體之產物。產率:39.0g,179mmol,99%。1H NMR(400MHz,DMSO-d 6 )δ 8.03(d,J=7.3Hz,1H),6.83(d,J=7.3Hz,1H)。
步驟2. 合成7-溴-3,4-二氫吡啶并[2,1-c][1,4]噁
-1,6-二酮(C42)。
分四個相同批次進行此轉化。將1,2-二溴乙烷(9.48g,50.5mmol)添加至含C41(10.0g,45.9mmol)及碳酸銫(37.4g,115mmol)之N,N-二甲基甲醯胺(50mL)懸浮液中。於95℃攪拌該反應混合物2小時,屆時將其冷卻至約30℃並與其他三批合併。將此物質倒入二氯甲烷(600mL)中及於室溫攪拌10分鐘,隨後過濾。使用二氯甲烷(200mL)洗滌該濾餅,及在減壓下將已合併之濾液濃縮至乾燥。該殘留物與二氯甲烷(100mL)混合,於25℃攪拌20分鐘,並隨後過濾。將收集之固體溶於二氯甲烷(500mL)與甲醇(30mL)之混合物中,並通過矽膠(10g)過濾。在真空中濃縮此濾液並與二氯甲烷(50mL)及第三丁基甲醚(50mL)之混合物研磨,獲得呈淡黃色固體之產物。產率:13g,53mmol,29%。LCMS m/z 245.8[M+H]+。1H NMR(400MHz,CDCl3)δ 7.91(d,J=7.5Hz,1H),7.14(d,J=7.5Hz,1H),4.64(dd,J=5.3,5.1Hz,2H),4.36(dd,J=5.3,5.1Hz,2H)。
步驟3. 合成7-溴-2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(C43)。
將1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(97%,932mg,6.49mmol)添加至含C39(1.20g,4.33mmol)及C42(1.37g,5.61mmol)之N,N-二甲基甲醯胺(5mL)混合物中。於室溫攪拌該反應混合物2小時,隨後經三氟乙酸乙酯(1.3mL,10.9mmol)處理。在1小時後,添加氫氧化鈉水溶液(1M,10mL),並持續攪拌15分鐘。隨後使用乙酸乙酯萃取該混合物,使用水洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。在矽膠上層析(梯度:30%至100%乙酸乙酯於庚烷中)獲得呈油之產物。產率:1.76g,3.50mmol,81%。LCMS m/z 503.3,505.3[M+H]+。1H NMR(400MHz,CDCl3)δ 7.86(d,J=7.6Hz,1H),7.24-7.28(m,1H,假設;部分由溶劑峰遮蓋),7.07(d,J=7.6
Hz,1H),6.67(d,J=9.9Hz,1H),5.01(d,J=15.2Hz,1H),4.18(dd,J=6.0,5.8Hz,2H),3.52(ddd,ABXY圖案之一半,J=13,5.5,5.5Hz,1H),3.42(ddd,ABXY圖案之一半,J=13,6,6Hz,1H),3.11(d,J=15.2Hz,1H),1.82(s,3H),0.98(d,J=6.6Hz,1H),0.67(d,J=6.6Hz,1H)。
步驟4. 合成2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(C44)。
使用氮氣脫氣含參(二苄叉丙酮)二鈀(0)(98%,94.7mg,0.101mmol)與二-第三丁基[3,4,5,6-四甲基-2',4',6'-三(丙-2-基)吡苯-2-基]磷(95%,103mg,0.203mmol)之甲苯(10mL)混合物5分鐘,隨後於125℃加熱3分鐘。在分液燒瓶中,含C43(1.70g,3.38mmol)、3-甲基-1H-1,2,4-三唑(561mg,6.75mmol)及磷酸鉀(1.48g,6.97mmol)之甲苯(10mL)與1,4-二噁烷(10mL)之混合物使用氮氣脫氣10分鐘。將該觸媒溶液經由注射器轉移至該反應燒瓶,並於125℃加熱該反應混合物2小時,屆時將其分配在水與乙酸乙酯間。該有機層經硫酸鈉乾燥,過濾,並在真空中濃縮;矽膠層析(梯度:50%至100%乙酸乙酯於庚烷中)獲得呈淡白色固體之產物。產率:1.3g,2.6mmol,77%。LCMS m/z 506.4[M+H]+。1H NMR(400MHz,CDCl3),特徵峰:δ 9.52(br s,1H),8.21(d,J=7.9Hz,1H),7.38(d,J=7.8Hz,1H),7.25-7.31(m,1H,假設;部分由溶劑峰遮蓋),6.68(d,J=10.0Hz,1H),5.05(d,J=15.2Hz,1H),4.20-4.32(m,2H),3.53-3.62(m,1H),3.14(d,J=15.2Hz,1H),2.49(s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.69(d,J=6.5Hz,1H)。
步驟5. 2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(8)及2-{[(1aR,6bR)-4-氟-1a-
甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(9)之分離。
經由超臨界流體層析法[管柱:Phenomenex Lux Cellulose-4,5μm;流動相:30%(1:1乙腈/甲醇)於二氧化碳中]將化合物C44(1.3g,2.6mmol)分離為其組分對映體。將獲自分離之個別對映體溶於乙酸乙酯(10mL),經過注射過濾器,在真空中濃縮,隨後經乙醚沉澱;獲得呈固體之兩種對映體。實例8為第二洗脫之對映體。產率:415mg,0.821mmol,32%。LCMS m/z 506.4[M+H]+。1H NMR(400MHz,CDCl3)δ 9.53(br s,1H),8.21(d,J=7.9Hz,1H),7.38(d,J=7.8Hz,1H),7.29(dq,J=7.5,1.0Hz,1H),6.68(d,J=10.0Hz,1H),5.05(d,J=15.2Hz,1H),4.20-4.32(m,2H),3.57(ddd,ABXY圖案之一半,J=13.2,6.0,4.9Hz,1H),3.44-3.51(m,1H),3.14(d,J=15.2Hz,1H),2.48(s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.69(d,J=6.6Hz,1H)。
首先洗脫之對映體係化合物9。產率:412mg,0.815mmol,31%。LCMS m/z 506.4[M+H]+。1H NMR(400MHz,CDCl3)δ 9.52(br s,1H),8.21(d,J=7.9Hz,1H),7.38(d,J=7.9Hz,1H),7.28(dq,J=7.6,1.0Hz,1H),6.68(d,J=10.0Hz,1H),5.05(d,J=15.2Hz,1H),4.20-4.32(m,2H),3.57(ddd,ABXY圖案之一半,J=13.2,6.0,4.9Hz,1H),3.44-3.51(m,1H),3.14(d,J=15.2Hz,1H),2.49(s,3H),1.84(s,3H),1.00(d,J=6.6Hz,1H),0.69(d,J=6.7Hz,1H)。
2-{[(1aS,6bS)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(10)及2-{[(1aR,6bR)-4-氯-1a-甲基-5-(三氟甲
基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(11)
步驟1. 合成5-氯-2-碘-4-(三氟甲基)苯酚(C45)。
攪拌含3-氯-4-(三氟甲基)苯酚(3.00g,15.3mmol)及N-碘代琥珀醯亞胺(95%,3.61g,15.2mmol)之乙酸(10mL)混合物5分鐘,屆時添加硫酸(18M,0.25mL,4.5mmol)。在於室溫攪拌該反應混合物2天之後,將其分配在乙醚與水間。使用水及2M硫代硫酸鈉水溶液洗滌有機層,隨後經活性碳處理並經硫酸鎂乾燥。通過矽藻土墊及矽膠過濾該混合物,並在真空中濃縮該濾液以獲得含有產物、乙酸及溶劑之油(4.9g)。此物質不經額外純化即可用於下一步驟。GCMS m/z
322.0[M+]。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.95(s,1H),7.12(s,1H)。
步驟2. 合成(2E)-3-[5-氯-2-碘-4-(三氟甲基)苯氧基]丁-2-酸乙酯(C46)。
攪拌含C45(獲自先前步驟;4.9g,15.3mmol)與碳酸鉀(10.5g,76.0mmol)之乙腈(100mL)混合物10分鐘。添加丁-2-酸乙酯(2.0mL,17mmol),及於回流下加熱該反應混合物過夜;GCMS分析指出部分轉化為產物。將該反應混合物分配在1M鹽酸水溶液及1:1乙醚與庚烷之混合物間。使用水及飽和氯化鈉水溶液洗滌有機層,隨後經硫酸鈉乾燥,過濾,並在真空中濃縮。矽膠層析(梯度:0%至25%乙酸乙酯於庚烷中)獲得回收之C45(2.84g)及產物與去-碘類似物(0.88g)之混合物。回收之C45再次經反應條件並以相同方式處理,獲得呈緩慢固化之稠油之產物(1.2g)並回收C45(1.6g)。將此部分C45(1.2g,3.7mmol)溶於甲苯(10mL)並經1,4-二氮雜二環[2.2.2]辛烷(411mg,3.66mmol),接著丁-2-酸乙酯(1mL,9mmol)處理。於100℃加熱該反應混合物18小時,隨後冷卻至室溫並與0.88g上文分離之物質合併。將此混合物分配在乙醚與1M鹽酸水溶液間;使用1M鹽酸水溶液及水洗滌該有機層,隨後經硫酸鎂乾燥,過濾,並在減壓下濃縮。在矽膠上層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得額外呈油之產物(2.0g)。合併產率:經2步3.2g,7.4mmol,48%。GCMS m/z 434.1[M+]。1H NMR(400MHz,CDCl3)δ 8.14(s,1H),7.20(br s,1H),4.80-4.82(m,1H),4.14(q,J=7.1Hz,2H),2.54(d,J=0.6Hz,3H),1.26(t,J=7.1Hz,3H)。
步驟3. 合成6-氯-2-甲基-5-(三氟甲基)-1-苯并呋喃-3-甲酸乙酯(C47)。
使用氮氣淨化含C46(3.10g,7.13mmol)之乙腈(20mL)溶液10分
鐘,隨後經三乙胺(5.0mL,36mmol),接著雙(三-第三丁基膦)鈀(0)(184mg,0.360mmol)處理。於90℃加熱該反應混合物1小時,屆時將其分配在乙醚與1M鹽酸水溶液間。使用水及飽和氯化鈉水溶液洗滌有機層,經硫酸鎂乾燥,並經活性碳處理。通過矽藻土墊過濾該混合物,並在真空中濃縮該濾液。矽膠層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得呈淡白色/棕黃色固體之產物。產率:1.00g,3.26mmol,46%。GCMS m/z 306.1[M+]。1H NMR(400MHz,CDCl3)δ 8.33(s,1H),7.60(s,1H),4.44(q,J=7.1Hz,2H),2.80(s,3H),1.46(t,J=7.1Hz,3H)。
步驟4. 合成4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-甲酸(C48)。
使用第三丁醇鉀(1M溶液在四氫呋喃中;3.59mL,3.59mmol)處理含碘化三甲基氧化鋶(98%,820mg,3.7mmol)之二甲基亞碸(5mL)懸浮液中並容許於室溫攪拌20分鐘。添加含C47(1.00g,3.26mmol)之二甲基亞碸(5mL)及四氫呋喃(3mL)溶液,並持續攪拌1.5小時。於此點,引入額外碘化三甲基氧化鋶(98%,125mg,0.557mmol)及第三丁醇鉀(1M溶液在四氫呋喃中;0.5mL,0.5mmol),及容許該反應進行1.5小時。添加粉碎之氫氧化鉀顆粒(85%,540mg,8.2mmol),攪拌該反應混合物2小時;隨後經由添加1M鹽酸水溶液調節至pH 4至5。使用乙酸乙酯萃取該混合物,及使用水與飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮以獲得呈膏狀固體之產物(1.16g);藉由1H NMR分析此物質係不純,及不經額外純化即可用於以下步驟。1H NMR(400MHz,DMSO-d 6 ),僅產物峰:δ 13.2-13.4(v br s,1H),7.94(s,1H),7.35(s,1H),1.97(d,J=6.4Hz,1H),1.80(s,3H),1.07(d,J=6.4Hz,1H)。
步驟5. 合成4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]
苯并呋喃-6b-甲醯胺(C49)。
根據在實例6及7中針對由C37合成C38描述之方法將C48(獲自先前步驟;1.10g,3.1mmol)轉化為該產物。將該產物分離為稠油(1.1g),藉由1H NMR分析其係不純;此物質不經額外純化即可用於下一步驟。GCMS m/z 291.1[M+]。1H NMR(400MHz,DMSO-d 6 ),僅產物峰:δ 7.76(s,1H),7.33(s,1H),2.03(d,J=6.6Hz,1H),1.68(s,3H),0.79(d,J=6.6Hz,1H)。
步驟6. 合成1-[4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲胺(C50)。
將雙(2-甲氧基乙氧基)氫化鋁鈉(3.3M溶液在甲苯中;4.2mL,13.9mmol)添加至含C49(獲自先前步驟;1.0g,2.8mmol)之甲苯(25mL)與四氫呋喃(5mL)溶液中。在於室溫2小時後,在冰浴中冷卻該反應,使用氫氧化鈉水溶液(1M,25mL,25mmol)淬冷,經乙醚萃取。使用飽和氯化鈉水溶液洗滌有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮,獲得呈稠膠之產物(865mg)。藉由1H NMR分析,此物質係不純;其不經額外純化即可用於下一步驟。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.66(s,1H),6.94(s,1H),3.39(d,J=14.0Hz,1H),2.89(d,J=14.1Hz,1H),1.77(s,3H),1.01(d,J=6.4Hz,1H),0.54(d,J=6.3Hz,1H)。
步驟7. 合成2-{[(1aS,6bS)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(10)及2-{[(1aR,6bR)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(11)。
將1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(97%,671mg,4.68mmol)添加至含C50(獲自先前步驟;865mg,2.8mmol)及C10(993
mg,4.05mmol)之N,N-二甲基甲醯胺(5mL)混合物中。在2小時後,將三氟乙酸乙酯(0.93mL,7.8mmol)添加至該反應混合物,並持續攪拌1小時。添加氫氧化鈉水溶液(1M,10mL,10mmol)及攪拌該混合物15分鐘,屆時將其分配在水與乙酸乙酯間。使用水洗滌有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。在經由矽膠上層析(梯度:0%至10%甲醇於乙酸乙酯中)純化該殘留物後,使用乙醚將其研磨,及經由超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD-H,5μm;流動相:20%(1:1乙腈/甲醇)於二氧化碳中]將所得固體(470mg)分離為其組分對映體。隨後將各個對映體溶於乙酸乙酯(10mL)及經過注射過濾器。在真空中濃縮洗脫液並用乙醚研磨以獲得呈固體之各個產物。
化合物10為第二洗脫之對映體。產率:經4步114mg,0.226mmol,8%。LCMS m/z 505.4,507.4[M+H]+。1H NMR(400MHz,CD3OD)δ 8.31(br s,1H),7.79(s,1H),7.77(d,J=7.8Hz,1H),7.31(br s,1H),7.27(d,J=7.8Hz,1H),7.04(s,1H),4.85(d,J=15.1Hz,1H),4.33(ddd,ABXY圖案之一半,J=14,6,4Hz,1H),4.19(ddd,ABXY圖案之一半,J=14,9,4Hz,1H),3.73(ddd,ABXY圖案之一半,J=13,6,4Hz,1H),3.5-3.58(m,1H),3.50(d,J=15.3Hz,1H),2.23(br s,3H),1.87(s,3H),1.23(d,J=6.8Hz,1H),0.63(d,J=6.7Hz,1H)。
首先洗脫之對映體係11。產率:經4步122mg,0.242mmol,9%。LCMS m/z 505.4,507.3[M+H]+。1H NMR(400MHz,CD3OD)δ 8.30(br s,1H),7.79(s,1H),7.77(d,J=7.7Hz,1H),7.30(br s,1H),7.27(d,J=7.7Hz,1H),7.04(s,1H),4.85(d,J=15.2Hz,1H),4.33(ddd,ABXY圖案之一半,J=14,6,4Hz,1H),4.19(ddd,ABXY圖案之一半,J=14,9,4Hz,1H),3.73(ddd,ABXY圖案之一半,J=13,6,4Hz,1H),3.54(ddd,ABXY圖案之一半,J=13,9,4Hz,1H),3.50(d,J=15.3Hz,
1H),2.23(d,J=0.8Hz,3H),1.87(s,3H),1.23(d,J=6.8Hz,1H),0.63(d,J=6.6Hz,1H)。
2-{[(1aS,6bS)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(12)及2-{[(1aR,6bR)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(13)
步驟1. 合成4-溴-1-(二氟甲氧基)-2-氟苯(C51)。
於70℃下將4-溴-2-氟苯酚(2.78mL,25.4mmol)添加至碳酸銫(97%,12.8g,38.1mmol)、N,N-二甲基甲醯胺(100mL)及水(10mL)
之混合物中。隨後歷時30分鐘分步引入氯(二氟)乙酸鈉(9.69g,63.6mmol)。容許該反應混合物於70℃攪拌過夜,屆時將其冷卻至室溫並倒入水中。使用乙酸乙酯萃取所得混合物三次;按順序使用1M氫氧化鈉水溶液、水、及飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鎂乾燥,過濾,並在真空中濃縮。矽膠層析(梯度:0%至20%乙酸乙酯於庚烷中)獲得呈無色油之產物。產率:1.50g,6.22mmol,24%。1H NMR(400MHz,CDCl3)δ 7.36(dd,J=9.7,2.3Hz,1H),7.28(ddd,J=8.7,2.2,1.6Hz,1H),7.14(br dd,J=8.6,8.4Hz,1H),6.54(t,J HF=73.0Hz,1H)。
步驟2. 合成4-(二氟甲氧基)-3-氟苯酚(C52)。
使用氮氣淨化水(3mL)與1,4-二噁烷(3mL)之混合物15分鐘,屆時添加氫氧化鉀(85%,1.64g,24.8mmol)、參(二苄叉丙酮)二鈀(0)(57mg,62mmol)、及二-第三丁基[3,4,5,6-四甲基-2',4',6'-三(丙-2-基)聯苯-2-基]磷烷(97%,123mg,0.248mmol)。在添加C51(1.50g,6.22mmol)後,於100℃加熱該反應混合物1小時,隨後冷卻至室溫並經氫氧化鈉水溶液(1M,100mL)處理。使用乙醚(50mL)洗滌所得混合物,經由添加濃鹽酸調節至酸性pH,及經乙醚(2 x 150mL)萃取。合併此等萃取物,使用脫色碳處理,經硫酸鎂乾燥,過濾,並在真空中濃縮,獲得呈油之產物(1.36g)。藉由1H NMR分析此物質含有大量溶劑,及不經額外純化即可用於下一步驟。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.08(br dd,J=8.9,8.9Hz,1H),6.65(dd,J=11.6,2.9Hz,1H),6.56(ddd,J=8.9,2.9,1.5Hz,1H),6.45(t,J HF=73.9Hz,1H)。
步驟3. 合成2-溴-4-(二氟甲氧基)-5-氟苯酚(C53)。
在冰浴中冷卻含C52(獲自先前步驟;1.36g,6.22mmol,由1H NMR光譜分析估計含有~4.6mmol C52)之二氯甲烷(23mL)溶液並使
用溴(0.24mL,4.6mmol)以逐滴方式處理。容許將該反應混合物緩慢加熱至室溫過夜,屆時使用硫代硫酸鈉水溶液洗滌,經硫酸鎂乾燥,過濾,並在真空中濃縮。獲得呈油之產物(1.4g),藉由1H NMR分析判定其含有溶劑;此物質可直接用於下一步驟。GCMS m/z 256.0[M+]。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.40(br d,J=7.9Hz,1H),6.88(d,J=11.0Hz,1H),6.47(t,J HF=73.2Hz,1H),5.67-5.78(br s,1H)。
步驟4. 合成(2E)-3-[2-溴-4-(二氟甲氧基)-5-氟苯氧基]丁-2-酸乙酯(C54)。
將1,4-二氮雜二環[2.2.2]辛烷(589mg,5.25mmol)添加至含C53(獲自先前步驟;1.4g,由1H NMR光譜分析估計含有~4.3mmolC53)及丁-2-酸乙酯(0.90mL,7.7mmol)之甲苯(13mL)溶液中。於90℃加熱該反應混合物6小時,屆時將其冷卻至室溫並分配在1M鹽酸水溶液及乙醚間。按順序使用1M鹽酸水溶液、1M氫氧化鈉水溶液、及水洗滌該有機層。其隨後經硫酸鎂乾燥,過濾,並在真空中濃縮。在矽膠上層析(梯度:0%至5%乙酸乙酯於庚烷中)獲得呈稠油之產物。產率:在3步內1.23g,3.33mmol,54%。GCMS m/z 323,325[M-(OEt)]+。1H NMR(400MHz,CDCl3)δ 7.55(br d,J=7.9Hz,1H),6.99(d,J=10.0Hz,1H),6.56(t,J HF=72.5Hz,1H),4.78(s,1H),4.13(q,J=7.1Hz,2H),2.52(s,3H),1.25(t,J=7.1Hz,3H)。
步驟5. 合成5-(二氟甲氧基)-6-氟-2-甲基-1-苯并呋喃-3-甲酸乙酯(C55)。
使用氮氣淨化含C54(1.23g,3.33mmol)及三乙胺(2.0mL,14mmol)之乙腈(10mL)溶液15分鐘。引入雙(三-第三丁基膦)鈀(0)(170mg,0.33mmol),並於90℃加熱該反應混合物2小時,屆時將其冷卻至室溫並分配在庚烷與1M鹽酸水溶液間。使用1M鹽酸水溶液與水洗
滌該有機層,經硫酸鎂乾燥,過濾,並在真空中濃縮。將所得固體溶於甲醇(30mL)中,經脫色碳處理,攪拌10分鐘,並通過矽藻土過濾。在減壓下移除溶劑獲得淡白色固體產物。產率:510mg,1.77mmol,53%。GCMS m/z 288.1[M+]。1H NMR(400MHz,CDCl3)δ 7.83(d,J=7.8Hz,1H),7.27(d,J=9.6Hz,1H),6.57(t,J HF=73.8Hz,1H),4.42(q,J=7.2Hz,2H),2.77(s,3H),1.45(t,J=7.1Hz,3H)。
步驟6. 合成5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-甲酸(C56)。
將第三丁醇鉀(1.0M溶液,2.1mL,2.1mmol)添加至含碘化三甲基氧化鋶(98%,0.477g,2.12mmol)之二甲基亞碸(4.5mL)懸浮液中,及容許於室溫攪拌該混合物30分鐘。溶液隨後歷時15分鐘以逐滴方式引入含C55(510mg,1.77mmol)之四氫呋喃(2.5mL),並於室溫攪拌該反應混合物1小時。添加粉碎之氫氧化鉀顆粒(85%,0.292g,4.42mmol),使用水(25mL)稀釋並使用庚烷(50mL)洗滌。在冰浴中冷卻水層並經由添加濃鹽酸調節pH 4至5。使用乙醚萃取該混合物,並使用水及飽和氯化鈉水溶液洗滌已合併之有機層,經硫酸鈉乾燥,過濾,並在真空中濃縮。獲得呈稠油之產物,在靜置時該產物固化為黃橙色固體。產率:214mg,0.780mmol,44%。LCMS m/z 273.4[M-H+]。1H NMR(400MHz,CDCl3)δ 7.52(d,J=7.9Hz,1H),6.68(d,J=10Hz,1H),6.48(t,J HF=73.9Hz,1H),2.04(d,J=6.2Hz,1H),1.88(s,3H),0.99(d,J=6.2Hz,1H)。
步驟7. 合成5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-甲醯胺(C57)。
使用在實例6及7中針對由C37合成C38描述之方法將化合物C56(214mg,0.780mmol)轉化為產物。獲得經由1H NMR分析含有大量溶劑之呈稠油之產物(200mg);此物質可直接用於下一步驟。
GCMS m/z 273.1[M+]。1H NMR(400MHz,CDCl3),僅產物峰:δ 7.33(d,J=7.6Hz,1H),6.73(d,J=10.2Hz,1H),6.49(t,J HF=73.5Hz,1H),5.77-5.99(br m,2H),2.11(d,J=6.3Hz,1H),1.74(s,3H),0.77(d,J=6.3Hz,1H)。
步驟8. 合成1-[5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲胺(C58)。
在冰浴中冷卻含C57(獲自先前步驟;200mg,<0.73mmol)之甲苯溶液並經雙(2-甲氧基乙氧基)氫化鋁鈉(3.3M溶液在甲苯中,0.56mL,1.8mmol)緩慢處理,同時保持內部反應溫度在低於15℃。在完成添加時,移除冰浴並容許將該反應加熱至室溫並攪拌過夜。再次添加雙(2-甲氧基乙氧基)氫化鈉鋁(3.3M溶液於甲苯中,2.2mL,7.3mmol),並持續於室溫攪拌24小時,屆時引入額外含雙(2-甲氧基乙氧基)氫化鈉鋁(3.3M溶液在甲苯中,2.7mL,8.9mmol)。在於室溫攪拌該反應混合物24小時後,於50℃加熱24小時。容許將其冷卻至室溫,在冰浴中進一步冷卻,並經由緩慢添加氫氧化鈉水溶液(1M,50mL)淬冷,同時維持內部溫度低於30℃。攪拌此混合物15分鐘,屆時使用乙醚(3 x 20mL)萃取;經硫酸鈉乾燥已合併之有機層,過濾,並在真空中濃縮以獲得經由1H NMR分析實質上不純之呈稠油之產物(105mg)。此物質直接用於下一步驟。GCMS m/z 242.1[M-NH3]+。
步驟9. 合成2-{[(1aS,6bS)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(12)及2-{[(1aR,6bR)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(13)。
將1,3,4,6,7,8-六氫-2H-嘧啶并[1,2-a]嘧啶(97%,94.7mg,0.660mmol)添加至含C58(獲自先前步驟;105mg,<0.40mmol)及C10(129mg,0.526mmol)之N,N-二甲基甲醯胺(1mL)混合物中,並於室溫攪拌該反應混合物2小時。添加三氟乙酸乙酯(0.12mL,1.01mmol),並在攪拌額外1小時後,使用氫氧化鈉水溶液(1M,1.5mL)處理該反應混合物及容許攪拌30分鐘,屆時使用乙酸乙酯萃取三次。使用飽和氯化鈉水溶液洗滌已合併之有機層兩次,經硫酸鎂乾燥,過濾,並在真空中濃縮。使該殘留物經矽膠上層析(梯度:0%至3%甲醇於二氯甲烷中),接著藉由超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD-H,5μm;流動相:30%(含有0.6%氫氧化銨之甲醇)在二氧化碳]純化。
化合物12係第二洗脫之對映體。產率:經三步4.4mg,9.0μmol,1.2%。LCMS m/z 487.3[M+H]+。滯留時間:3.86分鐘{經由超臨界流體層析法分析[管柱:Chiral Technologies Chiralpak AD-H,4.6 x 100mm,5μm;流動相:40%(含有0.6%氫氧化銨之甲醇)於二氧化碳中;流速:1.5mL/分鐘]}。。
首先洗脫之對映體係13。產率:經三步4.4mg,9.0μmol,1.2%。LCMS m/z 487.3[M+H]+。滯留時間:2.81分鐘(使用與12相同之分析系統)。
2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-[4-(羥甲基)-1H-咪唑-1-基]-3,4-二氫-2H-吡啶并[1,2-a]吡
-1,6-二酮(14)
使用肝微粒體(獲自雄性猴;1.5mg/mL)、氯化鎂(3.3mM)、及NADPH(1.3mM)之0.1M磷酸鉀緩衝液(pH 7.4,培育溶液總體積,40mL)培育化合物6(0.4mg,800nmol)。於37℃在水浴中搖晃該反應混合物67分鐘,屆時添加乙腈(40mL)並於1700g下旋轉該混合物5分鐘。上清液經真空離心至約15mL體積,向其中添加甲酸(0.5mL)、乙腈(0.5mL)及水(足以達到總體積50mL)。於40000g下旋轉此混合物30分鐘。經由反相層析(管柱:Agilent Polaris C18,5μm;流動相A:0.1%甲酸水溶液;流動相B:乙腈;梯度:1%至90% B))純化上清液以獲得產物。產率:17μg,32nmol,4%。LCMS m/z 521.1[M+H]+。1H NMR(600MHz,DMSO-d 6 ),特徵峰:δ 8.25(s,1H),7.84(d,J=7.8Hz,1H),7.52(s,1H),7.49(d,J=7.8Hz,1H),7.07-7.12(m,2H),4.58(d,J=15.0Hz,1H),4.39(s,2H),4.16-4.22(m,1H),4.13(ddd,ABXY圖案之一半,J=14,8,4Hz,1H),3.68-3.74(m,1H),3.54(d,J=15.1Hz,1H),3.50(ddd,J=13,8,4Hz,1H),1.80(s,3H),0.59(d,J=6.4Hz,1H)。
1.經由超臨界流體層析法(管柱:Chiral Technologies Chiralpak AD-3,3μm;流動相A:二氧化碳;流動相B:含有0.05%二乙胺之甲醇;梯度:5%至40% B)從消旋混合物分離實例15及16。分析型超
臨界流體層析法(管柱:Chiralpak AD-3,150 x 4.6mm,3μm;流動相A:二氧化碳;流動相B:含有0.05%二乙胺之甲醇;梯度:5%至40% B經5.5min,隨後40% B 2分鐘;流速:2.5mL/分鐘)產生滯留時間5.69分鐘(針對實例15),及滯留時間5.42分鐘(針對實例16)。
2.經由以N-碘代琥珀醯亞胺及硫酸處理含3-氟-4-(三氟甲基)苯酚之乙酸溶液合成必要5-氟-2-碘-4-(三氟甲基)苯酚。
3.經由超臨界流體層析法[管柱:Princeton PPU,5μm;流動相:30%(0.2%氫氧化銨於乙醇中)於二氧化碳中]從消旋混合物中分離實例17及18。在此系統中實例17係第二洗脫之對映體,實例18首先洗脫。
4.經由超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD,10μm;流動相:35%(含有0.1%氫氧化銨之甲醇)於二氧化碳中]從消旋混合物中分離實例19及20。在此系統中實例19係第二洗脫之對映體,實例20首先洗脫。
5.在此情形下,未經由氫化進行苄基醚裂解;而是,經含2,3-二氯-5,6-二氰基-1,4-苯并醌之二氯甲烷處理獲得可使用硼氫化鈉還原之對應醛。
6.經由超臨界流體層析法[管柱:Chiral Technologies Chiralpak AD,5μm,流動相:40%(含有0.05%二乙胺之甲醇)在二氧化碳中]從消旋混合物中分離實例21及22。在此系統中實例21係第二洗脫之對映體,實例22首先洗脫。
使用過度表現人類WT-APP之CHO細胞測定化合物調節澱粉樣β蛋白質Aβ(1-42)之生產之能力。在96孔經組織培養物處理、透明板(Falcon)的基於DMEM/F12之培養基中,以22,000個細胞/100μL孔塗佈細胞並於37℃培育24h。將用於測試之化合物於100% DMSO中稀
釋,獲得用於IC50測定之十一個點、半對數、劑量效應。在新鮮製備之培養基中添加化合物,以達到1%最終DMSO。將適當媒劑或抑制劑對照物個別地添加至對照孔,以分別獲得最小或最大抑制值,於37℃培育該板~24h後,用於分析信號窗。此程序在各個孔中產生經過調理之培養基,並在下文描述之ELISA檢測步驟中測試孔之Aβ(1-42)含量。亦如下文描述,測試各個孔中殘留細胞培養物的細胞毒性。
藉由將含50μL/孔自製Aβ(1-42)特異性抗體(3μg/mL)之0.1M NaHCO3(pH 9.0)添加至黑色384-孔Maxisorp®板(Nunc)開始塗覆ELISA分析板;於4℃培育整夜。隨後從ELISA分析板吸出被捕獲之抗體並使用洗滌緩衝液(杜貝卡氏(Dulbecco’s)PBS,0.05% Tween 20)以Matrical Squirt板清洗儀洗滌該板,2 x 100μL,或以Thermo Combi洗滌該板,3 x 90μL。隨後將90μL/板阻斷緩衝液(杜貝卡氏PBS,1.0% BSA(Sigma A7030)添加至該板。讓其在環境溫度下培育最少2h。隨後移除阻斷緩衝液且隨後添加20μL/孔分析緩衝液(杜貝卡氏PBS,1.0% BSA(Sigma A7030),0.05% Tween 20)。此時,將35μL(在2012年8月之前40μL)(一式兩份)實驗性經調理培養基(如上文描述)轉移至含有捕獲抗體的已阻斷ELISA板之孔,接著於4℃培育過夜。亦在移除用於Aβ(1-42)分析之經調理培養基後,藉由根據製造商說明之比色分析細胞增殖分析法(CellTiter 96® AQueous One Solution Cell Proliferation Assay,Promega)測量對應之殘留細胞中之細胞毒性。
ELISA分析板於4℃培育過夜後,經由使用清洗緩衝液以Matrical Squirt板清洗儀的2 x 100μL清洗,或以Thermo Combi的3 x 90μL清洗,移除未結合之Aβ肽。添加於分析緩衝液中之銪(Eu)標記(常用標記,PerkinElmer)之Aβ(1-16)6e10單株抗體(Covance #SIG-39320),(50μL/孔Eu-6e10,在1:10,000下,20uM EDTA)。於環境溫度培育最少2h,接著使用清洗緩衝液以Matrical Squirt板清洗儀的2 x 100μL清
洗,或以Thermo Combi的3 x 90μL清洗,然後添加30μL/孔的Delfia增強溶液(PerkinElmer)。在環境溫度培育30至60min後,使用標準DELFIA TRF設置在EnVision板讀取器(PerkinElmer)上讀取該板。使用非線性回歸擬合分析(自製軟體)及最大及最小抑制對照的適當板平均值來進行包括抑制IC50測定之數據分析。
實例1至22之化合物及C22、C33、C40與C44之生物數據參見以下表7:
a.記錄之IC50值係來自單一測定。
b.記錄之IC50值係5次測定之幾何平均值。
Claims (14)
- 一種具有式II結構之化合物,
- 一種化合物,其係選自由下列組成之群:7-(4-甲基-1H-咪唑-1-基)-2-{[1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮 2-{[3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(3-甲基-1H-1,2,4-三唑-1-基)- 3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-5-(二氟甲氧基)-4-氟-1a-甲基-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-[4-(羥甲基)-1H-咪唑-1-基]-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aS,6bS)-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;7-(4-甲基-1H-咪唑-1-基)-2-{[(1aR,6bR)-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙 [b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aS,6bS)-3-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡吡啶并[1,2-a]吡-1,6-二酮;2-{[(1aR,6bR)-3-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮;或其醫藥上可接受之鹽。
- 一種2-{[(1aS,6bS)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-{[(1aR,6bR)-4-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-{[(1aS,6bS)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-{[(1aR,6bR)-3-氟-1a-甲基-5-(三氟甲氧基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二 氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-{[(1aS,6bS)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-{[(1aR,6bR)-4-氯-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b][1]苯并呋喃-6b-基]甲基}-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-(((1aS,6bS)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b]苯并呋喃-6b-基)甲基)-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-(((1aR,6bR)-4-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b]苯并呋喃-6b-基)甲基)-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-(((1aS,6bS)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b]苯并呋喃-6b-基)甲基)-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種2-(((1aR,6bR)-3-氟-1a-甲基-5-(三氟甲基)-1,1a-二氫-6bH-環丙[b]苯并呋喃-6b-基)甲基)-7-(4-甲基-1H-咪唑-1-基)-3,4-二氫-2H-吡啶并[1,2-a]吡-1,6-二酮,或其醫藥上可接受之鹽。
- 一種如請求項1至12中任一項之化合物或其醫藥上可接受之鹽之用途,其係用於製備減少有需要個體中澱粉樣β(Aβ)蛋白質之產生之藥物。
- 一種醫藥組合物,其包括如請求項1至12中任一項之化合物,或其醫藥上可接受之鹽,及醫藥上可接受之賦形劑。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562111222P | 2015-02-03 | 2015-02-03 | |
US62/111,222 | 2015-02-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201630913A TW201630913A (zh) | 2016-09-01 |
TWI616445B true TWI616445B (zh) | 2018-03-01 |
Family
ID=55299692
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105103193A TWI616445B (zh) | 2015-02-03 | 2016-02-01 | 新穎環丙苯并呋喃基吡啶并吡二酮類 |
Country Status (22)
Country | Link |
---|---|
US (2) | US20160222007A1 (zh) |
EP (1) | EP3253755B1 (zh) |
JP (1) | JP6628805B2 (zh) |
KR (1) | KR102000382B1 (zh) |
CN (1) | CN107406445B (zh) |
AR (1) | AR103582A1 (zh) |
AU (1) | AU2016214102B2 (zh) |
BR (1) | BR112017015693A2 (zh) |
CA (1) | CA2919338A1 (zh) |
DK (1) | DK3253755T3 (zh) |
EA (1) | EA033423B1 (zh) |
EC (1) | ECSP17050310A (zh) |
ES (1) | ES2818806T3 (zh) |
IL (1) | IL253635A0 (zh) |
MX (1) | MX368391B (zh) |
PE (1) | PE20171318A1 (zh) |
PH (1) | PH12017501369A1 (zh) |
SG (1) | SG11201705780PA (zh) |
TN (1) | TN2017000342A1 (zh) |
TW (1) | TWI616445B (zh) |
UY (1) | UY36546A (zh) |
WO (1) | WO2016125048A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102271305B1 (ko) | 2020-05-21 | 2021-06-30 | 주식회사 아리바이오 | 치매 예방 및 치료용 조성물 |
CN111978324A (zh) * | 2020-08-28 | 2020-11-24 | 开封康诺药业有限公司 | 一种多索茶碱的晶型及其制备方法 |
KR102272907B1 (ko) | 2020-11-05 | 2021-07-05 | 주식회사 아리바이오 | 치매 예방 및 치료용 조성물 |
KR102272910B1 (ko) | 2021-01-28 | 2021-07-06 | 주식회사 아리바이오 | 당뇨병을 동반한 치매 예방 및 치료용 조성물 |
KR102311224B1 (ko) | 2021-04-23 | 2021-10-13 | 주식회사 아리바이오 | Pde5 억제제와 글루코코르티코이드 수용체 길항제 병용투여를 통한 치매 예방 및 치료용 조성물 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201425311A (zh) * | 2012-09-21 | 2014-07-01 | Pfizer | 新穎之雙環吡啶酮 |
Family Cites Families (124)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2007107A (en) | 1934-03-07 | 1935-07-02 | Bottrill David Hugh | Combined soap and massage articles |
GB1419789A (en) | 1972-08-02 | 1975-12-31 | Pfizer | 2-trifluoromethyl-4-quinolinols |
WO1992000075A1 (en) | 1990-06-29 | 1992-01-09 | Pfizer Inc. | Pyridopyrazine derivatives for treating substance abuse and addiction |
DE69315920T2 (de) | 1992-09-04 | 1998-06-10 | Takeda Chemical Industries Ltd | Kondensierte heterozyklische Verbindungen, deren Herstellung und Verwendung |
ATE239797T1 (de) | 1993-01-25 | 2003-05-15 | Takeda Chemical Industries Ltd | Antikörper gegen beta-amyloid oder derivative davon und seine verwendung |
EP0733632B1 (en) | 1995-03-24 | 2003-06-04 | Takeda Chemical Industries, Ltd. | Cyclic compounds, their production and use as tachykinin receptor antagonists |
DE19709877A1 (de) | 1997-03-11 | 1998-09-17 | Bayer Ag | 1,5-Dihydro-pyrazolo[3,4-d]-pyrimidinon-derivate |
AU743827B2 (en) | 1997-04-09 | 2002-02-07 | Intellect Neurosciences, Inc. | Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof |
US8173127B2 (en) | 1997-04-09 | 2012-05-08 | Intellect Neurosciences, Inc. | Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof |
GB9722520D0 (en) | 1997-10-24 | 1997-12-24 | Pfizer Ltd | Compounds |
US6743427B1 (en) | 1997-12-02 | 2004-06-01 | Neuralab Limited | Prevention and treatment of amyloidogenic disease |
TWI239847B (en) | 1997-12-02 | 2005-09-21 | Elan Pharm Inc | N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease |
CN1229296C (zh) | 1998-03-03 | 2005-11-30 | Ppg工业俄亥俄公司 | 浸渍玻璃纤维束以及包括它的产品 |
US20020132817A1 (en) | 1998-03-19 | 2002-09-19 | Hideaki Natsugari | Heterocyclic compounds, their production and use |
CA2352612A1 (en) | 1998-11-27 | 2000-06-08 | Hideo Fukui | Pharmaceuticals |
WO2001062801A2 (en) | 2000-02-24 | 2001-08-30 | Washington University | Humanized antibodies that sequester amyloid beta peptide |
DE10045112A1 (de) | 2000-09-11 | 2002-03-21 | Merck Patent Gmbh | Verwendung von Indolderivaten zur Behandlung von Erkrankungen des zentralen Nervensystems |
AU3976402A (en) | 2000-11-03 | 2002-06-03 | Proteotech Inc | Methods of isolating amyloid-inhibiting compounds and use of compounds isolated from uncaria tomentosa and related plants |
WO2003016466A2 (en) | 2001-08-17 | 2003-02-27 | Eli Lilly And Company | ANTI-Aβ ANTIBODIES |
US20030195205A1 (en) | 2001-11-02 | 2003-10-16 | Pfizer Inc. | PDE9 inhibitors for treating cardiovascular disorders |
DE10238724A1 (de) | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
DE10238723A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
CA2498111A1 (en) | 2002-09-11 | 2004-03-25 | Merck & Co., Inc. | Dihydroxypyridopyrazine-1,6-dione compounds useful as hiv integrase inhibitors |
CA2501799C (en) | 2002-10-09 | 2008-06-17 | Pfizer Products Inc. | Pyrazole compounds for treatment of neurodegenerative disorders |
WO2004032868A2 (en) | 2002-10-09 | 2004-04-22 | Rinat Neuroscience Corp. | Methods of treating alzheimer's disease using antibodies directed against amyloid beta peptide and compositions thereof |
AU2003301439A1 (en) | 2002-10-16 | 2004-05-04 | Gilead Sciences, Inc. | Pre-organized tricyclic integrase inhibitor compounds |
US20040220186A1 (en) | 2003-04-30 | 2004-11-04 | Pfizer Inc. | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease |
BRPI0410630A (pt) | 2003-06-19 | 2006-06-13 | Pfizer Prod Inc | antagonista de nk1 |
CA2534532A1 (en) | 2003-08-21 | 2005-03-10 | Pfizer Products, Inc. | Compounds for the treatment of neurodegenerative disorders |
WO2005025616A1 (ja) | 2003-09-09 | 2005-03-24 | Takeda Pharmaceutical Company Limited | 抗体の用途 |
GB0327319D0 (en) | 2003-11-24 | 2003-12-24 | Pfizer Ltd | Novel pharmaceuticals |
US7572799B2 (en) | 2003-11-24 | 2009-08-11 | Pfizer Inc | Pyrazolo[4,3-d]pyrimidines as Phosphodiesterase Inhibitors |
US20070155731A1 (en) | 2004-01-28 | 2007-07-05 | Gabor Butora | Aminocyclopentyl pyridopyrazinone modulators of chemokine receptor activity |
CA2555071A1 (en) | 2004-02-02 | 2005-09-01 | Pfizer Products Inc. | Histamine-3 receptor modulators |
WO2005092099A1 (en) | 2004-03-09 | 2005-10-06 | Merck & Co., Inc. | Hiv integrase inhibitors |
GEP20084420B (en) | 2004-03-23 | 2008-07-10 | Pfizer Prod Inc | Use of imidazole compounds for the treatment of neurodegenerative disorders |
AU2005249363A1 (en) | 2004-04-14 | 2005-12-15 | Zhenhong R. Cai | Phosphonate analogs of HIV integrase inhibitor compounds |
US7456164B2 (en) | 2004-05-07 | 2008-11-25 | Pfizer, Inc | 3- or 4-monosubtituted phenol and thiophenol derivatives useful as H3 ligands |
EP1595881A1 (en) | 2004-05-12 | 2005-11-16 | Pfizer Limited | Tetrahydronaphthyridine derivates useful as histamine H3 receptor ligands |
JP5042828B2 (ja) | 2004-07-30 | 2012-10-03 | ライナット ニューロサイエンス コーポレイション | アミロイド−ベータ・ペプチドに対して向けられる抗体、および該抗体を用いる方法 |
GB0423356D0 (en) | 2004-10-21 | 2004-11-24 | Merck Sharp & Dohme | Therapeutic agents |
US20090074775A1 (en) | 2004-12-22 | 2009-03-19 | David Michael Holtzman | Use Of Anti-AB Antibody To Treat Traumatic Brain Injury |
UY29504A1 (es) | 2005-04-29 | 2006-10-31 | Rinat Neuroscience Corp | Anticuerpos dirigidos contra el péptido amiloide beta y métodos que utilizan los mismos. |
EP1881825B1 (en) | 2005-05-10 | 2013-07-24 | Merck Sharp & Dohme Corp. | Hiv integrase inhibitors |
BRPI0609225A2 (pt) | 2005-05-12 | 2010-03-09 | Pfizer | formas cristalinas anidras de n-[1-(2-etoxietil)-5-(n-etil-n-metilamino)-7-(4-metilpiridi n-2-il-amino)-1h-pirazolo[4,3-d]pirimidina-3-carbonil] metanossulfonamida, composição farmacêutica compreendendo as mesmas e uso das mesmas |
CA2608672A1 (en) | 2005-05-24 | 2006-11-30 | Pharmacia & Upjohn Company Llc | Pyridine [3,4-b] pyrazinones as pde-5 inhibitors |
CA2603830A1 (en) | 2005-05-24 | 2006-11-30 | Pharmacia & Upjohn Co Llc | PYRIDINE [2,3-B] PYRAZINONES |
WO2006126083A1 (en) | 2005-05-24 | 2006-11-30 | Pharmacia & Upjohn Company Llc | Pyridine [3 , 4-b] pyrazinone compounds as pde-5 inhibitors |
CA2607499C (en) | 2005-06-22 | 2010-11-30 | Pfizer Products Inc. | Histamine-3 receptor antagonists |
US8158673B2 (en) | 2005-10-27 | 2012-04-17 | Pfizer Inc. | Histamine-3 receptor antagonists |
WO2007061923A2 (en) | 2005-11-18 | 2007-05-31 | Takeda San Diego, Inc. | Glucokinase activators |
US20070117839A1 (en) | 2005-11-24 | 2007-05-24 | Eisai R&D Management Co., Ltd. | Two cyclic cinnamide compound |
NZ568050A (en) | 2005-11-24 | 2010-09-30 | Eisai R&D Man Co Ltd | Morpholine type cinnamide compound |
WO2007063385A2 (en) | 2005-12-01 | 2007-06-07 | Pfizer Products Inc. | Spirocyclic amine histamine-3 receptor antagonists |
WO2007069053A1 (en) | 2005-12-14 | 2007-06-21 | Pfizer Products Inc. | Benzimidazole antagonists of the h-3 receptor |
KR20080095885A (ko) | 2006-01-20 | 2008-10-29 | 쉐링 코포레이션 | 벤젠설포닐-크로만, 티오크로만, 테트라하이드로나프탈렌 및 관련된 감마 세크라타제 억제제 |
WO2007088462A1 (en) | 2006-02-01 | 2007-08-09 | Pfizer Products Inc. | Spirochromane antagonists of the h-3 receptor |
WO2007088450A2 (en) | 2006-02-01 | 2007-08-09 | Pfizer Products Inc. | Chromane antagonist of the h-3 receptor |
WO2007099423A1 (en) | 2006-03-02 | 2007-09-07 | Pfizer Products Inc. | 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists |
TWI378091B (en) | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
US20090163482A1 (en) | 2006-03-13 | 2009-06-25 | Mchardy Stanton Furst | Tetralines antagonists of the h-3 receptor |
MEP23808A (en) | 2006-04-21 | 2010-06-10 | Pfizer Prod Inc | Pyridine[3,4-b]pyrazinones |
WO2007136714A2 (en) | 2006-05-16 | 2007-11-29 | Gilead Sciences, Inc. | Integrase inhibitors |
KR20090018963A (ko) | 2006-05-19 | 2009-02-24 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 우레아계 신나미드 유도체 |
WO2007138431A2 (en) | 2006-05-30 | 2007-12-06 | Pfizer Products Inc. | Azabicyclic ether histamine-3 antagonists |
EP2124933B1 (en) | 2007-01-22 | 2012-10-17 | Pfizer Products Inc. | Tosylate salt of a therapeutic compound and pharmaceutical compositions thereof |
AU2008215948A1 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of AD and related conditions |
AU2008216842A1 (en) | 2007-02-12 | 2008-08-21 | Merck Sharp & Dohme Corp. | Piperidine derivatives |
TW200848054A (en) | 2007-02-28 | 2008-12-16 | Eisai R&D Man Co Ltd | Two cyclic oxomorpholine derivatives |
WO2008137102A2 (en) | 2007-05-04 | 2008-11-13 | Torreypines Therapeutics, Inc. | Methods of modulating amyloid beta and compounds useful therefor |
JP5209043B2 (ja) | 2007-05-07 | 2013-06-12 | メルク・シャープ・アンド・ドーム・コーポレーション | ガンマセクレターゼ調節剤 |
BRPI0811993A2 (pt) | 2007-05-11 | 2014-11-18 | Hoffmann La Roche | " hetarilanilinas como moduladores para beta-amiloide ". |
EP2152695A2 (en) | 2007-06-01 | 2010-02-17 | Schering Corporation | Gamma secretase modulators |
CN101932578A (zh) | 2007-06-01 | 2010-12-29 | 先灵公司 | γ分泌酶调节剂 |
WO2008156580A1 (en) | 2007-06-13 | 2008-12-24 | Merck & Co., Inc. | Triazole derivatives for treating alzheimer's disease and related conditions |
JP2010532354A (ja) | 2007-06-29 | 2010-10-07 | シェーリング コーポレイション | γセクレターゼモジュレーター |
PE20090957A1 (es) | 2007-08-06 | 2009-07-13 | Schering Corp | Moduladores de gamma secretasa |
AU2008292390B2 (en) | 2007-08-31 | 2013-04-04 | Eisai R & D Management Co., Ltd. | Polycyclic compound |
US7935815B2 (en) | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
CA2698341A1 (en) | 2007-09-06 | 2009-03-12 | Schering Corporation | Gamma secretase modulators |
AR068636A1 (es) | 2007-09-28 | 2009-11-25 | Schering Corp | Moduladores de la gamma secretasa |
GB0720444D0 (en) | 2007-10-18 | 2007-11-28 | Glaxo Group Ltd | Novel compounds |
US8487099B2 (en) | 2007-11-05 | 2013-07-16 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
CA2707722A1 (en) | 2007-12-06 | 2009-06-11 | Schering Corporation | Gamma secretase modulators |
CA2708300A1 (en) | 2007-12-11 | 2009-06-18 | Schering Corporation | Gamma secretase modulators |
JP2011506460A (ja) | 2007-12-11 | 2011-03-03 | シェーリング コーポレイション | γ−セクレターゼモジュレーター |
JP2011506445A (ja) | 2007-12-13 | 2011-03-03 | アムジエン・インコーポレーテツド | γ−セクレターゼ調節剤 |
US7923450B2 (en) | 2008-01-11 | 2011-04-12 | Hoffmann-La Roche Inc. | Modulators for amyloid beta |
CN101952275B (zh) | 2008-02-22 | 2014-06-18 | 弗·哈夫曼-拉罗切有限公司 | β-淀粉样蛋白的调节剂 |
MX2010009454A (es) | 2008-02-29 | 2010-11-25 | Schering Corp | Moduladores de gamma secretasa para el tratamiento de la enfermedad de alzheimer. |
US20100137320A1 (en) | 2008-02-29 | 2010-06-03 | Schering Corporation | Gamma secretase modulators |
BRPI0912539A2 (pt) | 2008-05-05 | 2015-10-13 | Amgen Inc | composto, composição farmacêutica , método para tratar uma doença, e, uso do composto. |
TW201006801A (en) | 2008-07-18 | 2010-02-16 | Lilly Co Eli | Imidazole carboxamides |
US8685972B2 (en) | 2008-08-13 | 2014-04-01 | Merck Sharp & Dohme Corp. | Pyrimidine derivatives for treatment of alzheimer's disease |
WO2010019392A1 (en) | 2008-08-13 | 2010-02-18 | Merck Sharp & Dohme Corp. | Purine derivatives for treatment of alzheimer's disease |
WO2010025197A1 (en) | 2008-08-27 | 2010-03-04 | Eisai R&D Management Co., Ltd. | Process for preparing certain cinnamide compounds |
CA2736924C (en) | 2008-10-09 | 2016-06-28 | F. Hoffmann-La Roche Ag | Modulators for amyloid beta |
AU2009313524A1 (en) | 2008-11-06 | 2010-05-14 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
EP2356115A1 (en) | 2008-11-06 | 2011-08-17 | Schering Corporation | Gamma secretase modulators |
CA2742897A1 (en) | 2008-11-06 | 2010-05-14 | Astrazeneca Ab | Modulators of amyloid beta. |
KR101293421B1 (ko) | 2008-11-10 | 2013-08-05 | 에프. 호프만-라 로슈 아게 | 헤테로사이클릭 감마 분비효소 조절제 |
WO2010071741A1 (en) | 2008-12-16 | 2010-06-24 | Merck Sharp & Dohme Corp. | Triazole derivatives for treatment of alzheimer's disease |
WO2010077582A1 (en) | 2008-12-16 | 2010-07-08 | Merck Sharp & Dohme Corp. | Triazole derivatives for treatment of alzheimer's disease |
PA8854101A1 (es) | 2008-12-18 | 2010-07-27 | Ortho Mcneil Janssen Pharm | Derivados de imidazol bicíclicos sustituidos como moduladores de gamma secretasa |
AR074702A1 (es) | 2008-12-22 | 2011-02-02 | Schering Corp | Moduladores de gamma secretasa y composiciones farmaceuticas que los contienen |
CA2747744A1 (en) | 2008-12-22 | 2010-07-01 | Theodros Asberom | Gamma secretase modulators |
TW201030002A (en) | 2009-01-16 | 2010-08-16 | Bristol Myers Squibb Co | Bicyclic compounds for the reduction of beta-amyloid production |
KR20110113197A (ko) | 2009-02-06 | 2011-10-14 | 오르토-맥닐-얀센 파마슈티칼스 인코포레이티드 | 감마 세크레타제 조절제로서의 신규 치환된 비사이클릭 헤테로사이클릭 화합물 |
TWI461425B (zh) | 2009-02-19 | 2014-11-21 | Janssen Pharmaceuticals Inc | 作為伽瑪分泌酶調節劑之新穎經取代的苯并唑、苯并咪唑、唑并吡啶及咪唑并吡啶衍生物類 |
JP2012121809A (ja) | 2009-02-26 | 2012-06-28 | Eisai R & D Management Co Ltd | 多環式化合物の製造法およびその中間体 |
CA2749702A1 (en) | 2009-02-26 | 2010-09-02 | Eisai R&D Management Co., Ltd. | Salt of tetrahydrotriazolopyridine derivative and crystal thereof |
JP2012051805A (ja) | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | テトラヒドロトリアゾロピリジン誘導体の製造方法 |
JP2012051806A (ja) | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | イミダゾリルピラジン誘導体 |
JP2012051807A (ja) | 2009-02-26 | 2012-03-15 | Eisai R & D Management Co Ltd | アリールイミダゾール化合物 |
WO2010100606A1 (en) | 2009-03-03 | 2010-09-10 | Pfizer Inc. | Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators |
CA2776480A1 (en) | 2009-10-20 | 2011-04-28 | Pfizer Inc. | Novel heteroaryl imidazoles and heteroaryl triazoles as gamma-secretase modulators |
CA2830027C (en) | 2011-03-31 | 2016-04-26 | Pfizer Inc. | Novel bicyclic pyridinones |
BR112014028395B1 (pt) * | 2012-05-16 | 2022-02-01 | Janssen Pharmaceuticals, Inc. | Derivados 3,4-di-hidro-2h-pirido[1,2-a]pirazina-1,6-diona substituídos úteis para o tratamento de (inter alia) doença de alzheimer e composição farmacêutica que os compreende |
TWI614238B (zh) | 2012-09-21 | 2018-02-11 | 必治妥美雅史谷比公司 | 雙(氟烷基)-1,4-苯并二氮呯酮化合物及其前藥 |
AU2013366668B2 (en) | 2012-12-20 | 2017-07-20 | Janssen Pharmaceutica Nv | Novel tricyclic 3,4-dihydro-2H-pyrido[1,2-alpha]pyrazine -1,6-dione derivatives as gamma secretase modulators |
KR102171710B1 (ko) * | 2013-01-17 | 2020-10-30 | 얀센 파마슈티카 엔.브이. | 감마 세크레타제 조절 인자로서의 신규 치환 피리도-피페라지논 유도체 |
CA2925743C (en) | 2013-10-04 | 2018-03-06 | Pfizer Inc. | Novel bicyclic pyridinones as gamma-secretase modulators |
US11497586B2 (en) | 2014-03-21 | 2022-11-15 | Align Technology, Inc. | Segmented orthodontic appliance with elastics |
EA031419B1 (ru) * | 2014-04-01 | 2018-12-28 | Пфайзер Инк. | ХРОМЕН И 1,1a,2,7b-ТЕТРАГИДРОЦИКЛОПРОПА[c]ХРОМЕН ПИРИДОПИРАЗИНДИОНЫ В КАЧЕСТВЕ МОДУЛЯТОРА ГАММА-СЕКРЕТАЗЫ |
-
2016
- 2016-01-26 CN CN201680008557.7A patent/CN107406445B/zh not_active Expired - Fee Related
- 2016-01-26 PE PE2017001310A patent/PE20171318A1/es not_active Application Discontinuation
- 2016-01-26 EP EP16702810.9A patent/EP3253755B1/en active Active
- 2016-01-26 EA EA201700356A patent/EA033423B1/ru unknown
- 2016-01-26 TN TNP/2017/000342A patent/TN2017000342A1/en unknown
- 2016-01-26 SG SG11201705780PA patent/SG11201705780PA/en unknown
- 2016-01-26 BR BR112017015693A patent/BR112017015693A2/pt active Search and Examination
- 2016-01-26 MX MX2017010019A patent/MX368391B/es active IP Right Grant
- 2016-01-26 AU AU2016214102A patent/AU2016214102B2/en not_active Ceased
- 2016-01-26 DK DK16702810.9T patent/DK3253755T3/da active
- 2016-01-26 WO PCT/IB2016/050384 patent/WO2016125048A1/en active Application Filing
- 2016-01-26 JP JP2017540574A patent/JP6628805B2/ja not_active Expired - Fee Related
- 2016-01-26 ES ES16702810T patent/ES2818806T3/es active Active
- 2016-01-26 KR KR1020177024302A patent/KR102000382B1/ko active IP Right Grant
- 2016-01-29 CA CA2919338A patent/CA2919338A1/en not_active Abandoned
- 2016-02-01 UY UY0001036546A patent/UY36546A/es not_active Application Discontinuation
- 2016-02-01 TW TW105103193A patent/TWI616445B/zh not_active IP Right Cessation
- 2016-02-01 AR ARP160100286A patent/AR103582A1/es unknown
- 2016-02-02 US US15/012,954 patent/US20160222007A1/en not_active Abandoned
- 2016-12-19 US US15/382,778 patent/US9765073B2/en active Active
-
2017
- 2017-07-24 IL IL253635A patent/IL253635A0/en unknown
- 2017-07-28 PH PH12017501369A patent/PH12017501369A1/en unknown
- 2017-08-03 EC ECIEPI201750310A patent/ECSP17050310A/es unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201425311A (zh) * | 2012-09-21 | 2014-07-01 | Pfizer | 新穎之雙環吡啶酮 |
Also Published As
Publication number | Publication date |
---|---|
ES2818806T3 (es) | 2021-04-14 |
IL253635A0 (en) | 2017-09-28 |
JP2018508494A (ja) | 2018-03-29 |
UY36546A (es) | 2016-08-31 |
PE20171318A1 (es) | 2017-09-07 |
DK3253755T3 (da) | 2020-09-28 |
CN107406445B (zh) | 2019-12-24 |
MX2017010019A (es) | 2017-10-24 |
BR112017015693A2 (pt) | 2018-03-20 |
KR102000382B1 (ko) | 2019-07-15 |
AU2016214102A1 (en) | 2017-07-27 |
EP3253755B1 (en) | 2020-08-26 |
WO2016125048A1 (en) | 2016-08-11 |
MX368391B (es) | 2019-09-30 |
CN107406445A (zh) | 2017-11-28 |
US20160222007A1 (en) | 2016-08-04 |
ECSP17050310A (es) | 2017-11-30 |
US20170096428A1 (en) | 2017-04-06 |
EA201700356A1 (ru) | 2018-01-31 |
EP3253755A1 (en) | 2017-12-13 |
AU2016214102B2 (en) | 2018-09-27 |
CA2919338A1 (en) | 2016-08-03 |
KR20170113603A (ko) | 2017-10-12 |
US9765073B2 (en) | 2017-09-19 |
TN2017000342A1 (en) | 2019-01-16 |
EA033423B1 (ru) | 2019-10-31 |
JP6628805B2 (ja) | 2020-01-15 |
TW201630913A (zh) | 2016-09-01 |
AR103582A1 (es) | 2017-05-17 |
SG11201705780PA (en) | 2017-08-30 |
PH12017501369A1 (en) | 2017-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI568733B (zh) | 新穎的唏及1,1a,2,7b-四氫環丙烷[c]唏吡啶并吡化合物 | |
TWI500616B (zh) | 新穎之雙環吡啶酮 | |
US10131669B2 (en) | Pyrazolopyrimidine compounds | |
TWI577681B (zh) | 咪唑并嗒化合物 | |
TWI616445B (zh) | 新穎環丙苯并呋喃基吡啶并吡二酮類 | |
TW201443048A (zh) | 氮雜苯并咪唑化合物 | |
EP3052495B1 (en) | Novel bicyclic pyridinones as gamma-secretase modulators | |
OA18058A (en) | Chromene and 1,1 A,2,7B-tetrahydrocyclopropa[C]chromene pyridopyrazinediones as gamma-secretase modulators. | |
US20160229847A1 (en) | Novel bicyclic pyridinones as gamma-secretase modulators |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |