JP5292381B2 - 化合物、及び、アミロイドベータの調節におけるその使用 - Google Patents
化合物、及び、アミロイドベータの調節におけるその使用 Download PDFInfo
- Publication number
- JP5292381B2 JP5292381B2 JP2010268183A JP2010268183A JP5292381B2 JP 5292381 B2 JP5292381 B2 JP 5292381B2 JP 2010268183 A JP2010268183 A JP 2010268183A JP 2010268183 A JP2010268183 A JP 2010268183A JP 5292381 B2 JP5292381 B2 JP 5292381B2
- Authority
- JP
- Japan
- Prior art keywords
- substituted
- compound
- unsubstituted
- imidazolyl
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 270
- 108010090849 Amyloid beta-Peptides Proteins 0.000 title description 6
- 102000013455 Amyloid beta-Peptides Human genes 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 74
- -1 4-substituted imidazolyl Chemical group 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 25
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 125000000304 alkynyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 6
- LIFBOSHUEFDJAP-UHFFFAOYSA-N 1h-imidazol-2-yl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=NC=CN1 LIFBOSHUEFDJAP-UHFFFAOYSA-N 0.000 claims 4
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- VYWBSPUCUFVURC-UHFFFAOYSA-N (3-acetylpyridin-2-yl)boronic acid Chemical compound CC(=O)C1=CC=CN=C1B(O)O VYWBSPUCUFVURC-UHFFFAOYSA-N 0.000 claims 1
- UQSUSQGEEGWGGM-UHFFFAOYSA-N (3-fluoropyridin-2-yl)-(1h-imidazol-2-yl)methanone Chemical compound FC1=CC=CN=C1C(=O)C1=NC=CN1 UQSUSQGEEGWGGM-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims 1
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 83
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 37
- 201000010099 disease Diseases 0.000 abstract description 26
- 230000001594 aberrant effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
- 239000000243 solution Substances 0.000 description 61
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 60
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 60
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 60
- 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 60
- 210000004027 cell Anatomy 0.000 description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- 239000000047 product Substances 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 108010064397 amyloid beta-protein (1-40) Proteins 0.000 description 28
- 108090000765 processed proteins & peptides Proteins 0.000 description 28
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 208000024827 Alzheimer disease Diseases 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000003556 assay Methods 0.000 description 24
- 230000000694 effects Effects 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 241001465754 Metazoa Species 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 239000012634 fragment Substances 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 239000007788 liquid Substances 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- 241000894007 species Species 0.000 description 20
- 230000035772 mutation Effects 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 19
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 18
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 125000000623 heterocyclic group Chemical group 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- 238000003776 cleavage reaction Methods 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- 102000001708 Protein Isoforms Human genes 0.000 description 16
- 108010029485 Protein Isoforms Proteins 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 16
- 150000001413 amino acids Chemical class 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 239000002243 precursor Substances 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 230000007017 scission Effects 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- 210000004556 brain Anatomy 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 13
- 206010002022 amyloidosis Diseases 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 13
- 239000000839 emulsion Substances 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 150000003585 thioureas Chemical class 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 12
- 239000002775 capsule Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical class BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 125000001183 hydrocarbyl group Chemical group 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 230000009261 transgenic effect Effects 0.000 description 11
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 239000003937 drug carrier Substances 0.000 description 10
- 230000004770 neurodegeneration Effects 0.000 description 10
- 208000015122 neurodegenerative disease Diseases 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 206010012289 Dementia Diseases 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 238000009833 condensation Methods 0.000 description 9
- 230000005494 condensation Effects 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 238000004007 reversed phase HPLC Methods 0.000 description 9
- 239000006228 supernatant Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 208000010877 cognitive disease Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000008176 lyophilized powder Substances 0.000 description 8
- 208000027061 mild cognitive impairment Diseases 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- 238000004806 packaging method and process Methods 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 229930006000 Sucrose Natural products 0.000 description 7
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 7
- 125000000732 arylene group Chemical group 0.000 description 7
- 229920001577 copolymer Polymers 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 239000008187 granular material Substances 0.000 description 7
- 125000005549 heteroarylene group Chemical group 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 125000005647 linker group Chemical group 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000005720 sucrose Substances 0.000 description 7
- 229960004793 sucrose Drugs 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- 150000003672 ureas Chemical class 0.000 description 7
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical group NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 6
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 6
- 102100021257 Beta-secretase 1 Human genes 0.000 description 6
- 101000894895 Homo sapiens Beta-secretase 1 Proteins 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 230000003942 amyloidogenic effect Effects 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 6
- 210000004900 c-terminal fragment Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000004949 mass spectrometry Methods 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000001537 neural effect Effects 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000080 wetting agent Substances 0.000 description 6
- VLKASLAMPHOPRG-UHFFFAOYSA-N 1-[4-(5-bromo-1,3-thiazol-2-yl)phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1C1=NC=C(Br)S1 VLKASLAMPHOPRG-UHFFFAOYSA-N 0.000 description 5
- PNMYCRFFSIZENL-UHFFFAOYSA-N 2-bromo-1-[4-(5-bromo-1,3-thiazol-2-yl)phenyl]ethanone Chemical compound C1=CC(C(=O)CBr)=CC=C1C1=NC=C(Br)S1 PNMYCRFFSIZENL-UHFFFAOYSA-N 0.000 description 5
- LSQSIVBJGPNNHI-UHFFFAOYSA-N 2-bromo-1-[4-(5-ethyl-1h-imidazol-2-yl)phenyl]ethanone Chemical compound N1C(CC)=CN=C1C1=CC=C(C(=O)CBr)C=C1 LSQSIVBJGPNNHI-UHFFFAOYSA-N 0.000 description 5
- 208000037259 Amyloid Plaque Diseases 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 5
- 208000005145 Cerebral amyloid angiopathy Diseases 0.000 description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 5
- 239000005977 Ethylene Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000007450 amyloidogenic pathway Effects 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 125000002619 bicyclic group Chemical group 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000008121 dextrose Substances 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000006215 rectal suppository Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 150000003557 thiazoles Chemical class 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- LCSOADGMTOXCFD-UHFFFAOYSA-N 1-[4-(4-ethylimidazol-1-yl)phenyl]ethanone Chemical compound C1=NC(CC)=CN1C1=CC=C(C(C)=O)C=C1 LCSOADGMTOXCFD-UHFFFAOYSA-N 0.000 description 4
- WEFGGGDJPYTAPQ-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)ethanethioamide Chemical compound NC(=S)CC1=CC=C(Cl)C(Cl)=C1 WEFGGGDJPYTAPQ-UHFFFAOYSA-N 0.000 description 4
- LKQQZQZAQABIRT-UHFFFAOYSA-N 2-bromo-1-[4-(4-methylimidazol-1-yl)phenyl]ethanone Chemical compound C1=NC(C)=CN1C1=CC=C(C(=O)CBr)C=C1 LKQQZQZAQABIRT-UHFFFAOYSA-N 0.000 description 4
- DXCQPISUWGKLIO-UHFFFAOYSA-N 2-bromo-1-[6-(4-methylimidazol-1-yl)pyridin-3-yl]ethanone Chemical compound C1=NC(C)=CN1C1=CC=C(C(=O)CBr)C=N1 DXCQPISUWGKLIO-UHFFFAOYSA-N 0.000 description 4
- 206010059245 Angiopathy Diseases 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 230000007082 Aβ accumulation Effects 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 201000010374 Down Syndrome Diseases 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 4
- 230000005856 abnormality Effects 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 125000002993 cycloalkylene group Chemical group 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000001962 electrophoresis Methods 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 239000008297 liquid dosage form Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- VOPMOBKGTXVXTO-UHFFFAOYSA-N n-(4-bromophenyl)-n-ethyl-4-(2-imidazol-1-ylphenyl)-1,3-thiazol-2-amine Chemical compound C=1C=C(Br)C=CC=1N(CC)C(SC=1)=NC=1C1=CC=CC=C1N1C=CN=C1 VOPMOBKGTXVXTO-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- OBQRODBYVNIZJU-UHFFFAOYSA-N (4-acetylphenyl)boronic acid Chemical compound CC(=O)C1=CC=C(B(O)O)C=C1 OBQRODBYVNIZJU-UHFFFAOYSA-N 0.000 description 3
- YDPOFJJODAJOQG-UHFFFAOYSA-N 1-[1-[4-[2-[4-(diethylamino)-2-methylanilino]-1,3-thiazol-4-yl]phenyl]triazol-4-yl]ethanol Chemical compound CC1=CC(N(CC)CC)=CC=C1NC1=NC(C=2C=CC(=CC=2)N2N=NC(=C2)C(C)O)=CS1 YDPOFJJODAJOQG-UHFFFAOYSA-N 0.000 description 3
- MBIOOPAWRAXSCZ-UHFFFAOYSA-N 2-bromo-1-[4-(4-methylimidazol-1-yl)phenyl]propan-1-one Chemical compound C1=CC(C(=O)C(Br)C)=CC=C1N1C=C(C)N=C1 MBIOOPAWRAXSCZ-UHFFFAOYSA-N 0.000 description 3
- GOYAFWRIXVODLF-UHFFFAOYSA-N 4-(4-imidazol-1-ylphenyl)-n-(4-piperidin-1-ylphenyl)-1,3-thiazol-2-amine Chemical compound C1CCCCN1C(C=C1)=CC=C1NC1=NC(C=2C=CC(=CC=2)N2C=NC=C2)=CS1 GOYAFWRIXVODLF-UHFFFAOYSA-N 0.000 description 3
- 208000024667 ABeta amyloidosis, Dutch type Diseases 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- 0 CC(*)C(C)(CCCCCCC1)C1N1NNNN1 Chemical compound CC(*)C(C)(CCCCCCC1)C1N1NNNN1 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 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 3
- 208000009829 Lewy Body Disease Diseases 0.000 description 3
- 208000012902 Nervous system disease Diseases 0.000 description 3
- 208000025966 Neurological disease Diseases 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 206010044688 Trisomy 21 Diseases 0.000 description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 150000001448 anilines Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940127204 compound 29 Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000036536 dutch type ABeta amyloidosis Diseases 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- QORVDGQLPPAFRS-XPSHAMGMSA-N galantamine hydrobromide Chemical group 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
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- ZUFVXZVXEJHHBN-UHFFFAOYSA-N hydron;1,2,3,4-tetrahydroacridin-9-amine;chloride Chemical compound [Cl-].C1=CC=C2C([NH3+])=C(CCCC3)C3=NC2=C1 ZUFVXZVXEJHHBN-UHFFFAOYSA-N 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- RQJTWDQTFKNVFQ-UHFFFAOYSA-N n-(4-bromophenyl)-4-(4-imidazol-1-ylphenyl)-n-(2-trimethylsilylethoxymethyl)-1,3-thiazol-2-amine Chemical compound C=1C=C(Br)C=CC=1N(COCC[Si](C)(C)C)C(SC=1)=NC=1C(C=C1)=CC=C1N1C=CN=C1 RQJTWDQTFKNVFQ-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 102200131815 rs63750264 Human genes 0.000 description 3
- 238000003118 sandwich ELISA Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 208000002320 spinal muscular atrophy Diseases 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- UVQWMZWLGCKIJT-UHFFFAOYSA-N tert-butyl n-(4-bromophenyl)-n-[4-(4-imidazol-1-ylphenyl)-1,3-thiazol-2-yl]carbamate Chemical compound C=1C=C(Br)C=CC=1N(C(=O)OC(C)(C)C)C(SC=1)=NC=1C(C=C1)=CC=C1N1C=CN=C1 UVQWMZWLGCKIJT-UHFFFAOYSA-N 0.000 description 3
- ODERQJGKXJGUSN-UHFFFAOYSA-N tert-butyl n-(4-ethoxy-2,5-dimethylphenyl)carbamate Chemical compound CCOC1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1C ODERQJGKXJGUSN-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 238000003260 vortexing Methods 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- FVQYTQBZPNEHIZ-UHFFFAOYSA-N (2-methyl-5-pyrrol-1-ylphenyl)thiourea Chemical compound C1=C(NC(N)=S)C(C)=CC=C1N1C=CC=C1 FVQYTQBZPNEHIZ-UHFFFAOYSA-N 0.000 description 2
- YKHPCLABGJYUMY-UHFFFAOYSA-N (4-ethoxy-2,5-dimethylphenyl)thiourea Chemical compound CCOC1=CC(C)=C(NC(N)=S)C=C1C YKHPCLABGJYUMY-UHFFFAOYSA-N 0.000 description 2
- XOXVILMPAVSNIV-UHFFFAOYSA-N (4-hydroxy-2,5-dimethylphenyl)thiourea Chemical compound CC1=CC(NC(N)=S)=C(C)C=C1O XOXVILMPAVSNIV-UHFFFAOYSA-N 0.000 description 2
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 2
- KLDVRZFPJKVZAZ-UHFFFAOYSA-N (5-bromo-2-methylphenyl)thiourea Chemical compound CC1=CC=C(Br)C=C1NC(N)=S KLDVRZFPJKVZAZ-UHFFFAOYSA-N 0.000 description 2
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- AKVFGYABFRPYER-UHFFFAOYSA-N 1-[6-(4-methylimidazol-1-yl)pyridin-3-yl]ethanone Chemical compound N1=CC(C(=O)C)=CC=C1N1C=C(C)N=C1 AKVFGYABFRPYER-UHFFFAOYSA-N 0.000 description 2
- AEYNYHSOGNVQRY-UHFFFAOYSA-N 1-n,1-n-diethyl-4-methylbenzene-1,3-diamine Chemical compound CCN(CC)C1=CC=C(C)C(N)=C1 AEYNYHSOGNVQRY-UHFFFAOYSA-N 0.000 description 2
- WGIMXKDCVCTHGW-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCCO WGIMXKDCVCTHGW-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 2
- KNPYXFJGOUDCIU-UHFFFAOYSA-N 2-[(3,4-dichlorophenyl)methyl]-4-[4-(4-methylimidazol-1-yl)phenyl]-1,3-thiazole Chemical compound C1=NC(C)=CN1C1=CC=C(C=2N=C(CC=3C=C(Cl)C(Cl)=CC=3)SC=2)C=C1 KNPYXFJGOUDCIU-UHFFFAOYSA-N 0.000 description 2
- WDGCBNTXZHJTHJ-UHFFFAOYSA-N 2h-1,3-oxazol-2-id-4-one Chemical class O=C1CO[C-]=N1 WDGCBNTXZHJTHJ-UHFFFAOYSA-N 0.000 description 2
- MJKVTPMWOKAVMS-UHFFFAOYSA-N 3-hydroxy-1-benzopyran-2-one Chemical compound C1=CC=C2OC(=O)C(O)=CC2=C1 MJKVTPMWOKAVMS-UHFFFAOYSA-N 0.000 description 2
- XDNZKXSSBKVMAT-UHFFFAOYSA-N 3-n,3-n-diethyl-4,6-dimethylbenzene-1,3-diamine Chemical compound CCN(CC)C1=CC(N)=C(C)C=C1C XDNZKXSSBKVMAT-UHFFFAOYSA-N 0.000 description 2
- DGFGRYUGZNOALD-UHFFFAOYSA-N 4-ethoxy-2,5-dimethylaniline Chemical compound CCOC1=CC(C)=C(N)C=C1C DGFGRYUGZNOALD-UHFFFAOYSA-N 0.000 description 2
- VSXMMRWKKMCSEP-UHFFFAOYSA-N 4-n,4-n-diethyl-2,5-dimethylbenzene-1,4-diamine Chemical compound CCN(CC)C1=CC(C)=C(N)C=C1C VSXMMRWKKMCSEP-UHFFFAOYSA-N 0.000 description 2
- HYQAPJKLBPOOMP-UHFFFAOYSA-N 4-n,4-n-diethyl-2,5-dimethylbenzene-1,4-diamine;thiourea Chemical compound NC(N)=S.CCN(CC)C1=CC(C)=C(N)C=C1C HYQAPJKLBPOOMP-UHFFFAOYSA-N 0.000 description 2
- NJQHZENQKNIRSY-UHFFFAOYSA-N 5-ethyl-1h-imidazole Chemical compound CCC1=CNC=N1 NJQHZENQKNIRSY-UHFFFAOYSA-N 0.000 description 2
- JQXMAWLOVPRNBN-UHFFFAOYSA-N 5-ethyl-4-(4-methylphenyl)sulfonyl-4,5-dihydro-1,3-oxazole Chemical compound CCC1OC=NC1S(=O)(=O)C1=CC=C(C)C=C1 JQXMAWLOVPRNBN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- 206010007509 Cardiac amyloidosis Diseases 0.000 description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 101000894883 Homo sapiens Beta-secretase 2 Proteins 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000015499 Presenilins Human genes 0.000 description 2
- 108010050254 Presenilins Proteins 0.000 description 2
- 108091000054 Prion Proteins 0.000 description 2
- 208000024777 Prion disease Diseases 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 description 2
- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000003954 Spinal Muscular Atrophies of Childhood Diseases 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 239000008122 artificial sweetener Substances 0.000 description 2
- 235000021311 artificial sweeteners Nutrition 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 208000029028 brain injury Diseases 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 208000025434 cerebellar degeneration Diseases 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125844 compound 46 Drugs 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 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 2
- 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 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- UKWLRLAKGMZXJC-QIECWBMSSA-L disodium;[4-chloro-3-[(3r,5s)-1-chloro-3'-methoxyspiro[adamantane-4,4'-dioxetane]-3'-yl]phenyl] phosphate Chemical compound [Na+].[Na+].O1OC2([C@@H]3CC4C[C@H]2CC(Cl)(C4)C3)C1(OC)C1=CC(OP([O-])([O-])=O)=CC=C1Cl UKWLRLAKGMZXJC-QIECWBMSSA-L 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 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 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002084 enol ethers Chemical class 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
- 208000015756 familial Alzheimer disease Diseases 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000008369 fruit flavor Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000006588 heterocycloalkylene group Chemical group 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 201000004815 juvenile spinal muscular atrophy Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 229960005015 local anesthetics Drugs 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 208000005264 motor neuron disease Diseases 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- VVYJLIDBZOEQDH-UHFFFAOYSA-N n-ethyl-4-(4-imidazol-1-ylphenyl)-n-(4-morpholin-4-ylphenyl)-1,3-thiazol-2-amine Chemical compound C=1C=C(N2CCOCC2)C=CC=1N(CC)C(SC=1)=NC=1C(C=C1)=CC=C1N1C=CN=C1 VVYJLIDBZOEQDH-UHFFFAOYSA-N 0.000 description 2
- KOFWDCGDINTHJC-UHFFFAOYSA-N n-ethyl-4-(4-imidazol-1-ylphenyl)-n-(4-piperidin-1-ylphenyl)-1,3-thiazol-2-amine Chemical compound C=1C=C(N2CCCCC2)C=CC=1N(CC)C(SC=1)=NC=1C(C=C1)=CC=C1N1C=CN=C1 KOFWDCGDINTHJC-UHFFFAOYSA-N 0.000 description 2
- 230000000626 neurodegenerative effect Effects 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920005597 polymer membrane Polymers 0.000 description 2
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 2
- 229940093625 propylene glycol monostearate Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 229940100618 rectal suppository Drugs 0.000 description 2
- 102200131751 rs63750579 Human genes 0.000 description 2
- 102220087752 rs754847137 Human genes 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class 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 2
- 230000028327 secretion Effects 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 235000019615 sensations Nutrition 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000003352 sequestering agent Substances 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- 229920002379 silicone rubber Polymers 0.000 description 2
- 239000004945 silicone rubber Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- HYAXOCCNXTUFSN-UHFFFAOYSA-N tert-butyl n-(4-hydroxy-2,5-dimethylphenyl)carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=C(C)C=C1O HYAXOCCNXTUFSN-UHFFFAOYSA-N 0.000 description 2
- XUBNRDSESBVDDV-UHFFFAOYSA-N tert-butyl n-(5-amino-2,4-dimethylphenyl)carbamate Chemical compound CC1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1N XUBNRDSESBVDDV-UHFFFAOYSA-N 0.000 description 2
- YGJCBABWDZHKCS-UHFFFAOYSA-N tert-butyl n-[4-(diethylamino)-2,5-dimethylphenyl]carbamate Chemical compound CCN(CC)C1=CC(C)=C(NC(=O)OC(C)(C)C)C=C1C YGJCBABWDZHKCS-UHFFFAOYSA-N 0.000 description 2
- QSGJKUDSRPEQKY-UHFFFAOYSA-N tert-butyl n-[5-(diethylamino)-2,4-dimethylphenyl]carbamate Chemical compound CCN(CC)C1=CC(NC(=O)OC(C)(C)C)=C(C)C=C1C QSGJKUDSRPEQKY-UHFFFAOYSA-N 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 125000000101 thioether group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 229940117013 triethanolamine oleate Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 208000032527 type III spinal muscular atrophy Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-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
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- LXQSOEIIWYHVFA-UHFFFAOYSA-N (3-methylsulfanylphenyl)thiourea Chemical compound CSC1=CC=CC(NC(N)=S)=C1 LXQSOEIIWYHVFA-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MRVQULNOKCOGHC-UHFFFAOYSA-N (4-bromophenyl)thiourea Chemical compound NC(=S)NC1=CC=C(Br)C=C1 MRVQULNOKCOGHC-UHFFFAOYSA-N 0.000 description 1
- IOQORVDNYPOZPL-VQTJNVASSA-N (5S,6R)-5-(4-chlorophenyl)-6-cyclopropyl-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]-5,6-dihydro-2H-1,2,4-oxadiazine Chemical compound ClC1=CC=C(C=C1)[C@@H]1NC(=NO[C@@H]1C1CC1)C1=NC(=C(C=C1)N1C=NC(=C1)C)OC IOQORVDNYPOZPL-VQTJNVASSA-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
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- ACTKAGSPIFDCMF-UHFFFAOYSA-N 1,3-oxazol-2-amine Chemical group NC1=NC=CO1 ACTKAGSPIFDCMF-UHFFFAOYSA-N 0.000 description 1
- FSZOBSMJJFHVCQ-UHFFFAOYSA-N 1-(3,4-difluorophenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(F)C(F)=C1 FSZOBSMJJFHVCQ-UHFFFAOYSA-N 0.000 description 1
- QIJNVLLXIIPXQT-UHFFFAOYSA-N 1-(4-fluorophenyl)propan-1-one Chemical compound CCC(=O)C1=CC=C(F)C=C1 QIJNVLLXIIPXQT-UHFFFAOYSA-N 0.000 description 1
- UXSNZYGTQTXRAD-UHFFFAOYSA-N 1-(6-chloropyridin-3-yl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)N=C1 UXSNZYGTQTXRAD-UHFFFAOYSA-N 0.000 description 1
- IAYSDKUKIIYRRA-UHFFFAOYSA-N 1-(isocyanatomethylsulfonyl)-4-methylbenzene Chemical compound CC1=CC=C(S(=O)(=O)CN=C=O)C=C1 IAYSDKUKIIYRRA-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- XVBLEUZLLURXTF-UHFFFAOYSA-N 2,4-dimethylbenzene-1,3-diamine Chemical compound CC1=CC=C(N)C(C)=C1N XVBLEUZLLURXTF-UHFFFAOYSA-N 0.000 description 1
- XIBIQFJKUZZLLX-UHFFFAOYSA-N 2,5-dibromo-1,3-thiazole Chemical compound BrC1=CN=C(Br)S1 XIBIQFJKUZZLLX-UHFFFAOYSA-N 0.000 description 1
- BWAPJIHJXDYDPW-UHFFFAOYSA-N 2,5-dimethyl-p-phenylenediamine Chemical compound CC1=CC(N)=C(C)C=C1N BWAPJIHJXDYDPW-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- QWZNCAFWRZZJMA-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)acetonitrile Chemical compound ClC1=CC=C(CC#N)C=C1Cl QWZNCAFWRZZJMA-UHFFFAOYSA-N 0.000 description 1
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- RXNZFHIEDZEUQM-UHFFFAOYSA-N 2-bromo-1,3-thiazole Chemical compound BrC1=NC=CS1 RXNZFHIEDZEUQM-UHFFFAOYSA-N 0.000 description 1
- WLRIUCQUMKJOGT-UHFFFAOYSA-N 2-bromo-1-(4-pyrrolidin-1-ylphenyl)ethanone Chemical compound C1=CC(C(=O)CBr)=CC=C1N1CCCC1 WLRIUCQUMKJOGT-UHFFFAOYSA-N 0.000 description 1
- ZWJCWDDFXKJCFL-UHFFFAOYSA-N 2-bromo-1-[4-(4-methylpiperazin-1-yl)phenyl]ethanone Chemical compound C1CN(C)CCN1C1=CC=C(C(=O)CBr)C=C1 ZWJCWDDFXKJCFL-UHFFFAOYSA-N 0.000 description 1
- NWWCJFJCEIFBAZ-UHFFFAOYSA-N 2-methyl-5-pyrrol-1-ylaniline Chemical compound C1=C(N)C(C)=CC=C1N1C=CC=C1 NWWCJFJCEIFBAZ-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- ODJQKYXPKWQWNK-UHFFFAOYSA-N 3,3'-Thiobispropanoic acid Chemical compound OC(=O)CCSCCC(O)=O ODJQKYXPKWQWNK-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- DABFCUNCEHNAEJ-UHFFFAOYSA-N 3-n,3-n-diethyl-4,6-dimethyl-1-n-[4-[4-(4-methylimidazol-1-yl)phenyl]-1,3-thiazol-2-yl]benzene-1,3-diamine Chemical class C1=C(C)C(N(CC)CC)=CC(NC=2SC=C(N=2)C=2C=CC(=CC=2)N2C=C(C)N=C2)=C1C DABFCUNCEHNAEJ-UHFFFAOYSA-N 0.000 description 1
- FHJRKGXJBXPBGA-UHFFFAOYSA-N 4-(1,3-benzothiazol-2-yl)-n-methylaniline Chemical compound C1=CC(NC)=CC=C1C1=NC2=CC=CC=C2S1 FHJRKGXJBXPBGA-UHFFFAOYSA-N 0.000 description 1
- HEWFZFDGDJSVHH-UHFFFAOYSA-N 4-(4-imidazol-1-ylphenyl)-n-(4-methoxyphenyl)-1,3-oxazol-2-amine Chemical compound C1=CC(OC)=CC=C1NC1=NC(C=2C=CC(=CC=2)N2C=NC=C2)=CO1 HEWFZFDGDJSVHH-UHFFFAOYSA-N 0.000 description 1
- GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 description 1
- FGYNZFHVGOFCMD-KHVHPYDTSA-N 4-[(e)-2-[4-[(e)-2-(4-hydroxyphenyl)ethenyl]-3-methoxyphenyl]ethenyl]phenol Chemical compound C=1C=C(\C=C\C=2C=CC(O)=CC=2)C(OC)=CC=1\C=C\C1=CC=C(O)C=C1 FGYNZFHVGOFCMD-KHVHPYDTSA-N 0.000 description 1
- MMZSWFABOCYZAY-UHFFFAOYSA-N 4-[6-(4-methylimidazol-1-yl)pyridin-3-yl]-n-(2-methyl-5-pyrrol-1-ylphenyl)-1,3-thiazol-2-amine Chemical class C1=NC(C)=CN1C1=CC=C(C=2N=C(NC=3C(=CC=C(C=3)N3C=CC=C3)C)SC=2)C=N1 MMZSWFABOCYZAY-UHFFFAOYSA-N 0.000 description 1
- JSWVCUXQICMATE-UHFFFAOYSA-N 4-amino-2,5-dimethylphenol Chemical compound CC1=CC(O)=C(C)C=C1N JSWVCUXQICMATE-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 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
- PRLVCTDWJRXYAX-UHFFFAOYSA-N 4-n,4-n-diethyl-2,5-dimethyl-1-n-[4-[4-(4-methylimidazol-1-yl)phenyl]-1,3-thiazol-2-yl]benzene-1,4-diamine Chemical class C1=C(C)C(N(CC)CC)=CC(C)=C1NC1=NC(C=2C=CC(=CC=2)N2C=C(C)N=C2)=CS1 PRLVCTDWJRXYAX-UHFFFAOYSA-N 0.000 description 1
- RXQNKKRGJJRMKD-UHFFFAOYSA-N 5-bromo-2-methylaniline Chemical compound CC1=CC=C(Br)C=C1N RXQNKKRGJJRMKD-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010002025 Amyloidosis senile Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 102000007371 Ataxin-3 Human genes 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102100022548 Beta-hexosaminidase subunit alpha Human genes 0.000 description 1
- 102100021277 Beta-secretase 2 Human genes 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- GZZSUYFMRSRCAJ-UHFFFAOYSA-N C(C1)C11N=COC1 Chemical compound C(C1)C11N=COC1 GZZSUYFMRSRCAJ-UHFFFAOYSA-N 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- SKWYGDIRUDYDSU-UHFFFAOYSA-N CC([n]1cnc(C)c1)Br Chemical compound CC([n]1cnc(C)c1)Br SKWYGDIRUDYDSU-UHFFFAOYSA-N 0.000 description 1
- XVSAOSPGDUFLCH-UHFFFAOYSA-N CC(c(cc1)ccc1-[n]1cnc(C)c1)=O Chemical compound CC(c(cc1)ccc1-[n]1cnc(C)c1)=O XVSAOSPGDUFLCH-UHFFFAOYSA-N 0.000 description 1
- QNNAIPFRKRPOBO-BENRWUELSA-N CC/C(/N)=C/N(C=C)c(cc1)ccc1C(CBr)=O Chemical compound CC/C(/N)=C/N(C=C)c(cc1)ccc1C(CBr)=O QNNAIPFRKRPOBO-BENRWUELSA-N 0.000 description 1
- OEYBHZLFZPRSOB-UHFFFAOYSA-N CCN(CC)c1c(C)cc(C)c(NC(N)=S)c1 Chemical compound CCN(CC)c1c(C)cc(C)c(NC(N)=S)c1 OEYBHZLFZPRSOB-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- FXJVNINSOKCNJP-UHFFFAOYSA-N Cc(cc1)ccc1S(O)=O Chemical compound Cc(cc1)ccc1S(O)=O FXJVNINSOKCNJP-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
- 239000004709 Chlorinated polyethylene Substances 0.000 description 1
- 206010009346 Clonus Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000001039 Dystrophin Human genes 0.000 description 1
- 108010069091 Dystrophin Proteins 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
- 238000012286 ELISA Assay Methods 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 208000034846 Familial Amyloid Neuropathies Diseases 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000003736 Gerstmann-Straussler-Scheinker Disease Diseases 0.000 description 1
- 206010072075 Gerstmann-Straussler-Scheinker syndrome Diseases 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 206010019889 Hereditary neuropathic amyloidosis Diseases 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 101001018100 Homo sapiens Lysozyme C Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 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 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102100033468 Lysozyme C Human genes 0.000 description 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- FBTRXCHSTSIDIS-UHFFFAOYSA-N N-(furan-2-yl)-1,3-thiazol-2-amine Chemical class N=1C=CSC=1NC1=CC=CO1 FBTRXCHSTSIDIS-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 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 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 101710187081 OX-2 membrane glycoprotein Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000016222 Pancreatic disease Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 206010033885 Paraparesis Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229920012485 Plasticized Polyvinyl chloride Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- 229920002367 Polyisobutene Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000032319 Primary lateral sclerosis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000010757 Reduction Activity Effects 0.000 description 1
- 206010038357 Renal amyloidosis Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 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 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000021811 Sandhoff disease Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000002548 Spastic Paraparesis Diseases 0.000 description 1
- 208000020339 Spinal injury Diseases 0.000 description 1
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 208000032859 Synucleinopathies Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000022292 Tay-Sachs disease Diseases 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 239000003490 Thiodipropionic acid Substances 0.000 description 1
- 208000000323 Tourette Syndrome Diseases 0.000 description 1
- 208000030886 Traumatic Brain injury Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010046298 Upper motor neurone lesion Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010063661 Vascular encephalopathy Diseases 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- JXYHFGIKANBXOA-UHFFFAOYSA-N [4-(diethylamino)-2-methylphenyl]thiourea Chemical compound CCN(CC)C1=CC=C(NC(N)=S)C(C)=C1 JXYHFGIKANBXOA-UHFFFAOYSA-N 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 description 1
- 230000007815 allergy Effects 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
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960000510 ammonia Drugs 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 101150031224 app gene Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride 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
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 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
- 230000001588 bifunctional effect Effects 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 208000013677 cerebrovascular dementia Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960004926 chlorobutanol 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
- 235000012000 cholesterol Nutrition 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical class [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 230000003918 constitutive secretory pathway Effects 0.000 description 1
- 230000009519 contusion Effects 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 210000003618 cortical neuron Anatomy 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 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
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000008355 dextrose injection Substances 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000005105 dialkylarylsilyl group Chemical group 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 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
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics 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
- 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
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 229920005558 epichlorohydrin rubber Polymers 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- HQQADJVZYDDRJT-UHFFFAOYSA-N ethene;prop-1-ene Chemical group C=C.CC=C HQQADJVZYDDRJT-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229940108366 exelon Drugs 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 201000007891 familial visceral amyloidosis Diseases 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- CYEFKCRAAGLNHW-UHFFFAOYSA-N furan-3-ylboronic acid Chemical compound OB(O)C=1C=COC=1 CYEFKCRAAGLNHW-UHFFFAOYSA-N 0.000 description 1
- 229960002024 galantamine hydrobromide Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000008675 hereditary spastic paraplegia Diseases 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
- 238000013537 high throughput screening Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960004337 hydroquinone Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 208000036260 idiopathic disease Diseases 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229920000554 ionomer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960000829 kaolin Drugs 0.000 description 1
- 206010023497 kuru Diseases 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229940041669 mercury Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- JKENWCYKZBBBTB-UHFFFAOYSA-N n,n-diethyl-4-methyl-3-nitroaniline Chemical compound CCN(CC)C1=CC=C(C)C([N+]([O-])=O)=C1 JKENWCYKZBBBTB-UHFFFAOYSA-N 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 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
- 239000004533 oil dispersion Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000024691 pancreas disease Diseases 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 238000009512 pharmaceutical packaging Methods 0.000 description 1
- 239000011129 pharmaceutical packaging material Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229960000969 phenyl salicylate Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001490 poly(butyl methacrylate) polymer Polymers 0.000 description 1
- 229920001084 poly(chloroprene) Polymers 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229920001195 polyisoprene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000001282 primary progressive aphasia Diseases 0.000 description 1
- 208000022256 primary systemic amyloidosis Diseases 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
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 1
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- GWHQHAUAXRMMOT-MBANBULQSA-N rivastigmine tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 GWHQHAUAXRMMOT-MBANBULQSA-N 0.000 description 1
- 102200131747 rs1800557 Human genes 0.000 description 1
- 102200131812 rs63749964 Human genes 0.000 description 1
- 102200131746 rs63750066 Human genes 0.000 description 1
- 102200131810 rs63750264 Human genes 0.000 description 1
- 102200131813 rs63750264 Human genes 0.000 description 1
- 102200131750 rs63750579 Human genes 0.000 description 1
- 102200131756 rs63750643 Human genes 0.000 description 1
- 102200131752 rs63750671 Human genes 0.000 description 1
- 102220032734 rs63750851 Human genes 0.000 description 1
- 102220032732 rs63750868 Human genes 0.000 description 1
- 102200131757 rs63750973 Human genes 0.000 description 1
- 102200131753 rs63751039 Human genes 0.000 description 1
- 102200131811 rs63751122 Human genes 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- DCQXTYAFFMSNNH-UHFFFAOYSA-M sodium;2-[bis(2-hydroxyethyl)amino]ethanol;acetate Chemical compound [Na+].CC([O-])=O.OCCN(CCO)CCO DCQXTYAFFMSNNH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000005717 substituted cycloalkylene group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229960003565 tacrine hydrochloride Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229920001897 terpolymer Polymers 0.000 description 1
- PDVYKGNQYPQALA-UHFFFAOYSA-N tert-butyl n-(4-amino-2,5-dimethylphenyl)carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=C(C)C=C1N PDVYKGNQYPQALA-UHFFFAOYSA-N 0.000 description 1
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 235000019303 thiodipropionic acid Nutrition 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical class [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 201000007905 transthyretin amyloidosis Diseases 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000005106 triarylsilyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-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
- 125000002948 undecyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920011532 unplasticized polyvinyl chloride Polymers 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000002569 water oil cream Substances 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Description
本発明は、式(I)の構造を有する新規の化合物、並びに医薬品として許容されるその塩及びそのプロドラッグを提供する。
(A)−LA−(B)−LB−(C)−LC−(D) (I)
[式中、
Aは、
(式中、
各Eは独立してN、NR、C、CR1、S又はOであり、(但し4個以下のEがヘテロ原子である);
Rは水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換シクロアルキル、又は置換若しくは非置換アリールであり;
各R1は独立して水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノ、置換若しくは非置換シクロアルキル、又は置換若しくは非置換アリールである)であり;或いは
Aは、
(式中、各Mは独立してCR1又はNより選択される。但し3個以下のMがNである)
であり;
Bは、
(式中、
各Gは独立してCR2又はNであり(但し、3個以下のGがNである);
各R2は独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノより選択される)であるか;或いは、
BはAと共に縮合環系を形成し;
Cは、
(式中、
Jは、CR3、O、S、N、及びNRからなる群より選択され;
各Kは独立してN、NR、C、又は、CR3であり;
各R3は独立して水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換シクロアルキル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、又は置換若しくは非置換アルコキシである。但しCが
の場合はR3は−NH2でない)であり;或いは
Cは、
(式中、各Mは独立してCR1又はNから選択される。但し3個以下のMがNである)であり;
Dは、
(式中、各Eは独立してN、NR、C、CR1、S又はOである。但し4個以下のEがヘテロ原子である)であり;或いは
Dは、
(式中、
各Mは独立してCR5又はNから選択され(但し3個以下のMがNである);
各R5は独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換シクロアルキル、置換若しくは非置換のヘテロシクリル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換アミノ、又は置換若しくは非置換アルキルアミノより選択される)であり;
LAは任意選択であって、存在する場合は、共有結合、又は、
(式中、各R’は独立して水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、又は置換若しくは非置換シクロアルキルであり、zは1〜10である)からなる群より選択されるリンカーであり;
LBは独立して、共有結合、又は、
(式中、各R’は独立して水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、又は置換若しくは非置換シクロアルキルであり、zは1〜10である)からなる群より選択されるリンカーであり;
LCは、−O−、−S−、−S(O)−、−S(O)2−、−NR−、−C(O)−、−(C(R’)2)z−、又は−C(S)−であり;
但し、Aが
である場合は、LAは、−C(O)NH−、−CH2NH−、−CH2−O−、又は−C(O)N(CH3)−でなく;
式(I)の化合物は
でない]
を含むがこれらに限定はされないような、直鎖アルキル基の分枝鎖異性体もまた包含される。かくして、アルキル基には、第一級アルキル基、第二級アルキル基及び第三級アルキル基が包含される。好ましいアルキル基には、1から16個の炭素原子又は1から3個の炭素原子を有するアルキル基、例えばメチル、エチル、プロピル、及び−CH(CH3)2など、が包含される。
(式中、各R’は独立して水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、又は置換若しくは非置換シクロアルキルであり、zは1〜10である)
が包含される。ここで好ましい実施形態には、Lcが−NH−である式(I)の化合物が包含される。
であり、dは0〜5である、式(I)の化合物が包含される。存在する場合、好ましい実施形態の各R5は、独立して、ハロゲン、置換若しくは非置換C1〜C5アルキル、置換若しくは非置換C1〜C5アルコキシ、置換若しくは非置換の5員から6員ヘテロアリール、又はN(R”)2(各R”は独立して、置換若しくは非置換のC1〜C5アルキル又はC3〜C10シクロアルキルである)から選択される。Dの実施形態には更に、DがR5と共に縮合環系を形成する化合物も包含される。更に好ましい実施形態のDは、
から選択される。
であり、bは0〜2である、式(I)の化合物が包含される。例えば、Bの実施形態は、
から選択することができる。更に好ましい実施形態には、Bが
(式中、各R2が独立して、ハロゲン又は置換若しくは非置換C1〜C5アルキルから選択される)
から選択される、式(I)の化合物が包含される。
(式中、FはCH又はNである)
である、式(I)の化合物が包含される。更に好ましいAの実施形態には、R1がハロゲン又は置換若しくは非置換C1〜C5アルキルである化合物が包含される。
下記に示すのは、本発明の化合物を調製するための例示的、一般的なスキームである。合成手法のさらなる詳細については、本明細書の実施例において示す。本明細書の化合物は、当業者に周知の手順によって容易に調製可能であるから、本明細書の化合物を調製するために、以下に示す合成スキームの代わりに又はこれらに加えて、様々な手法を採用して構わない。
アミノチアゾール部分又はアミノオキサゾール部分を含む、本明細書の化合物(3)は、α−ハロゲン化ケトン誘導体(1)を、適当なチオ尿素又は尿素化合物(2)と連結することによって調製することができる。例えば、2−アミノチアゾール化合物を調製する汎用スキームを、以下のスキーム1に図示する。本発明化合物を調製するために、例えば環A、B、及びDを変えてスキーム1を調整することができる。
スキーム1で採用するのに好ましいハロゲン化ケトン誘導体としては、α−ブロモケトン誘導体が挙げられる。以下のスキーム3に示されるように、適当なアルキルケトンを臭素化した結果、α−ブロモケトン誘導体が生成する。
チオ尿素又は尿素誘導体(2)は、スキーム1で図示した一般的な縮合反応において用いられ、スキーム5によって調製することができる。一般的に尿素誘導体は、アニリン誘導体などの適当なアミンを、適切なイソチオシアネート化合物に付加することによって調製可能である。
上記スキーム1及びスキーム2で図示した一般的な縮合経路に加えて、下記スキーム6に示す改変スズキ(Suzuki)カップリング反応を用いて、様々な置換チアゾール及びピリジン誘導体を調製することもできる。
本発明の一態様は、Aβレベルを調節する方法、及びAβレベル異常に関連する疾患の治療方法であって、式(VII):
(A1−LA1)0−1−(B1)−LB1−(C1)−LC1−(D1) (VII)
[式中、
A1は任意選択であって、存在する場合は、5員又は6員、置換又は非置換の、シクロアルキル、ヘテロシクリル、アリール、ヘテロアリール、シクロアルキレン、ヘテロシクリレン、アリーレン、又はヘテロアリーレンであり;
B1は、5員又は6員、置換又は非置換の、シクロアルキレン、ヘテロシクリレン、アリーレン、又はヘテロアリーレンであり;或いは、B1がA1と共に縮合環系を形成し;
C1は、5員又は6員、置換又は非置換のアリーレン又はヘテロアリーレンであり;
D1は、5員又は6員、置換又は非置換のアリール、ヘテロアリール、アリーレン、又はヘテロアリーレンであり;且つ、
LA1は任意選択であって、存在する場合は共有結合又はリンカーであり;
LB1及びLC1は各々独立して共有結合又はリンカーである]
に対応する構造を有する化合物、並びに医薬品として許容されるその塩及びそのプロドラッグを使用し、
式(VII)の化合物がAβレベルを調節する、前記方法である。
A1が任意選択であり、存在する場合は
(式中、各Eは独立してN、NR、C、CR1、S又はOであり(但し4個以下のEがヘテロ原子である);
Rは水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換シクロアルキル、又は置換若しくは非置換アリールであり;
各R1は水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノ、置換若しくは非置換シクロアルキル、又は置換若しくは非置換アリールである)であるか;
或いはA1が、存在する場合、
(式中、各Mは独立してCR1又はNより選択され、ここで3個以下のMがNである)であり;
B1が、
(式中、各Gは独立してCR2又はNであり(但し3個以下のGがNである);
各R2は独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノより選択される)
であり;
C1が、
(式中、Jは、CR3、O、S、N、及びNRからなる群より選択され;
各Kは独立してN、NR、C、又はCR3であり;
R3は、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換シクロアルキル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、又は置換若しくは非置換アルコキシである)であるか;
或いはC1が、
(式中、各Mは独立してCR1又はNより選択される。但し、3個以下のMがNである)であり;
D1が、
(各Eは独立してN、NR、C、CR1、S又はOである。但し4個以下のEがヘテロ原子である)であるか;
或いはD1が、
(式中、各Mは独立してCR5又はNから選択され(但し3個以下のMがNである);
各R5は独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換シクロアルキル、置換若しくは非置換のヘテロシクリル、置換若しくは非置換アリール、置換若しくは非置換ヘテロアリール、置換若しくは非置換アミノ、又は置換若しくは非置換アルキルアミノより選択される)であり;
LA1(存在する場合)、及びLB1とLC1の各々が、独立して共有結合、又は、
(式中、各R’は独立して水素原子、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、又は置換若しくは非置換シクロアルキルであり、zは1から10である)からなる群より選択されるリンカーである、
式(VII)の化合物の使用、が包含される。
本発明の化合物及び組成物を、様々な障害を治療又は改善するために使用することができる。治療的適用において使用可能な化合物及び組成物は、一実施形態において、標的とする組織(すなわち、神経変性疾患に関しては脳;その他のアミロイド形成性状態に関しては個々の末梢器官)における生物学的利用率がかなり高く、毒性が十分に低い。当業者は、定法を用いて、本明細書に記載の化合物の医薬としての許容性を評価することができる。
語句「医薬品として許容される担体」は、特定の形態での投与に適することが当業者に知られているような、任意の担体を示す。更に、化合物は、組成物中で唯一の医薬活性成分として処方されてもよいし、他の活性成分と組み合わされてもよい。
経口用医薬品の投与形態は、固形、ゲル状又は液状のいずれであってもよい。固形の投与形態は錠剤、カプセル、顆粒剤、及び粉剤包である。経口錠剤としては、圧縮品、チュアブル錠、及び、腸溶コーティング錠、糖衣錠、又はフィルムコーティング錠が挙げられる。カプセルはハード又はソフトゼラチンカプセルであり、顆粒剤及び粉剤は、当業者に知られているその他成分と組み合わせて、非起沸又は起沸形態のいずれでも提供されてよい。
ある実施形態において、製剤は固形の投与形態であり、一実施形態において、カプセル又は錠剤である。錠剤、丸剤、カプセル、トローチなどは、次の成分:結合剤;滑剤;希釈剤;潤滑剤(glidant);崩壊剤;着色剤;甘味料;香味料;湿潤剤;催吐コーティング;及びフィルムコーティング、又は性質が同様の化合物群のうち1つ又は複数を含有し得る。バインダーの例としては、ミクロクリスタリンセルロース、トラガカントガム、グルコース溶液、アラビアゴム漿、ゼラチン溶液、糖蜜、ポリビニルピロリドン、ポビドン、クロスポビドン、スクロース及び澱粉ペーストなどが挙げられる。滑剤としては、タルク、澱粉、マグネシウムステアレート又はカルシウムステアレート、石松子及びステアリン酸などが挙げられる。希釈剤としては、例えば、ラクトース、スクロース、澱粉、カオリン、塩、マンニトール及びリン酸二カルシウムなどが挙げられる。潤滑剤としては、コロイド状二酸化ケイ素などが挙げられるが、これに限定されない。崩壊剤としては、クロスカルメロースナトリウム、澱粉グリコール酸ナトリウム、アルギン酸、トウモロコシ澱粉、馬鈴薯澱粉、ベントナイト、メチルセルロース、寒天及びカルボキシメチルセスロースなどが挙げられる。着色料としては、例えば、任意の、認可実証済みの水溶性FD及びC染料、その混合物;アルミナ水和物上に懸濁された水不溶性FD及びC染料などが挙げられる。甘味料としては、スクロース、ラクトース、マンニトール、及び、サッカリンなどの人口甘味料、及び、噴霧乾燥香味料の任意のもの、などが挙げられる。香味料としては、植物から抽出された天然香味料、例えばフルーツ香料、及び、心地よい感覚を生むような、化合物人工ブレンド品(例えばペパーミント、サリチル酸メチル、但しこれらに限定されない)などが挙げられる。湿潤剤としては、プロピレングリコールモノステアレート、ソルビタンモノオレエート、ジエチレングリコールモノラウレート、及びポリオキシエチレンラウリルエーテルなどが挙げられる。催吐コーティングとしては、脂肪酸、脂肪、ワックス、セラック、アンモニアセラック、及びセルロースアセテートフタレートなどが挙げられる。フィルムコーティングとしては、ヒドロキシエチルセルロース、ナトリウムカルボキシメチルセルロース、ポリエチレングリコール4000、及びセルロースアセテートフタレートなどが挙げられる。
経口用の液状投与形態としては、水性溶液、エマルジョン、非起沸性の顆粒から再構成した溶液及び/又は懸濁液、並びに、起沸性顆粒から再構成した起沸性製剤などが挙げられる。水溶液としては、例えば、エリキシル剤及びシロップなどが挙げられる。エマルジョンは、水中油型又は油中水型のいずれであってもよい。
非経口投与(一実施形態では、皮下、筋肉内又は静脈内のいずれかの注射で特徴付けられる)もまた、本発明で企図される。注射剤は、従来の形態で、液体中の溶液又は懸濁液、注射する前に液体中に溶解又は懸濁するのに適した固形形態、又はエマルジョンのどの形態として調製してもよい。上記注射剤、溶液及びエマルジョンは更に、1つ又は複数の賦形剤を含有する。適当な賦形剤は、例えば、水、食塩水、デキストロース、グリセロール又はエタノールである。更に、所望の場合は、投与される医薬組成物が更に、微量の非毒性助剤物質、例えば湿潤剤又は乳化剤、pH緩衝剤、安定剤、溶解促進剤、及びその他の助剤、例えば酢酸ナトリウム、ソルビタンモノラウレート、トリエタノールアミンオレエート及びシクロデキストリンなどを含有していてもよい。
本発明はまた、液剤、乳剤、及び他の混合物としての投与用に再構成できる凍結乾燥粉末も対象とする。凍結乾燥粉末はまた、固形剤又はゲル剤として再構成及び調剤してもよい。
局所用混合物は局部及び全身投与用に記載されているように調製する。得られた混合物は、溶液、懸濁液、エマルジョン等とすることができ、クリーム、ジェル、軟膏、乳剤、液剤、エリキシル剤、ローション、懸濁剤、チンキ剤、パスタ、フォーム、エアロゾール、洗浄剤、スプレー、坐剤、バンデージ、皮膚パッチ、又は局所投与に適した任意の他の製剤として製剤する。
本発明では、イオントフォレーシス及びエレクトロフォレーシスデバイスを含む経皮パッチ、並びに直腸投与などの他の投与経路も企図される。
本発明で提供される化合物又は医薬品として許容されるその誘導体は、特定の組織、受容体又は治療する対象の体の他の部分を標的とするよう製剤することもできる。多くのこのようなターゲティング法が当業者によく知られている。本発明では、このようなターゲティング法はいずれも本発明組成物に使用することが企図される。ターゲティング法の非限定例としては、例えば、米国特許第6,316,652号、第6,274,552号、第6,271,359号、第6,253,872号、第6,139,865号、第6,131,570号、第6,120,751号、第6,071,495号、第6,060,082号、第6,048,736号、第6,039,975号、第6,004,534号、第5,985,307号、第5,972,366号、第5,900,252号、第5,840,674号、第5,759,542号及び第5,709,874号を参照されたい。
別の実施形態では、化合物を他の治療剤と組み合わせて、又は逐次的に投与することができる。このような他の治療剤には、アミロイドーシス並びに神経変性疾患及び障害の1つ又は複数の症状を治療、予防、又は改善することが知られている治療剤が包含される。このような治療剤には、ドネペジル塩酸塩(Aracept)、リバスチグミン酒石酸塩(Exelon)、タクリン塩酸塩(Cognex)及びガランタミン臭化水素酸塩(Reminyl)が包含されるが、これらに限定されるものではない。
本発明の他の態様によれば、キットが提供される。本発明によるキットには、本発明の化合物又は組成物を含む包装容器が含まれる。
本明細書中に記載の化合物には、Aβレベルを調節する化合物が含まれる。当分野で知られている且つ/又は本明細書中に記載されている様々なアッセイを用いて、Aβレベルを調節する活性について化合物を評価することができる。一般に、APP若しくはその断片及び/又はAβの供給源を化合物と適切な時間接触させ、以下に記載のようにAβのレベルを直接又は間接的に評価する。化合物の存在下におけるAβのレベルを適切な対照(ベヒクル対象や陽性対照など)中のレベルと比較して、化合物がAβレベルを調節するかどうかを決定する。
Aβを調節することにおける化合物の活性を評価するために使用したAPP、アミロイド前駆体断片の供給供給源及び/又はAβは、検出する産物並びにアッセイの性質に依存する。例えば、γ−セクレターゼによるAPP又はアミロイド前駆体断片の切断を調節することにおける化合物の活性を評価するためには、C99などの、β−セクレターゼによる切断の産物に対応するAPPのC末端断片を用いることができる。APP産生のすべての段階における化合物の効果を評価する場合は、完全長のAPPが好ましいかもしれない。
化合物の活性の評価に有用なトランスジェニック動物は、本明細書中に記載のように、任意の所望の野生型又は突然変異体APP、アミロイド前駆体断片若しくはAβアイソフォームを発現することができる。その結果もたらされる動物は、ヒトの疾患のモデル、特にアルツハイマー病並びに他の神経変性及びアミロイド関連疾患のモデルとして有利に役割を果たすことができる。トランスジェニック動物には、それだけには限定されないがマウス、ラット及びハムスターを含めたげっ歯類、ヒツジ、ヤギ、ニワトリ、ブタ、ウシ、サル、霊長類並びに他のヒトでない哺乳動物が含まれる。
化合物の活性の評価に有用な細胞は、本明細書中に記載のように、任意の所望の野生型又は突然変異体APP及び/若しくはAβアイソフォームを、内因的に又は組換えのどちらかによって発現することができる。細胞は、ヒト及び上述のトランスジェニック動物などの他の哺乳動物を含めた任意の動物由来の初代細胞又は細胞系であることができる。細胞は、神経系列(例えば皮質神経細胞、小グリア細胞、グリア細胞、アストロサイト)、線維芽細胞、リンパ球及び上皮細胞などの任意の分化した系列由来であるか、又は全能性若しくは多能性であることができる(Freshney,R.I.、(2000)、「動物細胞の培養:基本技術の手引き」(”Culture of Animal Cells:A Manual of Basic Technique”)第4版、Wiley−Liss参照)。Aβを調節することにおける化合物の活性を評価するために適切な例示的な細胞系は、本明細書中の実施例部分に記載されているSH−SY5Y−APP751である。さらなる例示的な細胞系はHGBであり、これは内在APPを発現する。
Aβのレベルを直接評価するアッセイを用いて、Aβを調節する能力について化合物を評価することができる。従って、化合物がAβを調節する能力は、特定のAβペプチド(Aβ43、Aβ42、Aβ40、Aβ39、Aβ38、Aβ37、Aβ34、11−43、11−42、11−40、11−39、11−38、11−37、11−34など)の量を決定することによって、Aβペプチドの量を総合的に決定することによって、第2のAβペプチドの量に対する特定のAβペプチドの量(Aβ42対Aβ40の比など)を決定することによって、特定の形態のAβ(単量体、オリゴマー、若しくは原線維状;溶液中、若しくは溶菌班中に凝集して;特定のコンホメーションなど)の量又は相対的な量を決定することによって、且つ/或いは特定の位置のAβ(細胞内、膜関連若しくは細胞外、又は特定の組織若しくは体液中など)の量又は相対的な量を決定することによって、評価することができる。
或いは、Aβのレベルを間接的に評価するアッセイを用いて、Aβを調節する能力について化合物を評価することができる。当業者は、Aβレベルの調節を評価するための適切なアッセイを決定することができる。例えば、切断されていないAPPの量、又はAβ以外のAPPのプロセッシングの産物の量を評価することができる。
代表的なα−ブロモケトン誘導体の調製
代表的なα−ブロモケトン誘導体を、代表的なチオ尿素との縮合用に調製した。代表的なα−ブロモケトン誘導体の合成に用いた典型的な手順を以下に示す。
乾燥エタノール60mL中にトシルメチルイソシアネート(TosMIC、3.90g、20mmol)及びプロピオンアルデヒド(1.5mL、20.4mmol)を含む攪拌している懸濁液に、微粉状シアン化ナトリウム(0.098g、2mmol)を加えた。反応混合物は透明になり、オキサゾリンの白色結晶は15分で沈殿し始めた。反応物を続けて、更に30分間攪拌した。この混合物をろ過し、結晶をエーテル−ヘキサン(1:1)で洗浄した後、乾燥した。化合物15を、収率81%で得た(4.1g)。構造は、CDCl3中、1H NMRで確認した。LC−MS:[M+1]=254。純度は、>98%であった。
耐圧フラスコ中で、化合物15(1.1g、4.3mmol)を、アンモニアの乾燥メタノール(30mL)飽和溶液に溶解した。反応混合物を、100〜110℃で18時間攪拌した。溶媒を蒸発させ、生成物をフラッシュクロマトグラフィーでCH2Cl2−MeOHを用いて溶離して精製した。化合物16を、淡黄色油状物として単離した(収率72%、0.3g)。構造はCDCl3中、1H NMRにより、また、純度はCH2Cl2−MeOH(9:1)中、TLCにより確認した。純度は、>95%であった。
NaH(60%油分散液中0.068g、1.7mmol)を、室温で攪拌しながら、化合物16(0.180g、1.8mmol)のDMF(6mL)溶液に加えた。混合物を15分間攪拌し、4’−フルオロアセトフェノン(0.215g、1.56mmol)のDMF(2mL)溶液を加えた。反応混合物を80℃で1時間加熱し、次いで冷却し、水で希釈し、EtOAcで抽出した。有機層をブラインで洗浄し、乾燥し、蒸発させて、黄色固体を得た。室温で静置すると直ぐに、化合物17は結晶化して、白色針状物を形成した。収量は、0.270g、67%であった。構造は、CDCl3中、1H NMRで確認した。LC−MS:[M+1]=215。純度は、>98%であった。
ケトン17(0.160g、0.66mmol)を、30%酢酸/HBr(5mL)に溶解し、その後、臭素(0.104g、0.66mmol)を加えた。反応混合物を室温で1時間攪拌し、次いで、冷水(10mL)に注いだ。生成物を、酢酸エチル(20mL)で抽出した。合わせた有機層を水及びブラインで洗浄し、乾燥し、蒸発させて黄色固体を得て、酢酸エチル:ヘキサン(1:1)で結晶化し、0.170g(77%)の化合物18を得た。構造は、CDCl3中、1H NMRで確認した。LC−MS:[M+1]=294。純度は、>95%であった。
1−(6−クロロ−ピリジン−3−イル)−エタノン(7.00g、45.16mmol)及び4−メチルイミダゾール(11.11g、135.50mmol)を、DMSO(35ml)中で混合し、その後、K2CO3を加えた。混合物を、高速で攪拌しながら、110℃で22時間加熱した。次いで、混合物を室温に冷却し、氷水(400ml)に注ぎ、15分間激しく攪拌した。得られた沈殿をろ過で回収し、水で穏やかに洗浄した。得られた物質を真空で乾燥して、19を黄褐色固体として得た(6.1g、67%)。
化合物19(6.1g、30.30mmol)を、30%HBr/AcOH(75ml)に懸濁させた。臭素(4.82g、30.30mmol)を1時間かけて滴下して加えた。反応物を、室温で2時間攪拌した。反応混合物を氷水600mLに注ぎ、高速で15分間攪拌した。得られた沈殿をろ過で回収し、水で洗浄した。化合物を空気乾燥して、20を黄色固体として得た(10.6g、80%)。
2−ブロモチアゾール(1g、6.1mmol)をフラスコに入れ、トルエン:EtOH(4:1、80mL:20mL)を加え、更に4−アセチルフェニルボロン酸(1.2g、7.32mmol)、炭酸ナトリウム(2.16g、20.4mmol)、及び水(3mL)を加えた。反応混合物を、30分間、それに窒素をバブリングさせることで脱気した。続けて、Pd(PPh3)4を加え、反応混合物を80℃で17時間加熱し、その後、室温まで冷やした。EtOAc(3×100mL)及び水(100mL)を加えた。有機抽出物を水(l00mL)、ブライン(l00mL)で洗浄し、MgSO4で乾燥し、ろ過し、カラムクロマトグラフィー(120g ISCOカートリッジ)により精製した。化合物1219を、白色粉末として単離した(974mg、79%、C11H9NOSの質量、計算値:203.3、観測値:204.2[M+1])。化合物1219(204mg、1mmol)を、30%HBrの酢酸(3mL)溶液に溶解し、その後、臭素(160mg、1mmol)を滴下して加えた。反応混合物を、室温で6時間攪拌し、その後、それを氷水に注ぎ、10分間攪拌し、沈殿をろ過した。化合物1221を、黄色粉末として単離した(257mg、92%、C11H8BrNOSの質量、計算値:281.2、観測値:282.1[M+1])。
上述したものと同様の手順で、化合物1220を2,5−ジブロモチアゾール(809mg、4.94mmol)から出発することにより調製した。1−[4−(5−ブロモ−チアゾール−2−イル)−フェニル]−エタノン1220を淡黄色粉末として単離した(500mg、43%、C11H8BrNOSの質量、計算値:283.2、観測値:284.1[M+1])。2−ブロモ−1−[4−(5−ブロモ−チアゾール−2−イル)−フェニル]−エタノン1222を、淡黄色粉末として単離した(436mg、77%、C11H7BrNOSの質量、計算値:360.1、観測値:361.6[M+1])。
チオ尿素/尿素誘導体の調製
チオ尿素誘導体は、アニリン誘導体をイソチオシアン酸アリール誘導体と結合させることにより調製した。大半のアニリン化合物は市販されており、且つ/又はよく知られた方法を用いて合成された。
THF40mL中に4−アミノ−2,5−ジメチル−フェノール(20mmol、2.74g)を含む溶液に、Boc無水物(22mmol、4.8g)及びTEA(30mmol、4.17mL)をそれぞれ加えた。室温で一晩攪拌後、反応混合物を濃縮してTHFを除き、残渣を水(50mL)及び酢酸エチル(80mL)に再溶解させた。水層を酢酸エチル(3×50mL)で抽出した。合わせた有機層をNa2SO4で乾燥した。溶媒の除去後、粗生成物をフラッシュクロマトグラフィーにより精製して(ISCO system、5〜40% 酢酸エチル/ヘキサン)、表題化合物35を得た(90%の収率)。
DMF5mL中に化合物35(4mmol、948mg)を含む溶液に、炭酸カリウム(K2CO3、8mmol、1.1g)及びブロモエタン(4.8mmol、523mg)を加えた。反応物を60℃で一晩攪拌した。水(2mL)を加えて、未反応の炭酸カリウムを溶解し、次いで、反応混合物を酢酸エチル(3×10mL)で抽出した。有機層を合わせて、Na2SO4で乾燥させた。溶媒の除去後、粗生成物をフラッシュクロマトグラフィー(0〜30%酢酸エチル/ヘキサン)を用いることにより精製し、表題生成物36(90%の収率)を得た。
ジクロロメタン10mL中に36(950mg、3.6mmol)を含む溶液に、トリフルオロ酢酸(5mL)を加えた。反応混合物を2時間攪拌した。この時点で、LC−MSは反応が完了したことを示した。反応フラスコを濃縮し、溶媒及びほとんどのTFAを除去した。次いで、残渣を高真空で24時間、更に乾燥させ、表題化合物37をTFA塩として得た。
THF40mL中に2,5−ジメチルベンゼン−1,4−ジアミン(30mmol、4.1g)を含む溶液に、Boc無水物(33mmol、7.2g)及びTEA(45mmol、6.26mL)をそれぞれ加えた。室温で一晩攪拌後、反応混合物を濃縮してTHFを除去し、残渣を水及び酢酸エチルに再溶解させた。水層を酢酸エチル(3×80mL)で抽出した。有機層を合わせて、Na2SO4で乾燥した。溶媒の除去後、粗生成物をフラッシュクロマトグラフィー(5〜50%酢酸エチル/ヘキサン)を用いて精製し、表題化合物40(90%を越える収率)を得た。
DMF3mL中に40(5mmol、1.18g)を含む溶液に、炭酸カリウム(K2CO3、15mmol、2.07g)及びブロモエタン(12.5mmol、1.36g、0.93mL)を加えた。反応物を70℃で一晩攪拌した。水(3mL)を加えて、未反応の炭酸カリウムを溶解させ、反応混合物を酢酸エチル(3×10mL)で抽出した。有機層を合わせてNa2SO4で乾燥させた。溶媒の除去後、粗生成物をシリカゲルクロマトグラフィー(0〜30%酢酸エチル/ヘキサン)を用いて精製し、表題化合物41を得た(75%の収率)。
ジクロロメタン2mL中に41を含む溶液に、トリフルオロ酢酸(1mL)を加えた。反応混合物を2時間攪拌した。この時点で、LC−MSは反応が完了したことを示した。反応物を濃縮し、溶媒及びほとんどのTFAを除去した。次いで、残渣を高真空で24時間更に乾燥させ、表題化合物42をTFA塩として得た(100%の収率)。
THF40mL中に2,6−ジメチルベンゼン−1,3−ジアミン(30mmol、4.1g)を含む溶液に、Boc無水物(33mmol、7.2g)及びTEA(45mmol、6.26mL)をそれぞれ加えた。室温で一晩攪拌後、反応混合物を濃縮してTHFを除き、残渣を水及び酢酸エチルに再溶解させた。水層を酢酸エチル(3×80mL)で抽出した。有機層を合わせて、Na2SO4で乾燥した。溶媒を除去後、粗生成物をフラッシュクロマトグラフィー(5〜50%酢酸エチル/ヘキサン)を用いて表題化合物45を得た(95%の収率)。
DMF3mL中に45(5mmol、1.18g)を含む溶液に、炭酸カリウム(K2CO3、15mmol、2.07g)及びブロモエタン(12.5mmol、1.36g、0.93mL)を加えた。反応物を70℃で一晩攪拌した。水(3mL)を加えて、未反応の炭酸カリウムを溶解させ、次いで反応混合物を酢酸エチル(3×10mL)で抽出した。有機層を合わせてNa2SO4で乾燥させた。溶媒の除去後、粗生成物をフラッシュクロマトグラフィー(0〜30%酢酸エチル/ヘキサン)を用いて精製し、表題化合物46を得た(80%の収率)。
ジクロロメタン10mL中に46(1.16g、4.0mmol)を含む溶液に、トリフルオロ酢酸(5mL)を加えた。反応混合物を2時間攪拌した。この時点で、LC−MSは反応が完了したことを示した。反応物を濃縮し、溶媒及びほとんどのTFAを除去した。次いで、残渣を高真空で24時間、更に乾燥させ、表題化合物46をTFA塩として得た(100%の収率)。
代表的なα−ブロモケトンと典型的なチオ尿素との縮合
代表的なα−ブロモケトン誘導体(0.08mmol、下記表3の「ブロモケトン」欄参照)を、4−ジエチルアミノ−2−メチル−フェニル−チオ尿素67(0.08mmol)の1mL DMF溶液と混合した。反応物を、任意にボルテックスで攪拌しながら、70℃で4〜6時間攪拌した。室温に冷却後、反応混合物をアセトニトリル/水/TFAグラジエントを用いたC18カラムの逆相HPLC(Gilson 215)に直接注入し、表題生成物を単離した。表題生成物をTFA塩として真空で濃縮した。
代表的なチアゾールの調製
A. 環状部の付加及びN−置換
様々な代表的N−置換チアゾール含有化合物を以下に示す代表的な経路により調製した。更に、この経路は代表的なチアゾール化合物に環状部を付加する他の手順を示す。
化合物1203(400mg、1.0mmol)を、窒素雰囲気下で無水ピリジン(5mL)に懸濁させ、その後、ジ−tert−ブチルジカルボネート(262mg、1.2mmol)を加えた。反応混合物を室温で16時間攪拌し(5分後、反応物が透明になった)、その後、それを氷水に注いだ。10分間の攪拌後、混合物をろ過し、沈殿物を2時間吸引して乾燥させた。化合物1204を、灰白色の粉末として単離した(460mg)。質量分析の期待値=497、観測値=498[M+1]。
化合物1204(500mg、1.26mmol)を、窒素雰囲気下で無水DMF(7mL)に入れ、その後、NaHに加えた(95%粉末35mg、1.38mmol)。室温で10分間攪拌後、2−(トリメチルシリル)エトキシメチルクロリド(0.25mL、1.38mmol)を加えた。反応混合物を、室温で3時間攪拌し、その後、水(50mL)及びEtOAc(3×50mL)を注意深く加えた。有機抽出物を、水(100mL)、ブライン(100mL)で洗浄し、MgSO4で乾燥し、ろ過した。真空で溶媒を除去することにより、化合物25を黄色油状物として得たが、これは静置すると固化した(530mg)。
ヒートガンで乾燥し、窒素をパージしたバイアル中で、(+/−)−BINAP(l0mg、0.015mmol)を無水トルエン(1mL)に溶解した。2分後、Pd2(dba)3(3mg、0.0025mmol)、化合物1208(53mg、0.1mmol)、及びピペリジン(11mg、0.12mmol)を反応フラスコに加えた。室温で5分間攪拌後、NaOtBu(14mg、0.14mmol)を加え、反応混合物を90℃で18時間加熱し、その後0.45μmのフィルターを通し、次いでHPLC精製した。化合物1209を茶色油状物として単離した(1.3mg)。質量分析の期待値=401、観測値=402[M+1]。
化合物1203(200mg、0.5mmol)を、窒素雰囲気下、無水DMF(7mL)に入れ、その後、NaHを加えた(95%粉末17mg、0.65mmol)。室温で10分間攪拌後、ブロモエタン(0.05mL、0.65mmol)を加え、反応混合物を90℃で2時間攪拌し、その後、水(50mL)及びEtOAc(3×50mL)を注意深く加えた。有機抽出物を水(100mL)、ブライン(100mL)で洗浄し、MgSO4で乾燥し、ろ過した。真空で溶媒を除去し、化合物1205を淡黄色固体として得た(200mg)。質量分析の期待値=425、観測値=426[M+1]。
ヒートガンで乾燥し、窒素をパージしたバイアル中で、(+/−)−BINAP(10mg、0.015mmol)を無水トルエン(1mL)に溶解した。2分後、Pd2(dba)3(3mg、0.0025mmol)、化合物1205(43mg、0.1mmol)、及びピペリジン(11mg、0.12mmol)を加えた。室温で5分間攪拌後、NaOtBu(14mg、0.14mmol)を加え、反応混合物を90℃で23時間加熱し、その後0.45μmのフィルターを通し、次いでHPLC精製した。化合物1206を茶色油状物として単離した(12mg)。質量分析の期待値=429、観測値=430[M+1]。
ヒートガンで乾燥し、窒素をパージしたバイアル中で、(+/−)−BINAP(l0mg、0.015mmol)を無水トルエン(1mL)に溶解した。2分後、Pd2(dba)3(3mg、0.0025mmol)、化合物1205(43mg、0.1mmol)、及びモルホリン(11mg、0.12mmol)を反応フラスコに加えた。室温で5分間攪拌後、NaOtBu(14mg、0.14mmol)を加え、反応混合物を90℃で23時間加熱し、その後0.45μmのフィルターを通し、次いでHPLCで精製した。化合物1207を茶色油状物として単離した(21mg)。質量分析の期待値=431、観測値=432[M+1]。
ブロモケトン誘導体とチオ尿素誘導体との縮合後、環状基に加えて、非環状官能基を代表的なチアゾール化合物に付加した。以下の典型的な経路に示すように、チアゾール1208をN−アルキル化して1209を調製した。N,N,ジエチルアミンを加えることにより1210を生じ、次いで、N−脱保護により1211を得た。
スターラーバーを含む乾燥したねじ蓋付きバイアルに、トリス(ジベンジリデンアセトン)二パラジウム(0)(0.066g、0.146mmol)、トリ(tert−ブチル)ホスフィン(ヘキサン中10%溶液0.44ml、0.146mmol)、化合物1209の乾燥トルエン溶液(トルエン15ml中1.62、2.92mmol)、ジエチルアミン(0.90ml、8.76mmol)、及びナトリウムtert−ブトキシド(0.420g、4.38mmol)を共に加えた。バイアルを窒素でフラッシュし、きつくキャップした。次いで、混合物を90℃の油浴中で1時間攪拌した。次いで、トルエンを減圧下で除去した。次いで、物質をCH2Cl2及びシリカゲルに再懸濁させた。次いで、CH2Cl2を減圧下で除去し、化合物をシリカゲルに吸収させた。次いで、物質をカラムクロマトグラフィーにより、EtOAc/ヘキサンを用いて溶離して精製し、生成物1210を淡黄色半固体として得た(0.842g、52%)。LC/MS:[M+1]+=548.4。C30H41N5OSSi=547.8。
化合物1210を、DMF(5ml)及び2M HCl水溶液(5ml)に溶解し、室温で1.5時間攪拌した。次いで、生成物を逆相HPLCにより精製した。純粋な画分を合わせて、減圧下で濃縮して乾燥した。得られた物質をCH2Cl2(250ml)に溶解し、2×飽和NaHCO3(100mL)及び1×ブライン(100mL)で洗浄した。有機層をMgSO4で乾燥し、ろ過し、減圧下で濃縮して1211を白色固体として得た(遊離塩基)(0.610g、51%)。LC/MS:[M+H]+=418.5。C24H27C5S=417.5。
化合物1211(遊離塩基)(0.610g、1.46mmol)を、MeOH(2ml)にある程度溶解させた。次いで、2M HCl/Et2O(1.46ml、2.92mmol)を加え、溶液を澄ませた。この溶液を窒素ガス流を用いて最小容量に濃縮した。次いで、Et2O(5ml)を加え、化合物を粉砕して白色固体とし、これを2×Et2O(5ml)で洗浄し、窒素気流で乾燥させた。次いで、物質を穏やかに加熱しながら乾燥EtOH(1.5ml)に再溶解させた。混合物を冷却し、化合物を結晶化させた。結晶をろ過で回収し、2×Et2O(1ml)で洗浄し、真空で乾燥させて二塩酸塩を灰白色固体として得た(0.320g、26%)。
硫化水素(ガス)を、(3,4−ジクロロ−フェニル)−アセトニトリル(1.86g、10mmol、1.0当量))及びトリエチルアミン(10mmol、1当量)のエタノール(10ml)溶液中で約1時間バブリングさせた。1時間後、反応混合物をキャップし、室温で一晩攪拌した。TLCは、大半のニトリルがチオアセトアミドに変換されたことを示した。過剰のH2Sを、反応混合物中に30分間、窒素をバブリングさせることにより除去した。次いで、反応混合物を濃縮し、シリカゲルクロマトグラフィー(ISCO system、30〜60%酢酸エチル/ヘキサン)により精製して表題化合物(1213)を得た(55%の収率)。
チオアセトアミド1213(0.08mmol)及び2−ブロモ−1−[4−(4−メチル−イミダゾール−1−イル)−フェニル]−エタノン(0.08mmol)10を、DMF1mlに溶解した。反応物を70℃で6時間攪拌した。室温に冷却後、反応混合物をアセトニトリル/水/TFAグラジエント及びC18固定相を用いて逆相HPLC(Gilson 215)に直接注入して単離し、次いで濃縮して表題生成物1214をTFA塩として得た。
4−アジド−ブロモアセトフェノン28(0.300g、1.24mmol)及び(4−ジエチルアミノ−2−メチル−フェニル)−チオ尿素75(0.293g、1.24mmol)を、スターラーバーを含む20mLのシンチレーションバイアルで混合した。無水EtOH(5ml)を加え、混合物を65℃の油浴で攪拌しながら2.5時間加熱した。黒色に近い、透明な溶液が得られた。この溶液を冷却し、減圧下でEtOHを除去して紫色油状物を得たが、これは室温で2日間、静置すると結晶化し、1216aが紫色固体として得られた(0.465g、99%)。%)。LC/MS:[M+1]+=379.0。C20H22N6S=378.5。
スターラーバーを含むねじ蓋付きバイアルに、化合物1216a(0.100g、0.26mmol)、アスコルビン酸ナトリウム(0.005g、0.026mmol)、硫酸銅(II)五水和物(0.001g、0.0026mmol)、及びブト−3−イン−2−オール(0.018g、0.26mmol)を加えた。Tert−ブチルアルコール(1ml)及び水(1ml)をバイアルに加え、バイアルをキャップした。混合物を、室温で16時間、激しく攪拌した。溶媒を減圧下で除去し、得られた残渣をDMF(1.5ml)に再溶解させた。次いで、生成物を逆相HPLCで単離した。純粋な画分を減圧下で濃縮して1218aをトリフルオロ酢酸塩(ditrflouroacetatesalt)として得た(0.038g、21%)。LC/MS:[M+1]+=449.1。C24H28N6OS=448.5。
Aβ調節を評価するためのELISAアッセイ
化合物について、細胞間質でAβ42及びAβ40レベルを調節する活性を、後述のサンドイッチELISAアッセイを用いて評価した。
APP発現神経芽腫細胞系は、ATCCから入手したヒトSH−SY5Y細胞(accession no.CRL−2266)に、ベクターpcDNA.1に含まれるヒトAPP751をコードするDNAを安定的に導入することにより生成した。細胞を384ウェルプレートに蒔き(SH−SY5Y−APPが形質移入された細胞約20,000個/ウェル)、少なくとも18時間付着させた。次いで、細胞を培地(DMEM、10% FBS、100ユニット/ml ペニシリン、0.1mg/ml ストレプトマイシン)中で洗浄し、適当な濃度の化合物を含む培地30μlを加えた。
化合物を、DMSO(溶媒)に懸濁させた。化合物が細胞間質(extracellular medium)のAβ42レベルを低下させる活性を有するか否かを決定するための最初のアッセイを、単一濃度、すなわち、30μMの化合物を用いて行った。化合物を細胞に加え、化合物の存在下で細胞を18〜22時間インキュベートした。この濃度の化合物と接触した細胞の細胞間質のAβ42レベル(後述のサンドイッチELISAアッセイで評価される)が、溶媒単独と接触した細胞(陰性対照)の細胞間質のレベルの約60%未満であったときには、その後、化合物を一連の濃度範囲で評価して、Aβ42レベル及びAβ40レベルを低下させるその能力(potency)(すなわち、そのIC50値)を決定した。
細胞間質のAβレベルを、捕獲抗体として、Aβ42−又はAβ40−選択的抗体を用いた組織培養皿のウェルから得た上清のサンドイッチELISAアッセイにより評価した。免疫測定を実行する前に、白色のマイクロタイター384ウェルプレートを、一晩、〜5μl/mlのAβ42−又はAβ40−選択的モノクローナル抗体のTBS溶液25μlでコーティングした。
化合物の細胞毒性の評価
化合物の細胞毒性を評価するために、上記実施例7に記載した化合物で処理した細胞の上清を除去し、10体積%の細胞生存度指示色素AlamarBlue(商標)(Biosource、San Diego)を含む溶液を加えた。細胞を37℃で3時間インキュベートし、その後、CytoFluor(Applied Biosystems)分光光度計で、530−nmの励起フィルター及び580−nmの発光フィルターを用いて、蛍光を判定した。表11に示した化合物で処理した細胞は、対照細胞に比べてAlamarBlueの蛍光で40%未満の減少を示した。
Aβ調節を評価するためのFRETアッセイ
化合物について、細胞間質中のAβ42及びAβ40レベルを調節する活性を、以下のような均一時間分解蛍光(HTRF)アッセイを用いて評価した。
Claims (26)
- 下記式(I)の構造を有する化合物。
[式中、
Aは、
(式中、
各Eは独立してCR1であり;
各R1は独立して水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノ、置換若しくは非置換シクロアルキル、又は置換若しくは非置換アリールである)であり;
Bは、
(式中、
各Gは独立してCR2又はNであり(但し1個又は2個のGがNである);
各R2は独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルケニル、置換若しくは非置換アルキニル、置換若しくは非置換アルコキシ、置換若しくは非置換アルキルアミド、置換若しくは非置換アルキルアミノ、置換若しくは非置換アミノより選択される)であり;
Rは、独立して、水素原子、ハロゲン、置換若しくは非置換アルキル、置換若しくは非置換アルコキシ、置換若しくは非置換シクロアルキル、置換若しくは非置換アリール、又は置換若しくは非置換へテロアリールであり;
Xはハロゲンである] - Aが非置換のイミダゾリルである、請求項1に記載の化合物。
- Aが置換イミダゾリルである、請求項1に記載の化合物。
- Aが4−置換イミダゾリルである、請求項5に記載の化合物。
- 前記イミダゾリルがアルキルで置換されている、請求項5に記載の化合物。
- 前記イミダゾリルがC1−C5アルキルで置換されている、請求項5に記載の化合物。
- 前記イミダゾリルがメチルで置換されている、請求項8に記載の化合物。
- 前記イミダゾリルがエチルで置換されている、請求項8に記載の化合物。
- 前記イミダゾリルがハロゲンで置換されている、請求項5に記載の化合物。
- 前記イミダゾリルが塩素で置換されている、請求項11に記載の化合物。
- 前記イミダゾリルが臭素で置換されている、請求項11に記載の化合物。
- Bが非置換のピリジニルである、請求項1に記載の化合物。
- 少なくとも1つのR2がハロゲンである、請求項1に記載の化合物。
- 前記ハロゲンがフッ素である、請求項15に記載の化合物。
- 少なくとも1つのR2が任意に置換されているアルコキシである、請求項1に記載の化合物。
- 少なくとも1つのRが水素元素である、請求項1に記載の化合物。
- 各Rが水素元素である、請求項1に記載の化合物。
- Xが塩素である、請求項1に記載の化合物。
- Xが臭素である、請求項1に記載の化合物。
- Xがヨウ素である、請求項1に記載の化合物。
- アセチルピリジニル−ボロン酸を任意に置換されているイミダゾールに適当な溶媒中で適当な条件で接触させて、イミダゾリルピリジルケトンを形成し、次いで、該イミダゾリルピリジルケトンを臭素と適当な条件で接触させて、式(I)の化合物を形成する工程を含む、請求項1に記載の化合物を製造する方法。
- クロロピリジニル−アルカノンを任意に置換されているイミダゾールに適当な溶媒中で適当な条件で接触させて、イミダゾリルピリジルケトンを形成し、次いで、該イミダゾリルピリジルケトンを臭素と適当な条件で接触させて、式(I)の化合物を形成する工程を含む、請求項1に記載の化合物を製造する方法。
- 3−フルオロ,4−クロロピリジニル−アルカノンを任意に置換されているイミダゾールに適当な溶媒中で適当な条件で接触させて、イミダゾリルフルオロピリジルケトンを形成し、次いで、該イミダゾリルフルオロピリジルケトンを臭素と適当な条件で接触させて、式(I)の化合物を形成する工程を含む、請求項1に記載の化合物を製造する方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47088403P | 2003-05-14 | 2003-05-14 | |
US60/470,884 | 2003-05-14 | ||
US53226003P | 2003-12-22 | 2003-12-22 | |
US60/532,260 | 2003-12-22 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006533094A Division JP4847868B2 (ja) | 2003-05-14 | 2004-05-14 | 化合物、及び、アミロイドベータの調節におけるその使用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2011079852A JP2011079852A (ja) | 2011-04-21 |
JP5292381B2 true JP5292381B2 (ja) | 2013-09-18 |
Family
ID=33555297
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006533094A Expired - Fee Related JP4847868B2 (ja) | 2003-05-14 | 2004-05-14 | 化合物、及び、アミロイドベータの調節におけるその使用 |
JP2010268183A Expired - Fee Related JP5292381B2 (ja) | 2003-05-14 | 2010-12-01 | 化合物、及び、アミロイドベータの調節におけるその使用 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2006533094A Expired - Fee Related JP4847868B2 (ja) | 2003-05-14 | 2004-05-14 | 化合物、及び、アミロイドベータの調節におけるその使用 |
Country Status (11)
Country | Link |
---|---|
US (5) | US7244739B2 (ja) |
EP (1) | EP1628666B1 (ja) |
JP (2) | JP4847868B2 (ja) |
KR (1) | KR20060023529A (ja) |
CN (1) | CN102584813B (ja) |
AU (1) | AU2004247013B2 (ja) |
BR (1) | BRPI0410348A (ja) |
CA (1) | CA2525547C (ja) |
IL (1) | IL171471A (ja) |
MX (1) | MXPA05012281A (ja) |
WO (1) | WO2004110350A2 (ja) |
Families Citing this family (215)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE360392T1 (de) * | 2000-11-02 | 2007-05-15 | Cornell Res Foundation Inc | In vivo multiphoton diagnostische detektion und bilddarstellung einer neurodegenerativen erkrankung |
CA2525547C (en) * | 2003-05-14 | 2012-07-03 | Torreypines Therapeutics, Inc. | Compounds and uses thereof in modulating amyloid beta |
CA2542031A1 (en) | 2003-10-10 | 2005-04-21 | Bayer Pharmaceuticals Corporation | Pyrimidine derivatives for treatment of hyperproliferative disorders |
KR101164258B1 (ko) | 2003-12-23 | 2012-07-11 | 아스텍스 테라퓨틱스 리미티드 | 단백질 키나아제 조절제로서의 피라졸 유도체 |
JP4101852B2 (ja) | 2004-05-26 | 2008-06-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | シンナミド化合物 |
AU2005290226A1 (en) | 2004-07-16 | 2006-04-06 | Sunesis Pharmaceuticals, Inc. | Thienopyrimidines useful as Aurora kinase inhibitors |
BRPI0515505A (pt) | 2004-09-20 | 2008-07-29 | Xenon Pharmaceuticals Inc | derivados heterocìclicos e sua utilização como inibidores da estearoil-coa desaturase |
AR051090A1 (es) | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa |
US8071603B2 (en) | 2004-09-20 | 2011-12-06 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
US7592343B2 (en) | 2004-09-20 | 2009-09-22 | Xenon Pharmaceuticals Inc. | Pyridazine-piperazine compounds and their use as stearoyl-CoA desaturase inhibitors |
EP1814551A2 (en) | 2004-09-20 | 2007-08-08 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase |
AR051026A1 (es) | 2004-09-20 | 2006-12-13 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa |
CA2580844A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as mediators of stearoyl-coa desaturase |
US7449486B2 (en) * | 2004-10-19 | 2008-11-11 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
ES2338904T3 (es) | 2004-10-26 | 2010-05-13 | EISAI R&D MANAGEMENT CO., LTD. | Forma amorfa de compuestos de cinamida. |
UA95907C2 (en) * | 2005-05-02 | 2011-09-26 | Эррей Биофарма Инк. | Mitotic kinesin inhibitors and methods of use thereof |
UA92746C2 (en) | 2005-05-09 | 2010-12-10 | Акилайон Фармасьютикалз, Инк. | Thiazole compounds and methods of use |
BRPI0608810A2 (pt) | 2005-05-11 | 2010-01-26 | Abbott Lab | antagonistas do receptor vanilóide subtipo 1 (vr1) e seus usos |
AU2006343359A1 (en) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
WO2006136821A1 (en) | 2005-06-22 | 2006-12-28 | Astex Therapeutics Limited | Pharmaceutical compounds |
JP5345842B2 (ja) | 2005-06-23 | 2013-11-20 | アステックス・セラピューティクス・リミテッド | プロテインキナーゼモジュレーターとしてのピラゾール誘導体を含む医薬組み合わせ |
JP5341516B2 (ja) * | 2005-09-13 | 2013-11-13 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 2−アニリン−4−アリール置換チアゾール誘導体 |
KR20080076907A (ko) * | 2005-11-18 | 2008-08-20 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 신나미드 유도체의 제조 방법 |
WO2007058304A1 (ja) * | 2005-11-18 | 2007-05-24 | Eisai R & D Management Co., Ltd. | シンナミド化合物の塩またはそれらの溶媒和物 |
JP5221144B2 (ja) | 2005-11-24 | 2013-06-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | モルホリンタイプ・シンナミド化合物 |
TWI370130B (en) | 2005-11-24 | 2012-08-11 | Eisai R&D Man Co Ltd | Two cyclic cinnamide compound |
US8022075B2 (en) | 2005-11-30 | 2011-09-20 | Fujifilm Ri Pharma Co., Ltd. | Diagnostic and remedy for disease caused by amyloid aggregation and/or deposition |
CN101351451B (zh) | 2005-12-29 | 2013-02-20 | 莱西肯医药有限公司 | 多环氨基酸衍生物及其使用方法 |
TWI378091B (en) * | 2006-03-09 | 2012-12-01 | Eisai R&D Man Co Ltd | Multi-cyclic cinnamide derivatives |
AR059898A1 (es) | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2 |
CN101460483B (zh) | 2006-03-31 | 2013-05-08 | 詹森药业有限公司 | 作为组胺h4受体调节剂的苯并咪唑-2-基嘧啶和吡嗪 |
EP2402319B1 (en) * | 2006-03-31 | 2017-08-30 | Novartis AG | DGAT Inhibitors |
WO2007135970A1 (ja) * | 2006-05-19 | 2007-11-29 | Eisai R & D Management Co., Ltd. | ヘテロ環系-シンナミド誘導体 |
US20100105904A1 (en) * | 2006-05-19 | 2010-04-29 | Teiji Kimura | Urea type cinnamide derivative |
AU2007266890B2 (en) | 2006-05-30 | 2011-02-17 | Astrazeneca Ab | 1, 3, 4 -oxadiazole derivatives as DGAT1 inhibitors |
TW200811134A (en) | 2006-07-12 | 2008-03-01 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
SA07280403B1 (ar) | 2006-07-28 | 2010-12-01 | إيساي أر أند دي منجمنت كو. ليمتد | ملح رباعي لمركب سيناميد |
US8324257B2 (en) * | 2006-10-03 | 2012-12-04 | Array Biopharma Inc. | Mitotic kinesin inhibitors and methods of use thereof |
JP5160764B2 (ja) * | 2006-10-13 | 2013-03-13 | 全薬工業株式会社 | 特定の構造の複素環化合物を含む抗鬱剤、脳保護剤、アミロイドβ沈着抑制剤または老化抑制剤 |
JP2010506917A (ja) | 2006-10-20 | 2010-03-04 | メルク エンド カムパニー インコーポレーテッド | ボンベシンレセプターサブタイプ3モジュレーターとしての置換イミダゾール |
JP2010506916A (ja) | 2006-10-20 | 2010-03-04 | メルク エンド カムパニー インコーポレーテッド | ボンベシンレセプターサブタイプ3モジュレーターとしての置換イミダゾール |
CA2666310C (en) | 2006-10-20 | 2012-07-31 | Merck & Co., Inc. | Substituted imidazoles as bombesin receptor subtype-3 modulators |
KR101450356B1 (ko) | 2006-11-24 | 2014-10-15 | 에이씨 이뮨 에스.에이. | 알츠하이머와 같은 아밀로이드 또는 아밀로이드-유사 단백질과 관련된 질환의 치료를 위한 n-(메틸)-1h-피라졸-3-아민, n-(메틸)-피리딘-2-아민 및 n-(메틸)-티아졸-2-아민 유도체 |
UA99270C2 (en) | 2006-12-12 | 2012-08-10 | Лексикон Фармасьютикалз, Инк. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
AU2008215948A1 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of AD and related conditions |
US8252803B2 (en) * | 2007-02-12 | 2012-08-28 | Merck Sharp & Dohme Corp. | Piperidine derivatives |
PE20081791A1 (es) | 2007-02-28 | 2009-02-07 | Eisai Randd Man Co Ltd | Dos derivados ciclicos de oxomorfolina |
TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
GB0704932D0 (en) | 2007-03-14 | 2007-04-25 | Astex Therapeutics Ltd | Pharmaceutical compounds |
WO2008137102A2 (en) * | 2007-05-04 | 2008-11-13 | Torreypines Therapeutics, Inc. | Methods of modulating amyloid beta and compounds useful therefor |
EP2155737A1 (en) | 2007-05-07 | 2010-02-24 | Schering Corporation | Gamma secretase modulators |
CN101675045B (zh) * | 2007-05-11 | 2012-11-28 | 弗·哈夫曼-拉罗切有限公司 | 作为β-淀粉样蛋白调节剂的杂芳基苯胺 |
CA2687262A1 (en) * | 2007-05-16 | 2008-11-20 | Naoyuki Shimomura | One-pot production process for cinnamide derivative |
WO2008147557A2 (en) * | 2007-05-22 | 2008-12-04 | Achillion Pharmaceuticals, Inc. | Heteroaryl substituted thiazoles and their use as antiviral agents |
CN101932578A (zh) | 2007-06-01 | 2010-12-29 | 先灵公司 | γ分泌酶调节剂 |
AU2008263207B2 (en) | 2007-06-01 | 2013-10-03 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
WO2008156580A1 (en) * | 2007-06-13 | 2008-12-24 | Merck & Co., Inc. | Triazole derivatives for treating alzheimer's disease and related conditions |
CN101743242A (zh) * | 2007-06-29 | 2010-06-16 | 苏尼西斯制药有限公司 | 用作raf激酶抑制剂的杂环化合物 |
AR067354A1 (es) * | 2007-06-29 | 2009-10-07 | Sunesis Pharmaceuticals Inc | Compuestos utiles como inhibidores de la raf quinasa |
EP2185522A1 (en) * | 2007-08-06 | 2010-05-19 | Schering Corporation | Gamma secretase modulators |
US8293757B2 (en) | 2007-08-22 | 2012-10-23 | Irm Llc | 5-(4-(haloalkoxy)phenyl) pyrimidine-2-amine compounds and compositions as kinase inhibitors |
CN101815713B (zh) * | 2007-08-31 | 2013-09-11 | 卫材R&D管理有限公司 | 多环化合物 |
US7935815B2 (en) * | 2007-08-31 | 2011-05-03 | Eisai R&D Management Co., Ltd. | Imidazoyl pyridine compounds and salts thereof |
JP2009079037A (ja) * | 2007-09-06 | 2009-04-16 | Sumitomo Chemical Co Ltd | アミロイドβタンパク質の蓄積を抑制するための医薬組成物 |
MX2010002674A (es) | 2007-09-06 | 2010-03-25 | Schering Corp | Moduladores de gamma secretasa. |
EP2203439B1 (en) | 2007-09-14 | 2011-01-26 | Ortho-McNeil-Janssen Pharmaceuticals, Inc. | 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h, 1'h-ý1, 4'¨bipyridinyl-2'-ones |
EP2205565B1 (en) | 2007-09-14 | 2013-04-17 | Janssen Pharmaceuticals, Inc. | 1,3-disubstituted-4-phenyl-1 h-pyridin-2-ones |
EA019085B1 (ru) | 2007-09-14 | 2014-01-30 | Янссен Фармасьютикалз, Инк. | 1',3-двузамещенные 4-(арил-х-фенил)-1н-пиридин-2-оны |
JO2784B1 (en) | 2007-10-18 | 2014-03-15 | شركة جانسين فارماسوتيكا ان. في | 5,3,1 - Triazole substitute derivative |
WO2009050186A1 (en) | 2007-10-18 | 2009-04-23 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4-triazoles |
WO2009059214A1 (en) * | 2007-11-02 | 2009-05-07 | The Regents Of The University Of California | Abeta-binding small molecules |
MX2010005028A (es) | 2007-11-05 | 2010-05-27 | Schering Corp | Moduladores de gamma secretasa. |
EP2220083B1 (en) | 2007-11-14 | 2017-07-19 | Janssen Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
US20110092554A1 (en) * | 2007-11-19 | 2011-04-21 | Richard Chesworth | 1,3,5 tri-subtituted benzenes for treatment of alzheimer's disease and other disorders |
CA2707712A1 (en) | 2007-12-06 | 2009-06-11 | Schering Corporation | Gamma secretase modulators |
MX2010006244A (es) * | 2007-12-06 | 2010-12-02 | Schering Corp | Moduladores de gamma secretasa. |
CN101945868A (zh) | 2007-12-11 | 2011-01-12 | 先灵公司 | γ分泌酶调节剂 |
US20110166132A1 (en) * | 2007-12-13 | 2011-07-07 | Amgen Inc. | Gamma Secretase Modulators |
WO2009086277A1 (en) | 2007-12-20 | 2009-07-09 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
AR069802A1 (es) | 2007-12-20 | 2010-02-17 | Astrazeneca Ab | Compuestos de carbamoilo como inhibidores de dgat1 190 |
WO2009080533A1 (en) | 2007-12-21 | 2009-07-02 | F. Hoffmann-La Roche Ag | Heteroaryl derivatives as orexin receptor antagonists |
ATE535515T1 (de) * | 2008-01-11 | 2011-12-15 | Hoffmann La Roche | Modulatoren für amyloid beta |
CN101925607A (zh) * | 2008-01-28 | 2010-12-22 | 卫材R&D管理有限公司 | 结晶性的肉桂酰胺化合物或其盐 |
RU2010137300A (ru) | 2008-02-22 | 2012-03-27 | Ф. Хоффманн-Ля Рош Аг (Ch) | Модуляторы бета-амилоида |
US20110105436A1 (en) * | 2008-03-10 | 2011-05-05 | Auckland Uniservices Limited | Heteroaryl compounds, compositions, and methods of use in cancer treatment |
CA2714662C (en) | 2008-03-19 | 2016-05-10 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4-triazoles as nicotinic acetylcholine receptor modulators |
CL2009001125A1 (es) | 2008-05-09 | 2011-02-11 | Janssen Pharmaceutica Nv | Compuestos derivados de pirazol trisustituido, moduladores alostericos positivos de los receptores ach nicotinicos; composicion farmaceutica que los comprende; proceso de preparacion de la composicion; y su uso en el tratamiento de enfermedades de snc o inflamatorias. |
WO2009140621A2 (en) * | 2008-05-15 | 2009-11-19 | Duke University | Compositions and methods relating to heat shock transcription factor activating compounds and targets thereof |
US9315449B2 (en) | 2008-05-15 | 2016-04-19 | Duke University | Substituted pyrazoles as heat shock transcription factor activators |
US8362050B2 (en) | 2008-06-24 | 2013-01-29 | Irm Llc | Compounds and methods for modulating G protein-coupled receptors |
US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
EP2303841A1 (en) | 2008-07-14 | 2011-04-06 | Gilead Sciences, Inc. | Oxindolyl inhibitor compounds |
EP2303881A2 (en) | 2008-07-14 | 2011-04-06 | Gilead Sciences, Inc. | Fused heterocyclyc inhibitors of histone deacetylase and/or cyclin-dependent kinases |
US8134000B2 (en) | 2008-07-14 | 2012-03-13 | Gilead Sciences, Inc. | Imidazolyl pyrimidine inhibitor compounds |
CA2731323A1 (en) | 2008-07-28 | 2010-02-04 | Gilead Sciences, Inc. | Cycloalkylidene and heterocycloalkylidene histone deacetylase inhibitor compounds |
MX2011002042A (es) | 2008-09-02 | 2011-06-20 | Ortho Mcneil Janssen Pharm | Derivados de 3-azabiciclo[3.1.o]hexilo como moduladores de los receptores del glutamato metabotropico. |
JP5771525B2 (ja) * | 2008-09-18 | 2015-09-02 | セダーズ−シナイ メディカル センター | アルツハイマー病を検出するための光学的方法 |
CA2736924C (en) | 2008-10-09 | 2016-06-28 | F. Hoffmann-La Roche Ag | Modulators for amyloid beta |
MX2011003691A (es) | 2008-10-16 | 2011-09-06 | Ortho Mcneil Janssen Pharm | Derivados de indol y benzomorfolina como moduladores de los receptores de glutamato metabotropico. |
EP2367826A4 (en) | 2008-11-06 | 2012-07-04 | Astrazeneca Ab | MODULATORS OF THE PROTEIN -AMYLOID |
JP5378532B2 (ja) * | 2008-11-10 | 2013-12-25 | エフ.ホフマン−ラ ロシュ アーゲー | 複素環γ−セクレターゼモジュレーター |
AU2009314049B2 (en) | 2008-11-13 | 2015-03-05 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
US8809318B2 (en) | 2008-11-13 | 2014-08-19 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
RU2512283C2 (ru) | 2008-11-28 | 2014-04-10 | Янссен Фармасьютикалз, Инк. | Производные индола и бензоксазина в качестве модуляторов метаботропных глутаматных рецепторов |
WO2010071741A1 (en) | 2008-12-16 | 2010-06-24 | Merck Sharp & Dohme Corp. | Triazole derivatives for treatment of alzheimer's disease |
US20110313001A1 (en) * | 2008-12-16 | 2011-12-22 | Christian Fischer | 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 |
WO2010075203A1 (en) | 2008-12-22 | 2010-07-01 | Schering Corporation | Gamma secretase modulators |
AU2009330234A1 (en) | 2008-12-22 | 2011-07-07 | Merck Sharp & Dohme Corp. | Gamma secretase modulators |
GB0900388D0 (en) * | 2009-01-12 | 2009-02-11 | Addex Pharmaceuticals Sa | New compounds |
US8946426B2 (en) * | 2009-02-06 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | Substituted bicyclic heterocyclic compounds as gamma secretase modulators |
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 |
PE20120172A1 (es) * | 2009-02-26 | 2012-03-08 | Eisai Randd Man Co Ltd | Compuestos heterociclicos fusionados que contiene nitrogeno como inhibidores de la produccion de beta-amiloide |
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 |
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 |
US8703954B2 (en) | 2009-02-26 | 2014-04-22 | Eisai R&D Management Co., Ltd. | Salt of tetrahydrotriazolopyridine derivative and crystal thereof |
WO2010145883A1 (en) * | 2009-05-07 | 2010-12-23 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Novel substituted indazole and aza-indazole derivatives as gamma secretase modulators |
US9023767B2 (en) * | 2009-05-07 | 2015-05-05 | Memorial Sloan-Kettering Cancer Center | γ-Secretase substrates and methods of use |
EA020671B1 (ru) | 2009-05-12 | 2014-12-30 | Янссен Фармасьютикалз, Инк. | ПРОИЗВОДНЫЕ 1,2,4-ТРИАЗОЛО[4,3-a]ПИРИДИНА И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ПОЛОЖИТЕЛЬНЫХ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ mGluR2 |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
CN102439008B (zh) | 2009-05-12 | 2015-04-29 | 杨森制药有限公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其用于治疗或预防神经和精神病症的用途 |
CN102459159A (zh) | 2009-06-08 | 2012-05-16 | 吉利德科学股份有限公司 | 烷酰基氨基苯甲酰胺苯胺hdac抑制剂化合物 |
WO2010144378A2 (en) | 2009-06-08 | 2010-12-16 | Gilead Colorado, Inc. | Cycloalkylcarbamate benzamide aniline hdac inhibitor compounds |
WO2010147973A1 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
WO2010147969A2 (en) | 2009-06-16 | 2010-12-23 | Schering Corporation | Gamma secretase modulators |
US20120245158A1 (en) | 2009-06-16 | 2012-09-27 | Xianhai Huang | Gamma secretase modulators |
WO2010146395A1 (en) | 2009-06-19 | 2010-12-23 | Astrazeneca Ab | Pyrazine carboxamides as inhibitors of dgat1 |
JP2012180281A (ja) * | 2009-06-29 | 2012-09-20 | Dainippon Sumitomo Pharma Co Ltd | 新規オキサジアゾール誘導体 |
CN102482276A (zh) | 2009-07-13 | 2012-05-30 | 武田药品工业株式会社 | 杂环化合物及其用途 |
US8946266B2 (en) | 2009-07-15 | 2015-02-03 | Janssen Pharmaceuticals, Inc. | Substituted triazole and imidazole derivatives as gamma secretase modulators |
US8580833B2 (en) | 2009-09-30 | 2013-11-12 | Transtech Pharma, Inc. | Substituted imidazole derivatives and methods of use thereof |
EP2311823A1 (en) | 2009-10-15 | 2011-04-20 | AC Immune S.A. | 2,6-Diaminopyridine compounds for treating diseases associated with amyloid proteins or for treating ocular diseases |
EP2499282B1 (en) | 2009-11-09 | 2015-04-22 | NeuroGenetic Pharmaceuticals, Inc. | Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor |
EP2523949B1 (en) | 2010-01-15 | 2014-08-20 | Janssen Pharmaceuticals Inc. | Novel substituted triazole derivatives as gamma secretase modulators |
US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
EP2536283B8 (en) | 2010-02-18 | 2015-11-04 | vTv Therapeutics LLC | Phenyl-heteroaryl derivatives and methods of use thereof |
EP2382944B1 (de) | 2010-04-30 | 2014-06-11 | Ivoclar Vivadent AG | Dentalofen |
GB201007286D0 (en) | 2010-04-30 | 2010-06-16 | Astex Therapeutics Ltd | New compounds |
US9403815B2 (en) * | 2010-06-24 | 2016-08-02 | The Regents Of The University Of California | Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms |
EA201390333A1 (ru) | 2010-09-02 | 2013-08-30 | Такеда Фармасьютикал Компани Лимитед | Конденсированные триазолы для лечения или профилактики умеренного когнитивного нарушения |
US9632088B2 (en) | 2010-09-07 | 2017-04-25 | Memorial Sloan-Kettering Cancer Center | Methods and compositions for gamma-secretase assay |
US9271967B2 (en) | 2010-11-08 | 2016-03-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
JP5852666B2 (ja) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4−トリアゾロ[4,3−a]ピリジン誘導体およびmGluR2受容体のポジティブアロステリックモジュレーターとしてのそれらの使用 |
JP5852665B2 (ja) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4−トリアゾロ[4,3−a]ピリジン誘導体およびmGluR2受容体のポジティブアロステリックモジュレーターとしてのそれらの使用 |
GB201020179D0 (en) | 2010-11-29 | 2011-01-12 | Astex Therapeutics Ltd | New compounds |
US8865754B2 (en) | 2011-03-03 | 2014-10-21 | Proteotech Inc. | Compounds for the treatment of neurodegenerative diseases |
CN103502225B (zh) | 2011-03-24 | 2015-11-25 | 杨森制药公司 | 作为γ分泌酶调节剂的经取代的三唑基哌嗪以及三唑基哌啶衍生物 |
WO2012154520A1 (en) | 2011-05-10 | 2012-11-15 | Merck Sharp & Dohme Corp. | Pyridyl aminopyridines as syk inhibitors |
WO2012154518A1 (en) | 2011-05-10 | 2012-11-15 | Merck Sharp & Dohme Corp. | Bipyridylaminopyridines as syk inhibitors |
EP2706853B1 (en) | 2011-05-10 | 2017-06-14 | Merck Sharp & Dohme Corp. | Aminopyrimidines as syk inhibitors |
IN2014MN00258A (ja) | 2011-07-15 | 2015-09-25 | Janssen Pharmaceuticals Inc | |
GB201118675D0 (en) | 2011-10-28 | 2011-12-14 | Astex Therapeutics Ltd | New compounds |
GB201118652D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
GB201118656D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
GB201118654D0 (en) | 2011-10-28 | 2011-12-07 | Astex Therapeutics Ltd | New compounds |
EP2664619B1 (en) | 2012-05-16 | 2017-07-12 | Manros Therapeutics | Purine derivatives as tools for screening anti-Alzheimer compounds |
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 |
GB201209613D0 (en) | 2012-05-30 | 2012-07-11 | Astex Therapeutics Ltd | New compounds |
GB201209609D0 (en) | 2012-05-30 | 2012-07-11 | Astex Therapeutics Ltd | New compounds |
EP2687528A1 (en) * | 2012-07-17 | 2014-01-22 | Ares Trading S.A. | Fused triazole derivatives as gamma secretase modulators |
US9717710B2 (en) | 2012-10-05 | 2017-08-01 | Vtv Therapeutics Llc | Treatment of mild and moderate Alzheimer's disease |
US10112943B2 (en) | 2012-12-20 | 2018-10-30 | Janssen Pharmaceutica Nv | Substituted imidazoles as gamma secretase modulators |
WO2014111457A1 (en) | 2013-01-17 | 2014-07-24 | Janssen Pharmaceutica Nv | Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators |
WO2014138368A1 (en) | 2013-03-06 | 2014-09-12 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine modulators of the histamine h4 receptor |
EP2968296B1 (en) | 2013-03-12 | 2020-09-02 | The Regents of the University of California | Gamma-secretase modulators |
GB201307577D0 (en) | 2013-04-26 | 2013-06-12 | Astex Therapeutics Ltd | New compounds |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
NZ713762A (en) | 2013-06-27 | 2018-03-23 | Pfizer | Heteroaromatic compounds and their use as dopamine d1 ligands |
US20150045353A1 (en) * | 2013-08-09 | 2015-02-12 | Neurogenetic Pharmaceuticals, Inc. | Formulations containing gamma secretase modulators, methods for preparation and delivery thereof |
US9453002B2 (en) | 2013-08-16 | 2016-09-27 | Janssen Pharmaceutica Nv | Substituted imidazoles as N-type calcium channel blockers |
RU2016111138A (ru) | 2013-08-28 | 2017-10-04 | Медивэйшн Текнолоджиз, Инк. | Гетероциклические соединения и способы их применения |
KR102281803B1 (ko) * | 2013-09-04 | 2021-07-28 | 엘로라 테라퓨틱스, 인크. | 간 x 수용체 (lxr) 조절인자 |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
WO2015109109A1 (en) | 2014-01-15 | 2015-07-23 | Forum Pharmaceuticals Inc. | Fused morpholinopyrimidines and methods of use thereof |
US10562897B2 (en) | 2014-01-16 | 2020-02-18 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators |
ES2860298T3 (es) | 2014-01-21 | 2021-10-04 | Janssen Pharmaceutica Nv | Combinaciones que comprenden moduladores alostéricos positivos del receptor glutamatérgico metabotrópico de subtipo 2 y su uso |
MY182627A (en) | 2014-01-21 | 2021-01-27 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
HUE053654T2 (hu) | 2014-03-26 | 2021-07-28 | Astex Therapeutics Ltd | FGFR- és CMET-inhibitorok kombinációi a rák kezelésére |
JO3512B1 (ar) | 2014-03-26 | 2020-07-05 | Astex Therapeutics Ltd | مشتقات كينوكسالين مفيدة كمعدلات لإنزيم fgfr كيناز |
JP6980385B2 (ja) | 2014-03-26 | 2021-12-15 | アステックス、セラピューティックス、リミテッドAstex Therapeutics Limited | Fgfr阻害剤とigf1r阻害剤の組合せ |
CA2956871C (en) | 2014-08-01 | 2021-05-18 | Nuevolution A/S | Compounds active towards bromodomains |
AU2015299142B2 (en) | 2014-08-04 | 2020-05-07 | Nuevolution A/S | Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases |
US10472346B2 (en) | 2014-10-31 | 2019-11-12 | The General Hospital Corporation | Potent gamma-secretase modulators |
US10221172B2 (en) | 2015-01-13 | 2019-03-05 | Vanderbilt University | Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction |
EP3053920B1 (en) * | 2015-02-05 | 2020-04-08 | AB Science | Compounds with anti-tumoral activity |
JOP20200201A1 (ar) | 2015-02-10 | 2017-06-16 | Astex Therapeutics Ltd | تركيبات صيدلانية تشتمل على n-(3.5- ثنائي ميثوكسي فينيل)-n'-(1-ميثيل إيثيل)-n-[3-(ميثيل-1h-بيرازول-4-يل) كينوكسالين-6-يل]إيثان-1.2-ثنائي الأمين |
CA2977401A1 (en) * | 2015-02-27 | 2016-09-01 | The Regents Of The University Of California | Small molecules that enable cartilage rejuvenation |
JP2018507235A (ja) | 2015-03-04 | 2018-03-15 | メディベイション テクノロジーズ エルエルシー | ステロール調節エレメント結合タンパク質(srebp)阻害剤 |
CA2978627A1 (en) | 2015-03-04 | 2016-09-09 | Medivation Technologies, Inc. | Srebp blockers for use in treating liver fibrosis, elevated cholesterol and insulin resistance |
US10478494B2 (en) | 2015-04-03 | 2019-11-19 | Astex Therapeutics Ltd | FGFR/PD-1 combination therapy for the treatment of cancer |
DK3280401T3 (da) * | 2015-04-07 | 2021-11-15 | Ela Pharma Ltd | Sammensætninger til behandling og/eller forebyggelse af celle- eller vævsnekrose specielt rettet mod kathepsin c og/eller cela1 og/eller cela3a og/eller strukturelt relaterede enzymer dertil |
US9802927B2 (en) | 2015-06-10 | 2017-10-31 | Denali Therapeutics, Inc. | Oxadiazine compounds and methods of use thereof |
WO2016202935A1 (en) | 2015-06-19 | 2016-12-22 | Bayer Pharma Aktiengesellschaft | Glucose transport inhibitors |
MX2018003564A (es) | 2015-09-23 | 2018-06-18 | Janssen Pharmaceutica Nv | 1,4-benzodiazepinas biheteroarilo sustituidas y usos de las mismas para el tratamiento del cancer. |
EP3353177B1 (en) | 2015-09-23 | 2020-06-03 | Janssen Pharmaceutica NV | Tricyclic heterocycles for the treatment of cancer |
JP6904612B2 (ja) | 2016-12-16 | 2021-07-21 | パイプライン セラピューティクス, インコーポレイテッド | 蝸牛シナプス障害を処置する方法 |
CN111148743B (zh) | 2017-10-06 | 2023-12-15 | 福马治疗有限公司 | 抑制泛素特异性肽酶30 |
WO2019190823A1 (en) | 2018-03-28 | 2019-10-03 | Vtv Therapeutics Llc | Pharmaceutically acceptable salts of [3-(4- {2-butyl-1-[4-(4-chlorophenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine |
WO2019190822A1 (en) | 2018-03-28 | 2019-10-03 | Vtv Therapeutics Llc | Crystalline forms of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine |
CN108997328B (zh) * | 2018-09-06 | 2021-06-08 | 广东东阳光药业有限公司 | 亚氨基噻二嗪二氧化物衍生物及其用途 |
US20200115389A1 (en) | 2018-09-18 | 2020-04-16 | Nikang Therapeutics, Inc. | Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors |
EA202190960A1 (ru) | 2018-10-05 | 2021-06-28 | Форма Терапьютикс, Инк. | Конденсированные пирролины, которые действуют как ингибиторы убиквитин-специфической протеазы 30 (usp30) |
TWI767148B (zh) | 2018-10-10 | 2022-06-11 | 美商弗瑪治療公司 | 抑制脂肪酸合成酶(fasn) |
WO2020076668A1 (en) | 2018-10-10 | 2020-04-16 | Vtv Therapeutics Llc | Metabolites of [3-(4-{2-butyl-l-[4-(4-chloro-phenoxy)-phenyl]-lh-imidazol-4-yl } -phen ox y)-prop yl] -diethyl-amine |
CA3121202A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
IL294092A (en) * | 2019-12-20 | 2022-08-01 | Ikena Oncology Inc | History of 4-phenyl-n-(phenyl)thiazol-2-amine and related compounds as aryl hydrocarbon receptor (ahr) agonists for the treatment of eg mixed angiogenesis or inflammatory disorders |
US11447479B2 (en) | 2019-12-20 | 2022-09-20 | Nuevolution A/S | Compounds active towards nuclear receptors |
TWI794742B (zh) | 2020-02-18 | 2023-03-01 | 美商基利科學股份有限公司 | 抗病毒化合物 |
AU2021244215A1 (en) | 2020-03-26 | 2022-10-13 | Seagen Inc. | Methods of treating multiple myeloma |
EP4126874A1 (en) | 2020-03-31 | 2023-02-08 | Nuevolution A/S | Compounds active towards nuclear receptors |
US11613532B2 (en) | 2020-03-31 | 2023-03-28 | Nuevolution A/S | Compounds active towards nuclear receptors |
JP2023526332A (ja) | 2020-05-15 | 2023-06-21 | アルゲン バイオテクノロジーズ,インク. | 特定の化学組成物およびその使用方法 |
CN117120444A (zh) | 2021-04-16 | 2023-11-24 | 吉利德科学公司 | 使用酰胺制备卡巴核苷的方法 |
DE202023102123U1 (de) | 2023-04-21 | 2023-05-02 | Mohammad Tauquir Alam | Morpholinyl-Phenylamino-Thiazol-Derivate als DNA-Gyrase-Inhibitoren |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6184A (en) * | 1849-03-13 | Door-lock | ||
US3710795A (en) * | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
US4044126A (en) * | 1972-04-20 | 1977-08-23 | Allen & Hanburys Limited | Steroidal aerosol compositions and process for the preparation thereof |
GB1429184A (en) * | 1972-04-20 | 1976-03-24 | Allen & Hanburys Ltd | Physically anti-inflammatory steroids for use in aerosols |
USRE28819E (en) * | 1972-12-08 | 1976-05-18 | Syntex (U.S.A.) Inc. | Dialkylated glycol compositions and medicament preparations containing same |
US4410545A (en) * | 1981-02-13 | 1983-10-18 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4328245A (en) * | 1981-02-13 | 1982-05-04 | Syntex (U.S.A.) Inc. | Carbonate diester solutions of PGE-type compounds |
US4358603A (en) * | 1981-04-16 | 1982-11-09 | Syntex (U.S.A.) Inc. | Acetal stabilized prostaglandin compositions |
US4410645A (en) * | 1981-06-15 | 1983-10-18 | Ppg Industries, Inc. | Aqueous sizing composition and sized glass fibers and method |
US4409239A (en) * | 1982-01-21 | 1983-10-11 | Syntex (U.S.A.) Inc. | Propylene glycol diester solutions of PGE-type compounds |
JPS62142168A (ja) | 1985-10-16 | 1987-06-25 | Mitsubishi Chem Ind Ltd | チアゾ−ル誘導体及びそれを有効成分とするロイコトリエンきつ抗剤 |
DE3601196A1 (de) * | 1986-01-17 | 1987-07-23 | Merck Patent Gmbh | 1,4-dihydropyridine |
US4826990A (en) | 1987-09-30 | 1989-05-02 | American Home Products Corporation | 2-aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents |
US5052558A (en) | 1987-12-23 | 1991-10-01 | Entravision, Inc. | Packaged pharmaceutical product |
US5033252A (en) * | 1987-12-23 | 1991-07-23 | Entravision, Inc. | Method of packaging and sterilizing a pharmaceutical product |
US5028875A (en) * | 1989-04-27 | 1991-07-02 | Texas Tech University | Linear rotary differential capacitance transducer |
JPH0727609Y2 (ja) * | 1989-07-03 | 1995-06-21 | アルプス電気株式会社 | 可変抵抗器 |
US5585112A (en) * | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
IT1246382B (it) * | 1990-04-17 | 1994-11-18 | Eurand Int | Metodo per la cessione mirata e controllata di farmaci nell'intestino e particolarmente nel colon |
AU646877B2 (en) | 1990-06-15 | 1994-03-10 | Scios Nova Inc. | Transgenic non-human mammal displaying the amyloid-forming pathology of alzheimer's disease |
US5048736A (en) * | 1990-06-26 | 1991-09-17 | Anatra Enterprises, Inc. | Coupon holder |
US5543390A (en) * | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
JP2786336B2 (ja) | 1991-03-04 | 1998-08-13 | 富士写真フイルム株式会社 | 免疫分析要素および免疫分析方法 |
US5672805A (en) * | 1991-07-18 | 1997-09-30 | The Regents Of The University Of California | Transgenic mice expressing the neurotoxic C-terminus of β-amyloid precursor protein |
WO1993007296A1 (en) * | 1991-10-03 | 1993-04-15 | Indiana University Foundation | Method for screening for alzheimer's disease |
DE69233109T2 (de) * | 1992-01-07 | 2004-05-19 | Elan Pharmaceuticals, Inc., San Francisco | Transgene tiermodelle fur alzheimer-krankheit |
US6010715A (en) * | 1992-04-01 | 2000-01-04 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
US6024975A (en) * | 1992-04-08 | 2000-02-15 | Americare International Diagnostics, Inc. | Method of transdermally administering high molecular weight drugs with a polymer skin enhancer |
US5604102A (en) * | 1992-04-15 | 1997-02-18 | Athena Neurosciences, Inc. | Methods of screening for β-amyloid peptide production inhibitors |
US5323907A (en) | 1992-06-23 | 1994-06-28 | Multi-Comp, Inc. | Child resistant package assembly for dispensing pharmaceutical medications |
US5958883A (en) * | 1992-09-23 | 1999-09-28 | Board Of Regents Of The University Of Washington Office Of Technology | Animal models of human amyloidoses |
WO1994018172A1 (en) * | 1993-02-01 | 1994-08-18 | Yoshitomi Pharmaceutical Industries, Ltd. | Imidazolylbenzene compound and use thereof as medicine |
US6274552B1 (en) * | 1993-03-18 | 2001-08-14 | Cytimmune Sciences, Inc. | Composition and method for delivery of biologically-active factors |
JP2950520B2 (ja) * | 1993-04-02 | 1999-09-20 | アンティキャンサー インコーポレーテド | 毛胞に有益な配合物を送達する方法 |
US5523092A (en) * | 1993-04-14 | 1996-06-04 | Emory University | Device for local drug delivery and methods for using the same |
US5985307A (en) * | 1993-04-14 | 1999-11-16 | Emory University | Device and method for non-occlusive localized drug delivery |
DE4320432A1 (de) * | 1993-06-21 | 1994-12-22 | Bayer Ag | Substituierte Mono- und Bipyridylmethylderivate |
US6004534A (en) * | 1993-07-23 | 1999-12-21 | Massachusetts Institute Of Technology | Targeted polymerized liposomes for improved drug delivery |
EP0730643B1 (en) * | 1993-10-27 | 2001-01-10 | Elan Pharmaceuticals, Inc. | Transgenic animals harboring app allele having swedish mutation |
JPH07132033A (ja) * | 1993-11-12 | 1995-05-23 | Hoechst Japan Ltd | アルツハイマー病モデルトランスジェニック動物 |
US5759542A (en) * | 1994-08-05 | 1998-06-02 | New England Deaconess Hospital Corporation | Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases |
EP0778886A4 (en) * | 1994-09-01 | 2001-05-02 | TRANSGENIC ANIMAL EXPRESSING A FAMILY FORM OF A HUMAN AMYLOID PRECURSOR PROTEIN | |
US5660854A (en) * | 1994-11-28 | 1997-08-26 | Haynes; Duncan H | Drug releasing surgical implant or dressing material |
US6187992B1 (en) * | 1994-12-05 | 2001-02-13 | Merck & Co., Inc. | Transgenic mouse having a disrupted amyloid precursor protein gene |
US5983134A (en) * | 1995-04-23 | 1999-11-09 | Electromagnetic Bracing Systems Inc. | Electrophoretic cuff apparatus drug delivery system |
US6316652B1 (en) * | 1995-06-06 | 2001-11-13 | Kosta Steliou | Drug mitochondrial targeting agents |
US6167301A (en) * | 1995-08-29 | 2000-12-26 | Flower; Ronald J. | Iontophoretic drug delivery device having high-efficiency DC-to-DC energy conversion circuit |
US6039975A (en) * | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
WO1997036898A1 (en) | 1996-04-03 | 1997-10-09 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
TW345603B (en) * | 1996-05-29 | 1998-11-21 | Gmundner Fertigteile Gmbh | A noise control device for tracks |
US5985317A (en) * | 1996-09-06 | 1999-11-16 | Theratech, Inc. | Pressure sensitive adhesive matrix patches for transdermal delivery of salts of pharmaceutical agents |
KR100353304B1 (ko) * | 1996-10-01 | 2002-09-30 | 에스알아이 인터내셔널 | 맛이 차폐된 마이크로캡슐 조성물 및 이것의 제조 방법 |
US6131570A (en) * | 1998-06-30 | 2000-10-17 | Aradigm Corporation | Temperature controlling device for aerosol drug delivery |
US6187797B1 (en) | 1996-12-23 | 2001-02-13 | Dupont Pharmaceuticals Company | Phenyl-isoxazoles as factor XA Inhibitors |
US5860957A (en) * | 1997-02-07 | 1999-01-19 | Sarcos, Inc. | Multipathway electronically-controlled drug delivery system |
US6120751A (en) * | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6060082A (en) * | 1997-04-18 | 2000-05-09 | Massachusetts Institute Of Technology | Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery |
US5948433A (en) * | 1997-08-21 | 1999-09-07 | Bertek, Inc. | Transdermal patch |
ATE387192T1 (de) * | 1997-10-28 | 2008-03-15 | Bando Chemical Ind | Dermatologisches pflaster und verfahren zur herstellung seiner basisschicht |
CA2318368C (en) * | 1998-01-28 | 2007-09-11 | Shionogi & Co., Ltd. | Novel tricyclic compound |
US6048736A (en) * | 1998-04-29 | 2000-04-11 | Kosak; Kenneth M. | Cyclodextrin polymers for carrying and releasing drugs |
US6037621A (en) * | 1998-07-29 | 2000-03-14 | Lucent Technologies Inc. | On-chip capacitor structure |
EP1137415A4 (en) | 1998-12-07 | 2002-03-20 | Smithkline Beecham Corp | MYT1 KINASE INHIBITORS |
EP1146875A4 (en) | 1998-12-07 | 2002-05-02 | Smithkline Beecham Corp | MYT1 KINASE INHIBITORS |
US6271359B1 (en) | 1999-04-14 | 2001-08-07 | Musc Foundation For Research Development | Tissue-specific and pathogen-specific toxic agents and ribozymes |
US6256533B1 (en) * | 1999-06-09 | 2001-07-03 | The Procter & Gamble Company | Apparatus and method for using an intracutaneous microneedle array |
US6080082A (en) * | 1999-06-11 | 2000-06-27 | Eaton Corporation | Engine output torque control for powertrain with engageable positive clutches |
JP2001114690A (ja) * | 1999-08-06 | 2001-04-24 | Takeda Chem Ind Ltd | p38MAPキナーゼ阻害剤 |
US6261595B1 (en) * | 2000-02-29 | 2001-07-17 | Zars, Inc. | Transdermal drug patch with attached pocket for controlled heating device |
WO2001087845A2 (en) * | 2000-05-15 | 2001-11-22 | Fujisawa Pharmaceutical Co., Ltd. | N-containing heterocyclic compounds and their use as 5-ht antagonists |
JP2002121597A (ja) | 2000-10-18 | 2002-04-26 | Mitsui Chemicals Inc | 漂白剤組成物 |
US6511229B2 (en) | 2000-12-21 | 2003-01-28 | Teradyne, Inc. | Methods and apparatus for controlling access to an optical interface |
WO2002083667A2 (en) * | 2001-04-13 | 2002-10-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
PT1392287E (pt) * | 2001-05-25 | 2007-02-28 | Schering Corp | Métodos para tratamento de doença de alzheimer e/ou regulação dos níveis de peptídeos β amilóide num sujeito |
WO2003007955A2 (en) * | 2001-07-20 | 2003-01-30 | Cancer Research Technology Limited | Biphenyl apurinic/apyrimidinic site endonuclease inhibitors to treat cancer |
WO2003027105A1 (en) * | 2001-09-26 | 2003-04-03 | Bayer Pharmaceuticals Corporation | Substituted 3-pyridyl thiophenes as c17,20 lyase inhibitors |
US20050065118A1 (en) * | 2001-10-16 | 2005-03-24 | Jing Wang | Organosulfur inhibitors of tyrosine phosphatases |
US20030158199A1 (en) * | 2002-01-25 | 2003-08-21 | Kylix, B.V. | Novel compounds for inhibition of Tie-2 |
JP2003313176A (ja) * | 2002-04-24 | 2003-11-06 | Sankyo Co Ltd | アミノアゾール誘導体 |
WO2004002480A1 (en) | 2002-06-27 | 2004-01-08 | Novo Nordisk A/S | Novel glucagon antagonists/inverse agonists |
GB2408071B (en) | 2002-08-17 | 2005-10-19 | Siemens Magnet Technology Ltd | Pressure relief valve for a helium gas compressor |
AU2003259965A1 (en) | 2002-08-20 | 2004-03-11 | Neurogenetics, Inc. | Methods and compositions for modulating amyloid beta |
AR042052A1 (es) | 2002-11-15 | 2005-06-08 | Vertex Pharma | Diaminotriazoles utiles como inhibidores de proteinquinasas |
CA2525547C (en) * | 2003-05-14 | 2012-07-03 | Torreypines Therapeutics, Inc. | Compounds and uses thereof in modulating amyloid beta |
-
2004
- 2004-05-14 CA CA2525547A patent/CA2525547C/en active Active
- 2004-05-14 EP EP04752297.4A patent/EP1628666B1/en not_active Not-in-force
- 2004-05-14 KR KR1020057021516A patent/KR20060023529A/ko not_active Application Discontinuation
- 2004-05-14 AU AU2004247013A patent/AU2004247013B2/en not_active Ceased
- 2004-05-14 MX MXPA05012281A patent/MXPA05012281A/es active IP Right Grant
- 2004-05-14 WO PCT/US2004/015239 patent/WO2004110350A2/en active Application Filing
- 2004-05-14 US US10/846,941 patent/US7244739B2/en active Active
- 2004-05-14 BR BRPI0410348-3A patent/BRPI0410348A/pt not_active IP Right Cessation
- 2004-05-14 JP JP2006533094A patent/JP4847868B2/ja not_active Expired - Fee Related
- 2004-05-14 CN CN201210015057.XA patent/CN102584813B/zh not_active Expired - Fee Related
-
2005
- 2005-10-19 IL IL171471A patent/IL171471A/en active IP Right Grant
-
2007
- 2007-06-19 US US11/765,397 patent/US7799808B2/en not_active Expired - Fee Related
- 2007-07-17 US US11/779,249 patent/US7781442B2/en active Active
-
2010
- 2010-08-23 US US12/861,782 patent/US8017629B2/en not_active Expired - Fee Related
- 2010-09-03 US US12/875,935 patent/US8119680B2/en not_active Expired - Fee Related
- 2010-12-01 JP JP2010268183A patent/JP5292381B2/ja not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
JP2011079852A (ja) | 2011-04-21 |
BRPI0410348A (pt) | 2006-05-30 |
EP1628666A4 (en) | 2007-12-05 |
US20100331551A1 (en) | 2010-12-30 |
US7799808B2 (en) | 2010-09-21 |
CA2525547C (en) | 2012-07-03 |
IL171471A (en) | 2013-02-28 |
KR20060023529A (ko) | 2006-03-14 |
US20050070538A1 (en) | 2005-03-31 |
US8017629B2 (en) | 2011-09-13 |
MXPA05012281A (es) | 2006-05-19 |
AU2004247013B2 (en) | 2010-07-08 |
CN102584813A (zh) | 2012-07-18 |
CN102584813B (zh) | 2016-07-06 |
WO2004110350A3 (en) | 2005-03-03 |
JP2007504282A (ja) | 2007-03-01 |
US8119680B2 (en) | 2012-02-21 |
US7244739B2 (en) | 2007-07-17 |
EP1628666A2 (en) | 2006-03-01 |
US7781442B2 (en) | 2010-08-24 |
US20070260058A1 (en) | 2007-11-08 |
EP1628666B1 (en) | 2015-09-23 |
US20070249833A1 (en) | 2007-10-25 |
AU2004247013A1 (en) | 2004-12-23 |
CA2525547A1 (en) | 2004-12-23 |
JP4847868B2 (ja) | 2011-12-28 |
WO2004110350A2 (en) | 2004-12-23 |
US20100324032A1 (en) | 2010-12-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5292381B2 (ja) | 化合物、及び、アミロイドベータの調節におけるその使用 | |
KR102331422B1 (ko) | 아이소인돌린 조성물 및 신경퇴행성 질환을 치료하는 방법 | |
JP6360147B2 (ja) | グリコシダーゼ阻害剤 | |
WO2008137102A2 (en) | Methods of modulating amyloid beta and compounds useful therefor | |
JP2016040276A (ja) | 熱ショック転写因子活性化化合物及びそのターゲットに関連する組成物及び方法 | |
RU2501792C2 (ru) | Соединения, композиции и способы, предназначенные для лечения бета-амилоидных заболеваний и синуклеинопатий | |
DK3125888T3 (en) | 2,4-THIAZOLIDINEDION DERIVATIVES IN THE TREATMENT OF CENTRAL Nervous System Disorders | |
JP6069661B2 (ja) | 種々のアミロイドβペプチドアロフォームレベルの調節における組成物及びその使用 | |
KR20070083781A (ko) | 신나미드 화합물의 비정질체 | |
US20130035342A1 (en) | Compound Suitable for the Treatment of Synucleopathies | |
JP2021510151A (ja) | アルツハイマー病等のタウ凝集体に関連する障害の治療、緩和、または予防のための1,3,4,5−テトラヒドロ−2h−ピリド(4,3−b)インドール誘導体 | |
CN114945569A (zh) | 吡咯烷衍生物,以及包含其的用于预防或治疗β-淀粉样蛋白或Tau蛋白相关疾病的药物组合物 | |
JP2013526597A (ja) | アミロイド病変の治療および予防のためのフルフェノキシン誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130301 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130524 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130610 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5292381 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |