CN113149979B - 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 - Google Patents
一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN113149979B CN113149979B CN202110244786.1A CN202110244786A CN113149979B CN 113149979 B CN113149979 B CN 113149979B CN 202110244786 A CN202110244786 A CN 202110244786A CN 113149979 B CN113149979 B CN 113149979B
- Authority
- CN
- China
- Prior art keywords
- sirt2
- compound
- preparation
- disease
- substituted coumarin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 coumarin compound Chemical class 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 235000001671 coumarin Nutrition 0.000 title claims abstract description 38
- 229960000956 coumarin Drugs 0.000 title claims abstract description 36
- IOJUPLGTWVMSFF-UHFFFAOYSA-N cyclobenzothiazole Natural products C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 108010041216 Sirtuin 2 Proteins 0.000 claims abstract description 57
- 102000000477 Sirtuin 2 Human genes 0.000 claims abstract description 57
- 150000001875 compounds Chemical group 0.000 claims abstract description 57
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 230000002018 overexpression Effects 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 150000004775 coumarins Chemical class 0.000 claims description 8
- LYASTVLDAJIXBL-UHFFFAOYSA-N 1,3-benzothiazole-2-carboxamide Chemical group C1=CC=C2SC(C(=O)N)=NC2=C1 LYASTVLDAJIXBL-UHFFFAOYSA-N 0.000 claims description 6
- BIVMXYHSBRLPDE-UHFFFAOYSA-N 8-bromochromen-2-one Chemical compound C1=CC(=O)OC2=C1C=CC=C2Br BIVMXYHSBRLPDE-UHFFFAOYSA-N 0.000 claims description 6
- 239000007821 HATU Substances 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 4
- 208000013403 hyperactivity Diseases 0.000 claims description 4
- QHHHLHCCVDMOJI-UHFFFAOYSA-N 1,3-thiazol-4-amine Chemical compound NC1=CSC=N1 QHHHLHCCVDMOJI-UHFFFAOYSA-N 0.000 claims description 3
- 208000016097 disease of metabolism Diseases 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000006806 disease prevention Effects 0.000 claims 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract description 27
- 230000002401 inhibitory effect Effects 0.000 abstract description 15
- 230000000694 effects Effects 0.000 abstract description 14
- 230000001681 protective effect Effects 0.000 abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 10
- 208000005890 Neuroma Diseases 0.000 abstract description 9
- 125000001624 naphthyl group Chemical group 0.000 abstract description 5
- 208000024891 symptom Diseases 0.000 abstract description 5
- 210000004027 cell Anatomy 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- OCZAKUGLJAFZCW-UHFFFAOYSA-M [Br-].[Mg+]CC1=CC=C(Cl)C=C1 Chemical compound [Br-].[Mg+]CC1=CC=C(Cl)C=C1 OCZAKUGLJAFZCW-UHFFFAOYSA-M 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000004896 high resolution mass spectrometry Methods 0.000 description 18
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 18
- 229910001623 magnesium bromide Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 229910052717 sulfur Inorganic materials 0.000 description 10
- 239000011593 sulfur Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 102000011990 Sirtuin Human genes 0.000 description 9
- 108050002485 Sirtuin Proteins 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 6
- 125000005518 carboxamido group Chemical group 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
- 239000006184 cosolvent Substances 0.000 description 6
- 229910052805 deuterium Inorganic materials 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 5
- 229940077388 benzenesulfonate Drugs 0.000 description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 210000005036 nerve Anatomy 0.000 description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 5
- HNDXKIMMSFCCFW-UHFFFAOYSA-M propane-2-sulfonate Chemical compound CC(C)S([O-])(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-M 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 4
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
- QMBCIAHVWMFOKB-UHFFFAOYSA-N 2-chloro-1,3-benzothiazol-4-amine Chemical compound NC1=CC=CC2=C1N=C(Cl)S2 QMBCIAHVWMFOKB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- SVENPFFEMUOOGK-SDNWHVSQSA-N (e)-2-cyano-3-[5-(2,5-dichlorophenyl)furan-2-yl]-n-quinolin-5-ylprop-2-enamide Chemical compound ClC1=CC=C(Cl)C(C=2OC(\C=C(/C#N)C(=O)NC=3C4=CC=CN=C4C=CC=3)=CC=2)=C1 SVENPFFEMUOOGK-SDNWHVSQSA-N 0.000 description 2
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 101100069026 Arabidopsis thaliana GK-2 gene Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 101001135571 Mus musculus Tyrosine-protein phosphatase non-receptor type 2 Proteins 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 108010033276 Peptide Fragments Proteins 0.000 description 2
- 102000007079 Peptide Fragments Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 101150068874 SIRT2 gene Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 230000006378 damage Effects 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 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 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 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 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229950006238 nadide Drugs 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008299 semisolid dosage form Substances 0.000 description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical class [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 229960002920 sorbitol Drugs 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 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
- 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 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-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
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 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
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 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 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 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
- 102000004899 14-3-3 Proteins Human genes 0.000 description 1
- 101710112812 14-3-3 protein Proteins 0.000 description 1
- MENAYYMPBRSAAE-AWEZNQCLSA-N 3-[[5-[[(2s)-1-carboxy-3-oxopropan-2-yl]carbamoyl]pyridin-2-yl]methylsulfamoyl]benzoic acid Chemical compound N1=CC(C(=O)N[C@@H](CC(=O)O)C=O)=CC=C1CNS(=O)(=O)C1=CC=CC(C(O)=O)=C1 MENAYYMPBRSAAE-AWEZNQCLSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102000005446 Anaphase-Promoting Complex-Cyclosome Human genes 0.000 description 1
- 108010031677 Anaphase-Promoting Complex-Cyclosome Proteins 0.000 description 1
- 238000009010 Bradford assay Methods 0.000 description 1
- 206010006100 Bradykinesia Diseases 0.000 description 1
- 101001059929 Caenorhabditis elegans Forkhead box protein O Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 102000009562 Forkhead Box Protein O3 Human genes 0.000 description 1
- 108010009307 Forkhead Box Protein O3 Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 102100034523 Histone H4 Human genes 0.000 description 1
- 102000003893 Histone acetyltransferases Human genes 0.000 description 1
- 108090000246 Histone acetyltransferases Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101000971351 Homo sapiens KRR1 small subunit processome component homolog Proteins 0.000 description 1
- 101100365815 Homo sapiens SIRT2 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 102100021559 KRR1 small subunit processome component homolog Human genes 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- DTERQYGMUDWYAZ-UHFFFAOYSA-N N-acetyl-N-thioacetyl-Lysine Natural products CC(=O)NCCCCC(N)C(O)=O DTERQYGMUDWYAZ-UHFFFAOYSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-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
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 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 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 102000003802 alpha-Synuclein Human genes 0.000 description 1
- 108090000185 alpha-Synuclein Proteins 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 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
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 210000005064 dopaminergic neuron Anatomy 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000003209 gene knockout Methods 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
- 239000003906 humectant Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-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
- 239000002674 ointment Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000003938 response to stress Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 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
Images
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
- C07D417/12—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
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种8‑(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用,所述8‑(苯并噻唑酰胺)取代香豆素类化合物的结构如式(I)所示,其中,A环独立地选自苯基、萘基、5‑14元芳杂环基。本发明所涉及的8‑(苯并噻唑酰胺)取代香豆素类化合物是一种全新的化合物结构,其具有较强的SIRT2抑制活性,其中18个化合物的体外SIRT2抑制活性IC50达到微摩尔水平,且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备用于治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用,尤其涉及一种能够抑制SIRT2活性或表达的8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用。
背景技术
帕金森病是一种常见的神经退行性疾病,其临床主要表现为患者行动迟缓、肌僵直以及静止性震颤。帕金森病的病理改变主要体现在中脑黑质多巴胺能神经元的变性坏死,及由此引起纹状体多巴胺含量的显著减少。帕金森病患者承受着生理和心理上的沉重负担。但是目前没有药物能够对帕金森病神经细胞的退行性病变起到保护作用。市场上对于帕金森病的治疗药物(如左旋多巴)主要是针对疾病症状进行缓解,长期服用这类药物给患者带来很严重的副反应。因此,探索新的帕金森病治疗方法,发现新的帕金森病治疗药物具有非常重要的意义。
Sirtuin是一类组蛋白乙酰基转移酶,其酶学活性主要表现为去除组蛋白或其他蛋白中赖氨酸残基上的乙酰基团。在该过程中,Sirtuin依赖烟酰胺腺嘌呤二核苷酸(NAD+)作为底物之一。Sirtuin家族的基因序列在不同物种中相对保守。晶体结构研究表明,Sirtuin由大小两个结构域组成。大的结构域序列比较保守,具有NAD和NADP结合酶的特征。相比之下小的结构域序列变化比较大。Sirtuin的活性中心位于大小结构域之间的裂隙部分。人源的Sirtuin家族包括七种成员:SIRT1-7,分别定位于不同的亚细胞部位,结合并作用于不同的底物,包括p53、α-tubulin、FOXO等,从而实现不同的生物调节功能。Sirtuin的生物学功能是目前生命医学的研究热点,其功能主要体现在与代谢、衰老、长寿、应激反应和基因组稳定等相关的领域。
作为Sirtuin家族中的重要一员,SIRT2主要分布于细胞质中,其作用的底物蛋白包括α-tubulin、histone H4、p53、FOXO和14-3-3protein。SIRT2的功能研究表明:SIRT2通过去乙酰化H4-K16调控细胞有丝分裂的进程;SIRT2通过激活APC/C系统的活性来维持基因组的稳定;SIRT2介导Receptor-interacting protein 1和3(RIP1和RIP3)的相互结合从而调控细胞坏死的进程。最新的研究表明:抑制SIRT2的活性在治疗帕金森病方面具有潜在的价值,具体体现在:(1)SIRT2在成年大脑的中枢神经系统高丰度表达并调节相关生理代谢;(2)SIRT2的siRNA和小分子抑制剂AGK2能够挽救α-synulein造成的神经细胞毒性,AGK2也能够在体内剂量依赖性地保护转基因帕金森病果蝇模型的神经细胞减少凋亡;(3)SIRT2通过去乙酰化FOXO3a来提高Bim在RNA和蛋白水平的表达,促使MPTP作用的帕金森病细胞模型的凋亡以及MPTP作用的小鼠模型大脑中的细胞凋亡。但是,敲除SIRT2基因的小鼠大脑中显示出很明显减少黑质纹状体损伤的现象;(4)另外,SIRT2的小分子抑制剂AK-7能够明显减少另一种神经退化性疾病-Huntington疾病转基因小鼠大脑中突变Huntingtin的聚集,并且能够明显提高Huntington病转基因小鼠的行为表现以及延长其存活时间。现有技术中具有代表性的SIRT2小分子抑制剂包括如下几种:
鉴于SIRT2小分子抑制剂在治疗帕金森病方面的潜在活性,设计合成新的SIRT2抑制剂是目前研究的热点之一。
发明内容
针对现有技术的不足,本发明的目的在于提供一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用,尤其提供一种能够抑制SIRT2活性或表达的8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用。本发明开发了一类结构新型的8-(苯并噻唑酰胺)取代香豆素类化合物,且其具有显著的SIRT2抑制活性,并且对SIRT2具有较好的选择性,可用于帕金森病、代谢类疾病、肿瘤等的预防和治疗。
为达到此发明目的,本发明采用以下技术方案:
第一方面,本发明提供一种8-(苯并噻唑酰胺)取代香豆素类化合物,所述8-(苯并噻唑酰胺)取代香豆素类化合物的结构如式(I)所示:
其中,A环独立地选自苯基、萘基、5-14元芳杂环基(例如5元芳杂环基、6元芳杂环基、7元芳杂环基、8元芳杂环基、9元芳杂环基、10元芳杂环基、11元芳杂环基、12元芳杂环基、13元芳杂环基、14元芳杂环基);
所述苯基、萘基、5-14元芳杂环基无取代或被1-5个(例如1个、2个、3个、4个、5个)Ra取代;Ra各自独立地选自氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-8烷基氧基、C1-8烷基羰基、C1-8烷基氧羰基、C1-8烷基、C3-8环烷基、苯基;
在所述Ra中,所述C1-8烷基、C3-8环烷基、苯基无取代或被1-5个(例如1个、2个、3个、4个、5个)Rb取代;所述Rb各自独立地选自氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-8烷基羰基。
上述C1-8是指取代基的碳原子数为1个、2个、3个、4个、5个、6个、7个、8个;C3-8是指取代基的碳原子数为3个、4个、5个、6个、7个、8个。
本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物是一种全新的化合物结构,且其体外SIRT2抑制活性达到50%以上,其中18个化合物的体外SIRT2抑制活性IC50达到微摩尔水平,尤其是其中11个化合物的IC50值达到10-7mol/L水平,其中5个化合物的IC50值达到10-8mol/L水平,显示出良好的SIRT2抑制活性,且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备用于治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。
优选地,式(I)中,A环独立地选自苯基、萘基、5-14元芳杂环基(例如5元芳杂环基、6元芳杂环基、7元芳杂环基、8元芳杂环基、9元芳杂环基、10元芳杂环基、11元芳杂环基、12元芳杂环基、13元芳杂环基、14元芳杂环基);
所述苯基、萘基、5-14元芳杂环基无取代或被1-5个(例如1个、2个、3个、4个、5个)Ra取代;Ra各自独立地选自氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-6烷基氧基、C1-6烷基羰基、C1-6烷基氧羰基、C1-6烷基、C3-6环烷基、苯基;
在所述Ra中,所述C1-6烷基、C3-6环烷基、苯基无取代或被1-5个(例如1个、2个、3个、4个、5个)Rb取代;所述Rb各自独立地选自氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-6烷基羰基。
上述C1-6是指取代基的碳原子数为1个、2个、3个、4个、5个、6个;C3-6是指取代基的碳原子数为3个、4个、5个、6个。
优选地,所述8-(苯并噻唑酰胺)取代香豆素类化合物的结构如式(IA)所示:
其中,R1、R2、R3、R4、R5独立选自氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、叠氮基、甲磺酰基、异丙磺酰基、苯磺酰基、氨基磺酰基、甲磺酸酯基、异丙磺酸酯基、苯磺酸酯基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-4烷基氧基、C1-4烷基羰基、C1-4烷基氧羰基、C1-4烷基、苯基。
上述C1-4是指取代基的碳原子数为1个、2个、3个、4个。
优选地,所述8-(苯并噻唑酰胺)取代香豆素类化合物的结构如式(IB)所示:
其中,R1、R2、R3、R4、R5独立选自氢、氘、卤素、羟基、巯基、氨基、氰基、硝基、甲磺酰基、三氟甲基、三氟甲基氧基、甲酰氨基、C1-4烷基氧基、C1-4烷基羰基、C1-4烷基;X独立选自N或者C。
上述C1-4是指取代基的碳原子数为1个、2个、3个、4个。
进一步优选地,所述8-(苯并噻唑酰胺)取代香豆素类化合物选自如下所示的结构(分别以结构式表示或以系统命名表示):
第二方面,本发明提供如第一方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐或包含其的药物组合物;
优选地,所述药物组合物还包含药学上可接受的药用辅料,例如载体、稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、乳化剂、助溶剂、增溶剂、渗透压调节剂、表面活性剂、包衣材料、着色剂、pH调节剂、抗氧剂、抑菌剂或缓冲剂等。
本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物的药学上可接受的盐为8-(苯并噻唑酰胺)取代香豆素类化合物与选自如下的酸形成的盐:盐酸、氢溴酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。优选为盐酸、氢溴酸、对甲苯磺酸或三氟乙酸。
第三方面,本发明提供如第一方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物的制备方法,所述制备方法包括:
其反应式如下所示:
优选地,所述N-(2-氯苯并[d]噻唑-4-基)-2-氧代-2H-色烯-8-羧酰胺的制备方法包括如下步骤:
(1)将8-溴香豆素先与正丁基锂混合,再于真空条件下与CO2气体混合,反应,得到香豆素-8-羧酸;
(2)将香豆素-8-羧酸与HATU、DIPEA、2-氯苯并[d]噻唑-4-胺混合,反应,得到N-(2-氯苯并[d]噻唑-4-基)-2-氧代-2H-色烯-8-羧酰胺;
其反应式如下所示:
本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物的制备方法简单易操作,合适工业化生产,具有实用性。
作为本发明的优选技术方案,所述8-(苯并噻唑酰胺)取代香豆素类化合物的制备方法包括如下步骤:
(1)将正丁基锂(正己烷溶液)于-78℃在氮气保护下缓慢添加至8-溴香豆素的无水四氢呋喃溶液中。在-78℃下搅拌3小时后,将溶液在液氮浴中冷冻,然后抽真空,随后引入由BaCO3与浓硫酸反应生成的CO2气体。将混合物在-78℃下搅拌2小时,然后在室温下用饱和NH4Cl水溶液淬灭反应。用盐酸调pH值约为5,乙酸乙酯萃取三次,饱和食盐水洗涤一次,合并的有机相用无水硫酸钠干燥并浓缩。用硅胶柱纯化即得香豆素-8-羧酸。
(2)在单口瓶中加入香豆素-8-羧酸、缩合剂HATU、2-氯苯并[d]噻唑-4-胺、DIPEA、超干二氯甲烷。室温搅拌5小时。TLC检测反应完全。混合液中加入水,用乙酸乙酯萃取三次,用饱和食盐水洗涤,无水硫酸钠干燥。硅胶柱纯化即得产物。
(3)在0℃下将各种芳香类溴化镁的乙醚溶液滴加到搅拌的N-(2-氯苯并[d]噻唑-4-基)-2-氧代-2H-色烯-8-羧酰胺的无水二氯甲烷溶液中。滴加完成后,将反应液在0℃下搅拌1小时,然后以使反应温度保持在10℃以下的速率逐滴加入水。恢复至室温后,将反应液用水和二氯甲烷稀释并通过硅藻土垫。将有机相浓缩,硅胶柱纯化即得产物。
第四方面,本发明提供一种如第一方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物或如第二方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物在制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物中的应用。
优选地,所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症包括帕金森病、代谢性疾病或肿瘤。
第五方面,本发明还提供一种如第一方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物或如第二方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物在制备SIRT2抑制剂中的应用。
第六方面,本发明提供一种治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的方法,该方法包括:给有需要的受试者使用治疗和/或预防有效量的如第一方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物或如第二方面所述的8-(苯并噻唑酰胺)取代香豆素类化合物的立体异构体、其药学上可接受的盐、包含其的药物组合物。
优选地,所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症包括帕金森病、代谢性疾病或肿瘤。
下面对本发明的各个方面和特点作进一步的描述。
本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。以下提供本发明化合物各种基团的定义,除另行定义外,它们在说明书和权利要求书中统一使用。
如本发明所提及的,术语“卤”、“卤素”、“卤素原子”、“卤代”等表示氟、氯、溴或碘,特别是表示氟、氯或溴。
如本发明所提及的,术语“烷基”是指具有指定数目碳原子数的烷基,其可以为直链或支链的烷基,例如所述的“C1-8烷基”时,是指碳原子数为1、2、3、4、5、6、7、8的烷基,可以包括C1-8烷基、C1-7烷基、C2-8烷基、C2-7烷基、C2-6烷基、C3-8烷基、C3-7烷基、C3-6烷基等表示的子范围的基团,以及优选的具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基,进一步优选甲基,异丙基。例如所述的“C1-6烷基氧基”、“C1-6烷基甲酰基”、“C1-6烷基氧甲酰基”或“C1-6烷基”中的“C1-6烷基”,是指碳原子数为1、2、3、4、5、6的烷基,可以包括C1-5烷基、C1-4烷基、C2-6烷基、C2-5烷基、C2-4烷基、C3-6烷基、C3-5烷基、C3-4烷基等表示的子范围的基团,以及优选的具体基团例如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、己基,进一步优选甲基。例如所述的“C1-4烷基羰基”或“C1-4烷基氧羰基”中的“C1-4烷基”,是指碳原子数为1、2、3、4的烷基,可以包括C1-4烷基、C2-4烷基等表示的子范围的基团,以及优选的具体基团如甲基、乙基、正丙基、异丙基。
如本发明所提及的,术语“环烷基”是指具有指定数目环碳原子数的环状烷基,例如提及的“C3-8环烷基”时,其指碳原子数为3、4、5、6、7、8的环烷基,可以包括C3-7环烷基、C3-4环烷基、C4-6环烷基等表示的子范围的基团,以及优选的具体基团例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基,进一步优选环丙基,环戊基、环己基。例如所述的“C3-6环烷基”,是指碳原子数为3、4、5、6的环烷基,可以包括C3-6环烷基、C3-5环烷基、C4-5环烷基等表示的子范围的基团,以及优选的具体基团例如环丙基、环丁基、环戊基、环己基、环庚基,进一步优选环丙基,环戊基、环己基。
如本发明所提及的,术语“芳杂环基”是指包含1至4个杂原子的杂环芳香族体系,所述的杂原子包括氮、氧和硫的杂原子。如本发明所提及的,“5-14元芳杂环基”是指含有5-14个环原子的杂环芳香族体系。具体实施例包括含有1个碳原子和4个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如四氮唑基;含有2个碳原子和3个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如1,2,3-三氮唑基、1,2,4-三氮唑基、噁二唑基、噻二唑基;含有3个碳原子和2个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基;含有4个碳原子和1-2个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如吡咯基、呋喃基、噻吩基、哒嗪基、嘧啶基、吡嗪基;含有5个碳原子和1个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如吡啶基,优选吡啶基;含有6个碳原子和3个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如苯并三唑基;含有7个碳原子和2个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如苯并咪唑基、苯并吡唑基;含有8个碳原子和1-2个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如吲哚基、苯并呋喃基、苯并噻吩基、苯并吡嗪基、苯并嘧啶基、苯并哒嗪基;含有9个碳原子和1个选自氮、氧、硫的杂原子的芳基,优选的具体基团例如喹啉基、异喹啉基。
如本发明所提及的,术语“有效量”是指可在受试者中实现治疗和/或预防本发明所述疾病或病症的剂量。
如本发明所提及的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗和/或预防本发明所述疾病或病症。
如本发明所提及的,术语“受试者”可以指患者或者其它接受本发明所涉及化合物、药用盐或其药物组合物以治疗和/或预防本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
如本发明所提及的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症既可以指一种身体状态,例如呈帕金森病症的身体状态,也可以指一种疾病状态,例如表现为帕金森病等疾病状态。在本文中对于身体状态和疾病状态不作区分,或者二者可以相互指代,例如“帕金森病”与“帕金森症”可以互换使用。
如本发明所提及的,术语“药学上可接受的”例如在描述“药学上可接受的盐”时,表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质,例如在为进行手性拆分时所形成的作为中间体的盐,虽然这种中间体的盐并不能直接给予受试者,但该盐可在为获得本发明终产物中起作用。
本发明再一方面还涉及以本发明化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量%。
本发明化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度,患者或动物的个体情况,给药途径和剂型等可以有大范围的变化。一般来讲,本发明所涉及化合物其每天的合适剂量范围为0.001-150mg/kg体重,优选为0.1-100mg/kg体重,更优选为1-60mg/kg体重,最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药,这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
相对于现有技术,本发明具有以下有益效果:
本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物是一种全新的化合物结构,且其体外SIRT2抑制活性达到50%以上,其中18个化合物的体外SIRT2抑制活性IC50达到微摩尔水平,尤其是其中11个化合物的IC50值达到10-7mol/L水平,其中5个化合物的IC50值达到10-8mol/L水平,显示出良好的SIRT2抑制活性,且对神经瘤细胞具有显著的保护效果。因此可以被广泛用于制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物或制备用于治疗和/或预防帕金森病、代谢性疾病、肿瘤的药物。
附图说明
图1是试验例3中本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物对SH-SY5Y细胞损伤的保护作用的结果统计图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
对于以下全部实施例或制备例,可以使用本领域技术人员已知的标准操作和纯化方法。除非另有说明,所有温度以℃(摄氏度)表示,化合物的结构是通过核磁共振谱(NMR)和/或质谱(MS)来确定。
对于以下全部实施例或制备例,化合物的结构是通过核磁共振氢谱(1H NMR)或质谱(MS)来确定的。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。核磁共振谱用Mercury-300或Mercury-400型核磁共振仪测定,氘代氯仿(CDCl3)或氘代二甲基亚砜(DMSO-d6)作溶剂,四甲基硅烷(TMS)或3-(三甲基硅基)氘代丙酸钠(TSM)为内标。
电子天平采用日本Yanaco LY-300型电子天平。
柱层析使用200~300目或300~400目硅胶为载体。
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。
其中,
HATU为2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluor-ophosphat,即2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。
DIPEA为N,N-diisomromylethylamine,即N,N-二异丙基乙胺。
DMF为N,N-dimethylformamide,即N,N-二甲基甲酰胺。
下述制备例和实施例中所涉及的原料来源如下:
8-溴香豆素购于上海阿拉丁生化科技股份有限公司,CAS:33491-30-4;
2-氯苯并[d]噻唑-4-胺购于上海博拓生物科技有限公司,CAS:855283-00-0;
制备例1
本制备例制备如下式所示的中间体3,合成路线为:
(1)将正丁基锂(1.60M正己烷溶液)(14.00mL,22.33mmol)于-78℃在氮气保护下缓慢添加至8-溴香豆素(5.00g,22.33mmol)的无水四氢呋喃(30mL)溶液中。在-78℃下搅拌3小时后,将溶液在液氮浴中冷冻,然后抽真空,随后引入由BaCO3(5.29g,26.80mmol)与浓硫酸(1.43mL,26.80mmol)反应生成的CO2气体。将混合物在-78℃下搅拌2小时,然后在20℃下用饱和NH4Cl水溶液淬灭反应。用盐酸调pH值为5,乙酸乙酯(15mL×3)萃取三次,饱和食盐水洗涤一次,合并的有机相用无水硫酸钠干燥并浓缩。用硅胶柱纯化即得产物香豆素-8-羧酸(1.57g,收率37%)。
(2)在单口瓶中加入香豆素-8-羧酸(1.50g,7.90mmol),缩合剂HATU(3.60g,9.48mmol),2-氯苯并[d]噻唑-4-胺(1.45g,7.90mmol),DIPEA(2.75mL,15.80mmol),超干二氯甲烷(15mL)。20℃下搅拌5小时。TLC检测反应完全。混合液中加入水,用乙酸乙酯(15mL×3)萃取三次,用饱和食盐水洗涤,无水硫酸钠干燥。硅胶柱纯化即得产物N-(2-氯苯并[d]噻唑-4-基)-2-氧代-2H-色烯-8-羧酰胺(2.17g,收率77%)。
实施例1
本实施例制备化合物1:N-(2-(4-氯苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
在0℃下将4-氯苄溴化镁的乙醚溶液(3.00M,2.81mL,8.43mmol)滴加到搅拌的N-(2-氯苯并[d]噻唑-4-基)-2-氧代-2H-色烯-8-羧酰胺(2.00g,5.62mmol)的无水二氯甲烷(10mL)溶液中。滴加完成后,将反应液在0℃下搅拌1小时,然后保持反应液温度在10℃以下,缓慢逐滴加入水。恢复至20℃后,将反应液用50mL的水和二氯甲烷(1:1)稀释并通过硅藻土垫。将有机相浓缩,硅胶柱纯化即得白色固体产物0.62g,产率25%。对产物进行如下表征:
1H NMR(400MHz,CDCl3):δ8.15-8.35(m,2H),7.63-7.79(m,5H),7.10-7.34(m,4H),6.02(m,1H),3.81(s,2H).
HR-MS(ESI):[M+H]+C24H16ClN2O3S计算值447.0570,实测值447.0556.
实施例2
本实施例制备化合物2:N-(2-(3-氯苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.15-8.35(m,2H),7.63-7.79(m,5H),7.12-7.44(m,4H),6.02(m,1H),3.85(s,2H).
HR-MS(ESI):[M+H]+C24H16ClN2O3S计算值447.0570,实测值447.0578.
实施例3
本实施例制备化合物3:N-(2-(2-氯苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.15-8.35(m,2H),7.63-7.79(m,5H),7.10-7.39(m,4H),6.02(m,1H),3.86(s,2H).
HR-MS(ESI):[M+H]+C24H16ClN2O3S计算值447.0570,实测值447.0578.
实施例4
本实施例制备化合物4:N-(2-(4-甲基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.05-8.25(m,2H),7.60-7.84(m,5H),7.11-7.15(m,4H),6.25(m,1H),3.81(s,2H),2.34(s,3H).
HR-MS(ESI):[M+H]+C25H19N2O3S计算值427.1116,实测值427.1105.
实施例5
本实施例制备化合物5:N-(2-(3-硝基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.15-8.35(m,2H),7.62-7.78(m,5H),7.11-7.52(m,4H),6.02(m,1H),3.85(s,2H).
HR-MS(ESI):[M+H]+C24H16N3O5S计算值458.0811,实测值458.0843.
实施例6
本实施例制备化合物6:N-(2-(2-氰基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.13-8.32(m,2H),7.58-7.82(m,5H),7.15-7.42(m,4H),6.02(m,1H),3.92(s,2H).
HR-MS(ESI):[M+H]+C25H16N3O3S计算值438.0912,实测值438.0945.
实施例7
本实施例制备化合物7:N-(2-(4-氟苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.14-8.34(m,2H),7.62-7.98(m,5H),7.14-7.38(m,4H),6.02(m,1H),3.83(s,2H).
HR-MS(ESI):[M+H]+C24H16FN2O3S计算值431.0866,实测值431.0884.
实施例8
本实施例制备化合物8:N-(2-(4-甲磺酰苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.13-8.37(m,2H),7.61-7.87(m,5H),7.13-7.37(m,4H),5.87(m,1H),3.74(s,2H),3.32(s,3H).
HR-MS(ESI):[M+H]+C25H19N2O5S2计算值491.0735,实测值491.0757.
实施例9
本实施例制备化合物9:N-(2-(4-三氟甲基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.14-8.37(m,2H),7.64-7.86(m,5H),7.13-7.37(m,4H),5.87(m,1H),3.84(s,2H).
HR-MS(ESI):[M+H]+C25H16F3N2O3S计算值481.0834,实测值481.0867.
实施例10
本实施例制备化合物10:N-(2-(4-苯基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.11-8.35(m,2H),7.74-7.94(m,5H),7.51-7.52(m,4H),7.23-7.41(m,5H),6.21(m,1H),3.81(s,2H).
HR-MS(ESI):[M+H]+C30H21N2O3S计算值489.1273,实测值489.1291.
实施例11
本实施例制备化合物11:N-(2-(4-羟基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.11-8.37(m,2H),7.64-7.85(m,5H),7.13-7.37(m,4H),5.87(m,1H),3.84(s,2H).
HR-MS(ESI):[M+H]+C24H17N2O4S计算值429.0909,实测值429.0924.
实施例12
本实施例制备化合物12:N-(2-(4-甲氧基苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.10-8.27(m,2H),7.67-7.89(m,5H),7.24-7.47(m,4H),6.12(m,1H),3.80-3.85(m,5H).
HR-MS(ESI):[M+H]+C25H19N2O4S计算值443.1066,实测值443.1074.
实施例13
本实施例制备化合物13:N-(2-(3,4-二氟苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.11-8.28(m,2H),7.65-7.93(m,5H),7.22-7.45(m,3H),6.05(m,1H),3.83(s,2H).
HR-MS(ESI):[M+H]+C24H15F2N2O3S计算值449.0771,实测值449.0784.
实施例14
本实施例制备化合物14:N-(2-(3-溴-4-氯苄)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.10-8.28(m,2H),7.65-7.92(m,5H),7.27-7.49(m,3H),6.21(m,1H),3.85(s,2H).
HR-MS(ESI):[M+H]+C24H15BrClN2O3S计算值524.9675,实测值524.9684.
实施例15
本实施例制备化合物15:N-(2-(7-溴奈-1-基)甲基)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.10-8.35(m,3H),7.61-7.97(m,8H),7.49(m,1H),7.10(m,1H),6.25(m,1H),4.25(s,2H).
HR-MS(ESI):[M+H]+C28H18BrN2O3S计算值541.0222,实测值541.0245.
实施例16
本实施例制备化合物16:N-(2-(3-氯萘-1-基)甲基)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.09-8.32(m,3H),7.51-7.97(m,9H),7.11(m,1H),6.25(m,1H),4.24(s,2H).
HR-MS(ESI):[M+H]+C28H18ClN2O3S计算值497.0727,实测值497.0739.
实施例17
本实施例制备化合物17:N-(2-(喹啉-5-基)甲基)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.80-8.82(m,2H),8.35-8.45(m,2H),7.51-7.97(m,9H),6.25(m,1H),3.81(s,2H).
HR-MS(ESI):[M+H]+C27H18N3O3S计算值464.1069,实测值464.1079.
实施例18
本实施例制备化合物18:N-(2-(7-溴-喹啉-5-基)甲基)苯并噻唑-4-基)-2-氧代-2H-色原烯-8-酰胺,其结构如下所示:
1H NMR(400MHz,CDCl3):δ8.80-8.92(m,2H),8.35-8.45(m,2H),7.51-7.97(m,8H),6.25(m,1H),3.80(s,2H).
HR-MS(ESI):[M+H]+C27H17BrN3O3S计算值542.0174,实测值542.0198.
试验例1
SIRT2抑制剂的体外活性筛选:
人SIRT2基因的全长表达序列ORF为1170bp(Accession No.:NM_012237),所表达的SIRT2蛋白大小为43KDa。SIRT2重组蛋白的表达纯化步骤如下:SIRT2基因被克隆到表达载体pET-15b(引物如下Forward:5’-TAATACGACTCACTATAGGG-3’;backward:5’-TTCACTTCTGAGTTCGGCATG-3’),表达的SIRT2蛋白在N末端含有用于纯化的标签His6。质粒被转化到E.coli BL2(DE3),经过1mM IPTG诱导,在18℃表达6小时。离心收集诱导的大肠杆菌细胞,冻于-20℃。细菌沉淀重悬于15mL的细胞裂解液(50mM Tris-HCl pH 8.0,300mMNaCl),细菌样品采用超声破碎10min,之后在4℃离心(12000×g,20min)去除沉淀。重组表达的可溶性SIRT2蛋白存在于上清中。将上清通过Ni2+NTA-agarose matrix柱(Qiagen)进行纯化。在纯化的过程中,首先用上样液(50mM Tris-HCl pH 8.0,300mM NaCl)洗掉没有结合的蛋白,之后逐渐提高咪唑的浓度(0-200mM)洗去非特异性结合的蛋白,最后得到纯化的重组SIRT2蛋白。采用PD-10柱子去除咪唑,并用Bradford方法测定纯化的SIRT2蛋白浓度。重组SIRT2蛋白贮存于保存液中(50mM Tris-HCl,pH 8.0,265mM NaCl,0.2mM DTT,and 10%glycerol),放置于-20℃。
根据文献的报道,建立了SIRT2酶活性测定方法。首先合成SIRT2的作用底物肽段Ac-Gln-Pro-Lys-[Lys-(Ac)]-AMC作为酶活性测定方法中的底物。所连接的荧光标签为AMC(7-Amino-4-methylcoumarin)。整个测定过程包括两个步骤:催化反应在60μL的反应液中进行(25mM Tris-HCl,pH 8.0,137mM NaCl,2.7mM KCl,1mM MgCl2 and 1mg/ml BSA),加入500μM NAD+、50μM底物肽段、1.0μg的SIRT2和不同浓度的化合物1-18。反应放置37℃2个小时。在这个反应中,小分子肽段上Lysine残基的乙酰基团被不同程度地去除。之后向反应溶液中加入60μL的样品处理液(50mM Tris-HCl,pH 8.0,100mM NaCl,Trypsin和4mMnicotinamide)并混合,放置于37℃20分钟。将酶标仪设置为激发光355nm,吸收光为460nm,测定吸收强度。试验中的每个化合物每个浓度都有2个平行试验,并设置合理的对照,实验结果采用处理软件GraphPad Prism计算每个抑制剂的抑制活性IC50。结果如表1所示(其中AGK为阳性对照组):
表1
由表1数据可知:受试的18个化合物的体外SIRT2抑制活性IC50均达到微摩尔水平,尤其是其中11个化合物的IC50值达到了10-7mol/L水平,其中5个化合物的IC50值达到了10- 8mol/L水平,显示出本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物具有良好的SIRT2抑制活性。
试验例2
化合物对神经瘤细胞SH-SY5Y的细胞毒性测定:
本试验例测定化合物对神经瘤细胞SH-SY5Y的细胞毒性,从而用于确定下一步的帕金森细胞模型保护试验的剂量。对于细胞毒性的测定,具体的实验步骤如下:将培养的神经瘤细胞SH-SY5Y种植于96孔的细胞培养板,每孔大约6000细胞。经过过夜培养,换取新的培养液,并在每孔中加入不同浓度的化合物1-18(0.01,0.05,0.1,0.5,1,5,10,20,50,100,200μM),并设置不同的对照样品。细胞在37℃下继续培养48小时。在每孔中加入10μL染料(Invitrogen)继续放置37℃培养大约2个小时,可以观察到染色液颜色变化,在酶标仪下读取吸收值的变化(Ex:530nm;Em:590nm)。试验中化合物的每个浓度都有2个平行试验。实验结果采用数据处理软件GraphPad Prism计算每个化合物的细胞毒性CC50。结果如表2所示(其中Taxol为阳性对照组):
表2
由表2数据可知:受试的18个化合物对SH-SY5Y的细胞毒性IC50均大于20μM,即本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物对SH-SY5Y细胞并无明显抑制活性。
试验例3
筛选对帕金森病细胞模型具有保护活性的化合物:
对于帕金森病细胞模型保护作用的筛选试验,采用目前普遍认可的神经毒剂MPP+(5mM)作用于神经瘤细胞SH-SY5Y来构建帕金森病细胞模型。这种神经毒剂作用于SH-SY5Y细胞从而影响α-synuclein在细胞内的不正常积聚,并造成类似帕金森病的神经毒性。具体的实验方法如下:将大约20000的SH-SY5Y细胞种植于96孔细胞板中,过夜培养。对照试验control采用不加神经毒剂,其他各组每孔中加入神经毒剂MPP+(5mM),MPP+组为不加保护化合物,保护试验的培养孔中同时分别加入化合物1-18(10μM)(其中AGK为阳性对照),继续培养48小时,测定帕金森病细胞模型的细胞活性,从而评估他们对于帕金森细胞模型的保护作用。对于试验结果的数据分析采用GraphPad Prism。结果如图1所示。
由图1可知:受试的18个化合物均能够在一定程度上保护MPP+神经毒剂对于SH-SY5Y细胞的损伤,表明本发明所涉及的8-(苯并噻唑酰胺)取代香豆素类化合物具有对神经瘤细胞的保护效果;并且其中化合物2,5,9,13对于神经瘤细胞的保护效果更为明显。
申请人声明,本发明通过上述实施例来说明本发明的一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
Claims (7)
2.一种包含权利要求1所述的8-(苯并噻唑酰胺)取代香豆素类化合物的药物组合物。
3.如权利要求2所述的药物组合物,其特征在于,所述药物组合物还包含药学上可接受的药用辅料。
6.如权利要求1所述的8-(苯并噻唑酰胺)取代香豆素类化合物或如权利要求2所述的药物组合物在制备用于治疗和/或预防与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症的药物中的应用。
7.如权利要求6所述的应用,其特征在于,所述与SIRT2活性过高或者与SIRT2过度表达有关的疾病或病症为帕金森病、代谢性疾病或肿瘤。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110244786.1A CN113149979B (zh) | 2021-03-05 | 2021-03-05 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
PCT/CN2022/077605 WO2022183961A1 (zh) | 2021-03-05 | 2022-02-24 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110244786.1A CN113149979B (zh) | 2021-03-05 | 2021-03-05 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113149979A CN113149979A (zh) | 2021-07-23 |
CN113149979B true CN113149979B (zh) | 2022-11-25 |
Family
ID=76884205
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110244786.1A Active CN113149979B (zh) | 2021-03-05 | 2021-03-05 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113149979B (zh) |
WO (1) | WO2022183961A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113149979B (zh) * | 2021-03-05 | 2022-11-25 | 朗捷睿(苏州)生物科技有限公司 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR055041A1 (es) * | 2005-03-23 | 2007-08-01 | Merck Frosst Canada Ltd | Tiadiazoles y oxadiazoles como inhibidores de la sintesis de leucotrienos. composiciones farmaceuticas. |
US20080293785A1 (en) * | 2006-04-11 | 2008-11-27 | Connolly Peter J | Substituted benzothiazole kinase inhibitors |
CN101711759B (zh) * | 2008-10-06 | 2011-08-31 | 中国人民解放军第二军医大学 | 一种香豆素类化合物在制备肿瘤生长抑制药物中的应用 |
CN101967135B (zh) * | 2010-09-16 | 2013-04-03 | 中科院广州化学有限公司 | 一种4-芳基香豆素类化合物的制备方法 |
US9637773B2 (en) * | 2011-01-13 | 2017-05-02 | Enzo Life Sciences, Inc. | Compounds and methods for detection of enzymes that remove formyl, succinyl, methyl succinyl or myristoyl groups from ε-amino lysine moieties |
CN108299401B (zh) * | 2018-04-26 | 2020-06-30 | 红河学院 | 一种3-苄基取代香豆素—咪唑盐类化合物及其制备方法 |
CN108715589B (zh) * | 2018-06-19 | 2021-04-20 | 华侨大学 | 一种用作caspase-3激活剂的香豆素类衍生物及其应用 |
CN113149979B (zh) * | 2021-03-05 | 2022-11-25 | 朗捷睿(苏州)生物科技有限公司 | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 |
-
2021
- 2021-03-05 CN CN202110244786.1A patent/CN113149979B/zh active Active
-
2022
- 2022-02-24 WO PCT/CN2022/077605 patent/WO2022183961A1/zh active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CN113149979A (zh) | 2021-07-23 |
WO2022183961A1 (zh) | 2022-09-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2477968T3 (es) | Compuesto de triazolopiridina, y acción del mismo como inhibidor de prolil-hidroxilasa e inductor de la producción de eritropoyetina | |
TWI491591B (zh) | 吲哚化合物及其醫藥用途 | |
US11731986B2 (en) | Inhibitors of low molecular weight protein tyrosine phosphatase (LMPTP) and uses thereof | |
EP1539759B1 (en) | Novel imidazopyridines and their use | |
CN109705071B (zh) | Hdac抑制剂及其制备方法和用途 | |
HUE027149T2 (en) | Pyrrolidinones as Metap-2 inhibitors | |
JP6122862B2 (ja) | 1−(5,6−ジクロロ−1h−ベンゾ[d]イミダゾール−2−イル)−1h−ピラゾール−4−カルボン酸のメグルミン塩製剤 | |
ES2949357T3 (es) | Inhibidores de 3-fosfoglicerato deshidrogenasa y usos de los mismos | |
IL258779A (en) | Characteristics of Sestrin-gator2 interaction and uses | |
TW201021798A (en) | Amide acetate derivative having inhibitory activity on endothelial lipase | |
WO2007001335A2 (en) | Ramoplanin derivatives possessing antibacterial activity | |
MX2010011097A (es) | Compuesto de aciltiourea o sal del mismo, y uso del mismo. | |
WO2019154395A1 (zh) | 四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 | |
BR112014003063B1 (pt) | 3,4-DI-HIDRO-lH-[l,8]NAFTIRIDINONAS SUBSTITUÍDAS COM CICLOPENTA[C]PIRROL ANTIBACTERIANAS, COMPOSIÇÃO FARMACÊUTICA COMPREENDENDO OS REFERIDOS COMPOSTOS, PROCESSOS PARA PREPARAÇÃO DESTES E USO | |
CN107445896A (zh) | 一种具有抗肿瘤活性的苯基异羟肟酸类化合物及其应用 | |
CN113149979B (zh) | 一种8-(苯并噻唑酰胺)取代香豆素类化合物及其制备方法和应用 | |
CN107849009B (zh) | 一种八氢环戊二烯并[c]吡咯衍生物及其制备方法和在医药上的用途 | |
CN112939955B (zh) | 一种8-(吡啶酰胺)取代香豆素类化合物及其制备方法和应用 | |
CN113149970B (zh) | 一种8-(吡啶三氮唑)取代香豆素类化合物及其制备方法和应用 | |
JP2004505983A (ja) | ピラゾール−チアゾール化合物、これらを含む医薬組成物、およびサイクリン依存性キナーゼの阻害のためのこれらの使用方法 | |
WO2013131465A1 (zh) | N-(4-(3-氟苄氧基)-3-氯苯基)-6-(5-((2-(甲基亚砜基)乙基氨基)甲基)-2-呋喃基)-喹唑啉-4-胺二甲苯磺酸盐的多晶型物及其制备方法和用途 | |
CA2516263C (en) | Benzofuranoxyethylamines as antidepressants and anxiolytics | |
CN113149971B (zh) | 一种8-(吲哚三氮唑)取代香豆素类化合物及其制备方法和应用 | |
JP2024523020A (ja) | Cdkキナーゼ阻害剤として使用される化合物およびその応用 | |
EP2980087B1 (en) | Prodrugs of bicyclic substituted pyrimidine type pde-5 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |