CN114957250B - N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 - Google Patents
N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 Download PDFInfo
- Publication number
- CN114957250B CN114957250B CN202210588890.7A CN202210588890A CN114957250B CN 114957250 B CN114957250 B CN 114957250B CN 202210588890 A CN202210588890 A CN 202210588890A CN 114957250 B CN114957250 B CN 114957250B
- Authority
- CN
- China
- Prior art keywords
- chloride
- compound
- zch
- indol
- reaction
- 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 indol-4-yl Chemical group 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 5
- 239000012964 benzotriazole Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical compound NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 4
- CEOCVKWBUWKBKA-UHFFFAOYSA-N 2,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1Cl CEOCVKWBUWKBKA-UHFFFAOYSA-N 0.000 claims description 3
- JBLIDPPHFGWTKU-UHFFFAOYSA-N 2,6-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=CC=C1Cl JBLIDPPHFGWTKU-UHFFFAOYSA-N 0.000 claims description 3
- NZCKTGCKFJDGFD-UHFFFAOYSA-N 2-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Br NZCKTGCKFJDGFD-UHFFFAOYSA-N 0.000 claims description 3
- CJGKOPNIXJWHKF-UHFFFAOYSA-N 2-chloro-5-methylpyridin-4-amine Chemical compound CC1=CN=C(Cl)C=C1N CJGKOPNIXJWHKF-UHFFFAOYSA-N 0.000 claims description 3
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 claims description 3
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 claims description 3
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 claims description 3
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 claims description 3
- AVTLLLZVYYPGFX-UHFFFAOYSA-N 4-ethylbenzoyl chloride Chemical compound CCC1=CC=C(C(Cl)=O)C=C1 AVTLLLZVYYPGFX-UHFFFAOYSA-N 0.000 claims description 3
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 claims description 3
- WNLMYNASWOULQY-UHFFFAOYSA-N 4-tert-butylbenzoyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)C=C1 WNLMYNASWOULQY-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 claims description 3
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical group OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims description 3
- XNLBCXGRQWUJLU-UHFFFAOYSA-N naphthalene-2-carbonyl chloride Chemical compound C1=CC=CC2=CC(C(=O)Cl)=CC=C21 XNLBCXGRQWUJLU-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229940005657 pyrophosphoric acid Drugs 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 238000006561 solvent free reaction Methods 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 abstract description 20
- 102000013498 tau Proteins Human genes 0.000 abstract description 16
- 108010026424 tau Proteins Proteins 0.000 abstract description 16
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 abstract description 11
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 abstract description 11
- 230000006951 hyperphosphorylation Effects 0.000 abstract description 9
- 230000007131 anti Alzheimer effect Effects 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 7
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 6
- 230000003013 cytotoxicity Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 18
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- RSINFFVFOTUDEC-UHFFFAOYSA-N 2,5-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC=C1Cl RSINFFVFOTUDEC-UHFFFAOYSA-N 0.000 description 2
- GGHLXLVPNZMBQR-UHFFFAOYSA-N 3,5-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC(Cl)=C1 GGHLXLVPNZMBQR-UHFFFAOYSA-N 0.000 description 2
- PBOOZQFGWNZNQE-UHFFFAOYSA-N 3-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Br)=C1 PBOOZQFGWNZNQE-UHFFFAOYSA-N 0.000 description 2
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 102000012440 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- XNFQWPRVANWQOP-UHFFFAOYSA-N O=C(C1=CC=CC=C1)NC1=CC=NC2=C1C1=CC=CC=C1N2 Chemical compound O=C(C1=CC=CC=C1)NC1=CC=NC2=C1C1=CC=CC=C1N2 XNFQWPRVANWQOP-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 229940022698 acetylcholinesterase Drugs 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect 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
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QIAMRMDFJCKFNO-UHFFFAOYSA-N n-(2-chloropyridin-4-yl)benzamide Chemical compound C1=NC(Cl)=CC(NC(=O)C=2C=CC=CC=2)=C1 QIAMRMDFJCKFNO-UHFFFAOYSA-N 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- LPZOCVVDSHQFST-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CC LPZOCVVDSHQFST-UHFFFAOYSA-N 0.000 description 1
- KDRNOBUWMVLVFH-UHFFFAOYSA-N 2-methyl-n-(2,2,6,6-tetramethylpiperidin-4-yl)prop-2-enamide Chemical compound CC(=C)C(=O)NC1CC(C)(C)NC(C)(C)C1 KDRNOBUWMVLVFH-UHFFFAOYSA-N 0.000 description 1
- BPMFPOGUJAAYHL-UHFFFAOYSA-N 9H-Pyrido[2,3-b]indole Chemical class C1=CC=C2C3=CC=CC=C3NC2=N1 BPMFPOGUJAAYHL-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 101100394734 Aspergillus oryzae (strain ATCC 42149 / RIB 40) hepG gene Proteins 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 102000038625 CMGCs Human genes 0.000 description 1
- 108091007913 CMGCs Proteins 0.000 description 1
- 101000741929 Caenorhabditis elegans Serine/threonine-protein phosphatase 2A catalytic subunit Proteins 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 1
- 101000740112 Homo sapiens Membrane-associated transporter protein Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102100037258 Membrane-associated transporter protein Human genes 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229940122777 Tau aggregation inhibitor Drugs 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000007791 alzheimer disease like pathology Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 238000007422 luminescence assay Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- PNWVOLKZHJEWQU-UHFFFAOYSA-N n-pyridin-4-ylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NC1=CC=NC=C1 PNWVOLKZHJEWQU-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004537 potential cytotoxicity Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940048084 pyrophosphate Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种N‑(9H‑吡啶[2,3‑b]吲哚‑4‑基)芳基甲酰胺类衍生物及其制备方法与应用。N‑(9H‑吡啶[2,3‑b]吲哚‑4‑基)芳基甲酰胺类衍生物具有较好的GSK‑3β抑制活性，其中化合物ZCH‑9在高微摩尔浓度下展现出了较低的细胞毒性且在冈田酸(OKA)诱导的SH‑SY5Y细胞模型中能够有效地抑制tau蛋白的过度磷酸化。在制备抗阿尔茨海默病药物领域，具有重要的实用价值和应用前景。本发明还提供了的制备上述衍生物的方法，合成步骤简便且易于操作。
Description
技术领域
本发明涉及医药技术领域，特别是制备抗阿尔茨海默病药物技术领域，具体是一种N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类抗阿尔茨海默病化合物及其制备方法与应用。
背景技术
阿尔茨海默病(Alzheimer's disease，AD)的治疗是神经病学领域尚未满足的一个重要医疗需求，尽管有大量的投资和研究，AD的病理过程和确切的分子机制仍不清楚，目前尚无有效的治疗方法。AD是一种与年龄相关的神经退行性疾病，通常伴有这些临床表现，如进行性记忆丧失、认知功能下降和其他精神相关症状。到2050年，这种疾病的流行率将在全世界翻三倍。
AD的病理学假说主要包括β淀粉样蛋白(β-amyloid protein,Aβ)沉积、Tau蛋白过度磷酸化形成神经纤维缠结、胆碱能假说、炎症假说、氧化应激与自由基损伤假说、金属离子假说、线粒体功能失调假说等。由此研发的各种抗AD药物临床试验的不断失败，导致许多假说受到了质疑，而Tau病理假说近年来受到了更多的关注，特别是有证据表明Tau病理与认知功能衰退的关系更密切，因此针对Tau病理的药物开发则是一直被关注的热点。目前，针对Tau病理治疗的方法主要包括开发蛋白激酶抑制剂、Tau聚集抑制剂、微管蛋白稳定剂以及免疫治疗等。
近年来，随着人们对“疾病、靶点、药物”认识的不断加深，多靶点药物研发成为研究热点。在Tau病理过程中，CMGC激酶家族的糖原合成激酶3β(Glycogen synthase kinase-3β，GSK-3β)发挥着重要作用，GSK-3β是Tau病理发展的关键限速酶，目前很多针对其开发的小分子抑制剂已进入了临床研究。GSK-3β是一种丝/苏氨酸蛋白激酶，其在中枢神经系统中最为丰富，表达水平随着年龄的增长而增加，其在AD患者的大脑中过度活跃，是抗AD治疗的一个经典靶点。越来越多的研究表明：一方面，GSK-3β介导Tau蛋白的过度磷酸化，使神经纤维缠结增多从而产生神经毒性；另一方面，GSK-3β的激活可调节APP的裂解并介导β-分泌酶过度激活，从而参与AD脑内Aβ的形成和积累，并参与大脑老化。除此之外，GSK-3β激活引起Tau蛋白的过度磷酸化，还可使微管蛋白解聚，影响轴突运输功能，并能促进乙酰胆碱酯酶的表达，进而使乙酰胆碱含量大量降低，影响认知功能。
发明内容
本发明提供一种N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用。该类化合物有较好的GSK-3β抑制活性，可以作为新型抗阿尔茨海默病先导化合物。
技术方案：
一种N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物或其药学上可接受的盐，该衍生物的结构如通式I所示：
其中，R为H或C1-C6烷基；
Ar为C1-C6烷基、C1-C6烷氧基、取代或未取代的6-10元芳基或5-10元杂环基，所述的杂环基含有1-3个N、O或S的杂原子；所述取代基为C1-C6烷基、C1-C6烷氧基或者卤素。
优选为，下列化合物或其药学上可接受的盐，选自：
上述化合物的制备方法，包括如下步骤：
1)通式II所示化合物与芳基甲酰氯进行酰胺缩合反应，反应介质为二氯甲烷，以三乙胺作为碱，反应条件为0℃冰浴条件下滴加芳基甲酰氯，后室温反应反应时间为2-3小时，得到通式III所示化合物；
2)使通式III所示化合物与苯并三唑进行无溶剂反应，将通式III所示化合物与过量苯并三唑混合加热至熔融状态，反应条件为160-180℃，反应时间为3-4小时，得到通式IV所示化合物；
3)使通式IV所述化合物进行扣环反应，反应介质为焦磷酸，反应条件为170℃，反应时间为2小时，得到式I所示化合物；
其中，
式中，R为H或C1-C6烷基。
优选的，步骤1)中式II所示化合物为2-氯吡啶-4-胺或者2-氯-5-甲基吡啶-4-胺。
优选的，步骤1)中芳基甲酰氯选自苯甲酰氯、3-甲基苯甲酰氯、4-甲基苯甲酰氯、2-氯苯甲酰氯、2,6-二氯苯甲酰氯、2-溴苯甲酰氯、3-溴苯甲酰氯、烟酰氯、4-溴苯甲酰氯、2,5-二氯苯甲酰氯、4-叔丁基苯甲酰氯、3,5-二氯苯甲酰氯、2-萘甲酰氯、3-氯苯甲酰氯、2,4-二氯苯甲酰氯、4-氯苯甲酰氯或者4-乙基苯甲酰氯。
一种药物组合物，含有所述的化合物或其药学上可接受的盐以及药学上可接受的辅料。
所述化合物添加一种或者多种药学上可接受的辅料制成的制剂，所述制剂的剂型剂型为胶囊剂、丸剂、片剂、颗粒或注射剂。
所述的化合物或其药学上可接受的盐在制备治疗阿尔茨海默病药物中的应用。
所述的化合物或其药学上可接受的盐在制备GSK-3β抑制剂中的应用。
有益效果：
N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物具有较好的GSK-3β抑制活性，其中化合物ZCH-9在高微摩尔浓度下展现出了较低的细胞毒性且在冈田酸(OKA)诱导的SH-SY5Y细胞模型中能够有效地抑制tau蛋白的过度磷酸化。在制备抗阿尔茨海默病药物领域，具有重要的实用价值和应用前景。本发明还提供了的制备上述衍生物的方法，合成步骤简便且易于操作。
附图说明
图1为化合物ZCH-0、ZCH-1和ZCH-9对SH-SY5Y细胞系的细胞毒性作用；
图2为化合物ZCH-0、ZCH-1和ZCH-9对HepG2细胞系的毒性作用；
图3为化合物ZCH-0、ZCH-1和ZCH-9对HL-7702细胞系的毒性作用；
图4为化合物ZCH-9在OKA诱导的SH-SY5Y细胞模型中对tau蛋白过度磷酸化的影响。
具体实施方式
下面通过具体实施例对本发明进行说明，但本发明并不局限于此。
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和生物材料，如无特殊说明，均为市售。
实施例1 N-(9H-吡啶并[2,3-b]吲哚-4-基)苯甲酰胺的制备(化合物ZCH-1)
步骤1)N-(2-氯吡啶-4-基)苯甲酰胺的合成
于100mL圆底烧瓶中，向50ml二氯甲烷中2-氯吡啶-4-胺(2.00g，1当量)和三乙胺(1.5当量)的搅拌溶液中，在冰浴下缓慢滴加相应的苯甲酰氯(1.2当量)，并在室温条件下反应2-3小时。然后，在减压下浓缩混合溶液，并在水相和乙酸乙酯相之间分配三次。将合并的有机相在无水硫酸钠上干燥，并在减压下浓缩以获得目标化合物，而无需进一步纯化。
步骤2)N-(2-(1H苯并[d][1,2,3]三唑-1-基)吡啶-4-基)苯甲酰胺的合成
于100mL圆底烧瓶中，将N-(2-氯吡啶-4-基)苯甲酰胺(2.00g，1当量)和过量的苯并三唑(3-5当量)混合并在160-180℃下加热以保持熔融状态3-4小时。反应完成并冷却至室温后，添加适量的DMF以完全溶解反应混合物。然后，将混合物溶液倒入PH＝11-13的氢氧化钠水溶液中，搅拌15分钟。过滤后，干燥所得固体残渣，并用甲醇重结晶，得到目标化合物N-(2-(1H苯并[d][1,2,3]三唑-1-基)吡啶-4-基)苯甲酰胺。1H NMR(600MHz,DMSO-d6)δ10.96(s,1H),8.82(d,J＝1.9Hz,1H),8.61(dd,J＝2.1,1.2Hz,1H),8.60(d,J＝0.8Hz,1H),8.21(dt,J＝8.4,1.0Hz,1H),8.05(t,J＝1.3Hz,1H),8.03(d,J＝1.5Hz,1H),7.93(dd,J＝5.6,1.9Hz,1H),7.72(ddd,J＝8.2,6.9,1.1Hz,1H),7.69–7.64(m,1H),7.62–7.58(m,2H),7.56(ddd,J＝8.1,7.0,1.1Hz,1H).
步骤3)N-(9H-吡啶并[2,3-b]吲哚-4-基)苯甲酰胺的合成
于100ml圆底烧瓶中，将获得的N-(2-(1H苯并[d][1,2,3]三唑-1-基)吡啶-4-基)苯甲酰胺(500mg，1当量)分批添加到预先预热至170℃的熔融焦磷酸(H4P2O4)(16当量)中，并保持反应2小时。之后，将冰水倒入反应混合物中，并用10％氢氧化钠溶液将溶液pH值调节至9-10。将溶液静置6小时以上，过滤，并将所得固体残留物风干。然后通过硅胶柱层析直接纯化，得到黄色固体的目标产物N-(9H-吡啶并[2,3-b]吲哚-4-基)苯甲酰胺，产率20.7％。1H NMR(600MHz,DMSO-d6)δ11.84(s,1H),8.71(d,J＝1.6Hz,1H),7.95(d,J＝5.6Hz,1H),7.83–7.72(m,2H),7.71–7.61(m,2H),7.57(t,J＝7.6Hz,2H),7.47(d,J＝8.4Hz,1H),6.59(s,2H),6.45(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ196.31,154.84,150.72,147.56,140.68,139.10,132.34,130.08(2C),128.90,128.83(2C),127.38,124.14,121.31,110.05,103.03,100.88.HR-ESI-MS:288.1123[M+H]+,(calcd for C18H13N3O,288.1131).
选用其它的芳基甲酰氯，采用与上完全相同的制备方法，得到其它N-(2-氯吡啶-4-基)芳基甲酰胺，然后获得其他N-(2-(1H苯并[d][1,2,3]三唑-1-基)吡啶-4-基)芳基甲酰胺，最后再扣环获得其他的N-(9H-吡啶并[2,3-b]吲哚-4-基)芳基甲酰胺。
实施例2 N-(3-甲基-9H-吡啶[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-2)
通过将实施例1中步骤1使用的2-氯吡啶-4-胺替换成2-氯-5-甲基吡啶-4-胺，制备得到了N-(3-甲基-9H-吡啶[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-2)，为黄色固体，产率15.7％。1H NMR(600MHz,DMSO-d6)δ11.72(s,1H),8.77(d,J＝1.6Hz,1H),7.91–7.88(m,1H),7.78(d,J＝1.2Hz,1H),7.76(d,J＝1.5Hz,1H),7.67(dd,J＝8.5,1.6Hz,1H),7.65(d,J＝7.4Hz,1H),7.57(t,J＝7.7Hz,2H),7.45(d,J＝8.4Hz,1H),6.24(s,2H),2.20(s,3H).13CNMR(151MHz,DMSO-d6)δ196.26,153.82,148.63,147.83,141.03,139.17,132.30,130.08(2C),128.82(2C),128.61,127.32,124.31,121.13,109.94,109.38,100.61,14.67.HR-ESI-MS:302.1280[M+H]+,(calcd for C19H15N3O,302.1288).
实施例3 3-甲基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-3)
通过将实施例1中步骤1使用的苯甲酰氯替换成3-甲基苯甲酰氯，制备得到了3-甲基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-3)，为白色固体，产率15.8％。1H NMR(600MHz,DMSO-d6)δ11.82(s,1H),8.70(d,J＝1.6Hz,1H),7.95(d,J＝5.6Hz,1H),7.66(dd,J＝8.4,1.6Hz,1H),7.58(d,J＝2.1Hz,1H),7.55–7.51(m,1H),7.47(d,J＝3.9Hz,1H),7.45(t,J＝6.2Hz,2H),6.58(s,2H),6.44(d,J＝5.6Hz,1H),2.40(s,3H).13C NMR(151MHz,DMSO-d6)δ196.44,154.83,150.71,147.54,140.64,139.17,138.17,132.95,130.40,129.04,128.65,127.38,127.36,124.07,121.31,109.99,103.01,100.87,21.42.HR-ESI-MS:302.1285[M+H]+,(calcd for C19H15N3O,302.1288).
实施例4 4-甲基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-4)
通过将实施例1中步骤1使用的苯甲酰氯替换成4-甲基苯甲酰氯，制备得到了4-甲基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-4)，为白色固体，产率9.2％。1HNMR(600MHz,DMSO-d6)δ11.81(s,1H),8.67(d,J＝1.6Hz,1H),7.95(d,J＝5.6Hz,1H),7.69(s,1H),7.67(d,J＝9.6Hz,2H),7.46(d,J＝8.4Hz,1H),7.37(d,J＝7.8Hz,2H),6.57(s,2H),6.44(d,J＝5.6Hz,1H),2.42(s,3H).13C NMR(151MHz,DMSO-d6)δ196.02,154.81,150.69,147.52,142.59,140.50,136.32,130.36(2C),129.39(2C),129.21,127.15,124.05,121.21,110.01,102.97,100.88,21.62.HR-ESI-MS:302.1280[M+H]+,(calcd forC19H15N3O,302.1288).
实施例5 2-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-5)
通过将实施例1中步骤1使用的苯甲酰氯替换成2-氯苯甲酰氯，制备得到了2-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-5)，为黄色固体，产率2％。1H NMR(600MHz,DMSO-d6)δ11.90(s,1H),8.78(d,J＝1.7Hz,1H),7.95(d,J＝5.6Hz,1H),7.62–7.59(m,1H),7.58–7.55(m,1H),7.51(dd,J＝5.7,1.5Hz,1H),7.50(dd,J＝3.4,1.2Hz,2H),7.42(d,J＝8.4Hz,1H),6.64(s,2H),6.46(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ194.40,154.99,150.82,147.69,141.64,139.94,131.55,130.31,130.22,129.44,128.06,128.04,127.67,123.54,121.84,110.32,103.28,100.85.HR-ESI-MS:322.0740[M+H]+,(calcd for C18H12ClN3O,322.0742).
实施例6 2,6-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-6)
通过将实施例1中步骤1使用的苯甲酰氯替换成2,6-二氯苯甲酰氯，制备得到了2,6-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-6)，为黄色固体，产率5.6％。1H NMR(600MHz,DMSO-d6)δ11.95(s,1H),8.82(s,1H),7.96(d,J＝5.6Hz,1H),7.63(d,J＝8.1Hz,2H),7.60–7.54(m,1H),7.51(d,J＝8.3Hz,1H),7.44(d,J＝8.5Hz,1H),6.69(s,2H),6.47(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ191.62,155.03,150.84,147.78,142.07,138.62,131.92,131.31(2C),128.99(2C),127.46,127.10,123.28,122.13,110.74,103.38,100.78.HR-ESI-MS:356.0345[M+H]+,(calcd for C18H11Cl2N3O,356.0352).
实施例7 2-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-7)
通过将实施例1中步骤1使用的苯甲酰氯替换成2-溴苯甲酰氯，制备得到了2-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-7)，为黄色固体，产率3.6％。1HNMR(600MHz,DMSO-d6)δ11.90(s,1H),8.79(d,J＝1.6Hz,1H),7.95(d,J＝5.6Hz,1H),7.76(d,J＝7.9Hz,1H),7.54(t,J＝7.4Hz,1H),7.51–7.48(m,1H),7.48–7.44(m,2H),7.41(d,J＝8.5Hz,1H),6.64(s,2H),6.46(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ195.09,154.99,150.82,147.69,142.00,141.64,133.26,131.60,129.33,128.25,128.11,127.71,123.55,121.90,119.20,110.29,103.29,100.84.HR-ESI-MS:366.0237[M+H]+,(calcd forC18H12BrN3O,366.0237)。
实施例8 3-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-8)
通过将实施例1中步骤1使用的苯甲酰氯替换成3-溴苯甲酰氯，制备得到了3-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-8)，为黄色固体，产率7.7％。1HNMR(600MHz,DMSO-d6)δ11.88(s,1H),8.74–8.67(m,1H),7.95(d,J＝5.6Hz,1H),7.87(d,J＝1.8Hz,1H),7.87–7.81(m,1H),7.76–7.66(m,2H),7.53(t,J＝7.8Hz,1H),7.49(d,J＝8.4Hz,1H),6.61(s,2H),6.45(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ194.77,154.88,150.69,147.63,141.40,140.94,134.91,132.24,131.04,129.08,128.22,127.32,124.39,122.23,121.30,110.30,103.06,100.80.HR-ESI-MS:366.0235[M+H]+,(calcd forC18H12BrN3O,366.0237).
实施例9 N-(9H-吡啶基[2,3-b]吲哚-4-基)烟酰胺(化合物ZCH-9)
通过将实施例1中步骤1使用的苯甲酰氯替换成烟酰氯，制备得到了N-(9H-吡啶基[2,3-b]吲哚-4-基)烟酰胺(化合物ZCH-9)，为黄色固体，产率10.2％1H NMR(600MHz,DMSO-d6)δ11.90(s,1H),9.29(dd,J＝2.4,0.9Hz,1H),8.84(dd,J＝4.8,1.6Hz,1H),8.49–8.45(m,1H),8.40(d,J＝5.3Hz,1H),7.90–7.86(m,1H),7.65(ddd,J＝7.9,4.8,0.9Hz,1H),7.51(dt,J＝8.1,0.9Hz,1H),7.44(ddd,J＝8.2,7.1,1.2Hz,1H),7.38(d,J＝5.4Hz,1H),7.19(ddd,J＝8.1,7.1,1.1Hz,1H).13C NMR(151MHz,DMSO-d6)δ164.89,153.87,152.98,149.49,146.73,139.01,136.25(2C),130.49,126.60,124.22(2C),119.99,119.72,111.76,111.32,109.82.HR-ESI-MS:289.1082[M+H]+,(calcd for C17H12N4O,289.1084).
实施例10 4-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-10)
通过将实施例1中步骤1使用的苯甲酰氯替换成4-溴苯甲酰氯，制备得到了4-溴-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-10)，为黄色固体，产率12.2％。1HNMR(600MHz,DMSO-d6)δ11.97–11.80(m,1H),8.69(d,J＝1.7Hz,1H),7.96(d,J＝5.6Hz,1H),7.77(d,J＝8.2Hz,2H),7.71(td,J＝5.8,2.8Hz,3H),7.49(d,J＝8.4Hz,1H),6.62(s,2H),6.46(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ195.32,154.82,150.70,147.55,140.81,138.13,132.11(2C),131.89(2C),128.51,127.19,126.26,124.34,121.23,110.30,103.04,100.83.HR-ESI-MS:366.0241[M+H]+,(calcd for C18H12BrN3O,366.0237).
实施例11 2,5-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-11)
通过将实施例1中步骤1使用的苯甲酰氯替换成2,5-二氯苯甲酰氯，制备得到了2,5-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-11)，为黄色固体，产率4.1％。1H NMR(600MHz,DMSO-d6)δ11.96(s,1H),8.75(d,J＝1.8Hz,1H),7.96(d,J＝5.6Hz,1H),7.63(s,3H),7.60(dd,J＝8.5,1.7Hz,1H),7.46(d,J＝8.5Hz,1H),6.67(s,2H),6.47(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ192.85,154.99,150.79,147.72,141.83,141.60,132.50,131.94,131.34,129.06,129.01,127.83,127.54,123.96,121.81,110.57,103.32,100.81.HR-ESI-MS:356.0353[M+H]+,(calcd for C18H11Cl2N3O,356.0352).
实施例12 4-叔丁基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-12)
通过将实施例1中步骤1使用的苯甲酰氯替换成4-叔丁基苯甲酰氯，制备得到了4-叔丁基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-12)，为黄色固体，产率13.5％。1H NMR(600MHz,DMSO-d6)δ11.81(s,1H),8.72(s,1H),7.95(d,J＝5.6Hz,1H),7.73(d,J＝7.9Hz,2H),7.66(d,J＝8.1Hz,1H),7.58(d,J＝8.0Hz,2H),7.46(d,J＝8.4Hz,1H),6.59(s,2H),6.44(d,J＝5.5Hz,1H),1.34(s,9H).13C NMR(151MHz,DMSO-d6)δ195.93,155.34,154.84,150.69,147.52,140.53,136.30,130.22(2C),129.19,127.33,125.65(2C),123.90,121.29,109.96,102.97,100.87,35.27,31.41.HR-ESI-MS:344.1750[M+H]+,(calcd for C22H21N3O,344.1757).
实施例13 3,5-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-13)
通过将实施例1中步骤1使用的苯甲酰氯替换成3,5-二氯苯甲酰氯，制备得到了3,5-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-13)，为黄色固体，产率2.4％。1H NMR(600MHz,DMSO-d6)δ11.91(s,1H),8.69(s,1H),7.95(s,1H),7.91(s,1H),7.80–7.72(m,1H),7.69(s,2H),7.50(d,J＝8.6Hz,1H),6.64(s,2H),6.44(s,1H).13C NMR(151MHz,DMSO-d6)δ193.49,154.89,150.63,147.67,142.62,134.68(2C),131.37,128.31(2C),127.66,127.30,124.66,121.27,110.59,110.55,103.07,100.72.HR-ESI-MS:356.0348[M+H]+,(calcd for C18H11Cl2N3O,356.0352).
实施例14 N-(9H-吡啶基[2,3-b]吲哚-4-基)-2-萘酰胺(化合物ZCH-14)
通过将实施例1中步骤1使用的苯甲酰氯替换成2-萘甲酰氯，制备得到了N-(9H-吡啶基[2,3-b]吲哚-4-基)-2-萘酰胺(化合物ZCH-14)，为黄色固体，产率8.4％。1H NMR(600MHz,DMSO-d6)δ11.85(s,1H),8.77(d,J＝1.6Hz,1H),8.34(d,J＝1.7Hz,1H),8.10(t,J＝8.7Hz,2H),8.05(d,J＝8.2Hz,1H),7.96(d,J＝5.6Hz,1H),7.90(dd,J＝8.4,1.8Hz,1H),7.77(dd,J＝8.4,1.6Hz,1H),7.67(ddd,J＝8.2,6.8,1.3Hz,1H),7.61(ddd,J＝8.1,6.8,1.3Hz,1H),7.50(d,J＝8.4Hz,1H),6.57(s,2H),6.44(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ196.40,154.84,150.68,147.54,140.67,136.38,134.99,132.48,131.44,129.89,129.19,128.61,128.51,128.13,127.33,127.29,126.30,124.36,121.25,110.21,102.97,100.88.HR-ESI-MS:338.1283[M+H]+,(calcd for C22H15N3O,338.1288).
实施例15 3-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-15)
通过将实施例1中步骤1使用的苯甲酰氯替换成3-氯苯甲酰氯，制备得到了3-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-15)，为黄色固体，产率12.7％。1HNMR(600MHz,DMSO-d6)δ11.88(s,1H),8.71(s,1H),7.96(d,J＝5.6Hz,1H),7.74(s,1H),7.74–7.65(m,3H),7.59(t,J＝7.8Hz,1H),7.49(d,J＝8.4Hz,1H),6.61(s,2H),6.45(d,J＝5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ194.86,154.88,150.69,147.63,141.20,140.95,133.72,132.02,130.80,129.39,128.71,128.25,127.33,124.39,121.31,110.30,103.06,100.81.HR-ESI-MS:322.0739[M+H]+,(calcd for C18H12ClN3O,322.0742).
实施例16 2,4-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-16)
通过将实施例1中步骤1使用的苯甲酰氯替换成2,4-二氯苯甲酰氯，制备得到了2,4-二氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-16)，为黄色固体，产率5.6％。1H NMR(600MHz,DMSO-d6)δ11.93(s,1H),8.71(s,1H),7.95(d,J＝5.7Hz,1H),7.85–7.76(m,1H),7.61(d,J＝8.6Hz,1H),7.60–7.56(m,1H),7.54(d,J＝8.2Hz,1H),7.44(d,J＝8.5Hz,1H),6.65(s,2H),6.46(d,J＝5.7Hz,1H).13C NMR(151MHz,DMSO-d6)δ193.54,154.97,150.75,147.70,141.72,138.78,135.31,131.65,130.93,129.87,127.94,127.83,127.65,124.06,121.71,110.54,103.27,100.81.HR-ESI-MS:356.0347[M+H]+,(calcd forC18H11Cl2N3O,356.0352).
实施例17 4-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-17)
通过将实施例1中步骤1使用的苯甲酰氯替换成4-氯苯甲酰氯，制备得到了4-氯-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-17)，为黄色固体，产率11.6％。1HNMR(600MHz,DMSO-d6)δ11.86(s,1H),8.67(d,J＝1.7Hz,1H),7.95(d,J＝5.6Hz,1H),7.78(s,1H),7.77(s,1H),7.70(dd,J＝8.4,1.6Hz,1H),7.64(s,1H),7.62(s,1H),7.48(d,J＝8.4Hz,1H),6.59(s,2H),6.44(d,J＝5.7Hz,1H).13C NMR(151MHz,DMSO-d6)δ195.17,154.84,150.66,147.59,140.78,137.80,137.20,131.97(2C),128.96(2C),128.53,127.16,124.32,121.21,110.27,103.01,100.80.HR-ESI-MS:322.0736[M+H]+,(calcd forC18H12ClN3O,322.0742).
实施例18 4-乙基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-18)
通过将实施例1中步骤1使用的苯甲酰氯替换成4-乙基苯甲酰氯，制备得到了4-乙基-N-(9H-吡啶基[2,3-b]吲哚-4-基)苯甲酰胺(化合物ZCH-18)，为黄色固体，产率7.5％。1H NMR(600MHz,DMSO-d6)δ11.81(s,1H),8.69(d,J＝1.6Hz,1H),7.95(d,J＝5.6Hz,1H),7.71(s,1H),7.70(s,1H),7.66(dd,J＝8.4,1.6Hz,1H),7.46(d,J＝8.4Hz,1H),7.41(s,1H),7.39(s,1H),6.58(s,2H),6.44(d,J＝5.6Hz,1H),2.73(d,J＝7.6Hz,1H),2.71(d,J＝7.6Hz,1H),1.25(t,J＝7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ196.00,154.82,150.69,148.65,147.52,140.51,136.56,130.45(2C),129.21,128.22(2C),127.22,124.00,121.24,109.99,102.97,100.88,28.65,15.70.HR-ESI-MS:316.1436[M+H]+,(calcd forC20H17N3O,316.1444).
实施例19 GSK-3β抑制试验(ADP-Glo发光试验)
向每个孔中添加1μL(5μM)试验化合物(溶解于10mM二甲基亚砜中并在激酶缓冲液中预稀释至所需浓度)、2μL酶和2μL含有25μMATP和0.2μg/μL GSK-3β底物的底物/ATP混合物。25℃孵育60分钟后，用5μL ADP-Glo试剂停止酶反应并清除剩余ATP 40分钟。随后加入10μL激酶检测试剂，将ADP转化为ATP，持续30分钟。最后用多功能微孔板读取器记录发光值。激酶缓冲液的制备：40mM Tris，PH 7.5；20mM MgCl2；0.1mg/mlBSA；50μL DTT。
表1化合物的IC50(单位μM)值
aData are the mean of at least two independent determinations(mean±SD).
b％inhibition of GSK-3βwith the inhibitor at 5μM.
cIC50 values for GSK3β.
实施例20细胞毒性测试(MTT试验)
将SH-SY5Y、HL-7702和HepG2细胞接种在96孔板中，并在培养箱中培养过夜。使用或不使用不同浓度的所选化合物处理细胞24小时、48小时和72小时。然后，在培养基中添加20μL MTT(5mg/ml)试剂并培养4小时。吸入培养基后，使用150ml二甲基亚砜溶解形成的福尔马赞结晶，并在490nm处使用微孔板读取器(美国Elx 800Bio-Tek)进行测量。每个实验至少重复三次，添加浓度分别为0μM(空白)、20μM、40μM、60μM、80μM、100μM和120μM。见图1-3，图1为化合物ZCH-0、ZCH-1和ZCH-9对SH-SY5Y细胞系的细胞毒性作用；图2为化合物ZCH-0、ZCH-1和ZCH-9对HepG2细胞系的毒性作用；图3为化合物ZCH-0、ZCH-1和ZCH-9对HL-7702细胞系的毒性作用。数据是至少三次独立实验测定获得(mean±SD)。
越来越多的证据表明，由于其强大的细胞毒性，α-咔波林衍生物作为抗肿瘤试剂具有巨大的优势。因此，考虑到ZCH-1和ZCH-9显示出最潜力的GSK-3β抑制作用，通过MTT法(分别图1-3)评估了这些化合物对浓度范围为20-120μM的SH-SY5Y、HepG2和HL-7702细胞系的潜在细胞毒性。与化合物ZCH-0和ZCH-1相比，候选化合物ZCH-9对这三种细胞系都显示出更高的安全性。此外，ZCH-9在浓度为20μM时，在24小时、48小时和72小时的处理中没有显示出明显的细胞毒性，而在使用更高浓度的ZCH-9处理后，这三个细胞的细胞存活率以浓度依赖性的方式显著降低。鉴于化合物ZCH-9在高微摩尔范围内表现出低细胞毒性，因此选择该化合物进行以下western blot分析。
实施例21抑制tau蛋白过度的磷酸化的能力(Western blot分析)
处理后的细胞孵育36小时后，收集SH-SY5Y细胞，提取总蛋白并用BCA测定。在100℃变性5分钟后，用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)分离蛋白质样品。将蛋白质转移到聚偏氟乙烯(PVDF)膜上，并在室温下用5％BSA密封2小时。相应的一级抗体(T-GSK-3β和p-GSK-3β-S9来自细胞信号技术，T-tau、p-tau-S396和GAPDH购自Wanleibio)在4℃下培养过夜，二级抗体在25℃下培养1小时。最后，将条带依次曝光，并使用ImageJ软件计算灰度值以计算相对表达。
图4中(A)为用化合物ZCH-9处理后，在模型细胞中关键蛋白的表达水平；(B)为p-GSK-3β-S9的表达水平；(C)为p-tau-S396的表达水平。数据是至少三次独立实验测定获得(mean±SD)。
OKA作为一种有效的、选择性的蛋白磷酸酶PP1和PP2A抑制剂，可抑制磷酸酶的活性，导致丝氨酸/苏氨酸激酶的过度磷酸化。在此，OKA被认为是研究GSK-3β级联参与tau异常磷酸化并导致AD样病理的调节机制的有力探针。为了在细胞水平上评估ZCH-9的GSK-3β抑制活性，通过50nM OKA处理SH-SY5Y细胞系36小时，成功建立了用于蛋白免疫印迹分析的细胞模型，并选择选择性GSK-3β抑制剂SB415286作为阳性对照。如图4所示，经ZCH-9处理后，p-tau-S396的表达水平显著降低，p-GSK-3β-S9的表达水平以浓度依赖的方式有效增强。GSK-3β活性可以通过磷酸化来调节。丝氨酸9(S9)的磷酸化抑制GSK3β的活性。毫无疑问，ZCH-9被评估具有抑制GSK-3β活性和降低改善OKA诱导的神经细胞tau过度磷酸化的能力。
综上所述，通过激酶活性测试和细胞测试实验结果表明，本发明的化合物展现出了有潜力的GSK-3β抑制活性，特别是化合物ZCH-9的IC50值达到了低微摩尔级别。此外，化合物ZCH-9在高微摩尔浓度下展现出了较低的细胞毒性，在冈田酸(OKA)诱导的SH-SY5Y细胞模型中能够有效地抑制tau蛋白的过度磷酸化。总体而言，该系列衍生物的激酶抑制活性还有较大的提升空间。本发明所述的N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物是一类通过靶向GSK-3β，且具较大有潜力的新型抗阿尔茨海默病化合物。
Claims (6)
1.一种N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物或其药学上可接受的盐，其特征在于，选自：
2.一种如权利要求1所述的化合物的制备方法，其特征在于：包括如下步骤：
1)通式II所示化合物与芳基甲酰氯进行酰胺缩合反应，反应介质为二氯甲烷，以三乙胺作为碱，反应条件为0℃冰浴条件下滴加芳基甲酰氯，后室温反应反应时间为2-3小时，得到通式III所示化合物；
2)使通式III所示化合物与苯并三唑进行无溶剂反应，将通式III所示化合物与过量苯并三唑混合加热至熔融状态，反应条件为160-180℃，反应时间为3-4小时，得到通式IV所示化合物；
3)使通式IV所述化合物进行扣环反应，反应介质为焦磷酸，反应条件为170℃，反应时间为2小时，得到权利要求1所述的化合物；
其中，
步骤1)中式II所示化合物为2-氯吡啶-4-胺或者2-氯-5-甲基吡啶-4-胺；
步骤1)中芳基甲酰氯选自苯甲酰氯、3-甲基苯甲酰氯、4-甲基苯甲酰氯、2-氯苯甲酰氯、2,6-二氯苯甲酰氯、2-溴苯甲酰氯、烟酰氯、4-溴苯甲酰氯、4-叔丁基苯甲酰氯、2-萘甲酰氯、3-氯苯甲酰氯、2,4-二氯苯甲酰氯或者4-乙基苯甲酰氯。
3.一种药物组合物，含有权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的辅料。
4.根据权利要求3所述的药物组合物，其特征在于：由如权利要求1所述化合物添加一种或者多种药学上可接受的辅料制成的制剂，所述制剂的剂型为胶囊剂、丸剂、片剂、颗粒或注射剂。
5.如权利要求1所述的化合物或其药学上可接受的盐在制备治疗阿尔茨海默病药物中的应用。
6.如权利要求1所述的化合物或其药学上可接受的盐在制备GSK-3β抑制剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210588890.7A CN114957250B (zh) | 2022-05-26 | 2022-05-26 | N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210588890.7A CN114957250B (zh) | 2022-05-26 | 2022-05-26 | N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114957250A CN114957250A (zh) | 2022-08-30 |
| CN114957250B true CN114957250B (zh) | 2023-05-09 |
Family
ID=82955430
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210588890.7A Active CN114957250B (zh) | 2022-05-26 | 2022-05-26 | N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114957250B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115850270B (zh) * | 2022-12-07 | 2024-05-14 | 潍坊医学院 | α-咔啉类化合物或其药物组合物及其制备方法和用途 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107216328A (zh) * | 2017-07-06 | 2017-09-29 | 贵州医科大学 | 一种α‑卡波林类化合物的合成方法 |
| CN113072552B (zh) * | 2021-03-04 | 2022-11-04 | 中国人民解放军北部战区总医院 | β-咔波啉类GSK3β/DYRK1A双重抑制剂及其制备方法和抗阿尔兹海默病的应用 |
| CN114181207B (zh) * | 2021-12-27 | 2022-12-13 | 中国人民解放军北部战区总医院 | β-咔波啉类化合物及其制备方法和抗阿尔兹海默病的应用 |
-
2022
- 2022-05-26 CN CN202210588890.7A patent/CN114957250B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114957250A (zh) | 2022-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6095844B2 (ja) | テトラヒドロピロロチアジン化合物 | |
| US8084454B2 (en) | Compounds with anti-cancer activity | |
| KR20170081184A (ko) | Ｂａｃｅ1 저해제로서의 2-아미노-6-(디플루오로메틸)-5,5-디플루오로-6-페닐-3,4,5,6-테트라하이드로피리딘 | |
| JP5747142B2 (ja) | Ｄｙｒｋを阻害する化合物を含有する医薬組成物 | |
| JP2016511237A (ja) | 選択的ｈｄａｃ３阻害剤 | |
| US20050176792A1 (en) | Ketone substituted benzimidazole compounds | |
| WO2010013168A1 (en) | 3',6-substituted indirubins and their biological applications | |
| MXPA05001371A (es) | Arilcicloalquilaminas aciladas y su uso como productos farmaceuticos. | |
| JP2006526571A (ja) | α−ケトカルボニルカルパイン阻害剤 | |
| JP2008503575A (ja) | ５−アリール−１ｈ−ピロロ［２，３ｂ］ピリジン−３−カルボキサミド又は５−アリール−１ｈ−ピロロ［２，３ｂ］ピリジン−３−カルボン酸の新規な誘導体 | |
| CN114957250B (zh) | N-(9H-吡啶[2,3-b]吲哚-4-基)芳基甲酰胺类衍生物及其制备方法与应用 | |
| EP1080083A1 (de) | Neue heterocyclisch substituierte amide mit cystein-protease hemmender wirkung | |
| CA2696429A1 (en) | Pyrrole compounds having sphingosine-1-phosphate receptor agonist or antagonist biological activity | |
| CN108929312A (zh) | 具有cdk或hdac抑制活性的新型苯并杂环联嘧啶抑制剂 | |
| JPWO2007086354A1 (ja) | 新規ヒスチジン誘導体 | |
| WO2017071479A1 (zh) | 一种谷氨酰胺酰基环化酶抑制剂 | |
| DE10133665A1 (de) | Carbonsäurederivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Herstellung | |
| CN110627767B (zh) | 选择性丁酰胆碱酯酶抑制剂或其可药用的盐、其制备方法及用途 | |
| Mishra et al. | Development of novel N-(6-methanesulfonyl-benzothiazol-2-yl)-3-(4-substituted-piperazin-1-yl)-propionamides with cholinesterase inhibition, anti-β-amyloid aggregation, neuroprotection and cognition enhancing properties for the therapy of Alzheimer's disease | |
| Abouzid et al. | Synthesis and biological evaluation of new heteroaryl carboxylic acid derivatives as anti-inflammatory-analgesic agents | |
| US8049037B2 (en) | Sphingosine-1-phosphate (S1P) receptor antagonists and methods for use thereof | |
| JP2021120391A (ja) | ８−ヒドロキシキノリン誘導体のエナンチオマーとその合成 | |
| CN115232126B (zh) | 一种β-卡波林-1,2,3-三唑化合物及其制备方法与抗阿尔兹海默病的应用 | |
| JP2005501800A (ja) | ジヒドロピラゾロピリジン化合物およびその医薬用途 | |
| AU2011256989B2 (en) | 8-hydroxy-quinoline derivatives |
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 |