CN115724824A - 3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 - Google Patents
3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 Download PDFInfo
- Publication number
- CN115724824A CN115724824A CN202111022118.0A CN202111022118A CN115724824A CN 115724824 A CN115724824 A CN 115724824A CN 202111022118 A CN202111022118 A CN 202111022118A CN 115724824 A CN115724824 A CN 115724824A
- Authority
- CN
- China
- Prior art keywords
- acid
- amidoalkylthio
- compound
- phthalide
- pharmaceutically acceptable
- 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.)
- Granted
Links
- -1 phthalide compound Chemical class 0.000 title claims abstract description 65
- WNZQDUSMALZDQF-UHFFFAOYSA-N isobenzofuranone Natural products C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 201000004810 Vascular dementia Diseases 0.000 claims abstract description 10
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 7
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 6
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 6
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 208000016988 Hemorrhagic Stroke Diseases 0.000 claims abstract description 5
- 208000032382 Ischaemic stroke Diseases 0.000 claims abstract description 5
- 208000028389 Nerve injury Diseases 0.000 claims abstract description 5
- 208000020658 intracerebral hemorrhage Diseases 0.000 claims abstract description 5
- 230000008764 nerve damage Effects 0.000 claims abstract description 5
- 208000004296 neuralgia Diseases 0.000 claims abstract description 5
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 5
- 201000011240 Frontotemporal dementia Diseases 0.000 claims abstract description 4
- 201000002832 Lewy body dementia Diseases 0.000 claims abstract description 4
- 208000024777 Prion disease Diseases 0.000 claims abstract description 4
- 208000030886 Traumatic Brain injury Diseases 0.000 claims abstract description 4
- 210000000653 nervous system Anatomy 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 18
- 125000005506 phthalide group Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- JKNKNWJNCOJPLI-ZETCQYMHSA-N (3s)-3-hydroxy-3h-2-benzofuran-1-one Chemical compound C1=CC=C2[C@@H](O)OC(=O)C2=C1 JKNKNWJNCOJPLI-ZETCQYMHSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 4
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 4
- 206010065040 AIDS dementia complex Diseases 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 235000011007 phosphoric acid Nutrition 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 3
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 2
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 2
- 229930182847 D-glutamic acid Natural products 0.000 claims description 2
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 claims description 2
- 229930195721 D-histidine Natural products 0.000 claims description 2
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 claims description 2
- 229930182819 D-leucine Natural products 0.000 claims description 2
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims description 2
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 claims description 2
- 229930182818 D-methionine Natural products 0.000 claims description 2
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 claims description 2
- 229930182832 D-phenylalanine Natural products 0.000 claims description 2
- 229930182820 D-proline Natural products 0.000 claims description 2
- 229930182827 D-tryptophan Natural products 0.000 claims description 2
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 claims description 2
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 claims description 2
- 229930195709 D-tyrosine Natural products 0.000 claims description 2
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 claims description 2
- 229930182831 D-valine Natural products 0.000 claims 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 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229940024606 amino acid Drugs 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- VERAMNDAEAQRGS-UHFFFAOYSA-N butane-1,4-disulfonic acid Chemical class OS(=O)(=O)CCCCS(O)(=O)=O VERAMNDAEAQRGS-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 235000019136 lipoic acid Nutrition 0.000 claims description 2
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002663 thioctic acid Drugs 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims 1
- 229930195711 D-Serine Natural products 0.000 claims 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- 239000004395 L-leucine Substances 0.000 claims 1
- 235000019454 L-leucine Nutrition 0.000 claims 1
- 229960003767 alanine Drugs 0.000 claims 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims 1
- 150000002191 fatty alcohols Chemical class 0.000 claims 1
- 229960003136 leucine Drugs 0.000 claims 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 claims 1
- 229960005190 phenylalanine Drugs 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- 229960004295 valine Drugs 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 16
- 208000009829 Lewy Body Disease Diseases 0.000 abstract description 3
- 206010012289 Dementia Diseases 0.000 abstract description 2
- 241000725303 Human immunodeficiency virus Species 0.000 abstract 2
- 230000000694 effects Effects 0.000 description 28
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 24
- 230000005764 inhibitory process Effects 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- 230000003078 antioxidant effect Effects 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229950005197 butylphthalide Drugs 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000002158 endotoxin Substances 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- 230000036542 oxidative stress Effects 0.000 description 10
- 102100033639 Acetylcholinesterase Human genes 0.000 description 9
- 108010022752 Acetylcholinesterase Proteins 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 229940022698 acetylcholinesterase Drugs 0.000 description 9
- 229910021645 metal ion Inorganic materials 0.000 description 8
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 7
- GLEVLJDDWXEYCO-UHFFFAOYSA-N Trolox Chemical compound O1C(C)(C(O)=O)CCC2=C1C(C)=C(C)C(O)=C2C GLEVLJDDWXEYCO-UHFFFAOYSA-N 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 239000007853 buffer solution Substances 0.000 description 7
- 208000015122 neurodegenerative disease Diseases 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003963 antioxidant agent Substances 0.000 description 6
- 235000006708 antioxidants Nutrition 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 230000004770 neurodegeneration Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000003642 reactive oxygen metabolite Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000008506 pathogenesis Effects 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 4
- 102100032404 Cholinesterase Human genes 0.000 description 4
- 208000036110 Neuroinflammatory disease Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 208000026106 cerebrovascular disease Diseases 0.000 description 4
- 238000010668 complexation reaction Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000003959 neuroinflammation Effects 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 229960003135 donepezil hydrochloride Drugs 0.000 description 3
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 229940118019 malondialdehyde Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- LXEKPEMOWBOYRF-QDBORUFSSA-N AAPH Chemical compound Cl.Cl.NC(=N)C(C)(C)\N=N\C(C)(C)C(N)=N LXEKPEMOWBOYRF-QDBORUFSSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000009191 jumping Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000005056 memory consolidation Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960004136 rivastigmine Drugs 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- SZMVXHRECFRCKQ-UHFFFAOYSA-M 2-ethanethioyloxyethyl(trimethyl)azanium;iodide Chemical compound [I-].CC(=S)OCC[N+](C)(C)C SZMVXHRECFRCKQ-UHFFFAOYSA-M 0.000 description 1
- KZSWBRBLFHVBGW-UHFFFAOYSA-N 3h-2-benzofuran-1-one;phenol Chemical compound OC1=CC=CC=C1.C1=CC=C2C(=O)OCC2=C1 KZSWBRBLFHVBGW-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 1
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- RVTSFXDCTMVQAB-UHFFFAOYSA-N C(CCC)C1OC(=O)C2=CC=CC=C12.C(CCC)C1OC(=O)C2=CC=CC=C12 Chemical compound C(CCC)C1OC(=O)C2=CC=CC=C12.C(CCC)C1OC(=O)C2=CC=CC=C12 RVTSFXDCTMVQAB-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010061951 Methemoglobin Proteins 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 108091007187 Reductases Proteins 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004945 acylaminoalkyl group Chemical group 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000002555 anti-neurodegenerative effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 201000011529 cardiovascular cancer Diseases 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
- 231100000063 excitotoxicity Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007986 glycine-NaOH buffer Substances 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 229960000967 memantine hydrochloride Drugs 0.000 description 1
- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类3‑(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经***相关疾病药物中的用途,包括但不限于血管性痴呆、阿尔茨海默氏病、额颞叶痴呆、Prion病、路易体痴呆、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、缺血性脑卒中、出血性脑卒中以及脑外伤引起的神经损伤等疾病;
Description
技术领域
本发明属药物化学领域,涉及一类3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经***相关疾病药物中的用途,包括但不限于血管性痴呆、阿尔茨海默氏病、额颞叶痴呆、Prion病、路易体痴呆、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、缺血性脑卒中、出血性脑卒中以及脑外伤引起的神经损伤等疾病。
背景技术
神经退行性疾病是指由慢性进行性中枢神经组织退行性变性而产生的疾病总称,包括阿尔茨海默氏病(Alzheimer’s disease, AD)、帕金森氏病(Parkinson’s disease,PD)、亨廷顿氏病(Huntington disease, HD)、肌萎缩侧索硬化症(Amyotrophic lateralsclerosis, ALS)和多发性硬化症(Multiple sclerosis, MS)等,其发病机制与氧化应激、神经炎症及相应的损伤密切相关。氧化应激是由活性氧(Reactive oxygen species, ROS)自由基介导的,包括超氧阴离子、过氧化氢和羟基自由基等。在正常生理条件下,ROS生成水平与机体抗氧化能力处于动态平衡状态,当ROS的产生超过细胞抗氧化能力则会发生氧化应激(Oxidative stress),而大脑对氧化应激尤为敏感,从而诱发多种神经***疾病。另有研究发现,血管性痴呆、HIV相关痴呆病、神经性疼痛、缺血性脑卒中、出血性脑卒中以及脑外伤引起的神经损伤等也与机体的氧化应激和神经炎症密切相关。
血管性痴呆(Vascular Dementia, VD)是由各种类型的脑血管疾病(包括缺血性脑血管病、出血性脑血管疾病、急性和慢性缺氧性脑血管疾病等)所致的智能及认知功能障碍的临床综合征。血管性痴呆由于发病机制复杂,目前尚无能够阻滞疾病发展的药物,临床治疗以改善脑部血液循环、脑代谢以及加强脑部营养为主。
阿尔茨海默症(老年痴呆症, AD)是一种以进行性认知障碍和记忆力损害为主的中枢神经***退行性疾病,其发病率呈逐年上升趋势,成为仅次于心血管病和癌症的高发性疾病。随着全球人口老龄化进程的加快,其发病率呈明显上升趋势。据估计,目前全球有超过5000万人患痴呆症,其治疗护理费用总额在2018年已超过1万亿美元,到2050年患病人数将会增加到1.52亿。由于AD临床表现为记忆能力、定向能力、思维和判断能力减退,以及日常生活能力降低,甚至出现异常精神行为症状等,使患者护理难度较大,给社会和家庭带来沉重负担。目前已批准用于治疗轻/中度AD的药物有乙酰胆碱酯酶(AChE)抑制剂,以及用于重度AD治疗的N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。但临床使用表明,这些药物可通过提高患者体内乙酰胆碱水平或者抑制兴奋性氨基酸的兴奋毒性来缓解AD症状,但不能有效阻止或逆转病程,而且还会引起幻觉、意识混沌、头晕、恶心、肝脏毒性、食欲不振以及大便频繁等严重毒副作用,因而长期疗效不甚理想。因此,临床上迫切需要研发兼具AD症状改善和病程改变的新型AD治疗药物。
AD属多种因素引起的疾病,发病机理复杂,其发病机制至今还未完全阐明。但研究表明,患者脑内乙酰胆碱水平的下降、β-淀粉样蛋白的过度生成与沉积、脑血管内的血小板聚集、金属离子代谢紊乱、Ca2+平衡失调、tau-蛋白过度磷酸化导致的神经纤维缠结、谷氨酸受体活性过高、氧化应激产生大量活性氧(ROS)和自由基以及神经炎症反应等多种因素在AD的发病过程中扮演重要角色。针对上述发病因素,研究人员采用传统“一药一靶”药物设计策略,发现了大量对某一靶点具有高活性和高选择性的药物,如:胆碱酯酶抑制剂和N-甲基-D-天冬氨酸受体拮抗剂等。但这些药物存在作用靶点单一、临床使用毒副作用较多、对AD患者的长期疗效欠佳等问题。
近年来,随着对神经退行性疾病致病机理的不断阐明,发现神经退行性疾病的发生和发展具有多机制、多因素作用的特点,不同机制之间又相互关联相互影响,构成了该类疾病发生和发展过程中复杂的网络调控***。显然,研发可同时作用于神经退行性疾病病理过程中多个环节的治疗药物是目前的必然选择。基于上述结果,研究人员提出了“多靶点导向药物”策略来研发抗神经退行性疾病药物。所谓“多靶点药物”是指单一化学实体同时作用于疾病网络中的多个靶点,对各靶点的作用可产生协同效应,使总效应大于各单效应之和。多靶点药物与多药联合应用以及复方药物的主要区别在于:可减少服药量、提高治疗效果、避免药物之间的相互作用以及由此带来的毒副作用,均一的药代动力学特性,便于使用等。因此,研发具有新型化学结构、新型作用机制,且具有多靶点作用、低毒副作用的抗神经退行性疾病治疗药物是当前的重要方向。
丁苯酞(Butylphthalide)(商品名:恩必普®)是我国研制的抗脑缺血损伤药物,具有抗血小板聚集、抗血栓、减轻脑水肿、减少梗死面积、改善线粒体功能和脑微循环、抑制神经细胞凋亡等多种生物活性。近年来研究还发现,丁苯酞还对血管性痴呆、阿尔茨海默病、癫痫以及帕金森病等中枢性疾病也有一定疗效;作用机制研究表明,丁苯酞对Aβ诱导神经毒性、Aβ或脂多糖(LPS)介导神经炎症、对神经细胞的氧化应激损伤等均具有一定保护作用,显示其在治疗神经退行性疾病方面具有一定潜力。但上述研究结果也显示,丁苯酞虽具有多样生物活性,但这些活性(特别是:抗氧化应激、抗神经炎症、抑制Aβ聚集等)均较弱,且无AChE抑制活性(抑制该酶对改善AD和VD患者症状至关重要)、也无金属离子络合作用,可能是导致该药物在临床上治疗效果欠佳的主要原因;此外,该药物在常温下为油状液体、由于脂溶性太大而极难溶于水,进一步限制了其在临床上的广泛应用。显然,在以丁苯酞为先导物的结构修饰中,发现可增加水溶性且同时具有抗氧化应激、金属离子络合、抑制β-淀粉样蛋白的过度生成与沉积、以及抗神经炎症反应的多靶点苯酞类化合物有可能对治疗和/或预防神经退行性相关疾病取得突破。
发明内容
本发明目的在于公开一类3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐。
本发明另一目的在于公开该类3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐的制备方法。
本发明的又一目的在于公开包含该类3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐的药物组合物。
本发明再一目的在于公开该类3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐具有多靶点作用,可用于制备治疗和/或预防神经***相关疾病药物中的用途,包括但不限于血管性痴呆、阿尔茨海默氏病、额颞叶痴呆、Prion病、路易体痴呆、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、缺血性脑卒中、出血性脑卒中以及脑外伤引起的神经损伤等疾病。
本发明所公开的3-(酰胺烷硫基)苯酞类化合物(I)的化学结构通式为:
式中:
表示天然或非天然氨基酸残基;X表示O、S或NR3,R3表示H、C1~C6烷基、苯基;n表示1-5;R1和R2各自独立地表示H、C1~C6烷基、C1~C6烷氧基、卤素、CN或NR4R5,R4和R5各自独立地表示H、C1~C6烷基;R1和R2在其相应苯环上任意可能的位置;所述化合物中与硫原子相邻的碳原子具有手性,其构型为R、S、或R与S的任意比例混合物;所述“卤素”是指F、Cl、Br或I;“天然或非天然氨基酸”是指:甘氨酸、L-或D-丙氨酸、氨基异丁酸、γ-氨基丁酸、L-或D-缬氨酸、L-或D-脯氨酸、L-或D-赖氨酸、L-或D-亮氨酸、L-或D-甲硫氨酸、L-或D-丝氨酸、L-或D-O-苄基丝氨酸、L-或D-组氨酸、L-或D-酪氨酸、L-或D-苯甘氨酸、L-或D-苯丙氨酸、L-或D-色氨酸、L-或D-天冬氨酸、L-或D-谷氨酸。
本发明所公开的3-(酰胺烷硫基)苯酞类化合物(I)可通过以下方法制备得到:
以相应的3-羟基苯酞类化物(1)为起始原料,在适当溶剂和酸作用下与相应的酰胺烷硫醇类化物(2)直接缩合,即得相应的3-(酰胺烷硫基)苯酞类化合物(I);其反应式如下:
式中:R、R1、R2、X和n的定义与3-(酰胺烷硫基)苯酞类化合物(I)的化学结构通式相同。
对于上述合成路线,其具体制备方法描述如下:
3-羟基苯酞类化物(1)与酰胺烷硫醇类化物(2)在适当溶剂和酸作用下缩合,得到相应的3-(酰胺烷硫基)苯酞类化合物(I);其中,反应所用溶剂为:C2-6脂肪酸、C2-6脂肪酸与C1-6脂肪醇所形成酯、氯仿、二氯甲烷、1,2-二氯乙烷、氯苯、邻二氯苯、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、苯、甲苯、乙腈、1,4-二氧六环、乙二醇二甲醚、甲烷磺酸、乙烷磺酸或C5-8烷烃,优选溶剂为甲苯、氯仿、二氯甲烷、乙酸、乙酸乙酯、甲烷磺酸、乙烷磺酸或乙腈;所用酸为盐酸、硫酸、苯磺酸、对甲苯磺酸、樟脑磺酸、C1-6烷基磺酸、磷酸、高氯酸、三氟乙酸、三氟甲磺酸或硝酸,优选酸为硫酸、对甲苯磺酸、甲烷磺酸、乙烷磺酸或三氟乙酸;但当反应溶剂为甲烷磺酸或乙烷磺酸时,则不需要再加酸;3-羟基苯酞类化物(1):酰胺烷硫醇类化物(2):酸的摩尔投料比为1.0:0.9~3.0:0~5.0,优选摩尔投料比为1.0:1.0~2.0:1.0~3.0,反应温度为0~150℃,优选反应温度为室温~120℃;反应时间为1~120小时,优选反应时间为2~72小时。
按照上述方法所得之3-(酰胺烷硫基)苯酞类化合物(I)可与任何合适的酸通过药学上常规的成盐方法制得其药物学上可接受的盐,所述的酸为:盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸(如:甲酸、乙酸、丙酸等)、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸(如:甲基磺酸、乙基磺酸等)、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸。
本发明的起始原料——3-羟基苯酞类化物(1)和酰胺烷硫醇类化物(2)可用本领域常见的技术制得,包括但不局限于以下文献中所公开的方法:1、Kukreja, Gagan et al.WO 2021033141;2、Zhou, Muxing et al.Angewandte Chemie International Edition, 2021, 60(3), 1641;3、Polec, Iwona et al.European Journal of Organic Chemistry, 2002, (6), 1033;4、Sun Zheng et al.Synthesis, 2021, 53(9), 1663;5、Krishna, Yarkali et al.Organic Letters, 2019, 21(20), 8444;6、Achmatowicz,Michal et al.Journal of Organic Chemistry, 2009, 74(2), 795;7、Stobaugh, J. F.et al.Journal of Organic Chemistry, 1984, 49(22), 4306;8、Fatome, Marc et al.European Journal of Medicinal Chemistry, 1988, 23(3), 257;9、Shair, MatthewD. et al.WO 2001057526。
本发明所公开的药物组合物包括治疗有效量的一种或多种3-(酰胺烷硫基)苯酞类化合物(I)或其药学上可接受的盐,该药物组合物可进一步含有一种或多种药学上可接受的载体或赋形剂。所述“治疗有效量”是指引起研究者或医生所针对的组织、***或动物的生物或医药反应的药物或药剂的量;所述“组合物”是指通过将一种以上物质或组份混和而成的产品;所述“药学上可接受的载体”是指药学上可接受的物质、组合物或载体,如:液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊物质,它们携带或转运某种化学物质。本发明所提供的药物组合物其理想的比例是,3-(酰胺烷硫基)苯酞类化合物(I)或其药学上可接受的盐作为活性成分占总重量比2%~99.5%。
本发明所公开的3-(酰胺烷硫基)苯酞类化合物(I)及其药学上可接受的盐进行了如下的生物活性筛选:
(1)3-(酰胺烷硫基)苯酞类化合物(I)对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性
向96孔板中依次加入1.0 mmol/L碘化硫代乙酰胆碱或碘化硫代丁酰胆碱30 μL、pH7.4的PBS缓冲液40 μL、待测化合物溶液20 μL(DMSO含量小于1%)和10 μL乙酰胆碱酯酶(大鼠脑皮层5%匀浆上清液,pH7.4的磷酸缓冲液作匀浆介质)或丁酰胆碱酯酶(大鼠血清25%上清液,pH7.4磷酸缓冲液作匀浆介质)溶液,加毕混匀后,37℃孵育15min,向各孔中加入0.2%的5,5’-二硫代-双(2-硝基苯甲酸)(DTNB)溶液30 μL显色,用酶标仪测定405nm处各孔的光密度(OD值),与不加待测样品的空白孔比较,计算化合物对酶的抑制率(酶抑制率(%)=(1-样品组OD值/空白组OD值)×100%);选择化合物的五至六个浓度,测定其酶抑制率,并以该化合物摩尔浓度的负对数与酶的抑制率线性回归,求得50%抑制率时的摩尔浓度即为该化合物的IC50。测定结果表明,本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)对乙酰胆碱酯酶均具有显著抑制作用,其IC50为0.16µM~20.0µM。测定结果还显示,3-(酰胺烷硫基)苯酞类化合物(I)对乙酰胆碱酯酶的抑制活性显著高于对丁酰胆碱酯酶的抑制活性(选择性大于10倍以上)。另外,测定结果还显示,在临床上使用的卡巴拉汀对AChE抑制的IC50为12.3 µM,对丁酰胆碱酯酶抑制的IC50为3.0 µM;并且对照化合物丁苯酞和3-羟基苯酞类化物(1)对乙酰胆碱酯酶抑制的IC50均大于200 µM。
(2)3-(酰胺烷硫基)苯酞类化合物(I)的抗氧化活性(ORAC-FL方法)
参照文献(Qiang, X.M. et al. Eur. J Med. Chem. 2014, 76, 314-331)所报道的方法进行测定,即:6-羟基-2,5,7,8-四甲基色烷-2-羧酸(Trolox)用pH7.4的PBS缓冲液配成10-80 μmol/L的溶液,荧光素(fluorescein)用pH7.4的PBS缓冲液配成250 nmol/L的溶液,2,2’-偶氮二异丁基脒二盐酸盐(AAPH)使用前用pH7.4的PBS缓冲液配成40 mmol/L的溶液。向96孔板中加入50-10 μmol/L的化合物溶液和荧光素溶液,混匀,37°C孵育15min,加入AAPH溶液,使每孔总体积为200 μL,混匀,立即置于Varioskan Flash MultimodeReader (Thermo Scientific)仪中,在485 nm激发波长和535 nm发射波长下连续测定90min。计算出荧光衰减曲线下面积AUC,其中以1-8μmol/L的Trolox作为标准,以不加待测样品为空白,化合物的抗氧化活性结果表达为Trolox的当量,其计算公式为:[(AUC Sample-AUC blank)/(AUC Trolox-AUC blank)]×[(concentration of Trolox/concentrationof sample)],每个化合物每次测定3个复孔,每组实验独立重复三次。测定结果表明,本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)的抗氧化活性为Trolox的0.55~2.2倍,说明该类化合物具有较强抗氧化活性,而对照化合物丁苯酞的抗氧化活性为Trolox的0.19倍。测试结果还发现,本发明实施例中所用的起始原料—酰胺烷硫醇类化物(2)也具有较强抗氧化活性,其抗氧化活性相当于其相应的3-(酰胺烷硫基)苯酞类化合物(I),而3-羟基苯酞类化物(1)几乎无抗氧化活性(其抗氧化强度均小于Trolox的0.15倍);且将3-(酰胺烷硫基)苯酞类化合物(I)中3-位的S原子用CH2替换,所得相应的3-(酰胺烷基)苯酞类化合物的抗氧化活性至少降低2-3倍。
(3)3-(酰胺烷硫基)苯酞类化合物(I)对Aβ1-42自身聚集的抑制活性
参照文献(Qiang, X.M. et al. Eur. J Med. Chem. 2014, 76, 314-331)所报道的方法进行测定,即:预处理后的Aβ1-42用DMSO配成储备液,使用前用pH7.4的PBS缓冲液稀释至50μM;待测化合物用DMSO配成2.5 mM储备液,使用前用pH7.4的PBS缓冲液稀释至相应浓度,取20μL的Aβ1-42溶液+20μL的待测化合物溶液、20μL的Aβ1-42溶液+20μL的PBS缓冲液(含2%DMSO)于96孔板中,37°C孵育24h,然后加入160μL含有5μM硫黄素T的50mM的甘氨酸-NaOH缓冲液(pH=8.5),振摇5s后立即用多功能酶标仪在446nm激发波长和490nm发射波长下测定荧光值;Aβ1-42+待测化合物的荧光值记为IFi,Aβ1-42+PBS缓冲液的荧光值记为IFc,只含有PBS缓冲液的荧光值记为IF0,化合物抑制Aβ1-42自身聚集的抑制率为:100-(IFi-IF0)/(IFc-IF0)*100;选择化合物的五至六个浓度,测定其抑制率;每个化合物每个浓度复测三次,以姜黄素为阳性对照。测定结果表明,本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)对Aβ1-42自身聚集均具有显著抑制活性,在20.0 µM浓度下对Aβ1-42自身聚集的抑制率在25.2%~60.0%之间;而临床上广泛使用的抗AD药物:多奈哌齐、卡巴拉汀、盐酸美金刚胺、以及对照化合物丁苯酞和3-羟基苯酞类化物(1)在25.0 µM浓度下对Aβ1-42自身聚集的抑制率均小于15.0%。
(4)3-(酰胺烷硫基)苯酞类化合物(I)与金属离子络合作用的测定
用甲醇溶解CuCl2、ZnCl2、FeSO4、AlCl3及待测化合物,配成75 μmol/L的溶液,向96孔板中加入100μL待测化合物溶液和100μL金属离子溶液,混匀,室温静置30 min,在Varioskan Flash Multimode Reader (Thermo Scientific)仪上记录混合物在200-600nm范围内的紫外吸收曲线,并以100μL待测化合物溶液和100 μL甲醇混合液为对照,观察金属离子与待测化合物混合液的最大吸收峰的红移现象及最大吸收峰的强度。测定结果表明,本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)均表现出对Cu2+和Fe2+有选择性络合作用,并且本发明实施例中所用的酰胺烷硫醇类化物(2)对上述金属离子也表现出络合作用;而对照化合物丁苯酞和3-羟基苯酞类化物(1)对上述四种金属离子均无络合作用。
(5)3-(酰胺烷硫基)苯酞类化合物(I)对神经炎症的抑制活性
(a)化合物和脂多糖(LPS)对BV-2细胞活性的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板,置37℃,5%CO2细胞培养箱内培养24h待细胞贴壁后换为无血清的新鲜培养液90μL,分别加入各浓度待测化合物10μL预孵育30 min,每个浓度3个平行孔,同时设空白对照组;然后加或不加LPS,置37℃,5%CO2细胞培养箱内继续培养24h,加入MTT溶液,37℃孵育4h,弃去上清液,每孔加入200μLDMSO溶液,轻微振荡10min后,用酶标仪在490nm处测定OD值,计算各受试样品不同浓度所测得OD值的均值,并按下列公司计算细胞存活率:细胞存活率(%)= 给药组OD均值/对照组OD均值×100%。测试结果表明,本发明实施例中所公开的所有3-(酰胺烷硫基)苯酞类化合物(I)、所用起始原料——酰胺烷硫醇类化物(2)和LPS在不超过30μM浓度下均未显示出细胞毒性(抑制率小于<10%)。
(b)3-(酰胺烷硫基)苯酞类化合物(I)对LPS诱导的BV-2细胞释放NO的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板,置37℃,5%CO2细胞培养箱内培养24 h待细胞贴壁后换为无血清的新鲜培养液90 μL,分别加入各浓度待测化合物10μL预孵育30 min,每个浓度3个平行孔,同时设空白对照组;然后加入LPS刺激,置37℃,5%CO2细胞培养箱内继续培养24 h,取不同处理组细胞培养上清液,加入等体积的Griess试剂I和等体积的Griess试剂II,室温避光反应10 min,在540 nm处测定吸光度以检测细胞上清液中NO水平(具体操作按照NO检测试剂盒说明书进行)。测试结果表明,本发明实施例中所公开的所有3-(酰胺烷硫基)苯酞类化合物(I)在0.5 μM至25 μM浓度范围内均显示出较强的抑制LPS诱导的BV-2细胞NO生成作用(在5.0 μM浓度下的抑制率均超过30.0%),并具有明显的量效关系;且它们的抑制活性显著强于相同浓度下的对照化合物丁苯酞和3-羟基苯酞类化物(1)(在5.0 μM浓度下的抑制率均小于12.0%),表明本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)具有显著的抗神经炎症活性。研究还发现,本发明实施例中所用起始原料—酰胺烷硫醇类化物(2)也具有显著抗神经炎症活性(在5.0 μM浓度下对LPS诱导的BV-2细胞NO生成的抑制率均超过25.0%);但将3-(酰胺烷硫基)苯酞类化合物(I)中3-位的S原子用CH2替换,所得相应的3-(酰胺烷基)苯酞类化合物的抗神经炎症活性显著降低(在5.0 μM浓度下的抑制率均小于12.0%)。
(6)3-(酰胺烷硫基)苯酞类化合物(I)对NaNO2所致小鼠学习记忆巩固障碍的影响
亚硝酸钠(NaNO2)能将红细胞中的血红蛋白氧化为高铁血红蛋白,且高剂量的NaNO2可使体内还原型小分子(GSH)及还原酶系(SOD、GPx、GR)的含量显著下降,进而引起脂质过氧化和蛋白质羰基化,导致氧化应激,因此NaNO2诱导的小鼠模型常被用于抗氧化应激候选药物的体内活性筛选。
SPF级ICR小鼠,初始体重为18-22克,随机分为:正常组、模型组、阳性对照组(丁苯酞)、阳性对照组(盐酸多奈哌齐)、受试药高中低剂量组(25.0 mg/kg、10.0 mg/kg、4.0 mg/kg),每组10只。跳台试验前,向各组小鼠分别灌胃相应的化合物(每天2次,中间间隔12小时,持续4天),正常组和模型组小鼠灌胃同等体积的0.5% CMC-Na溶液;在第三天第二次给药后1.0小时,将小鼠置于跳台仪适应3分钟,然后再将其置于圆形平台,通以36V交流电训练5分钟,记录小鼠第一次跳下平台的时间作为训练潜伏期;训练后向除正常组的各组小鼠皮下注射NaNO2生理盐水溶液(90.0 mg/kg);次日最后一次给药后1小时,再用跳台仪对小鼠进行测试,记录小鼠第一次跳下平台的时间作为测试潜伏期,以及在5分钟内跳下平台被电击的次数作为错误次数。行为学测试结束后将小鼠断头取脑,并在冰层上分离小鼠大脑皮层,然后按测试要求进行匀浆,匀浆上清液用于小鼠大脑皮层丙二醛(MDA)和SOD含量测定。
测定结果表明,所测试的3-(酰胺烷硫基)苯酞类化合物(I)(实施例化合物1-2-4、1-2-5、5-2-1、5-2-2、5-5-1、5-5-2)对NaNO2致小鼠学习记忆巩固障碍均具有剂量依赖性的改善作用(延长潜伏期并减少错误次数),与模型组比较均有统计学差异(p<0.001),且活性显著高于相同剂量下的丁苯酞(p<0.001),也强于相同剂量下的临床用药盐酸多奈哌齐(p<0.01);同时,将相应的3-(酰胺烷硫基)苯酞类化合物(I)中3-位的S原子用CH2替换,所得3-(酰胺烷基)苯酞类化合物对NaNO2致小鼠学习记忆巩固障碍活性与盐酸多奈哌齐相当,但弱于相应的3-(酰胺烷硫基)苯酞类化合物(I)(p<0.01)。另外,测定结果还显示,所测试的3-(酰胺烷硫基)苯酞类化合物(I)在高中低剂量下均可不同程度地降低小鼠大脑皮层的MDA含量,并提升SOD活性,具有剂量依赖性,其活性也显著高于相同剂量下的丁苯酞(p<0.001);因此本发明实施例中所公开的3-(酰胺烷硫基)苯酞类化合物(I)可缓解由NaNO2引起的小鼠中枢氧化应激。
具体实施方式
通过下面的实施例可对本发明进行进一步的描述,然而本发明的范围并不限于下述实施例;本领域的专业人员能够理解,在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
实施例1 3-(酰胺烷硫基)苯酞类化合物(I)的制备通法
方法一:将3.0 mmol相应的3-羟基苯酞类化物(1)、4.5 mmol酰胺烷硫醇类化物(2)、3.3 mmol对甲苯磺酸和30 ml氯仿加入反应瓶中,升温至50-60℃搅拌反应5~30.0小时(反应进程用TLC跟踪);反应结束后,将反应液冷至室温,加入50 mL去离子水,用饱和碳酸钠水溶液调节反应液pH至碱性,用150 mL二氯甲烷分三次萃取,有机层合并后用饱和氯化钠水溶液洗涤,经无水硫酸钠干燥后过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化(洗脱液:二氯甲烷/甲醇=20~70/1 v/v),即可得到相应的目标物(收率:22.6%~76.2%,以相应产物的理论值计算),其结构均经1H-NMR、13C-NMR和ESI-MS确证;化合物纯度经HPLC测定均大于96.5%。
方法二:将3.0 mmol相应的3-羟基苯酞类化物(1)、3.6 mmol酰胺烷硫醇类化物(2)和10 ml甲烷磺酸加入反应瓶中,室温搅拌反应5~60.0小时(反应进程用TLC跟踪);反应结束后,加入50 mL去离子水,用饱和碳酸钠水溶液调节反应液pH至碱性,用150 mL二氯甲烷分三次萃取,有机层合并后用饱和氯化钠水溶液洗涤,经无水硫酸钠干燥后过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化(洗脱液:二氯甲烷/甲醇=20~70/1 v/v),即可得到相应的目标物(收率:30.0%~80.5%,以相应产物的理论值计算),其结构均经1H-NMR、13C-NMR和ESI-MS确证;化合物纯度经HPLC测定均大于96.2%。
采用上述两种通法制备得到的目标物结构如下:
部分化合物的NMR数据如下:
1H NMR (CDCl3): 7.89 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H),7.66-7.64 (m, 1H), 7.60-7.55(m, 2H), 6.62 (s, 1H), 3.41-3.37(m, 3H), 2.95(brs, 2H), 2.74-2.68 (m, 2H), 2.32-2.27 (m, 1H), 1.90 (t, J = 7.2 Hz, 2H),0.99 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3): 173.5,169.5, 146.7, 134.6, 130.1, 126.1, 125.6, 123.2, 85.2, 59.9, 38.3, 30.7,29.7, 28.5, 19.5, 17.4;
1H NMR (CDCl3): 7.46 (brs, 1H), 7.19 (s, 1H), 7.17 (s, 1H), 5.86 (s,1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.32-3.25 (m, 3H), 2.54-2.47 (m, 1H), 2.35-2.23 (m, 2H), 2.09 (brs, 2H),1.73-1.70 (m, 2H), 0.97 (d, J = 6.8 Hz, 3H),0.79 (d, J = 6.8 Hz, 3H)。
实施例2 3-(酰胺烷硫基)苯酞类化合物(I)与酸成盐制备通法
在反应瓶中加入按照上述实施例1所得之3-(酰胺烷硫基)苯酞类化合物(I)1.0mmol和异丙醇30 ml,搅拌均匀后加入3.0 mmol相应的酸,室温搅拌反应30分钟后减压蒸除溶剂,残余物经重结晶,即得3-(酰胺烷硫基)苯酞类化合物的盐,其化学结构经1H NMR和ESI-MS确证。
Claims (9)
1.一类3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐,其特征在于该类化合物的化学结构通式如(I)所示:
式中:
表示天然或非天然氨基酸残基;X表示O、S或NR3,R3表示H、C1~C6烷基、苯基;n表示1-5;R1和R2各自独立地表示H、C1~C6烷基、C1~C6烷氧基、卤素、CN或NR4R5,R4和R5各自独立地表示H、C1~C6烷基;R1和R2在其相应苯环上任意可能的位置;所述化合物中与硫原子相邻的碳原子具有手性,其构型为R、S、或R与S的任意比例混合物;所述“卤素”是指F、Cl、Br或I;“天然或非天然氨基酸”是指:甘氨酸、L-或D-丙氨酸、氨基异丁酸、γ-氨基丁酸、L-或D-缬氨酸、L-或D-脯氨酸、L-或D-赖氨酸、L-或D-亮氨酸、L-或D-甲硫氨酸、L-或D-丝氨酸、L-或D-O-苄基丝氨酸、L-或D-组氨酸、L-或D-酪氨酸、L-或D-苯甘氨酸、L-或D-苯丙氨酸、L-或D-色氨酸、L-或D-天冬氨酸、L-或D-谷氨酸。
3.如权利要求1所述的3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐,其特征在于R1和R2优选自H、OCH3、Cl、Br、Me2N、CH3或CN。
4.如权利要求1所述的3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐,其特征在于X优选自O、S、NH、NCH3或NPh。
5.如权利要求1-4所述的3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐,其特征在于所述的药学上可接受的盐为此类3-(酰胺烷硫基)苯酞类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸的盐。
7.如权利要求6所述3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐的制备方法,其特征在于反应所用溶剂为:C2-6脂肪酸、C2-6脂肪酸与C1-6脂肪醇所形成酯、氯仿、二氯甲烷、1,2-二氯乙烷、氯苯、邻二氯苯、N,N-二甲基甲酰胺、四氢呋喃、2-甲基四氢呋喃、苯、甲苯、乙腈、1,4-二氧六环、乙二醇二甲醚、甲烷磺酸、乙烷磺酸或C5-8烷烃;所用酸为盐酸、硫酸、苯磺酸、对甲苯磺酸、樟脑磺酸、C1-6烷基磺酸、磷酸、高氯酸、三氟乙酸、三氟甲磺酸或硝酸;但当反应溶剂为甲烷磺酸或乙烷磺酸时,则不需要再加酸;3-羟基苯酞类化物(1):酰胺烷硫醇类化物(2):酸的摩尔投料比为1.0:0.9~3.0:0~5.0,反应温度为0~150℃;反应时间为1~120小时。
8.一类药物组合物,其特征在于包含如权利要求1-5任一项所述的3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
9.如权利要求1-5任一项所述的3-(酰胺烷硫基)苯酞类化合物或其药学上可接受的盐在制备治疗和/或预防神经***相关疾病药物中的用途,这类神经***相关疾病为:血管性痴呆、阿尔茨海默氏病、额颞叶痴呆、Prion病、路易体痴呆、帕金森氏症、亨廷顿氏症、HIV相关痴呆症、多发性硬化症、肌萎缩侧索硬化症、神经性疼痛、缺血性脑卒中、出血性脑卒中以及脑外伤引起的神经损伤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111022118.0A CN115724824B (zh) | 2021-09-01 | 2021-09-01 | 3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111022118.0A CN115724824B (zh) | 2021-09-01 | 2021-09-01 | 3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115724824A true CN115724824A (zh) | 2023-03-03 |
CN115724824B CN115724824B (zh) | 2024-03-15 |
Family
ID=85292211
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111022118.0A Active CN115724824B (zh) | 2021-09-01 | 2021-09-01 | 3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115724824B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4443435A (en) * | 1980-04-21 | 1984-04-17 | Merck & Co., Inc. | Prodrugs of 6-mercaptopurine and 6-mercaptopurine ribosides and therapeutic compositions and methods employing them |
CN110698445A (zh) * | 2018-07-09 | 2020-01-17 | 四川大学 | 一类3-胺烷基苯酞类化合物、其制备方法和用途 |
CN112010827A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类苄胺基苯酞类化合物、其制备方法和用途 |
CN112010837A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类吡啶甲胺基苯酞类化合物、其制备方法和用途 |
-
2021
- 2021-09-01 CN CN202111022118.0A patent/CN115724824B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4443435A (en) * | 1980-04-21 | 1984-04-17 | Merck & Co., Inc. | Prodrugs of 6-mercaptopurine and 6-mercaptopurine ribosides and therapeutic compositions and methods employing them |
CN110698445A (zh) * | 2018-07-09 | 2020-01-17 | 四川大学 | 一类3-胺烷基苯酞类化合物、其制备方法和用途 |
CN112010827A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类苄胺基苯酞类化合物、其制备方法和用途 |
CN112010837A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类吡啶甲胺基苯酞类化合物、其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
CN115724824B (zh) | 2024-03-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5649585B2 (ja) | ベンゾアリールウレイド化合物、及びこれを含有する神経退行性脳疾患予防又は治療用組成物 | |
JP5913651B2 (ja) | 疼痛および他の疾患の処置のための化合物および方法 | |
CN108101780B (zh) | 一类氟比洛芬查尔酮类化合物、其制备方法和用途 | |
CN109265362B (zh) | 一类2,5-二羟基对苯二甲酰胺类化合物、其制备方法和用途 | |
CN112010827A (zh) | 一类苄胺基苯酞类化合物、其制备方法和用途 | |
CN111170884B (zh) | 一类水杨酰胺类化合物、其制备方法和用途 | |
CN114478450A (zh) | 苄氧基苯酞类化合物、其制备方法和用途 | |
CA2828831C (en) | Compounds and methods for the treatment of pain and other disorders | |
CN114478451B (zh) | 6-(羟基苄氧基)苯酞曼尼希碱类化合物、其制备方法和用途 | |
CN115974854B (zh) | 苯酚基烯基苯酞吡唑酮类化合物及其制备方法和用途 | |
CN113185447B (zh) | 邻苯二甲酰半胱酰胺类化合物、其制备方法和用途 | |
CN108727352B (zh) | 一类哌啶烷氨甲酰基苯酞类化合物、其制备方法和用途 | |
CN105732479B (zh) | 一种4-环胺烷氧基-3-甲氧基肉桂酸苯酰胺类化合物、制备方法及其用途 | |
CN115724824B (zh) | 3-(酰胺烷硫基)苯酞类化合物、其制备方法和用途 | |
CN114805263B (zh) | 3-(羟基苄基)苯酞类化合物、其制备方法和用途 | |
US20110230452A1 (en) | Compounds and methods for the treatment of pain and other diseases | |
CN109912448B (zh) | 一类苄胺基氟比洛芬酰胺类化合物、其制备方法和用途 | |
CN115724779B (zh) | 酰胺烷二硫化合物、其制备方法和用途 | |
CN110698445A (zh) | 一类3-胺烷基苯酞类化合物、其制备方法和用途 | |
JP2011231022A (ja) | イミダゾロン誘導体 | |
CN115724786B (zh) | 酰胺烷二硫邻苯二甲酰亚胺类化合物、其制备方法和用途 | |
CN113105409B (zh) | 2-(羟基苄基)苯并[d]异噻唑酮类化合物、其制备方法和用途 | |
CN110003034B (zh) | 一类羟基氟比洛芬曼尼希碱类化合物、其制备方法和用途 | |
CN114315689B (zh) | 二硫烷基邻苯二甲酰亚胺类化合物、其制备方法和用途 | |
EP2921486B1 (en) | Compositions and methods for treating beta-amyloid related diseases |
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 |